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19 criticalcare NEJMGroup collection 2015

Critical
Care


Clinical Collections — Critical Care
Source: The New England Journal of Medicine

Table of Contents
CRITICAL CARE — INTRODUCTON
CRITICAL CARE SERIES OPENING EDITORIAL


8




Critical Care — An All-Encompassing Specialty
Simon Finfer and Jean-Louis Vincent
Aug 15, 2013 


SEVERE SEPSIS AND SEPTIC SHOCK
11

Case Challenge

13

Review Article: Severe Sepsis and Septic Shock
Derek C. Angus and Tom van der Poll
Aug 29, 2013



25

Correspondence
Nov 21, 2013

27

Case Challenge Answer

Related Content
28

 o Protocol-Based Approaches Work? Evidence from ProCESS and
D
Other Trials

29

A Randomized Trial of Protocol-Based Care for Early Septic Shock
The ProCESS Investigators
Mar 18, 2014



40

Editorial: The ProCESS Trial — A New Era of Sepsis Management
Craig M. Lilly
Mar 18, 2014



42

Correspondence
Jul 24, 2014

46

Goal-Directed Resuscitation for Patients with Early Septic Shock
The ARISE Investigators and the ANZICS Clinical Trials Group
Oct 16, 2014



57

Correspondence
Jan 8, 2015

60

Trial of Early, Goal-Directed Resuscitation for Septic Shock
Paul R. Mouncey et al.
Mar 17, 2015

71

Systemic Inflammatory Response Syndrome Criteria in Defining Severe Sepsis
Kirsi-Maija Kaukonen et al.
Mar 17, 2015
continued

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

RESUSCITATION FLUIDS
  82 Case Challenge
  84 Review Article: Resuscitation Fluids
John A. Myburgh and Michael G. Mythen
Sep 26, 2013



  93 Correspondence
Dec 19, 2013

  96 Case Challenge Answer

Related Content
  98 Albumin Replacement in Patients with Severe Sepsis or Septic Shock
Pietro Caironi et al.
Apr 10, 2014



108 Correspondence
Jul 3, 2014

CIRCULATORY SHOCK
111 Case Challenge
113 Review Article: Circulatory Shock
Jean-Louis Vincent and Daniel De Backer
Oct 31, 2013



122 Correspondence
Feb 6, 2014

124 Case Challenge Answer

Related Content
125 High versus Low Blood-Pressure Target in Patients with Septic Shock
Pierre Asfar et al.
Apr 24, 2014

136 Editorial: Is there a Good MAP for Septic Shock?
James A. Russell
Apr 24, 2014



139 Correspondence
Jul 17, 2014

VENTILATOR-INDUCED LUNG INJURY
143 Case Challenge
145 Review Article: Ventilator-Induced Lung Injury
Arthur S. Slutsky and V. Marco Ranieri
Nov 28, 2013



156 Correspondence
Mar 6, 2014

158 Case Challenge Answer
continued

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

VENTILATOR-INDUCED LUNG INJURY (continuted)
Related Content
160 Special Article: Driving Pressure and Survival in the Acute Respiratory Distress Syndrome
Marcelo B.P. Amato et al.
Feb 19, 2015



169 Editorial: Driving Pressure and Respiratory Mechanics in ARDS
Stephen H. Loring and Atul Malhotra
Feb 19, 2015

ACUTE LIVER FAILURE
172 Case Challenge
174 Review Article: Acute Liver Failure
William Bernal and Julia Wendon
Dec 26, 2013



184 Correspondence
Mar 20, 2014

186 Case Challenge Answer

SEDATION AND DELIRIUM IN THE INTENSIVE CARE UNIT
189 Case Challenge
191 Review Article: Sedation and Delirium in the Intensive Care Unit
Michael C. Reade and Simon Finfer
Jan 30, 2014



202 Correspondence
Apr 17, 2014

204 Case Challenge Answer

BLEEDING AND COAGULOPATHIES IN CRITICAL CARE
207 Case Challenge
209 Review Article: Bleeding and Coagulopathies in Critical Care
Beverly J. Hunt
Feb 27, 2014



222 Correspondence
May 29, 2014

224 Case Challenge Answer

Related Content
226 Age of Transfused Blood in Critically Ill Adults
Jacques Lacroix et al.
Mar 17, 2015
continued

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

FEEDING CRITICALLY ILL PATIENTS
236 Case Challenge
238 Review Article: Nutrition in the Acute Phase of Critical Illness
Michael P. Casaer and Greet Van den Berghe
Mar 27, 2014



248 Correspondence
Mar 27, 2014

251 Case Challenge Answer

Related Content
253 Trial of the Route of Early Nutritional Support in Critically Ill Adults
Sheila E. Harvey
Oct 30, 2014



265 Editorial: The Route of Early Nutrition in Critical Illness
Deborah Cook and Yaseen Arabi
Oct 30, 2014



267 Correspondence
Jan 29, 2015

270 Early versus On-Demand Nasoenteric Tube Feeding in Acute Pancreatitis
Olaf J. Bakker et al.
Nov 20, 2014



281 Correspondence
Feb 12, 2015

ICU-ACQUIRED WEAKNESS AND RECOVERY FROM CRITICAL ILLNESS
284 Case Challenge
286 Review Article: ICU-Acquired Weakness and Recovery from Critical Illness
John P. Kress and Jesse B. Hall
Apr 24, 2014



296 Correspondence
Jul 17, 2014

298 Case Challenge Answer

TRAUMATIC INTRACRANIAL HYPERTENSION
301 Case Challenge
303 Review Article: Traumatic Intracranial Hypertension
Nino Stocchetti and Andrew I.R. Maas
May 29, 2014



313 Correspondence
Sep 4, 2014

315 Case Challenge Answer
continued

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

DYING WITH DIGNITY IN THE INTENSIVE CARE UNIT
318 Case Challenge
320 Review Article: Dying with Dignity in the Intensive Care Unit
Deborah Cook and Graeme Rocker
Jun 26, 2014

329 Case Challenge Answer

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CRITICAL CARE COLLECTION —
INTRODUCTION
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Cardiology
Dermatology
Emergency Medicine
Gastroenterology
General Medicine
Hospital Medicine
Infectious Diseases
Neurology
Oncology and Hematology
Pediatrics and Adolescent Medicine
Physician’s First Watch
Psychiatry
Women’s Health

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Caring for acute, severe illness in specialized units accounts for a substantial fraction of
today’s hospital-based health care. The NEJM Group’s “Collection on Critical Care” is
based on a series of review articles on Critical Care Medicine published in the New England
Journal of Medicine between August 2013 and June 2014. This series was not meant to be a
comprehensive review of the entire field, but rather covered 11 topics that the series editors, Jean-Louis Vincent and Simon Finfer, thought would be of interest to the critical care
specialist. (See the editorial that opened the series – the next item in this collection.)
When originally published the series was widely read, attracting over 50,000 views of each
article within the first few months of publication. One of the series’ features was a case
challenge that was published a fortnight before a related review article; the “answers” to
that challenge were published with the review article itself. We encourage you to read the
case before reading the review, and only then to look at the answer.
Critical care is changing rapidly. The review articles were current at the time of their
publication, but to provide an indication of issues that were raised by each article we also
include in this collection the “Letters to the Editor” along with the authors’ replies that
were published in the Journal. Although we have examined the series to be sure that there
are no areas where new consensus has arisen, the onus lies with you the reader to regard
each article as a foundation that was current at the time of publication.
To provide insight into new work that has appeared in the Journal since each review was
published, this collection also contains selected original articles from the Journal (and
­related editorials when appropriate) on the topics that were part of the review article
series.
We hope that you find this Critical Care Collection of value for its convenience and utility.
We urge you to follow the Journal closely as we work hard to identify and publish the most
important work in critical care.

