sepsis

Sepsis
Second Edition
Sepsis
Second Edition
Guillermo Ortiz-Ruiz, MD
Professor of Pulmonary and Critical Care Medicine
Universidad del Bosque
Bogotá, Colombia
Marco A. Perafán, MD
Professor of Cardiology and Critical Care Medicine
Fundacion Clinica Shaio
Bogotá, Colombia
Eugen Faist, MD
Professor, Department of Surgery
Klinikum Grosshadern, University of Munich
Munich, Germany
Carmelo Dueñas Castell, MD
Professor of Pulmonary and Critical Care Medicine
Hospital Bocagrande
Cartagena, Colombia
Editors
Guillermo Ortiz-Ruiz, MD Marco A. Perafán, MD
Pulmonary and Critical Care Medicine Intensive Care Unit
Universidad del Bosque Fundacion Clinica Shaio
Bogotá, Colombia Bogotá, Colombia
Eugen Faist, MD Carmelo Dueñas Castell, MD
Department of Surgery Pulmonary and Critical Care Medicine
Klinikum Grosshadern Hospital Bocagrande
University of Munich Cartagena, Colombia
Munich, Germany
Library of Congress Control Number: 2005935333
ISBN-10: 0-387-29816-9
ISBN-13: 978-0387-29816-0
Printed on acid-free paper.
© 2006 Springer Science+Business Media, Inc.
All rights reserved. This work may not be translated or copied in whole or in part without the
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Preface
The mortality of severe sepsis (infection-induced organ dysfunction or hypoper-
fusion abnormalities) and septic shock (hypotension not reversed with fluid resus-
citation and associated with organ dysfunction or hypoperfusion abnormalities)
remains unacceptably high. Similar to an acute myocardial ischemic attack and
an acute brain attack, the speed and appropriateness of therapy administered in
the initial hours after the syndrome develops likely influence the outcome.
The care of critically ill patients in a modern intensive care unit (ICU) results
in a large societal burden in terms of both manpower and monetary cost. The
high cost of critical care can largely be attributed to high overhead costs (e.g.,
need for experienced staff and expensive equipment), and high demand for ICU
services. With the continued increase in healthcare costs, there is an increas-
ing need to establish whether new therapies are not only effective, but also cost-
effective. Although this is true throughout medicine, the issue of cost-
effectiveness is especially important in critical care medicine. ICU costs in the
United States exceed $150 billion, representing up to one third of all hospital
costs. Furthermore, attempts to reduce ICU costs by other mechanisms, such as
reduction in lengths of stay, have proven to be difficult.
The concern over the financial effect of new therapies in the ICU is so
intense that scrutiny begins even before therapies are approved by the Food and
Drug Administration (FDA). Before ever gaining approval, the antiendotoxin
monoclonal antibody HA-1A stimulated considerable furor and debate not
only in the medical literature, but also in the national media over its anticipated
cost. Currently, the FDA does not explicitly consider cost when evaluating new
therapies. However, infections have placed pressure on the agency. It is perhaps
as a consequence of this pressure that many recent antisepsis biologic therapies
have been burdened with proving their ability to decrease mortality to gain FDA
approval. This burden is greater than that faced by many less expensive therapies
(e.g., antibiotics).
This book provides both a summary of this expanding field and a practical
approach for clinicians to treat patients with sepsis syndrome and its compli-
cations in the critical care unit. The focus of this effort is to provide a clinical
approach to specific at-risk populations who present with sepsis. This approach,
v
vi
Preface
rather than an organism-directed organization, has been used because of our firm
belief that one must consider the clinical and epidemiological picture of the
patient before one can consider a specific microbial cause for a sepsis syndrome.
This clinical approach must have a firm scientific foundation.
This book begins with a scientific review of the Latin American epidemiologi-
cal approach to sepsis syndrome. It provides the principles for clinical assessment
of different kinds of clinical complications as well as therapeutic strategies in this
clinical field. This book is edited by four physicians with experience and interest
in different aspects of the critical care point of view: three experts in the field
from Colombia, as well as the international perspective of Dr. E. Faist from
Germany. In this way, we believed that we could identify and recruit authoritative
authors for each chapter. We are grateful to our contributing authors for all of
their efforts toward this project.
Guillermo Ortiz-Ruiz
Marco A. Perafán
Carmelo Dueñas Castell
Eugen Faist
Bogotá, Colombia
Munich, Germany
Contents
1. When to Transfuse Septic Patients . . . . . . . . . . . . . . . . . . . . . . . . . 1
Carmelo dueñas Castell
2. Sepsis Occurrence and Its Prognosis in Latin America . . . . . . . . . 11
Fabián Jaimes and Rodolfo J. Dennis
3. Novel Therapies in Critically Ill Septic Patients . . . . . . . . . . . . . . . 25
Jean-Louis Vincent, Carla Marie Clausi, and
Alejandro Bruhn
4. Dissemination Control of the Antimicrobial Resistance in
the Intensive Care Unit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Carlos Arturo Alvarez and Jorge Alberto Cortés
33
5. Diaphragmatic Dysfunction in Intensive Care . . . . . . . . . . . . . . . . 47
Guillermo Ortiz-Ruiz
6. Myocardial Depression in Sepsis and Septic Shock . . . . . . . . . . . . 55
Justin Wong and Anand Kumar
7. Toward a Consensus on Intraabdominal Hypertension . . . . . . . . . . 74
Manu LNG Malbrain, Michael Sugrue,
Michael Cheatham, and Rao Ivatury
8. Resuscitation Goals in Severe Sepsis and Septic Shock . . . . . . . . . 92
Fernando Pálizas
9. Coagulation Disorders in Critically Ill Septic Patients . . . . . . . . . . 103
Marcela Granados
10. Vasopressors in Sepsis: Do They Change the Outcome? . . . . . . . . 121
Marco A. González and Christhiaan D. Ochoa
vii
viii Contents 11. Lactic Acidosis in Critically Ill Septic Patients . . . . . . . . . . . . . . . 12. Delirium in Septic Patients: An Unrecognized Vital 136
Daniel De Backer Organ Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Timothy D. Girard and E. Wesley Ely
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
126
List of Contributors
Carlos Arturo Alvarez, MD
Chief, Infectology Unit, Hospital Universitario San Ignacio; Department of
Internal Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
Alejandro Bruhn, MD
Department of Intensive Care, Erasme Hospital, Free University of Brussels,
Belgium
Carmelo Dueñas Castell, MD
Professor of Medicine, Universidad de Cartagena; Intensive Care Unit Director,
Hospital Bocagrande; Intensive Care Director, Clinica Madre Bernarda,
Cartagena, Colombia
Michael Cheatham, MD, FACS, FCCM
Director, Surgical Intensive Care Units, Orlando Regional Medical Center,
Orlando, FL, USA
Carla Marie Clausi, MD
Department of Intensive Care, Erasme Hospital, Free University of Brussels,
Belgium
Jorge Alberto Cortés, MD
Infectology Unit, Hospital Universitario San Ignacio; Department of Internal
Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
Daniel De Backer, MD, PhD
Department of Intensive Care, Erasme University Hospital, Free University of
Brussels, Belgium
Rodolfo J. Dennis, MD, MSc
Professor of Medicine, Pontificia Universidad Javeriana; Department of Internal
Medicine, Fundacion Cardioinfinatil, Bogotá, Colombia
ix
x
List of Contributors
E. Wesley Ely, MD, MPH
Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt Univer-
sity School of Medicine; Veterans Affairs Tennessee Valley Geriatric Research,
Education, and Clinical Center, Nashville, TN, USA
Eugen Faist, MD
Professor, Department of Surgery, Klinikum Grossharern, University of Munich,
Munich, Germany
Timothy D. Girard, MD
Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt Univer-
sity School of Medicine, Nashville, TN, USA
Marco A. González, A., MD
Department of Critical Care Medicine, Medellín Clinic and Universidad Pontifi-
cia Bolivariana, Medellín, Colombia
Marcela Granados, MD, FCCM
Director, Fellowship Program in Critical Care, Section of Critica Care Medicine,
Universidad Del Valle, Cali, Colombia
Rao Ivatury, MD
Professor, Department of Surgery, Director, Trauma, Critical Care and Emergency
Surgery, Virginia Commonwealth University Medical Center, Richmond, VA,
USA
Fabián Jaimes, MD, MSc, PhDc
Assistant Professor of Medicine and Clinical Epidemiology, Universidad de
Antioquia, Medellín, Colombia
Anand Kumar, MD, FRCPC
Associate Professor of Medicine, Section of Critical Care Medicine, Health
Sciences Center, University of Manitoba, Winnipeg, Canada; Associate Professor
of Medicine, Division of Cardiovascular Diseases and CCM, Cooper Hospital/
University Medical Center, University of Medicine and Dentistry, New Jersey,
Camden, New Jersey, USA
Manu LNG Malbrain, MD
Director, Intensive Care Unit, ZiekenhuisNetwerk Antwerpen, Antwerp,
Belgium
Cristhiaan D. Ochoa, MD
Research Fellow, Pulmonary and Critical Care Unit, Department of Medicine,
Massachusetts General Hospital and Harvard Medical School, Boston, MA,
USA
List of Contributors
xi
Guillermo Ortiz-Ruiz, MD
Professor, Pulmonary and Critical Care Medicine, Universidad del Bosque; Chief,
Intensive Care Unit, Hospital Santa Clara, Bogotá, Colombia
Fernando Pálizas, MD
Intensive Care Unit Director, Clinica Bazterrica, Buenos Aires, Argentina
Marco Antonio Perafán C., MD
Professor of Cardiology and Critical Medicine, Chief, Intensive Care Unit,
Fundacion Clinica Shaio, Bogotá, Colombia
Michael Sugrue, MD
Director of Trauma, Liverpool Hospital, University of New South Wales, Sydney,
Australia
Jean-Louis Vincent, MD, PhD, FCCP
Professor, Department of Intensive Care, Erasme Hospital, Free University of
Brussels, Belgium
Justin Wong, MD, FRCPC
Fellow, Section of Critical Care Medicine, Health Sciences Center, University of
Manitoba, Winnipeg, Canada
1
When to Transfuse Septic Patients
Carmelo dueñas Castell
Patients who enter the intensive care unit (ICU) frequently have anemia and 70%
to 95% of patients in ICU have a hemoglobin count lower than normal.1–4
Why Critical Patients Have Anemia
The cause of anemia is multifactorial:
1. Hemodilution. Generally due to crystalloid infusions to keep the hemody-
namics parameters.
2. Increased blood loss: There are many reasons for critical patients’ blood
loss:
a. Bleeding: Digestive, trauma, loss because of procedures, etc.2–4
b. Phlebotomies.3–4 Pioneer studies reported a blood loss from phleboto-
mies from 60 to 70 cc/day.5 Recent publications have established some
minor losses that are the result of technological advances and a more
rational use of the blood.6
c. Reduction of half-life of the red cells: Not much is known about the half-
life of the red cells in critical patients. However, the red cell destruction
can be mediated by the systemic inflammation, activation of the comple-
ment, and the macrophages.7 Anemia of chronic disorders or anemia by
inflammation reduces the half-life of the red cells to less than 90 days.8,9
3. Decrease or alteration in blood production: Chronic inflammatory disorders
lead to a reduction in the production of red cells.10 More than 90% of critical
patients have low levels of serum iron and capacity to bind the iron2,11 with
high levels of ferritin,5,12 although the levels of erythropoietin are only
slightly increased with little evidence of response from the reticulocytes to
the endogen erythropoietin.2 There are at least four contributing factors to
the erythropoietin levels2,13–15:
a. Direct inhibition to the erythropoiesis by circulating inflammatory medi-
ators, among them interleukins 1, 6, and tumor necrosis factor.
b. Reduction of available iron.
1
2
C.D. Castell
c. Unsuitably low levels of erythropoietin.
d. Poor response of the precursor cells of the red cell to erythropoietin.2
Others: Deficiency of folic acid has been found in 25% of critical
patients.2
How Much Blood Is Transfused in ICU?
More than half of the patients in ICU receive red blood cell transfusion during
their stay in intensive care3,4,16 and it can be up to 85% of patients who stay more
than 1 week in ICU.17
Paradoxically, many patients tolerate hemoglobin levels near 7 without com-
plications.1–4 A liberal transfusion strategy of red blood cells, in which a transfu-
sion is made to keep the hemoglobin above 10 g/dL, has been associated with
deplorable clinic outcomes.2–4,16
The transfusion in clinical practice has been subjected to multiple careful
examinations in the past 20 years.2–4,18,19 But transfusion methods have not changed
in the past century.20,21
Sepsis and Transfusion
The frequency of sepsis has increased 139% from 1979 to 1987.22 It is estimated
that 18 million people per year suffer from sepsis.22 With a mortality of approxi-
mately 30%, sepsis is considered the leading cause of death worldwide.23 In Table
1.1 the epidemiologic studies that evaluate sepsis are shown. From them, the
importance of this pathology in critical patients can be seen.
The recommendations and present practices to use blood components to treat
sepsis are based on the extrapolation of results of heterogeneous groups of critical
patients, from studies in noncritical patients and from consensus guides.29 In an
Table 1.1. Sepsis Epidemiologic Studies Worldwide
Author, year
(reference)
Alberti, 200224
Padkin, 200325
Annane, 200326
EPISEPSIS, 200427
Finfer, 200428
Countries
6 European
countries,
Canada, Israel
England, Wales
and, Northern
Ireland
France
France
Australia and
New Zealand
Number of Incidence Mortality
ICU entries
evaluated
14,364 21.1% 22.1% vs.
43.6%
56,673 27.1% 35% vs. 47%
100,554 8.2% 5,878 11.8% 60.1%
3,738 14.6% 35% vs.
41.9%
26.5% vs.
32.4%
1. When to Transfuse Septic Patients
3
observation study in the United States, 11% of the patients with a diagnosis of
sepsis entry had hemoglobin <8.21 The optimum hemoglobin for patients with
sepsis is uncertain. This is an essential aspect, as the hemoglobin in patients
with sepsis varies between 8 to 10 g/dL.29 The hemoglobin reduction in septic
patients is related to different factors, as discussed above, and frequently presents
in this type of patient29: (1) ineffective erythropoiesis, and (2) hemodilution, a
reduction of 1–3 g in hemoglobin is expected during the reanimation from septic
shock with crystalloids and colloids.29
In the majority of patients, this grade of anemia is tolerated well as the reduc-
tion in the viscosity decreases the afterload, increases the venous return, and
increases the beating volume and the cardiac output.29 The reduction in the blood
viscosity can compensate for other rheological changes of the septic patients,
making the microvascular flow easy. However, different factors can affect the
capacity of the patient to tolerate the reduction in the hematocrit and these should
be taken into account:
1. The cardiac disorder, when presented in the septic patient, because it can limit
the compensation of the cardiac output as a result of reduced viscosity.29
2. In hypermetabolic stages, the increase in the cardiac output may not be enough
to compensate the reduction in the oxygen-carrying capacity caused by the
anemia.
3. The incapacity to extract oxygen related to anatomic anomalies, such as coro-
nary illness or physiological changes due to sepsis, which can cause major
oxygen dependence.30,31
The transfusion risks are well described and should be similar in septic patients.
However, secondary immunosuppression to transfusion can be particularly impor-
tant in septic patients. Thus, an increase of nosocomial infection with poor prog-
nosis in transfused patients has been reported.30–36
It is not easy to establish a causal association between transfusion and clinical
outcomes due to the factors of confusion and because of the design of the
studies.37,38 However, the literature suggests an increase in mortality in transfused
patients.29–38 Later we will review the complications caused by red blood cell
transfusion.
What Is the Appropriate Hemoglobin Level at Which to
Transfuse Red Blood Cells in Patients with Sepsis?
The optimal level of hemoglobin in severe sepsis has not been investigated spe-
cifically. For this reason the final decision must be based on wise and reasonable
analysis of the risks and benefits of the anemia compared to the risks and benefits
of the transfusion.
It is believed that red blood cell transfusion increases the oxygen-carrying
capacity, benefits the tissues, and minimizes or prevents ischemia. The transfusion
effects in septic patients have been evaluated in different studies (see Table
4
C.D. Castell
1.2).39–48 From these studies it can be surmised that red blood cell transfusion
obviously improves the hemoglobin level and increases the oxygen-carrying
capacity for the tissues, but the changes in the consumption of oxygen are very
erratic, the improvement of the tissue oxygenation is not demonstrated, and it has
not generated favorable clinical outcomes.39–48
At the same time, transfusion increases the pulmonary vascular resistance and
the intrapulmonary shunt, consequences that can be catastrophic in the septic
patient.29
The Spanish group also did not find benefit with the use of supranormal oxygen
values in 63 patients with severe sepsis and septic shock.49 On the contrary, there
was an increase of 13% in mortality in this transfused group.
A possible explanation for the poor results in cellular oxygenation derived from
red blood cell transfusion is that the cells have been stored in blood banks. The
European and American studies on transfusions demonstrate that the time of
storage of the transfused blood was 16 days for the European study and 21 days
for the American study.3,21,29,50
A study of septic patients showed that the stored red cells do not improve the
oxygen-carrying capacity, have reduced levels of 2,3-disphosphoglycerate, and
Table 1.2. Studies that Evaluate the Effect of the Transfusion on the Oxygen-Carrying
Capacity and Its Consumption
Number Transfusion Hemoglobin
of patients change
Gilbert, 198639 17 To get Hb 10–12 8.6 to 10–12
Mink, 199040 8 10.2 to 13.2
Lucking, 199041 7 Conrad, 199042 19 8–10 cc/kg in Steffes, 199143 21 1–2 U in 2 h 9.3 to 10.7
1–2 h
10–15 cc/kg in
1–3 h
591 cc in 4.2 h
Silverman, 199244 19 2U 8.4 to 10.6
Marik, 199345 23 3 U 90–120 min 9.0 to 11.9
Lorente, 199346 16 800 cc in 90 min 9.6 to 11.6
Gramm, 199647 19 1–2 U 9.4 to 11.5
Fernandez, 200148 10 1 U in 1 h 9.4 to 10.1
Study
9.3 to 12.4
8.3 to 10.7
Results
Increase of DO2 and
VO2 only in those
with high lactate
Increase in DO2 but
not increase in VO2
Increase in DO2, VO2
Increase in DO2 but
not in VO2
Increase in DO2 and
VO2 in normal
lactate
Increase in DO2 but
not in VO2
Increase in DO2 but
not in VO2. Increase
in SVR and PVR
Increase in DO2 but
not in VO2. Increase
in SVR and PVR
Increase in DO2 but
not in VO2
No improvement of
lactate, DO2, VO2,
increase in PVR
1. When to Transfuse Septic Patients
5
cannot transport oxygen.45,50–55 Additionally, they have a reduced deformity and
can produce splanchnic ischemia.21,29,45,50,55–58 Reaffirming the infrequent use of
transfused red blood cells in tissue oxygenation, a recent study of 51 patients with
anemia who had cardiovascular surgery demonstrated that red blood cell transfu-
sion only improved the systemic oxygen-carrying capacity, without generating
benefits at the cellular oxygenation level. On the contrary, oxygen ventilation at
100% improved not only the systemic oxygen but also the tissue oxygen.59 On
the other hand, improving the cardiac output, with inotropics, for example, can
have a better risk/cost/benefit relationship than red blood cell transfusion when
looking at tissue oxygenation factors.60
In the United States more than 10 million units of red blood cells are transfused
each year.54 Despite great technological and scientific advances, there are still
complications derived from red blood cell transfusion54,55:
1. Infectious complications
a. Infections by the virus that causes acquired immune deficiency syndrome
(HIV): The risk for HIV infection per unit of transfused blood has been
estimated as 1 : 676,000 (from 1 : 200,000–1 : 2,000,000).
b. Viral hepatitis: The risk of infection per unit of transfused blood is 1 : 63,000
for hepatitis B and 1 : 103,000 for hepatitis C.
c. Other viruses: Such as parvovirus.
d. Creutzfeldt-Jakob illness.
e. Bacterial contamination: This is more frequent for blood platelet transfu-
sion, but it has been described that this can occur in 1 per each million
units of red blood cells transfused.54,55
2. Noninfectious complications54,55
a. Hemolytic and alloimmunization reactions: These are less frequent
each time. However, they are present in 0.5 to 1.4% of the transfusions.
These reactions can cause death in 1 : 250,000 to 1 : 1,000,000
transfusions.
b. Transfusion-related acute lung injury: It is not an usual reported complica-
tion despite being the third most frequent cause of death associated with
transfusion.56 It is a disease that generally presents within 4 h after the
transfusion.54–57 It occurs in one out of 5,000 transfusions. If all the blood
components have been implicated in this pathology, it is associated more
frequently with total blood transfusion, red blood cells, blood platelets, and
frozen fresh plasma.56 For its diagnosis it is necessary to exclude volume
overload, sepsis, and cardiogenic pulmonary edema.56
c. Immunomodulation: This refers to the phenomenon in which the allogenic
blood transfusion generates an immune response in the host that makes the
patient vulnerable to infections, recurrence of malignancy, or reactivation
of latent viral infections.54,55
d. Hypotensive transfused reactions: These are more frequent in patients who
receive angiotensin-converting enzyme inhibitors or patients exposed to
extracorporeal circulation.54,55
6
C.D. Castell
A recent publication states that the frequency of complications associated
with transfusion depends on the development index of the country.60 Thus,
in countries with a low index of economic development, the risk of these com-
plications is higher than in countries with a high index of development.61
Given that increase in risk, it is suggested that in developing countries
the level of hemoglobin transfused should be less than the level in developed
countries.61
The evidence of transfusion effects from several important clinical studies can
be summarized from some Canadian studies and from the CCCTG (controlled
clinical trial of transfusion in critical care—Canadian Critical Care Trials Group)
study, which suggests that a hemoglobin count of 7 to 9 g/dL is adequate for the
majority of critical patients and this level is not associated with increased
mortality.21,29,51–53
However, in favor of transfusion for septic patients the Rivers study proposes
a hemoglobin level of 10 g/dL in patients with low oxygen venous saturation
during the first 6 h of reanimation of the septic shock and severe sepsis.62 These
studies demonstrated that achieving the previously proposed goals reduced mor-
tality rates. For every six patients who received treatment as proposed by the
Rivers study, one life could be saved.62 Patients who were transfused in those first
6 h and in whom the proposed goals were met received fewer liquids and fewer
transfusions. Thus, during the first 6 h of reanimation of a septic patient, specific
levels of central venous pressure (CVP), mean arterial pressure (MAP), diuresis,
and mixed venous saturation should be achieved. When the mixed venous satura-
tion is low, despite obtaining the goals of CVP (8–12 mmHg) and MAP (65–
90 mmHg), the administration of red blood cells and dobutamine should be
considered. This has been verified in a recent review from the Society of Critical
Care Medicine (SCCM).63
From the Rivers study, a metaanalysis from a study in cardiovascular surgery,
the literature establishes that only when goals are achieved or are normalized to
the maximum early in treatment are clinical outcomes obtained.59,64,65 This would
suggest that in the studies where therapy was started too late, the usefulness of
treatment has not been demonstrated. Another possible explanation for the studies
that have not reported the usefulness of transfusion is that it would require 540
patients in each study group to detect clinically important differences in mortal-
ity.52 Thus, the mortality in sepsis is not reduced by normalizing the maximum
oxygen-carrying capacity because:
1. Treatment is given too late.
2. The majority of patients are not able to obtain supranormal values.
3. A cause/effect relationship between normalizing the maximum oxygen deliv-
ery and reducing mortality has not been demonstrated.
a. If a causal effect exists, the association between the two will always be
there, but it might not be found.
b. If a causal effect does not exist, aggressively increasing the contribution
of supranormal values could be dangerous.
1. When to Transfuse Septic Patients
7
Short-term physiological studies suggest that flow, tissue, or cellular factors
can be more important than the oxygen arterial content in improving tissue oxy-
genation.21,29,39,45,50 Clinical studies to evaluate the long-term physiological effects
or the impact on outcomes from transfusions have not been conducted for septic
patients. However, Neilipovitz and Hébert66 suggest that the results of CCCTG
are applicable in septic patients.
More than pursuing a magical number of hemoglobin, the reasonable use of labo-
ratory tests to reduce the frequency and amount of phlebotomy, control the hemor-
rhage quickly, optimize the oxygenation, and guarantee an adequate intravascular
volume must be performed before considering red blood cell transfusion.
Some septic patients need a high level of hemoglobin. Thus, the level of
transfusion used in septic patients requires individualization and consideration
of altered physiological function. Specific group of patients, such as those
with myocardial ischemia or severe hypoxemia, require higher levels of hemo-
globin, but the effectiveness of transfusion in these patients is inadequately
characterized.31,32 More studies are required to characterize the course of anemia
in sepsis and evaluate the impact of transfusion to define a clear course of action.
But while studies continue, experience and clinical judgment define the
treatment.
In summary, within the first 6 hours for septic patients, using Rivers’s proposed
goals, obtain hemoglobin of 10 g/dL to guarantee mixed venous saturation above
70%. Once the hypoperfusion has been obtained and in the absence of special
circumstances such as acute coronary illness or acute hemorrhage, a red blood
cell transfusion should be made only when the hemoglobin is under 7 g/dL to
keep the hemoglobin between 7 and 9 g/dL.29
References
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erythropoietin response as causes of the anemia of critical illness. J Crit Care
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3. Vincent JL, Baron JF, Reinhart K, et al. Anemia and blood transfusion in critically ill
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necrosis factor-alpha (TNF-alpha): reversal with exogenous erythropoietin (EPO).
Exp Hematol 1990;18:109–13.
14. Jelkmann W, Pagel H, Wolff M, et al. Monokines inhibiting erythropoietin production
in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci 1992;50:
301–8.
15. Hellwig-Burgel T, Rutkowski K, Metzen E, et al. Interleukin-1beta and tumor necrosis
factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. Blood 1999;
94:1561–7.
16. Littenberg B, Corwin H, Gettinger A, et al. A practice guideline and decision aide for
blood transfusion. Immunohematology 1995;11:88–92.
17. Groeger JS, Guntupalli KK, Strosberg M, et al. Descriptive analysis of critical care
units in the United States: patient characteristics and intensive care unit utilization.
Crit Care Med 1993;21:279–91.
18. Consensus Conference: Perioperative red blood cell transfusion. JAMA 1988;260:
2700–3.
19. American College of Physicians: Practice strategies for elective red blood cell transfu-
sion. Ann Intern Med 1992;116:403–6.
20. Spence RK, Cernaianu AC, Carson J, et al. Transfusion and surgery. Curr Probl Surg
1993;30:1101–80.
21. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfu-
sion in the critically ill—current clinical practice in the United States. Crit Care Med
2004;32:39–52.
22. Centers for Disease Control and Prevention. Current trends increase in National
Hospital Discharge Survey rates for septicemia—United States, 1979–1987. MMWR
1990;39(2):31–4.
23. Slade E, Tamber PS, Vincent JL. The surviving sepsis campaign: raising awareness
to reduce mortality. Crit Care 2003;7(1):1–2.
24. Alberti C, Brun-Buisson C, Burchardi H, et al. Epidemiology of sepsis and infection
in ICU patients from an international multicentre cohort study. Intensive Care Med
2002;28(2):108–21.
25. Padkin A, Goldfrad C, Brady AR, et al. Epidemiology of severe sepsis occurring in
the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit
Care Med 2003;31(9):2332–8.
26. Annane D, Aegerter P, Jars-Guincestre MC, et al. Current epidemiology of septic
shock: The CUB-Rea network. Am J Respir Crit Care Med 2003;168(2):165–72.
27. The EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and
outcome of severe sepsis in French intensive care units. Intensive Care Med 2004;
30(4):580–8.
1. When to Transfuse Septic Patients
9
28. Finfer S, Bellomo R, Lipman J, et al. Adult-population incidence of severe sepsis in
Australian and New Zealand intensive care units. Intensive Care Med 2004;30(4):
589–96.
29. Zimmerman JL. Use of blood products in sepsis: An evidence-based review. Crit Care
Med 2004;32:S542–7.
30. Claridge JA, Sawyer RG, Schulman AM, et al: Blood transfusions correlate with
infections in trauma patients in a dose-dependent manner. Am Surg 2002;68:
566–72.
31. Chelemer SB, Prato S, Cox PM, et al. Association of bacterial infection and red blood
cell transfusion after coronary artery bypass surgery. Ann Thorac Surg 2002;73:
138–42.
32. Hill GE, Frawley WH, Griffith KE, et al. Allogeneic blood transfusion increases the
risk of postoperative bacterial infection: a metaanalysis. J Trauma 2003;54:908–14.
33. Malone DL, Dunne J, Tracy JK, et al. Blood transfusion, independent of shock sever-
ity, is associated with worse outcome in trauma. J Trauma 2003;54:898–907.
34. Leal-Noval SR, Rincón-Ferrari MD, García-Curiel A, et al. Transfusion of blood
components and postoperative infection in patients undergoing cardiac surgery. Chest
2001;119:1461–8.
35. Taylor RW, Manganaro L, O’Brien J, et al. Impact of allogenic packed red cell transfu-
sion on nosocomial infection rates in the critically ill patient. Crit Care Med 2002;
30:2249–54.
36. Shorr AF, Mei-Sheng D, Kelly KM, et al. Red blood cell transfusion and ventilator-
associated pneumonia: A potential link? Crit Care Med 2004;32:666–74.
37. Vamvakas EC, Blajchman MA. Deleterious clinical effects of transfusion-associated
immunomodulation: fact or fiction? Blood 2001;97:1180–95.
38. Vamvaka EC, Carven JH. RBC transfusion and postoperative length of stay in the
hospital or the intensive care unit among patients undergoing coronary artery bypass
graft surgery: the effects of confounding factors. Transfusion 2000;40:832–9.
39. Gilbert EM, Haupt MT, Mandanas RY, et al. The effect of fluid loading, blood transfu-
sion, and catecholamine infusion on oxygen delivery and consumption in patients with
sepsis. Am Rev Resp Dis 1986;134:873–8.
40. Mink RB, Pollack MM. Effect of blood transfusion on oxygen consumption in pedi-
atric septic shock. Crit Care Med 1990;18:1087–91.
41. Lucking SE, Williams TM, Chaten FC, et al. Dependence of oxygen consumption on
oxygen delivery in children with hyperdynamic septic shock and low oxygen extrac-
tion. Crit Care Med 1990;18:1316–19.
42. Conrad SA, Dietrich KA, Hebert CA, et al. Effect of red cell transfusion on oxygen
consumption following fluid resuscitation in septic shock. Circ Shock 1990;31:
419–29.
43. Steffes CP, Bender JS, Levinson MA. Blood transfusion and oxygen consumption in
surgical sepsis. Crit Care Med 1991;19:512–17.
44. Silverman HJ, Tuna P. Gastric tonometry in patients with sepsis, effects of dobutamine
infusions and packed red blood cell transfusions. Chest 1992;102:184–8.
45. Marik PE, Sibbald WJ. Effect of stored-blood transfusion on oxygen delivery in
patients with sepsis. JAMA 1993;269:3024–9.
46. Lorente JA, Landín L, dePablo R, et al. Effects of blood transfusion on oxygen trans-
port variables in severe sepsis. Crit Care Med 1993;21:1312–18.
47. Gramm J, Smith S, Gamelli RL, et al. Effect of transfusion on oxygen transport in
critically ill patients. Shock 1996;5:190–3.
10
C.D. Castell
48. Fernandes CJ, Akamine N, DeMarco FVC, et al. Red blood cell transfusion does not
increase oxygen consumption in critically ill septic patients. Crit Care 2001;5:
362–7.
49. Alia I, Esteban A, Gordo F, et al. A randomized and controlled trial of the effect of
treatment aimed at maximizing oxygen delivery in patients with severe sepsis or septic
shock. Chest 1999;115:453–61.
50. Ward NS, Levy MM. Blood transfusion practice today. Crit Care Clin 2004;20:
179–86.
51. Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled
clinical trial of transfusion in critical care. N Engl J Med 1999;340:409–17.
52. Hébert PC, Yetisir E, Martin C, et al. Is a low transfusion threshold safe in critically
ill patients with cardiovascular diseases? Crit Care Med 2001;29:227–34.
53. Hébert PC, Blajchman MA, Cook DJ, et al. Do blood transfusions improve outcomes
related to mechanical ventilation? Chest 2001;119:1850–7.
54. Goodenough LT, Brecher ME, Kanter MH, et al. Transfusion medicine: blood transfu-
sion. N Engl J Med 1999;340:438–47.
55. Park KW, Chandhok D. Transfusion-associated complications. Int Anesthesiol Clin
2004;42(3):11–26.
56. Looney MR, Gropper MA, Matthay MA. Transfusion-related acute lung injury. Chest
2004;126:249–58.
57. Napolitano LM, Corwin HL. Efficacy of red blood cell transfusion in the critically ill.
Crit Care Clin 2004;20:255–68.
58. Hebert PC, Van der Linden P, Biro G, et al. Physiologic aspects of anemia. Crit Care
Clin 2004;20:187–212.
59. Suttner S, Piper SN, Kumle B, et al. The influence of allogeneic red blood cell trans-
fusion compared with 100% oxygen ventilation on systemic oxygen transport and
skeletal muscle oxygen tension alter cardiac surgery. Anesth Analg 2004;99:2–11.
60. Linden PA, De Hert S, BS, De Groote F, et al. Comparative effects of red blood
cell transfusion and increasing blood flow on tissue oxygenation in oxygen supply-
dependent conditions. Am J Respir Crit Care Med 2001;163:1605–8.
61. Marcucci C, Madjdpour C, Spahn DR. Allogeneic blood transfusions: benefit, risks
and clinical indications in countries with a low or high human development index.
Brit Med Bull 2004;70:15–28.
62. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of
severe sepsis and septic shock. N Engl J Med 2001;345:1368–77.
63. Rhodes A, Bennett ED. Early goal-directed therapy: an evidence-based review. Crit
Care Med 2004;32:S448–50.
64. Kern JW, Shoemaker WC. Meta-analysis of hemodynamic optimization in high-risk
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65. Pölönen P. A prospective, randomized study of goal-oriented hemodynamic therapy
in cardiac surgical patients. Anesth Analg 2000;90:1052–9.
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2
Sepsis Occurrence and Its Prognosis in
Latin America
Fabián Jaimes and Rodolfo J. Dennis
At the annual congress of the European Society of Intensive Care Medicine
(ESICM, October 2002), the Surviving Sepsis Campaign issued their “Barcelona
Declaration,” a call for global action against sepsis. The campaign, a collaborative
effort of the European Society of Intensive Care Medicine (ESICM), the Society
of Critical Care Medicine (SCCM), and the International Sepsis Forum (ISF), esti-
mates that the number of sepsis cases has now reached 18 million annually. With a
mortality rate of close to 30%, sepsis is still considered a leading cause of death
worldwide.1 As such, any effort made toward improving prevention, diagnosis, and
treatment represents a potentially valuable response to an urgent need.
This chapter provides an overview of sepsis global epidemiology, as well as
an outline regarding the description and characterization of the problem in Latin
America. It should be noted that there are specific characteristics between de-
veloped and developing countries that may impact the occurrence of sepsis and
its consequences. Specifically, Latin America exhibits substantial differences in
ethnic background, cultural heritage, health services, and clinical research. These
features support the importance of exploring, from an epidemiologic and clinical
point of view, the sepsis panorama in our setting.
In the Latin American context, the approach to the problem has been limited and
in many instances susceptible to bias, in the estimates obtained. Unfortunately, it is
unlikely that this situation represents a benign scenario of perhaps lower incidence or
better prognosis. More studies are needed in the Latin American context if an accurate
description of the epidemiology of sepsis, including its risk factors and clinical
course, is to be obtained in the different populations at risk. These studies should build
on the studies already conducted, and should address the limitations observed.
Sepsis Definition
Any description of the occurrence, determinants, and consequences of sepsis
needs to start with the caveats surrounding its definition, which we attempt to
provide next. Over the past three decades, the syndrome now commonly referred
to as “sepsis” has alternately been called septicemia,2 sepsis syndrome,3 and,
11
12
F. Jaimes and R.J. Dennis
simply, sepsis, the last definition described jointly with the closely related concept
of systemic inflammatory response syndrome (SIRS).4 A 1992 statement from the
American College of Chest Physicians/Society of Critical Care Medicine (ACCP/
SCCM) Consensus Conference4 hypothesized that sepsis is a systemic response
to infection, the latter defined as a process whereby pathogenic or potentially
pathogenic microorganisms invade normally sterile tissue, fluids, or body cavi-
ties. According to this definition, a diagnosis of sepsis requires the presence of
both infection, usually caused by bacteria, and SIRS. Following the same model,
sepsis with evidence of organic dysfunction would be characterized as severe
sepsis; and sepsis with acute circulatory failure characterized by persistent hypo-
tension unexplained by other causes, would be defined as septic shock.4 SIRS is
generally considered to be present when subjects are shown to have more than
one of the following four clinical findings:
1. Body temperature >38°C or <36°C;
2. Heart rate >90 beats min−1;
3. Hyperventilation, evidenced by a respiratory rate >20 breaths min−1 or PaCO2
<32 mm Hg;
4. White blood cell (WBC) count >12,000 cells μL−1 or <4,000 μL−1 or with
>10% immature forms.
However, as Jaimes et al. showed in a recent work5 and has been pointed out
by other authors,6,7 despite the fact that the SIRS definition is inclusive to the
extent that a systemic inflammatory response can be triggered by a variety of
conditions (infectious and noninfectious), this particular combination of criteria
is neither specific nor sensitive enough to be useful for medical decision making,
or to establish an accurate operative definition for the syndrome.
Today, it seems clear that even though no epidemiological evidence exists to
support a change in the syndrome’s definition, the list of signs and symptoms
of sepsis could be more inclusive to reflect clinical bedside experience. Accord-
ing to the last International Sepsis Definition Conference,8 a diagnosis of sepsis
should be considered in the presence of a documented or suspected infection,
concurrent with some markers of general illness, inflammation, hemodynamic
disturbance, organ dysfunction, and tissue perfusion abnormalities (Table 2.1).
Notwithstanding the lack of conclusive criteria to define sepsis, the definitions
of severe sepsis (sepsis complicated by organ dysfunction) and septic shock (sys-
tolic blood pressure below 90 mm Hg or a reduction of >40 mm Hg from baseline
despite adequate volume resuscitation, in the absence of other causes for hypoten-
sion) remain without controversy. In fact, most studies about sepsis epidemiology,
and virtually all recent clinical trials testing new therapies, have focused on these
two study populations. Unfortunately, this simple classification and range of defini-
tions have strong limitations for an accurate characterization of sepsis, mainly for
the early staging of patients. Therefore, the International Sepsis Definitions Con-
ference,8 on the basis of contributions previously arising in the Fifth Toronto Sepsis
Roundtable,9 has proposed a classification scheme called PIRO. This staging
system is intended for use in patient stratification based on their Predisposition, the
type and extent of the Infection, the nature and magnitude of the host Response,
2. Sepsis Occurrence
13
Table 2.1. Potential Variables Associated with Sepsis (modified from reference 8)
General variables
Temperature >38.3°C or <36°C
Heart rate >90 beats min−1
Tachypnea (respiratory rate >20 breaths min−1 in adults)
Altered mental status
Inflammatory variables
WBC >12,000 μL−1, <4,000 μL−1 or with >10% immature forms
Plasma C-reactive protein >2 SD above the normal value
Plasma procalcitonin >2 SD above the normal value
Hemodynamic variables
Systolic blood pressure <90 mm Hg or mean arterial blood pressure <70 mm Hg
Mixed venous oxygen saturation >70%
Cardiac index >3.5 L*min-1
Organ dysfunction variables
PaO2/FIO2 <300
Urine output <0.5 mL*kg-1*hr-1 or creatinine increase >0.5 mg/dL
International normalized ratio (INR) >1.5 or aPTT >60 sec
Platelet count <100,000 μL-1
Plasma total bilirubin >4 mg/dL
Tissue perfusion variables
Hyperlactatemia >1 mmol/L
Decreased capillary refill or mottling
and the degree of associated Organ dysfunction. A comprehensive empirical evalu-
ation and further validation of the PIRO approach, however, is needed.
