Severe sepsis and septic shock

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 Pol , M.D., Ph.D.
From the CRISMA (Clinical Research, Inves-tigation, and Systems Modeling of Acute Sepsis is one of the oldest and most elusive syndromes in medicine. Hippocrates claimed that sepsis (σ ´ ηψις) was the process by which flesh rots, Illness) Center, Department of Critical Care Medicine, University of Pittsburgh swamps generate foul airs, and wounds fester.1 Galen later considered sepsis School of Medicine, Pittsburgh (D.C.A.); a laudable event, necessary for wound healing.2 With the confirmation of germ and the Center for Experimental and Mo- theory by Semmelweis, Pasteur, and others, sepsis was recast as a systemic infec- lecular Medicine, Division of Infectious Diseases, and Center for Infection and tion, often described as "blood poisoning," and assumed to be the result of the Immunity Amsterdam, Academic Medical host's invasion by pathogenic organisms that then spread in the bloodstream. Center, University of Amsterdam, Am- However, with the advent of modern antibiotics, germ theory did not fully explain sterdam (T.P.). Address reprint requests to Dr. Angus at the Department of Criti- the pathogenesis of sepsis: many patients with sepsis died despite successful erad- cal Care Medicine, University of Pitts- ication of the inciting pathogen. Thus, researchers suggested that it was the host, burgh, 614 Scaife Hall, 3550 Terrace St., not the germ, that drove the pathogenesis of sepsis.3 Pittsburgh, PA 15261, or at [email protected]; or to Dr. van der Poll at the In 1992, an international consensus panel defined sepsis as a systemic inflam- Division of Infectious Diseases, Academ- matory response to infection, noting that sepsis could arise in response to mul- ic Medical Center, Meibergdreef 9, Rm. tiple infectious causes and that septicemia was neither a necessary condition nor G2-130, 1105 AZ Amsterdam, the Nether-lands, or at [email protected].
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 This article was updated on November codified "septic shock" as sepsis complicated by either hypotension that is refrac- 21, 2013, at NEJM.org.
tory to fluid resuscitation or by hyperlactatemia. In 2003, a second consensus N Engl J Med 2013;369:840-51.
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 Copyright 2013 Massachusetts Medical Society. 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 com- plicated by acute organ dysfunction.
Incidence and Causes 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., mechani- cal ventilation), and epidemiologic studies thus count the "treated incidence" rath- er 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 n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. critical care medicine the world in which ICU care is scarce, is largely encoding proteins implicated in the pathogene- unknown. Extrapolating from treated incidence sis of sepsis, including cytokines and other me- rates in the United States, Adhikari et al. estimated diators involved in innate immunity, coagula- up to 19 million cases worldwide per year.10 The tion, and fibrinolysis. However, findings are true incidence is presumably far higher.
often inconsistent, owing at least in part to the Severe sepsis occurs as a result of both com- heterogeneity of the patient populations stud- munity-acquired and health care–associated in- ied.19,20 Although a recent genomewide associa- fections. Pneumonia is the most common cause, tion study21 explored drug responsiveness in accounting for about half of all cases, followed by sepsis, no such large-scale studies of susceptibil- intraabdominal and urinary tract infections.7,8,11,12 ity to or outcome of sepsis have been performed.