— Jeffrey M. Drazen, M.D.
Editor-in-Chief, New England Journal of Medicine
Distinguished Parker B. Francis Professor of
Medicine
Harvard Medical School
July 2015
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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

e d i t or i a l

Critical Care — An All-Encompassing Specialty
Simon Finfer, M.D., F.C.I.C.M., and Jean-Louis Vincent, M.D., Ph.D.
The August 29 issue of the Journal will include
the first in a series of review articles on critical
care. Critical care is a young specialty that is
generally considered to have developed from the
successful use of invasive ventilation during the
1952 polio epidemic in Copenhagen. In his report
of the response to that epidemic, Ibsen described
much more than the use of invasive ventilation;
he also described collaborative, multidisciplinary
care that can serve as a model for critical care
services to this day.1 He described managing severe infections and respiratory failure, providing
cardiovascular support with resuscitation fluids
and vasopressors, monitoring ventilation by measuring carbon dioxide, placing nasogastric tubes
to feed patients, and conducting daily multidisciplinary rounds. He also described the importance of backup systems when patients’ lives are
so dependent on technology that even brief technical failures will prove fatal.1
From these beginnings, critical care has
spread to most countries in the world. In many
developed societies, the number of critical care
beds is increasing while total number of acute
care hospital beds is decreasing; the proportion
of acute care hospital beds that are intensive
care unit (ICU) beds is increasing substantially.2
Critical care services consume a high proportion of health care budgets. In 2005, critical
care services in the United States were estimated to cost $81.7 billion, or 0.66% of the gross
domestic product.3
Although the organization of critical care services varies from country to country, it is clear
that taken at its broadest definition, critical care
is an all-encompassing specialty with almost
limitless boundaries. Critical care involves the
use of life-sustaining, high-technology medicine

n engl j med 369;7

catering to a patient population that extends to
both extremes of age. In adult ICUs, the average
age is increasing and is now commonly well
over 60 years. Although ICUs admitting patients
for preplanned brief stays after planned major
surgery have very low mortality rates, the rates in
adult ICUs among patients admitted “for cause”
are generally around 15% in developed countries.
In a recent study of Medicare beneficiaries in
the United States, 29.2% of patients had been
treated in an ICU during the last month of their
lives.4 Currently, most deaths in ICUs are expected, and ICU clinicians regularly face the decision of when to change the focus of treatment
from attempting to cure to providing palliative
care. Compassionate care of dying patients requires that critical care practitioners add yet another essential skill set to their more obvious
background knowledge and procedural skills
designed to sustain life.
In 2013, critical care practitioners may recognize many of the problems faced by Ibsen in
1952. Although we have much more highly developed technology available, our patients are often much older, and many have multiple coexisting diseases. Determining how best to use the
available technology for our patients’ benefit can
be determined only through high-quality research.
To the credit of our specialty, large national and
international clinical-trial networks are systematically evaluating both established and new
treatments in high-quality large-scale trials.5
Most of these trials are funded by competitive,
peer-reviewed grants, and many of the trial reports have been published in the Journal.6-11
Although we cannot cover anywhere near the
full range of critical care practice in our series,
we have invited our authors to address many of

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

The

n e w e ng l a n d j o u r na l

the core issues faced in the ICU. Coming reviews will address the management of severe
sepsis, the choice and use of resuscitation fluids,
and the treatment of shock. In addition, they
will address newer issues that are a product of
our success in supporting older, sicker patients
through longer stays in the ICU — problems
such as the management of delirium, ICUacquired weakness, and recovery from prolonged
critical illness.
In preparation for the start of the series, we
have posted a case at NEJM.org that highlights
issues raised in the review article on sepsis, the
first in the series. As the series progresses, each
installment of the case will be accompanied,
2 weeks before publication of the review article,
by questions about the diagnosis or management
of the condition to be explored in that month’s
critical care review article. We encourage you to
follow the case and tell us how you would manage the patient’s treatment. We will post the results of the online polling to coordinate with
publication of the actual review article.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
From the George Institute for Global Health and Royal North
Shore Hospital, University of Sydney, Sydney (S.F.); and the Department of Intensive Care Medicine, Université Libre de Bruxelles, and the Department of Intensive Care, Erasme University
Hospital — both in Brussels (J.L.V.).

of

m e dic i n e

1. Ibsen B. The anaesthetist’s viewpoint on the treatment of

respiratory complications in poliomyelitis during the epidemic
in Copenhagen, 1952. Proc R Soc Med 1954;47:72-4.
2. Halpern NA, Pastores SM, Greenstein RJ. Critical care medicine in the United States 1985-2000: an analysis of bed numbers,
use, and costs. Crit Care Med 2004;32:1254-9.
3. Halpern NA, Pastores SM. Critical care medicine in the United
States 2000-2005: an analysis of bed numbers, occupancy rates,
payer mix, and costs. Crit Care Med 2010;38:65-71.
4. Teno JM, Gozalo PL, Bynum JP, et al. Change in end-of-life
care for Medicare beneficiaries: site of death, place of care, and
health care transitions in 2000, 2005, and 2009. JAMA 2013;
309:470-7.
5. Cook D, Brower R, Cooper J, Brochard L, Vincent JL. Multicenter clinical research in adult critical care. Crit Care Med
2002;30:1636-43.
6. Hébert PC, Wells G, Blajchman MA, et al. A multicenter,
randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-17. [Erratum,
N Engl J Med 1999;340:1056.]
7. The SAFE Study Investigators. A comparison of albumin and
saline for fluid resuscitation in the intensive care unit. N Engl J
Med 2004;350:2247-56.
8. NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009;
360:1283-97.
9. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal
volumes for acute lung injury and the acute respiratory distress
syndrome. N Engl J Med 2000;342:1301-8.
10. Young D, Lamb SE, Shah S, et al. High-frequency oscillation
for acute respiratory distress syndrome. N Engl J Med 2013;368:
806-13.
11. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency
oscillation in early acute respiratory distress syndrome. N Engl J
Med 2013;368:795-805.
N Engl J Med 2013; 369:669
DOI: 10.1056/NEJMe1304035
Copyright © 2013 Massachusetts Medical Society.