Global Perspective
The first relevant study that raised public awareness regarding the burden of
sepsis, came from the U.S. Centers for Disease Control and Prevention (CDC)
in 1990.10 The data were obtained from the National Hospital Discharge Survey
(NHDS) of CDC’s National Center for Health Statistics (NCHS). The report used
the discharge diagnosis of septicemia (a systemic disease associated with the
presence and persistence of pathogenic microorganisms or their toxins in the
blood; International Classification of Diseases, Ninth Revision, Clinical Modifi-
cation codes 038.0–038.9).
The report included all records from 1979 through 1987, of subjects 1 year of
age or older in which a discharge diagnosis of septicemia was recorded. In the
9-year period, septicemia rates increased 139%, from 73.6 per 100,000 (164,000
discharges) to 175.9 per 100,000 (425,000 discharges). Although the septicemia
rate increased for all age groups, the increase was greatest (162%) for persons
65 years of age or older (from 326.3 per 100,000 in 1979 to 854.7 per 100,000
by 1987). The fatality rate for patients with a discharge diagnosis of septicemia
declined during the study period for all age groups, from 31.0% to 25.3%.
However, even by 1987, patients were at significantly greater risk for death if
septicemia was one of the discharge diagnoses (relative risk: 8.6; 95% confidence
interval: 8.14–9.09).10
14
F. Jaimes and R.J. Dennis
The most comprehensive study on the clinical significance of the early stages
of the septic syndrome, however, came in 1995 from Rangel-Fausto et al. at the
University of Iowa Hospital and Clinics.11 The authors assessed the incidence
of SIRS, sepsis, severe sepsis, and septic shock among 3,708 patients admitted
during a 9-month period in 3 intensive care units (ICUs) and 3 wards of a 900-
bed teaching hospital. They found that 68% of patients studied met at least two
criteria for SIRS at some point during their hospital stay. Of those patients with
SIRS, 26% developed microbiologically confirmed sepsis, 18% developed severe
sepsis, and 4% developed septic shock. Positive blood cultures were found in
16.5% of samples drawn from patients with sepsis, in 25.4% of those with severe
sepsis, and in 69% of those with septic shock. A noticeable finding was that less
than 50% of all episodes were documented microbiologically, although this pro-
portion increased from 42% when patients only met criteria for SIRS, to 57% in
patients with septic shock. Since clinical suspicion of infection is deemed as
enough evidence to start antibiotics, the precise cause of the systemic inflam-
matory response in these culture-negative populations is generally unknown.
However, they had similar morbidity and mortality rates when compared with
the respective culture-positive populations.11
Clearly, these definitions are self-contained, as severe sepsis includes sepsis and
in turn, sepsis includes SIRS. Therefore, only in a tautological sense may we con-
sider a truthful continuum through different stages of an inflammatory response
from SIRS to septic shock. Indeed, in the study by Rangel-Fausto et al., among
patients with sepsis (n = 649) just 44% (n = 285) had earlier met at least two criteria
for SIRS, and of those who met the criteria for severe sepsis (culture-proven;
n = 467), 271 (58%) had been classified previously as sepsis or SIRS. On the other
hand, however, 32% and 36% of patients having 2 or 3 SIRS criteria, respectively,
developed culture-proven sepsis by day 14, and 45% of those with 4 criteria devel-
oped sepsis between day 14 and 21 thereafter. Conversely, microbiologically con-
firmed sepsis appears at high risk of evolving rapidly to severe sepsis, as shown
by the 64% proportion of cases subsequently developing severe sepsis within a
median of 1 day after sepsis. Thus, even without a categorical progression, it is
clear there is a close relationship among clinical stages reflecting some degree of
systemic inflammation and the presence of infection. Independent of whether
infection is finally confirmed, the outcome seems similar, in terms of mortality and
most of the organ dysfunctions, within each corresponding stage.
In another similar study published in 1997, Sands et al. evaluated the incidence
of the “sepsis syndrome” in both the ICU and ward population at 8 academic ter-
tiary care medical centers.12 Each center monitored a weighted random sample of
ICU patients and non-ICU patients who had blood cultures drawn during a 15-
month period. Sepsis syndrome was defined as the presence of either a positive
blood culture or the combination of fever, tachypnea, tachycardia, clinically sus-
pected infection, and any one of seven confirmatory criteria, all of them related to
organ dysfunction. In total, 12,759 patients were monitored and 1,342 episodes of
sepsis syndrome were documented. The extrapolated, weighted estimate of hospi-
tal-wide incidence of sepsis syndrome was 2.0 ± 0.16 cases per 100 admissions.
2. Sepsis Occurrence
15
The unadjusted attack rate for sepsis syndrome between individual centers ranged
from 1.1 to 3.3 cases per 100 admissions. Patients in ICUs accounted for 59% of
total extrapolated cases, non-ICU patients with positive blood cultures for 11%,
and non-ICU patients with negative blood cultures for 30%. Septic shock was
present at onset of the sepsis syndrome in 25% of patients. Bloodstream infection
was documented in 28% of patients, and the total mortality at day 28 was 34%.
It is generally agreed that the most compelling evidence of systemic infection
is bacteremia. For this reason, some studies on the incidence of sepsis have
focused on bacteremia. Requesting blood cultures, as in the study of Sands et al.
mentioned above, is considered a proxy for risk of infection or clinical sepsis.
Although clinically appealing and intuitively sound, this last “surrogate marker”
is not reproducible enough and should only be considered with caution. There
are patients with potential infection who may not have a blood culture performed,
and other patients without infection who have cultures requested inappropriately.
Furthermore, since patients with comorbidities are often suspected of being at
increased risk for infection, clinicians may have a lower threshold for sending
blood cultures in these patients. Therefore, any analysis about these cases should
take into account the real denominator of population at risk. Nevertheless, posi-
tive blood cultures clearly identify infected individuals at higher risk of mortality,
and appropriate inferences may be derived from this study population.
Despite the widely ranging definition, two recent reports have added important
information regarding the epidemiology of sepsis in the United States in the past
20 years.13,14 Angus et al., based on a patient register from seven state hospitals’
discharge databases during 1995, gave a national estimate for severe sepsis of 3
cases per 1,000 population and 2.26 cases per 100 hospital discharges.13 Almost
70% (510,000 patients) of severe sepsis cases received intensive care. The esti-
mated mortality rate was 28.6%, or 215,000 deaths nationally, and the average
cost per case was $22,100, with an annual total cost of U.S.$16.7 billion. Martin
et al., with a more restrictive definition including only a few codes from the ICD-
9-CM and working on data from the NHDS, demonstrated an increase in the
incidence of sepsis from 82.7 cases per 100,000 population in 1979 to 240.4 per
100,000 population in 2000.14 This represents an annualized increase of 8.7%.
The authors also described a decline in overall in-hospital mortality, from 27.8%
during the period from 1979 through 1984, to 17.9% during the period from 1995
through 2000, yet the absolute number of deaths continued to increase.
These results, as well as those from the first CDC report,10 may be limited by
the quality of the database and the inability to audit those data. Moreover, the
accuracy of ICD-9-CM coding for the identification of specific medical condi-
tions, and sepsis in particular, remains controversial.15 Although administrative
datasets have become essential resources for epidemiological investigations in
which the prospective identification of patients is difficult or not feasible, strict
reliance on them for sepsis surveillance or research planning may be prone to
substantial random and systematic error.
The first European hospital-wide epidemiologic study in bacteremia and sepsis
of which we are aware was a French multicenter study conducted in 1993 in 24
16
F. Jaimes and R.J. Dennis
public or public-affiliated hospitals.16,17 The authors performed a 2-month prospec-
tive survey of 85,750 admissions to adult wards and ICUs and recorded an overall
incidence rate of bacteremia of 9.8 per 1,000 admissions, more than eightfold
higher in ICUs (69/1,000) than in wards (8.2/1,000). Of the 842 bacteremic epi-
sodes detected, 63% occurred in medical wards, 19% in ICUs, and 18% in surgical
wards. The authors considered that extrapolating these results to the whole country
would give a figure of approximately 67,500 bacteremic episodes per year.18 Of
note, nearly half of bacteremic episodes were of nosocomial origin, and although
ICU patients were at much higher risk of severe sepsis than ward patients, bacte-
remic severe sepsis was proportionally less often encountered in ICU than in
non-ICU patients. This suggests, as a remarkable concern vis-à-vis previous
studies, an important subset of patients besides those in intensive care unit, which
traditionally has been considered the natural setting for sepsis occurrence.19
Despite the broad distribution of sepsis and severe bacterial infections among
hospitalized patients, all of the recent studies outside the United States have
considered exclusively patients admitted to ICUs.20–24 Whether on prospective
cohorts20,23,24 or with administrative databases,21,22 all but one20 have focused on
severe sepsis or septic shock (Table 2.2).
The wide range of incidence and mortality rates may reflect different defini-
tions of outcome measures, as well as differences in data collection procedures
or methodological approaches. Three of these studies additionally provide some
Table 2.2. Worldwide Studies on the Epidemiology of Sepsis
Author, year
(reference)
Alberti,
2002 (20)
Padkin,
2003 (21)
Annane,
2003 (22)
EPISEPSIS,
2004 (23)
Finfer,
2004 (24)
a
Country
Six
European
countries,
Canada,
and Israel
England,
Wales, and
Northern
Ireland
Francec
France
Australian
and New
Zealand
Research
design
Outcome Incidence Mortality
Prospective 14,364 Infectious 21.1% 22.1% vs.
cohort study episodes 43.6%a
Administrative 56,673 Severe 27.1% 35% vs.
database sepsis 47%b
Administrative 100,554 8.2% 60.1%
database
Prospective
cohort study
Prospective 5,878
cohort study
Community vs. hospital acquired infection.
ICU vs. hospital mortality.
c
Paris and its suburbs.
d
30 days vs. 2 months mortality.
e
ICU vs. 28-day mortality.
b
Number of
ICU
admissions
screened
3,738
Septic
shock
Severe
sepsis or
Shock
Severe
sepsis
14.6% 35% vs.
41.9%d
11.8% 26.5% vs.
32.4%e
2. Sepsis Occurrence
17
understanding about time trends.21–23 Padkin et al. collected data from the British
Intensive Care National Audit and Research Centre from 1996 to 1999.21 They
described an increase in the incidence of severe sepsis from 25.9% in 1996 to
29.7% in 1999. In the same period, there was a slight decrease in hospital mortal-
ity rates, from 50.2% to 47%. The CUB-Réa Network22 is a database with infor-
mation from 35 ICUs in Paris and its suburbs. It found that the overall frequency
of septic shock increased from 7 to 9.7 per 100 admissions, from 1993 to 2000,
respectively. The crude mortality rate in the same population declined from 62.1%
in 1993 to 55.9% in 2000. Similarly, the EPISEPSIS Study Group23 compared
the current findings with their previous studies performed in 1993.16,17 The data
suggest an increase in the attack rate of severe sepsis in ICU patients over the
past decade, from 8.4% and 6.3% to 14.6% and 9%, for clinically and microbio-
logically documented severe sepsis, respectively. The 42% hospital mortality rate
recorded in the current study is substantially lower than the 59% corresponding
rate recorded in the previous period.
In short, a scan of the global panorama clearly shows that sepsis is a common
and frequently fatal condition in developed countries. It consumes considerable
resources, and although the overall mortality rate among patients with sepsis
seems to be declining, the incidence and the number of sepsis-related deaths have
increased significantly over the past two decades.
The Latin American View
For this view of the panorama of sepsis in Latin America, three databases were
systematically searched during 2004 by one of the authors (FJ): PUBMED
(National Library of Medicine), EMBASE (EMBASE.comSM), and LILACS (Lit-
eratura Latino Americana e do Caribe em Ciências da Saúde). The latter is pro-
duced by Biblioteca Regional de Medicina (BIREME) and the Pan-American
Health Organization (PAHO), at the Latin American and Caribbean Health Sci-
ences Information Center in São Paulo, Brazil, since 1982 (www.bireme.org/
accessed May 2004).
Different combinations of the terms “sepsis,” “septicemia,” “bacteremia,”
“sepsis syndrome,” “epidemiology,” “incidence,” and “prevalence” were used for
the search strategy. For PUBMED and EMBASE, the search strategy also included
additional terms for “Latin America,” “South America,” “Central America,” or
restriction to Spanish language. The first step was the screening of more than
1,000 potentially related titles, most of them from LILACS, and the second stage
was a detailed review of selected abstracts. This process yielded 20 references
from studies published from 1990 to 2004.5,25–43 A relevant finding was the sig-
nificant number of high-quality papers regarding neonatal sepsis and severe
infections in pediatric populations. For adult patients, however, the number and
scope of the investigations appeared to be more limited. Additionally, there was
available only the abstract for one study,25 and 7 out of the remaining 1826,28,29,34,38,40,41
analyzed sepsis as a secondary outcome among a wide definition of nosocomial
infections (Table 2.3).
dysfunction at 5
ICUs (n = 102)
Admissions at 254
ICUs (n = 895)
Patients with non
traumatic SIRSf
Characterization of
sepsis patients
Characterization of
bacteremic patients
Nosocomial infection
Not reportedc
25/1,000 (hospital
discharges)
45.8% vs. 58.2%b
Mortality
18
F. Jaimes and R.J. Dennis
Sepsis, severe sepsis,
septic shock
bacteremia
596/6605h (blood
cultures)
219/1,241c (nosocomial
Not reported
2. Sepsis Occurrence
19
20
F. Jaimes and R.J. Dennis
The studies reviewed were extremely heterogeneous in design, population,
sample size, end-points, and subject follow-up. Furthermore, the fundamental
challenge of lack of consensus on the clinical definition of sepsis seems more
critical in the Latin American literature. Thus, it is impossible to infer any overall
estimator about the magnitude of the problem in Latin America. On the other
hand, some data suggest that in terms of frequency and mortality, the picture of
sepsis and severe systemic infections may be even worse than in developed
countries. What follows is a brief analytical description of the most relevant
studies encountered.
Zanon et al., in 10 hospitals during 1990,25 using ICD-9-CM codes for septi-
cemia, estimated a mortality of 46% and 58% for community and nosocomial
acquired sepsis, respectively. In spite of potential underreporting, the incidence
of bacteremia in these hospitals were roughly similar to European estimates.16
Studies performed at ICUs27,30,33,34,39 between 1993 and 2001 demonstrated a
mortality ranging from 33.6% in a cross-sectional study by Ponce de Leon et al.
in Mexico34 to 56% in a retrospective case-series by Bilevicius et al. in
Brazil.39
All studies, except one,33 recruited a general population of sepsis patients,
without restrictions to organ dysfunction (i.e., severe sepsis) or septic shock.
Thus, a higher mortality rate on this latter subset is to be expected, which has
comprised the usual study population for European and North American
studies.13,22–24 Two prospective cohort studies from Colombia5,35 in infected
patients admitted to the emergency room with SIRS found a mortality rate
between 24% and 31%, which increased to 40% for patients in the ICU or with
positive blood cultures.36 Ponce de León et al., at a tertiary center in Mexico,28
described a rate of nosocomial bacteremia without an identifiable source—called
“primary bacteremia”—of 25/1,000 discharges in 1994, with a mortality rate of
40%. This subset of primary bacteremia may represent less than 20% of the total
affected population with bacteremia or sepsis.44,45 Jaimes et al.31,32 estimated that
severe infections and bacteremia were the main causes for emergency admission
in 7 out of 100 patients at a university hospital, and blood cultures were requested
in 2 out of 10 inpatients at some time during their hospitalization.32,43 Silva et
al.,47 in a good study recently conducted in 5 mixed ICUs in Brazil, prospectively
followed 1,383 consecutive adult admissions for the development of sepsis.
Sepsis and related conditions were diagnosed following the ACCP/SCCM crite-
ria. In this highly selected population of critically ill patients, the incidence
density for sepsis, for the total cohort, was 57.9 per 1,000 patient-days, and for
those surviving longer than 24 hours, 61.4 per 1,000 patient-days. They found a
trend for increased mortality from sepsis, severe sepsis, and septic shock: 34%,
47%, and 52%, respectively.
Sifuentes et al.,37 at a referral center in Mexico, conducted the only study that
allows for some approach regarding time trends. They described an overall fre-
quency of bacteremia of 18% among patients with blood cultures. The overall
mortality rates were 70% and 30% for nosocomial and community acquired
bacteremia, respectively. They randomly analyzed samples of positive blood
2. Sepsis Occurrence
21
cultures in three different periods: from 1981 to 1984, from 1985 to 1988, and
from 1989 to 1992. Interestingly, the overall mortality rate remained practically
without change through the three study periods: 29.5%, 27.5%, and 27%, respec-
tively. The authors pointed out that the mortality rate remained constant, even
after adjusting for source of bacteremia (community or nosocomially acquired,
figures not shown in the original report).
As an additional concern, only the studies by Hernandez et al.33 and Silva et
47
al. showed a mean age higher than 50 years in patients with sepsis (mean = 61;
range = 18–87, and mean = 66 years, IQR: 48–78 years, respectively). All of the
remaining study populations, whether in ICUs, general wards, or emergency
rooms, exhibited mean ages at or below 50 years. These results strongly contrast
with North American and European studies, in which the mean age has been at
or above 60 years.13,14,20,22,24 Whatever demographic or epidemiologic explanation
we have, it seems that we are facing sepsis in a younger and probably “healthier”
population, but with morbidity and mortality rates that are at least as high as those
from developed countries.
Finally, Ponce de Leon et al.,34 in a cross-sectional study in 254 multidisci-
plinary ICUs through Mexico in 1995, demonstrated a 1-day point prevalence of
16% and 17% for sepsis and severe sepsis or septic shock, respectively. For dis-
eases with short duration and early mortality, such as sepsis, prevalence studies
may underestimate their frequency, and they do not provide a true estimate of
risk. Even so, these figures are higher than those corresponding in prospective
cohort studies performed at European and Australian ICUs.23,24,46
Conclusion
Sepsis is an increasing problem everywhere. It bears a high burden of mortality,
morbidity, and resource consumption. In the Latin American context, unfortu-
nately, the approach to the problem has been marginal and in many instances
prone to bias in the estimates obtained. Unfortunately, it is unlikely that this situ-
ation represents a benign scenario of perhaps lower incidence or better prognosis.
Instead, it seems that the first two points of the action plan stated by the “Barce-
lona Declaration”1 are particularly necessary in our setting:
• “Increase awareness of health care professionals, governments, health and
funding agencies, and the public of the high frequency and mortality associated
with sepsis.”
• “Improve the early and accurate diagnosis of sepsis by developing a clear and
clinically relevant definition of sepsis and disseminating it to our peers.”
More studies are needed in the Latin American context, if an accurate descrip-
tion of the occurrence of sepsis, including its risk factors and clinical course, is
to be obtained in different populations at risk, not only in patients admitted to
ICUs. These studies should build on the studies conducted, but addressing the
limitations observed.
22
F. Jaimes and R.J. Dennis
References
1. Slade E, Tamber PS, Vincent JL. The Surviving Sepsis Campaign: raising awareness
to reduce mortality. Crit Care 2003;7(1):1–2.
2. Pierce G, Murray PR. Current controversies in the detection of septicemia. Eur J Clin
Microbiol 1986;5:487–91.
3. Bone RC, Fisher CJ Jr, Clemmer TP, et al. Sepsis syndrome: a valid clinical entity.
Methylprednisolone Severe Sepsis Study Group. Crit Care Med 1989;5:389–93.
4. American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference. Definitions for sepsis and organ failure and guidelines for the use of
innovative therapies in sepsis. Crit Care Med 1992;20:864–74.
5. Jaimes F, Garces J, Cuervo J, et al. The systemic inflammatory response syndrome
(SIRS) to identify infected patients in the emergency room. Intensive Care Med
2003;29:1368–71.
6. Vincent J-L. Dear SIRS, I’m sorry to say that I don’t like you. Crit Care Med
1997;25:372–4.
7. Marshall JC. SIRS and MODS: What is their relevance to the science and practice of
intensive care? Shock 2000;14:586–9.
8. Levy MM, Fink MP, Marshall JC, et al. 2001 SCCM/ESICM/ACCP/ATS/SIS Inter-
national Sepsis Definitions Conference. Crit Care Med 2003;31:1250–6.
9. Marshall JC, Vincent J-L, Fink MP, et al. Measures, markers, and mediators:
Toward a staging system for clinical sepsis. A report of the Fifth Toronto Sepsis
Roundtable, Toronto, Ontario, Canada, October 25–26, 2000. Crit Care Med 2003;31:
1560–7.
10. Centers for Disease Control and Prevention. Current Trends Increase in National
Hospital Discharge Survey Rates for Septicemia—United States, 1979–1987. MMWR
1990;39(2):31–4.
11. Rangel-Frausto S, Pittet D, Costignan M, et al. The natural history of the systemic
inflammatory response syndrome. JAMA 1995;273:117–23.
12. Sands KE, Bates DW, Lanken PN, et al. Epidemiology of sepsis syndrome in 8 aca-
demic medical centers. Academic Medical Center Consortium Sepsis Project Working
Group. JAMA 1997;278(3):234–40.
13. Angus DC, Linde-Zwirble WT, Lidicker J, et al. Epidemiology of severe sepsis in the
United States: Analysis of incidence, outcome, and associated costs of care. Crit Care
Med 2001;29:1303–10.
14. Martin GS, Mannino DM, Eaton S, et al. The epidemiology of sepsis in the United
Sates from 1979 through 2000. N Engl J Med 2003;348:1546–54.
15. Ollendorf DA, Fendrick AM, Massey K, et al. Is sepsis accurately coded on hospital
bills? Value Health 2002;5(2):79–81.
16. Brun-Buisson C, Doyon F, Carlet J. Bacteremia and severe sepsis in adults: a multi-
center prospective survey in ICUs and wards of 24 hospitals. French Bacteremia-
Sepsis Study Group. Am J Respir Crit Care Med 1996;154(3):617–24.
17. Brun-Buisson C, Doyon F, Carlet J, et al. Incidence, risk factors, and outcome of
severe sepsis and septic shock in adults. A multicenter prospective study in intensive
care units. French ICU Group for Severe Sepsis. JAMA 1995;274(12):968–74.
18. Brun-Buisson C. The epidemiology of the systemic inflammatory response. Intensive
Care Med 2000;26 Suppl 1:S64–74.
19. Moss M, Martin GS. A global perspective on the epidemiology of sepsis. Intensive
Care Med 2004;30(4):527–9.
2. Sepsis Occurrence
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20. Alberti C, Brun-Buisson C, Burchardi H, et al. Epidemiology of sepsis and infection
in ICU patients from an international multicentre cohort study. Intensive Care Med
2002;28(2):108–21.
21. Padkin A, Goldfrad C, Brady AR, et al. Epidemiology of severe sepsis occurring in
the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit
Care Med 2003;31(9):2332–8.
22. Annane D, Aegerter P, Jars-Guincestre MC, et al. Current Epidemiology of Septic
Shock: The CUB-Rea Network. Am J Respir Crit Care Med 2003;168(2):165–72.
23. The EPISEPSIS Study Group. EPISEPSIS: a reappraisal of the epidemiology and
outcome of severe sepsis in French intensive care units. Intensive Care Med 2004;
30(4):580–8.
24. Finfer S, Bellomo R, Lipman J, et al. Adult-population incidence of severe sepsis in
Australian and New Zealand intensive care units. Intensive Care Med 2004;30(4):
589–96.
25. Zanon U, Pereira Lde O, Kelm LS, et al. Septicemia: incidencia, mortalidade, letali-
dade e condicioes predisponentes em 10 hospitais brasileiros e 23,079 pacientes. Rev
Med St Casa 1990;2(3):213–8.
26. Del Rio J, Hernandez JM, Peon A, et al. Infeccion nosocomial. Estudio de 2 años.
Revista Cubana de Cirugia 1993;32(1):14–23.
27. Pazmiño L, Cifuentes A. Estudio epidemiologico de 435 pacientes septicos en una
unidad de cuidados intensivos general. Revista Hospital Eugenio Espejo 1993;3(1):
1–13.
28. Ponce de Leon S, Rivera I, Romero C, et al. [The risk factors in primary bacteremias:
a case-control study]. Gac Med Mex 1994;130(5):368–72; discussion 373.
29. Bembibre R, Gonzales E, Quintero C. Sepsis nosocomial. Revista Cubana de Medi-
cina 1997;36(2):95–9.
30. Arcienega TL, Barron M. Caracteristicas de infecciones en Unidad de Terapia Inten-
siva. Experiencia durante periodo de diez años. Archivos Bolivianos de Medicina
1998;5(58):25–30.
31. Jaimes F, Valencia M, Vélez L. Significado Clínico de los Hemocultivos. Una Cohorte
Retrospectiva en el Hospital San Vicente de Paul. Infectio 1998;2(2):69–76.
32. Jaimes F, Martinez CE, Valencia M, et al. Prediccion de mortalidad en pacientes con
bacteremia y sepsis. Acta Medica Colombiana 1999;24(3):96–101.
33. Hernandez G, Dougnac A, Castro J, et al. [Systemic inflammatory response syndrome:
is it comparable with severe sepsis?]. Rev Med Chil 1999;127(11):1339–44.
34. Ponce de Leon-Rosales SP, Molinar-Ramos F, Dominguez-Cherit G, et al. Prevalence
of infections in intensive care units in Mexico: a multicenter study. Crit Care Med
2000;28(5):1316–21.
35. Jaimes F, Garcés J, Cuervo J, et al. Factores pronósticos en el síndrome de respuesta
inflamatoria sistémica (SRIS). Desarrollo de un índice de severidad. Acta Medica
Colombiana 2001;26(4):149–57.
36. Zapata L, Jaimes F, Garces J, et al. Descripción de una cohorte de pacientes con cri-
terios de síndrome de respuesta inflamatoria sistémica en dos hospitales de tercer
nivel. Iatreia 2001;14(1):26–34.
37. Sifuentes-Osornio J, Guerrero-Almeida MC, Ponce de Leon-Garduno LA, et al.
[Trends for bacteremia and risk factors for death in a tertiary hospital in Mexico City.
1981–1992]. Gac Med Mex 2001;137(3):191–202.
38. Morales C, Fresneda G, Guanche H. Prevalencia puntual de infeccion nosocomial.
Revista Cubana de Enfermeria 2001;17(2):84–9.
24
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39. Bilevicius E, Dragosavac D, Dragosavac S, et al. Multiple organ failure in septic
patients. Braz J Infect Dis 2001;5(3):103–10.
40. Lujan M. Tendencias y pronosticos de las infecciones nosocomiales en la provincia
de cienfuegos. Revista Cubana de Higiene y Epidemiologia 2002;40(1):20–5.
41. Cordero DM, Garcia AL, Barreal RT, et al. Comportamiento de la infeccion nosoco-
mial en las unidades de terapia en un periodo de 5 años. Revista Cubana de Higiene
y Epidemiologia 2002;40(2):79–88.
42. Notario R, Borda N, Gambande T, et al. [Bacteremia in 2 hospitals in Rosario,
Argentina]. Rev Argent Microbiol 2003;35(3):167–70.
43. Jaimes F, Arango C, Ruiz G, et al. Predicting bacteremia at the bedside. Clin Infect
Dis 2004;38(3):357–62.
44. Wenzel RP. Perspective: treating sepsis. N Engl J Med 2002;347:966–7.
45. Angus DC, Wax RS. Epidemiology of sepsis: an update. Crit Care Med 2001;29:
S109–16.
46. Alberti C, Brun-Buisson C, Goodman SV, et al. Influence of systemic inflammatory
response syndrome and sepsis on outcome of critically ill infected patients. Am J
Respir Crit Care Med 2003;168(1):77–84.
47. Silva E, Almeida P, Beltrami A, et al. Brazilian sepsis epidemiological study (BASES
study). Crit Care Med 2004;8:R251–60.
3
Novel Therapies in Critically Ill
Septic Patients
Jean-Louis Vincent, Carla Marie Clausi, and Alejandro Bruhn
Introduction
Sepsis, the inflammatory response to infection, is perhaps the most common
disease encountered by the critical care physician, complicating some 30% to
40% of ICU admissions and accounting for considerable morbidity and mortality.
Septic shock affects some 10% to 15% of intensive care unit patients and carries
mortality rates of 50% to 60%. Recent years have seen major advances in the
understanding of the pathophysiology of sepsis and, as a result, new treatments
and approaches to management have become available.
The search to find effective therapies for sepsis, one of the most common disease
processes on the intensive care unit, has been rewarded in recent years with the
development and licensing of drotrecogin alfa (activated), the first of the so-called
immunomodulatory drugs to be shown to improve outcomes in patients with severe
sepsis. This milestone in the history of sepsis research has added new impetus to
the ongoing quest for strategies to help decrease the still high mortality rates associ-
ated with this condition. This chapter presents some of the recent advances in sepsis
management, including corticosteroids and drotrecogin alfa (activated), before
reflecting on some of the possible interventions and drugs of the future.
Immunomodulatory Therapies: Present
Corticosteroids
Corticosteroids have been considered as being of potential benefit in sepsis for
years, but when high doses were found to be of no benefit,1,2 they were discon-
tinued. However, recent studies have suggested that more physiological doses can
be beneficial.3–5 Annane et al.5 demonstrated improved survival in patients with
septic shock and relative adrenal insufficiency treated with a 50 mg intravenous
bolus of hydrocortisone every 6 h and fludrocortisone (50 μg tablet once daily)
for 7 days. So far, this strategy has only been tested in patients with septic shock,
and further study is needed to define its effectiveness in patients with less severe
25
26
J.-L. Vincent et al.
forms of sepsis. In addition, definitions of relative adrenal insufficiency are not
clear, and if corticosteroid administration is to be guided by ACTH stimulation
tests, which test should be used?
Drotrecogin Alfa (Activated)
A landmark year in the history of sepsis was 2001—after many years of appar-
ently fruitless research into immunomodulatory therapies for sepsis, drotrecogin
alpha (activated) was licensed by the FDA for the treatment of adult patients with
severe sepsis or septic shock. U.S. licensing was followed by acceptance in
Europe and other countries worldwide, and this drug now forms part of standard-
of-care management for patients with severe sepsis at high risk of death.6 The
development of drotrecogin alfa (activated), a recombinant version of a natural
anticoagulant protein, activated protein C, was the result of insight into the im-
portant links between the coagulation system and the inflammatory response to
sepsis.7 In a multicenter randomized controlled trial involving 1,690 patients, the
drug, at a dose of 24 μg/kg/h, was shown to improve survival from 30.8% in the
placebo group to 24.7% in the drotrecogin alfa (activated) group, giving a 19.4%
relative reduction in mortality rate (i.e., only 16 patients needed to be treated to
save one life).8 Drotrecogin alfa (activated) was also shown to improve organ
function, causing significantly faster resolution of cardiovascular and respiratory
dysfunction and significantly slower onset of hematologic organ dysfunction
compared with placebo patients.9 Importantly, too, its effects on outcome are
sustained beyond the traditional 28-day endpoint. There is an increased risk of
bleeding with drotrecogin alfa, with serious bleeding events occurring during the
infusion period in 2.8% of patients and during the 28-day study period in 5.3%
of patients.10 Of the bleeding events during the infusion period, 43% were pro-
cedure related. The instructions for the use of drotrecogin alfa (activated), there-
fore, clearly state that patients at high risk of bleeding should not be given the
drug, and it is contraindicated in patients with active internal bleeding, recent
hemorrhagic stroke, intracranial or intraspinal surgery, severe head trauma, pres-
ence of an epidural catheter, intracranial neoplasm, or evidence of cerebral her-
niation. In addition, infusion should be interrupted for surgery or invasive
interventions. Importantly, treatment with drotrecogin alfa (activated) seems to
be most effective when started early,11 and it should not be reserved as a last-resort
option. Although expensive, its cost-effectiveness profile seems to be in keeping
with other commonly used interventions in intensive care.12,13
Immunomodulatory Therapies: Future
The complexities of the immune response to sepsis are far from being clearly
defined and the interactions of one mediator on another make it difficult to deter-
mine the effects of interfering with the activity of any individual player. This is a
field of intensive experimental research activity, as results repeatedly demonstrate
3. Novel Therapies in Septic Patients
27
the intricacies of this amazing network of mediators and cells. It is not possible to
discuss here all the potential agents of the future, many of which have yet to be
discovered (!), but I will discuss some of the leading areas of current research.
Hemoperfusion Strategies
By removing inflammatory mediators, blood purification systems could poten-
tially improve outcomes, and several strategies have been suggested, although
this remains a controversial field. Continuous hemofiltration was not shown to
reduce mediator levels or the extent of subsequent multiple organ dysfunction14
and is not recommended for the treatment of sepsis independent of renal replace-
ment needs.6 However, research is continuing in an attempt to find the combina-
tion of membrane and ultrafiltration rate that may benefit septic patients. Coupled
plasma filtration adsorption (CPFA) nonselectively reduces the circulating levels
of pro- and antiinflammatory mediators, and early studies have suggested that
CPFA improves blood pressure and restores immune function in patients with
septic shock.15,16 Further studies are clearly needed to confirm these results.
New Antiendotoxin Strategies
Endotoxin is a key initiator of sepsis. Once in the circulation, endotoxin binds to
lipopolysaccharide binding protein (LBP), which can transfer endotoxin to cell
bound or soluble CD14 (resulting in cellular activation), or to lipoproteins (result-
ing in endotoxin inactivation). Normal plasma lipoprotein concentrations provide
an excess of endotoxin-binding sites, but in acute illness, lipoprotein levels are
reduced.17,18 Experimental studies in human volunteers and animal models have
shown that high-density lipoprotein (HDL) can block the effects of endotoxin.19,20
Experimental studies with an emulsion of phospholipid, the predominant lipid in
HDL, also reported significantly lowered serum endotoxin and tumor necrosis
factor (TNF)-alpha, preserved cardiac output and ejection fraction, and attenuated
increases in systemic and pulmonary vascular resistances.21 Phase II clinical trials
with this phospholipid emulsion are ongoing.
Apoptosis Inhibition
Apoptosis is the programmed death of cells and is essential for homeostatic cell
turnover. However, sepsis is associated with disordered apoptosis with increased
lymphocyte and epithelial cell apoptosis. Caspase-inhibitors,22 which prevent
apoptosis, and other strategies to limit apoptosis23–25 have improved survival in
animal models of sepsis, and antiapoptotic strategies may have a place in the
future treatment of sepsis.
High-Mobility Group B-1 Protein
High-mobility group B-1 protein (HMGB1) is a late mediator of systemic inflam-
mation, released from endotoxin-stimulated macrophages some 8–12 h after the
28
J.-L. Vincent et al.
release of the early cytokines. Activities of HMGB1 include activation of mac-
rophages to release TNF and IL-1, stimulation of neutrophil and smooth muscle
cell chemotaxis, and induction of epithelial cell permeability.26 In animal models,
ethyl pyruvate inhibits systemic HMGB1 release and prevents the lethal sequelae
of endotoxemia or peritonitis even when the first dose is given 24 h after the
induction of sepsis.26,27 The potential broader therapeutic time frame for treat-
ments targeted against HMGB1 makes this an interesting goal for future clinical
research.
Poly (ADP) Ribose Polymerase/Synthetase (PARP/PARS)
PARP is involved in modulating nuclear-factor kappa B (NF-κB)-mediated tran-
scription of various inflammatory mediators including inducible nitric oxide
synthase (iNOS) and intercellular adhesion molecule (ICAM). Pharmacological
inhibition of PARP improved survival in a porcine model of severe hypodynamic
sepsis induced by E. coli clot implantation and has been shown to improve hemo-
dynamics and outcome in various animal models of endotoxemia.28 However, a
randomized controlled clinical study of the NOS inhibitor in septic shock, 546C88,
showed increased mortality rates in the treated patients,29 and we need to have a
clearer understanding of the interactions between PARP/PARS and NO before
this area of immunomodulation undergoes clinical testing.
General Management
Although the development of specific sepsis-directed immunomodulatory thera-
pies is exciting, these agents are of little benefit if used alone, and must be used
in conjunction with other general management strategies, including optimal
hemodynamic resuscitation and metabolic support.
Optimal Hemodynamic Support
Optimal hemodynamic support depends on adequate fluid resuscitation and the
use of vasoactive agents when fluids alone fail to achieve the desired endpoints.
Comprehensive guidelines on hemodynamic management of the patient with
septic shock have been published recently.6 Importantly, early hemodynamic
optimization is most effective at reducing mortality.30 The “best” choice of fluid
has generated some debate, although there are no data indicating that any one
fluid is superior to another and in making a selection, the clinician needs to take
into account the different properties and side effects of the available solutions
and specific characteristics of the patient in question, including hemodynamic
stability, coagulation profile, and renal function. Some fluids (e.g., some hydroxy-
ethyl starch solutions or hemoglobin solutions) may have specific effects on the
microcirculation that may make them of greater use in the septic patient, but this
requires further study. Patients with shock may also have a relative vasopressin
3. Novel Therapies in Septic Patients
29
deficiency, and the administration of low doses of vasopressin may be a valuable
strategy. Some studies have indicated that patients with septic shock may benefit
from the administration of a continuous infusion of low doses of vasopressin in
terms of reduced catecholamine requirements and improved renal function,31,32
but prospective randomized clinical trials need to confirm these findings.
Glucose Control
In an important study, Van den Berghe et al.33 randomized more than 1,500 ICU
patients to intensive management aimed at keeping blood sugar levels within tight
limits of 80 to 110 mg/dL versus conventional management of hyperglycemia;
mortality rates were reduced from from 8.0 to 4.6% (p < .04) in the intensive
treatment group. In addition, intensive treatment was associated with shorter ICU
stays, less requirement for renal replacement therapy, less hyperbilirubinemia,
fewer blood stream infections, fewer ICU neuropathies, and a reduced need for
transfusion. Further study has suggested that these results were indeed due to the
control of glucose levels rather than to the insulin administered.34,35 Although this
study did not focus on septic patients, septic complications were reduced, and it
would seem reasonable that glucose levels should also be carefully monitored
and adjusted in patients already presenting with sepsis. In addition, while the
strategy appears to be a simple way to improve outcomes, it poses several logistic
problems including increased nursing time, additional blood sampling, and risk
of hypoglycemia. Specially designed insulin protocols may help limit these
difficulties.36,37
Nutrition
Nutritional support is important in the management of the septic patient. Early
nutrition seems to be beneficial in all acutely ill patients, except maybe those who
have a risk of gut hypoperfusion associated with hemodynamic instability. The
enteral route is preferred because it helps to maintain the integrity of the gut
mucosa or because it avoids the possibly harmful effects of parenteral nutrition.
Immunonutrition (using enteral solutions enhanced with various amino acids and
fatty acids) may have beneficial effects by improving the host response to the
acute disease,38 but further study is needed to better define which constituents
should be included.
Conclusion
The past few years have seen exciting developments in the treatment of severe
sepsis and septic shock. The standard, and still vitally important, management of
severe sepsis relies on adequate resuscitation with fluids and vasoactive agents,
eradication of the causative infection using antibiotics and surgical removal
where necessary, and individual organ support including renal dialysis and
30
J.-L. Vincent et al.
Table 3.1. The PIRO Concept to Characterize Sepsis39
P:
I:
R:
O:
Predisposing factors: age, sex, genetic factors, immunodepression,
Infection: local or systemic, causative microorganism(s), source,
Response: fever, white blood cell count, increase in CRP, tachycardia,
Organ dysfunction: renal dysfunction, alterations in gas exchange, coagulation abnormalities.
mechanical ventilation. Importantly, early resuscitation is associated with im-
proved outcomes.30 Corticosteroids, drotrecogin alfa (activated), and careful
glucose control must now also form part of management protocols.
The future will see many more agents being tested, and some will also be
shown to improve outcomes. The challenge then will be to determine which
drug(s) to give to which patient. Genetic typing and improved markers of sepsis
and of the inflammatory response may help define an individual ICU sepsis
package for each patient. The recently suggested PIRO (predisposition, infection,
immune response, organ dysfunction) system of “staging” sepsis (see Table 3.1)39
will also help to characterize patients, to target treatments, and to monitor response
to therapy.
References
1. Bone RC, Fisher CJJ, Clemmer TP, et al. A controlled clinical trial of high-dose
methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med
1987;317:653–8.
2. The Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of
high-dose glucocorticoid therapy on mortality in patients with clinical signs of sys-
temic sepsis. N Engl J Med 1987;317:659–65.
3. Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic shock with supra-
physiologic doses of hydrocortisone. Crit Care Med 1998;26:645–50.
4. Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone reverse hyper-
dynamic septic shock: a prospective, randomized, double-blind, single-center study.
Crit Care Med 1999;27:723–32.
5. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA
2002;288:862–71.
6. Dellinger RP, Carlet JM, Masur H, et al. Surviving sepsis campaign guidelines for
management of severe sepsis and septic shock. Crit Care Med 2004;32:858–73.
7. Amaral A, Opal SM, Vincent JL. Coagulation in sepsis. Intensive Care Med 2004;
30:1032–40.
8. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.
9. Vincent JL, Angus DC, Artigas A, et al. Effects of drotrecogin alfa (activated) on organ
dysfunction in the PROWESS trial. Crit Care Med 2003;31:834–40.
10. Bernard GR, Macias WL, Joyce DE, et al. Safety assessment of drotrecogin alfa
(activated) in the treatment of adult patients with severe sepsis. Crit Care 2003;7:
155–63.
11. Vincent JL, Levy MM, Macias WL, et al. Early intervention with drotrecogin alfa
(activated) improves survival benefit. Crit Care Med 2003;3:834–40.
3. Novel Therapies in Septic Patients
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12. Manns BJ, Lee H, Doig CJ, et al. An economic evaluation of activated protein C
treatment for severe sepsis. N Engl J Med 2002;347:993–1000.
13. Angus DC, Linde-Zwirble WT, Clermont G, et al. Cost-effectiveness of drotrecogin
alfa (activated) in the treatment of severe sepsis. Crit Care Med 2003;31:1–11.
14. Cole L, Bellomo R, Hart G, et al. A phase II randomized, controlled trial of continuous
hemofiltration in sepsis. Crit Care Med 2002;30:100–6.
15. Ronco C, Brendolan A, Lonnemann G, et al. A pilot study of coupled plasma filtration
with adsorption in septic shock. Crit Care Med 2002;30:1250–5.
16. Formica M, Olivieri C, Livigni S, et al. Hemodynamic response to coupled plasma-
filtration-adsorption in human septic shock. Intensive Care Med 2003;29:703–8.
17. Gordon BR, Parker TS, Levine DM, et al. Low lipid concentrations in critical
illness: implications for preventing and treating endotoxemia. Crit Care Med 1996;
24:584–9.
18. van Leeuwen HJ, Heezius EC, Dallinga GM, et al. Lipoprotein metabolism in patients
with severe sepsis. Crit Care Med 2003;31:1359–66.
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density lipoprotein during human endotoxemia. J Exp Med 1996;184:1601–8.
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physiologic and tumor necrosis factor alpha responses to lipopolysaccharide in rabbits.
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ment improved cardiopulmonary function and survival in porcine sepsis. Am J Physiol
Regul Integr Comp Physiol 2003;284:R550–7.
22. Hotchkiss RS, Chang KC, Swanson PE, et al. Caspase inhibitors improve survival in
sepsis: a critical role of the lymphocyte. Nat Immunol 2000;1:496–501.
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in sepsis improves survival in mice. Proc Natl Acad Sci USA 1999;96:14541–6.
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septic survival: differential effects on macrophage apoptotic and functional capacity.
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27. Ulloa L, Ochani M, Yang H, et al. Ethyl pyruvate prevents lethality in mice with
established lethal sepsis and systemic inflammation. Proc Natl Acad Sci USA 2002;
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28. Pacher P, Cziraki A, Mabley JG, et al. Role of poly(ADP-ribose) polymerase
activation in endotoxin-induced cardiac collapse in rodents. Biochem Pharmacol
2002;64:1785–91.
29. Lopez A, Lorente JA, Steingrub J, et al. Multiple-center, randomized, placebo-
controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on
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severe sepsis and septic shock. N Engl J Med 2001;345:1368–77.
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of vasodilatory septic shock. J Trauma 1999;47:699–703.
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national Sepsis Definitions Conference. Crit Care Med 2003;31:1250–6.
4
Dissemination Control of
the Antimicrobial Resistance in
the Intensive Care Unit
Carlos Arturo Alvarez and Jorge Alberto Cortés
Introduction
The impact of antimicrobial resistance (AMR) in the ICU is serious and it is more
frequent each time with the consequent effect over morbimortality.1–3 According
to an AMR surveillance study, in more than 100 intensive care units (ICU) in
the United States the following percentages of resistant bacterias were found:
methicillin-resistant Staphylococcus aureus (MRSA), 57.1%; methicillin-
resistant coagulase-negative Staphylococcus (MR CNS), 89.1%; vancomycin-
resistant Enterococcus faecium (VRE), 27.5%; imipenem-resistant Pseudomonas
aeruginosa, 22.3%; third-generation cephalosporin-resistant Enterobacter spp.,
32.2%.3 The presence of AMR additionally contributes to a considerable increase
in care costs4–7 and a major morbimortality.8–10
Cause of Antimicrobial Resistance in ICU
The causes of AMR appearance or increase are multiple and can be summarized
in factors that depend on the bacteria—the host and the environment. AMR inci-
dence in the ICU is generally the reflection of the institution resistance situation,
since in it, not only the critical patients but also AMR from other services or
institutions are concentrated here. In addition, ICUs play a critical role in an AMR
emergency because they facilitate a high percentage of patients who are taking
extended-spectrum antibiotics, patient germ dissemination, patients with severe
diseases, invasive procedures, and the transference of colonized or infected
patients between services. In Figure 4.1, the possible reasons in which AMR
is selected and disseminated in the ICU are schematized (it has been modified
since the concepts proposed by Lipsitch and Samore).11 Because these are not
the only factors, antimicrobial and nonfulfillment measures to prevent and
control the infection constitute, without any doubt, the main reasons for resistance
in the ICU.
33
34
C.A. Alvarez and J.A. Cortés
S
Antibiotic
treatment
S
S
A
S
S
B
S
S
S
S
S
Antibiotic
treatment
S
S
S
C
Antibiotic
treatment
S
S
S
D
Resistant bacteria
S
S
S
Sensitive bacteria
Figure 4.1. Mechanisms of transmission of the bacterial resistance.
The Use of Antimicrobial Agents
The appearance and use of antibiotics go hand in hand with the appearance of
resistance. However, resistance is not found in the same percentage for all anti-
biotics and for all germs. The differences depend on the intrinsic features of the
germs and molecules and the manner in which we use them.
Certain bacterias, such as P. aeruginosa and Acinetobacter baumanii, can
generate a resistance of 20% to antibiotics during their administration mainly
because of a high possibility of using different resistance mechanisms.12–16 In
the P. aeruginosa case, the studies made during treatment showed an adjusted
risk to developing resistance that varies according to the antibiotic used:
imipenem, 2.8; piperacillin, 1.7; ciprofloxacin, 0.8, and ceftazidime, 0.716.
4. Dissemination Control of the Antimicrobial Resistance in the ICU
35
Other germs such as Stenotrophomonas maltophilia already have natural resis-
tance mechanisms to carbapenems, so use of antimicrobials is needed only to
favor dissemination when the bacterial flora that competes with them (Figure
4.1d) is eliminated.
The appearance of new mutations or the phenotopic expression from resistance
genes has a low spontaneous incident. When it appears, it mainly induces anti-
biotic pressure. Such is the case of the extended-spectrum beta-lactamases
(EESBL), in which the change of one amino acid in a resistant gene assists the
appearance of new enzymes within that major spectrum.17 However, when the
pharmacokinetic and pharmacodynamic features allow it, this process can be
accelerated; such is the case in the relationship between MRSA and some quino-
lones.18 In the case of the EESBL, certain cephalosporins have a major capacity
of resistance induction.19 Therefore, the patterns of use of the different cephalo-
sporins have determined the appearance of the different types of EESBL.20
Another appearance mode of AMR is the selection of resistant flora. This
feature occurs with all antibiotics, and the difference among the molecules
depends on the spectrum of each one: the more extensive spectrum the anti-
microbial has, the more extensive the change generated in the normal flora will
be.21 The bacterial populations are not homogeneous and many times the patients
are colonized by resistant strains. In Table 4.1 examples of bacterial resistance
inductive antibiotics are illustrated.
Table 4.1. Examples of Resistance Induction Produced by Antibiotics
Antibiotic used
Gentamicin
Second- and third-
generation
cephalosporin
Cefoxitin, third-
generation
cephalosporin,
aminopenicillins
Ceftazidime and
ticarcillin
Quinolones:
ciprofloxacin
Imipenem
Vancomycin
Metronidazole,
cephalosporins
Induced resistance
To aminoglycosides
EEBL
Observation
Depending on the
geographic area
Reference
42
43–45
AmpC 46–48
Overexpression of the flow 12
pump MexAMexBoprM;
resistance to quinolones,
carbapenems, tetracyclines,
chloramphenicol
Flow pumps induction,
quinolone resistance
oprD-: carbapenem
resistance
Appearance of vancomycin-
resistant Enterococcus spp.
(VRE)
VRE appearance
Related to pharmacokinetics
of the medicine
Related to the appearance
of Acinetobacter spp. and
S. maltophilia
12, 49, 50
51
30, 52
Associated to the effect
over the anaerobic flora
52
36
C.A. Alvarez and J.A. Cortés
Nonfulfillment of Control Measures
The lack of adequate adherence to handwashing and the violation of isolation
protocols are responsible for the colonization, infection, and AMR persistence in
the majority of ICUs (Figure 4.1).
AMR can be transmitted in a clone or polyclone mode. The former occurs due
to failure to follow hygienic rules. An AMR from a patient can be disseminated
among other patients and inclusively colonize the environment. In this case, the
resistance profile of the isolated germ is the same (i.e., MRSA persistence). The
latter mode of dissemination occurs through the use of antimicrobials in the ICU,
which can generate the appearance of AMR and the resistance profile can be
different. Even more so, the bacterias can be different among patients depending
on the type of antibiotic used in each case. Finally, in many ICUs the problem is
mixed: an AMR is selected by antibiotic pressure, and then it is disseminated due
to the lack of hygiene measures.
Control of the Resistance Dissemination
The following strategies are used to control bacterial resistance22:
1. Implementation of an antimicrobial resistance periodic monitoring system in
community and nosocomial isolations.
2. Implementation of a periodic monitoring system of antibiotic use according
to the location in the hospital or prescription service.
3. Monitor of the relationship between the use of antibiotics and antimicrobial
resistance: assignment of responsibilities through practical guides or other
institutional policies.
4. Preventive applications of isolation contact in known patients or those with
suspicious colonization or infection by germs that are epidemiologically
important.
Measures for Settlement of Control Infection
Containment measures to control infection, such as the isolation of patients,
handwashing, wearing gloves, and an adequate use of face shield, plus a wise
evaluation of the antibiotic use in the services are some of the strategies recom-
mended to prevent the appearance and selection of resistant germs.23,24 These
strategies are detailed below.
Control Program Implementation
Implementation of the adopted measures by the personnel is a determinant of the
efficacy of the AMR control program. The control program must have adequate
resources as well as provide training and motivation for the entire health team.
Also it is best to audit the practices periodically (isolation techniques and the
4. Dissemination Control of the Antimicrobial Resistance in the ICU
37
antibiotic use) in order to verify the concordance between the reality of use and
the strategy adopted in the guidelines.
Identification of the Infected Carrier or Colonized Patients
Infected patients must be identified quickly. At the moment that an AMR is
detected, the appropriate measures must be taken without delay. In certain cases,
the isolation of carrier patients should be recommended. This isolation should be
selective and done quickly in cases of possible epidemic or if the patients show,
at the moment of admission, risk factors of carrying AMR (for instance, hospi-
talization in another third-level institution). This would consist of an active search
for AMR as well as for MRSA or VRE, in nasal fossae, the rectum, and so forth.
In a study in an ICU, with high rates of colonization, strategies of microbiological
isolation in all patients when they enter the unit and the wearing of gloves in all
patients or those selected as high risk25 were proposed. The lesson is that once
the germs are identified, the patients should be suitably isolated.
Technical Isolation
Technical isolation measures will establish barriers around the colonized or
infected patient. These contact precautions include wearing sterile gloves, a rein-
forcement of washing and antisepsis of hands (especially when leaving the room
or cubicle), the use of other protections (face shields and gowns when there is
close contact and risk of splashes), and the individualization of care materials
(e.g., stethoscope, pulsoximeter). The cleaning and disinfection of the environ-
ment, in particular the surfaces located near the carrier patient, must be done
regularly.
Geographic Isolation
Geographic isolation utilizes an individual room or a place of handwashing or an
alcohol dispenser near the patient’s bed. Entry into the isolation rooms must be
limited as well as the circulation of carrier patients. One must not forget that the
hands are the main reservoir and provider of transmission.
Isolation Measures
Isolation measures are all those strategies used to establish barriers to microorgan-
isms transmission. There are some general hygienic precautions that are applied
to all patients independent of their infectious status. These measures have been
called by the U.S. Centers for Disease Control (CDC) and the French recom-
mendations24,26 the “Standard Measures” and are listed here and summarized in
Table 4.2.
Hygienic Handwashing
Handwashing is the most effective general measure to control infection dissemi-
nation in the ICU.
38
C.A. Alvarez and J.A. Cortés
Table 4.2. Standard Precautions to Respect During the Treatment of Every Patient
Strategy
Hygienic handwashing
Wearing gloves
Gloves must be changed between
two patients and between two
activities in the same patient
Use of gown, eye protection, and face
shield
Contaminated material
Contaminated surfaces
Transport of biological samples,
clothes, and contaminated material
Recommendation
Before contact with the patient and after discarding
the gloves
Between two activities in the same patient
Between two patients
If there is risk of contact with blood or another human
fluid, mucus, or nonintact skin of the patient,
especially at the moment of interventions with a
puncture risk (hemocultures, inserting or removing
poisonous accesses, catheter, taking blood samples,
etc.) and with the manipulation of tubes with
biological samples, clothes, and dirty material AND
During all procedures in which hands are in contact
with the patient’s injuries
If in the care or treatment of the patient there is a risk
of splashing or spraying of blood or another human
fluid (aspiration, endoscopy, operative functions,
autopsy, manipulation of material, dirty clothes, etc.)
Sharp or stabbing items: Do not recap or remove cap
from disposable syringes or used needles by hand,
discard them after use, and place them in appropriate
puncture-resistant containers
Clean and disinfect with the appropriate disinfectants
all surfaces contaminated by splashes and sprays of
blood or other human fluids
Biological samples, clothes, and instruments
contaminated by blood or other human fluids must
be transported with an impermeable packing,
hermetically sealed
Wearing Gloves
It must always be taken into consideration that the main objective of gloves is to
protect the patient. As a consequence, avoid frequent practices such as bathing
the patient, and then, with the same gloves, doing other activities. Always take
off the gloves, wash hands, and put another pair of gloves on when different
procedures are done for the same patient.
Isolation Measures
In addition to the standard measures, it is necessary to take particular precautions
of geographic or technical isolation in order to prevent the transmission or diffu-
sion of microorganisms. These particular precautions are defined according to the
infectious agent (reservoirs, ways of transmission, resistance in the external
environment) and the infection (location and seriousness). In Table 4.3 the isola-
tion measures are summarized according to the transmission type and the related
microorganisms.
4. Dissemination Control of the Antimicrobial Resistance in the ICU
39
Table 4.3. Particular Precautions to Take into Consideration as a Complement to the
Standard Precautions According to the Infection
Transmitted by air
➱ Measles
➱ Varicella
➱ Tuberculosis
Transmitted by drops Transmitted by contact
➱ Infections by H. Influenzae type B ➱ Infections or colonizations of
➱ N. meningitidis skin, injuries, gastrointestinal
➱ Multiresistant S. pneumoniae tract, respiratory tract by
➱ Mycoplasma multiresistant germs
➱ Influenza ➱ Enteric infections
➱ Parvovirus B19 ➱ C. difficile
➱ German measles ➱ Shigella
➱ Diphtheria ➱ Hepatitis A
➱ Adenovirus ➱ E. coli 0157:H7
➱ VSR and parainfluenza
➱ Enterovirus
➱ Zoster varicella
➱ Herpes simplex
➱ Forunculosis
➱ Scabiosis
➱ Pediculosis
➱ Impetigo
Protective isolation must be provided for patients who have decreased immune
defenses in order to protect them against external contamination as well as to
avoid contact with microorganisms. The measures include the regulation of
people circulation, the use of individual rooms, the use of sterile protectors
(gowns, gloves, masks), and nutrition without raw products. Some recomenda-
tions related to the risk are:
• If there is transmission risk by interhuman contact (take contact precautions),
• If it is by airborne transmission (air precautions), and
• If there is orotracheobronchial secretions transmission (drops precautions)
(Tables 4.3 and 4.4).
Table 4.4. Particular Precautions to Take into Consideration as a Complement to the
Standard Precautions in the Function of the Transmission Route of the Infection
Air Drop Contact
precautions precautions precautions
Handwashing Standard Standard Material and clothes Standard Standard Hygienic (before and after)
Individual room + + Patient transport To limit To limit +
Eye protection, face shield + + Standard
Gloves Standard Standard At the entrance of the room
Gown Standard Standard At the contact with the patient
or the environment*
Standard
To limit
* In the case of isolation due to suspicion of colonization or infection by multiresistant germs, wearing
gowns will depend on the possibility of close contact with the skin or contaminated injuries of the
patient. + = use the precautions.
40
C.A. Alvarez and J.A. Cortés
All colonized and infected patients with AMR must be isolated. The decontami-
nation of colonized patients is not recommended. The efficiency of the chemical
decontamination in AMR has been demonstrated only in MRSA nasal carrier
patients in which the use of mupirocin temporarily eradicates its presence.27,28
Searching for and decontaminating personnel is not necessary because they are
rarely carriers in a lasting manner (only temporarily), after contact with the
patients. In cases of outbreaks, where the reservoirs are in the environment (P.
aeruginosa, Acinetobacter spp.), complementary measures should be taken in
order to clean and disinfect the environment.
It is recommended to start a relative information system of an AMR carrier
with the objective to identify the AMR carrier patients quickly in the moment
of their transfer. The system should include information related to the
agencies that received the patient temporarily, ensured her or his transfer. This
is especially a concern to those providing diagnostic images, as well as in
the surgery rooms and the departments or centers where the patients were
hospitalized.
Antibiotic Control
Good Use of Antibiotics
This section emphasizes the importance of an antibiotic policy inside the hospital
and the ICU. The recommendations for clinical practice and the efficiency or resist-
ance to their use have been demonstrated in studies for more than 20 years.22,29–31
The patient must be treated with the most effective and the least toxic antibiotic
for the required period of time and with the adequate doses to cure and prevent
an infection, producing the least possible amount of resistance. Enacting this rule
is difficult, as most often the initiation of an antibiotic is empirical. The following
are some of the strategies that have demonstrated to be efficient to fulfill this
objective.
Antibiotic Restriction
Restricting antibiotics is one of the most commonly used measures and consists
of the prescription limitation of one of the molecules or antibiotic families. The
strategies to control the limitation are diverse:
• Prescription authorization granted to only a limited number of physicians.
• Authorization in the pharmacy to dispatch antibiotics for only certain patholo-
gies and for a brief period of time.
• Authorization granted only with previous justification.
• No purchase and no prescription authorizations as a policy from the managing
department of the institution or unit.
• Implementation of additional forms for the antibiotics, their doses, and the
appropriate intervals.32
4. Dissemination Control of the Antimicrobial Resistance in the ICU
41
The implementation of multidisciplinary strategies is more appropriate than
individual strategies. The more useful ones are academic input; feedback from
the infirmary, physicians, and pharmacologist; the local adoption of handling
guides; and the assisted computerized prescription.31,33 Bisson et al. found
that restricting the use of third-generation cephalosporins decreases the incid-
ence of fecal colonization of E. coli and Klebsiella spp., which are EEBL
producers.34
Antibiotic Rotation
Rotating antibiotics is another measure in which the use of antibiotic A or a family
is restricted for a predetermined period of time and it is replaced by B; then a
new one, C, is used, or A is used again.35 This strategy tries to anticipate a resist-
ance occurring by predetermined rotation guidelines.36,37 There are certain limit-
ations to this strategy in the available studies38:
• The studies have small sample size and are not comparable.
• In some studies, other control measures were done in parallel, and it is difficult
to evaluate the impact in each intervention separately.
• The intervention time varies from months to 10 years. Consideration should
also be given to the fact that the adequate time to avoid the resistance occurring
between microorganisms is different, and this can make it difficult to determine
the time of each cycle.
• Almost all of the studies were done to control an outbreak or to decrease high
resistance, but not to avoid the resistance occurring, which should be the initial
objective here.
One must be careful that the clinical abuse of an antibiotic does not become
habitual. If a strategy is decided upon, it should be taken into account not to
include an inductor molecule of resistance in the antibiotic’s cyclical replacement.
It is possible that the cyclical use of antibiotics amounts to a restriction of them
for certain periods of time.
Antibiotic Combinations
Remember that the use of two or more antibiotics in order to decrease the resist-
ance is a theoretic approximation, validated in infections such as tuberculosis,
leprosy, and malaria, but its clinical usage to control AMR in the ICU has been
demonstrated in an anecdotal way, and if the dynamic of the occurrence of the
resistance is taken into consideration (Figure 4.1), an even higher pressure pro-
duces higher resistance. In ICUs there is discussion about whether use of the
combination of β-lactams and aminoglycosides is not only effective but if the
occurrence of the resistance decreases. Recently, two metaanalyses, one in neu-
tropenic patients39 and another in patients with gram-negative bacteremias,40 did
not find a difference in the mortality in patients with monotherapy versus com-
bined therapy. Additionally, in the first study the same rate of superinfections with
42
C.A. Alvarez and J.A. Cortés
AMR in the two groups was found but with a decrease in the adverse effects in
the monotherapy group.
A Strategy in Real Life
The control resistance policy has been considered a problem for everybody and
for this reason the first recommendation is to count on support from everybody.
Thus, teamwork is essential among the clinical laboratory, pharmacy, ICU
personnel, the infectious diseases unit, and the administrative component of the
institution.
A second recommendation is establishing clear guidelines as to when to start
an antibiotic treatment, and once it is decided to do so, to keep in mind the fea-
tures of the microbial flora of each unit and the pharmacokinetic/pharmacody-
namic parameters of antimicrobials. To improve the use of antibiotics, it is
recommended for physicians to know the profile of the antimicrobial susceptibil-
ity and, based on this, to design guides and protocols for their own unit. Treat
infections, not colonizations. The unnecessary treatment in colonization cases
increases the resistance to the antibiotics used.
A third recommendation is to restrict the use of antibiotics in order to protect
the environment and restrain the resistance from occurring. The selection is done
with two criteria:
• The demonstration of being a main inductor of resistance, such as ceftazidime,
cefotaxime, ceftriaxone, cefoxitin, imipenem, and gentamicin. These are not
the only inductors, but they are the most important ones to stimulate the appear-
ance of β-lactams.
• Selection of multiresistant flora to selective antibiotic pressure. This is the case
with ciprofloxacin and vancomycin.
This does not mean that these medications can never be prescribed, but they
must be prescribed only in strict situations according to the policies established
in the protocols. The way to determine restriction depends on the features of
the hospital: human resources, technical and administrative support, and so
forth.
Resistance Surveillance to Antibiotics
The resistance surveillance to antibiotics is complementary to the nosocomial
infections. This is essential, as it not only helps in the selection of antibiotics,
but also provides valuable information on the epidemiology and the prevention
of nosocomial infections. This surveillance has the following objectives:
• To guide the selection of individual therapeutics.
• To define the protocols of the first-intention antibiotic therapy against well-
defined medical situations, especially in presumptive treatments.
• To guide and reinforce the measures taken to control the infections caused by
AMR.
4. Dissemination Control of the Antimicrobial Resistance in the ICU
43
• To help distinguish the bacterial strains responsible for the nosocomial infec-
tions from the ones responsible for acquired infections in the community.
Certain types of resistance, can, in effect, be considered as real markers of
hospital acquisition: MRSA, production of EEBL, or resistance to certain
aminoglycosides in E. coli, P. mirabilis, or Klebsiella spp. strains.
• To identify the multiresistant bacteria (MRB) defined by a phenotype of resist-
ance associated with various antibiotics that can compromise the therapeutic
possibilities (MRSA, VRE, production of EEBL in enterobacteria, resistance
to the carbapenems of P. aeuruginosa, Acinetobacter spp., S. maltophilia, etc.).
The identification of a cross-transmission of multiresistant strains must initiate
measures to prevent the epidemic diffusion inside the unit and the hospital. The
frequency of AMR acquisitions in a clinical service or hospital must be con-
sidered as a quality marker of the organization of the services.41
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10. Nguyen MH, Yu VL, Morris AJ, et al. Antimicrobial resistance and clinical outcome
of Bacteroides bacteremia: findings of a multicenter prospective observational trial.
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11. Lipsitch M, Samore MH. Antimicrobial use and antimicrobial resistance: a population
perspective. Emerg Infect Dis 2002;8:347–54.
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12. Livermore DM. Of Pseudomonas, porins, pumps and carbapenems. J Antimicrob
Chemother 2001;47:247–50.
13. Danes C, Navia MM, Ruiz J, et al. Distribution of beta-lactamases in Acinetobacter
baumannii clinical isolates and the effect of Syn 2190 (AmpC inhibitor) on the MICs
of different beta-lactam antibiotics. J Antimicrob Chemother 2002;50:261–4.
14. Giamarellou H. Prescribing guidelines for severe Pseudomonas infections. J Anti-
microb Chemother 2002;49:229–33.
15. Quinn JP. Clinical problems posed by multiresistant nonfermenting gram-negative
pathogens. Clin Infect Dis 1998;27 Suppl 1:S117–24.
16. Carmeli Y, Troillet N, Eliopoulos GM, et al. Emergence of antibiotic-resistant Pseu-
domonas aeruginosa: comparison of risks associated with different antipseudomonal
agents. Antimicrob Agents Chemother 1999;43:1379–82.
17. Rasmussen BA, Bradford PA, Quinn JP, et al. Genetically diverse ceftazidime-
resistant isolates from a single center: biochemical and genetic characterization of
TEM-10 beta-lactamases encoded by different nucleotide sequences. Antimicrob
Agents Chemother 1993;37:1989–92.
18. Weber SG, Gold HS, Hooper DC, et al. Fluoroquinolones and the risk for
methicillin-resistant Staphylococcus aureus in hospitalized patients. Emerg Infect Dis
2003;9:1415–22.
19. Muller A, Lopez-Lozano JM, Bertrand X, et al. Relationship between ceftriaxone use
and resistance to third-generation cephalosporins among clinical strains of Enterobac-
ter cloacae. J Antimicrob Chemother 2004;54:173–7. Epub 2004 May 18.
20. Wang H, Kelkar S, Wu W, et al. Clinical isolates of Enterobacteriaceae producing
extended-spectrum beta-lactamases: prevalence of CTX-M-3 at a hospital in China.
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21. Sullivan A, Edlund C, Nord CE. Effect of antimicrobial agents on the ecological
balance of human microflora. Lancet Infect Dis 2001;1:101–14.
22. Shlaes DM, Gerding DN, John JF, Jr., et al. Society for Healthcare Epidemiology of
America and Infectious Diseases Society of America Joint Committee on the Preven-
tion of Antimicrobial Resistance: guidelines for the prevention of antimicrobial resis-
tance in hospitals. Clin Infect Dis 1997;25:584–99.
23. Fridkin SK. Increasing prevalence of antimicrobial resistance in intensive care units.
Crit Care Med 2001;29:N64–8.
24. Ministere de la solidarite. 100 Recommandations pour la surveillance at la prevention
des infections nosocomiales. Paris, 1999.
25. Trick WE, Weinstein RA, DeMarais PL, et al. Colonization of skilled-care
facility residents with antimicrobial-resistant pathogens. J Am Geriatr Soc 2001;
49:270–6.
26. Pirwitz S. HICPAC guidelines for isolation precautions: Hospital Infection Control
Practices Advisory Committee. Am J Infect Control 1997;25:287–8.
27. Scully BE, Briones F, Gu JW, et al. Mupirocin treatment of nasal staphylococcal colo-
nization. Arch Intern Med 1992;152:353–6.
28. Perl TM, Cullen JJ, Wenzel RP, et al. Intranasal mupirocin to prevent postoperative
Staphylococcus aureus infections. N Engl J Med 2002;346:1871–7.
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tions of the Hospital Infection Control Practices Advisory Committee (HICPAC).
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31. Gross PA, Pujat D. Implementing practice guidelines for appropriate antimicrobial
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teral antibiotic use in Colombia. J Clin Epidemiol 2003;56:1013–20.
33. Geissler A, Gerbeaux P, Granier I, et al. Rational use of antibiotics in the intensive
care unit: impact on microbial resistance and costs. Intensive Care Med 2003;29:
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34. Bisson G, Fishman NO, Patel JB, et al. Extended-spectrum beta-lactamase-producing
Escherichia coli and Klebsiella species: risk factors for colonization and impact of
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35. Pujol M, Gudiol F. Evidence for antibiotic cycling in control of resistance. Curr Opin
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aminoglycoside combination therapy in cancer patients with neutropaenia. Cochrane
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J Antimicrob Chemother 2002;49:3–5.
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371S–2S.
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cephalosporins. Epidemiol Infect 1991;106:121–32.
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Escherichia coli. J Hosp Infect 1999;43:39–48.
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U.S. adult intensive care units. Ann Intern Med 2001;135:175–83.
5
Diaphragmatic Dysfunction in
Intensive Care
Guillermo Ortiz-Ruiz
Mechanical ventilation is a method of vital support that is considered useful in a
great number of patients who are treated in the intensive care unit (ICU). The
benefits of using mechanical ventilation are not only found in the gas exchange
but also in preventing respiratory muscle fatigue and muscle fiber damage in the
septic patient and perfusion of vital organs, as it decreases the consumption of
oxygen from the respiratory muscles.1,2
As with all therapeutic interventions, mechanical ventilation, although it has great
benefits such as those mentioned above, can produce undesirable effects in patients
to whom it is applied, such as infection, barotraumas, cardiovascular compromises,
tracheal injuries, oxygen toxicity, and pulmonary injury induced by the ventilation.3
Therapeutic intervention, in this case mechanical ventilation, should be used
within the context in which it works, that is, for critical patients with local or
general hypoperfusion, organic dysfunction, and in a large percentage of patients
with a sepsis diagnosis. This chapter discusses the structural and functional
changes that occur in the diaphragm of a critical patient during hospitalization in
the ICU.4
An increase in studies related to diaphragm function is seen in the international
medical literature, in which the patient is treated with mechanical ventilation for
conditions in which the muscle is inactive. This phenomenon is known as dia-
phragmatic dysfunction induced by a ventilator (DDIV).
In general, critical care providers spend a great amount of time removing
mechanical ventilation. It has been estimated that 20% to 25% of the patients
who have been given mechanical ventilation have difficulties suspending it, with
40% of the mechanical ventilation time invested in this process.5 The respiratory
muscles and especially the diaphragm play an important role in determining the
success in removing mechanical ventilation,1 and it is probable that the DDIV
has a great impact in daily clinical practice despite some recent observations made
in patients who have had trouble being weaned from mechanical ventilation
where no clear association between the presence of diaphragmatic fatigue and
failure in the process could be found.6
From the clinical point of view, DDIV is considered a diagnosis of exclusion,
based on an appropriate clinical history, preferably using the mechanical ventila-
tion in a controlled mode and excluding other causes of diaphragm weakness.2
47
48
G. Ortiz-Ruiz
The typical scenario is of a patient who has difficulty being weaned from mechani-
cal ventilation after using it in a controlled mode. In this case the failure to wean
is related to the dysfunction of the inspiratory muscles. Other causes of muscle
weakness such as shock, sepsis, malnutrition, hydroelectrolytic disorders,7 and
neuromuscular disorders acquired in the intensive care unit8 must be excluded
before proposing the diagnosis of DDIV.
There is evidence found in clinical studies in relation to the existence of DDIV.
Studies conducted with animals have shown consistently that the use of mechani-
cal ventilation in a controlled mode is associated with a decrease in the capacity
to generate strength from the diaphragm.9–14 In healthy diaphragms from live
species of animals studied, a marked diminution in the generation of transdia-
phragmatic pressure is observed during phrenic nerve stimulation through the
maximum and submaximum frequencies.9–11 This happens in a time-dependent
manner, meaning that the decrease of strength is detected as early as one day in
rabbits11 and three days in pigs,10 and it worsens as time extends.
It is also observed that diaphragm resistance is severely altered, as indicated
in the reduction of the capacity to keep inspiratory strength against a load.9 Dimi-
nution in the diaphragmatic capacity to generate forces should not be attributed
to changes in the lung volume or in abdominal distension.9,10 It has been shown
that transmission of the nerve impulse by the phrenic nerve and in the neuromus-
cular joint remains intact.10 However, it has also been documented that there is a
decrease of the potential of muscle action after the controlled use of mechanical
ventilation, suggesting an incapacity in the excitement of the fiber or disengage-
ment in the mechanism of excitation-contraction.10
It is important to recognize from the structural point of view that these changes
in the diaphragmatic function are not related directly or exclusively to muscular
atrophy, which suggests that besides the macroscopic changes, many of the
pathophysiologic changes in DDIV are located at a cell or subcell level inside
the same diaphragmatic muscle fibers.14
Although the evidence of DDIV in animals models is convincing, the evidence
obtained in relation to the existence of DDIV in humans is less conclusive. This,
in part, can be explained by the considerable confusion regarding contributing
factors (comorbidity, medications, ventilator modes, previous illnesses) as well
as the inability of measuring the diaphragmatic function directly in critical care.
In a recent publication of a study of 33 patients clinically stable in mechanical
ventilation with a variety of previous illnesses, a decrease of around 50% in the
transdiaphragmatic pressure was found after magnetic stimulation.15 Although the
study is not explicitly in relation to ventilator strategy, it can be speculated that
at least some of the patients were handled in a controlled mode.
Structural Diaphragmatic Changes Associated with DDIV
Even though the reduction in strength generated by the diaphragm after the use
of the mechanical ventilation cannot be exclusively attributed to muscular atrophy,
the proteolysis that occurs in these patients in a systemic manner and contributes
5. Diaphragmatic Dysfunction in Intensive Care
49
to the diaphragmatic thinness can also contribute to the incapacity to generate
maximum inspiratory pressures. Furthermore, due to diaphragmatic atrophy, and
an inverse relationship with the possibility of generating maximum strength, this
atrophy will increase the risk of developing fatigue once spontaneous ventilation
is resumed.16
In experimental studies it has been observed in animals that the use of mechani-
cal ventilation in a controlled manner is associated with a diminution of the dia-
phragm mass and the atrophy of the muscular fibers.9,12 The diaphragmatic atrophy
is developed very quickly, as early as within 18 h, compared with the time for
development of atrophy in other muscular groups.17
In general terms, atrophy due to disuse can be the result of a reduction of
protein synthesis18 or an increase of proteolysis.19 The increase of proteolysis has
been documented in rat diaphragms within 18 h of mechanical ventilation in a
controlled mode.17 In these studies an association between oxidative stress and
activation of the route of proteasome has been found, in which it modulates in a
preponderant manner the muscular proteolysis in critical patients who frequently
reach the catabolic stage.
Oxidative Stress
Use of controlled mechanical ventilation is associated with an increase in the
oxidative stress in the diaphragm, which is demonstrated through an increase in
the protein oxidation and products derived from the lipid peroxidation.17 These
changes occur as quickly as within 6 h from initiation of mechanical ventilation,
a scenario in which the enzymes are produced in antioxidant activity as the
superoxide dismutase are also increased, suggesting that the antioxidant defenses
try simultaneously to limit the unchained cell damage.20
The changes related to an increase in oxidative stress have been associated in
a direct manner with diaphragmatic dysfunction and weakness,21 probably due to
the contractile protein elements involved in the excitative process, where contrac-
tion and generation of strength can modify its structure for its oxidation. One
study20 showed the diaphragmatic protein oxidation associated with the use of
mechanical ventilation, through the dosage of insoluble proteins in a stage of
oxidation with molecular weights of 200, 128, 85, and 40 kd. This increases the
possibility that the actin and myosin would also be victims of oxidative modifica-
tion during controlled mechanical ventilation. This hypothesis awaits confirma-
tion through the demonstration of a structural modification of these proteins.
Structural abnormalities have been found in diaphragmatic muscular fibers after
2 or 3 days of mechanical ventilation.11–14 The predominant findings are myofibril
disruptions and the presence of very small abnormal mitochondria with solutions
of focal continuity in its cellular membrane.14 Some studies show similar changes
in the external intercostal muscles of animals exposed to mechanical ventilation.14
The injury mechanisms have not been identified clearly but at least three plau-
sible explanations have been proposed: first, the activation of calpains, proteases
with the ability to degrade sarcomeric proteins17; second, direct cellular damage
50
G. Ortiz-Ruiz
derived from an increase of oxidative stress17; and finally, the injury generated
by the diaphragmatic muscle activity during mechanical ventilation. This last
explanation makes reference especially to the moment in which the muscle
resumes a workload after an inactivity period, or “atrophy for use.”22 These find-
ings suggest that part of the clinical manifestation of DDIV can be the increase
in the susceptibility of the diaphragm for the induced injury due to the muscle
contraction when it resumes its ventilation function as well as during the attempt
to end mechanical ventilation.
Searching deeper into the more molecular level, it is known that myosin heavy
chains create the most important structural component of this protein and they
are the key to classifying traditionally the muscular fibers into those of slow
contraction (type I) and fast contraction (type II). The muscle can modify the
profile of myosin heavy chains because of atrophy or preferential hypertrophy of
the fibers that have a specific type of myosin heavy chains2 or transform from
one type to another.
Mechanical ventilation for the short term (48 hours) rather than long term
results in the least meaningful modifications of the diaphragm myosin chains. It
has been shown in rats exposed to mechanical ventilation, after 18 hours, that not
only type I fibers but also type II fibers decreased their size, but there is a greater
grade of atrophy in type II fibers.17 In rabbits, after two days of mechanical ven-
tilation in a controlled manner, atrophy of the respiratory muscles is observed
and there is a diminution of the transversal area of type II fibers.14 It is probable
that this transition from fast fibers to slow fibers that are resistant to fatigue is
associated with a decrease in the capacity to generate strength.23
However, evaluation of the diaphragmatic structure during more prolonged
episodes of mechanical ventilation seems to have different results11–13 after two
to four days of mechanical ventilation. The rats’ diaphragms show an increase in
the percentage of the muscular fibers called hybrids, with coexpression of the fast
and slow isoforms of the myosin heavy chain. This is found only at the expense
of type II13 fibers and would indicate a late transformation of type I fibers to type
II fibers.
In the extremity muscles, inactivity during short periods of time can result in
a transformation of type II fibers to type I, but long periods of inactivity generate
an increase in type II fibers.4 The time required to observe these changes in the
extremity muscles is higher than in the diaphragm, which suggests that the dia-
phragm is particularly a muscle vulnerable to fatigue.
It is not clear if enzymatic metabolic changes associated with DDIV can
happen, although a study shows an increase in the activity of the citrate synthetase
after 18 h of mechanical ventilation.24 Longer periods of mechanical ventilation
have not been associated with significant changes in the involved enzymes in the
Krebs cycle or in diaphragmatic anaerobic glycolysis.11,12 On the other hand, a
decrease in the efficiency of the mitochondrial oxidative phosphorylation has
been suggested in rabbits that used mechanical ventilation for two days.14
Recent publications25 show that with rats exposed to hard respiratory exercises,
an increase of the plasmatic cytokine levels not produced by the circulating
5. Diaphragmatic Dysfunction in Intensive Care
51
monocytes is observed. Being well documented as to diaphragmatic local cyto-
kine production pro- and antiinflammatory in a time-dependent way, it can be
speculated that these cytokines are taken into circulation and could be responsible
for the systemic effects associated with changes in the respiratory pattern26 or
fatigue sensation.27
Clinical Implications
The most relevant clinical implications for the information provided in this
chapter is that during short periods of mechanical ventilation, weakness and
diaphragmatic structural changes can occur with the expected sequences that
follow in the process of mechanical ventilation weaning. The experimental data
also support the idea that the intercostals muscles can be compromised in a
similar way.14
In clinical practice, there are more questions than answers in relation to mus-
cular performance and especially in the diaphragmatic muscle. One of the main
points of controversy is if there is a minimum level of muscular effort that allows
physicians to prevent or revert the DDIV once it has been established. Logically,
this would be related to the partial support modes during mechanical ventilation.