Blood cultures are typically positive in only one third of cases, and in up to a third of cases, Clinical Fe atur es cultures from all sites are negative.7,11,13,14 Staphy- lococcus aureus and Streptococcus pneumoniae are the The clinical manifestations of sepsis are highly most common gram-positive isolates, whereas variable, depending on the initial site of infec- Escherichia coli, klebsiella species, and Pseudomonas tion, the causative organism, the pattern of acute aeruginosa predominate among gram-negative iso- organ dysfunction, the underlying health status lates.11,14 An epidemiologic study of sepsis of the patient, and the interval before initiation showed that during the period from 1979 to of treatment. The signs of both infection and or- 2000, gram-positive infections overtook gram- gan dysfunction may be subtle, and thus the negative infections.15 However, in a more recent most recent international consensus guidelines study involving 14,000 ICU patients in 75 coun- provide a long list of warning signs of incipient tries, gram-negative bacteria were isolated in 62% sepsis (Table 1).5 Acute organ dysfunction most of patients with severe sepsis who had positive commonly affects the respiratory and cardiovas- cultures, gram-positive bacteria in 47%, and cular systems. Respiratory compromise is classi- cally manifested as the acute respiratory distress Risk factors for severe sepsis are related both syndrome (ARDS), which is defined as hypox- to a patient's predisposition for infection and to emia with bilateral infiltrates of noncardiac ori- the likelihood of acute organ dysfunction if in- gin.22 Cardiovascular compromise is manifested fection develops. There are many well-known risk primarily as hypotension or an elevated serum factors for the infections that most commonly lactate level. After adequate volume expansion, precipitate severe sepsis and septic shock, includ- hypotension frequently persists, requiring the ing chronic diseases (e.g., the acquired immuno- use of vasopressors, and myocardial dysfunction deficiency syndrome, chronic obstructive pul- may occur.23 monary disease, and many cancers) and the use The brain and kidneys are also often affected. of immunosuppressive agents.7 Among patients Central nervous system dysfunction is typically with such infections, however, the risk factors manifested as obtundation or delirium. Imaging for organ dysfunction are less well studied but studies generally show no focal lesions, and probably include the causative organism and the findings on electroencephalography are usually patient's genetic composition, underlying health consistent with nonfocal encephalopathy. Criti- status, and preexisting organ function, along cal illness polyneuropathy and myopathy are with the timeliness of therapeutic intervention.16 also common, especially in patients with a pro- Age, sex, and race or ethnic group all influence longed ICU stay.24 Acute kidney injury is mani- the incidence of severe sepsis, which is higher in fested as decreasing urine output and an in- infants and elderly persons than in other age creasing serum creatinine level and frequently groups, higher in males than in females, and requires treatment with renal-replacement ther- higher in blacks than in whites.7,17 apy. Paralytic ileus, elevated aminotransferase There is considerable interest in the contribu- levels, altered glycemic control, thrombocytope- tion of host genetic characteristics to the inci- nia and disseminated intravascular coagulation, dence and outcome of sepsis, in part because of adrenal dysfunction, and the euthyroid sick syn- strong evidence of inherited risk factors.18 Many drome are all common in patients with severe studies have focused on polymorphisms in genes sepsis.5 n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. 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)TachypneaAltered mental statusSubstantial 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 formsElevated 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)§ 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]) 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 lac- tate 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 adminis- tration of an intravenous fluid bolus.
death from septic shock were often in excess of 80% as recently as 30 years ago.25 However, with Before the introduction of modern intensive care advances in training, better surveillance and with the ability to provide vital-organ support, monitoring, and prompt initiation of therapy to severe sepsis and septic shock were typically le- treat the underlying infection and support failing thal. Even with intensive care, rates of in-hospital organs, mortality is now closer to 20 to 30% in n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. critical care medicine many series.7,26 With decreasing death rates, at- four main classes — toll-like receptors, C-type tention has focused on the trajectory of recovery lectin receptors, retinoic acid inducible gene 1–like among survivors. Numerous studies have sug- receptors, and nucleotide-binding oligomerization gested that patients who survive to hospital dis- domain–like receptors — have been identified, charge after sepsis remain at increased risk for with the last group partially acting in protein death in the following months and years. Those complexes called inflammasomes (Fig. 1).31 who survive often have impaired physical or neu- These receptors recognize structures that are rocognitive functioning, mood disorders, and a conserved among microbial species, so-called low quality of life.27 In most studies, determining pathogen-associated molecular patterns, result- the causal role of sepsis in such subsequent disor- ing in the up-regulation of inflammatory gene ders has been difficult. However, a recent analy- transcription and initiation of innate immunity. sis of the Health and Retirement Study, involving The same receptors also sense endogenous mol- a large, longitudinal cohort of aging Americans, ecules released from injured cells, so-called suggested that severe sepsis significantly acceler- damage-associated molecular patterns, or alarm- ated physical and neurocognitive decline.28 ins, such as high-mobility group protein B1, S100 proteins, and extracellular RNA, DNA, and his- tones.32 Alarmins are also released during sterile injury such as trauma, giving rise to the concept 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 inflamma- tion. 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 dis- sponse 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 transmem- which 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 antithrom- and 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 mo- lence) and the host (genetic characteristics and lecular link between coagulation and inflamma- coexisting 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 endo- tions (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.