A Role for Finasteride in the Prevention of Prostate Cancer?
Michael LeFevre, M.D., M.S.P.H.
All medical care should seek to achieve one or
more of these three goals: to relieve suffering, to
prevent future suffering, or to prolong life. Preventive services, by definition, are utilized to
prevent future suffering or prolong life. We
should offer preventive services when science assures us that across the population of patients
we serve, we do more good than harm.
How would we know if a preventive service
accomplishes one or more of these three goals?
All-cause mortality is the most appealing outcome in a prevention trial because it clearly reflects the goal of prolonging life, and it is not
subject to the difficulties of accurately assigning
a specific cause of death. All clinicians who
struggle with completing a death certificate can
670

n engl j med 369;7

identify with the challenge that researchers face
in the ascertainment of cause of death. But at
any specific age, most single diseases play a relatively small role in overall mortality. It is much
easier to demonstrate a reduction in diseasespecific mortality.
Prostate cancer is a logical target for a preventive service, with most of the public discourse about prostate-cancer prevention today
focusing on screening. Screening seeks to identify cancers in asymptomatic persons with the
hope of altering the natural history of those
cancers that are destined to cause suffering
without doing too much harm in the process. In
the multicenter Prostate, Lung, Colorectal, and
Ovarian Cancer Screening Trial1 conducted in

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

SEVERE SEPSIS AND SEPTIC SHOCK
This area is one of the most controversial in medicine. Over the past 20 years we have become better and better
at recognizing sepsis clinically, understanding its pathobiology and organizing its treatment.
Since the accompanying review article was published, a trio of similarly designed studies, one performed in the
United States, one largely in Australia and New Zealand, and one in the United Kingdom, have been completed
and published in the Journal. These trials show that our current recognition and management of sepsis has advanced substantially over what it was at the turn of the 21st century. The articles describing these studies have
been included in this collection.

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

Case Challenge

Severe Sepsis and Septic Shock
Simon Finfer, M.D., and Jean-Louis Vincent, M.D., Ph.D., Editors
A 77-year-old man is admitted to the ICU after an emergency laparotomy for a perforated sigmoid colon with
marked peritoneal contamination. He is mechanically ventilated and hypotensive. What should be done first?

Presentation of Case
A 77-year-old man is admitted to the intensive care unit (ICU) of a university hospital from the operating room.
Earlier the same day, he had presented to the emergency department with abdominal pain. His medical history
included treated hypertension and hypercholesterolemia, previous heavy alcohol intake, and mild cognitive impairment. In the emergency department, he was drowsy and confused when roused and was peripherally cold
with cyanosis. The systemic arterial blood pressure was 75/50 mm Hg, and the heart rate was 125 beats per minute. The abdomen was tense and distended. After the administration of 1 liter of intravenous crystalloid to restore
the blood pressure, a computed tomographic scan of the abdomen showed extraluminal gas and suspected extraluminal feces consistent with a perforated sigmoid colon. He was treated with intravenous antibiotics and taken to
the operating room for laparotomy. During this procedure, gross fecal peritonitis from a perforated sigmoid colon
was confirmed; resection of the sigmoid colon with closure of the rectal stump and creation of an end colostomy
(Hartmann’s procedure) was performed with extensive peritoneal toilet and washout.

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine
On arrival in the ICU, he is still anesthetized, the trachea is intubated, and the lungs are mechanically ventilated
with a fraction of inspired oxygen of 0.4; the arterial blood pressure is supported with a norepinephrine infusion.
When the patient was in the operating room, he received a total of 4 liters of crystalloid. On his arrival in the ICU,
the vital signs are a blood pressure of 88/52 mm Hg, heart rate of 120 beats per minute in sinus rhythm, central venous pressure of 6 mm Hg, and temperature of 35.6°C. An analysis of arterial blood shows a pH of 7.32, a partial
pressure of carbon dioxide of 28 mm Hg, a partial pressure of oxygen of 85 mm Hg, and a lactate level of 3.0 mmol
per liter.

Case Challenge Question
What therapy should be instituted to reduce this patient’s risk of dying from septic shock?
A.  Treatment with intravenous immune globulin (gamma globulin).
B.  Treatment with intravenous hydrocortisone (at a dose of 50 mg every 6 hours).
C.  Treatment with a hydroxymethylglutaryl coenzyme A reductase inhibitor (statin).

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

review article
Critical Care Medicine
Simon R. Finfer, M.D., and Jean-Louis Vincent, M.D., Ph.D., Editors

Severe Sepsis and Septic Shock
Derek C. Angus, M.D., M.P.H., and Tom van der Poll, M.D., Ph.D.
From the CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute
Illness) Center, Department of Critical
Care Medicine, University of Pittsburgh
School of Medicine, Pittsburgh (D.C.A.);
and the Center for Experimental and Molecular Medicine, Division of Infectious
Diseases, and Center for Infection and
Immunity Amsterdam, Academic Medical
Center, University of Amsterdam, Amsterdam (T.P.). Address reprint requests
to Dr. Angus at the Department of Critical Care Medicine, University of Pittsburgh, 614 Scaife Hall, 3550 Terrace St.,
Pittsburgh, PA 15261, or at angusdc@
upmc.edu; or to Dr. van der Poll at the
Division of Infectious Diseases, Academic Medical Center, Meibergdreef 9, Rm.
G2-130, 1105 AZ Amsterdam, the Netherlands, or at t.vanderpoll@amc.uva.nl.
This article was updated on November
21, 2013, at NEJM.org.
N Engl J Med 2013;369:840-51.
DOI: 10.1056/NEJMra1208623
Copyright © 2013 Massachusetts Medical Society.

A correction was made to this article after
publication on November 21, 2013, and is
reflected in this PDF.

S

epsis is one of the oldest and most elusive syndromes in medicine.
Hippocrates claimed that sepsis (σηψις)
´
was the process by which flesh rots,
swamps generate foul airs, and wounds fester.1 Galen later considered sepsis
a laudable event, necessary for wound healing.2 With the confirmation of germ
theory by Semmelweis, Pasteur, and others, sepsis was recast as a systemic infection, often described as “blood poisoning,” and assumed to be the result of the
host’s invasion by pathogenic organisms that then spread in the bloodstream.
However, with the advent of modern antibiotics, germ theory did not fully explain
the pathogenesis of sepsis: many patients with sepsis died despite successful eradication of the inciting pathogen. Thus, researchers suggested that it was the host,
not the germ, that drove the pathogenesis of sepsis.3
In 1992, an international consensus panel defined sepsis as a systemic inflammatory response to infection, noting that sepsis could arise in response to multiple infectious causes and that septicemia was neither a necessary condition nor
a helpful term.4 Instead, the panel proposed the term “severe sepsis” to describe
instances in which sepsis is complicated by acute organ dysfunction, and they
codified “septic shock” as sepsis complicated by either hypotension that is refractory to fluid resuscitation or by hyperlactatemia. In 2003, a second consensus
panel endorsed most of these concepts, with the caveat that signs of a systemic
inflammatory response, such as tachycardia or an elevated white-cell count, occur
in many infectious and noninfectious conditions and therefore are not helpful in
distinguishing sepsis from other conditions.5 Thus, “severe sepsis” and “sepsis”
are sometimes used interchangeably to describe the syndrome of infection complicated by acute organ dysfunction.