Probably an absolute answer to this question does not exist. One can think that
an alternative to resolving muscular inactivity during the controlled ventilation
is partial support, but the course of recovery as well as the specific type of support
and time for its application are unknown. Moreover, some studies in peripheral
skeletal muscles make reference to a period of muscular “vulnerability” when
they try to resume their functions, engendering a structural fiber injury.22 Studies
with tetraplegic patients have shown that the use of a phrenic pacemaker can
diminish the diaphragmatic atrophy through a gradual instauration.28
Another question related to DDIV is whether the programmed parameters in the
mechanical ventilation influence the development of DDIV frequency, PEEP
(positive end expiratory pressure), tidal volume, and so forth. During mechanical
ventilation the diaphragm is exposed to a repetitive and intermittent shortening.
This creates a change in the tidal volume, and the respiratory frequencies used will
necessarily affect the frequency and the extension of the shortening. The use of
PEEP favors this shortening as it keeps the functional residual capacity stable.
Some studies have shown that the shortening in the skeletal muscle can be
harmful and avoiding this can diminish the loss of sarcomeres.4 Two studies that
included the use of PEEP associated with a controlled mode of mechanical ven-
tilation showed a major shortening of the sarcomeres with significant decrease in
its optimum length, a finding that suggests a mechanism of sarcomere loss.17–19
A clinical trial that had as its objective to demonstrate the influence of albuterol
in the diaphragmatic contractility in patients with chronic obstructive pulmonary
disease (COPD) exposed to mechanical ventilation concluded that the positive
changes observed after the intervention are exclusively due to a diminishing of
the lung hyperinflation and the improvement of diaphragmatic strength.30 This
52
G. Ortiz-Ruiz
makes one think that the diaphragmatic position, especially its shortening level
associated with the programmed parameters in the ventilator, must be taken into
consideration in the generation and the evaluation of the interventions for
DDIV.
A recent publication31 of a study made with rabbits compared the effect of
mechanical ventilation in a controlled mode with the assist control ventilation
mode in the generation of strength and expression of muscular atrophy factor in
the diaphragm. It was observed that there was a preservation of contractility
conditions with the partial use of the diaphragm during the mechanical ventilation
and a decrease in the expression of the atrophy factor. For patients who will be
exposed to mechanical ventilation for a prolonged period of time it is better to
use ventilation in which the diaphragm participates during each breath, and the
use of sedatives drugs and muscle relaxants in high doses in which the diaphrag-
matic movement is inhibited should be avoided.
Another question that might have a relevant clinical application is related to the
previous stage of diaphragmatic dysfunction in the appearance of DDIV. It high-
lights that the majority of the studies made with animals showed a previously
healthy diaphragm, which makes it difficult to deduct how mechanical ventitation
influences a diaphragm that has been previously altered. This is the case, for
instance, where an increase of oxidative stress is demonstrated not only in a
sepsis condition but also in patients exposed to mechanical ventilation, which can
diminish the capacity to generate strength in the diaphragm in a transitory
manner.17–29 What we do not know is if the same happens in previously altered
diaphragms that have been exposed to a major load and with probable major basal
oxidative stress. The literature does not give us answers to this question.
The literature supports a relation to the loss or diminution of the diaphragm in
generating the load during mechanical ventilation, and many times with septic
patients it is multifactorial in that phenomena such as atrophy, oxidative stress,
myofibrilar disruption, and remodeling processes are involved, making it difficult
to establish the specific influence of each of them as well as the role of other
mechanisms such as in the case of apoptosis. The studies in animals suggest that
all these changes develop quickly, often within hours, a phenomenon that has
been evident when the diaphragm of vegetative state postmortem patients is
examined.
At a time when there is great uncertainty related to this pathology, the question
would be whether to avoid DDIV. Based on what we know, the first conclusion
would be to avoid the use of mechanical ventilation in a controlled mode, espe-
cially in elderly patients who have a greater chance of developing muscle atrophy
from inactivity.4
Some studies have tried to prove that the strategy of partial support could
counteract DDIV.4 Moreover, some medical indications, in which classically
ventilation was considered with a controlled strategy, as in the case of the syn-
drome of acute respiratory distress, consider the best strategy to be partial
support.29 Furthermore, some years ago it was considered that patients who had
previously shown a failure after the removal of the mechanical ventilation should
thereafter have a controlled strategy applied to revert the muscular fatigue.
5. Diaphragmatic Dysfunction in Intensive Care
53
However, the present evidence suggests that there is no clear support for leaving
these muscles in complete rest after a failure in weaning from the mechanical
ventilation.31
As for not using ventilation measures, it is recommended to provide adequate
nutrition and to avoid the use of systemic corticoids as these therapeutic measures
are also associated in a synergic manner with muscular atrophy. The present evi-
dence solidly suggests that mechanical ventilation is associated with lung injury.
Also evidence is growing as to the structural and functional injuries this interven-
tion can cause in the respiratory muscles. There is no doubt that at the present
time there are large gaps in knowledge about the mechanisms that conduct DDIV
and one hopes that they can be resolved. Overall it is most important to remember
that the diaphragm is a malleable and vulnerable structure, not an inert organ that
can be replaced easily by a mechanical ventilator.
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29. Supinski G, Nethery D, DiMarco A. Effect of free radical scavengers on endotoxin-
induced respiratory muscle function. Am Rev Respir Dis 1993;148:1318–24.
30. Hatipoglu V, Laghi F, Tobin M. Does inhaled albuterol improve diaphragmatic
contractility in patients with chronic obstructive pulmonary disease? Am J Respir
Crit Care Med 1994;160:1916–21.
31. Sassoon C, Zhu E, Caiozzo V. Assist-control mechanical ventilation attenuates ventila-
tor induced diaphragmatic dysfunction. Am J Respir Crit Care Med 2004;170:
626–32.
6
Myocardial Depression in Sepsis and
Septic Shock
Justin Wong and Anand Kumar
Introduction
In the setting of severe sepsis and septic shock, myocardial depression is common
despite an apparently normal or increased cardiac output. Myocardial depression
represents a spectrum of cardiac dysfunction present in varying degrees in virtu-
ally all cases of sepsis and septic shock. This myocardial depression persists
throughout the course of the disorder and either improves with patients’ recovery
or accompanies them to their death. If a patient does survive, myocardial function
usually returns to baseline within 7 to 10 days. The pathogenesis of the myocar-
dial dysfunction derives from a cascade of events triggered by the initial inciting
infection. This cascade results in the production of a variety of endogenous
inflammatory cytokines (e.g., TNF-α, IL-1β) and other factors (e.g., lysozyme,
platelet activating factor, leukotrienes, prostaglandins), which cause severe car-
diovascular derangement including myocardial depression. The exact sequence
of events leading to myocardial depression have not been fully elucidated but
likely involve, in part, nitric oxide dependent and independent pathways and early
events of programmed myocardial cell death (apoptosis).
Despite advances in modern medical knowledge and treatment of sepsis and
septic shock, its incidence and mortality continue to rise. Over the past 40 years,
age-adjusted mortality has increased from 0.5 to 0.7 per 100,000 episodes of
sepsis and septic shock.1 The incidence of severe sepsis in the United States is
750,000 cases per year, with 215,000 deaths annually.2 The majority of these
patients die of refractory hypotension and cardiovascular collapse.
Sepsis has been defined as the systemic inflammatory response to infection.3
The inciting focus of sepsis, either an organism, component of an organism, or
product of the organism, causes local and systemic release of a wide variety of
inflammatory mediators like tumor necrosis factor-α (TNF-α), interleukin-1β
(IL-1β),4 platelet activating factor (PAF),5,6 oxygen free radicals,7 interferon
gamma (IFN-γ),8 and arachidonic acid metabolites9 from monocytes/macrophages
and other cells.4 In order to maintain a homeostasis (and likely as part of a
feedback mechanism), several antiinflammatory mediators are also released
as part of the cascade including interleukin-10 (IL-10), transforming growth
55
56
J. Wong and A. Kumar
factor-β (TGF-β), and interleukin-1 receptor antagonist (IL-1ra). If the balance
is sufficiently shifted in favor of the inflammatory component, cardiovascular
stress may result. An inability to respond adequately to this challenge, on the
basis of either excessive cardiovascular dysfunction or limited cardiovascular
reserve, results in septic shock. One of the components of septic cardiovascular
stress (whether overt shock is present or not) is myocardial depression.
This chapter reviews the following aspects of septic myocardial dysfunction:
right and left ventricular failure, systolic and diastolic dysfunction, and cardio-
vascular prognosticating factors. Potential pathophysiologic mechanisms of myo-
cardial depression from organ to molecular/cellular level are also examined.
Clinical Manifestations of Cardiovascular Dysfunction
Historical Perspectives
Prior to the introduction of new techniques such as the balloon-tipped pulmonary
artery catheter (PAC) and echocardiography to assess cardiovascular perfor-
mance, much of our understanding of septic hemodynamics was based on clinical
findings. There were two distinct clinical presentations of septic shock: warm
shock characterized by high cardiac output (CO), warm dry skin, bounding
pulses, and hypotension; and cold shock characterized by low CO, cold clammy
skin, and diminished pulses.10 Clowes et al.11 went on to describe a relationship
between warm and cold shock as a continuum in which either recovery or pro-
gression to death occurred. This notion was supported by other studies showing
a correlation between survival and a high cardiac index (CI).10,12 However, all
these studies used central venous pressure (CVP) as a reflection of left ventricular
end-diastolic volume (LVEDV) and adequacy of resuscitation. The importance
of adequate volume status and its relation to survival and CI was suggested in
only a handful of studies.13,14 Based on evidence collected over the past four
decades, we now know that CVP is a poor measure of preload in critically ill
patients, particularly septic patients.15 In addition to allowing the routine measure-
ment of cardiac output, the introduction of the PAC enabled the routine measure-
ment of preload as pulmonary capillary wedge pressure (PCWP). Using the PAC,
several studies have now shown that adequately resuscitated septic shock patients
have a persistent hyperdynamic state, high CO, and low SVR (systemic vascular
resistance).16,17 In nonsurvivors this hyperdynamic state usually persists until
death (Figure 6.1).18,19
Since cardiac output is the product of heart rate (HR) and stroke volume (SV),
septic patients can have a hyperdynamic circulation (high CO, low SV) even in
the setting of significant myocardial depression as manifested by decreased left
ventricular stroke work index (LVSWI).20 Myocardial dysfunction could be
explained by a change in contractility or compliance. Radionuclide cineangiog-
raphy (RNCA) and its application to critically ill patients have offered insight
into the relative contribution of decreased contractility and compliance in myo-
cardial depression.
6. Myocardial Depression in Sepsis and Septic Shock
57
7
6
5
4
3
2
Survivors
1
All Patients
Nonsurvivors
0
1
2
4
7
10
1
2
4
7
10
Time (days)
Figure 6.1. The mean (±SEM) cardiac index plotted against time for all patients, survi-
vors, and nonsurvivors. The hatched areas show the normal range. All groups maintained
an elevated cardiac index throughout the study period. The difference between the survi-
vors and nonsurvivors was not statistically significant.
Ventricular Function
Elements of both right and left ventricular dysfunction exist in sepsis and septic
shock; the relative contribution and importance of each to clinical manifestations
are not clearly delineated. Similarly, there are elements of systolic and diastolic
dysfunction in patients with septic myocardial depression, and a controversy
regarding their relative roles in generating clinical manifestations has been argued.
It is broadly accepted that in patients who survive their episode of septic shock,
cardiac function returns to baseline within 7 to 10 days.
Left Ventricular Function
Systolic dysfunction has been shown to be impaired in septic patients in a number
of studies. Parker et al.21 demonstrated that survivors had decreased left ventricu-
lar ejection fraction (LVEF) and acute left ventricular (LV) dilatation evidenced
by increased LVEDV index (LVEDVI) (Figure 6.2) using RNCA. These changes
in survivors corrected to baseline in 7 to 10 days. Nonsurvivors sustained normal
LVEF and LVEDVI until death. Despite systolic dysfunction, these patients
58
J. Wong and A. Kumar
100
Survivors (n=33)
90
All Patients
Nonsurvivors (n=21)
80
70
60
50
40
30
20
10
1
2
4
7
10
1
2
4
7
10
Time (days)
Figure 6.2. The mean (±SEM) left ventricular ejection fraction (LVEF) plotted versus
time for all patients, survivors and nonsurvivors. Overall, septic shock patients showed a
decreased LVEF at the time of initial assessment. This effect was due to marked early
depression of LVEF among survivors that persisted for up to 4 days and returned to normal
within 7 to 10 days. Nonsurvivors maintained LVEF in the normal range. The hatched
area represents the normal range.
maintained a high CO and low SVR as shown by the PAC. In a later study,
Ognibene et al.22 compared left ventricular performance curves (plotting LVSWI
vs. LVEDVI) of septic and nonseptic critically ill patients (Figure 6.3). They
showed a flattening of the curve in septic shock patients, with significantly
smaller LVSWI increments in response to similar LVEDVI increments when
compared to nonseptic critically ill controls. In the years since these observations,
other studies have confirmed the presence of significant left ventricular systolic
dysfunction in septic patients.23–26
Diastolic dysfunction in septic patients is less clearly defined. The acute LV
dilatation shown by Parker et al.21 and a concordant relation between PAWP and
LVEDV do not support the presence of significant diastolic dysfunction. However,
more recent studies using echocardiography have shown impaired compliance as
evidenced by slower left ventricular filling,27 aberrant left ventricular relaxa-
tion,28,29 and failure of ventricular dilatation25,26 in septic patients. The clinical
impact and relative contribution of diastolic dysfunction to myocardial depression
is yet to be elucidated.
6. Myocardial Depression in Sepsis and Septic Shock
59
Right Ventricular Function
The peripheral vasodilatation seen in sepsis leads to decreased left ventricular
afterload and eventually preload. The increase in cardiac output can be limited
by decreased preload if the patient is not adequately volume resuscitated. However,
the right ventricular (RV) afterload is frequently elevated due to increased pul-
monary vascular resistance (PVR) from acute lung injury.30 Because of the vari-
ability in RV afterload, it may not behave like the LV in septic patients. This is
the reason for a number of studies looking into RV function in sepsis.
Systolic RV dysfunction has been shown by decreased right ventricular ejection
fraction (RVEF) and RV dilatation in volume resuscitated patients.31–34 Kimchi et
al.31 and Parker et al.33 showed that RV dysfunction can occur even in the absence
of increased pulmonary artery pressures and pulmonary vascular resistance, sug-
gesting that increased RV afterload may not be the sole explanation for RV
dysfunction in septic shock. Parker et al.33 also showed that RV and LV function
60
50
40
30
Control
Septic without shock
Septic shock
0
80
90
100
110
120
EDVI (ml/ml2)
Figure 6.3. Frank-Starling ventricular performance relationship for each of the three
patient groups. Data points plotted represent the mean prevolume and postvolume infusion
values of end-diastolic volume index (EDVI) and left ventricular stroke work index
(LVSWI) for each patient group. Control patients showed a normal increase of EDVI and
LVSWI in response to volume infusion. The absolute increases of EDVI and LVSWI in
patients with sepsis without shock were less than those of control subjects, but the
slope of the curve is similar to control patients. Patients with septic shock had a greatly
diminished response and showed a marked rightward and downward shift of the Frank-
Starling relationship.
60
J. Wong and A. Kumar
paralleled each other in dysfunction and recovery (Figure 6.4). In this study sur-
vivors showed RV dilatation and decreased RVEF and right ventricular stroke
work index (RVSWI), which normalized in 7 to 14 days. As with the LV, the RV
was only moderately dilated and RVEF marginally decreased; both persisted
through their course of sepsis.
Diastolic dysfunction of the RV has also been demonstrated in a number of
studies. Kimchi et al.31 noticed a lack of correlation between right atrial pressure
and right ventricular end-diastolic volume (RVEDV), suggesting altered RV
compliance. In another study, a subgroup of patients who were volume loaded
demonstrated increase in CVP but not right ventricular end-diastolic volume
index (RVEDVI).32 As in the LV, the relative contribution of systolic and diastolic
dysfunction in the RV is unknown.
Cardiovascular Prognostic Factors in Septic Shock
The cardiac index (CI) appears not to be a reliable predictor of mortality in septic
shock. Despite early evidence suggesting low CI as a poor prognostic factor,10–13
introduction of the PAC has shown that septic shock patients, when adequately
fluid-resuscitated, have a high CI and low SVR among both survivors and non-
130
.50
.40
.30
.20
110
100
90
80
.10
0
A
120
0
Initial
Final
B
Initial
Final
Figure 6.4. Serial changes in right ventricular ejection fraction and end-diastolic volume
index during septic shock in humans. (A) Mean initial and final right ventricular ejection
fractions for survivors (closed circles, p < 0.001) and nonsurvivors (open circles,
p < 0.001). (B) Mean initial and final right ventricular end-diastolic volume index for
survivors (closed circles, p < 0.05) and nonsurvivors (open circles, p = not significant).
The right ventricle, similar to the left, undergoes dilation with a drop in ejection fraction
with the acute onset of septic shock. In 7 to 10 days, right ventricular dilation and
decreased ejection fraction revert to normal in survivors.
6. Myocardial Depression in Sepsis and Septic Shock
61
survivors.16,17 Armed with the PAC, other hemodynamic parameters were inves-
tigated as prognostic indicators.
Baumgartner et al.35 recognized that patients with extremely high CI
(>7.0 L/min/m2) and accordingly low SVR had poor outcomes. Groenveld et al.36
also found nonsurvivors had lower SVRs than survivors after matching other
characteristics, concluding that there may be a link between outcome in septic
shock and the degree of peripheral vasodilation.
Parker et al.18 reviewed hemodynamic data from septic shock patients on pre-
sentation and at 24 hours to identify prognostic value. On presentation, only heart
rate <106 beats/min suggested a favorable outcome. At 24 hours, heart rate < 95
beats/min, systemic vascular resistance index (SVRI) > 1529 dynes⋅sec⋅cm5/m2,
a decrease in heart rate > 18 beats/min, and a decrease in CI > 0.5 L/min/m2 all
predicted survival. In a subsequent study,19 the same authors confirmed previous
findings of decreased LVEF and increased LVEDVI in survivors of septic shock
but not in nonsurvivors, a finding that has been confirmed by other groups.25,26
Although myocardial depression has been historically linked to increased mortal-
ity, these data may imply that depression, at least as manifested by decreased
ejection fraction with ventricular dilatation, may actually represent an adaption
to stress rather than a maladaptive manifestation of injury.
From the studies of Parker et al.18,19 it is apparent that, despite not developing
significant LV dilatation overall, nonsurvivors could be divided into two patterns:
those with progressively declining LVEDVI and CI, and the others with incre-
mental increases in LVEDVI while maintaining CI. Based on this, Parker et al.
described different hemodynamic collapse profiles leading to death in septic
shock.18,19 First, some patients die from refractory hypotension secondary to dis-
tributive shock with preserved or elevated CI. The other pattern consists of car-
diogenic form of septic shock with decreased CI and a mixture of cardiogenic and
distributive shock patterns. The explanation of the two patterns came from a study
by Parker et al.19 It appears that patients who cannot dilate their LV (decreasing
CI and LVEDVI) die from a cardiogenic form of septic shock. The other fatal
pattern consists of those patients who can dilate their LV and preserve CI (increase
LVEDVI while maintaining CI) but eventually die of distributive shock.
The prognostic value of RV hemodynamic parameters has been debated. A
number of studies31–34 have shown that RV dilatation and decreased RVEF, if
persistent, is associated with poor prognosis.33,34 However, Vincent et al.34 sug-
gested that high initial RVEF portends a good prognosis. On the other hand,
Parker et al.33 found that the survivors had a lower RVEF. The answer to this
question requires additional investigation.
The other prognostic parameter is response of hemodynamic parameters to
dynamic challenges, namely dobutamine. Nonsurvivors of septic shock have a
blunted response to dobutamine,37–39 whereas survivors demonstrated increased
SVI (stroke work index), increased mixed venous oxygen saturation, ventricular
dilatation, and a decrease in diastolic blood pressure after a dobutamine
challenge. The above response to dobutamine predicts survival in patients with
septic shock.
62
J. Wong and A. Kumar
Etiology of Myocardial Depression in
Sepsis and Septic Shock
The exact sequence of events in the pathophysiology of septic myocardial depres-
sion has only begun to be elucidated in recent years. There are likely a multitude
of mechanisms and factors that play a role. A number of potential pathogenic
mechanisms have been proposed. The two major theories have been myocardial
hypoperfusion and a circulating myocardial depressant substance.
Organ Level
Myocardial Hypoperfusion
The potential of myocardial hypoperfusion leading to myocardial depression via
global ischemia has been largely dismissed by a number of studies. Cunnion
et al.40 inserted thermodilution catheters into the coronary sinus of septic patients
and measured serial coronary flow and metabolism (Figure 6.5). Normal or ele-
vated coronary flow was present in septic patients in comparison to normal con-
trols with comparable heart rates. There was also no difference in myocardial
600
Normal subjects
500
Septic shock patients
400
300
200
100
N=
25
3
253
3
0
Heart rate
less than 100
p = NS
Heart rate
greater than 100
p<.01
Figure 6.5. Mean coronary sinus blood flow (CSBF) in seven patients with septic shock
compared with normal subjects. Flow measurements were stratified into heart rates above
and below 100 beats/min. Coronary blood flow in septic shock patients equaled (heart rate
< 100/min) or exceeded (heart rate > 100/min) coronary blood flow in control patients.
6. Myocardial Depression in Sepsis and Septic Shock
63
blood flow between septic patients who did and did not developed myocardial
dysfunction. There also was no net lactate production.
Dhainaut et al.41 also confirmed these findings while employing similar methods.
In addition to human studies, a canine model of sepsis study42 showed that myo-
cardial high energy phosphates and oxygen utilization were preserved in septic
shock. Both of these observations argue against neither global myocardial isch-
emia nor hypoperfusion.
Perfusion aside, there is evidence for myocardial cell injury evidenced by
increased troponin I levels in septic shock.43 A study by Elst et al.44 examined
levels of troponin I and T in patients with septic shock. A correlation between
LV dysfunction and TnI (troponin I) positivity (78% vs. 9% in cTnI negative
patients p < .001) existed. They also found that older patients with underlying
cardiovascular disease more often had both troponin positivity and LV dysfunc-
tion. However, whether the clinically inapparent myocardial cell injury contrib-
utes to or is a consequence of septic shock is yet to be determined.44 Although
troponin is used as a marker of myocardial injury (particularly in the context of
myocardial ischemia), it does not specifically suggest myocardial hypoperfusion
in other contexts.
Myocardial Depressant Substances
The theory of a circulating myocardial depressant factor was put forth by Wiggers
et al.45 in 1947 in the context of hemorrhagic shock. The presence of such a factor
was confirmed by Brand and Lefer46 in 1966. Lefer’s work prompted further
research into septic myocardial depressant substances.46–54
A number of endogenous substances have been implicated as potential causes
of septic myocardial depression. These have included estrogenic compounds,
histamine, eicosanoids/prostaglandins, and several novel substances that could
never be effectively isolated46–54 (for review55). In the past decade, the dominant
focus has been on inflammatory cytokines.
In one of the seminal studies in the field, Parillo et al. in 198556 showed
a link between myocyte depression and septic serum from a patient with sepsis-
associated myocardial depression. The serum from patients demonstrated concen-
tration-dependent depression of in vitro myocyte contractility (Figure 6.6). Parillo
et al. were also able to correlate a temporal and qualitative relationship between
in vivo myocardial depression (decrease LVEF) and in vitro cardiac myocyte
depression induced by serum from corresponding patients. In another study57
investigators noted that higher levels of myocardial depressant activity correlated
with higher peak serum lactate, increased ventricular filling pressures, increased
LVEDVI, and higher mortality (36% vs. 10%) when compared with patients with
lower or absent activity levels.
Potential circulating myocardial depressant substances include arachidonic
acid metabolites, platelet activating factor, histamine, and endorphins. Filtration
studies57 found that the substance was water soluble, heat labile, and greater than
64
J. Wong and A. Kumar
60
50
40
30
20
Normal
Subjects
Decreased
ejection
fraction
due to
structural
heart disease
Critically
ill
nonseptic
patients
Septic
shock
patients:
acute
phase
10
0
-10
-20
-30
-40
-50
Patient who survived
Patient who died
Mean for patient group
Septic
shock
patients:
recovery
phase or
presepsis
phase
-60
-70
Figure 6.6. The effect of serum from septic shock patients and control groups on the
extent of myocardial cell shortening of spontaneously beating rat heart cells in vitro. Septic
shock patients during the acute phase demonstrated a statistically significant lower extent
of shortening (p < .001) compared with any other group.
10 kd. These characteristics pointed toward a protein or polypeptide consistent
with cytokines such as TNF-α and IL-1β.
TNF-α likely has a role as a myocardial depressant substance for a number of
reasons. TNF-α shares the same biochemical profile as myocardial depressant
substances.56,58 Clinically, TNF-α is associated with fever, increased lactic acid,
disseminated intravascular coagulation, acute lung injury, and death. The hemo-
dynamic effects of TNF-α are similar to sepsis, in particular hypotension,
increased cardiac output, and low systemic vascular resistance.59,60
Healthy human volunteers given TNF-α infusions have similar responses.61,62
Experimentally, TNF-α given to in vitro and ex vivo animal and human myocar-
dial tissue demonstrated a concentration dependent depression of contractility.49,63
Kumar et al.64 showed that removal of TNF-α from patients serum with septic
shock decreased the myocardial depression. Also, Vincent et al.65 in a pilot study
showed improved LVSWI with administration of anti-TNF-α monoclonal anti-
body, even though there was no survival benefit.
IL-1β produces similar hemodynamic responses to TNF-α. IL-1β levels are
also elevated in sepsis and septic shock.66 In vitro and ex vivo myocardial con-
tractility is depressed when cardiac tissue is exposed to IL-1β.63,67,68 Removal of
IL-1β via immunoabsorption from septic human serum attenuates the depression
of cardiac myocytes.64 The effects of IL-1β antagonist on cardiac function and
survival are unimpressive69–71 even though metabolic derangements are attenuated
by IL-1β antagonist.70,71
6. Myocardial Depression in Sepsis and Septic Shock
65
It is likely that cytokines such as TNF-α and IL-β, rather than working in isola-
tion, synergize to exert their depressant effects. In isolation, TNF-α and IL-1β
require very high concentration to induce in vitro rat myocyte depression.64
However, when combined, they act synergistically and require concentrations 50
to 100 times lower than those required individually.64,72 These concentrations are
within the range of those found in septic shock patients.
Another recent series of studies by Pathan et al. have strongly implicated cir-
culating IL-6 as an important myocardial depressant substance in human septic
shock.73–75 These investigators have demonstrated that meningococcal sepsis is
associated with induction of IL-6 expression in blood mononuclear cells and that
the level of serum IL-6 corresponds with the degree of cardiac function in such
patients. Further, they have recently shown that IL-6 depresses contractility of
myocardial tissue in vitro and that neutralization of IL-6 in serum from patients
with meningococcal septic shock neutralizes this effect.73
Evidence for other potential myocardial depressant substances continue to be
developed. Recently, Mink et al. have implicated lysozyme c (consistent with that
found in the spleen, leukocytes in the spleen or other organs) as a potential myo-
cardial depressant substance (MDS).47 In the canine model of E. coli sepsis lyso-
zyme c caused myocardial depression and attenuated response to beta-agonists.47
The potential mechanism proposed was lysozyme binding or hydrolyzing the
membrane glycoprotein of cardiac myocytes, thereby affecting signal transduction
(linking physiologic excitation with physiologic contraction). The levels of lyso-
zyme c were found to be elevated in the heart and spleen, but not in lymphocytes
when compared to preseptic levels.47 Mink et al. went on further to show that
pretreatment with an inhibitor of lysozyme (N,N′,N′′-triacetylglucosamine) pre-
vented myocardial depression in canine sepsis.76 However, the effect of this lyso-
zyme inhibitor (TAC) was only seen in pretreatment and early treatment groups
(1.5 hours after onset of septic shock) and not in late treatment groups (greater
than 3.5 hours).76
An important microbial factor that has recently been shown to potentially exert
hemodynamic and myocardial depressant activity in sepsis and septic shock is
bacterial nucleic acid. Several investigators have demonstrated that unique aspects
of bacterial nucleic acid structure may allow bacterial DNA to generate a shock
state similar to that produced by endotoxin when administered to animals.77
Extending these observations, we have recently demonstrated depression of
rat myocyte contraction with bacterial DNA and RNA.78 This effect was
more marked when DNA and RNA came from pathogenic strains of S. aureus
and E. coli. These effects were not seen when the rat myocyte was pretreated
with DNase and RNase.
Cellular Level
The sequence of mechanisms leading from an MDS to cellular dysfunction
remains substantially opaque. There are several potential mechanisms that may
66
J. Wong and A. Kumar
play a role at the cellular level. Overproduction of nitric oxide (NO) and derange-
ments of calcium physiology in the myocardial cell are two potential cellular
mechanisms.
In vitro, myocyte depression in response to inflammatory cytokines can be
divided into early and late phases. Early depression of cardiac myocyte depres-
sion occurs within minutes of exposure to either TNF-α or IL-1β, or TNF-α and
IL-1β given together or as septic serum.64,79 TNF-α also demonstrates the ability
to cause rapid myocardial depression in dogs.60,80 Besides the early effects of
TNF-α, IL-1β and supernatants of activated macrophages also have a later, pro-
longed effect on in vitro myocardial tissue.67,68,80,81 This late phase establishes
within hours and lasts for days. This suggests a different mechanism from early
myocardial depression.
Production of NO may be a potential explanation for both early and late myo-
cardial depression. NO is produced from conversion of L-arginine to L-citrulline
by nitric oxide synthase (NOS). NOS has two forms: one is constitutive (cNOS)
and the other is inducible (iNOS). NO produced by cNOS appears to have a regu-
latory role in cardiac contractility.82–84 However, when cardiac myocytes are
exposed to supraphysiologic levels of NO or NO donors (nitroprusside and
SIN-1), there is a reduction in myocardial contractility.85 Paulus et al.86 infused
nitroprusside into coronary arteries, which decreased intraventricular pressures
and improved diastolic function.
Current evidence suggests that early myocyte dysfunction may occur through
generation of NO and resultant cyclic guanosine monophosphate (cGMP) via
cNOS activation in cardiac myocytes and adjacent endothelium.72,79,87 Late myo-
cardial depression may be secondary to induction of synthesis of iNOS NO.68,79,88,89
In addition, the generation of peroxynitrite via interaction of the free radical NO
group and oxygen may also play a role in more prolonged effects.90 We
have demonstrated that the early phase may involve both a NO dependent but
β-adrenergic-independent mechanism and a NO-independent defect of β-
adrenoreceptor signal transduction.55,87,91,92 Others have shown that IL-6 can cause
both early and late NO-mediated myocardial depression in an avian myocardial
cell model via sequential activation of cNOS followed by induction of iNOS, a
finding that could explain recent human data implicating IL-6 in meningococcal
septic myocardial dysfunction.73,74,93–95 This study suggests the role for sequential
production of NO from cNOS and iNOS in the pathogenesis of myocardial
depression from cytokines.
Potential Therapies
In the minority of cases where septic myocardial depression may be sufficiently
expressed clinically to require treatment, options are available. Epinephrine, dobu-
tamine, milrinone, and digoxin have all been shown to improve cardiac function
in low-output septic shock.96–98 However, these modalities are supportive in nature
and do not specifically attempt to neutralize myocardial depressant pathways.
6. Myocardial Depression in Sepsis and Septic Shock
67
Research into the pathophysiology of sepsis-induced myocardial depression
naturally leads to potential specific therapies to reverse septic myocardial dys-
function. Several investigators have examined the use of various hemofiltration
modalities in septic shock.53,99–102 However, results have been highly inconsistent.
Mink et al.99 utilized continuous arteriovenous hemofiltration combined with
systemic vasopressor therapy to reverse cardiac depression and hypotension in
an endotoxicosis-equivalent canine E. coli sepsis model. Freeman and colleagues,
however, were unable to demonstrate such a benefit.100
Inflammatory cytokine antagonists are another area of research. As previously
mentioned TNF-α monoclonal antibodies have improved LV function when given
to patients in septic shock65 despite failing to show a survival benefit. IL-1β
antagonists have shown mixed results. Despite the absence of a survival benefit,
attenuation of metabolic derangements in septic shock was noted,70,71 although
no hemodynamic benefit was apparent.69
Further down the sequence of pathogenesis in septic myocardial depression are
the therapeutic potential of NO scavengers or NO inhibitors. Methylene blue (NO
scavenger) has been shown to attenuate the hemodynamic alterations in a random-
ized open label pilot of 20 patients with sepsis.103 Suzuki et al.104 used an inhibitor
of iNOS (L-canavanine) in septic rats which showed prevention of myocardial
contractility depression. However, L-canavanine itself depressed myocardial con-
tractility via decreased coronary blood flow, an effect that was thought to be
potentially responsible for the increased mortality in the only randomized double-
blinded clinical study of a NOS inhibitor in clinical septic shock.105,106
Conclusion
Myocardial dysfunction is an important component in the hemodynamic collapse
induced by sepsis and septic shock. A series of inflammatory cascades triggered
by the inciting infection generate circulatory myocardial depressant substances,
including TNF-α, IL-1β, PAF, and lysozyme. Their effects are partly mediated
through NO generation. How NO depresses cardiac contractility is largely
unknown. The research into the pathophysiology of septic myocardial depression
will hopefully yield potential therapies. Until then, volume resuscitation, with
inotropic and vasopressor support, is the current standard of care to restore tissue
perfusion.
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66. Hesse DG, Tracey KJ, Fong Y, et al. Cytokine appearance in human endotoxemia
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7
Toward a Consensus on
Intraabdominal Hypertension
Manu LNG Malbrain, Michael Sugrue, Michael Cheatham, and
Rao Ivatury
Introduction
There has been an exponentially increasing interest in intraabdominal hyper-
tension (IAH) and the abdominal compartment syndrome (ACS) over the past
decade; however, until now no uniform definitions have been suggested. Defini-
tions of IAH or ACS stand or fall with the accuracy and reproducibility of the
IAP measurement method.1 Not only the absolute numbers but also the use of
mean, median, or maximal IAP values will influence the incidence of IAH.2 Dif-
ferent threshold values have been suggested for IAH and ACS and some have
interchanged the terms IAH and ACS. Others suggested terms as surgical or
medical ACS, but with ever changing definitions. To date it is therefore very dif-
ficult to interpret the literature data, and a consensus on definitions of issues
related to IAH is needed in order to approach scientific accuracy in comparing
different clinical reports and to plan for future clinical trials. These definitions
should be comprehensive, detailed, simple, practical, and acceptable to the major-
ity of the scientific community working in this particular field. Until such a con-
sensus is achieved, this chapter will provide some definitions to be used as a basis
for it, so that the data and results from future studies can be more easily
compared.3
Definitions
Intraabdominal Pressure (IAP)
The IAP is the steady state of pressure concealed within the abdominal cavity.
The IAP shifts with respiration as evidenced by an inspiratory increase (diaphrag-
matic contraction) and an expiratory decrease (relaxation). A normal IAP value
is around 5 mmHg, but can be substantially higher in the morbidly obese or the
postoperative period. For example, it has been demonstrated that increased sagit-
tal abdominal diameter in morbidly obese patients is associated with elevated
IAP in the absence of other significant pathophysiology.4 Previous studies have
74
7. Intraabdominal Hypertension
75
documented that recent abdominal operations are associated with elevations of
IAP.5,6 Before the diagnosis of pathological IAP or intraabdominal hypertension,
which may potentially require therapeutic intervention, can be made, a sustained
increase in the IAP reflecting a new pathological phenomenon or entity in the
abdominal cavity needs to be demonstrated.7
IAP Measurement
Clinical examination of the abdomen or the use of an abdominal perimeter are
inaccurate for the prediction of the hidden IAP.8–12 Therefore, the correct IAP value
needs to be measured. Since the abdomen and its contents can be considered as
relatively noncompressive and primarily fluid in character, behaving in accor-
dance to Pascal’s law, the IAP can be measured in nearly every part of it.13 Differ-
ent direct and indirect measurement methods have been suggested in the literature.
Most of the currently used indirect methods were summarized in a recent review
on this topic.1 The IAP should be expressed in mmHg and measured at end-expira-
tion in the complete supine position, ensuring that abdominal muscle contractions
are absent and the transducer zeroed at the level of midaxillary line (conversion
factor from mmHg to cmH2O is 1.36). Until other methods are available, the
bladder is considered as the indirect gold standard for intermittent IAP measure-
ment. Figure 7.1 shows a diagram for intermittent bladder pressure measurement.
Recently, new measurement kits, either via a Foley Manometer (Holtech Medical,
Kopenhagen, Denmark), AbViser-valve (Wolfe Tory Medical, Salt Lake City,
Utah, USA), or continuous IAP measurement via a balloon-tipped stomach catheter
(Spiegelberg, Hamburg, Germany) have become commercially available.1
A continuous IAP tracing can also be obtained via a standard 18 Fr three-way
Foley bladder catheter. The continuous IAP measurement is performed via the
irrigation port of the three-way catheter, in which continuous sterile normal saline
irrigation is maintained and connected through a two-way stopcock and normal
saline filled tubing to a pressure transducer placed in line with the iliac crest at
the midaxillary line.14 The transducer is zeroed and the continuous IAP measure-
ment is recorded on the bedside monitor.
Abdominal Perfusion Pressure
Analogous to the widely accepted and utilized concept of cerebral perfusion
pressure (CPP), calculated as mean arterial pressure (MAP) minus intracranial
pressure (ICP) (CPP = MAP − ICP), the abdominal perfusion pressure (APP),
calculated as MAP minus IAP (APP = MAP − IAP), has been suggested as a
useful endpoint for resuscitation.15,16
Intraabdominal Hypertension (IAH)
The exact level of IAP that defines IAH still remains a subject of debate. In the
early surgical literature the level of 15 to 18 mmHg (20 to 25 cmH2O) came
76
A
B
M. Malbrain et al.
7. Intraabdominal Hypertension
77
forward. Burch et al. defined a grading system of IAH/ACS to guide therapy:
grade I corresponds to a bladder pressure of 7.5 to 11 mmHg, grade II to > 11 to
18 mmHg, grade III to > 18 to 25 mmHg, and grade IV > 25 mmHg.17 Obviously,
pathological IAP is a continuum ranging from mild increases without clinical
adverse effects to a substantial elevation with grave consequences to all organ
systems. Although the use of a single IAP parameter to define IAH could be
questioned, it is important that a consensus on this point is reached in the
future.
