SEPSIS is defined as the systemic inflammatory response that occurs during severe infection.1–4
Severe sepsis is the syndrome of sepsis that is complicated by the development of organ failure.5–7
Patients with sepsis often present in dramatic fashion with high spiking fevers, shock, and respiratory failure.2–7
Due in part to this striking presentation, the prevailing theory of sepsis for many years had been that sepsis represented an uncontrolled inflammatory response.5
Lewis Thomas popularized this concept when he hypothesized that it was the host response, rather than the microorganisms, most responsible for the morbidity and mortality associated with the disorder. He conjectured: “the microorganisms that seem to have it in for us turn out to be more like bystanders …. It is our response to their presence that makes the disease. Our arsenals for fighting off bacteria are so powerful … that we are more in danger from them than the invaders.”8
The discovery of a number of potent cytokines, including tumor necrosis factor (TNF) and interleukin-1 (IL-1), which are increased in patients with sepsis and which when injected into animals reproduced many of the clinical and laboratory features of sepsis, supported this theory and led to the concept of sepsis as a “cytokine storm.”5–7
In selected instances of sepsis (for example, meningococcemia), circulating TNF-α concentrations are increased markedly and correlate with survival. Based on this theory that the host “cytokine storm” response causes uncontrolled hyperinflammation and organ injury, pharmaceutical companies initiated numerous clinical trials (e.g.
, TNF and IL-1 antagonists) in sepsis.9–13
The results of more than 25 trials of various antiinflammatory agents showed no benefit or, in some cases, worsened survival. These dismal results caused some investigators to call for a reevaluation of our fundamental understanding of the pathophysiology of sepsis.5
As investigators took a new look at previous studies of the host response in sepsis and as additional studies were performed, evidence mounted that a proinflammatory and an opposing antiinflammatory response occurred concurrently in patients with sepsis.5
Studies of circulating cytokines in patients with sepsis showed that in addition to proinflammatory cytokines, the potent antiinflammatory cytokine IL-10 was present in excess. Van Dissel et al.
examined cytokine profiles and mortality in 464 patients admitted to the hospital with presumed infections and reported that a high ratio of IL-10 to TNF-α was associated with a fatal outcome in patients with community-acquired infection.16
Other investigators reported that sepsis induced defects in the production of both pro- and antiinflammatory cytokines (i.e.
, a global depression in all cell cytokine production).17–20
Ertel et al.
stimulated whole blood from septic and nonseptic critically ill patients with lipopolysaccharide and reported that production of TNF-α, IL-1β, and IL-6 in septic patients' blood was frequently less than 10–20% that of control nonseptic patients.17
Similarly, Sinistro et al.
stimulated peripheral blood monocytes from septic or control patients and quantitated the percentage of cells producing proinflammatory cytokines.20
Less than 5% of monocytes from septic patients produced cytokines, a value less than one third the percentage of cytokine-producing cells of controls.20
Weighardt et al.
studied lipopolysaccharide-stimulated production of cytokines by monocytes in patients with sepsis after abdominal surgery.21
Postoperative sepsis was associated with an immediate defect in monocyte production of pro- and antiinflammatory cytokines. Patient survival was associated with recovery of the inflammatory but not antiinflammatory response. Collectively, these blood studies indicate that pro- and antiinflammatory cytokines can be produced rapidly after sepsis onset and that sepsis does not always induce unbridled hyperinflammation.
The seminal discovery of cell signaling receptor pathways involving pathogen recognition led to further advances in our understanding of sepsis but also yielded surprising results. Cells of the innate immune system recognize pathogens and initiate responses via
pattern-recognition receptors termed Toll-like receptors (TLRs).22–24
TLRs are a family of cell pattern recognition receptors that recognize molecules that are widely shared by various pathogens, including Gram-positive and Gram-negative bacteria, fungi, and viruses.22
After TLR activation by the pathogenic antigens, adapter proteins are recruited, and there is subsequent rapid activation of numerous protein kinases.23
Ultimately, cell signaling leads to induction of genes involved in the regulation of inflammation with increased production of pro- and antiinflammatory cytokines. Investigators initially assumed that blocking these receptors might ameliorate the symptoms of sepsis, and studies in mice with genetic deletion of TLRs did show that these mice are highly resistant to lethal endotoxin.23
However, studies in TLR knockout mice and studies in which the TLR pathway was pharmacologically inhibited demonstrated higher
mortality in TLR-deficient mice than in control mice when more clinically relevant authentic bacterial models of sepsis were used.25
These studies, which demonstrate that blocking TLRs can have detrimental effects in sepsis, are analogous to studies showing that blocking TNF, a key proinflammatory cytokine that is released after TLR activation of macrophages, worsens survival in animal models of sepsis.27
For example, Moore et al.
reported that blocking TNF-α in murine sepsis caused by Klebsiella pneumoniae
resulted in decreased bacterial clearance and worsened survival.28
Rijneveld et al.
observed that blocking TNF enhanced bacterial outgrowth and increased mortality in a murine pneumococcal pneumonia model of sepsis.27
In a related manner, studies show that TNF and IL-1 antagonists that are used in the treatment of patients with autoimmune diseases (e.g.