Incidence a nd C ause s
The incidence of severe sepsis depends on how acute organ dysfunction is defined
and on whether that dysfunction is attributed to an underlying infection. Organ
dysfunction is often defined by the provision of supportive therapy (e.g., mechanical ventilation), and epidemiologic studies thus count the “treated incidence” rather than the actual incidence. In the United States, severe sepsis is recorded in 2% of
patients admitted to the hospital. Of these patients, half are treated in the intensive
care unit (ICU), representing 10% of all ICU admissions.6,7 The number of cases in
the United States exceeds 750,000 per year7 and was recently reported to be rising.8
However, several factors — new International Classification of Diseases, 9th Revision
(ICD-9) coding rules, confusion over the distinction between septicemia and severe
sepsis, the increasing capacity to provide intensive care, and increased awareness
and surveillance — confound the interpretation of temporal trends.
Studies from other high-income countries show similar rates of sepsis in the
ICU.9 The incidence of severe sepsis outside modern ICUs, especially in parts of
840

n engl j med 369;9
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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

critical care medicine

the world in which ICU care is scarce, is largely
unknown. Extrapolating from treated incidence
rates in the United States, Adhikari et al. estimated
up to 19 million cases worldwide per year.10 The
true incidence is presumably far higher.
Severe sepsis occurs as a result of both community-acquired and health care–associated infections. Pneumonia is the most common cause,
accounting for about half of all cases, followed by
intraabdominal and urinary tract infections.7,8,11,12
Blood cultures are typically positive in only one
third of cases, and in up to a third of cases,
cultures from all sites are negative.7,11,13,14 Staphylococcus aureus and Streptococcus pneumoniae are the
most common gram-positive isolates, whereas
Escherichia coli, klebsiella species, and Pseudomonas
aeruginosa predominate among gram-negative isolates.11,14 An epidemiologic study of sepsis
showed that during the period from 1979 to
2000, gram-positive infections overtook gramnegative infections.15 However, in a more recent
study involving 14,000 ICU patients in 75 countries, gram-negative bacteria were isolated in 62%
of patients with severe sepsis who had positive
cultures, gram-positive bacteria in 47%, and
fungi in 19%.12
Risk factors for severe sepsis are related both
to a patient’s predisposition for infection and to
the likelihood of acute organ dysfunction if infection develops. There are many well-known risk
factors for the infections that most commonly
precipitate severe sepsis and septic shock, including chronic diseases (e.g., the acquired immunodeficiency syndrome, chronic obstructive pulmonary disease, and many cancers) and the use
of immunosuppressive agents.7 Among patients
with such infections, however, the risk factors
for organ dysfunction are less well studied but
probably include the causative organism and the
patient’s genetic composition, underlying health
status, and preexisting organ function, along
with the timeliness of therapeutic intervention.16
Age, sex, and race or ethnic group all influence
the incidence of severe sepsis, which is higher in
infants and elderly persons than in other age
groups, higher in males than in females, and
higher in blacks than in whites.7,17
There is considerable interest in the contribution of host genetic characteristics to the incidence and outcome of sepsis, in part because of
strong evidence of inherited risk factors.18 Many
studies have focused on polymorphisms in genes
n engl j med 369;9

encoding proteins implicated in the pathogenesis of sepsis, including cytokines and other mediators involved in innate immunity, coagulation, and fibrinolysis. However, findings are
often inconsistent, owing at least in part to the
heterogeneity of the patient populations studied.19,20 Although a recent genomewide association study21 explored drug responsiveness in
sepsis, no such large-scale studies of susceptibility to or outcome of sepsis have been performed.

Cl inic a l Fe at ur e s
The clinical manifestations of sepsis are highly
variable, depending on the initial site of infection, the causative organism, the pattern of acute
organ dysfunction, the underlying health status
of the patient, and the interval before initiation
of treatment. The signs of both infection and organ dysfunction may be subtle, and thus the
most recent international consensus guidelines
provide a long list of warning signs of incipient
sepsis (Table 1).5 Acute organ dysfunction most
commonly affects the respiratory and cardiovascular systems. Respiratory compromise is classically manifested as the acute respiratory distress
syndrome (ARDS), which is defined as hypoxemia with bilateral infiltrates of noncardiac origin.22 Cardiovascular compromise is manifested
primarily as hypotension or an elevated serum
lactate level. After adequate volume expansion,
hypotension frequently persists, requiring the
use of vasopressors, and myocardial dysfunction
may occur.23
The brain and kidneys are also often affected.
Central nervous system dysfunction is typically
manifested as obtundation or delirium. Imaging
studies generally show no focal lesions, and
findings on electroencephalography are usually
consistent with nonfocal encephalopathy. Critical illness polyneuropathy and myopathy are
also common, especially in patients with a prolonged ICU stay.24 Acute kidney injury is manifested as decreasing urine output and an increasing serum creatinine level and frequently
requires treatment with renal-replacement therapy. Paralytic ileus, elevated aminotransferase
levels, altered glycemic control, thrombocytopenia and disseminated intravascular coagulation,
adrenal dysfunction, and the euthyroid sick syndrome are all common in patients with severe
sepsis.5

14
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841


Clinical Collections — Critical Care
Source: The New England Journal of Medicine

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 1. Diagnostic Criteria for Sepsis, Severe Sepsis, and Septic Shock.*
Sepsis (documented or suspected infection plus ≥1 of the following)†
General variables
Fever (core temperature, >38.3°C)
Hypothermia (core temperature, <36°C)
Elevated heart rate (>90 beats per min or >2 SD above the upper limit of the normal range for age)
Tachypnea
Altered mental status
Substantial edema or positive fluid balance (>20 ml/kg of body weight over a 24-hr period)
Hyperglycemia (plasma glucose, >120 mg/dl [6.7 mmol/liter]) in the absence of diabetes
Inflammatory variables
Leukocytosis (white-cell count, >12,000/mm3)
Leukopenia (white-cell count, <4000/mm3)
Normal white-cell count with >10% immature forms
Elevated plasma C-reactive protein (>2 SD above the upper limit of the normal range)
Elevated plasma procalcitonin (>2 SD above the upper limit of the normal range)
Hemodynamic variables
Arterial hypotension (systolic pressure, <90 mm Hg; mean arterial pressure, <70 mm Hg; or decrease in systolic
pressure of >40 mm Hg in adults or to >2 SD below the lower limit of the normal range for age)
Elevated mixed venous oxygen saturation (>70%)‡
Elevated cardiac index (>3.5 liters/min/square meter of body-surface area)§
Organ-dysfunction variables
Arterial hypoxemia (ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen, <300)
Acute oliguria (urine output, <0.5 ml/kg/hr or 45 ml/hr for at least 2 hr)
Increase in creatinine level of >0.5 mg/dl (>44 μmol/liter)
Coagulation abnormalities (international normalized ratio, >1.5; or activated partial-thromboplastin time, >60 sec)
Paralytic ileus (absence of bowel sounds)
Thrombocytopenia (platelet count, <100,000/mm3)
Hyperbilirubinemia (plasma total bilirubin, >4 mg/dl [68 μmol/liter])
Tissue-perfusion variables
Hyperlactatemia (lactate, >1 mmol/liter)
Decreased capillary refill or mottling
Severe sepsis (sepsis plus organ dysfunction)
Septic shock (sepsis plus either hypotension [refractory to intravenous fluids] or hyperlactatemia)¶
* Data are adapted from Levy et al.5
† In children, diagnostic criteria for sepsis are signs and symptoms of inflammation plus infection with hyperthermia or
hypothermia (rectal temperature, >38.5°C or <35°C, respectively), tachycardia (may be absent with hypothermia), and at
least one of the following indications of altered organ function: altered mental status, hypoxemia, increased serum lactate level, or bounding pulses.
‡ A mixed venous oxygen saturation level of more than 70% is normal in newborns and children (pediatric range, 75 to 80%).
§ A cardiac index ranging from 3.5 to 5.5 liters per minute per square meter is normal in children.
¶ Refractory hypotension is defined as either persistent hypotension or a requirement for vasopressors after the administration of an intravenous fluid bolus.