Antiinflammatory Mechanisms
Knowledge of pathogen recognition has in- The immune system harbors humoral, cellular, creased tremendously in the past decade. Patho- and neural mechanisms that attenuate the poten- gens activate immune cells through an interac- tially harmful effects of the proinflammatory tion with pattern-recognition receptors, of which response (Fig. 1).30 Phagocytes can switch to an n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. Excessive inflammation causing collateral damage (tissue injury) Perpetuation of inflammation molecular patterns Load VirulencePathogen-associated molecular patterns CytokinesProteasesReactive oxygen species Complement products Coagulation proteases Necrotic cell death
Inhibition of proinflammatory
of immune cells
gene transcription
Apoptosis of T, B, and dendritic cells Soluble cytokine receptors Host cell
Negative regulators Expansion of regulatory of TLR signaling Epigenetic regulation Host factors
suppressor cells adrenal axis
Inhibition of proinflammatory
Immunosuppression with enhanced susceptibility to secondary infections Figure 1. The Host Response in Severe Sepsis.
The host response to sepsis is characterized by both proinflammatory responses (top of panel, in red) and antiinflammatory immunosup- pressive responses (bottom of panel, in blue). The direction, extent, and duration of these reactions are determined by both host factors (e.g., genetic characteristics, age, coexisting illnesses, and medications) and pathogen factors (e.g., microbial load and virulence). In- flammatory responses are initiated by interaction between pathogen-associated molecular patterns expressed by pathogens and pattern- recognition receptors expressed by host cells at the cell surface (toll-like receptors [TLRs] and C-type lectin receptors [CLRs]), in the endosome (TLRs), or in the cytoplasm (retinoic acid inducible gene 1–like receptors [RLRs] and nucleotide-binding oligomerization domain–like receptors [NLRs]). The consequence of exaggerated inflammation is collateral tissue damage and necrotic cell death, which AUTHOR PLEASE 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.
antiinflammatory phenotype that promotes tis- T cells. The acetylcholine release targets α7 cho- sue repair, and regulatory T cells and myeloid- linergic receptors on macrophages, suppressing derived suppressor cells further reduce inflam- the release of proinflammatory cytokines.36 In mation. In addition, neural mechanisms can animal models of sepsis,35 disruption of this inhibit inflammation.35 In the so-called neuroin- neural-based system by vagotomy increases sus- flammatory reflex, sensory input is relayed ceptibility to endotoxin shock, whereas stimula- through the afferent vagus nerve to the brain tion of the efferent vagus nerve or α7 cholinergic stem, from which the efferent vagus nerve acti- receptors attenuates systemic inflammation.
vates the splenic nerve in the celiac plexus, re- Patients who survive early sepsis but remain sulting in norepinephrine release in the spleen dependent on intensive care have evidence of im- and acetylcholine secretion by a subset of CD4+ munosuppression, in part reflected by reduced n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. critical care medicine Loss of barrier function
↑ Tissue
protein C receptor ↑ S1P3 and
↓ Protein C
↓ Activated protein C
↑ Angiopoietin 2
and ↑ thrombin
↓ Blood pressure
↑ PAI-1
↓ Red-cell
↓ VE cadherin and
and cell death
and interstitial Figure 2. Organ Failure in Severe Sepsis and Dysfunction of the Vascular Endothelium and Mitochondria.