, etanercept in patients with rheumatoid arthritis) actually increase the risk of sepsis. The recent failure of the TLR 4 antagonist eritoran in a phase 3 clinical trial in sepsis underscores the difficulty in treating sepsis by blocking the ability of cells to recognize and respond to pathogens.§
The “take home” message from these various TLR antagonism studies seems to be that one must approach cautiously the idea of blocking the ability of the host to sense and respond to invading pathogens. Teleologically, these receptors exist to serve as an early warning of infection and help mount an expeditious response. It is possible that in selected individuals, down-modulation of this pathway may be advisable, but it must be done in a graded fashion and perhaps only after the initial immune response has been activated.
Current Understanding of the Host Immunologic Response in Sepsis
Although there is still considerable debate, a growing consensus is that sepsis initiates pro- and antiinflammatory responses, both of which begin rapidly after life-threatening infection.14
Although pro- and antiinflammatory processes begin promptly after sepsis onset, in general there is predominance of an initial hyperinflammatory phase, the magnitude of which is determined by a number of factors, including pathogen virulence, bacterial load, host genetic factors, and host comorbidities (fig. 1
). For example, a previously healthy young adult who experiences meningococcemia likely will exhibit a profound hyperinflammatory cytokine-storm–mediated response manifested by cardiovascular collapse, high fever, and multiorgan failure. If death occurs in the first few days of the illness, it most likely will be attributable to this uncontrolled cytokine-mediated response. In contrast, an elderly patient with diabetes who has required long-term hemodialysis and who experiences pneumonia may not manifest any overt signs of sepsis other than decreased mental status, hypothermia, glucose intolerance, and inability to tolerate dialysis because of hypotension. In such a patient, there may be little if any evidence of a hyperinflammatory phase of sepsis; instead, signs of an antiinflammatory response may predominate.
Insights into Sepsis from Postmortem Studies
With improved treatment algorithms (see below), most patients survive the initial hyperinflammatory phase of sepsis and enter a more protracted phase of sepsis characterized by increasing immunosuppression.31
Postmortem studies of patients who died of sepsis have provided critical insights into the mechanisms and magnitude of immunosuppression in sepsis. We performed rapid tissue harvesting at the bedside of patients dying of sepsis and demonstrated that patients had a striking apoptosis-induced loss of cells of the innate and adaptive immune system (fig. 2
The types of immune cells that are lost include CD4 and CD8 T cells, B cells, dendritic cells, and monocytes. The loss of these immune effector cells is particularly notable given that the loss occurs during severe infection, a time when clonal expansion of T cells should be taking place. Subsequent postmortem studies of pediatric and neonatal patients who died of sepsis also showed profound loss of immune cells in fatal sepsis, thereby supporting the results of the previous adult postmortem study.36
Thus, severe depletion of immune effector cells is a universal finding in all age groups during sepsis.
It is informative to examine the impact of loss of CD4 and CD8 T cells and of monocytes or macrophages on host immunity. CD4 T cells are known as “helper” cells because they coordinate the activity of many other immune cells. For example, in response to antigenic stimulation, CD4 T cells secrete cytokines, including interferon-γ, which induce activation of monocytes or macrophages. CD4 T cells also secrete cytokines that induce B-cell expansion, resulting in increased antibody formation. CD8 T cells help to fight infection by recognizing and inducing lysis of host cells that have become infected with intracellular bacterial or viral pathogens. CD8 T cells are also important in preventing reactivation of latent viruses. Macrophages are mature monocytes that function to activate T cells by antigen presentation. Macrophages are also professional phagocytic cells that engulf and destroy pathogens. The net impact of the loss of these various immune cells is to compromise severely the host's ability to combat the invading pathogens.
In addition to the loss of many essential immune cells, there is an inhibitory effect of the uptake of apoptotic immune cells on the surviving cells.38
As noted previously, the immune effector cells die by apoptosis in sepsis and are rapidly consumed by professional phagocytic cells. Although uptake of necrotic cells induces a proinflammatory response from phagocytic cells by stimulating the release of TNF-α, uptake of apoptotic cells induces an immunosuppressive response by inducing release of the antiinflammatory cytokines IL-10 and tumor growth factor-β. This effect compounds the loss of the important immune cells by further compromising host immune defenses. Other mechanisms of immunosuppression that have been identified in sepsis include decreased expression of activating cell-surface molecules, such as HLA-DR, T cell “exhaustion,” and increased suppressor cells (T regulatory cells and myeloid-derived suppressor cells).40–46
Another interesting finding from a recent postmortem study done by our group is the potential role of the host parenchymal cells in modulating the immune response. New evidence indicates that endothelial and epithelial cells can express a variety of immunosuppressive molecules that are potent modulators of immune cell function.47
The expression of these immune regulatory molecules on local parenchymal cells may explain particular organ susceptibility. In this regard, immunohistochemical staining of lungs from patients who died of sepsis showed dramatic up-regulation of the negative immunomodulatory molecule herpes-virus-entry-mediator compared on lungs from nonseptic control patients (unpublished data, R.S.H., 2011). This finding may be one explanation for the increased susceptibility of the lungs to nosocomial infection.