Currently, the definition of IAH in the literature varies most commonly between
12 and 25 mmHg.2,9,18–27 Some studies have shown deleterious effects on organ
function after increases in IAP as low as 10 or 15 mmHg, respectively.3,16,28–31 A
recent, and so far the only, multicenter study aimed at establishing the prevalence,
etiology, and predisposing factors associated with IAH in a mixed population of
Figure 7.1. (A) A closed needle-free revised method for measurement of intraabdominal
pressure. A sterile Foley catheter is used and the urinary drainage system connected. Using
a sterile field and gloves, the drainage tubing is cut (with sterile scissors) 40 cm after the
culture aspiration port after disinfection. A ramp with three stopcocks (Manifold set, Pvb
Medizintechnik Gmbh, a SIMS Trademark, 85614 Kirchseeon, Germany, REF: 888-103-
MA-11;or any other manifold set or even three stopcocks connected together will do the
job) is connected to a conical connection piece (Conical Connector with female or male
lock fitting, B Braun, Melsungen, Germany, REF: 4896629 or 4438450) at each side with
a male/male adaptor (Male to Male connector piece, Vygon, Ecouen, France, REF: 893.00
or 874.10). The ramp is then inserted in the drainage tubing. A standard intravenous (IV)
infusion set is connected to a bag of 1,000 mL of normal saline and attached to the first
stopcock. A 60 mL syringe is connected to the second stopcock and the third stopcock is
connected to a pressure transducer via rigid pressure tubing. The system is flushed with
normal saline and the pressure transducer is zeroed at the symphysis pubis (or the midaxil-
lary line when the patient is in the completely supine position). The pressure transducer
is fixed at the symphysis or the thigh. At rest the three stopcocks are turned “off” to the
IV bag, the syringe and transducer giving an open path for urine to flow into the urometer
or drainage bag; said otherwise, the three stopcocks are turned “on” to the patient. To
measure IAP, the urinary drainage tubing is clamped distal to the ramp device and the
third stopcock is turned “on” to the transducer and the patient and “off” to the drainage
system. The third stopcock also acts as a clamp. The first stopcock is turned “off” to the
patient and “on” to the IV infusion bag, the second stopcock is turned “on” to the IV bag
and the 60 mL syringe. Hence, 50 mL of normal saline can be aspirated from the
IV bag into the syringe. The first stopcock is turned “on” to the patient and “off” to the
IV bag and the 50 mL of normal saline is instilled in the bladder through the urinary cath-
eter. The first and second stopcock are then turned “on” to the patient, and thus turned
“off ” to IV tubing and the syringe. The third stopcock already being turned “on” to the
transducer and patient allows the immediate IAP reading on the monitor. (B) Mounted
patient view of the device and close-up of manifold and conical connection pieces. (Both
reprinted with permission from Malbrain ML. Different techniques to measure intra-
abdominal pressure (IAP): time for a critical re-appraisal. Intensive Care Med
2004;30(3):357–371, © Springer.)
78
M. Malbrain et al.
intensive care patients defined IAH as a maximal IAP value of 12 mmHg or more
in at least one measurement.2 With the lack of a consensus, and in order to exclude
brief, temporary elevations of IAP that are not clinically significant, we suggest
that IAH be defined as a consistent increased IAP value of ≥12 mmHg that is
recorded by a minimum of three standardized pressure measurements that are
conducted 4 to 6 hours apart. After establishing this minimum threshold for
defining IAH, stratification or gradation of the pathological IAP values, as Burch
et al. suggested, is probably needed to calibrate and quantify the “threat” of the
insult to produce clinically significant manifestations.
Abdominal Compartment Syndrome (ACS)
Most syndromes are preceded by a prodromal phase during which a number of
nonspecific symptoms and signs appear. ACS is no exception to this general rule,
and IAH represents the prodromal phase of ACS. Within the last statement rests
the theoretical distinction between IAH and ACS, namely that IAH in combina-
tion with overt organ dysfunction represents ACS (Figure 7.2). In practice that
Normal
abdominal
pressure
0
5
10
15
20
Abdominal
compartment
syndrome
25
30
35
40
Intraabdominal pressure (mmHg)
Figure 7.2. Distinctions between normal intraabdominal pressure (IAP), intraabdominal
hypertension (IAH), and abdominal compartment syndrome (ACS). The shaded area
illustrating IAH may undergo shifts to the right or left depending on the clinical scenario.
7. Intraabdominal Hypertension
79
pathological point is harder to elucidate, hence the indistinct margins defining
IAH and the modest change in organ dysfunction. As with prediction of outcome
in the critically ill, the extremes are obvious, but with those in the middle range
prediction of survival or death is difficult. Patients with an IAP of less than
15 mmHg and organ dysfunction explicable by their underlying pathology are
unlikely to benefit from abdominal decompression.
A more accurate definition of ACS will require a combination of numerical
value identified with increased IAP with the significant clinical consequences
of the prolonged IAH (i.e., the development of disturbances in the different
organ systems). In a recent study by Malbrain et al.,2 ACS was defined as
IAP ≥ 20 mmHg with failure of one or more organ systems. They defined organ
failure as a sequential organ failure assessment (SOFA) organ subscore ≥3.32
The SOFA score includes the sum of six organ system scores (respiratory,
cardiovascular, renal, coagulation, liver, and neurologic) ranging from 0 (normal)
to 4 (severe derangement) for each organ system. The SOFA score is calculated
using the worst values of the day and does not account for organ systems that are
not included in the score, of which the most important is the gastrointestinal
system. Until a consensus agreement on a definition of ACS is reached, we
submit the following to be used in future clinical studies: ACS is defined as IAH
with a gradual and consistent increased IAP value of ≥20 mmHg recorded during
a minimum of three standardized measurements that are performed 1 to 6 hours
apart and that is directly associated with single or multiple organ system failure
which was not previously present (as assessed by the daily SOFA or equivalent
scoring system; organ failure is defined as a SOFA organ system score of ≥3).
In contrast to IAH, the ACS should not be graded, since ACS is an all or
nothing phenomenon. Further assessment of organ function can be done by
examining the direct clinical effects of ACS on different variables (see Organ
Function Assessment, below).
Classification of IAH/ACS
With the increasing recognition of ACS as a significant contributor to the devel-
opment of multiple organ failure in critically ill patients and the multitude of
conditions associated with ACS, it is useful to categorize ACS according to the
underlying pathology. In trauma patients, primary ACS has been defined as a
recognized complication of damage control laparotomy, and secondary ACS as
a condition reported in patients without abdominal injury who require aggressive
fluid resuscitation.26,33 In the intensive care environment, primary ACS has been
considered as surgical (e.g., ruptured abdominal aortic aneurysm, abdominal
trauma) and secondary ACS as medical (e.g., pneumonia with septic shock, toxin
release, capillary leak, and massive fluid overload).3 Occasionally a combination
of the two may occur, for example when a patient develops sepsis and capillary
leak with fluid overload after initial surgical stabilization for trauma.34 This
overlap of clinical conditions and potential etiologies has added to the confusion
80
M. Malbrain et al.
regarding the definitions. Additional difficulty arises when patients develop ACS
after previous surgical treatment for the prevention of IAH.22,35–37 For further
fine-tuning and classification of IAH/ACS four essential questions need to be
answered with regard to the duration (chronic, acute, subacute, hyperacute), the
initial underlying problem (intra- or extraabdominal), the etiology (medical,
surgical, trauma, or burn), and the localized or generalized character.
The following examples and suggestions for definitions were recently
suggested3,31:
Hyperacute IAH lasts only seconds or minutes: laughing, straining, coughing,
sneezing, defecation, or physical activity.
Acute IAH occurs within hours: trauma or intraabdominal hemorrhage of any
cause (e.g., ruptured abdominal aortic aneurysm).
Subacute IAH occurs within days: most medical causes (e.g., fluid resuscitation
and capillary leak).
Chronic IAH occurs within months or years: morbid obesity, intraabdominal
tumor (large ovarian cyst, fibroma), chronic ascites (liver cirrhosis or CAPD),
or pregnancy.
Primary ACS: defined as a condition associated with injury or disease in the
abdomino-pelvic region (e.g., severe acute pancreatitis, spleen rupture).
Secondary ACS: refers to conditions that do not originate from the abdominal
cavity (such as pneumonia with sepsis and capillary leak, major burns, and
other conditions requiring massive fluid resuscitation).
Tertiary ACS: refers solely to the condition where ACS develops following pro-
phylactic or therapeutic surgical or medical treatment of primary or secondary
ACS (e.g., persistence of ACS after decompressive laparotomy, formerly
termed the open abdomen compartment syndrome).35
Some examples of classification are:
1. A patient with chronic liver failure complicated with variceal bleeding and
cardiorespiratory collapse and an IAP of 18 mmHg: chronic, primary, medical,
grade II IAH.
2. A patient with penetrating thoracic injury, presenting with cardiorespiratory
collapse requiring massive resuscitation develops an increased IAP above
21 mmHg on the third day of hospitalization: subacute, secondary, trauma,
grade III IAH.
3. A patient with a septic shock due to localized intestinal perforation and an IAP
of 25 mmHg: acute, primary, medical, grade IV IAH.
Organ Function Assessment
After identification of the at-risk patient by means of IAP thresholds and SOFA
score, the impact of IAH on the different organ-specific parameters should be
assessed.
7. Intraabdominal Hypertension
81
Abdominal Assessment
Ongoing assessment of IAP should be done by either intermittent or continuous
IAP monitoring, together with APP. However, the bladder pressure alone can
never be considered as a surrogate tool for bedside clinical examination of the
patient. IAH should be seen as an “organ failure” for which specific interventions
may be considered, depending on the actual IAP level, such as diagnostic (CT
scan,38 echocardiography,39 correct interpretation of intrathoracic blood and filling
pressures3,40), therapeutic (the use of higher PEEP levels,3,41 the application of
externally continuous negative abdominal pressure42), and surgical (damage
control surgery, decompressive laparotomy). Abdominal wall complications
(infections, necrosis, hernias) can occur during peritoneal dialysis due to dimin-
ished abdominal wall compliance and rectus sheath blood flow.43
Cardiovascular Assessment
Cardiovascular failure is defined by the SOFA score as the need for vasopressors
(either dopamine >5μgr or (nor)epinephrine <0.1μgr). Cardiovascular dysfunc-
tion is defined by the SOFA score as the need for vasopressors (either dopamine
<5μgr or dobutamine at any dose).
As originally described over 80 years ago by Emerson, rising IAP increases
intrathoracic pressure through cephalad deviation of the diaphragm.44 Increased
intrathoracic pressure significantly reduces venous return and cardiac output
and compresses both the aorta and pulmonary parenchyma, raising systemic
vascular resistance.45–50 Such alterations have been demonstrated to occur at an
IAP of only 10 mmHg.46,50 Hypovolemic patients, those with marginal cardiac
contractility, those requiring positive pressure ventilation (with high PEEP), and
those with chronic obstructive lung disease (and auto-PEEP) appear to sustain
reductions in cardiac output at lower levels of IAP than do normovolemic
patients.47,48
In summary, IAH decreases venous return and cardiac output, while systemic
and pulmonary vascular resistances increase, heart rate remains stable or may
increase, the mean arterial pressure initially increases but afterward decreases,
and pulmonary arterial pressure increases. The left ventricular compliance and
regional wall motion decreases. As a result IAH makes preload assessment diffi-
cult since pulmonary artery wedge pressure and central venous pressure rise
despite the reduced venous return and cardiac output, while transmural filling
pressures usually remain stable or may even decrease. Volumetric and functional
hemodynamic parameters on the other hand will better reflect the true volemic
status and the volume responsiveness of the patient: global and right ventricular
end-diastolic and intrathoracic blood volumes remain stable or may decrease,
extravascular lung water increases (in the presence of capillary leak), and stroke
volume and pulse pressure variations remain stable or may increase. Finally, there
is an increased risk for peripheral edema and venous thrombosis due to the
increased femoral vein pressures and the reduced venous blood flow and the
82
M. Malbrain et al.
resulting rise in venous hydrostatic pressure. This may lead to fatal pulmonary
embolism on decompression.3
Pulmonary Assessment
Respiratory failure is defined by the SOFA score as a paO2/FiO2 ratio <200 with
the need for respiratory support in the form of mechanical ventilation. Respiratory
dysfunction is defined by the SOFA score as a paO2/FiO2 ratio <300 regardless
of the need for respiratory support.
Increases in intrathoracic pressure, through cephalad elevation of the diaphragm,
also result in extrinsic compression of the pulmonary parenchyma with development
of alveolar atelectasis, decreased diffusion of oxygen and carbon dioxide across the
pulmonary capillary membrane, and increased intrapulmonary shunt fraction and
alveolar dead space.46,47,49,50 This dysfunction begins at an IAP of 15 mmHg and is
accentuated by the presence of hypovolemia.50 In combination, these effects lead to
the arterial hypoxemia and hypercarbia that characterize ACS.28,46,50
In summary, IAH increases intrathoracic and pleural pressure leading to edema
and atelectasis, causing a decrease in functional residual capacity and all other
lung volumes (mimicking restrictive lung disease). In mechanically ventilated
patients auto-PEEP, peak, plateau, and mean airway pressures increase (possibly
leading to alveolar barotrauma), while dynamic and static total respiratory system
compliance drop (due to a diminished chest wall compliance, with reduced spon-
taneous tidal volumes, while lung compliance remains unchanged, thus the lower
inflection point increases while the upper inflection point shifts to the left). IAH
hence results in hypercarbia, hypoxia with a drop in paO2/FiO2 ratio, increased
dead-space ventilation, and intrapulmonary shunt. Lung neutrophils are activated
with increased pulmonary inflammatory infiltration and alveolar edema (extra-
vascular lung water increases), increased risk for pulmonary infection, and com-
pression atelectasis, all resulting in difficult and prolonged ventilation and
weaning.3
Renal Assessment
Renal failure is defined by the SOFA score as a serum creatinine level ≥3.5 mg/dL
(≥300 μmol/L) or oliguria <500 mL/day. Renal dysfunction is defined by the
SOFA score as a serum creatinine level ≥2 mg/dL (≥170 μmol/L).
Elevated IAP significantly decreases renal artery blood flow and compresses
the renal vein, leading to impaired venous drainage and renal dysfunction and
failure.51,52 There seems also to be an indirect effect by arterial vasoconstriction
mediated by the stimulation of the sympathetic nervous and renin-angiotensin-
aldosterone systems. Oliguria develops at an IAP of 15 mmHg and anuria at
30 mmHg in the presence of normovolemia and at lower levels of IAP in the
patient with hypovolemia.52 Renal perfusion pressure (RPP) and renal filtration
gradient (FG) have been proposed as key factors in the development of IAP-
induced renal failure.53 The FG is the mechanical force across the glomerulus and
7. Intraabdominal Hypertension
83
equals the difference between the glomerular filtration pressure (GFP) and the
proximal tubular pressure (PTP): FG = GFP − PTP. In the presence of IAH, PTP
may be assumed to equal IAP, and GFP can be estimated as MAP − IAP. The FG
can then be calculated by the formula: FG = MAP − 2*IAP. Thus, changes in IAP
have a greater impact upon renal function and urine production than will changes
in MAP. It should not be surprising, therefore, that decreased renal function, as
evidenced by development of oliguria, is one of the first visible signs of IAH.
In summary, IAH decreases RPP, the FG, and renal blood flow. Oliguria devel-
ops, tubular dysfunction increases, glomerular filtration rate drops, renal vascular
resistance increases, renal vein and ureter compression increases, renin, aldoste-
rone, and antidiuretic hormone levels increase, while adrenal blood flow usually
remains preserved.3
Gastrointestinal Assessment
Gastrointestinal failure is not defined by a SOFA subscore. The gut appears to be
particularly sensitive to IAH with virtually all intraabdominal and retroperitoneal
organs demonstrating decreased blood flow in the presence of elevated IAP.54
Reductions in mesenteric blood flow may appear with an IAP of only 10 mmHg.55
Celiac artery blood flow is reduced by up to 43%, and superior mesenteric artery
blood flow by as much as 69% in the presence of an IAP of 40 mmHg.55,56 The
negative effects of IAP on mesenteric perfusion are augmented by the presence
of hypovolemia or hemorrhage.20,49,55 Bowel ischemia and inadequate perfusion
initiate a vicious cycle of worsening perfusion, increased capillary leak, decreased
intramucosal pH, and systemic metabolic acidosis.20,48,57 An IAP of 20 mmHg
diminishes intestinal mucosal perfusion and has been speculated as a possible
mechanism for subsequent development of bacterial translocation, sepsis, and
multiple system organ failure.20,48,56–58 Bacterial translocation to mesenteric lymph
nodes has been demonstrated to occur in the presence of hemorrhage with a sus-
tained IAP of only 10 mmHg during a period of only 30 minutes.58
In summary, IAH decreases abdominal perfusion pressure, as well as celiac
blood flow, superior mesenteric artery blood flow, the blood flow to all intra-
abdominal organs, and in particular mucosal blood flow. Intramucosal gastric pH
drops, while regional CO2 and the CO2-gap increase. IAH also leads to mesenteric
vein compression, promoting venous hypertension and intestinal edema and vis-
ceral swelling, which triggers a vicious cycle. Enteral feeding becomes difficult,
intestinal permeability increases, and bacterial translocation may occur, finally
leading to multiple system organ failure. IAH increases the risk for gastrointesti-
nal ulcer (re)bleeding, and the increased variceal wall stress may lead to varciceal
(re)bleeding. Finally, there is an increased risk for peritoneal adhesions.3
Hepatic Assessment
Hepatic failure is defined by the SOFA score as a serum bilirubin level ≥6 mg/dL
(≥102 μmol/L). Hepatic dysfunction is defined by the SOFA score as a serum
bilirubin level ≥2 mg/dL (≥33 μmol/L).
84
M. Malbrain et al.
Hepatic artery blood flow is directly affected by IAP-induced decreases in
cardiac output, while hepatic vein and portal vein blood flow are reduced by
extrinsic compression.48 These changes have been documented with IAP eleva-
tions of only 10 mmHg and in the presence of both normal cardiac output and
mean arterial blood pressure.48
In summary, IAH decreases hepatic artery flow and portal venous blood flow,
while portocollateral flow increases, lactate clearance drops, glucose metabolism
diminishes, mitochondrial and cytochrome P450 function decreases, as well as
the plasma disappearance rate for indocyanine green.3
Neurologic Assessment
Neurologic failure is defined by the SOFA score as a Glasgow Coma Scale <10.
Neurologic dysfunction is defined by the SOFA score as a Glasgow Coma Scale
<13.
In summary, IAH increases intracranial pressure (ICP) by transdiaphragmatic
IAP transmission, leading to an elevation of pleural and central venous pressure;
these elevations are sustained as long as the IAH is present.59,60 The combination
of elevated central venous pressure and increased ICP can lead to a substantial
decrease in cerebral perfusion pressure, especially in hypotensive, hypovolemic
patients where it can lead to progressive cerebral ischemia. The IAP has also been
suggested as the cause of idiopathic intracranial hypertension in the morbidly
obese4,61–63 or the neurologic deterioration in patients with multiple trauma but
without overt neurotrauma.64 This hypothesis makes laparoscopy less indicated
and less safe in patients with intracranial pathology.3
Treatment
Patients with organ dysfunction and an IAP above 20 mmHg should undergo
decompressive surgery.65 But what of those between 15 to 20 mmHg with mild
organ dysfunctions? This defines the group with IAH but potential ACS. A judg-
ment call between risk and benefit is required. On balance, from the available
accumulating evidence, such patients should probably be decompressed and the
diagnosis confirmed or refuted retrospectively. It is within this narrow no-man’s-
land of IAH between normal IAP and ACS that our efforts should be concentrated
in an attempt to clarify definitions and thereby treatment options. Reliance on
standard hemodynamic parameters is too crude, but measurement of splanchnic
perfusion is too difficult in the clinical scenario to be currently applicable. The
exact causative role of bacterial and vasoactive mediator translocation in the
genesis and evolution of multisystem organ failure is a further controversial area
of critical care medicine.56,66 It is indisputable, though, that the gut is sensitive to
low-flow states and is rendered ischemic at pressures below those expected to
induce the ACS; therefore, any attempt should be made to prevent the develop-
ment of overt ACS.
7. Intraabdominal Hypertension
85
Different medical treatment procedures have been suggested to decrease IAP.16
These include the use of paracentesis, gastric suctioning, rectal enemas, gastro-
prokinetics (cisapride, metoclopramide, domperidone, erythromycin), colonopro-
kinetics (prostygmine), furosemide either alone or in combination with human
albumin 20%, continuous venovenous hemofiltration with aggressive ultrafiltra-
tion, continuous negative abdominal pressure, and finally sedation and curariza-
tion. Curarization has been shown to decrease IAP, a phenomenon known for a
long time in the operating theater.67,68 Fentanyl, on the contrary, may acutely
increase IAP by stimulation of active phasic expiratory activity.69
Since no low-morbidity procedure is available to decompress ACS, Voss et al.
developed a percutaneous procedure to increase abdominal capacity and to
decrease IAP, based on the principles of abdominal wall components separation.70
This minimally invasive procedure was feasible and effective in a porcine
model of ACS. In burn patients a similar procedure had the same beneficial
effects.71
In an interesting and original study it was recently demonstrated that the appli-
cation of external negative abdominal pressure (NEXAP) was able to decrease
IAP in 30 ICU patients; however, baseline IAP values were quite low.42 This study
hence confirms previous animal results.72,73
Implications for Future Research?
Studies examining the prevalence and incidence of IAH/ACS should be based on
the above cited definitions and classifications. The results should be given for
mean, median, and maximal IAP values on admission and during the study stay.
The ideal frequency for IAP measurement also needs to be elucidated as well as
the diurnal and nocturnal variations during continuous IAP monitoring, since this
may affect the mean and maximal daily IAP levels as well as the incidence and
prevalence of IAH when different thresholds are used.
Studies examining IAP thresholds should be based on the analysis of receiver
operating characteristics (ROC) and the area under the ROC curve.74 As an
example, in a recent retrospective study ROC curves were generated for IAP and
APP in order to identify the threshold values of each endpoint that were most
predictive of patient outcome.15 ROC curves graph the sensitivity of a diagnostic
test (true positive proportion) versus one minus specificity (false positive propor-
tion) and provide an improved measure of the overall discriminatory power of a
test as they assess all possible threshold values. A test that always predicts sur-
vival has an area under the ROC curve of 1.0, and a test that predicts survival no
more often than would be done by chance has an area under the ROC curve of
0.5. The point on the ROC curve closest to the upper left corner is generally
considered to optimize the sensitivity and specificity of the test. In this study, the
area under the ROC curve was 0.726 for APP and 0.748 for IAP (Figure 7.3).
Although the areas under the ROC curves for APP and IAP are not statistically
different, the curves demonstrate that the sensitivity and specificity of APP are
86
M. Malbrain et al.
1.0
APP = 60 mmHg
0.8
APP = 50 mmHg
0.6
APP = 40 mmHg
0.4
IAP = 25 mmHg
0.2
IAP = 20 mmHg
APP
IAP
IAP = 15 mmHg
0.0
0.0
0.2
0.4
0.6
0.8
1.0
1-Specificity
Figure 7.3. Receiver operator characteristic (ROC) curves for IAP and APP with clini-
cally useful decision points (IAP has been plotted against mortality instead of survival as
in the original study while APP is plotted against survival). IAP—intraabdominal pressure,
APP—abdominal perfusion pressure.
both superior to that of IAP for the clinically useful decision thresholds. Main-
tenance of an APP of at least 50 mmHg appears to maximize both the sensitivity
(76%) and specificity (57%) of APP as a predictor of patient survival. The com-
monly utilized MAP resuscitation endpoint of 70 mmHg achieved a sensitivity of
only 57% and specificity of 61%. Although an IAP threshold of 30 mmHg
achieved a sensitivity of 70% and specificity of 72%, this endpoint exceeds what
is now recognized as being clinically acceptable, and its application would place
the patient at risk for significant end-organ malperfusion. Within the currently
advocated ranges of 10 to 25 mmHg, IAP was specific but not sensitive for pre-
dicting patient outcome. APP appears to be a clinically superior resuscitation
endpoint and predictor of patient survival during treatment of IAH and ACS as
it addresses not only the severity of IAH, but also the adequacy of end-organ
perfusion.
7. Intraabdominal Hypertension
87
Studies examining new devices to measure IAP should always compare the
new IAP measurement method with some form of gold standard. The validation
of the new technique should not be limited to the analysis of (significant) correla-
tion coefficients with R2 (since a good correlation coefficient is not enough to
compare two different methods) but should go further into detail with an analysis
according to Bland and Altman, who proposed to test for a systematic bias, preci-
sion, and agreement between two methods by plotting the mean difference against
the mean of two measurements.75
Future research should not only focus on epidemiology. The crucial question
before widespread acceptance, practice, and clinical use of IAP still remains
unanswered to date: Is IAP a phenomenon or an epiphenomenon? The impact
that IAP has on therapeutic decision making and outcome when an intervention
is undertaken to influence IAP have still to be studied. Before IAP is accepted as
a valid tool in practice, it has to be demonstrated that interventions to treat ACS
alter patient outcome (if not mortality, then at least morbidity). Maybe it is now
time for such multicenter, multinational interventional studies.
Conclusion
All definitions of a clinical situation or syndrome fail to include all possible
conditions and variations of an inherently complex phenomenon. Nevertheless,
in order to approach scientific accuracy in comparing different clinical reports
and to plan for future clinical trials, definitions are required that are comprehen-
sive, detailed, simple, practical, and acceptable to the majority of the scientific
community working in the particular field. This review does not, and cannot,
provide bullet-proof definitions for all issues associated with increased IAP, but
puts forward arguments and suggestions that may serve as a springboard for
further consensus-building endeavors. These definitions also allow better com-
parisons of data between groups of researchers and may lead to refined and better
definitions themselves.
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8
Resuscitation Goals in Severe Sepsis
and Septic Shock
Fernando Pálizas
Introduction
One of the main consequences of systemic inflammatory response syndrome
(SIRS)1 is the generalized arterial and venous vasodilatation produced by the
increase in the production of large amounts of nitric oxide (NO).2 The intensity
of the arterial vasodilatation is correlated with the severity of the hemodynamic
derangement that occurs in severe sepsis and with the outcome of these
patients.3
Overt hypotension occurs when the increase in cardiac output is not able to
compensate arterial vasodilatation. One hindrance to increasing cardiac output to
the proper levels is the presence of myocardial depression.4
Plasma volume expanders, vasoconstrictors, and inotropes are the main basic
tools available for treatment of hypotension and shock in sepsis. The proper use
of these therapeutic tools in hemodynamic resuscitation maneuvers can make the
difference between a good outcome or the evolution to multiorgan dysfunction
syndrome (MODS)1 and death.
The basic principles for use of plasma volume expanders and vasoactive drugs
in initial resuscitation of severe sepsis and septic shock are:
• Plasma volume expanders are the main therapeutic tool to resuscitate severe
sepsis and septic shock patients (they must be used cautiously in cardiac
failure).
• Due to the intensity of vasodilatation, the volume of plasma expanders to be
used is very important (3,000 to 6,000 mL of crystalloids). It is recommended
to infuse this volume in a short period of time (30 to 120 minutes).
• Generalized edema is unavoidable after proper volume expansion due to the
presence of “leaking” capillaries.5,6
• Vasoconstrictors will be used only if normal pressure is not achieved with
adequate volume expansion.
• The dosage of vasoconstrictors used in sepsis to achieve normal arterial pres-
sure is much higher than in nonseptic patients. This is due to the important
decrease in the number and sensitivity of adrenergic receptors.3
92
8. Resuscitation in Sepsis and Septic Shock
93
• Dopamine and noradrenaline are the vasoconstrictors recommended to treat
hypotension in sepsis. There is no evidence to recommend one drug over the
other. Some authors recommend using dopamine up to a maximum dose of 25
to 30 μg/kg/min. If at that point normal pressure has not been achieved, infusion
should be switched to a noradrenaline infusion.
• The goal to achieve in terms of mean arterial pressure (MAP) will be 65 to
70 mmHg. There is no difference in outcome or progression of organ dysfunc-
tions when pressure is raised up to 75 or 85 mmHg.7
• When arterial pressure has been normalized and a raise in cardiac output is
needed, the use of dobutamine is recommended. If a drop in arterial pressure
is seen with dobutamine infusion, adrenaline infusion can be tried.
Central Venous Pressure in Hypotensive Septic Patients
The level of jugular distention and, when available, central venous pressure
(CVP), will be useful to evaluate right ventricle preload. This is essential to guide
the amount of volume expansion needed in the initial resuscitation of hypotensive
septic patients. When plasma volume is expanded, the value of CVP accepted
as a goal by most experts is between 8 and 12 mmHg (approximately 10 to
15 cmH2O).8 If initial values are higher, resuscitation should start directly with
vasoconstrictors like dopamine or noradrenaline. If values are lower than
10 cmH2O, a challenge with aggressive volume expansion has to be implemented.
In some patients with intermediate values a moderate volume expansion test can
also be tried to evaluate the response.
It is necessary to recall here that CVP values are “permissive” and not “manda-
tory.” This means that if the goal value of CVP has not been achieved when
arterial pressure has already risen to normal, expansion maneuvers must be
stopped. When a septic patient is normotensive, the volume will not be expanded,
although the CVP is zero.
Vasoconstrictors Infusion
If restoration of normal MAP values is not achieved after adequate volume expan-
sion, it is recommended to start with an infusion of a vasoconstrictor, such
as dopamine or noradrenaline. If the MAP value is between 50 and 60 mmHg,
infusion of vasoconstrictors should start with a dopamine infusion with an
initial dose of 5 to 10 μg/kg/min or noradrenaline with an initial dose of
0.05 to 0.1 μg/kg/min. The dose will be raised to reach a MAP of 65 to
70 mmHg.
In patients with severe hypotension (<50 mmHg), infusion must be started with
a high-dose regimen and, when normotension is achieved, the infusion will be
changed to a “reasonable” dose regimen, dopamine at approximately 20 μg/kg/
min or noradrenaline 0.15 to 0.20 μg/kg/min. Adjustments will be done to main-
tain a MAP of 65 to 70 mmHg.
94
F. Pálizas
Initial Hemodynamic Management
Hernandez et al.9 developed a noradrenaline-based strategy of initial resuscitation
of septic shock. It has been validated through years of experience, and the mortal-
ity of septic shock patients managed with this approach is approximately 30%.
The strategies of this approach include:
1. Plasma volume expansion: Start a rapid infusion of saline (30 to 60 min) to
achieve a CVP of 10 to 12 mmHg. If a Swan-Ganz catheter has already been
inserted, saline infusion will be stopped when wedge pressure reaches 14 to
16 mmHg.
2. If MAP remains <65 mmHg, a noradrenaline infusion is started using an
initial dose of 0.05 μg/kg/min. If hypotension persists, infusion dose is incre-
mented in steps of 0.05 μg/kg/min up to a normotensive level (70 mmHg). When
a dose of noradrenaline higher than 0.1 to 0.2 μg/kg/min is needed, a pulmonary
artery catheter is inserted to guide ulterior hemodynamic maneuvers.
3. Nurses will adjust noradrenaline infusion hourly to the minimum dose
required to maintain a MAP of 70 mmHg. CVP or wedge pressure will also be
measured hourly to maintain appropriate preload values (see step 1).
4. When a stable value of MAP is achieved, different signs and symptoms are
used to evaluate tissue perfusion:
• Skin perfusion
• Oliguria (<0.5 mL/kg/h)
• Lactate levels
• Cardiac index (CI) <2.5 L/min/m2
If one of these signs indicates abnormal tissue perfusion, dobutamine infusion is
started using an initial dose of 2 μg/kg/min. This dose will be increased using
steps of 2 μg/kg/min until signs of tissue hypoperfusion are improved or a cardiac
rate >140 x’ or hypotension appears.
5. If it is not possible to achieve a MAP ≥ 70 mmHg using noradrenaline,
adrenaline infusion is started at a dose of 0.05 μg/kg/min. The dose will be
increased in steps of 0.05 μg/kg/min up to a value of MAP of 70 mmHg. In this
moment of the resuscitation protocol the patient should be connected to mechani-
cal ventilation (if the patient has not been ventilated previously).
6. Once the patient becomes stable and if the CI is lower than 2.5 L/min/m2,
dobutamine is started following the recommendations of point 4.
Septic Shock: Hemodynamic, and “Metabolic” Disease
Oxygen “Debt” Concept
When different strategies of treatment for septic shock are analyzed, most
physicians tend to believe that septic shock is mainly a hemodynamic problem.
Therapeutic maneuvers usually end when clinical or instrumental hemodynamic
goals are achieved.
8. Resuscitation in Sepsis and Septic Shock
95
It is well established that hypotension is the main goal of initial resuscitation
in septic shock, but we must consider the “metabolic” aspects of shock in the
therapeutic strategies if we want to improve morbidity and mortality.
Crowell and Smith,10 in a remarkable experiment published in 1964, have set
the basis for our modern view of therapy for different forms of shock. The model
used by these authors consisted of a severe model of hemorrhagic shock provoked
by bleeding dogs through a catheter placed in the aorta. Blood extracted from
dogs was stored in a reservoir to be reinfused later in the experiment. MAP was
maintained at a constant level of 30 mmHg during different periods of time in
different groups of animals. Besides the MAP, oxygen consumption (VO2) was
also measured during the experiment.
After hemorrhagic shock was started, blood extracted and stored was reinfused
at different established periods of time in different groups of dogs. MAP and VO2
oxygen consumption were measured during the shock period and after blood
reinfusion up to compensation or death of the animals (Figure 8.1).
As it is shown in Figure 8.1, the difference between basal VO2 and the level
of VO2 reached during the shock period was called “oxygen debt.” It was
measured and registered minute to minute. When the oxygen debt was projected
to the duration of the shock period, the total amount of oxygen debt was estab-
lished. The longer the period of shock, the higher the magnitude of oxygen
debt.
When blood was reinfused in a short period of time (20 to 30 min) after the
beginning of hemorrhage, all the animals recovered their basal values of MAP.
VO2 also recovered very quickly, but VO2 values achieved were much higher
than basal values. These high values were sustained during a period of time long
enough to balance the magnitude of oxygen debt acquired during the shock
160
140
120
100
Hemorrhage
Debt
Payment
VO2
Oxygen
Debt
80
60
40
20
MAP
0
0
5
Treatment
7,5 10 15 20 25 30 35 40 45 50 55 60
Figure 8.1. Shock, oxygen debt, and early resuscitation.
Source: Adapted from Crowell and Smith.10
Minutes
96
F. Pálizas
Hemorrhage
120
Late Resuscitation
100
80
VO2
60
40
20
Treatment
MAP
0
0
20
45
70
Minutes
Figure 8.2. Shock, oxygen debt, and late resuscitation.
Source: Adapted from Crowell and Smith.10
period. This period of “overconsumption” of oxygen is known as the period of
“debt payment.”
When blood was reinfused late (more than 45 min) after the beginning of
hemorrhagic shock, MAP was partially restored but after several minutes it
tended to fall again and all the animals eventually died. Looking at the behavior
of VO2, it was clear that it never reached values of “overconsumption”; therefore,
oxygen debt was never paid (Figure 8.2).
If shock severity and treatment were equivalent, why was there a difference in
outcome between these experiments? The answer appears to be easy: the differ-
ence was secondary to the treatment delay in late resuscitation. Forty years ago
the authors tried to explain the findings described. They argued that after a long
period of time without treatment, the cumulative oxygen debt reached a level
high enough to produce an irreversible status in tissue metabolism. The amount
of the oxygen debt necessary to produce this metabolic picture in this experimen-
tal model was 120 mL/kg. When this level of oxygen debt was surpassed the
animals reached a status of “irreversible shock.” After this period, the treatment
failed to restore normal physiology in all the animals. These arguments seem to
be valid after 40 years of evolution in the knowledge of shock physiopathology.
As a matter of fact, this concept constitutes the main basis of modern research
aimed to improve outcome in the treatment of septic shock.11
Comparing the Crowell and Smith experiment and real patients with shock,
several differences are easily found. First, in real life the exact moment of shock
beginning is frequently unknown, and second, we can hardly define the amount
of oxygen debt the patient has accumulated. Is the patient just starting to accu-
mulate oxygen debt or is the patient very close to the point of no return (irrevers-
8. Resuscitation in Sepsis and Septic Shock
97
ible shock)? These questions teach us that two patients with an identical clinical
picture of septic shock may have very different outcomes after the resuscitation
maneuvers depending on the magnitude of the cumulated oxygen debt.
After all the arguments discussed it can be concluded that:
• All septic shock patients must be aggressively managed as if they were reaching
the irreversible shock point.
• The goals of resuscitation will be accomplished only when the hemodynamic
alterations and the oxygen debt have been restored to normal.
Evaluation of Oxygen Debt
One of the main problems intensivists have to deal with is how to take the concept
of oxygen debt and irreversible shock into clinical practice. A clear method to
assess the exact amount of oxygen debt has not been described, but different
approaches have been proposed to solve this issue:
1. Hyperresuscitation: This strategy was described several years ago by
Shoemaker et al.12,13 The purpose of this strategy is to ensure the tissues a huge
oxygen supply, irrespective of the magnitude of oxygen debt. The original descrip-
tion of this approach was based upon the introduction of a pulmonary artery
catheter. After hemodynamic measurements were made, plasma volume expand-
ers or vasoactive drugs were used to reach “high” levels of oxygenation parame-
ters. The goals defined were:
a. Cardiac index
>4.5 L/min/m2
b. Oxygen transport >600 mL/min/m2
c. VO2
>170 mL/min/m2
Although this approach seems reasonable, the success of its implementation has
been argued by different investigators and its use is still controversial.
2. Arterial lactate levels: As one main product of anaerobic metabolism, arte-
rial lactate has been proposed as a marker of severity in shock of different etiolo-
gies. The higher the lactate values, the higher the mortality in all types of shock.
Most authors agree that in low-flow states, as in hypovolemic and cardiogenic
shock, a good correlation exists between lactate levels and the magnitude of
anaerobic metabolism. When a high level of lactate is observed in low-flow states,
maneuvers aimed to raise cardiac output are recommended by most experts. The
problem is different in sepsis due to the important amount of lactate that can be
produced by metabolic disturbances not related to tissue hypoxia.14 Some authors
have proposed that only 30% of arterial lactate measured in sepsis is secondary
to anaerobic metabolism. Probably, high lactate levels are more closely related
to tissue hypoxia in the beginning of septic shock than late in sepsis
evolution.15
3. Mixed or central venous oxygen: Venous oxygen is the result of the balance
between oxygen supply to the tissues and the amount of oxygen consumed.16,17
When hemoglobin saturation in mixed or central venous blood is higher than 65
to 70%, a good supply of oxygen to tissues can be assumed.18 The use of this
98
F. Pálizas
parameter to guide maneuvers in “late” resuscitation in critically ill patients did
not improve outcome.19 More recently, a central venous oxygen saturation guided
protocol improved the evolution and reduce mortality in a group of patients with
septic shock.11 The main difference in this protocol was that resuscitation maneu-
vers started immediately after admission of the septic shock patients in the
emergency department. This approach was called the “early goal-directed resus-
citation protocol.”
4. Indirect parameters of tissue perfusion. Gut PCO2: It has been shown recently
that digestive mucosa production of CO2 is closely related to the magnitude of
mucosal perfusion.20 Because the digestive tract is one of the first regions to suffer
a dramatic decrease in blood flow in shock states, tonometric pCO2 values have
been used as an early warning of general circulatory derangements.21 Some publi-
cations have shown that gastric tonometry is a good therapeutic guide to use in
resuscitation maneuvers in critically ill patients. A decrease in the number of organ
dysfunctions and also a decrease in mortality have been shown when gastric
tonometry was used as a guide in early resuscitation strategies.22
Oxygen Debt to Guide Resuscitation Timing
Previously in this chapter the importance of rapid correction of hemodynamic
and oxygenation parameters has been established. However, the therapeutic atti-
tude of emergency department physicians and intensivists may vary depending
on the evolution period of shock when the patients are admitted. Three different
situation can be described:
1. The ideal scenario would be to predict the appearance of shock. In this
theoretical situation, therapeutic maneuvers could be directed to “prevent” the
generation of hypotension and oxygen debt. It has been called “preventive resus-
citation.” In the clinical field, high-risk preoperative patients can be assimilated
into this group.
2. The second clinical scenario is the initial treatment of septic shock, imme-
diately after the hospital admission. In this situation all the therapeutic efforts
have to be directed to a rapid resuscitation of hypotension and of oxygenation
parameters. The first 6 h of this resuscitation strategy have been called “early
resuscitation.”
3. When patients are seen more than 6 h after the beginning of septic shock,
the efficacy of resuscitation procedures decreases and the strategy may vary in
comparison with previous situations. This strategy is called “late resuscitation”
and it probably includes most of the treatments implemented in the ICU.
A scheme of the timing of resuscitation strategies is described here and sum-
marized in Figure 8.3.
Preventive Resuscitation
Different authors have shown that the use of the already mentioned “hyperresus-
citation” parameters result in a significant decrease in mortality when they are
8. Resuscitation in Sepsis and Septic Shock
99
Shock
0-6 Hs
Preventive
Resuscitation
Early
Resuscitation
> 6 Hs
Late
Resuscitation
Figure 8.3. Timing of resuscitation strategies in shock.
used as a preventive resuscitation strategy in high-risk surgical patients. Due to
the severity of previous chronic diseases or the severity of acute situations, these
patients have a perioperative mortality higher than 20%.