Sepsis is associated with microvascular thrombosis caused by concurrent activation of coagulation (mediated by tissue factor) and im-pairment of anticoagulant mechanisms as a consequence of reduced activity of endogenous anticoagulant pathwDr (mediated 7/24/13 vated protein C, antithrombin, and tissue factor pathway inhibitor), plus impaired fibrinolysis owing to enhancAuthor ase of plasminogen activator inhibitor type 1 (PAI-1). The capacity to generate activated protein C is impaired at least in part by reduced expression of two endothelial receptors: thrombomodulin (TM) and the endothelial protein C receptor. Thrombus formation is further facilitated by neu-trophil extracellular traps (NETs) released from dying neutrophils. Thrombus formation results in tissue hypo ME perfusion, which is aggra- vated by vasodilatation, hypotension, and reduced red-cell deformability. Tissue oxygenation is further impaired by the loss of barrier 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 ( Figure has been redrawn and type has been reset S1P1) and S1P3 within 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 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 tients who had died of sepsis in the ICU.37 Be- patients frequently have ongoing infectious foci, sides the spleen, the lungs also showed evidence despite antimicrobial therapy, or reactivation of of immunosuppression; both organs had en- latent viral infection.38,39 Multiple studies have hanced expression of ligands for T-cell inhibi- documented reduced responsiveness of blood tory receptors on parenchymal cells.37 Enhanced leukocytes to pathogens in patients with sep- apoptosis, especially of B cells, CD4+ T cells, sis,30 findings that were recently corroborated by and follicular dendritic cells, has been implicat- postmortem studies revealing strong functional ed in sepsis-associated immunosuppression and impairments of splenocytes obtained from pa- death.40,41 Epigenetic regulation of gene expres- n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. dysfunction pressure Surviving
therapy intravascular Treatment
intravenous dose Table 2. Guidelines
n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. critical care medicine sion may also contribute to sepsis-associated Although the mechanisms that underlie organ failure in sepsis have been only partially eluci- (A) nasopharyngeal capillary dated, impaired tissue oxygenation plays a key role (Fig. 2). Several factors — including hypo- tension, reduced red-cell deformability, and microvascular thrombosis — contribute to dimin- ished oxygen delivery in septic shock. Inflamma- evidence, cannula tion can cause dysfunction of the vascular endo- thelium, 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 mech- anisms impairs cellular oxygen use.44 Moreover, injured mitochondria release alarmins into the extracellular environment, including mitochon- examination of and drial DNA and formyl peptides, which can acti- vate neutrophils and cause further tissue injury.45 use during resistance ICU suggested), therapy 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 manage- ment of severe sepsis and septic shock (Table 2).23 The most important elements of the guidelines are organized into two "bundles" of care: an ini- tial management bundle to be accomplished with- in 6 hours after the patient's presentation and a to respiratory equivalent) management bundle to be accomplished in the gastrointestinal acute recommendation ICU.23 Implementation of the bundles is associ- ated with an improved outcome.46,47 The principles of the initial management bundle are to provide cardiorespiratory resusci- tation and mitigate the immediate threats of uncontrolled infection. Resuscitation requires the use of intravenous fluids and vasopressors, with of with (2C).