Evidence of Immunosuppression in Sepsis
Careful consideration of many of the problems that occur in patients with sepsis reveals compelling evidence for immunosuppression as a major pathogenic mechanism. Here again, postmortem studies of patients who died of sepsis revealed important findings. Torgersen et al.
reviewed postmortem findings in 235 surgical intensive care unit (ICU) patients who were admitted with a diagnosis of sepsis.49
At death, approximately 80% of patients had an unresolved septic focus. Only 52 of 97 autopsy-confirmed pneumonias were diagnosed appropriately during the patients' stay in the ICU. Peritonitis also accounted for a large percentage of unresolved septic foci. The important message is that many patients in the ICU do not get better because there is still ongoing infection. Despite broad-spectrum antibiotics and aggressive source control measures, infections are not eradicated and/or new secondary hospital-acquired infections develop in many ICU patients. One key factor in the failure to eliminate the pathogens is the patients' compromised immunologic defenses. Therapies that would enhance patient immunity could prevent multiple organ failure and improve survival by assisting the body in eliminating the invading pathogens and preventing acquisition of new infections.
Other supporting evidence for immunosuppression in patients with sepsis is provided by inspection of the type of pathogens that frequently are sources of secondary infection. The secondary hospital-acquired infections include virulent organisms, such as Staphylococcus aureus
, and those that are not particularly dangerous to nonimmunosuppressed patients (e.g.
, Stenotrophomonas maltophilia
, Acinetobacter calcoaceticus-baumannii
, and Candida albicans
The fact that many ICU patients ultimately die of sepsis caused by these relatively avirulent organisms highlights the profound nature of the patients' immunosuppression.
Additional compelling evidence for immunosuppression in sepsis includes studies documenting reactivation of common latent viruses. It has been recognized for a long time that immunocompromised patients (e.g.
, patients with human immunodeficiency virus-1 or those treated with chemotherapy) experience reactivation of latent cytomegalovirus and herpes simplex virus. Similarly, recent studies in patients with sepsis have shown that a significant percentage also experience viral reactivation.51
Limaye et al.
examined the incidence of reactivation of cytomegalovirus in 120 critically ill patients, many of whom had sepsis.52
These individuals had normal immunity before their illness. Cytomegalovirus viremia occurred in 33% of patients and was associated with prolonged hospitalization and death. In a related study, Luyt et al.
reported a 21% incidence of herpes simplex virus bronchopneumonitis, which was attributed to viral reactivation in critically ill, immunocompetent patients requiring prolonged ventilatory support.51
It is probable that only a modest number of patients in these two studies had clinically significant viral infections. Rather, these investigations support the concept that critically ill patients who have normal immunity before hospitalization become profoundly immunocompromised during a protracted illness, thereby enabling reactivation of latent viruses, which may become clinically relevant.
Biomarkers as an Essential Guide to Immunotherapy
A big hurdle to the effective use of immunomodulatory therapy (i.e.
, the use of agents that can up- or down-modulate the intensity of the host immune response) will be the ability to determine whether the patient is in the hyper- or hypoinflammatory phase of the disorder. Quantitation of circulating blood concentrations of specific markers that are indicative of the state of the patient's immune status (biomarkers) would be of enormous benefit. A recent study used just such a strategy. Patients whose circulating mononuclear cells demonstrated decreased cell expression of HLA-DR as detected by flow cytometry were treated with the immunostimulant granulocyte macrophage colony-stimulating factor (GM-CSF) to help activate and induce proliferation of existing immune effector cells.53
Although it was a small phase 2 study, septic patients with low HLA-DR expression who were treated with GM-CSF had a shorter duration of mechanical ventilation and ICU and hospital stays. In addition to HLA-DR, other potential biomarkers that could be used to immunophenotype the patient immune effector cells include markers of T-cell exhaustion (programmed cell death 1 [PD-1] and PD-ligand 1) and T regulatory cells, potent inhibitors of T-cell activation. The use of phenotypic markers combined with functional studies examining the production of pro- and antiinflammatory cytokines in diluted whole blood could provide an accurate assessment of patient immune status. In this regard, a recent clinical study in pediatric patients with sepsis quantitated the production of TNF-α in lipopolysaccharide-stimulated blood samples. Patients with a TNF-α production of less than 200 pg/ml were treated with GM-CSF.54
Pediatric septic patients treated with GM-CSF had restoration of blood TNF-α production and had a marked reduction in newly acquired nosocomial infections compared with control patients.
In addition to the expression of the monocyte human leukocyte antigen-D receptor, other potential indicators of the host immune status that might be used clinically are cell-surface expression markers on CD4 and CD8 T cells. T cells express various proteins that either augment or suppress cell activation, and this protein expression is readily assessed by flow cytometry. Our laboratory has quantitated T-cell expression of a number of these immunomodulatory proteins and correlated the expression of these markers with a measure of severity of illness called the Sequential Organ Failure Assessment score (fig. 3
). Although results are preliminary, there is an inverse correlation of expression of several positive costimulatory molecules (i.e.
, CD28 and OX40) on CD8 T cells with more severe organ failure (higher Sequential Organ Failure Assessment scores). We are also examining expression of negative costimulatory molecules on T cells. The results of these cell-surface expression studies could be combined with the results of studies of other markers of sepsis, such as procalcitonin, to provide a more global picture of host immunity. Although there are problems with the sensitivity and specificity of procalcitonin as a marker for severity of sepsis, persistently increased concentrations reflect a poor prognosis. Although any one of these markers does not necessarily reveal the overall immunologic status of a patient, it is likely that an appropriate combination of the results of multiple tests will yield more accurate assessments of immune competence, thus leading to more individualized, goal-directed therapies.