In these protocols,12,13,23,24 a pulmonary artery catheter is inserted prior to or
immediately after surgery and maneuvers are oriented to reach the hyperresuscita-
tion values. Patients with severe sepsis and septic shock are considered high-risk
patients when they have to go to the operating room. In this type of situation a
preventive strategy may be implemented. Three randomized trials have shown an
important decrease in mortality using this strategy. A recent multicenter trial25
showed no difference when this strategy was implemented. However, some
experts think that this group of patients does not qualify as high risk because the
mortality observed in the control group was “only” 7%.
Early Resuscitation
As previously mentioned, initial resuscitation goals in septic shock are mainly
directed to normalize hemodynamic parameters. The importance of the “ade-
quate” payment of oxygen debt to improve outcome was also widely discussed.
Recently, Rivers et al.11 published a new strategy based upon these principles that
have changed the way patients are managed during this special period. The strat-
egy was called “early goal-directed therapy” and it stated what to do in the first
6 h of resuscitation. This first 6 h could be christened as the “golden” hours of
hemodynamic resuscitation in septic shock.
Rivers et al. studied septic shock patients immediately after their admission to
the emergency department. The main aim of the study was to compare the
outcome of septic shock patients resuscitated with a special goal-directed protocol
with the outcome of “normal” resuscitation strategy during the first 6 h after
admission.
Patients were randomized to enter the “normal” or the “goal-directed” groups.
The parameter used to guide resuscitation in the goal-directed group was the
100
F. Pálizas
“central” venous O2 saturation, measured with a special catheter inserted into the
jugular vein. (See “Evaluation of Oxygen Debt.”) The first part of the study in
both groups was similar, and the first objective was to raise up MAP to 65 mmHg
using crystalloids to expand plasma volume. If a CVP of 8 to 12 mmHg was
achieved without normalization of MAP, dopamine infusion was started.
If central venous O2 saturation was lower than 70% after hemodynamic com-
pensation, additional maneuvers aimed to increase cardiac output were imple-
mented in the goal-directed group. The authors use red cells transfusion to
increase the O2 carrying capacity and dobutamine (5 to 20 μg/kg/min) to increase
cardiac output. If venous saturation were still below the target, sedation and
mechanical ventilation were implemented to decrease VO2.
To reach the resuscitation target in the “goal-directed” group during the first
6 h, a higher volume of crystalloids (5,000 vs. 3,500 mL), a higher number of red
cells in the transfusion (64.1 vs. 18.5%) and more prescriptions of dobutamine
infusion were needed.
After this study period, patients were moved to the ICU to follow normal
therapeutic protocols implemented by physicians unaware of the study. The most
important finding of the study was the important decrease in mortality observed
in the goal-directed group compared with the normal group (30.5% vs. 46.5%
mortality). The incidence of organ dysfunction was also lower in the goal-directed
group.
As a conclusion it can be stated:
a. Shock septic patients must be resuscitated as soon as possible after hospital
admission.
b. An aggressive initial resuscitation protocol aimed to correct hemodynamic
parameters should be implemented.
c. A parameter capable of evaluating tissue oxygenation should be used as a
guide to resuscitation after hypotension is normalized during the first 6 h of
treatment.
Late Resuscitation
With the initial therapeutic maneuvers already described, most of the patients
become normotensive and tissue oxygenation and perfusion were restored.
However, a portion of these patients become hemodynamically “unstable.”
Hemodynamic instability means that these patients may present, after initial
compensation, one of the following:
•
•
•
•
•
•
Requirement of new maneuvers of volume expansion
Increase in vasoconstrictor doses previously sufficient
Use of two or more vasoactive drugs
Persistent oliguria
Severe metabolic acidosis
Need to use PEEP levels >10 cmH2O
8. Resuscitation in Sepsis and Septic Shock
101
When one of these situations is present in septic patients the adequate hemody-
namic management calls for insertion of a pulmonary artery catheter (PAC). PAC
is needed because clinical assessment of preload, systemic vascular resistance,
and cardiac output is absolutely inaccurate in this kind of patient.26
The main objective of PAC insertion is to evaluate hemodynamic variables to
use plasma expanders or vasoactive drugs properly. Besides that, several authors
tried to use the measurements derived from the use of PAC to implement
protocols aimed to pay oxygen debt.8 Hyperresuscitation goals, mixed venous O2
saturation, and gastric tonometry failed to improve outcome when they were used
as a therapeutic guide in late resuscitation protocols.19,22,27
Most experts recommend that therapeutic hemodynamic goals when PAC is
inserted are just normal hemodynamic and oxygenation parameters. Cardiac
index 2.8 to 3.0 L/min/m2, oxygen transport index 450 to 600 mL/min/m2, and
VO2 130 to 150 mL/min/m2 could be established as “reasonable” targets to achieve
in late resuscitation.8
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improved outcome in severe sepsis and septic shock. Crit Care Med 2004;32(8):
1637–42.
16. Krafft P, Steltzer H, Hiesmayr M, et al. Mixed venous oxygen saturation in critically
ill septic shock patients: the role of defined events. Chest 1993;103:900–6.
17. Lee J, Wright F, Barber R, et al. Central venous oxygen saturation in shock: a study
in man. Anesthesiology 1972;36:472–8.
18. Scheinman MM, Brown MA, Rapaport E. Critical assessment of use of central venous
oxygen saturation as a mirror of mixed venous oxygen in severely ill cardiac patients.
Circulation 1969;40:165–72.
19. Gattinoni L, Brazzi L, Pelosi P, et al. A trial of goal-oriented hemodynamic therapy
in critically ill patients. N Engl J Med 1995;333:1025–32.
20. Dubin A, Murias G, Estenssoro E, et al. Intramucosal-arterial PCO2 gap fails to reflect
intestinal dysoxia in hypoxic hypoxia. Crit Care 2002;6(6):514–20.
21. Clark CH, Gutierrez G. Gastric intramucosal pH: a noninvasive method for the indi-
rect measurement of tissue oxygenation. Am J Crit Care 1992;1(2):53–60.
22. Gutierrez G, Palizas F, Doglio G, et al. Gastric intramucosal pH as a therapeutic index
of tissue oxygenation in critically ill patients. Lancet 1992;339(8787):195–9.
23. Boyd O, Ground RM, Bennet ED. A randomised clinical trial of the effect of deliberate
perioperative increase of oxygen delivery on mortality in high risk surgical patients.
JAMA 1993;270:2699.
24. Lobo SMA, Salgado PF, Castillo V, et al. Effects of maximizing oxygen delivery on
morbidity and mortality in high risk surgical patients. CCM 2000;28:3396.
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pulmonary-artery catheters in high-risk surgical patients. N Engl J Med 2003;348(1):
5–14.
26. Connors AFJ, Speroff T, Dawson NV, et al. The effectiveness of right heart catheter-
ization in the initial care of critically ill patients. JAMA 1996;276:889–97.
27. Hayes MA, Timmins AC, Yau EHS, et al. Elevation of systemic oxygen delivery in
the treatment of critically ill patients. N Engl J Med 1994;330:1717–22.
9
Coagulation Disorders in Critically Ill
Septic Patients
Marcela Granados
Sepsis still causes the majority of morbidity and mortality in intensive care units,
even though we try to understand and control it. Intervention with antibodies and
antiinflammatories has not given the hoped-for results. In recent years, there has
been enthusiasm for modifying directly the clotting system of critically ill patients,
especially those with sepsis.1
The Normal Clotting System
The traditional view of the clotting system has changed radically in recent years:
the traditional view of the platelet plug, coagulation cascade, and fibrinolytic
system has shifted to the current view of a complex system where different cell
surfaces besides the vascular endothelium2 and receptors share multiple inter-
actions with other systems, like the complement and kinin system. These are not
completely understood, and complex transformations are affected by inflamma-
tory mediators.
The objective of these reactions is to maintain a normal state of homeostasis.
That is to say that all of these mechanisms must avoid hematic loss by extra-
vasation and must keep blood fluidity, which is necessary to carry nutrients to
the tissues and remove waste products. This can be viewed as a perfectly designed
self-conservation system in human beings.3,4
The coagulation system can be activated by different factors, not only the
endothelium damage as we previously thought. Once this process is started, three
phases that were recently described occur:
1. Initiation phase
2. Amplification phase
3. Propagation phase
Initiation Phase
The initiation phase begins with the activation of the tissue factor on the cellular
surface. Then it binds with factor VII (Figure 9.1). Tissue factor is expressed by
103
104
M. Granados
Figure 9.1. Initation phase.
epithelial cells, macrophages, and other cell types that are normally separated from
blood and circulating coagulation factors. Classically, thrombin generation is trig-
gered when disruption of vascular integrity allows plasma coagulation factors to
contact extravascular tissue. Thus the coagulation cascade provides a mechanism
for converting mechanical information in the form of tissue damage or vascular
leak into biochemical information in the form of the active protease thrombin.
Tissue factor is expressed at low levels on circulating monocytes and
leukocyte-derived microparticles. These sources of intravascular tissue factor can
be tethered to activated platelets and endothelial cells and concentrated in this
way at sites of injury or inflammation.5,6 This alters the local balance between
activation and inhibition of the coagulation cascade and triggers thrombin produc-
tion. Tissue factor is also expressed at low levels by cytokine-stimulated endo-
thelial cells, perhaps to promote thrombin generation at sites of inflammation.7
Amplification Phase
The amplification phase occurs when the activation of the tissue factor and factor
VII starts the “thrombin explosion.” Thrombin is the main effector protease of
the coagulation cascade, a series of zymogen conversions that is triggered when
circulating coagulation factors contact tissue factor. Tissue factor is a type 1
integral membrane protein that functions as an obligate cofactor for activation of
zymogen factor X by factor VIIa. Factor Xa (with the assistance of cofactor factor
Va) then converts prothrombin to active thrombin. Other zymogen conversions
provide both amplification and negative feedback loops that regulate thrombin
production. Thrombin is short lived in the circulation and, in the context of a
normal endothelium, its actions tend to terminate its production. Thus thrombin
is thought to act near the site at which it is produced.8 Thrombin also has a host
of direct actions on cells.9 It triggers shape change in platelets and the release
of the platelet activators ADP, serotonin, and thromboxane A2, as well as
9. Coagulation Disorders in Critically Ill Septic Patients
105
chemokines and growth factors. It also mobilizes the adhesion molecule P-selec-
tin and the CD40 ligand to the platelet surface10,11 and activates the integrin
αIIb/β3.12 The latter binds fibrinogen and von Willebrand factor (vWF) to mediate
platelet aggregation. Thrombin also triggers expression of procoagulant activity
on the platelet surface, which supports the generation of additional thrombin.13
In cultured endothelial cells, thrombin causes release of vWF,14 the appearance
of P-selectin at the plasma membrane, and production of chemokines—actions
thought to trigger binding of platelets and leukocytes to the endothelial surface
in vivo.15,16 Endothelial cells also change shape and the endothelial monolayer
shows increased permeability in response to thrombin17—actions predicted to
promote local transudation of plasma proteins and edema.18 Thrombin can also
regulate blood vessel diameter by endothelium-dependent vasodilatation; in the
absence of endothelium, thrombin acting on smooth muscle cells evokes vaso-
constriction. In cultures of fibroblast or vascular smooth muscle cells, thrombin
regulates cytokine production and is mitogenic, and in T lymphocytes it triggers
calcium signaling and other responses. These cellular actions suggest that throm-
bin connects tissue damage to both hemostatic and inflammatory responses and
perhaps even to the decision to mount an immune response. They also raise the
possibility that regulation of endothelial and other cell types by thrombin might
have a role in leukocyte extravasations, vascular remodeling, or angiogenesis in
contexts other than tissue injury. The recent characterization of receptors that
mediate thrombin signaling provides an opportunity to test these ideas.
In summary, thrombin generation not only stimulates the formation of blood
clot but it also has antiinflammatory, anticoagulant, and antithrombolitic proper-
ties and it stimulates the cellular proliferation (Figure 9.2).
Antithrombolysis
Positive feedback for blood clot
Protein C activation
Prostacyclin (PGI2)
ANTICOAGULATION
PROCOAGULATION
THROMBIN
INFLAMATION
P and E selectin expression
PMN activation and chemotaxis
PAF activation
CELLULAR PROLIFERATION
Platelets
Fibroblasts
Figure 9.2. Propagation Phase: Thrombin actions.
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M. Granados
Propagation Phase
The propagation phase continues with thrombin converting circulating fibrinogen
to fibrin monomer, which polymerizes to form fibrin polymer, the fibrous matrix
of blood clots. This is observed after damage or inflammation, a procoagulant
reaction starts with the binding of small amounts of factor VII to tissue factor.
The complex then activates factor X and factor IX. Factor Xa generation later is
accelerated by formation of intrinsic factor Xasa, that is composed by IXa and
VIIIa binding to cell surface. Finally, factor Xa, formed by both enzymatic com-
plexes binding factor Va to the cell surface, produces prothrombinase complex
which converts prothrombin to thrombin. We can say that the procoagulant
system can synthesize in three dependent vitamin K enzymatic complexes, each
composed of one protease with serine residues and a proteic cofactor (Figure
9.3):19
1. Factor VII—tissue factor complex
2. Factor VIII—factor IX complex
3. Factor V—factor X complex
Figure 9.3. After mechanical or inflammatory damage, the procoagulant reaction begins
with the binding of the small quantities of preexistent factor Xa with tissue factor. This
complex activates factor X and factor IX. Generation of factor Xa later accelerates the
formation of the intrinsic factor Xasa complex, composed of factor IXa and factor VIIIa
binding to the membrane composed of factor IXa and factor VIIIa. Finally, factor Xa
formed by both enzymatic complexes binding with factor Va and the cell surface produces
the prothrombin compound which converts prothrombin to thrombin.
9. Coagulation Disorders in Critically Ill Septic Patients
107
Antithrombotic Mechanism
Anticoagulant compounds and mechanisms are found in the blood in a higher
than procoagulant amount. They comprise a dynamic system that includes the
thrombin-thrombomodulin complex, which is localized in the endothelium of the
blood vessels, active protein C, and antithrombin III, which are stoichiometric
inhibitors for proteases with serine residues. Another system, tissue factor pathway
inhibitor (FTPI), blocks the reaction of factor VII–factor Xa–tissue factor. Para-
doxically thrombin is not only a procoagulant and antifibrinolytic factor but also
an anticoagulant.20–22
This system is activated when the thrombin produced from the prothombinase
binding with thrombomodulin (Tm) is linked to the membrane surface, activates
protein C, and blocks thrombin-fibrinogen and factor V reaction. Activated protein
C acts with factors V and VIII are bound to the cell membrane. Then this natural
anticoagulant determines the half-life of these procoagulant factors. Protein C can
also bind factor Xa and IXa, inhibiting them in the same way. Antithrombin III
forms a complex with factor Xa, thrombin, and IXa residues, neutralizing the
residual procoagulant enzymes.
Of all the antithrombotic compounds, protein C–thrombomodulin and the
protein C receptor deserve special attention. Evidence for the existence of a
circulating thrombin-activated protein, autoprothrombin II-A, now referred to as
APC, was first presented in the early 1960s23 and was followed by the discovery
and isolation of its precursor, protein C (PC) in 1976.24–26 PC is a vitamin K–
dependent plasma glycoprotein that is synthesized by the liver and circulates as
a two-chain biologically inactive species.27 It is transformed to its active form,
APC, by thrombin-mediated cleavage of PC at the N-terminus. Effective activa-
tion of PC by thrombin requires the transmembrane glycoprotein, thrombomodu-
lin (TM), as a cofactor for thrombin,28 amplifying this event >1,000-fold. When
complexed with TM, thrombin has reduced procoagulant activity as exhibited by
its reduced ability to cleave fibrinogen, activate factor V, and trigger platelet
activation. Thus, thrombin’s substrate specificity is entirely switched by TM.
PC activation by the thrombin–TM complex is further enhanced (almost equal
to) 20-fold in vivo when PC is bound to the endothelial cell protein C receptor
(EPCR).29 Platelet factor 4 (PF4) may additionally accelerate PC activation by induc-
ing a conformational change in PC that increases its affinity for thrombin–TM.30
Why is the efficient but controlled generation of APC so important? First and
foremost, APC is a natural anticoagulant in that it suppresses further thrombin
formation by proteolytically destroying coagulation factors Va and VIIIa, facili-
tated by the cofactor for APC, protein S (PS). APC also may increase fibrinolytic
activity by neutralizing plasminogen activator inhibitor 1 (PAI-1). Overall, the
clinical relevance of PC activation by the thrombin–TM/thrombin–EPCR com-
plexes is evident from the hypercoagulable states in humans often associated with
functional deficiencies of PC or PS31,32 and in individuals with factor V Leiden
polymorphism, in which a mutation in factor Va renders it resistant to inactivation
by APC.
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M. Granados
The role of APC extends beyond hemostasis. APC has potent antiinflammatory
properties. Much effort has been expended to define the mechanisms by which
APC exerts its antiinflammatory properties. By downregulating thrombin genera-
tion through its actions on factors Va and VIIIa, APC interferes with thrombin-
induced proinflammatory activities that include platelet activation, cytokine-induced
chemotaxis for monocytes and neutrophils,33,34 and upregulation of leukocyte
adhesion molecules. However, APC also directly dampens inflammation by inhi-
biting monocyte/macrophage expression of tissue factor and tumor necrosis factor
(TNF)-α,35 nuclear factor (NF)-κB translocation, cytokine signaling, TNF-α–
induced upregulation of cell surface leukocyte adhesion molecules,36 and
leukocyte–endothelial cell interactions.37,38,39 Many of these protective effects of
APC are mediated by proteolytic cleavage of protease activated receptor 1
(PAR1).40,41,42 APC may also protect the vasculature by blocking p53-mediated
apoptosis in ischemic cerebral vasculature.43 In some models, the antiapoptotic
function of APC43 is independent of its anticoagulant function, requires EPCR as
a cofactor, and is mediated via PAR1.
TM is also a cofactor for thrombin-mediated activation of the thrombin-
activatable fibrinolysis inhibitor (TAFI).44 TAFI is a plasma procarboxypeptidase
B that, when activated to TAFIa, catalyzes the removal of the C-terminal basic
amino acid residues Lys and Arg. Inhibition of fibrinolysis is accomplished by
removal of Lys residues from modified fibrinogen, which impedes the conversion
of plasminogen to plasmin. Although the in vivo significance of TAFIa as a regu-
lator of fibrinolysis has not been clearly established,45 its potential role as a natural
antiinflammatory molecule is currently being explored, with recognition of its
ability to inactivate the potent anaphylatoxins C3a and C5a46 and the proin-
flammatory mediators bradykinin and osteopontin.47
It is less than 20 years ago that Esmon and Owen identified and isolated TM.48,49
Since that time, steady progress has been made in elucidating the molecular
mechanisms by which this single molecule regulates coagulation, inflammation,
fibrinolysis, and cellular proliferation. Although originally described as a vascular
endothelial cell receptor, TM has since been detected in a variety of cells and
tissues in adults and during development, including astrocytes, keratinocytes,
mesothelial cells, neutrophils, monocytes, and platelets.50–55 Consequently, it is
no surprise that it has functions beyond coagulation.
Encoded by an intronless gene, the mature single-chain glycoprotein in the
human is 557 amino acids long, structurally organized into five distinct domains.
From the intracellular C-terminus, TM has a short cytoplasmic tail, deletion of
which in mice has no effect on development, survival, coagulation, or inflamma-
tion.56 After a well-conserved membrane-spanning region, there is a serine/
threonine-rich domain with potential sites for O-linked glycosylation, which
support the attachment of a chondroitin sulfate (CS). Biochemical studies, yet to
be confirmed in vivo, indicate that the CS of TM enhances the PC cofactor activ-
ity of TM,57 accelerates the neutralization of thrombin by heparin–antithrombin
and by the protein C inhibitor, and facilitates binding of PF4 to PC to increase
its activation.
9. Coagulation Disorders in Critically Ill Septic Patients
109
Adjacent to the serine/threonine-rich region is the best-characterized domain,
which comprises six epidermal growth factor (EGF)-like repeats. This domain
has mitogenic effects on cultured fibroblasts and vascular smooth muscle cells,
mediated via activation of protein kinase C and mitogen-activated protein kinases
(MAPK). The clinical significance of these findings has not been established, but
they suggest a possible role in cellular proliferation and atherogenesis.58,59 EGF-
like repeats 3, 4, 5, and 6 (EGF3 to 6) have been studied in detail by several
groups and are essential for activation of PC and TAFI by thrombin.60–62 Via its
anion-binding exosite I, thrombin binds to EGF5 through EGF6, whereas EGF4
through EGF6 are required for activation of PC.63 In contrast, activation of TAFI
by thrombin–TM requires EGF3 through EGF6.64 Additional antifibrinolytic
activity is supported by the EGF-like repeats of TM, because they also accelerate
thrombin-mediated conversion of single-chain urokinase-type plasminogen acti-
vator (scu-PA) to thrombin-cleaved two-chain urokinase-type plasminogen
activator (tcu-PA/T),65 thereby interfering with the generation of plasmin.66,67
At the N-terminus of the molecule and joined to the first EGF-like repeat by
a 72-amino acid residue hydrophobic stretch, there is a 154-amino acid residue
module with homology to other C-type lectins.68,69 Electron microscopy and com-
puter models indicate that the lectin-like domain of TM is globular and situated
farthest from the plasma membrane, such that it might effectively and easily
interact with other molecules.70,71 Although lacking in anticoagulant function, this
domain plays a major role in inflammation and cell survival.
EPCR, constitutively expressed by endothelial cells, is structurally similar to
the major histocompatibility complex class 1/CDI family of proteins, which are
commonly involved in immunity/inflammation.72 EPCR accelerates thrombin-
mediated activation of PC while concentrating it near the surface of the vessel
wall. In contrast to TM, EPCR is more prominently expressed in large vessel
endothelial cells72,73 but is also detected in neutrophils. When APC is generated,
it remains bound to EPCR for a short time before associating with protein S on
the surface of platelets or endothelium, whereupon it cleaves its substrates, factors
Va/VIIIa, after which it is inactivated by α1-antitrypsin, the protein C inhibitor74
or α2-macroglobulin.75 In addition to its role in amplifying activation of PC,
EPCR switches the substrate specificity of APC, analogous to TM and thrombin.
When APC is released from EPCR, it has anticoagulant properties, yet when
transiently complexed with EPCR, APC cleaves PAR1, initiating intracellular
signaling that provides antiapoptotic protection.
TM functions as an antiinflammatory molecule at several levels. First, as a
critical cofactor in the activation of PC, TM has an obligate role in regulating the
antiinflammatory properties of APC. Thus, high levels of antiinflammatory/anti-
coagulant/vasculoprotective APC would be generated locally in the presence of
adequate or excess functional TM and thrombin. Indeed, in a vascular restenosis
model in rabbits, administration of TM via adenovirus prevented restenosis and
dampened the inflammatory response.76 Conversely, downregulation of TM would
be expected to yield low APC levels and a proinflammatory procoagulant diathe-
sis. In this respect, Weiler et al. demonstrated that mice with low APC levels
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M. Granados
(TMpro/pro mice) display a heightened inflammatory response to systemic endo-
toxemia.77 However, the story is more complicated, because the TMpro/pro mice,
when exposed to respiratory bacterial pathogens, did not generate a proinflam-
matory response, despite enhanced fibrin/fibrinogen deposition.78
There are additional indirect mechanisms by which TM may provide anti-
inflammatory protection. For example, the putative role that TAFIa plays in sup-
pressing complement activation also requires an intact thrombin–TM complex.
Recombinant soluble TM prevented leukocyte infiltration into the kidney in a rat
model of glomerulonephritis, an effect that was at least partly mediated through
an increase in TAFIa and subsequent complement inactivation.79 Furthermore,
when associated with TM, the proinflammatory properties of thrombin are
abrogated, and indeed reversed; thus TM, a “sink” for thrombin, once again
behaves effectively, albeit indirectly, as an antiinflammatory molecule. When TM
expression is downregulated by, for example, cytokines such as TNF-α or IL-1β,
thrombin would then be available to promote coagulation and inflammation.
It has long been recognized that C-type lectins, through interactions between
their carbohydrate recognition domains and carbohydrates attached to proteins,
often participate in innate immune functions, including complement activation,
leukocyte trafficking, and regulation of apoptosis.80,81 This observation prompted
us to explore the possibility that the C-type lectin-like domain of TM might play
a direct role in modulating inflammation. For this reason, transgenic mice that
lack the N-terminal lectin-like domain of TM (TMLeD/LeD) were generated.82
Although appearing normal under baseline conditions, further phenotypic analy-
sis revealed that they have reduced survival after endotoxin exposure, accumulate
more neutrophils in their lungs, respond with larger infarcts after myocardial
ischemia/reperfusion, and develop worse arthrogen-induced arthritis than their
wild-type counterparts.83 Notably, deletion of the lectin-like domain of TM did
not interfere with in vivo activation of PC, indicating that the apparent proinflam-
matory effect seen in the TMLeD/LeD mice was not caused by suppression of APC.
Rather, the lectin-like domain of TM was demonstrated to have direct antiinflam-
matory properties, conferring protection by interfering with neutrophil adhesion
to endothelial cells. Increased leukocyte adhesion to TMLeD/LeD endothelium was
at least partially explained by enhanced expression of leukocyte adhesion mole-
cules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1),
mediated by increased phosphorylation of MAPK (extracellular signal-regulated
kinase [ERK], ERK1/2), and activation of NF-κB. Recent studies further suggest
that the lectin-like domain of TM may be important to maintain the integrity of
cell–cell interactions, and thus might also prevent leukocyte transmigration.84
Overall, the lectin-like domain of TM dampens the response of the vascular
endothelium to proinflammatory stimuli by suppressing activation of well-
conserved intracellular signaling pathways. Notably, the mechanisms by which
APC and the lectin-like domain of TM exert their antiinflammatory effects are
similar, indicating the close coordination and importance of these apparently
redundant protective biologic systems.
From this discussion, it is apparent that TM, APC, and EPCR have diverse yet
distinct regulatory, structural, and functional motifs regulating multiple biological
9. Coagulation Disorders in Critically Ill Septic Patients
111
Figure 9.4. Protein C–thrombomodulin complex–protein C endothelial receptor.
functions, including coagulation, fibrinolysis, inflammation, and apoptosis. In
health and disease, these appear to be well integrated to maintain homeostasis.
Under normal conditions or in response to minor injury, the vascular endothelium
remains protected, as TM sequesters thrombin, generating adequate local levels
of APC to protect the vasculature from inflammatory, procoagulant, and proapop-
totic forces. Signals mediated directly by APC, the APC-EPCR complex via
PAR1, and the lectin-like domain of TM help to suppress cytokine release and
tissue factor expression by circulating leukocytes, interfere with endothelial cell
apoptosis, dampen endothelial cell activation of MAPKs, and prevent expression
of leukocyte adhesion molecules, impeding local accumulation of neutrophils and
monocytes (see Figure 9.4).
Fibrinolytic System
Once the blood clot is formed a process of vessel repair begins. There are three
principal activating substances of the fibrinolytic system: Hageman factor frag-
ments, urinary plasminogen activator or urokinase (uPA), and tissue plasminogen
activator (tPA). The main physiological regulators tPA and uPA spread to endo-
thelial cell and convert plasminogen into plasmin.
Plasmin breaks a fibrin polymer into small fragments that are eliminated
by the monocyte-macrophage system.85 The main stimulant for releasing tPA by
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M. Granados
endothelial cells is alpha-thrombin. Alpha-thrombin also stimulates the plasmino-
gen inhibitor, making a fine adjustment to that level. Plasmin degrades the
fibrinogen. However, this reaction remains localized due to activation of the tPA
and uPA made preferably over the plasminogen bound to the blood clot. That
occurs because the circulating plasmin is quickly bound and neutralized by alpha-
2 antiplasmin. In addition plasminogen activation inhibitor (PAI-1) release from
endothelial cell directly blocks the action of tPA.
Fibrinogen degradation products (FDPs) and fibrin have antithrombotic proper-
ties and they can destroy factors V and VIII:C. Due to this special effect the FDPs
have been termed antithrombin IV. Alpha-2 macroglobulin has the capacity to
inhibit the plasmin from forming a compound with it but more slowly than
alpha-2 antiplasmin.
Inflammatory Cascade, Coagulation, and Sepsis
There is evidence from many years ago that the inflammatory system and coagu-
lation are related not only in vertebrates but also in invertebrate animals. Both
are defense systems against infection or vascular damage. However, an alteration
in the balance of this system can produce disseminated intravascular coagulation
and multiple organic dysfunctions.
Implications of tissue factor, a glycoprotein 47 kd, are very relevant to sepsis.
This molecule is expressed in monocyte and endothelial cells, normally in small
amounts for its huge thrombogenic capacity. The relationship between sepsis and
tissue factor has been demonstrated in basic and clinical research. Inoculation of
endotoxin in healthy volunteers produces activation of the tissue factor–factor
VII complex, followed by the generation of fibrin without intrinsic activation.86
The same activation can be produced with inoculation of tumor necrosis factor-α
(TNF-α) interleukin-1(IL-1), and live bacteria (E. coli).87 On the other hand, a
decrease in the anticoagulant system has been demonstrated in sepsis which
worsens the panorama. One trial suggests that endothelial damage could inhibit
the expression of protein C–thrombomodulin, protein S, and factor Va.88 It also
has been demonstrated that endotoxin increases plasminogen activator inhibitor
(PAI-1)89 production and that it could affect lysis clot and bacterial depuration.
Why the coagulation system is changed to a hypercoagulated state in sepsis is
unknown, but it is clear that this condition produces thrombosis in small vessels
far from the original site of damage. This thrombosis can produce injury in other
tissues and organs (multiple organic dysfunctions). The explanation of this
paradox “systemic condition–local effect” is based in the endothelium. The vision
of the endothelium in a passive role to separate the blood around the tissue has
changed. We now know that endothelium is a system with many metabolic activi-
ties and multiple regulations.
Under normal conditions, liver, bone marrow, and the other organs continually
produce procoagulant and anticoagulant proteins and factors. This continual pro-
9. Coagulation Disorders in Critically Ill Septic Patients
113
duction is integrated in each of the vessels maintaining the homeostasis. In sepsis
there is an alteration in the production of these proteins and factors, likewise
monocytes can increase or induce the expression of tissue factor, producing an
imbalance in the system. Later in sepsis, when endothelium is involved further,
the situation is complicated with vasculitis, cytokine activation, and alteration of
the endothelium function, as already mentioned a condition of hypercoagulation.
These produce fibrin deposit in different organs and stimulation of fibrinolytic
mechanisms and disseminated intravascular coagulation (DIC).
Treatments and Therapies
Several trials have shown that anticoagulant proteins and factors could be sepsis
markers for its severity. These trials in septic patients have demonstrated how
protein C and antithrombin III are decreased and dimer D is increased, being a
blood marker of fibrin formation.90 Likewise, trials in animal models have shown
how infusion of activated protein C can prevent the appearance of septic shock
and death after an injection of lethal doses of E. Coli.91
Antithrombin III
It is well documented that the level of antithrombin III decreases in septic
patients. Fourrier et al.92 conducted a double-blind trial with 35 patients in septic
shock and documented DIC. Patients received either placebo or antithrombin III
(90–120 U/kg bolus and later 90–120 U/kg per day for 4 days). Although a reduc-
tion in mortality was found in favor of antithrombin group, the difference was
not statistically significant. Levels of antithrombin definitely were improved in
the antithrombin group, affecting levels of protein C and S. The authors suggested
that further studies should be done, probably with a greater number of patients.
Other double-blind trials with 34, 45, and 42 patients, respectively, found no
benefit either.93,94 In a later trial with 120 patients, Baudo et al.95 found a decrease
in mortality in patients treated with antithrombin in septic shock with a significant
statistical difference with respect to the placebo group. Finally, the trial of Warren
et al.,96 a prospective, randomized, double-blind trial with more than 2,000
patients, showed no improvement in survival after using antithrombin over 96 h
in patients, with severe sepsis and septic shock.
In conclusion, the use of antithrombin in sepsis is still debated, and despite a
decrease in DIC, has not consistently demonstrated a decrease in mortality.
Tissue Factor Pathway Inhibitor (TFPI)
Animal models have demonstrated that infusion of recombinant TFPI improved
the prognosis of sepsis induced by E. coli. Trials in human have not demonstrated
benefits to decrease mortality as was demonstrated by Abraham et al.97 They
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M. Granados
conducted a prospective, randomized, double-blind placebo controlled trial of
1,955 patients with severe sepsis with TFPI without improvement in mortality.
Protein C
Depletion of protein C is associated with a variety of critical illnesses including
sepsis. Lower levels are related to a worse prognosis. However, the question is:
Will the prognosis of the patients change by replenishing the level of protein C?
Lorente et al.98 researched the course of clotting abnormalities and the fibrinolytic
system in relation to patients with septic shock. The study included 48 patients,
of which 25 died. On days 1, 4, and 7 after admission, levels of protein C, S,
antithrombin, thrombin-antithrombin complex (TAT), dimer D, von Willebrand
related antigen, tPA-like activator antigen, uPA-like activator antigen, tPA inhibi-
tor antigen, plasminogen, alpha-2 antiplasmin, and fibrinogen were tested. They
proved alterations in both pathways of coagulation. All patients had low levels
of protein C, antithrombin, and TAT, especially those who did not survive.
Recently, Mesters et al.99 did a trial researching the prognostic value of activated
protein C and dimer D in 26 high-risk patients developing sepsis by neutropenia
induced by chemotherapy. They concluded that low levels of protein C could be
identified sooner in these patients and they speculate that replenishing protein C
could be beneficial. Ohishi et al.100 demonstrated that adding protein C to depleted
plasma slowed down the formation of fibrin, which would decrease intravascular
clotting. The latest double-blind trial named “Prowess Trial” conducted by
Bernard et al.101 included 1,690 septic patients who were randomized to receive
24 μg/kg/h of activated protein C (drotrecogin alpha) or placebo for 96 hours.
This showed a significant reduction of mortality (24.7% vs. 30.8%). Evidence up
to now indicates that the use of protein C in septic patients decreases mortality
but increases the risk of bleeding.
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10
Vasopressors in Sepsis: Do They
Change the Outcome?
Marco A. González and Cristhiaan D. Ochoa
Sepsis is the second most common disease in the intensive care unit (ICU), with
a mortality rate between 32% and 60%. The major cause of death among these
patients is multiorgan failure syndrome (MOFS), which takes place after a period
of systemic and regional hypoperfusion that keeps active the systemic inflamma-
tory and antiinflammatory systems.1,2
This hypoperfusion is caused by either an endothelial inflammatory process or
by a systemic vasodilatation in response to (1) nitric oxide (NO) production by
the inducible form of NO synthase (iNOS); (2) the ATP-dependent activation of
a potassium (K+) channel; or (3) insufficiency of vasopressin, as a consequence
of depletion of its stores.3 If this inflammatory process continues, it could lead
to a refractory vasodilatation, which is manifested by systemic hypotension, a
decrease in mixed venous oxygen saturation, lactic acidosis, bases deficit, and
clinical manifestations of organ hypoperfusion.
Besides targeting the underlying pathogen disease, the main goal should be
centered on aggressive resuscitation, an immunological intervention with current
therapies (i.e., activated protein C), optimal control of glycemia, and the diagnosis
and treatment of adrenal gland failure.4
Every treatment that has had a positive impact on the mortality of septic
patients used vasopressors; the most frequently used are noradrenaline, followed
by dobutamine, dopamine, and adrenaline.5–7 These medications are coadjuvants
in the treatment to maintain vascular tone, preventing vasodilatation and hypoten-
sion, which would contribute to multiorgan hypoperfusion.
The fluid status must be aggressively corrected in a shock patient while imple-
menting the antibiotic therapy and treating the infection. This adjustment should
be directed by a pulmonary artery catheter. After the volume status is corrected
the vasopressor that will be used should be selected. Options available are dobu-
tamine, dopamine, noradrenaline, adrenaline, and vasopressin.
The surviving sepsis guidelines for management of severe sepsis and septic
shock recommend inotropes and vasopressors with little scientific evidence;
however, in their daily practice intensivists use them to improve blood pressure
measurements of patients in septic shock.8 The question then is: Which vasoactive
should be used in order to have a positive impact on patient survival and to
prevent deleterious effects?
121
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M.A. González and C.D. Ochoa
The answer is still open to discussion since the experience that an intensivist
has with these types of patients is still the prevailing factor for selecting vasopres-
sors. The authors’ group, in particular, has decided that after achieving an ade-
quate volume status, noradrenaline is the first-line vasopressor to use. The
justification for this choice is explained below.
Noradrenaline
Noradrenaline (NE) constitutes 10% to 20% of suprarenal gland medulla cate-
cholamines; the difference with adrenaline centers in the lack of a methyl substi-
tute in the amine group. It has less adverse effects than adrenaline and it activates
α-adrenergic postsynaptic receptors 1 and 2 (α-1 and α-2), leading to vasocon-
striction. Additionally, it has a beta 1 (β-1) inotropic action. The pulmonary artery
vasoconstrictor effect is not important (an average of 5 to 10 torr increase), which
is why it could be used if heart failure is present in septic patients.9 Furthermore,
its vasoconstrictory effects do not affect the splanchnic bed flow as it is shown
in a large animal experiment by Bellomo and Giantomasso in which they docu-
mented that noradrenaline infusion increased blood flow in the splanchnic,
hepatic, and renal beds.10
NE dosage varies; it could be started as low as 0.05 μg/kg/min and may be
increased until reaching the goal preferred by the physician. Doses as high as
3.3 μg/kg/min have been described, but this is extremely rare in everyday practice
and could lead to a vasoconstrictor effect in peripheral beds, resulting in distal
necrosis.2
There is increasing evidence in the literature showing the benefits of NE in
comparison to other vasopressors. Martin et al. compared two groups of patients:
one received dopamine plus NE and the other received adrenaline and dopamine.
He clearly showed that the group receiving NE had a higher survival rate.11
Bellomo and Giantomasso10 demonstrated that the mortality rate, based on the
Simplified Acute Physiology Scale (SAPS) II score, of patients receiving NE was
lower than patients on adrenaline. The average dose received by the former group
was 0.86 μg/kg/min. The average infusion time was 88 hours. These studies
support the authors’ recommendation for using NE as the first-line vasopressor
in patients with refractory septic shock.12
Dobutamine
Dobutamine is a synthetic catecholamine with beta-1 and beta-2 (β-1; β-2)
activity. Dobutamine has less adverse effects that dopamine. The author’s group
uses it in combination with NE either when the resuscitation endpoints are not
reached or when the attending physician desires a higher cardiac index. The dose
utilized is 5 to 15 μg/kg/min. The pharmacological effect starts a few minutes
after the IV infusion and ends when the delivery is stopped.8
10. Vasopressors in Sepsis
123
Dobutamine has a coadjuvant role with the vasopressors in septic shock treat-
ment. The final goal of this mixture is to improve the cardiac index and mixed
venous oxygen saturation. Dobutamine has a chronotropic effect in addition to its
inotropic one, both of which could improve the systolic performance of a septic
heart. However, when the heart rate is disproportionately high, it increases the
systemic vasodilation, worsening the hypotension.8 Dobutamine improves cardiac
index and reduces pulmonary vascular resistance in patients with sepsis. These
effects restore the right heart contractility and increase splanchnic blood flow.