oxygen therapy and mechanical ventilation pro- vided as necessary. The exact components re- quired to optimize resuscitation, such as the septic insufficiency choice and amount of fluids, appropriate type end-expiratory bolus in and intensity of hemodynamic monitoring, and role of adjunctive vasoactive agents, all remain the protocol-specified subject of ongoing debate and clinical trials; many of these issues will be covered in this se- vasodilators absolute guidelines ries.23 Nonetheless, some form of resuscitation is For UG tinuous ministration and en The considered essential, and a standardized approach n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. has been advocated to ensure prompt, effective agents and agents exerting more pleiotropic ef- management.23 The initial management of in- fects. The specific agents can be divided into fection requires forming a probable diagnosis, those designed to interrupt the initial cytokine obtaining cultures, and initiating appropriate cascade (e.g., antilipopolysaccharide or anti–pro- and timely empirical antimicrobial therapy and inflammatory cytokine strategies) and those de- source control (i.e., draining pus, if appropriate). signed to interfere with dysregulated coagulation The choice of empirical therapy depends on (e.g., antithrombin or activated protein C).61 The the suspected site of infection, the setting in only new agent that gained regulatory approval which the infection developed (i.e., home, nurs- was activated protein C.62 However, postapproval ing home, or hospital), medical history, and lo- concern about the safety and efficacy of activated cal microbial-susceptibility patterns. Inappropri- protein C prompted a repeat study, which did not ate or delayed antibiotic treatment is associated show a benefit and led the manufacturer, Eli Lilly, with increased mortality.48,49 Thus, intravenous to withdraw the drug from the market.11 All other antibiotic therapy should be started as early as strategies thus far have not shown efficacy. With possible and should cover all likely pathogens. It the recent decision to stop further clinical devel- has not been determined whether combination opment of CytoFab, a polyclonal anti–tumor ne- antimicrobial therapy produces better outcomes crosis factor antibody (ClinicalTrials.gov number, than adequate single-agent antibiotic therapy in NCT01145560), there are no current large-scale patients with severe sepsis.50-53 Current guide- trials of anticytokine strategies in the treatment lines recommend combination antimicrobial of sepsis.
therapy only for neutropenic sepsis and sepsis Among the agents with broader immunomod- caused by pseudomonas species. Empirical anti- ulatory effects, glucocorticoids have received the fungal therapy should be used only in patients at most attention. Intravenous immune globulin is high risk for invasive candidiasis.50 also associated with a potential benefit,63 but The patient should also be moved to an ap- important questions remain, and its use is not propriate setting, such as an ICU, for ongoing part of routine practice.23 Despite a large num- care. After the first 6 hours, attention focuses on ber of observational studies suggesting that the monitoring and support of organ function, use of statins reduces the incidence or improves avoidance of complications, and de-escalation of the outcome of sepsis and severe infection,64 care when possible. De-escalation of initial broad- such findings have not been confirmed in ran- spectrum therapy may prevent the emergence of domized, controlled trials, so the use of statins resistant organisms, minimize the risk of drug is not part of routine sepsis care.23 toxicity, and reduce costs, and evidence from observational studies indicates that such an ap- PROBLEMS WITH therapeutic development
proach is safe.54 The only immunomodulatory Faced with these disappointing results, many ob- therapy that is currently advocated is a short servers question the current approach to the de- course of hydrocortisone (200 to 300 mg per day velopment of sepsis drugs. Preclinical studies for up to 7 days or until vasopressor support is commonly test drugs in young, healthy mice or no longer required) for patients with refractory rats exposed to a septic challenge (e.g., bacteria or septic shock.23 This recommendation is support- bacterial toxins) with limited or no ancillary treat- ed by a meta-analysis,55 but the two largest stud- ment. In contrast, patients with sepsis are often ies had conflicting results,56,57 and other clinical elderly or have serious coexisting illnesses, which trials are ongoing.58,59 may affect the host response and increase the risk of acute organ dysfunction. Furthermore, death in se arch for new ther apies the clinical setting often occurs despite the use of antibiotics, resuscitation, and intensive life sup- port, and the disease mechanisms in such cases One of the great disappointments during the past are probably very different from those underlying 30 years has been the failure to convert advances the early deterioration that typically occurs in ani- in our understanding of the underlying biologic mal models in the absence of supportive care. features of sepsis into effective new therapies.60 There are also large between-species genetic dif- Researchers have tested both highly specific ferences in the inflammatory host response.65 n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. critical care medicine In clinical studies, the enrollment criteria are survivors of sepsis opens up avenues to explore typically very broad, the agent is administered on agents currently being tested in patients with the basis of a standard formula for only a short dementia and related conditions.