Ou t c ome
Before the introduction of modern intensive care
with the ability to provide vital-organ support,
severe sepsis and septic shock were typically lethal. Even with intensive care, rates of in-hospital
842

n engl j med 369;9

death from septic shock were often in excess of
80% as recently as 30 years ago.25 However, with
advances in training, better surveillance and
monitoring, and prompt initiation of therapy to
treat the underlying infection and support failing
organs, mortality is now closer to 20 to 30% in

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

critical care medicine

many series.7,26 With decreasing death rates, attention has focused on the trajectory of recovery
among survivors. Numerous studies have suggested that patients who survive to hospital discharge after sepsis remain at increased risk for
death in the following months and years. Those
who survive often have impaired physical or neurocognitive functioning, mood disorders, and a
low quality of life.27 In most studies, determining
the causal role of sepsis in such subsequent disorders has been difficult. However, a recent analysis of the Health and Retirement Study, involving
a large, longitudinal cohort of aging Americans,
suggested that severe sepsis significantly accelerated physical and neurocognitive decline.28

four main classes — toll-like receptors, C-type
lectin receptors, retinoic acid inducible gene 1–like
receptors, and nucleotide-binding oligomerization
domain–like receptors — have been identified,
with the last group partially acting in protein
complexes called inflammasomes (Fig. 1).31
These receptors recognize structures that are
conserved among microbial species, so-called
pathogen-associated molecular patterns, resulting in the up-regulation of inflammatory gene
transcription and initiation of innate immunity.
The same receptors also sense endogenous molecules released from injured cells, so-called
damage-associated molecular patterns, or alarmins, such as high-mobility group protein B1, S100
proteins, and extracellular RNA, DNA, and histones.32 Alarmins are also released during sterile
Pathoph ysiol o gy
injury such as trauma, giving rise to the concept
Host Response
that the pathogenesis of multiple organ failure in
As the concept of the host theory emerged, it was sepsis is not fundamentally different from that in
first assumed that the clinical features of sepsis noninfectious critical illness.32
were the result of overly exuberant inflammation. Later, Bone et al.29 advanced the idea that Coagulation Abnormalities
the initial inflammatory response gave way to a Severe sepsis is almost invariably associated with
subsequent “compensatory antiinflammatory re- altered coagulation, frequently leading to dissponse syndrome.” However, it has become ap- seminated intravascular coagulation.33 Excess
parent that infection triggers a much more com- fibrin deposition is driven by coagulation
plex, variable, and prolonged host response, in through the action of tissue factor, a transmemwhich both proinflammatory and antiinflamma- brane glycoprotein expressed by various cell
tory mechanisms can contribute to clearance of types; by impaired anticoagulant mechanisms,
infection and tissue recovery on the one hand including the protein C system and antithromand organ injury and secondary infections on the bin; and by compromised fibrin removal owing
other.30 The specific response in any patient de- to depression of the fibrinolytic system (Fig. 2).33
pends on the causative pathogen (load and viru- Protease-activated receptors (PARs) form the molence) and the host (genetic characteristics and lecular link between coagulation and inflammacoexisting illnesses), with differential responses tion. Among the four subtypes that have been
at local, regional, and systemic levels (Fig. 1). The identified, PAR1 in particular is implicated in
composition and direction of the host response sepsis.33 PAR1 exerts cytoprotective effects when
probably change over time in parallel with the stimulated by activated protein C or low-dose
clinical course. In general, proinflammatory reac- thrombin but exerts disruptive effects on endotions (directed at eliminating invading pathogens) thelial-cell barrier function when activated by
are thought to be responsible for collateral tissue high-dose thrombin.34 The protective effect of
damage in severe sepsis, whereas antiinflamma- activated protein C in animal models of sepsis is
tory responses (important for limiting local and dependent on its capacity to activate PAR1 and
systemic tissue injury) are implicated in the en- not on its anticoagulant properties.34
hanced susceptibility to secondary infections.
Innate Immunity

Antiinflammatory Mechanisms
and Immunosuppression

Knowledge of pathogen recognition has increased tremendously in the past decade. Pathogens activate immune cells through an interaction with pattern-recognition receptors, of which

The immune system harbors humoral, cellular,
and neural mechanisms that attenuate the potentially harmful effects of the proinflammatory
response (Fig. 1).30 Phagocytes can switch to an

n engl j med 369;9

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843


Clinical Collections — Critical Care
Source: The New England Journal of Medicine

Proinflammatory response

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Excessive inflammation causing collateral damage (tissue injury)
Damage-associated
molecular patterns

Perpetuation of inflammation

Pathogen factors

Host–pathogen interaction

Load
Virulence
Pathogen-associated
molecular patterns
Cytokines
Proteases
Reactive oxygen species

Complement products

Coagulation proteases

Leukocyte activation

Complement activation

Coagulation activation

CLRs
TLRs

Neuroendocrine regulation

NLRs

Vagus
nerve

Apoptosis of T, B,
and dendritic cells

Celiac
ganglion

Liver,
intestine

Host cell

Spleen
Expansion of regulatory
T and myeloid
suppressor cells

Norepinephrine
Host factors
Environment
Genetics
Age
Other illnesses
Medications

Hypothalamic–
pituitary–
adrenal axis

Antiinflammatory response

Necrotic cell death

Inhibition of proinflammatory
gene transcription

Brain

RLRs

Endosome

Impaired function
of immune cells

Antiinflammatory cytokines
Soluble cytokine receptors
Negative regulators
of TLR signaling
Epigenetic regulation

Acetylcholine
Inhibition of proinflammatory
cytokine production

Adrenal
gland

Impaired
phagocytosis

Catecholamines
Cortisol

Immunosuppression with enhanced susceptibility to secondary infections

COLOR FIGURE
Figure 1. The Host Response in Severe Sepsis.
Draft
6
8/09/13
The host response to sepsis is characterized by both proinflammatory responses (top of panel, in red) and antiinflammatory immunosupAuthor Angus
pressive responses (bottom of panel, in blue). The direction, extent, and duration of these reactions are determined
by1 both host factors
Fig #
(e.g., genetic characteristics, age, coexisting illnesses, and medications) and pathogen factors (e.g., microbial Title
load and virulence). Inflammatory responses are initiated by interaction between pathogen-associated molecular patterns expressed by pathogens and patternME
recognition receptors expressed by host cells at the cell surface (toll-like receptors [TLRs] and C-type lectin receptors
[CLRs]), in the
DE
Drazen
endosome (TLRs), or in the cytoplasm (retinoic acid inducible gene 1–like receptors [RLRs] and nucleotide-binding
oligomerization
Artist
Knoper
domain–like receptors [NLRs]). The consequence of exaggerated inflammation is collateral tissue damage and necrotic
cell PLEASE
death,
which
AUTHOR
NOTE:
Figure has been redrawn and type has been reset
results in the release of damage-associated molecular patterns, so-called danger molecules that perpetuate inflammation
at least in part
Please check carefully
by acting on the same pattern-recognition receptors that are triggered by pathogens.
Issue date 8/29/13

antiinflammatory phenotype that promotes tissue repair, and regulatory T cells and myeloidderived suppressor cells further reduce inflammation. In addition, neural mechanisms can
inhibit inflammation.35 In the so-called neuroinflammatory reflex, sensory input is relayed
through the afferent vagus nerve to the brain
stem, from which the efferent vagus nerve activates the splenic nerve in the celiac plexus, resulting in norepinephrine release in the spleen
and acetylcholine secretion by a subset of CD4+
844

n engl j med 17
369;9

T cells. The acetylcholine release targets α7 cholinergic receptors on macrophages, suppressing
the release of proinflammatory cytokines.36 In
animal models of sepsis,35 disruption of this
neural-based system by vagotomy increases susceptibility to endotoxin shock, whereas stimulation of the efferent vagus nerve or α7 cholinergic
receptors attenuates systemic inflammation.
Patients who survive early sepsis but remain
dependent on intensive care have evidence of immunosuppression, in part reflected by reduced