Advances in Current Therapy: Antimicrobial Therapy
Treatment guidelines for sepsis have been developed under the collaborative leadership of various infectious disease and critical care professional societies and are described in the Surviving Sepsis Campaign and summarized in table 1
Numerous studies have shown that early and full implementation of “sepsis bundles” can lead to significant improvements in patient survival.32
Two key components in the successful management of sepsis are obtaining rapid control of the infectious source and providing immediate hemodynamic support to restore and maintain organ perfusion. A timely intervention to remove or reduce the infectious burden (e.g.
, surgical drainage) should be performed as soon as is feasible. Prompt antibiotic therapy is critical in improving survival. A key study demonstrated that for each hour that the administration of appropriate antibiotics was delayed, mortality increased by 7.6% in patients with septic shock.59
Empiric drug selection is also essential given studies documenting that failure to administer an antimicrobial with activity against the identified pathogen(s) leads to worse outcomes, including increased lengths of hospital stay and mortality.50
In addition to considering the likely pathogens according to the source(s) of infection, the intensivist must consider host risk factors for drug-resistant bacteria, including previous colonization with multidrug-resistant pathogens and recent antimicrobial use.66
Furthermore, not only is there a distinction between community-acquired infections and hospital-acquired infections, whereby hospital-onset infections generally are caused by more resistant pathogens, such as methicillin-resistant Staphylococcus aureus
and Pseudomonas aeruginosa
, but patients also must be assessed for health care-associated risk factors. Residence in a nursing home or long-term care facility, recent hospitalization, attendance at a hemodialysis clinic or infusion center for the administration of chemotherapy or antibiotics, and having received hospital care at home (e.g.
, intravenous therapy, wound care, or specialized nursing care) are all risks factors for infections with more resistant organisms. Patients with these risk factors are commonly infected with pathogens similar to those of nosocomial infections, and failure to recognize this is frequently a cause of inappropriate therapy leading to worse outcomes.63
Although this paradigm has been demonstrated most strongly for pneumonia, similar considerations should be made in treating infections at other sites, such as complicated intraabdominal infections and catheter-related bloodstream infections.69
The intensivist must also be aware of the institution-specific antibiogram to ensure the selection of appropriate empiric antibiotics. Development of protocols tailored to an institution can help to assure that these considerations are made when clinicians are selecting antimicrobial regimens.70
Another strategy that can be incorporated into such protocols is the consideration for empiric combination therapy directed against resistant Gram-negative organisms until a pathogen can be isolated and susceptibilities performed. This practice has been shown to improve the appropriateness of therapy, but the choice of agents may vary according to local susceptibilities.62
Once a microorganism has been isolated and susceptibilities determined, deescalation of the initial broad-spectrum therapy is warranted. This deescalation approach maximizes appropriate empiric antibiotic selection while minimizing antimicrobial exposure that otherwise may lead to development of antibiotic resistance, expose patients to unnecessary risk of drug toxicity, and lead to overgrowth of Clostridium difficile
, a major ICU pathogen.
Another key facet in antimicrobial therapy is prescription of adequate dosing. A study at our institution identified underdosing of fluconazole as an independent predictor for mortality in treating Candida
The importance of optimal dosing is appropriately receiving more attention in recent years given both the lack of new antimicrobials in development and the observation that worse outcomes are noted among patients infected with pathogens having increased minimum inhibitory concentrations (MICs) to the chosen antimicrobial, even when remaining within the “susceptible” range. For example, by the current Clinical and Laboratory Standards Institute breakpoints, all methicillin-resistant Staphylococcus aureus
isolates with a vancomycin MIC of ≤2 μg/ml are considered “susceptible” to vancomycin, yet several studies have reported increased mortality among patients treated with vancomycin for an methicillin-resistant Staphylococcus aureus
infection when the isolate has a MIC of 2 μg/ml compared with ≤1 μg/ml.77–79
Similarly, patients infected with Gram-negative pathogens having increased MICs are reported to have increased mortality.80
Given these findings, it may be preferred to treat such infections with alternative antibiotics (e.g.
, linezolid for methicillin-resistant Staphylococcus aureus
pneumonia) for which susceptibility testing has confirmed activity.
Another strategy being investigated to help combat the increasing challenge of drug-resistant pathogens is alteration of the antibiotic administration to optimize the pharmacokinetic–pharmacodynamic parameter that is essential for bacterial eradication. The two most commonly studied approaches are administration of β-lactams as continuous infusions and extended (over 3–4 h) intermittent infusions. The concept behind this strategy is to maximize the time that drug concentration remains above the MIC of the pathogen, which is the pharmacokinetic–pharmacodynamic parameter of interest for β-lactams. Initial Monte Carlo simulations based on pharmacokinetic data from critically ill patients have shown improved pharmacokinetic–pharmacodynamic target attainment with the application of extended and continuous infusions of piperacillin–tazobactam, cefepime, and meropenem.82–84
Although limited, early clinical data suggest that patient outcomes may be improved by this approach; however, conflicting reports exist.85
The clinical context in which this strategy makes most sense is in treating patients who are most likely to harbor pathogens with increased MICs (e.g.
, patients receiving recent previous antibiotic therapy or those with an extended hospital length of stay) with preserved renal function, and this population should be a focus of future investigations.