There are no studies showing improvement in mortality rates when dobutamine
was used in septic patients, but it was used by Rivers et al. in their classic paper
to achieve a higher mixed venous oxygen saturation endpoint after utilizing
intravenous fluids and vasopressors.5
Dopamine
Dopamine is the most popular catecholamine used in septic shock after adrena-
line. Its activity spectrum encompasses, depending upon the dosage, alpha, beta,
and dopa receptors. Vincent recommended dopamine as the first-line vasopressor
for septic shock in 2001.13 Dopaminergic effects that favor renal blood flow, with
low doses of 5 μg/kg/min and below, have been described. Unfortunately, an
Australian randomized, double-blind clinical trial showed that this catecholamine
did not prevent renal failure in septic shock patients.14 Subsequently, a metaanaly-
sis published in 2001 reported that there is no evidence to support its use in septic
shock.15 The surviving sepsis guidelines do not support dopamine as a renal pro-
tective agent. Dopamine has a grade-B evidence-based recommendation.8
The beta-1 stimulatory effect is reached with doses within the 5- to 10-μg/mL/
min range. At this point inotropic and chronotropic effects are both favored. This,
however, has deleterious consequences such as the increase in myocardium
oxygen consumption.16
In addition to its chronotropic effects, dopamine has immunologic and metabolic
effects. It diminishes cyclic adenosine monophosphate (cAMP) and inhibits prolif-
eration in lymphocytes, as well as immunoglobulins, cytokines, growth hormone,
and thyroid-stimulating hormone (TSH) production. It has been reported that dopa-
mine allows lymphocyte apoptosis. A number of studies have reported intestinal
ischemia as a consequence of dopamine infusions at different dosages.17
Vasopressin
Vasopressin (VP) levels are usually low in the late phase of septic shock. This
contributes to the refractory status of some vasodilatory shock. VP has anti-
diuretic effects when it binds V2 receptors in renal tubules; it also results in
vasoconstriction when it acts on V1 receptors present in vascular smooth muscle
cells.18
124
M.A. González and C.D. Ochoa
VP blocks directly ATP-dependent K+ channels in vascular smooth muscle
cells, preventing the vasodilatory status from continuing in septic shock. It also
blunts the cyclic guanosine monophosphate (cGMP) receptors’ response to nitric
oxide and atrial natriuretic peptide. The dosage for refractory hypotension due to
septic shock is 0.01 to 0.04 U/min. Larger doses show no benefit and may lead
to adverse effects.18–20
Laudry’s studies3 demonstrated that at this dosage, VP increases arterial
pressure, renal blood flow, and diuresis, but it did not increase the cardiac index.
There are no studies to report an increase in survival in septic patie nts treated
with VP.
Conclusion
The final event in septic shock is multiorgan failure syndrome as a consequence
of hypoperfusion resulting from a late, refractory vasodilatory shock. Before
starting vasoactive agents, the underlying infectious disease must be under treat-
ment, the volume status aggressively corrected, the immunomodulatory therapy
started, and adrenal gland failure ruled out. NE is the vasoactive agent with the
best results in refractory shock, and it is probably the vasoconstrictor that most
improves mortality in septic patients. VP levels are depleted in the late phase of
septic shock. If the patient is hypotensive, even though vasoactive agents and
inotropes are used, VP should be started at low doses.
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States from 1979 through 2000. N Engl J Med 2003;348(16):1546–54.
3. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med
2001;345(8):588–95.
4. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med
2003;348(2):138–50.
5. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of
severe sepsis and septic shock. N Engl J Med 2001;345(19):1368–77.
6. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of
hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA
2002;288(7):862–71.
7. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Engl J Med 2001;344(10):699–709.
8. Dellinger RP, Carlet JM, Masur H, et al. Surviving Sepsis Campaign guidelines for
management of severe sepsis and septic shock. Crit Care Med 2004;32(3):858–73.
9. Sharma VK, Dellinger RP, SCCM. International Sepsis Forum. The International
Sepsis Forum’s controversies in sepsis: my initial vasopressor agent in septic shock
is norepinephrine rather than dopamine. Crit Care 2003;7(1):3–5.
10. Vasopressors in Sepsis
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10. Bellomo R, Giantomasso DD. Noradrenaline and the kidney: friends or foes? Crit
Care 2001;5(6):294–8.
11. Martin C, Viviand X, Leone M, et al. Effect of norepinephrine on the outcome of
septic shock. Crit Care Med 2000;28(8):2758–65.
12. Morimatsu H, Singh K, Uchino S, et al. Early and exclusive use of norepinephrine in
septic shock. Resuscitation 2004;62(2):249–54.
13. Vincent JL, International Sepsis Forum. Hemodynamic support in septic shock. Inten-
sive Care Med 2001;27 Suppl 1:S80–92.
14. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early
renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand
Intensive Care Society (ANZICS) Clinical Trials Group. Lancet 2000;356(9248):
2139–43.
15. Kellum JA, M Decker J. Use of dopamine in acute renal failure: a meta-analysis. Crit
Care Med 2001;29(8):1526–31.
16. De Backer D, Creteur J, Silva E, et al. Effects of dopamine, norepinephrine, and epi-
nephrine on the splanchnic circulation in septic shock: which is best? Crit Care Med
2003;31(6):1659–67.
17. Asfar P, De Backer D, Meier-Hellmann A, et al. Clinical review: influence of vasoac-
tive and other therapies on intestinal and hepatic circulations in patients with septic
shock. Crit Care 2004;8(3):170–9.
18. Holmes CL, Patel BM, Russell JA, et al. Physiology of vasopressin relevant to man-
agement of septic shock. Chest 2001;120(3):989–1002.
19. Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on hemody-
namics and renal function in severe septic shock: a case series. Intensive Care Med
2001;27(8):1416–21.
20. Patel BM, Chittock DR, Russell JA, et al. Beneficial effects of short-term vasopressin
infusion during severe septic shock. Anesthesiology 2002;96(3):576–82.
11
Lactic Acidosis in Critically Ill
Septic Patients
Daniel De Backer
Introduction
Lactic acidosis is often observed in patients with septic shock and is undoubtedly
a sign of severity. Several animal studies have reported that lactic acidosis is
associated with tissue hypoxia that can be global but also sometimes more focal.
The hypoxic origin of lactic acidosis is more difficult to demonstrate in humans.
Although some studies have reported that lactate to pyruvate ratio may be ele-
vated, this is not always the case. In septic patients, and especially after hemo-
dynamic stabilization, lactic acidosis may be related to other factors including an
increased glycolysis (maybe under the influence of the activation of the Na/K
ATPase transporter), the inhibition of pyruvate dehydrogenase, and a decrease in
lactate clearance. Some organs produce lactate in larger amounts than others; in
particular, the gut and the lungs can markedly contribute to the sepsis-induced
hyperlactatemia. However, the net splanchnic lactate release is uncommon, as the
liver is usually able to consume large amounts of lactate unless it also becomes
hypoxic. Whatever its cause (hypoxic or not), lactic acidosis is associated with a
poor outcome. There is no specific therapy for lactic acidosis, but early recogni-
tion of lactic acidosis is mandatory as it allows the provision of early interventions
that can be lifesaving.
Patients with sepsis often present severe hemodynamic alterations, which
include myocardial depression, severe vasoplegia, regional blood flow redistribu-
tion, and microcirculatory alterations. These may be associated with a decrease
in oxygen availability to the tissues and ongoing tissue hypoxia, which can lead
to the development of multiple organ failure. Hence, the detection of tissue
hypoxia is essential to avoid the evolution to organ failure. Unfortunately, the
detection of tissue hypoxia is difficult at the bedside. In sepsis, the oxygen
demand can be elevated above the oxygen supply. Furthermore, an alteration in
oxygen extraction capabilities by the tissues can limit their oxygen consumption.
On the other hand, some tissues can decrease their metabolic needs to adapt to
the decreased oxygen availability (oxygen conformance). Thus the interpretation
of the classical hemodynamic parameters including cardiac output, oxygen deliv-
ery, oxygen consumption, and mixed-venous oxygen saturation can have serious
126
11. Lactic Acidosis in Critically Ill Septic Patients
127
limitations in this context. Measurements of blood lactate levels may be useful
to detect occult tissue hypoxia and also to monitor the effects of therapy. Lactic
acidosis is commonly observed in patients with severe sepsis and septic shock.
Although hyperlactatemia is often considered as a hallmark of ongoing tissue
hypoxia, this is not always the case, so erroneous conclusions may sometimes be
drawn leading to unjustified therapeutic interventions.
Lactate Metabolism
Glycolysis produces adenosine triphosphate (ATP), which is the source of energy
for cellular metabolism. First, one molecule of glucose is transformed into two
molecules of pyruvate, generating two molecules of ATP. This reaction occurs in
the cytoplasm of the cells and does not require the presence of oxygen. In the
second phase, which takes place in the mitochondria and requires oxygen, pyru-
vate enters the Krebs cycle generating CO2, H2O, and 18 ATP molecules (per
molecule of pyruvate). In normal conditions, a small amount of pyruvate is trans-
formed into lactate, generating two molecules of ATP for one molecule of pyru-
vate. Lactate can be retransformed in pyruvate in the liver and in the muscle (and
brain) using four molecules of ATP. Pyruvate is preferentially incorporated in the
Krebs cycle resulting in a 10 : 1 lactate to pyruvate ratio in normal conditions. In
the absence of oxygen, pyruvate cannot enter the Krebs cycle and is preferentially
transformed into lactate in order to maintain ATP production, even though this
metabolic pathway is less efficient. In some cells that do not have mitochondria,
such as red blood cells, large amounts will be produced even if oxygen is abun-
dant; however, lactate is rapidly cleared by the other organs. In anaerobic condi-
tions, lactate is produced in large amounts and pyruvate is rapidly consumed so
the lactate to pyruvate ratio increases. Ideally pyruvate measurements should be
obtained to separate hypoxic from nonhypoxic causes of lactate production;
unfortunately, pyruvate measurements are difficult to obtain and frequently un-
reliable in clinical practice.
Lactic Acidosis versus Hyperlactatemia?
The transformation of pyruvate into lactate produces equimolar amounts of H+.
In addition, H+ is also produced by the hydrolysis of ATP, and H+ molecules
accumulate as they are no longer used by cytochromes in hypoxic conditions.
This usually results in metabolic acidosis. However, arterial pH can be affected
in septic patients by many factors such as hyperventilation, administration of
bicarbonate (i.e., in continuous hemofiltration), concomitant renal failure, pre-
existing acid base disorders (such as metabolic alkalosis in a chronic obstructure
pulmonary disease (COPD) patient or due to abundant gastric losses), and
decreased albumin levels. Accordingly, hyperlactatemia and lactic acidosis may
be dissociated, especially in the less severe cases. On the other hand, septic
128
D. De Backer
patients can also present metabolic acidosis unrelated to tissue hypoxia (such as
in renal failure or hyperchloremia) and a concomitant hyperlactatemia. Hence,
metabolic acidosis may clearly be dissociated from hyperlactatemia.
Evidence for Hypoxic Origin of Lactate in Sepsis
Proof of the anaerobic generation of lactate is difficult to obtain in clinical condi-
tions. In experimental models of endotoxic shock, blood lactate concentrations
rise when oxygen consumption becomes dependent on oxygen delivery (VO2/
DO2 dependency), suggesting an anaerobic origin.1,2 In septic animals, the increase
in blood lactate levels was associated with a decrease in muscle3–5 and liver6 bio-
energetic status.
In septic patients, hyperlactatemia can also be observed, even when flow is
maintained. The hypoxic origin of the sepsis-induced hyperlactatemia is less
clear. In patients with acute circulatory failure who are treated with high doses
of vasoactive agents, there is a strong suspicion that hyperlactatemia is related to
tissue hypoxia.7–9 Levy et al.9 observed that hyperlactatemia was associated with
signs of anaerobic metabolism, as an increased lactate to pyruvate ratio and
decreased arterial ketone body ratio. In these patients, hyperlactatemia is often,
but not always, associated with metabolic acidosis. However, tissue hypoxia and
anaerobic metabolism cannot be sustained for long periods of time, as the energy
produced by anaerobic metabolism is quite low compared to aerobic metabolism.
Hence, it is unlikely that a mild hyperlactatemia (2 to 4 mEq/L) in hemodynami-
cally stable septic patients is related to tissue hypoxia.
Alternative Causes of Hyperlactatemia in Sepsis
Lactate can also be produced in increased amounts even in the presence of
oxygen. This may be due either to inhibition of several enzymes of the Krebs
cycle or to a massive production of pyruvate. Several experimental studies,
mainly in rodents, have reported that pyruvate dehydrogenase, an enzyme essen-
tial for the incorporation of pyruvate into the Krebs cycle, is inhibited after
endotoxin administration or cecal ligation.10,11 However, the impact of pyruvate
dehydrogenase inhibition in septic patients remains to be determined. In a ran-
domized study including 252 critically ill patients with lactic acidosis, Stacpoole
et al.12 observed that the administration of dichloroacetate, which stimulates the
oxidation of lactate to acetyl-coenzyme A, bypassing the pyruvate dehydroge-
nase, resulted in small and clinically insignificant changes in blood lactate levels
and arterial pH, while the hemodynamic state and outcome were unaffected. As
pyruvate dehydrogenase is an essential enzyme of the Krebs cycle, its inhibition
is a form of tissue hypoxia (cytopathic hypoxia), which, of course, cannot be
sustained for a long period of time without generating serious tissue damage.
11. Lactic Acidosis in Critically Ill Septic Patients
129
Another, and probably more important, effect is related to the mass effect of
increased pyruvate availability due to the acceleration of aerobic glycolysis in
sepsis. In hemodynamically stable septic patients with hyperlactatemia, Gore
et al.13 reported that lactate and pyruvate were both markedly increased. They
related this increase in lactate and pyruvate to an accelerated glucose turnover,
as glucose production was fourfold higher in septic patients compared to healthy
volunteers. Tissue hypoxia was not involved in these patients as pyruvate oxida-
tion was also fourfold higher than in healthy volunteers. It is likely that glycolysis
is increased in order to provide ATP to the Na/K ATPase ion exchanger14,15 that
is highly stimulated by endotoxin,16 catecholamines,17 and insulin.18 The implica-
tion of this exchanger is further highlighted by the fact that ouabain inhibits Na/K
ATPase and decreases muscle lactate production.15 Nevertheless, other experi-
mental models found that Na/K ATPase was reduced19 rather than increased;
hence its contribution is still hypothetical.
What are the clinical implications of glycolysis-induced hyperlactatemia? This
may be considered on one hand as a futile reaction, leading to the dissipation of
energy stores,20 but on the other hand some investigators consider that this may
be an adaptative phenomenon leading to increased energy production.21 This is
highlighted by the finding that white blood cells produce large amounts in lactate
in response to endotoxin exposure.22 In these cells, a very limited part of the ATP
production is of mitochondrial origin, and anaerobic glycolysis provides most of
the extra energy requirements for the activated white blood cells, which is associ-
ate with the release of large amounts of lactate. Although generated by anaerobic
metabolism, this increase in lactate production is not due to O2 deprivation.
Another possibility is that the increased glycolysis, which may affect both aerobic
and anaerobic glycolysis, may compensate for the impaired mithochondrial func-
tion.21 However, these observations do not imply a causal link, as coenzyme Q10,
which restored cytochrome function, was unable to restore glycolytic function.23
Hence, it is difficult to differentiate between these various possibilities.
On the other hand, lactate clearance may also be altered in sepsis. Blood lactate
concentrations are the result of the balance between lactate production, whatever
its cause and source, and lactate clearance. In normal conditions, at rest, the
liver accounts for more than half of lactate clearance, and kidneys and muscles
account for the remaining part. In sepsis, various factors may influence hepatic
lactate clearance, especially liver function and liver blood flow. Extreme condi-
tions of pH can also decrease lactate clearance. Renal lactate clearance is also
decreased as it occurs in the renal cortex, and this area is very sensitive to a
reduction in blood flow. In addition, striated muscle often fails to metabolize
lactate.
Using an external lactate load in hemodynamically stable septic patients,
Levraut et al.24 reported that lactate clearance was markedly altered in patients
with mildly elevated blood lactate levels (2 to 4 mEq/L) but not in patients with
normal blood lactate concentrations. Levraut et al. recently extended these find-
ings and reported that a low lactate clearance was associated with an impaired
outcome.25
130
D. De Backer
However, the role of the decreased lactate clearance needs to be somewhat
challenged. First, blood lactate concentrations are within normal values in patients
with very severely impaired liver function such as in ambulatory cirrhotic patients.
Hence, an increased blood lactate concentration suggests that lactate is actively,
or has been recently, produced in increased amounts; the impairment in liver
function can only be responsible for a delayed clearance, resulting in a more
severe and especially more prolonged hyperlactatemia. Second, all the above
causes of hyperlactatemia (hypoxia, increased glycolysis, inflammatory pro-
cesses) are associated with increased lactate production. Third, the methodology
of determination of lactate production is complicated and requires a steady state,
which may not be easily achieved in critically ill septic patients. Accordingly, it
is quite clear that lactate clearance is delayed in patients with septic shock, but
this alone cannot explain blood lactate levels. Rapidly increasing blood lactate
levels always represent increased lactate production, which may or may not be
of hypoxic origin.
Regional Lactate Production
The production of lactate may be selectively increased in some organs, either as
a result of regional blood flow alterations leading to local hypoxia or as a result
of focal inflammation. Animal studies have reported that the lungs are major
lactate producers in sepsis. In endotoxic dogs, Bellomo et al.26 reported that the
lungs released lactate while other organs still consumed lactate. In patients with
acute lung injury, several groups have reported that lung lactate production is
markedly increased. The lungs can produce tremendous amounts of lactate in
acute lung injury. De Backer et al.27 measured lung lactate production in critically
ill patients with acute respiratory failure of various origins and reported that
lactate production by the lungs necessitates the presence of an inflammatory
process (infection is not a prerequisite) that has to be severe (direct relationship
with the severity of the lung disease) and diffuse (absence of lactate production
in localized forms of lung disease).
Other organs can also produce lactate. Experimental studies suggest that the
gut can produce lactate, which is likely to be of hypoxic origin as indicated by
the increased portal lactate to pyruvate ratio.28 However, the liver is usually able
to clear this small amount of lactate produced by the gut, so there is no net lactate
release by the splanchnic area. Creteur et al.29 recently demonstrated that splanch-
nic lactate release occurred only when the liver is hypoxic, as indicated by a
decrease in oxygen delivery below liver critical oxygen delivery. In 90 patients
with severe sepsis, De Backer et al.30 reported that splanchnic lactate release was
uncommon (it occurred in only six patients) and was not related to arterial lactate
concentrations, abdominal infection, or indirect signs of gut or liver dysoxia
(estimated by gastric mucosal to arterial PCO2 gradient and mixed venous to
hepatic venous O2 saturation gradient). However, we cannot rule out that the gut
still produced lactate in some of these patients.
11. Lactic Acidosis in Critically Ill Septic Patients
131
Finally, any infected or inflamed organ can probably release lactate. We men-
tioned above the role of white blood cells, which, when activated, can produce
large amounts of lactate.22 Although generated by anaerobic metabolism, this
increase in lactate production is not due to O2 deprivation. Hence, large amounts
of lactate can be produced in inflammatory processes even in the absence of tissue
hypoxia.
Interpretation of Blood Lactate Concentrations
Increased blood lactate can only be caused by increased anaerobic or aerobic
lactate production, eventually combined with decreased lactate clearance (Figure
11.1). Tissue hypoxia should always be excluded first, as persistent tissue hypoxia
can lead to multiple organ failure and death. Tissue hypoxia can be global but
can also be localized, and special attention should be posted on regional circula-
tions. Sometimes tissue hypoxia can be due to mitochondrial impairment, such
as in cytopathic hypoxia.31,32 Aerobic lactate production, either global or focal
(especially in the lungs), is the result of activation of the inflammation cascade.
In this context, hyperlactatemia should be considered as a warning indicator of
Figure 11.1. Interpretation of hyperlactatemia. Blood lactate concentrations reflect the
balance between lactate production, either anaerobic, mainly in tissue hypoxia, or aerobic,
as a consequence of the sum of the endogenous basal lactate production and the additional
lactate production under the influence of overwhelming inflammation, and lactate clear-
ance, mainly by the liver. WBC, white blood cells. Source: De Backer.41
132
D. De Backer
a very severe inflammatory state, and one should always review the patient in
order to ensure that no focus of infection remains uncovered.
When an altered lactate clearance is involved, it can of course be due to an
altered liver metabolism, usually insensitive to hemodynamic manipulations, but
also to a decreased perfusion of the liver, which can be improved by hemody-
namic interventions.33
Prognostic Value
Lactic acidosis is associated with impaired survival, whatever its source. Several
studies have reported that admission blood lactate levels are strongly associated
with outcome.34,35 This relationship is not linear but rather sigmoidal, with values
below 2 mEq/L associated with nearly 100% survival, values between 4 and
5 mEq/L with 50% survival, and values above 10 mEq/L with lower than 50%
survival rates.36 Interestingly, the prognostic value was better for lactate than for
pyruvate or the lactate to pyruvate ratio, suggesting that the prognostic value is
not related to tissue hypoxia alone. The prognostic value can be even more accu-
rate when the evolution of blood lactate concentrations under the influence of
therapeutic interventions is taken into account. A decrease in blood lactate levels
and a smaller area under the curve during the first 24 h are associated with a better
outcome.37 In addition, persistent hyperlactatemia and increasing lactate levels
are associated with a worse outcome.
Treatment of Lactic Acidosis
There is no specific therapy for lactic acidosis; the only treatment will be treat-
ment of the underlying cause. Nevertheless, early recognition of hyperlactatemia
is essential, as early interventions targeted on hemodynamic endpoints can
decrease mortality in patients with severe sepsis and elevated blood lactate
levels.38 However, it has not been proven that specific interventions targeted to
normalize blood lactate concentrations can improve outcome.
Apart from the hemodynamic optimization in case of global or focal tissue
hypoxia, treatment of lactic acidosis is quite disappointing. In particular the
treatment of glycolitic disorders may not be beneficial. Treatment of pyruvate
dehydrogenase inhibition with dichloroacetate failed to improve the outcome
of septic patients.12 Some authors have suggest that beta-blocking agents
could be used to counteract the stimulation of the Na/K ATPase by catechol-
amines.17 Although this therapy might be considered in hemodynamically stable
septic patients, this treatment is clearly contraindicated in patients with septic
shock.
Finally, the correction of acidosis with bicarbonate is clearly not
indicated: bicarbonate administration can be either ineffective39 or even
deleterious.40
11. Lactic Acidosis in Critically Ill Septic Patients
133
Conclusion
Lactic acidosis is frequent in patients with septic shock and is associated with an
impaired outcome. Measurements of blood lactate concentrations are useful to
detect occult tissue hypoxia and to monitor the effects of therapy. Even though
hyperlactatemia can be due to other causes than tissue hypoxia, and in particular
to inflammatory processes so that hemodynamic interventions may not always be
warranted, the rapid recognition of lactic acidosis is essential as it allows the
provision of early interventions that can be lifesaving.
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12
Delirium in Septic Patients: An
Unrecognized Vital Organ Dysfunction
Timothy D. Girard and E. Wesley Ely
Introduction
Acute organ dysfunction is a defining feature of severe sepsis,1 with respiratory,
cardiovascular, and renal failure recognized in 46%, 24%, and 22% of patients
with severe sepsis, respectively.2 Acute brain dysfunction is much less frequently
diagnosed.3 Using ICD-9 codes for encephalopathy, transient organic psychosis,
and anoxic brain damage, Angus et al. found that acute central nervous system
(CNS) dysfunction was only reported in 9.3% of severe sepsis cases.2 Despite
these low documentation rates, it has long been recognized that delirium occurs
frequently in patients with severe sepsis. The previously common labels for
delirium in intensive care unit (ICU) patients—“ICU psychosis” and “ICU
syndrome”—are misnomers, implying that this syndrome is an expected, incon-
sequential outcome of intensive care.4 In fact, recent studies have revealed that
delirium in septic patients is both common and deleterious, and it can no longer
be regarded as simply a bothersome facet of an ICU stay. Instead, delirium rep-
resents the clinical manifestation of acute CNS dysfunction, independently con-
ferring increased risk for morbidity and mortality in patients with severe sepsis
even after considering coma.
Historical Perspectives on Delirium in Septic Patients
The association between infection and altered mental status was noted as early
as Hippocrates, who described patients with fever, abscesses, and “phrenitis.”5,6
Other notable physicians who recorded this observation included Galen6 and,
much later, Sir William Osler.7 In the past 25 years, several investigators have
worked to understand the mechanisms leading to CNS dysfunction in sepsis (see
Table 12.1).8–14 However, the clinical and pathological features of this syndrome
were not systematically studied until Jackson et al. published observations from
an autopsy series of 12 patients with “the encephalopathy of sepsis.”15 They
noted that the level of consciousness in these patients varied and coma was fre-
quent, computed tomographic head scans and cerebrospinal fluid examinations
136
12. Delirium in Septic Patients
137
Table 12.1. Early Clinical Investigations of Delirium in Patients with Severe Sepsis
Source/Ref.
Year
Pts.
Findings
Freund et al.8
1978
5 Reversal of CNS dysfunction occurred with BCAA treatment
Jackson et al.15
1985
12 Described clinical and pathologic features of delirium in septic pts.
1989
9 Cerebral blood flow was reduced in septic pts.
Bowton et al.12
Young et al.17
1990
69 Brain dysfunction occurred in 49 (71%) septic pts.
Sprung et al.16
1990 1333 Acutely altered mental status occurred in 307 (23%) of septic pts.
84 Hypotension was a significant predictor of delirium in septic pts.
Wijdicks et al.13 1992
Young et al.14
1992
62 Described the EEG findings that occur in septic pts. with delirium
1993 1758 Neurologic complications occurred in 217 (12%) medical ICU pts.
Bleck et al.18
Eidelman et al.19 1996
50 CNS dysfunction can be characterized by GCS
Note: Pts., patients; CNS, central nervous system; BCAA, branched chain amino acids; EEG,
electroencephalogram; ICU, intensive care unit; GCS, Glasgow Coma Scale.
were usually normal, and electroencephalograms (EEGs) revealed diffuse
abnormalities.
Several early studies evaluated the prevalence of delirium in septic patients.
Pine et al. evaluated 106 surgical patients with abdominal sepsis and found that
10 (9%) had CNS dysfunction, defined as inability to follow simple commands.3
Sprung et al. later published data from the large Veterans Administration Systemic
Sepsis Cooperative Study showing that 307 (23%) of the 1,333 septic patients
studied exhibited an acutely altered mental status.16 The same year Young et al.
reported that 49 (71%) of 69 patients with sepsis developed mild (17 patients) or
marked (32 patients) brain dysfunction.17 Bleck et al. evaluated 1,758 medical
ICU patients and reported that 217 (12%) patients developed neurologic com-
plications.18 Of these complications, metabolic encephalopathy was the most
common, and sepsis was the most frequent cause of encephalopathy. Lastly,
Eidelman et al. classified CNS dysfunction in septic patients by three different
methods and found that the prevalence ranged from 50% to 62% depending upon
the method of diagnosis.19
These and more recent studies have firmly established delirium as a common
clinical syndrome resulting from one or more etiologic processes.15 It is a rare
patient with severe sepsis who demonstrates no risk factor for delirium other than
infection and its associated inflammatory state. Instead, these critically ill patients
are subjected to multiple host, iatrogenic, and environmental factors, making it
difficult to attribute their delirium simply to sepsis alone. Therefore, the term
“septic encephalopathy” is now discouraged20; “delirium” more appropriately
describes the acute confusional state seen in patients with severe sepsis.
Pathogenesis of Delirium in Septic Patients
The pathogenesis of delirium in septic patients remains unclear and is likely
multifactorial.6 Multiple hypotheses exist and animal models have been devel-
oped that lend support to each. Early work documented the presence of dissemi-
nated microabscesses in the brains of some patients who had died of sepsis,
138
T.D. Girard and E.W. Ely
suggesting that infectious organisms may directly cause CNS dysfunction.11,15
However, other studies have failed to confirm these findings.18 More likely to be
of pathophysiologic importance are the profound inflammatory and coagulopathic
disturbances that are nearly universal in patients with sepsis. We will now outline
these briefly, acknowledging that a detailed review is beyond the scope of this
chapter.
The inflammatory mediators produced in sepsis—tumor necrosis factor-alpha
(TNF-α), interleukin-1 (IL-1), and other cytokines and chemokines—initiate a
cascade that leads to endothelial damage, thrombin formation, and microvascular
compromise.21 Animal models reveal that these inflammatory mediators cross the
blood-brain barrier,22 increase vascular permeability in the brain,23 and result in
EEG changes consistent with those seen in septic patients with delirium.6,24 This
may occur due to decreased cerebral blood flow, a result of the formation of
microaggregates of fibrin, platelets, neutrophils, and erythrocytes in the cerebral
microvasculature; as well as cerebral vasoconstriction occurring in response to
α1-adrenoceptor activity25; or due to interference with neurotransmitter synthesis
and neurotransmission.26
Additional potentially important etiologies of delirium in septic patients are
abnormalities in neurotransmitter levels. For example, acetylcholine depletion is
thought to be central to the pathophysiology of delirium. Inflammatory cytokines
as well as tissue hypoxia and hypoglycemia lead to reduced acetylcholine syn-
thesis resulting in delirium and cognitive impairment.26 Thus, there is a clear
association between anticholinergic drugs and the development of delirium. In
addition, the monoaminergic neurotransmitters are disturbed in delirium, with
increased dopaminergic release (i.e., dopamine excess) and neurotransmission
leading to psychotic symptoms. The deliriogenic effects of narcotics may be
mediated by their anticholinergic or dopaminergic properties while antipsychotics
such as haloperidol likely exert their treatment effects by increasing acetylcholine
and blocking dopamine.
Defining Delirium and Its Motoric Subtypes
The word “delirium” finds it root in the Latin word deliro, meaning “to be crazy,
deranged, or silly.” (The Latin word liro is an agricultural term meaning to
“plough correctly, in a straight line,” while deliro means to “plough out of your
furrow” like a madman.) Although the medical community has historically
reserved “delirium” to describe agitated, confused patients and has used “enceph-
alopathy” to describe lethargic, confused patients, the Diagnostic and Statistical
Manual of Mental Disorders, 4th edition (DSM-IV),27 does not make this distinc-
tion. It defines delirium as a confusional state characterized by acute onset, fluc-
tuating level of consciousness, inattention, and disorganized thinking. Additionally,
disruption of the sleep-wake cycle and psychomotor disturbances (e.g., hallucina-
tions) are associated features of delirium, yet they are not required for its
diagnosis.
12. Delirium in Septic Patients
139
Multiple schema exist for subtyping delirium, including hyperactive versus
hypoactive, cortical versus subcortical, anterior versus posterior cortical, right
versus left hemispheric, psychotic versus nonpsychotic, and acute versus chronic.28
While each of these frameworks has utility when attempting to understand
the pathophysiology of delirium, the most clinically relevant and therefore most
commonly accepted schema is that of hyperactive versus hypoactive, with the
distinguishing feature being the level of motor activity observed. Patients with
hyperactive delirium demonstrate psychomotor agitation, semipurposeful activity,
and emotional lability, while those with hypoactive delirium demonstrate
decreased responsiveness and lethargy.29,30 Although certain etiologies are
commonly associated with a particular subtype of delirium (e.g., alcohol with-
drawal and anticholinergic toxicity tend to cause hyperactive delirium, whereas
hepatic insufficiency and traumatic brain injury tend to cause hypoactive
delirium),28 patients with severe sepsis frequently develop mixed delirium, exhib-
iting features of both hyperactive and hypoactive subtypes during the course of
their illness.
In a study of 325 noncritically ill inpatients, Liptzin et al. diagnosed 125 with
delirium and identified 15% with hyperactive, 19% with hypoactive, 52% with
mixed, and 14% with neither subtype of delirium.31 More recently, Peterson et al.
reported on delirium subtypes evaluated among 307 medical ICU patients.32
Persistently hyperactive delirium was uncommon in both mechanically ventilated
and nonventilated patients, hypoactive delirium was less common in ventilated
patients (51 vs. 67%, p = .02), and mixed delirium was more common in venti-
lated patients than in nonventilated patients (47% vs. 29%, p = .008). These dif-
ferences are notable in patients with severe sepsis, a population frequently
requiring mechanical ventilation, and they may have prognostic and therapeutic
implications, a subject of ongoing investigations.
Risk Factors for Delirium in the Septic Patient
Multiple risk factors for the development of delirium in septic patients have been
identified. Infection itself was the most common etiology associated with the
development of delirium noted by Francis et al. in a study of 229 hospitalized
elderly patients.33 Other independent risk factors noted by Francis et al. included
severity of illness, dementia, hypo- or hypernatremia, fever or hypothermia,
azotemia, and use of psychoactive drugs. It is important to note that the majority
of patients with severe sepsis are exposed to multiple risk factors for delirium,
and these factors act in a dose-dependent fashion with rates of delirium increasing
as the number of risk factors rises.33 In a study of 48 medical ICU patients, the
majority of patients experienced over 10 risk factors for delirium.34
Risk factors for delirium in hospitalized elderly patients have been extensively
studied35–40 and are frequently of significance in patients with severe sepsis (Table
12.2). These risk factors can be divided into three categories: (1) baseline char-
acteristics, (2) features of acute illness, and (3) environmental or iatrogenic
140
T.D. Girard and E.W. Ely
Table 12.2. Risk Factors for Delirium in Patients with Severe Sepsis
Baseline Characteristics/Ref. Features of Acute Illness/Ref.
Increasing age35,37 Infection33,35
Cognitive impairment33,35,37,40 Severity of illness33,36,40
Hearing or vision impairment36 Metabolic disturbances33,36,37
Alcohol abuse37,40 (e.g., Na, K, BUN,
Depression40 glucose)
Fever or hypothermia33
Hypotension13
Iatrogenic Factors/Ref.
Medications33 (e.g., narcotics,35,38
benozodiazepines38)
Immobilization39 (e.g., catheters,
restraints)
Note: Na, sodium; K, potassium; BUN, blood urea nitrogen.
factors. Such a schema allows for easy identification of those risk factors most
appropriate for prevention or intervention.
Of particular importance in ICU patients, exposure to psychoactive medica-
tions (e.g., narcotic analgesics, benzodiazepines or other sedative/hypnotics, and
anticholinergics) has been shown to be an independent risk factor for delirium in
multiple studies.33,35,38 In septic patients, it is likely that drugs, used to improve
patients’ tolerance of interventions and mechanical ventilation, both induce delir-
ium and serve as a marker for underlying organic brain dysfunction present in
these patients. Ongoing research is under way to answer important questions
regarding the relationship between psychoactive medications and delirium, long-
term cognitive impairment, and health-related quality of life.
Prognostic Significance of Delirium in the ICU
Despite previous misconceptions that confusion in ICU patients was usually a
harmless component of the ICU course, it is well documented that delirium is an
independent risk factor for multiple adverse outcomes including death. CNS
dysfunction may lead to complications of mechanical ventilation, including
aspiration, nosocomial pneumonia, self-extubation, and reintubation. Abnormal
neurologic status was a significant predictor of failed extubation in studies of
neurosurgical41 and medical ICU patients.42 Moreover, delirium is associated with
increased length of hospital stay and a higher likelihood of discharge to a long-
term care facility.33,43
Delirium is also believed to be associated with the development of long-term
cognitive impairment. Nine prospective studies evaluating a total of 1,885 hos-
pitalized medical and surgical patients found that delirium was associated with
the development of dementia over 1 to 3 years from the time of hospital dis-
charge.44 A pilot study conducted 6 months after discharge in 34 patients who
received mechanical ventilation in a medical ICU documented neuropsychologi-
cal impairment in 11 (32%) patients.45 Additionally, learning and memory impair-
ment have recently been demonstrated in survivors of an animal model of sepsis
induced by cecal ligation and perforation.46 Ongoing research is being conducted
to confirm that ICU delirium is an independent risk factor for the development
of long-term neurocognitive dysfunction.
12. Delirium in Septic Patients
141
Finally, delirium in septic patients is an independent predictor of higher mortal-
ity. Sprung et al. noted that septic patients with delirium had a significantly higher
mortality than those who maintained a normal mental status (49 vs. 26%, p <
.001).16 Wijdicks et al. made the same observation in a study of 84 septic patients,
14 of whom developed altered mental status and focal neurologic abnormalities.13
Despite these studies, investigators in the past were uncertain whether delirium
was an independent risk factor for increased mortality or simply a marker of
higher severity of illness.19,33 To further address this question, Ely et al.
prospectively evaluated 275 mechanically ventilated medical ICU patients for the
development of delirium.47 Nearly half of these patients were admitted with
severe sepsis or acute respiratory distress syndrome (ARDS). After adjusting for
age, severity of illness, comorbid conditions, coma, and the use of sedatives and
analgesics, delirium was independently associated with a threefold increase in
the risk of death at 6 months (p = .008). Interestingly, delirium occurred just as
often among patients who never developed coma as it did among those who did
develop coma. The increased mortality rate associated with delirium was not
explained by the occurrence or duration of coma; in fact, the strength of the
association between delirium and mortality was actually greater after adjusting
for coma.47 Recently, these findings were confirmed in another prospective study
that evaluated 102 mechanically ventilated patients and showed that delirium was
independently associated with mortality after multivariate analysis (odds ratio,
13.0; 95% confidence interval, 2.69 to 62.91).48
Cost of Delirium in the ICU
The costs attributable to the care of patients with severe sepsis are massive and
growing. Angus et al. reported that in the United States alone the annual hospital
costs associated with the care of patients who developed severe sepsis is over
$16 billion, averaging $21,000 to $25,000 per patient.2 The highest costs are
incurred by those patients who require ICU care, which account for up to 50%
of all patients with severe sepsis. A significant portion of these costs may be
attributable to the development of delirium. In the only study to date to examine
the costs associated with delirium in ICU patients, Milbrandt et al. found that
patients who developed delirium at some time during their ICU stay incurred
significantly higher ICU and hospital costs than those who never developed
delirium.49 The increase in median ICU costs in patients with delirium was greater
than $9,000 per patient. Almost half of the patients evaluated in this study had
severe sepsis.
Although studies from developing nations are still lacking,50 it is estimated that
over 18 million cases of severe sepsis occur worldwide each year.51 With delirium
occurring in up to 80% of patients admitted to the ICU with severe sepsis,47
the increase in costs each year in the United States attributable to this often-
unrecognized organ dysfunction may be as high as $3 billion. Accurate estimates
are currently unavailable to allow for a reasonable projection of the increase in
142
T.D. Girard and E.W. Ely
ICU and hospital costs due to delirium worldwide, but the possibility that the
incidence of severe sepsis and associated delirium are higher in developing coun-
tries than in the United States52 further emphasizes the fact that the occurrence
of delirium in patients with severe sepsis is a major worldwide public health
problem.
Diagnosis and Assessment of Delirium in the ICU
It is important to note that health professionals commonly fail to recognize
delirium.33,53 This omission has been associated with unexpectedly high mortality
rates following emergency visits.54 In a survey of 912 healthcare professionals,55
Ely et al. found that delirium was considered a significant or very serious problem
in the ICU by 92%, yet underdiagnosis was acknowledged by 8 of 10
respondents.
As patients with severe sepsis frequently require mechanical ventilation and
its attendant need for sedation, the Surviving Sepsis Campaign clinical practice
guidelines recommend the use of a protocol that includes a sedation goal and the
use of a standardized sedation scale.56 Additionally, the Society of Critical Care
Medicine (SCCM) guidelines for the use of sedatives and analgesics in critically
ill patients recommend routine assessment for delirium in all ICU patients.57 The
routine use of well-validated, reliable, brief assessment tools easily equips critical
care nurses and doctors to monitor both level of arousal and content of conscious-
ness, allowing for goal-directed titration of sedatives as well as rapid recognition
of delirium.
Several sedation scales have been developed that provide standardized methods
for the assessment of a patient’s level of arousal or consciousness. Use of a
validated sedation assessment scale allows the multidisciplinary ICU team to use
a succinct, common language when discussing goals and treatments for patients.