period, there is little information on how the agent The designs of trials could be modified to changes the host response and host–pathogen more easily incorporate these ideas. For exam- interactions, and the primary end point is death ple, the considerable uncertainty at the begin- from any cause. Such a research strategy is prob- ning of a trial with regard to the appropriate ably overly simplistic in that it does not select pa- selection of patients and drug-administration tients who are most likely to benefit, cannot adjust strategy and the possibility of treatment inter- therapy on the basis of the evolving host response actions may be better handled with the use of and clinical course, and does not capture poten- a Bayesian design. A trial could commence with tially important effects on nonfatal outcomes.
multiple study groups that reflect the various un- certainties to be tested but then automatically nar- row assignments to the best-performing groups Consequently, hope is pinned on newer so-called on the basis of predefined-response adaptive precision-medicine strategies with better preclin- randomization rules. Such designs could be par- ical models, more targeted drug development, ticularly helpful when testing combination ther- and clinical trials that incorporate better patient apy or incorporating potential biomarkers of drug selection, drug delivery, and outcome measure- responsiveness.
ment. For example, options to enrich the pre- clinical portfolio include the study of animals that are more genetically diverse, are older, or have preexisting disease. Longer experiments Severe sepsis and septic shock represent one of with more advanced supportive care would allow the oldest and most pressing problems in medi- better mimicry of the later stages of sepsis and cine. With advances in intensive care, increased multiorgan failure, permitting the testing of awareness, and dissemination of evidence-based drugs in a more realistic setting and perhaps fa- guidelines, clinicians have taken large strides in cilitating the measurement of outcomes such as reducing the risk of imminent death associated cognitive and physical functioning. In addition, with sepsis. However, as more patients survive preclinical studies could be used to screen for sepsis, concern mounts over the lingering se- potential biomarkers of a therapeutic response quelae of what was previously a lethal event. for which there are human homologues.
Strategies are also needed to reach the many mil- Activated protein C mutants that lack antico- lions of patients with sepsis who are far from agulant properties are examples of more target- modern intensive care. At the same time, advanc- ed drug development and were shown to provide es in molecular biology have provided keen in- protection from sepsis-induced death in animals, sight into the complexity of pathogen and alarm without an increased risk of bleeding.66 Bio- recognition by the human host and important markers such as whole-genome expression pat- clues to a host response that has gone awry. terns in peripheral-blood leukocytes may aid in However, harnessing that information to provide stratifying patients into more homogeneous sub- effective new therapies has proved to be difficult. groups or in developing more targeted therapeu- To further improve the outcome of patients with tic interventions.67 The insight that severe sepsis sepsis through the development of new therapeu- can cause immunosuppression raises the possi- tic agents, newer, smarter approaches to clinical- bility of using immune-stimulatory therapy (e.g., trial design and execution are essential.
interleukin-7, granulocyte–macrophage colony- Dr. Angus reports receiving grant support through his insti- stimulating factor,68 or interferon-γ 69), but ide- tution from Eisai, consulting fees from Idaho Technology, Pfizer, ally, such therapy would be used only in patients Eisai, MedImmune, BioAegis, and Ferring, and fees from Eli in whom immunosuppression is identified or Lilly for serving as a member of a clinical-trial data and safety monitoring board. Dr. van der Poll reports receiving grant sup- predicted. Thus, such therapies could be deployed port through his institution from Sirtris Pharmaceuticals and on the basis of laboratory measures, such as consulting fees from Eisai. No other potential conflict of inter- monocyte HLA-DR expression. In addition, con- est relevant to this article was reported.
Disclosure forms provided by the authors are available with cern about accelerated neurocognitive decline in the full text of this article at NEJM.org.
n engl j med 369;9 nejm.org august 29, 2013 The New England Journal of Medicine Downloaded from nejm.org at PEKING UNIVERSITY THIRD HOSP on February 11, 2014. For personal use only. No other uses without permission. Copyright 2013 Massachusetts Medical Society. All rights reserved. 1. Majno G. The ancient riddle of sigma et al. Infection rate and acute organ dys-
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