Advances in Current Therapy: Hemodynamic Support
In 2001, Rivers et al.
published the results of their prospective trial evaluating early goal-directed therapy in the emergency department for patients with severe sepsis or septic shock.87
Early goal-directed therapy, which included crystalloid resuscitation to restore preload, vasopressors to maintain adequate mean arterial pressure, and administration of blood and/or dobutamine to achieve a goal central venous oxygen saturation, produced a 16% absolute risk reduction in in-hospital mortality. Since then, early goal-directed therapy has become a cornerstone of therapy for patients with septic shock, and its components are recommended in the “Surviving Sepsis” guidelines.55
Although practitioners generally agree with the concept of providing early resuscitation to achieve defined hemodynamic endpoints and optimization of organ perfusion, debate exists about the relative merit of each individual component.88
To this end, there are ongoing studies (Australasian Resuscitation in Sepsis Evaluation Randomized Controlled Trial, Protocolized Care for Early Septic Shock trial, and Protocolised Management in Sepsis trial) attempting to investigate in more detail the potential benefits of the various components of early goal-directed therapy.
Although vasopressors and inotropes have been used for decades to support blood pressure and hemodynamic goals when treating patients with septic shock, only recently have large, randomized, controlled trials (RCTs) compared the available agents with respect to patient outcomes. In the most current Surviving Sepsis guidelines, either norepinephrine or dopamine is recommended as the initial vasopressor of choice. Epinephrine and vasopressin are not recommended as the initial vasopressor, although vasopressin can be considered as an adjunct to norepinephrine.55
Recently, the CATS study group randomized 330 patients with septic shock to receive either epinephrine monotherapy or norepinephrine with or without dobutamine.90
Vasopressors were titrated to achieve a mean arterial pressure of 70 mmHg, and dobutamine was added to norepinephrine when cardiac index was less than 2.5 L/min per m2
. The primary outcome of 28-day mortality was not significantly different between the epinephrine and norepinephrine with or without dobutamine groups (40% vs.
34%, respectively, P
= 0.31), and rates of serious adverse events including arrhythmias were similar between the groups. Arterial pH and lactate were significantly lower in the epinephrine group early in the course of therapy but were similar between groups thereafter. Thus, this trial suggests that epinephrine may be a potential alternative to norepinephrine with or without dobutamine that warrants additional study.
To follow up a retrospective study that identified dopamine administration as an independent predictor for mortality among patients with shock, the Sepsis Occurrence in Acutely Ill Patients-2 investigators performed an RCT to directly compare norepinephrine and dopamine in patients with shock.91
A total of 1,679 patients were included: 1,044 with septic shock; 280 with cardiogenic shock; and 263 with hypovolemic shock. Overall, 28-day mortality was not different between the norepinephrine and dopamine groups (48.5% vs.
52.5%, respectively). In subgroup analysis, mortality was similar between groups in those with septic shock but was significantly increased in those with cardiogenic shock receiving dopamine. Notably, approximately one-fourth of patients receiving dopamine had an arrhythmic event, almost double the occurrence of this adverse event in the norepinephrine group. Another recent RCT comparing norepinephrine and dopamine among 252 patients with septic shock reported strikingly similar results.93
As a result of observations that patients with septic shock often have a relative vasopressin deficiency and that administration of vasopressin subsequently improves vascular tone, there has been much interest in the use of vasopressin in this population. Given previous reports of reduced catecholamine requirements in patients with severe septic shock, the authors of the Vasopressin and Septic Shock Trial hypothesized that the addition of vasopressin (0.01–0.03 U/min) to norepinephrine (as opposed to escalating doses of norepinephrine) would lead to improved 28-day survival and that this benefit would be most apparent in those with more severe shock (more than 15 μg/min norepinephrine equivalent).94
Instead, this trial of 778 patients with septic shock found no difference in 28-day mortality overall (35.4% vs.
39.3%,) but reported an ∼11% reduction in mortality in those with less severe shock (≤15 μg/min norepinephrine equivalent) who received vasopressin. Although these findings were in the opposite direction of the original hypothesis, laboratory models do provide a potential explanation relating to reduced vasopressin responsiveness in the septic shock state.95
The findings of the Vasopressin and Septic Shock Trial lead to interesting questions warranting additional study of the role of low-dose vasopressin in less-severe septic shock and suggest that the historical practice of adding vasopressin for patients receiving high doses of catecholamine does not improve patient outcomes. Practitioners should be cautioned against the use of vasopressin in patients with moderate to severe heart failure, acute coronary syndromes, or intestinal ischemia because such patients were excluded from Vasopressin and Septic Shock Trial because of concerns about concerns.
Taken together, these trials provide support for norepinephrine as the initial vasopressor of choice (compared with dopamine) because efficacy is at least similar and there is a significantly lower risk of arrhythmias. Recent evidence suggests that epinephrine may be an alternative to norepinephrine ± dobutamine, but given limitations of the current evidence, it remains a second-line agent. Finally, the adjunctive use of low-dose vasopressin in advanced septic shock does not appear to provide a survival benefit, but findings from the Vasopressin and Septic Shock Trial suggest a potential role in patients with less severe shock.
The Role of Corticosteroids in Sepsis
Low-dose corticosteroids have multiple systemic effects that may mitigate sepsis pathophysiology. One effect is improvement in vascular tone that is mediated by increasing sensitivity of smooth muscle to catecholamines and reducing nitric oxide formation.96
Indeed, in the two largest RCTs of corticosteroids in septic shock, the median duration of time until vasopressor withdrawal was ∼2 days shorter in groups receiving steroids.97
However, the question remains: do low-dose corticosteroids improve patient survival in septic shock? Unfortunately, the two RCTs mentioned were different in many ways and yielded conflicting results. In the previous study by Annane et al.