A sedation goal should be established by the interdisciplinary medical team and
regularly refined according to changes in a patient’s course of illness.57 The
Ramsay Scale was one of the first sedation scales developed and has been widely
used for 30 years.58 However, several recently developed instruments, including
the Sedation-Agitation Scale (SAS)59 and the Richmond Agitation-Sedation Scale
(RASS),60 have been better validated and are being widely implemented. The
RASS has been validated in multiple studies and was the first sedation scale
validated for its ability to follow level of arousal over consecutive days of ICU
care.61
The gold standard criteria for the diagnosis of delirium are outlined in the
DSM-IV as detailed previously (see “Defining Delirium and Its Motoric Sub-
types”). Several instruments have been developed to allow nonpsychiatrists to
make a formal diagnosis of delirium,62 including the Confusion Assessment
Method (CAM), a sensitive (94% to 100%), specific (90% to 100%), and reliable
instrument intended for use in the clinical evaluation of hospitalized, elderly,
medical and surgical patients.63 However, the usefulness of the CAM and most
12. Delirium in Septic Patients
143
other delirium assessment instruments is limited in nonverbal patients, because
a significant portion of septic patients require mechanical ventilation. Therefore,
the Confusion Assessment Method for the ICU (CAM-ICU) was developed and
validated in two cohorts of mechanically ventilated critically ill patients (Figure
12.1 and Table 12.3).64,65 This easy-to-use, quickly administered instrument
requires minimal training and was shown to have high sensitivity (93% to 100%),
specificity (98% to 100%), and interrater reliability (κ = 0.96).65 The CAM-ICU
has been translated into numerous languages (e.g., Spanish, Portuguese, French,
Dutch, Swedish, Greek, Italian, and Chinese) and is available for download via
an educational website (www.icudelirium.org). Its high reliability and validity
has also been confirmed in another language and region of the world.48
It is important to note that the disruptive, agitated behavior traditionally associ-
ated with delirium is typically present in less than half of the cases identified
when sensitive screening measures are utilized.33 The use of sensitive assessment
tools, such as the CAM-ICU, allows clinicians to avoid the mistake of failing to
recognize this vital organ dysfunction in patients with severe sepsis. Prior to the
development of the CAM-ICU, it was frequently thought that the mechanically
ventilated patient could not be properly evaluated for delirium due to the high
severity of illness and the use of endotracheal tubes and sedatives.20 ICU practi-
tioners are no longer limited in their assessment of the nonverbal septic patient,
and delirium assessment should be part of the daily neurologic assessment of
every mechanically ventilated patient in the ICU.
Figure 12.1. Diagnosis of delirium with the Confusion Assessment Method for the Inten-
sive Care Unit (CAM-ICU). Used with permission, copyright © 2002, E. Wesley Ely, MD,
MPH and Vanderbilt University, all rights reserved.
144
T.D. Girard and E.W. Ely
Table 12.3. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU)
Worksheet
CAM-ICU Features and Descriptions
1. Acute Onset or Fluctuating Course
Absent
Present
A. Is there evidence of an acute change in mental status from the baseline?
OR
B. Did the (abnormal) behavior fluctuate during the past 24 hours, that is, tend to come and go, or
increase and decrease in severity as evidenced by fluctuation on a sedation scale (e.g., RASS), GCS,
or previous delirium assessment?
2. Inattention
Absent
Present
Did the patient have difficulty focusing attention as evidenced by scores less than 8 on either the
auditory or visual component of the Attention Screening Examination (ASE)?*
3. Disorganized Thinking
Absent
Present
Is there evidence of disorganized or incoherent thinking as evidenced by incorrect answers to 2 or
more of the 4 questions and/or inability to follow the commands?
Questions (Alternate Set A and Set B):
Set A
1. Will a stone float on water?
2. Are there fish in the sea?
3. Does one pound weigh more than two pounds?
4. Can you use a hammer to pound a nail?
1.
2.
3.
4.
Set B
Will a leaf float on water?
Are there elephants in the sea?
Do two pounds weigh more than one pound?
Can you use a hammer to cut wood?
Other:
1. Are you having any unclear thinking?
2. Hold up this many fingers. (Examiner holds two fingers in front of patient.)
3. Now do the same thing with the other hand. (Examiner does not demonstrate for the patient with
this request.)
4. Altered Level of Consciousness
Absent
Present
Is the patient’s level of consciousness anything other than alert, such as vigilant, lethargic, or stupor-
ous (e.g., RASS other than “0” at time of assessment)?
Alert
spontaneously fully aware of environment and interacts appropriately
Vigilant
hyperalert
Lethargic
drowsy but easily aroused, unaware of some elements in the environment, or not
spontaneously interacting appropriately with the interviewer; becomes fully
aware and appropriately interactive when prodded minimally
Stuporous
becomes incompletely aware when prodded strongly; can be aroused only by
vigorous and repeated stimuli, and as soon as the stimulus ceases, stuporous
subject lapse back into the unresponsive state
Overall CAM-ICU (Features 1 and 2 and either Feature 3 or 4):
Yes
No
Note: RASS, Richmond Agitation-Sedation Scale; GCS, Glasgow Coma Scale.
* In performing the auditory ASE, the examiner says to the patient, “I am going to read you a series
of 10 letters. Whenever you hear the letter “A,” indicate by squeezing my hand,” then reads the
letters—S, A, V, E, A, H, A, A, R, T—counting correct responses when the patient squeezes on the
letter “A” and does not squeeze on any other letter. The visual ASE is used when the patient is unable
to perform the auditory ASE and utilizes a series of pictures provided in the CAM-ICU training
manual available at www.icudelirium.org.
Used with permission, copyright © 2002, E. Wesley Ely, MD, MPH and Vanderbilt University, all
rights reserved.
12. Delirium in Septic Patients
145
Approaches to Prevention and Treatment of Delirium in
Septic Patients
Severe sepsis is a multiorgan syndrome that is managed by a comprehensive
approach involving both prevention and treatment. Similarly, the clinician’s
response to delirium in patients with severe sepsis consists of a multidisciplinary
plan of prevention and treatment that includes eliminating modifiable risk factors,
performing frequent delirium assessments, and using pharmacologic therapies
thought to treat delirium when it is identified.
Prevention and Nonpharmacologic Strategies
Although they were not limited to patients with sepsis, several clinical trials have
evaluated multicomponent interventions designed to prevent delirium in hospital-
ized patients.66–69 Inouye et al. studied 852 older patients hospitalized with a
variety of medical illnesses. Standardized intervention protocols included repeated
reorientation with information boards and healthcare worker communication,
cognitively stimulating activities multiple times daily, a nonpharmacologic sleep
protocol enhanced by a sleep-friendly environment, frequent ambulation and
exercise, visual and hearing aids, and vigilant volume repletion to prevent dehy-
dration. This strategy resulted in a significant reduction in the incidence of delir-
ium (9.9% in the intervention group versus 15% in the control group, p = .02) as
well as in the duration of delirium.66 Unfortunately, there was no sustained benefit
noted in clinical outcomes at 6 months following hospital discharge.70 However,
this study and others should form the basis of future work in the arena of delirium
prevention. Despite the lack of clinical trials evaluating primary prevention of
delirium in critically ill patients, the approach to care utilized by Inouye et al.
should form the basis of nonpharmacologic attempts to prevent delirium in
patients with severe sepsis: frequent reorientation,66 daily interruption of seda-
tives,71 restoration of the sleep/wake cycle, minimization of unnecessary stimuli,
physical therapy,66 and early mobilization. Additionally, these interventions may
continue to be beneficial in the care of septic patients with established delirium,
and they should be combined with measures aimed at treating sepsis and correct-
ing associated metabolic derangements.
Pharmacologic Treatment
Pharmacologic management of delirium is frequently attempted in the ICU. Of
912 critical care practitioners surveyed, 717 (79%) reported that delirium requires
active intervention.55 Two-thirds considered haloperidol as the treatment of
choice. Although there remain no drugs with an FDA approval for the treatment
of delirium and we have no placebo-controlled trials to confirm the best treatment,
the SCCM and the American Psychiatric Association guidelines currently recom-
mend haloperidol as the treatment of choice.57,62 This and other neuroleptic agents
146
T.D. Girard and E.W. Ely
are felt to stabilize cerebral function by dopamine blockade and disinhibition of
acetylcholine. Of particular import in patients with severe sepsis, haloperidol is
known to have antiinflammatory properties, inhibiting the secretion of proinflam-
matory cytokines.72,73 This, along with its procognitive effects, may have resulted
in the 15.6% absolute reduction in the risk of hospital mortality noted in a recently
published retrospective cohort analysis of 989 mechanically ventilated, critically
ill patients.74 Several randomized, placebo-controlled clinical trials are currently
under way that are designed to evaluate the efficacy and safety of haloperidol in
the treatment of critically ill patients with delirium.
Perhaps as important as using appropriate pharmacologic agents to treat delir-
ium is withholding those agents known to incite or exacerbate delirium. Although
benzodiazepines are the drugs of choice for the treatment of alcohol withdrawal
(as well as other drug withdrawal syndromes), this class of drugs is not recom-
mended for the routine treatment of delirium due to the likelihood of promoting
confusion, oversedation, and respiratory depression. As stated previously (see
“Risk Factors for Delirium in the Septic Patient”), exposure to benzodiazepines
and narcotics is a significant independent risk factor for the development of
delirium, and use of these drugs should be guided by goal-directed sedation pro-
tocols that primarily employ intermittent bolus sedation.71,75,76
In the care of patients at risk for severe sepsis, it is imperative that clinicians
are focused on the diagnosis and treatment of delirium as well as to the signifi-
cance of the development of this syndrome. As delirium is often a manifestation
of an acute change in the patient’s clinical course, abrupt changes in mental status
should alert the healthcare team to evaluate the patient for shock, hypoxia, hyper-
carbia, hypoglycemia, or other metabolic derangements. After rapid evaluation
and treatment of these life-threatening problems, attention can be turned toward
the treatment of delirium.
Conclusion
Patients with severe sepsis are at high risk for morbidity and mortality. These
risks only increase with the failure of multiple organ systems. Although delirium
was previously often overlooked, practitioners are becoming increasingly aware
of the crucial role that acute CNS dysfunction plays in the course of severe sepsis.
Appropriate strategies for the prevention, diagnosis, and treatment of delirium in
critically ill patients as outlined in this chapter are the subject of ongoing inves-
tigations and should be part of every ICU clinician’s armamentarium in the care
of patients with severe sepsis.
Acknowledgments. Dr. Girard is supported by grant HL 07123 from the National
Heart, Lung, and Blood Institute, National Institutes of Health. Dr. Ely is a recipi-
ent of the Paul Beeson Faculty Scholar Award from the Alliance for Aging
Research and of a K23 from the National Institutes of Health (AG01023-01A1).
He has received research funding from Eli Lilly and Co. and Pfizer Inc.
12. Delirium in Septic Patients
147
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Index
A
Abdominal compartment syndrome
(ACS)
classification of, 79–80
definition of, 74, 78–80, 79
differentiated from intraabdominal
hypertension, 78–79
hypercarbia in, 82
hypoxemia in, 82
intraabdominal hypertension in,
78–80
organ dysfunction in, 78–79
prevention of, 84
primary, 79, 80
primary/secondary, 79–80
secondary, 79, 80
sequential organ failure association
(SOFA) score in, 79, 80
tertiary, 80
Abdominal perfusion pressure (APP)
assessment of, 75, 81
intraabdominal hypertension-related
decrease in, 83
receiver operating characteristics
(ROC) curves for, 85–86
as resuscitation endpoint, 86
Abdominal wall components separation,
85
Acidosis
lactic, 126–135
hypoxic, 126, 128
prognostic values of, 132
relationship to hyperlactatemia,
127–128
treatment of, 132
metabolic
as hemodynamic instability
indicator, 100
intraabdominal pressure-related,
83
Acinetobacter, antibiotic resistance in,
43
Acinetobacter baumanii, antibiotic
resistance in, 34
ACS. See Abdominal compartment
syndrome (ACS)
Adenosine triphosphate (ATP), 104–105,
127
Adenovirus infections, transmission of,
39
Adrenal insufficiency, 25, 26
Age factors, in sepsis, 21
Albuterol, 51
Alloimmunization reactions, red blood
cell transfusion-related, 5
American College of Chest Physicians/
Society of Critical Care Medicine
(ACCP/SCCM), 12, 20
American Psychiatric Association (APA),
145
Aminoglycosides, bacterial resistance to,
43
Aminopenicillins, bacterial resistance to,
35
Anemia, in septic patients, 1–10
causes of, 1–2
red blood cell transfusion therapy for,
1–10
Angiotensin-converting enzyme
inhibitors, 5
151
152
Index
Antibiotic control strategies, 40–42
antibiotic combinations, 41–42
antibiotic restriction, 40–41, 42
antibiotic rotation, 41
Antibiotics. See also names of specific
antibiotics
bacterial resistance to. See
Antimicrobial resistance
Anticholinergic drugs, as delirium cause,
138, 140
Anticoagulant/antithrombotic compounds,
in the blood, 107–111, 112–113
Antiendotoxin therapy, 27
Anti-inflammatory mediators, in sepsis, 55
Antimicrobial resistance, in the ICU. See
also names of specific antibiotics
causes of, 33–36
control of, 36–43
antibiotic control strategies for, 40–42
containment strategies for, 36–37
isolation strategies for, 37–40
resistance surveillance strategies for,
42–43
as multiresistance, 43
risk of, 34–35
transmission of, 34, 36
Antipsychotic drugs, as delirium cause,
138, 139, 140
Antithrombin, 114
Antithrombin III, 107
as sepsis treatment, 113
APC (autoprothrombin III-A), 107–108,
109–112
Apoptosis, in myocardial depression, 55
Apoptosis inhibition therapy, 27
APP. See Abdominal perfusion pressure
(APP)
Arachidonic acid metabolites, 55
as myocardial depressants, 63
Argentina, sepsis epidemiology in, 18
Arousal level, assessment of, 142
Atelectasis, alveolar, 82
Autoprothrombin III-A (APC), 107–108,
109–112
B
Bacteremia
epidemiological studies of, 15–16
in ICU versus non-ICU patients, 16
incidence of
in Europe, 15–16
in Mexico, 20
mortality rate in, in Mexico, 20–21
nosocomial
in Europe, 16
in Latin America, 19, 20
Bacterial nucleic acid, 66
“Barcelona Declaration,” 21
Benzodiazepines, as delirium cause,
146
Beta-lactamases, extended-spectrum
(EEBL), 35, 41, 43
Beta-lactams, 41, 42
Bicarbonate, contraindication as lactic
acidosis treatment, 132
Bilirubin, in sepsis, 13
Blood cultures, for bacteremia diagnosis,
15, 20–21
Blood flow
arterial, in intraabdominal
hypertension, 82, 83, 84
coronary sinus, 62–63
myocardial, 62–63
Blood loss, as anemia cause, 1
Body temperature, in systemic
inflammatory response syndrome
(SIRS), 12
Bolivia, sepsis epidemiology in, 18
Brazil, sepsis epidemiology in, 18, 19,
20
British Intensive Care National Audit
and Research Centre, 17
C
Calpains, 49–50
L-Canavanine, 67
Carbapenems, bacterial resistance to,
34–35, 43
Cardiac index
in hyperresuscitation, 97
in resuscitation, 94
during early resuscitation, 100
in sepsis, 13, 56
in septic shock, 60, 61
Cardiac output
in intraabdominal hypertension, 81
in septic shock, 56
in tissue hypoxia, 126–127
Index
Cardiovascular failure. See also Heart
failure
sepsis-related, 134, 137–138
Cardiovascular stress, 56
Caspase inhibitors, 27
Catheterization, pulmonary arterial
(PAC), 56, 60, 94, 97, 99, 101
Cefotaxime, bacterial resistance to, 42
Cefoxitin, bacterial resistance to, 42
Ceftazidime, bacterial resistance to, 34,
35, 42
Ceftriaxone, bacterial resistance to, 42
Celiac artery blood flow, 83
Centers for Disease Control and
Prevention (CDC), 13, 37
Central nervous system dysfunction,
sepsis-related, 134, 137–138
Central venous oxygen saturation, 97–98
Central venous pressure (CVP)
correlation with left ventricular end-
diastolic volume, 56
effect of red blood cell transfusions on,
6
in hypotension, 93
in intraabdominal hypertension, 81, 84
in resuscitation, 100
in septic shock, monitoring of, 94
Cephalosporins, bacterial resistance to,
33, 35
Cerebral perfusion pressure (CPP), 75
in intraabdominal hypertension, 84
Chemokines, 104–105
as delirium cause, 138
Chile, sepsis epidemiology in, 18
Cineangiography, radionuclide, 56
Ciprofloxacin, bacterial resistance to, 34,
35, 42
Citrate synthetase, 50
Clostridium difficile, transmission of, 39
Clothing, protective, 37, 38, 39
Coagulation
disorders of, 103–120
as delirium cause, 138
phases of
amplification phase, 104–105
initiation phase, 103–104
propagation of, 106
relationship to inflammatory system,
112–113
153
as sepsis-related hypercoagulation,
112–113
Coagulation cascade, 103, 104
Cognitive impairment, delirium-related, 140
Colombia, sepsis epidemiology in, 18,
19, 20
Coma, delirium-related, 136–137, 141
Confusion Assessment Method (CAM),
142–143
Confusion Assessment Method for the
ICU(CAM-ICU), 142–144
Consciousness, assessment of, 142
Containment strategies, for antimicrobial
resistance control, 36–37
Corticosteroids, 25–26, 53
Coupled plasma filtration adsorption
(CPFA), 27
C-reactive protein, 13
Creutzfeldt-Jakob disease, 5
Crystalloid infusions, during early
resuscitation, 100
Cuba, sepsis epidemiology in, 18, 19
CUB-Réa Network, 17
Cytokine antagonists, 67
Cytokines
as delirium cause, 138
in diaphragmatic dysfunction, 50–51
as septic myocardial depression cause,
55, 63–65
D
Delirium, in septic patients, 136–150
definition of, 138
diagnosis and assessment of, 142–144
healthcare costs of, 141–142
historical perspectives on, 136–137
mechanical ventilation-related, 139,
140, 141
assessment of, 143
pathogenesis of, 137–138
prevalence of, 141
prevention of, 145
prognostic significance of, 140–141
as “ICU psychosis,” 136
risk factors for, 139–140, 146
subtypes of, 139
as “ICU syndrome,” 136
treatment of, 145–146
underdiagnosis of, 142
154
Index
Dementia, delirium-related, 140 Encephalopathy
Diagnostic and Statistical Manual of definition of, 138
Mental Disorders-IV (DSM-IV), septic, 136–137
138, 142 Endorphins, as myocardial depressants,
Diaphragm, mechanical ventilation- 63
related dysfunction of, 47–54 Endothelial cell protein C receptors
calpains in, 49–50 (EPCRs), 107, 108, 109
clinical implications of, 51–53 Endothelium, in hypercoagulation, 112–113
cytokines in, 50–51 Endotoxemia, treatment of, 28
diagnosis of, 47–48 Endotoxin
diaphragmatic structural changes in, inhibition of, 27
48–49, 51, 52, 53 pyruvate dehydrogenase-inhibiting
in elderly patients, 52 effects of, 128
myosin heavy chains in, 50 tissue factor-factor VII complex-
oxidative stress in, 49–51, 52 activating effects of, 112
positive end expiratory pressure in, 51 Enteric infections, transmission of, 39
proteolysis in, 48–49 Enterobacter spp., cephalosporin
Dichloroacetate, 128, 132 resistance in, 33
Digoxin, as myocardial depression Enterococcus faecium, vancomycin
treatment, 66 resistance in, 33, 35
Dimer D, 113, 114 EPCRs (endothelial cell protein C
Diphtheria, transmission of, 39 receptors), 107, 108, 109
Disseminated intravascular coagulation, Epidemiology, of sepsis, 11–24
112, 113 global perspective on, 13–17
Dobutamine in Latin America, 17–21
hemodynamic effects of, 123 Epidermal growth factor, 109
as myocardial depression treatment, Epinephrine, as myocardial depression
66 treatment, 66
as septic shock treatment, 123 EPISSEPSIS Study Group, 17
use in resuscitation, 93, 94, 122 Erythropoiesis, 1–2, 3
in early resuscitation, 100 Escherichia coli, aminoglycoside
Dobutamine challenge, 61 resistance in, 43
Dopamine, 123 Escherichia coli infections
comparison with noradrenaline, 93 antibiotic control of, 41
dosage of, 93 transmission of, 39
use in resuscitation, 93 European Society of Intensive Care
in early resuscitation, 100 Medicine (ESICM), 11
Drotrecogin alpha (activated), 26, 30, External negative abdominal pressure
114 (NEXAP), 85
E F
Ecuador, sepsis epidemiology in, 18 Factor V, 106
Edema inhibition of, 107
intraabdominal hypertension-related, Factor V Leiden polymorphism, 107
81–82 Factor Va, inhibition of, 112
plasma volume expansion-related, 92 Factor VII, 103, 104, 106
Elderly patients, delirium risk factors in, Factor VIII, 106
139–140 Factor VIIIa, 106
Embolism, pulmonary, intraabdominal Factor IX, 106
hypertension-related, 81–82 Factor IXa, inhibition of, 107
Index
Factor X, 104, 106
Factor Xa, 104, 106
inhibition of, 107
Ferritin, 1
Fever, as delirium cause, 139, 140
Fibrinogen, 105
Fibrinogen degradable products, 112
Fibrinolysis, inhibition of, 108
Fibrinolytic system, 111–112
Fifth Toronto Sepsis Roundtable, 12
Fludrocortisone, 25–26
Folic acid deficiency, 2
Free radicals, 55
Furunculosis, transmission of, 39
G
Gentamicin, bacterial resistance to, 35, 42
German measles, transmission of, 39
Glasgow Coma Scale, 84
Gloves, protective, 37, 38, 39
Glucose control, 29
Glycolysis, as hyperlactatemia cause, 126,
127, 129, 130
H
Hageman factor fragments, 111
Haloperidol
anti-inflammatory properties of, 146
as delirium treatment, 138, 145
Handwashing, hygienic, 37, 38, 39
Heart failure, treatment of, 122
Heart rate
in sepsis, 13
in septic shock, 61
in systemic inflammatory response
syndrome (SIRS), 12
Hemodilution, as anemia cause, 1, 3
Hemodynamic resuscitation, in septic
patients, 29–30, 92–102
abdominal perfusion pressure in, 75
central venous pressure in, 93
early, 98, 99–100
goal-directed, 98, 99–100
“golden” hours of, 99
hemodynamic management in, 94–100
initial, 94–100
as hyperresuscitation, 97, 98–99
late, 97–98, 99, 100–101
oxygen debt in, 94–100
preventive, 98–99
155
Hemodynamics
of intraabdominal hypertension, 81–82
of sepsis, 13
in tissue hypoxia, 126–127
Hemodynamic support, 28–29
for critically ill septic patients, 28–29
Hemofiltration, as myocardial depression
treatment, 67
Hemoglobin levels
in ICU patients, 1
in septic patients, 2–3
Hemolytic reactions, red blood cell
transfusion-related, 5
Hemoperfusion therapy, 27
Hemophilus influenzae infections,
transmission of, 39
Hemorrhage, protein C-related, 114
Hepatic artery, blood flow in, 84
Hepatitis, red blood cell transfusion-
related transmission of, 5
Hepatitis A, transmission of, 39
Hepatitis B, red blood cell transfusion-
related transmission of, 5
Hepatitis C, red blood cell transfusion-
related transmission of, 5
Herpes simplex virus, transmission of, 39
High-density lipoprotein, endotoxin-
inhibiting effects of, 27
High-mobility group B-1 protein
(HMGB1), 27
Hippocrates, 134
Histamine, as myocardial depressant, 63
Human immunodeficiency virus (HIV)
infection, red blood cell
transfusion-related, 5
Hydrocortisone, 25–26
Hypercarbia, 82
Hypercoagulable states, 107
Hyperglycemia, 29
Hyperlactatemia, 126, 127
anaerobic metabolism associated with,
128
glycolysis-induced, 126, 127, 129, 130
inflammatory processes-related,
131–132, 133
prognostic value of, 132
relationship to
hypoxia, 128
lactate acidosis, 127–128
tissue hypoxia, 128
156
Index
Hypertension
idiopathic intracranial, 84
intraabdominal, 74–91
abdominal compartment syndrome-
related, 79
acute, 80
cardiovascular assessment in, 81–82
chronic, 80
classification of, 80
definition of, 75, 77–78
differentiated from acute
compartment syndrome, 78–79
gastrointestinal assessment in, 83
hepatic assessment in, 83–84
hyperacute, 80
neurologic assessment in, 84
organ function assessment in, 80–84
pulmonary assessment in, 82
renal assessment in, 82–83
subacute, 80
treatment of, 84–85
red blood cell transfusion-related, 5
Hyperventilation, in systemic
inflammatory response syndrome
(SIRS), 12
Hypoperfusion, 121
myocardial, 62–63
Hypotension, 92, 121
central venous pressure (CVP) in, 93
refractory, 55
vasodilatory, 124
as resuscitation goal, 95
treatment of, 94
Hypovolemia, 82
Hypoxemia, 82
Hypoxia
complications of, 126
cytopathic, 128, 131
detection of, 126
as lactic acidosis cause, 126, 128
relationship to hyperlactatemia, 128
I
IAP. See Intraabdominal pressure (IAP)
ICP. See Intracranial pressure
“ICU psychosis,” 136
“ICU syndrome,” 136
Imipenem, bacterial resistance to, 33, 34,
42
Immunocompromised patients. See also
Human immunodeficiency virus
(HIV) infection
protective isolation of, 39
Immunomodulation, red blood cell
transfusion-related, 5
Immunomodulatory therapies, 25–28
apoptosis inhibition, 27
corticosteroids, 25–26, 30
drotrecogin alpha (activated), 26, 30,
114
hemoperfusion strategies, 27
high-mobility group B-1 protein
(HMGB1) inhibition, 27
new antiendotoxin strategies, 27
poly (ADP) ribose polymerase/
synthetase (PARP/PARS), 28
Immunonutrition, 29
Impetigo, transmission of, 39
Infection, as delirium cause, 139, 140
Inflammation, in sepsis, 13
Inflammatory mediators
as delirium cause, 138
in sepsis, 55
Inflammatory processes, as sepsis-related
hypoperfusion cause, 121
Influenza, transmission of, 39
Insulin therapy, 29
Intercellular adhesion molecule (ICAM),
28
Interferon-γ, 55
Interleukin-1, 28
as delirium cause, 138
tissue factor-factor VII complex
activating property of, 112
Interleukin-1 receptor antagonist, 55–56
Interleukin-1β, 55
as myocardial depressant, 64–65, 66,
67
Interleukin-1β antagonists, as myocardial
depression treatment, 67
Interleukin-10, 55–56
International Sepsis Definition
Conference, 12
International Sepsis Forum, 11
Intestines, lactate production in, 130
Intraabdominal pressure (IAP), 74–75
definition of, 74
diurnal and nocturnal variations in, 85
Index
in intraabdominal hypertension, 75,
77–78
measurement of, 75, 81, 85–87
instrumentation for, 75, 76–77
normal values for, 74
receiver operating characteristics
(ROC) curves for, 85–86
therapeutic decrease in, 85
Intracranial pressure (ICP), 75
in intraabdominal hypertension, 84
normal, 78
Intrathoracic pressure
intraabdominal hypertension-related
increase in, 82
intraabdominal pressure-related
increase in, 81
Iron, serum levels of, 1
Ischemia, intestinal, 83
Isolation strategies, for antimicrobial
resistance control, 37–40
K
Klebsiella
aminoglycoside resistance in, 43
antibiotic control of, 41
L
β-Lactamases, extended-spectrum
(EEBL), 35, 41, 43
β-Lactams, 41, 42
Lactate. See also Acidosis, lactic;
Hyperlactatemia
clearance of, 126, 129–130
metabolism of, 127
production of, 126
in inflammatory processes, 131
regional, 130–131
in septic shock, 97
Laparoscopy, 84
Latin America, sepsis epidemiology in,
17–21
L-canavanine, 67
Lectins, C-type, 110
Left ventricular dysfunction, 56,
57–58
Left ventricular ejection fraction
(LVEF), 57–58
effect of myocardial depressant
substances on, 63
157
Left ventricular end-diastolic volume
index (LVEDVI), 57–58, 61
effect of myocardial depressant
substances on, 63
Left ventricular end-diastolic volume
(LVEDV), 56
Lipopolysaccharide binding protein
(LBP), 27
Liver, lactate metabolism in, 130, 132
Liver failure, intraabdominal
hypertension-related, 83
Lung, lactate production in, 130
Lung injury, red blood cell transfusion-
related, 5
Lysozyme c, 65, 67
M
Mean arterial pressure (MAP), 75
effect of red blood cell transfusions on,
6
in intraabdominal hypertension, 81
in renal failure, 83
in resuscitation, 86, 93, 100
in septic shock, 96
norepinephrine treatment of, 94
Measles, transmission of, 39
Mechanical ventilated patients,
haloperidol use in, 146
Mechanical ventilation
benefits of, 47
as delirium cause, 139, 140, 141
assessment of, 143
as diaphragmatic dysfunction cause,
47–54
calpains in, 49–50
clinical implications of, 51–53
cytokines in, 50–51
diagnosis of, 47–48
diaphragmatic structural changes in,
48–49, 51, 52, 53
in elderly patients, 52
myosin heavy chains in, 50
oxidative stress in, 49–51, 52
positive end expiratory pressure in,
51
proteolysis in, 48–49
during resuscitation, 94
sequential organ failure assessment
score as indication for, 82
158
Index
Mechanical ventilation (cont.)
weaning from, 47
intraabdominal hypertension-related
prolongation of, 82
Memory impairment, delirium-related, 140
Methicillin resistance
in coagulase-negative Staphylococcus,
33
in Staphylococcus aureus, 33
Methylene blue, as myocardial depression
treatment, 67
Mexico, sepsis epidemiology in, 18, 19,
20–21
Microplasma infections, transmission of,
39
Milrinone, as myocardial depression
treatment, 66
Mitogen-activated protein kinase
(MAPK), 109, 111
Mixed-venous oxygen saturation, in tissue
hypoxia, 126–127
Mortality rate
in bacteremia, in Mexico, 20–21
delirium-related, 141
effect of norepinephrine on, 122
in sepsis, 2, 55
in Latin America, 18, 19, 20
in septicemia
in Latin America, 18, 20
in the United States, 13
in septic shock, 25
in Brazil, 20
in severe sepsis, 15
in systemic inflammatory response
syndrome (SIRS), in Latin
America, 20
Multiple organ failure, 92
abdominal compartment syndrome-
related, 78–79
intraabdominal hypertension-related,
84
as mortality cause, 121
Mupirocin, 40
Myocardial depression, in sepsis and
septic shock, 55–73, 92
clinical manifestations of, 56–62
historical perspective on, 56
left ventricular function in, 57–58, 61
right ventricular function in, 57,
59–60
definition of, 55
etiology of, 62–66
at cellular level, 65–66
myocardial depressant substances in,
63–65
myocardial hypoperfusion in,
62–63
at organ level, 62–65
pathogenesis of, 55
Myocardial hypoperfusion, 62–63
Myosin heavy chains, 50
N
Na/K ATPase, 129, 132
Narcotics, as delirium cause, 138, 140,
146
National Center for Health Statistics, 13
National Hospital Discharge Survey
(NHDS), 13, 15
Neisseria meningitidis infections,
transmission of, 39
Neuroleptic agents, as delirium
treatment, 145–146
Neurotransmitters, in delirium, 138
Nitric oxide
in myocardial depression, 55, 65–66
as vasodilatation cause, 92, 121
Nitric oxide inhibitors, 67
Nitric oxide scavengers, 67
Nitric oxide synthase, 121
constitutive, 66
inducible, 66
inhibitor of, 67
in myocardial depression, 66
Nitric oxide synthase inhibitors, 28, 67
Norepinephrine (noradrenaline), 122
comparison with dopamine, 93
as septic shock treatment, 94
use in initial hemodynamic
resuscitation, 94
Novel therapies, in critically ill septic
patients, 25–32
general management strategies
glucose control, 29
hemodynamic support, 28–29
nutritional support, 29
Index
immunomodulatory therapies, 25–28
apoptosis inhibition, 27
corticosteroids, 25–26, 30
drotrecogin alpha (activated), 26,
30, 114
hemoperfusion strategies, 27
high-mobility group B-1 protein
(HMGB1) inhibition, 27
new antiendotoxin strategies, 27
poly (ADP) ribose polymerase/
synthetase (PARP/PARS), 28
Nuclear factor-κB, 28, 108, 110
Nucleic acid, bacterial, 66
Nutritional support, for critically ill septic
patients, 29
O
Oliguria
as hemodynamic instability indicator,
100
intraabdominal hypertension-related,
82
renal failure-related, 82
Osler, William, 134
Oxidative stress, 49–51, 52
Oxygen-carrying capacity, of tissue,
effect of red blood cell
transfusions on, 3, 4–5, 6–7
Oxygen consumption
in hyperresuscitation, 97
in shock, 95, 96
in tissue hypoxia, 126–127
Oxygen debt, in hemodynamic
resuscitation, 94–101
Oxygen delivery, in tissue hypoxia,
126–127
P
Partial pressure of oxygen in alveolar gas
(PaO2), in sepsis, 13
Parvovirus B19 infections, transmission
of, 39
red blood cell transfusion-related, 5
Pascal’s law, 75
Pediculosis, transmission of, 39
Peritoneal dialysis, abdominal wall
complications of, 81
Peritonitis, treatment of, 28
159
Phlebotomy, as anemia cause, 1
Phrenitis, 134
PIRO classification scheme, for sepsis,
12–13, 30
Plasma volume expanders, 92–93
Plasmin, 109, 111, 112
Plasminogen activation inhibitor (PAI-1),
112
Platelet activating factor, 55
as myocardial depressant, 63, 67
Pleural pressure, intraabdominal
hypertension-related increase in,
82
Poly (ADP) ribose polymerase/synthetase
(PARP/PARS), 28
Positive end-expiratory pressure (PEEP),
51
in late resuscitation, 100
Procalcitonin, 13
Procoagulant compounds, in sepsis,
112–113
Prokinetic drugs, 85
Protective clothing, 37, 38, 39
Protein C
activated, 26, 107
as septic shock treatment, 114
as sepsis marker, 113
Protein C-thrombomodulin, inhibition of,
112
Protein C-thrombomodulin complex-
protein C endothelial receptor, 110
Protein kinase C, 109
Protein S, 107
inhibition of, 112
Proteus mirabilis, aminoglycoside
resistance in, 43
Prothrombin, 106
Prowess Trial, 114
P-selectin, 105
Pseudomonas aeruginosa, antibiotic
resistance in, 33, 34–35, 43
Pulmonary arterial catheterization (PAC),
94, 97, 99, 101
Pulmonary capillary wedge pressure
(PCWP), 56
Pulmonary vascular resistance (PVR), 59
effect of red blood cell transfusions
on, 4
160
Index
Pyruvate, 127, 128, 129
Pyruvate dehydrogenase, 126, 128
inhibition of, 128
treatment of, 128, 132
Q
Quinolones, 35
R
Ramsay Scale, 142
Red blood cells, half life of, 1
Red blood cell transfusions, in septic
patients, 1–10
central venous pressure in, 6
complications of, 2, 4–6
during early resuscitation, 100
effect on oxygen-carrying capacity, 3,
4–5, 6–7
effect on pulmonary vascular
resistance, 4
hemoglobin levels in, 2, 3–4, 6, 7
mean arterial pressure in, 6
mixed venous saturation in, 6, 7
as nosocomial infection risk factor, 3
Renal artery, blood flow in, 82, 83
Renal dialysis, in septic patients,
29–30
Renal dysfunction, definition of, 82
Renal failure
definition of, 82
intraabdominal hypertension-related,
82–83
sepsis-related, 134, 137–138
Renal filtration gradient (FG), 82–83
Renal perfusion pressure (RPP), 82, 83
Respiratory failure, sepsis-related, 134
Resuscitation. See Hemodynamic
resuscitation
Richmond Agitation-Sedation Scale
(RASS), 142
Right ventricular dysfunction, in sepsis,
59–60
Right ventricular ejection fraction
(RVEF), 59, 60, 61
S
Scabies, transmission of, 39
Sedation-Agitation Scale (SAS), 142
Sedation scales, 142
Sepsis
age factors in, 21
annual number of cases, 141
definition of, 11–13, 55
duration of, 21
epidemiology of, in Latin America,
17–21
frequency of, 2
hemodynamics of, 13
ICD-9-CM coding for, 13, 15, 20
incidence of, 2
in Brazil, 20
inflammatory variables in, 13
mortality rate in, 2, 121
in Latin America, 18, 19, 20
organ dysfunction in, 13
pathophysiology of, 55–56
PIRO “staging” system of, 12–13, 30
severe, 12
economic cost of, 15
incidence of, 15, 55
mortality rate in, 15, 20
tissue perfusion in, 13
Sepsis syndrome, 11–12, 14–15
definition of, 14
incidence of, 14–15
Septicemia, 11–12
mortality rate in, 13
in Latin America, 18, 20
rates of, 13
Sequential organ failure assessment
(SOFA) score, in intraabdominal
hypertension, 81, 82, 83, 84
in cardiovascular failure, 81
in gastrointestinal failure, 83
in hepatic failure, 83
in neurologic failure, 84
in renal failure, 82
in respiratory failure, 82
Serotonin, 104–105
Shigella, transmission of, 39
Shock, septic, 12
cardiogenic, 61
cardiovascular prognostic factors in,
60–61
clinical presentations of, 56
cold, 56
distributive, 61
duration of, 21
Index
hemodynamic collapse profiles in, 61
hemodynamic resuscitation in,
92–102
“golden” hours of, 99
“metabolic” aspects of, 95–97
oxygen debt in, 94–101
hyperdynamic state in, 56, 57
mortality rate in, 25
in Brazil, 20
myocardial depression associated with,
55–73, 92
clinical manifestations of, 56–62
definition of, 55
etiology of, 62–66
pathogenesis of, 55
treatment of, 66–67
prevalence of, 15
in ICU patients, 25
vasopressin levels in, 123, 124
warm, 56
Society of Clinical Care Medicine
(SCCM), 6, 7, 11, 142
Standard precautions, for bacterial
infection control, 37–40
Staphylococcus, coagulase-negative,
methicillin resistance in, 33
Staphylococcus aureus, methicillin-
resistant (MRSA), 33
Stenotrophomonas maltophila, antibiotic
resistance in, 34–35, 43
Superior mesenteric artery blood flow, 83
Surviving Sepsis Campaign, 11, 142, 145
Systemic inflammatory response
syndrome (SIRS), 11–12, 55, 56,
60, 92
diagnostic criteria for, 12, 14
incidence of, 14
mortality rate in, in Latin America, 20
as sepsis component, 14
Systemic vascular resistance (SVR), in
septic shock, 60, 61
T
Tachypnea, in sepsis, 13
Thrombin, 104–105, 106, 107, 110
α-Thrombin, 111–112
Thrombin-activatable fibrinolysis inhibitor
(TAFI), 108, 109, 110
Thrombomodulin, 107, 108–111, 109–111
161
Thrombosis
sepsis-related, 112
venous, intraabdominal hypertension-
related, 81–82
Thromboxane A2, 104–105
Tissue factor, 103–104, 104, 112
inhibition of, 108
Tissue factor pathway inhibitor (TFPI),
107, 113
Tissue perfusion, in sepsis, 13
evaluation of, 94
Tissue plasminogen activator (tPA),
111–112
Tonometry, gastric, 98
Toronto Sepsis Roundtable, Fifth, 12
Transforming growth factor (TGF),
55–56
Troponins I and T, 63
Tuberculosis, transmission of, 39
Tumor necrosis factor, 28
Tumor necrosis factor-α , 27, 55, 108
as delirium cause, 138
hemodynamic effects of, 64
as myocardial depressant, 64–64, 65,
66, 67
tissue factor-factor VII complex
activating effects of, 112
Tumor necrosis factor-α monoclonal
antibodies, 64, 67
U
University of Iowa Hospital and Clinics,
14
Urokinase, 111, 112
V
Vancomycin, bacterial resistance to, 33,
35, 42
Varicella, transmission of, 39
Vasoactive drugs. See also
Vasoconstrictors; Vasopressors;
names of specific drugs
use in resuscitation, 92–93
Vasoconstriction, noradrenaline-mediated,
122
Vasoconstrictors, 92–93
dosage of, 92
guidelines for infusion of, 93
indication for use of, 92
162
Index
Vasodilatation, as sepsis-related
hypoperfusion cause, 121
Vasopressors, 121–125
dobutamine, 122–123
dopamine, 123
norepinephrine, 122
vasopressin, 123–124
Veterans Administration Systemic Sepsis
Cooperative Study, 137
Vitamin K, 106
von Willebrand factor, 105
W
White blood cell count, in systemic
inflammatory response syndrome
(SIRS), 12
White blood cells, lactate production in,
131