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Clinical Collections — Critical Care
Source: The New England Journal of Medicine

critical care medicine

Tissue hypoperfusion
Decreased anticoagulation

Increased coagulation

↑ Tissue
Monocyte

factor

Endothelial cell

↓Tissue

factor pathway
inhibitor

↓ Antithrombin

Microcirculation

Loss of barrier function

NETs
with trapped
platelets

S1P3

↓ Endothelial

↓ TM

protein C receptor

Vasodilatation

protein C

↓ Blood pressure

↓Fibrinolysis

↓ Red-cell
deformability

Neutrophil
Thrombus

S1P1

↑ S1P3 and
↓ S1P1

↓ Protein C
↓ Activated

↑ PAI-1

PAR1

Thrombosis

↓ Activated protein C
and ↑ thrombin

↓ VE cadherin and
↓Tight junctions

↑ Angiopoietin 2

Cell shrinkage
and cell death

Capillary leak
and interstitial
edema
Loss of
barrier function

Tissue

Tissue hypoperfusion

Release of
mitochondrial
contents

Mitochondrial
dysfunction

↓Tissue oxygenation

Organ failure
Figure 2. Organ Failure in Severe Sepsis and Dysfunction of the Vascular Endothelium and Mitochondria.
COLOR FIGURE and imSepsis is associated with microvascular thrombosis caused by concurrent activation of coagulation (mediated by tissue factor)
pairment of anticoagulant mechanisms as a consequence of reduced activity of endogenous anticoagulant pathways
by
actiDraft(mediated
6
7/24/13
Author
Angus
vated protein C, antithrombin, and tissue factor pathway inhibitor), plus impaired fibrinolysis owing to enhanced
release
of plasminogen
2
Fig #
activator inhibitor type 1 (PAI-1). The capacity to generate activated protein C is impaired at least in part by reduced
expression
of two
Title
endothelial receptors: thrombomodulin (TM) and the endothelial protein C receptor. Thrombus formation is further facilitated by neuME
trophil extracellular traps (NETs) released from dying neutrophils. Thrombus formation results in tissue hypoperfusion,
which is aggraDEby the
Drazen
vated by vasodilatation, hypotension, and reduced red-cell deformability. Tissue oxygenation is further impaired
loss of barrier
Artist
Knoper
function of the endothelium owing to a loss of function of vascular endothelial (VE) cadherin, alterations in endothelial cell-to-cell tight
AUTHOR PLEASE NOTE:
junctions, high levels of angiopoietin 2, and a disturbed balance between sphingosine-1 phosphate receptor 1 (S1P1)
S1P3
within
Figure hasand
been redrawn
and type
has been reset
Please check carefully
the vascular wall, which is at least in part due to preferential induction of S1P3 through protease activated receptor
1
(PAR1)
as
a
result
Issue date 8/29/13
of a reduced ratio of activated protein C to thrombin. Oxygen use is impaired at the subcellular level because of damage to mitochondria
from oxidative stress.

expression of HLA-DR on myeloid cells.37 These
patients frequently have ongoing infectious foci,
despite antimicrobial therapy, or reactivation of
latent viral infection.38,39 Multiple studies have
documented reduced responsiveness of blood
leukocytes to pathogens in patients with sepsis,30 findings that were recently corroborated by
postmortem studies revealing strong functional
impairments of splenocytes obtained from pan engl j med 369;9

tients who had died of sepsis in the ICU.37 Besides the spleen, the lungs also showed evidence
of immunosuppression; both organs had enhanced expression of ligands for T-cell inhibitory receptors on parenchymal cells.37 Enhanced
apoptosis, especially of B cells, CD4+ T cells,
and follicular dendritic cells, has been implicated in sepsis-associated immunosuppression and
death.40,41 Epigenetic regulation of gene expres-

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845


846

n engl j med19
369;9

1B

Target a hemoglobin level of 7 to 9 g/dl in patients without hypoperfusion, critical coronary artery disease or myocardial ischemia, or acute hemorrhage

nejm.org

1B
1A

Use weaning protocols

Use prone positioning in patients with sepsis-induced ARDS and a ratio of the partial pressure of arterial oxygen (mm Hg) to the fraction of inspired oxygen of
<100, in facilities that have experience with such practice

1C

2C

Use recruitment maneuvers in patients with severe refractory hypoxemia due to ARDS

Use a conservative fluid strategy for established acute lung injury or ARDS with no evidence of tissue hypoperfusion

2C

Administer higher rather than lower positive end-expiratory pressure for patients with sepsis-induced ARDS

Elevate the head of the bed in patients undergoing mechanical ventilation, unless contraindicated

1B
2C

Apply a minimal amount of positive end-expiratory pressure in ARDS

Use a low tidal volume and limitation of inspiratory-plateau-pressure strategy for ARDS

1A/1B

1C

Perform source control with attention to risks and benefits of the chosen method within 12 hr after diagnosis

of

Respiratory support

1B

n e w e ng l a n d j o u r na l

Reassess antibiotic therapy daily for de-escalation when appropriate

1B/1C

Perform imaging studies promptly to confirm source of infection

Administer broad-spectrum antibiotic therapy within 1 hr after diagnosis of either severe sepsis or septic shock

1C
UG

Obtain blood cultures before antibiotic therapy is administered

Infection control

2C

Avoid the use of dopamine except in carefully selected patients (e.g., patients with a low risk of arrhythmias and either known marked left ventricular systolic dysfunction or low heart rate)

Avoid the use of intravenous hydrocortisone if adequate fluid resuscitation and vasopressor therapy restore hemodynamic stability; if hydrocortisone is used, administer at a dose of 200 mg/day

2C

Add vasopressin (at a dose of 0.03 units/min) with weaning of norepinephrine, if tolerated

1C

UG

Use epinephrine when an additional agent is needed to maintain adequate blood pressure

The

Infuse dobutamine or add it to vasopressor therapy in the presence of myocardial dysfunction (e.g., elevated cardiac filling pressures or low cardiac output) or ongoing hypoperfusion despite adequate intravascular volume and mean arterial pressure

1B
2B

Use norepinephrine as the first-choice vasopressor to maintain a mean arterial pressure of ≥65 mm Hg

1C

1C

Avoid hetastarch formulations

UG

2C

Consider the addition of albumin when substantial amounts of crystalloid are required to maintain adequate arterial pressure

Continue fluid-challenge technique as long as there is hemodynamic improvement

1B

Begin initial fluid challenge in patients with tissue hypoperfusion and suspected hypovolemia, to achieve ≥30 ml of crystalloids per kilogram of body weight‡

1C

Begin initial fluid resuscitation with crystalloid and consider the addition of albumin

Grade†

Begin goal-directed resuscitation during first 6 hr after recognition

Resuscitation

Element of Care

Table 2. Guidelines for the Treatment of Severe Sepsis and Septic Shock from the Surviving Sepsis Campaign.*

Clinical Collections — Critical Care
Source: The New England Journal of Medicine
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* Data are adapted from Dellinger et al.23 ARDS denotes acute respiratory distress syndrome, and ICU intensive care unit.
† For all grades, the number indicates the strength of the recommendation (1, recommended; 2, suggested), and the letter indicates the level of evidence, from high (A) to low (D), with
UG indicating ungraded. Recommendations that are specific to pediatric severe sepsis include therapy with face-mask oxygen, high-flow nasal cannula oxygen, or nasopharyngeal continuous positive end-expiratory pressure in the presence of respiratory distress and hypoxemia (2C); use of physical examination therapeutic end points, such as capillary refill (2C); administration of a bolus of 20 ml of crystalloids (or albumin equivalent) per kilogram of body weight during a period of 5 to 10 minutes for hypovolemia (2C); increased use of inotropes
and vasodilators in septic shock with low cardiac output associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven absolute adrenal insufficiency (2C).
‡ The guidelines recommend completing the initial fluid resuscitation within 3 hours (UG).