, a more severely ill patient population was enrolled within 8 h of septic shock to receive the combination of hydrocortisone and fludrocortisone for 7 days (or placebo); the study reported a survival benefit in patients who had no response to an adrenocorticotrophic hormone test.97
In the more recent Corticosteroid Therapy of Septic Shock trial, patients could be enrolled within the first 72 h of sepsis onset, most commonly had an intraabdominal source of infection, and were randomized to receive hydrocortisone tapered over 11 days or placebo.98
Although the study was stopped short of the planned sample size of 800, analysis of the 499 included patients failed to demonstrate any difference in 28-day mortality, and this did differ according to adrenocorticotrophic hormone testing results. In addition, the Corticosteroid Therapy of Septic Shock trial suggested a greater occurrence of superinfection in those receiving corticosteroids, whereas the previous study did not. Therefore, it is difficult to identify a unifying interpretation of these two studies, and it is likely that in current practice we do not have the means to identify patients who are most likely to benefit from or be harmed by the administration of corticosteroids. The determining factor may be the immunologic state, as was discussed previously. Currently, the use of corticosteroids cannot be recommended as the standard of care, but it is reasonable to consider early in the course for patients with septic shock that does not respond to conventional measures and without regard to adrenocorticotrophic hormone testing. If administered, corticosteroids should be tapered as shock resolves. This is consistent with the most recent guidelines, in which the recommendation for corticosteroids was graded as weak (grade 2c).
Activated Protein C in Sepsis
Drotrecogin alfa (activated) (DrotAA) and its place in sepsis therapy continue be a source of great controversy.99–102
The recombinant human activated Protein C Worldwide Evaluation of Severe Sepsis (PROWESS) trial99
generated early excitement by demonstrating a mortality benefit (6.1% absolute risk reduction, 95% CI 1.9–10.4%; P
= 0.005) with the use of DrotAA, a therapy targeting key derangements in coagulation and inflammation known to occur in sepsis. However, subsequent studies100
have failed to demonstrate a consistent improvement in survival across various subgroups, and concerns remain regarding risk for serious bleeding and appropriate patient selection. A recent meta-analysis102
that included randomized, placebo-controlled trials in both adult and pediatric populations reported no survival advantage with the use of DrotAA in the overall population or in various subgroups. Given the remaining concerns and controversy surrounding the use of DrotAA in sepsis, the ongoing PROWESS-SHOCK likely will play a pivotal role in determining its place in therapy. At the current time, evidence suggests that those most likely to benefit from DrotAA are patients with a high risk for mortality (i.e.
, Acute Physiology and Chronic Health Evaluation [APACHE] II score ≥25, multiple organ dysfunction) who can begin the regimen within 24 h of sepsis onset and do not have significant risk factors for bleeding (i.e.
, significant coagulopathy, platelet count less than 30,000/mm3
). In the most recent Surviving Sepsis guidelines,5
the recommendation pertaining to patients with severe sepsis and a high risk of mortality has been downgraded to weak (grade 2b) and a lower strength of evidence (grade 2c) was assigned for patients within 30 days of surgery.
Improving Survival in Sepsis by Immunotherapy
Given the extensive apoptosis-induced depletion of immune effector cells (fig. 2
), one promising strategy is use of the antiapoptotic, immunostimulatory cytokine IL-7 (fig. 4
). IL-7 induces lymphocyte proliferation, restores lymphocyte effector function, and improves lymphocyte trafficking to sites of infection.103–106
There are several studies that cumulatively provide strong theoretical support for use of IL-7 in sepsis. IL-7 restored immunity in patients with persistent viral infections and improved survival in animal models of chronic viral disease and sepsis.106
It is currently being used in clinical trials to boost immunity in patients with chronic hepatitis C, human immunodeficiency virus, and cancer. It has an excellent safety profile and has been extremely well-tolerated.104
A second potential immunomodulatory therapy of sepsis involves blockade of negative costimulatory molecules present on the surface of T cells. In this regard, the recently identified receptor PD-1 has been shown to be a crucial modulator of host immune responses that is inducibly expressed primarily on CD4 and CD8 T cells.108
Signaling through PD-1 inhibits the ability of T cells to proliferate, produce cytokines, or perform cytotoxic functions. PD-1 expression is increased on circulating T cells from patients with sepsis, and animal models demonstrate that blockade of this pathway improves sepsis survival.42
Animal studies showing that blockade of PD-1 can improve pathogen clearance and current oncology trials of anti–PD-1 showing excellent clinical responses all support the potential efficacy of this drug as an effective immunomodulatory agent (fig. 4
A third potential therapy of sepsis is the use of extracorporeal blood purification. This therapeutic approach is based on the concept that the host inflammatory response can be modulated by hemofiltration to remove circulating inflammatory mediators. The basis of the theory of hemofiltration is to attenuate the inflammatory response by removing the very high peaks in proinflammatory cytokines that are produced. In addition, antiinflammatory cytokines will be removed. This approach has some advantages in that the cytokines are not completely blocked by this method; they are only decreased in concentration. Recent progress in the design of hemofiltration filters and dialysis equipment has improved the ease and efficiency of hemopurification. Several groups have reported improved clinical findings and decreased circulating cytokines in septic patients undergoing hemopurification.111
Anesthetic Management of the Septic Patient
Most of the previously discussed principles relating to the treatment of patients with sepsis are readily applicable to septic patients who require surgery. Thus, only a brief discussion of selected aspects of the anesthetic management of septic patients is provided here. The priority of management of septic patients is always the ABCs of resuscitation. First, ensure that the patient is stable to transport to the operating room. If the patient is not already intubated, secure the airway if there is any question that the patient might not tolerate transport. Central venous access often is appropriate for several reasons, including quantitation of central venous pressures to ensure adequacy of volume resuscitation, determination of central venous oxygen saturation (as recommended by the Society of Critical Care Medicine's Surviving Sepsis Campaign), and for administration of vasoactive agents such as norepinephrine if shock is present. Large-bore venous access and an arterial line often are required for expeditious volume resuscitation and for beat-to-beat quantitation of arterial blood pressure, respectively. Antibiotics should be administered as soon as possible if that has not already been done in the ICU or emergency department.