1B
Address goals of care, including treatment plans and end-of-life planning as appropriate

1B

2C

critical care medicine

Administer oral or enteral feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hr after a diagnosis
of severe sepsis or septic shock

Administer stress-ulcer prophylaxis to prevent upper gastrointestinal bleeding

2B

1B
Administer prophylaxis for deep-vein thrombosis

Use the equivalent of continuous venovenous hemofiltration or intermittent hemodialysis as needed for renal failure or fluid overload

1A
Use a protocol-specified approach to blood glucose management, with the initiation of insulin after two consecutive blood glucose levels of >180 mg/dl (10 mmol/
liter), targeting a blood glucose level of <180 mg/dl

General supportive care

1C

2C
Administer a short course of a neuromuscular blocker (<48 hr) for patients with early, severe ARDS

Avoid neuromuscular blockers if possible in patients without ARDS

Use sedation protocols, targeting specific dose-escalation end points

Central nervous system support

1B

Clinical Collections — Critical Care
Source: The New England Journal of Medicine

n engl j med 369;9

nejm.org

sion may also contribute to sepsis-associated
immunosuppression.42
Organ Dysfunction

Although the mechanisms that underlie organ
failure in sepsis have been only partially elucidated, impaired tissue oxygenation plays a key
role (Fig. 2). Several factors — including hypotension, reduced red-cell deformability, and
microvascular thrombosis — contribute to diminished oxygen delivery in septic shock. Inflammation can cause dysfunction of the vascular endothelium, accompanied by cell death and loss of
barrier integrity, giving rise to subcutaneous and
body-cavity edema.43 In addition, mitochondrial
damage caused by oxidative stress and other mechanisms impairs cellular oxygen use.44 Moreover,
injured mitochondria release alarmins into the
extracellular environment, including mitochondrial DNA and formyl peptides, which can activate neutrophils and cause further tissue injury.45

T r e atmen t
The Surviving Sepsis Campaign, an international
consortium of professional societies involved in
critical care, treatment of infectious diseases,
and emergency medicine, recently issued the third
iteration of clinical guidelines for the management of severe sepsis and septic shock (Table 2).23
The most important elements of the guidelines
are organized into two “bundles” of care: an initial management bundle to be accomplished within 6 hours after the patient’s presentation and a
management bundle to be accomplished in the
ICU.23 Implementation of the bundles is associated with an improved outcome.46,47
The principles of the initial management
bundle are to provide cardiorespiratory resuscitation and mitigate the immediate threats of
uncontrolled infection. Resuscitation requires the
use of intravenous fluids and vasopressors, with
oxygen therapy and mechanical ventilation provided as necessary. The exact components required to optimize resuscitation, such as the
choice and amount of fluids, appropriate type
and intensity of hemodynamic monitoring, and
role of adjunctive vasoactive agents, all remain the
subject of ongoing debate and clinical trials;
many of these issues will be covered in this series.23 Nonetheless, some form of resuscitation is
considered essential, and a standardized approach

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847


Clinical Collections — Critical Care
Source: The New England Journal of Medicine

The

n e w e ng l a n d j o u r na l

has been advocated to ensure prompt, effective
management.23 The initial management of infection requires forming a probable diagnosis,
obtaining cultures, and initiating appropriate
and timely empirical antimicrobial therapy and
source control (i.e., draining pus, if appropriate).
The choice of empirical therapy depends on
the suspected site of infection, the setting in
which the infection developed (i.e., home, nursing home, or hospital), medical history, and local microbial-susceptibility patterns. Inappropriate or delayed antibiotic treatment is associated
with increased mortality.48,49 Thus, intravenous
antibiotic therapy should be started as early as
possible and should cover all likely pathogens. It
has not been determined whether combination
antimicrobial therapy produces better outcomes
than adequate single-agent antibiotic therapy in
patients with severe sepsis.50-53 Current guidelines recommend combination antimicrobial
therapy only for neutropenic sepsis and sepsis
caused by pseudomonas species. Empirical antifungal therapy should be used only in patients at
high risk for invasive candidiasis.50
The patient should also be moved to an appropriate setting, such as an ICU, for ongoing
care. After the first 6 hours, attention focuses on
monitoring and support of organ function,
avoidance of complications, and de-escalation of
care when possible. De-escalation of initial broadspectrum therapy may prevent the emergence of
resistant organisms, minimize the risk of drug
toxicity, and reduce costs, and evidence from
observational studies indicates that such an approach is safe.54 The only immunomodulatory
therapy that is currently advocated is a short
course of hydrocortisone (200 to 300 mg per day
for up to 7 days or until vasopressor support is
no longer required) for patients with refractory
septic shock.23 This recommendation is supported by a meta-analysis,55 but the two largest studies had conflicting results,56,57 and other clinical
trials are ongoing.58,59

se a rch for ne w ther a pie s
Recent Failures

One of the great disappointments during the past
30 years has been the failure to convert advances
in our understanding of the underlying biologic
features of sepsis into effective new therapies.60
Researchers have tested both highly specific
848

n engl j med 369;9

of

m e dic i n e

agents and agents exerting more pleiotropic effects. The specific agents can be divided into
those designed to interrupt the initial cytokine
cascade (e.g., antilipopolysaccharide or anti–proinflammatory cytokine strategies) and those designed to interfere with dysregulated coagulation
(e.g., antithrombin or activated protein C).61 The
only new agent that gained regulatory approval
was activated protein C.62 However, postapproval
concern about the safety and efficacy of activated
protein C prompted a repeat study, which did not
show a benefit and led the manufacturer, Eli Lilly,
to withdraw the drug from the market.11 All other
strategies thus far have not shown efficacy. With
the recent decision to stop further clinical development of CytoFab, a polyclonal anti–tumor necrosis factor antibody (ClinicalTrials.gov number,
NCT01145560), there are no current large-scale
trials of anticytokine strategies in the treatment
of sepsis.
Among the agents with broader immunomodulatory effects, glucocorticoids have received the
most attention. Intravenous immune globulin is
also associated with a potential benefit,63 but
important questions remain, and its use is not
part of routine practice.23 Despite a large number of observational studies suggesting that the
use of statins reduces the incidence or improves
the outcome of sepsis and severe infection,64
such findings have not been confirmed in randomized, controlled trials, so the use of statins
is not part of routine sepsis care.23
PROBLEMS WITH therapeutic development