Before anesthetic agents are administered, the anesthetist should be certain that the patient has been adequately volume resuscitated. Many anesthetic agents will decrease preload (by increasing venous capacitance), decrease myocardial contractility, and/or decrease sympathetic tone, which will result in a precipitous decrease in arterial blood pressure during induction. Spinal or epidural local anesthetics cause abrupt loss of sympathetic tone, which may result in profound hypotension in the septic patient. Thus, the preferred method for anesthetizing the septic patient for abdominal or thoracic surgery usually is general anesthesia. In addition, septic patients often have abnormalities in their coagulation system, which may preclude the use of spinal or epidural anesthesia. However, in selected cases, regional anesthesia may be indicated. Although numerous laboratory studies have shown that anesthetics can modulate the immune response, most of the studies are in vitro or in animal models of questionable clinical relevance. Therefore, at the current time, no particular agent is recommended for modulation of the host immune response to sepsis.
Because of the effects of sepsis in delaying gastric emptying and thus increasing the risk of aspiration, the patient with sepsis should be considered to have a “full stomach.” In the rare cases in which the septic patient is hypertensive during the operation, short-acting antihypertensive agents should be used to control blood pressure because hypotension may ensue rapidly. Septic patients frequently experience pulmonary complications, including adult respiratory distress syndrome. Positive end-expiratory pressure is helpful in maintaining lung volumes and improving oxygenation.
In the future, immune based therapies in sepsis likely will be individualized based on particular laboratory and/or clinical findings (e.g., the use of GM-CSF based on monocyte HLA-DR expression). Similarly, flow cytometry studies that quantitate T-cell expression of PD-1/PD-ligand 1 or rapid whole-blood stimulation assays of cytokine secretion could be used to guide immunomodulatory therapies. Finally, patients with infections caused by opportunistic pathogens (e.g., Stenotrophomonas or Acinetobacter) or patients with cytomegalovirus or herpes simplex virus viral reactivation are obvious candidates for immune-enhancing therapy. Although it is conceivable that immune-stimulatory therapies could worsen the hyperinflammatory phase of sepsis or induce autoimmunity, clinical trials of interferon-γ, a potent immunostimulatory agent, granulocyte colony-stimulating factor, and GM-CSF in patients with various systemic inflammatory states, including sepsis and trauma, did not demonstrate these types of adverse effects. In addition, most patients with refractory sepsis are so significantly immunosuppressed that they are less likely to develop hyperinflammation.
In summary, sepsis can be considered a race to the death between invading pathogens and the host immune response, and the pathogens seek an advantage by disabling selected aspects of host defenses, including inducing apoptotic death of immune cells, decreasing monocyte major histocompatibility complex class-2 expression, increasing expression of negative costimulatory molecules, inducing antiinflammatory cytokine production, and increasing suppressor cells. Advances in immunology and in understanding the pathophysiologic basis of sepsis provide new therapeutic opportunities. Carefully designed trials of immunostimulatory agents in patients with demonstrable immunosuppression should be undertaken. Many potentially beneficial immunomodulatory agents are in clinical trials for other indications and have reasonable safety profiles. We hypothesize that an immunomodulatory approach would have wide-ranging effects and could represent a major advance in the field of infectious disease.
§ Eisai Pharmaceuticals: Press release as discussed in Wall Street Journal
, January 25, 2011. Cited Here...
‖ For the most current recommendations for the treatment of sepsis as formulated by several critical care groups, see www.survivingsepsis.org
. Accessed January 7, 2011. Cited Here...