Faced with these disappointing results, many observers question the current approach to the development of sepsis drugs. Preclinical studies
commonly test drugs in young, healthy mice or
rats exposed to a septic challenge (e.g., bacteria or
bacterial toxins) with limited or no ancillary treatment. In contrast, patients with sepsis are often
elderly or have serious coexisting illnesses, which
may affect the host response and increase the risk
of acute organ dysfunction. Furthermore, death in
the clinical setting often occurs despite the use of
antibiotics, resuscitation, and intensive life support, and the disease mechanisms in such cases
are probably very different from those underlying
the early deterioration that typically occurs in animal models in the absence of supportive care.
There are also large between-species genetic differences in the inflammatory host response.65

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In clinical studies, the enrollment criteria are
typically very broad, the agent is administered on
the basis of a standard formula for only a short
period, there is little information on how the agent
changes the host response and host–pathogen
interactions, and the primary end point is death
from any cause. Such a research strategy is probably overly simplistic in that it does not select patients who are most likely to benefit, cannot adjust
therapy on the basis of the evolving host response
and clinical course, and does not capture potentially important effects on nonfatal outcomes.
NEW STRATEGIES

Consequently, hope is pinned on newer so-called
precision-medicine strategies with better preclinical models, more targeted drug development,
and clinical trials that incorporate better patient
selection, drug delivery, and outcome measurement. For example, options to enrich the preclinical portfolio include the study of animals
that are more genetically diverse, are older, or
have preexisting disease. Longer experiments
with more advanced supportive care would allow
better mimicry of the later stages of sepsis and
multiorgan failure, permitting the testing of
drugs in a more realistic setting and perhaps facilitating the measurement of outcomes such as
cognitive and physical functioning. In addition,
preclinical studies could be used to screen for
potential biomarkers of a therapeutic response
for which there are human homologues.
Activated protein C mutants that lack anticoagulant properties are examples of more targeted drug development and were shown to provide
protection from sepsis-induced death in animals,
without an increased risk of bleeding.66 Biomarkers such as whole-genome expression patterns in peripheral-blood leukocytes may aid in
stratifying patients into more homogeneous subgroups or in developing more targeted therapeutic interventions.67 The insight that severe sepsis
can cause immunosuppression raises the possibility of using immune-stimulatory therapy (e.g.,
interleukin-7, granulocyte–macrophage colonystimulating factor,68 or interferon-γ69), but ideally, such therapy would be used only in patients
in whom immunosuppression is identified or
predicted. Thus, such therapies could be deployed
on the basis of laboratory measures, such as
monocyte HLA-DR expression. In addition, concern about accelerated neurocognitive decline in
n engl j med 369;9

survivors of sepsis opens up avenues to explore
agents currently being tested in patients with
dementia and related conditions.
The designs of trials could be modified to
more easily incorporate these ideas. For example, the considerable uncertainty at the beginning of a trial with regard to the appropriate
selection of patients and drug-administration
strategy and the possibility of treatment interactions may be better handled with the use of
a Bayesian design. A trial could commence with
multiple study groups that reflect the various uncertainties to be tested but then automatically narrow assignments to the best-performing groups
on the basis of predefined-response adaptive
randomization rules. Such designs could be particularly helpful when testing combination therapy or incorporating potential biomarkers of drug
responsiveness.

C onclusions
Severe sepsis and septic shock represent one of
the oldest and most pressing problems in medicine. With advances in intensive care, increased
awareness, and dissemination of evidence-based
guidelines, clinicians have taken large strides in
reducing the risk of imminent death associated
with sepsis. However, as more patients survive
sepsis, concern mounts over the lingering sequelae of what was previously a lethal event.
Strategies are also needed to reach the many millions of patients with sepsis who are far from
modern intensive care. At the same time, advances in molecular biology have provided keen insight into the complexity of pathogen and alarm
recognition by the human host and important
clues to a host response that has gone awry.
However, harnessing that information to provide
effective new therapies has proved to be difficult.
To further improve the outcome of patients with
sepsis through the development of new therapeutic agents, newer, smarter approaches to clinicaltrial design and execution are essential.
Dr. Angus reports receiving grant support through his institution from Eisai, consulting fees from Idaho Technology, Pfizer,
Eisai, MedImmune, BioAegis, and Ferring, and fees from Eli
Lilly for serving as a member of a clinical-trial data and safety
monitoring board. Dr. van der Poll reports receiving grant support through his institution from Sirtris Pharmaceuticals and
consulting fees from Eisai. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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Source: The New England Journal of Medicine

The

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of

m e dic i n e

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The

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c or r e sp ondence

Severe Sepsis and Septic Shock
To the Editor: We would like to address two
potentially confusing issues concerning venous
oxygen saturation (Svo2) as presented in Table 1
of the review by Angus and van der Poll (Aug. 29
issue).1 First, Table 1 suggests that Svo2 is raised
in “sepsis, severe sepsis, and septic shock.” Depending on the timing of patient presentation
and the type of sepsis and septic shock, Svo2 may
indeed be elevated as a result of microcirculatory
shunting or mitochondrial dysfunction. However,
in septic shock, Svo2 can be depressed, reflecting
an increase in the extraction of oxygen due to a
decrease in cardiac output.2-4 Timely treatment
to increase low Svo2 values in adults and children
may improve outcomes2,3 and has therefore been
added to current guidelines for the treatment of
sepsis.5 Second, Table 1 indicates that higher
Svo2 levels (70 to 80%) are normal in children.
As pediatric intensivists, we wish to point out
that the opposite may be true in children with
sepsis, since their cardiac output is more often
decreased rather than increased.3,4 This effect
compromises oxygen delivery and decreases Svo2
levels.4
Job Calis, M.D., Ph.D.
Job van Woensel, M.D., Ph.D.
Academic Medical Center
Amsterdam, the Netherlands
job.calis@gmail.com

Joris Lemson, M.D., Ph.D.
Radboud University Nijmegen Medical Center
Nijmegen, the Netherlands
No potential conflict of interest relevant to this letter was reported.
1. Angus DC, van der Poll T. Severe sepsis and septic shock.

N Engl J Med 2013;369:840-51.

2060

n engl j med 369;21

2. 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.
3. de Oliveira CF, de Oliveira DS, Gottschald AF, et al. ACCM/
PALS haemodynamic support guidelines for paediatric septic
shock: an outcomes comparison with and without monitoring
central venous oxygen saturation. Intensive Care Med 2008;34:
1065-75.
4. Deep A, Goonasekera CD, Wang Y, Brierley J. Evolution of
haemodynamics and outcome of fluid-refractory septic shock in
children. Intensive Care Med 2013;39:1602-9.
5. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis
Campaign: international guidelines for management of severe
sepsis and septic shock, 2012. Intensive Care Med 2013;39:165228.
DOI: 10.1056/NEJMc1312359

To the Editor: Angus and van der Poll describe
the clinical and mechanistic characteristics underlying sepsis and septic shock. In the section
of the article on coagulation abnormalities, although the authors focused on the molecular factors implicated in coagulation, they did not discuss the critical role of platelets in sepsis.1 Nor
did they address the diagnostic indications provided by measuring the immature platelet fraction.2 In a study conducted by myself and others,
published earlier this year,3 we reported that
changes in this marker of cellular reactivity, previously proposed as an inexpensive daily screening tool for bacterial infection in patients with
neutrophilia,2 precede the clinical manifestations
of sepsis.
Paying attention to this early cellular marker
has two advantages: it is easily measured during
routine laboratory blood testing, and it can reveal
the presence of sepsis before it becomes clinically manifest. Given that the immature platelet

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