1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, SCCM/ESICM/ACCP/ATS/SIS: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31:1250–6
2. O'Brien JM Jr, Ali NA, Aberegg SK, Abraham E: Sepsis. Am J Med 2007; 120:1012–22
3. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, Gomersall C, Sakr Y, Reinhart K, EPIC II Group of Investigators: International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009; 302:2323–9
4. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D, Sepsis Occurrence in Acutely Ill Patients Investigators: Sepsis in European intensive care units: Results of the SOAP study. Crit Care Med 2006; 34:344–53
5. Stearns-Kurosawa DJ, Osuchowski MF, Valentine C, Kurosawa S, Remick DG: The pathogenesis of sepsis. Annu Rev Pathol 2011; 6:19–48
6. Rittirsch D, Flierl MA, Ward PA: Harmful molecular mechanisms in sepsis. Nat Rev Immunol 2008; 8:776–87
7. Parrish WR, Gallowitsch-Puerta M, Czura CJ, Tracey KJ: Experimental therapeutic strategies for severe sepsis: Mediators and mechanisms. Ann N Y Acad Sci 2008; 1144:210–36
8. Thomas L: Germs. N Engl J Med 1972; 287:553–5
9. Bone RC, Fisher CJ Jr, Clemmer TP, Slotman GJ, Metz CA, Balk RA: A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock. N Engl J Med 1987; 317:653–8
10. Ziegler EJ, Fisher CJ Jr, Sprung CL, Straube RC, Sadoff JC, Foulke GE, Wortel CH, Fink MP, Dellinger RP, Teng NN, Allen IE, Berger HJ, Knatterud GL, LoBuglio AF, Smith CR: Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin: A randomized, double-blind, placebo-controlled trial. The Ha-1A Sepsis Study Group. N Engl J Med 1991; 324:429–36
11. Fisher CJ Jr, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RM, Benjamin E: Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996; 334:1697–702
12. Abraham E, Wunderink R, Silverman H, Perl TM, Nasraway S, Levy H, Bone R, Wenzel RP, Balk R, Allred R, Pennington JE, Wherry JC: Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome. A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 1995; 273:934–41
13. Fisher CJ Jr, Slotman GJ, Opal SM, Pribble JP, Bone RC, Emmanuel G, Ng D, Bloedow DC, Catalano MA, IL-1RA Sepsis Syndrome Study Group: Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: A randomized, open-label, placebo-controlled multicenter trial. Crit Care Med 1994; 22:12–21
14. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis. N Engl J Med 2003; 348:138–50
15. Munford RS, Pugin J: Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 2001; 163:316–21
16. van Dissel JT, van Langevelde P, Westendorp RG, Kwappenberg K, Frölich M: Anti-inflammatory cytokine profile and mortality in febrile patients. Lancet 1998; 351:950–3
17. Ertel W, Kremer JP, Kenney J, Steckholzer U, Jarrar D, Trentz O, Schildberg FW: Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood 1995; 85:1341–7
18. Munoz C, Carlet J, Fitting C, Misset B, Blériot JP, Cavaillon JM: Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest 1991; 88:1747–54
19. Rigato O, Salomao R: Impaired production of interferon-gamma and tumor necrosis factor-alpha but not of interleukin 10 in whole blood of patients with sepsis. Shock 2003; 19:113–6
20. Sinistro A, Almerighi C, Ciaprini C, Natoli S, Sussarello E, Di Fino S, Calò-Carducci F, Rocchi G, Bergamini A: Downregulation of CD40 ligand response in monocytes from sepsis patients. Clin Vaccine Immunol 2008; 15:1851–8
21. Weighardt H, Heidecke CD, Emmanuilidis K, Maier S, Bartels H, Siewert JR, Holzmann B: Sepsis after major visceral surgery is associated with sustained and interferon-gamma-resistant defects of monocyte cytokine production. Surgery 2000; 127:309–15
22. Modlin RL, Brightbill HD, Godowski PJ: The toll of innate immunity on microbial pathogens. N Engl J Med 1999; 340:1834–5
23. Vasselon T, Detmers PA: Toll receptors: A central element in innate immune responses. Infect Immun 2002; 70:1033–41
24. Underhill DM, Ozinsky A: Toll-like receptors: Key mediators of microbe detection. Curr Opin Immunol 2002; 14:103–10
25. Malley R, Henneke P, Morse SC, Cieslewicz MJ, Lipsitch M, Thompson CM, Kurt-Jones E, Paton JC, Wessels MR, Golenbock DT: Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection. Proc Natl Acad Sci U S A 2003; 100:1966–71
26. Hagberg L, Briles DE, Edén CS: Evidence for separate genetic defects in C3H/HeJ and C3HeB/FeJ mice, that affect susceptibility to gram-negative infections. J Immunol 1985; 134:4118–22
27. Rijneveld AW, Florquin S, Hartung T, Speelman P, van der Poll T: Anti-tumor necrosis factor antibody impairs the therapeutic effect of ceftriaxone in murine pneumococcal pneumonia. J Infect Dis 2003; 188:282–5
28. Moore TA, Lau HY, Cogen AL, Monteleon CL, Standiford TJ: Anti-tumor necrosis factor-alpha therapy during murine Klebsiella pneumoniae bacteremia: Increased mortality in the absence of liver injury. Shock 2003; 20:309–15
29. Remick DG: Pathophysiology of sepsis. Am J Pathol 2007; 170:1435–44
30. Monneret G, Venet F, Pachot A, Lepape A: Monitoring immune dysfunctions in the septic patient: A new skin for the old ceremony. Mol Med 2008; 14:64–78
31. Riedemann NC, Guo RF, Ward PA: The enigma of sepsis. J Clin Invest 2003; 112:460–7
32. Barochia AV, Cui X, Vitberg D, Suffredini AF, O'Grady NP, Banks SM, Minneci P, Kern SJ, Danner RL, Natanson C, Eichacker PQ: Bundled care for septic shock: An analysis of clinical trials. Crit Care Med 2010; 38:668–78
33. Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, Matuschak GM, Buchman TG, Karl IE: Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 1999; 27:1230–51
34. Hotchkiss RS, Tinsley KW, Swanson PE, Schmieg RE Jr, Hui JJ, Chang KC, Osborne DF, Freeman BD, Cobb JP, Buchman TG, Karl IE: Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans. J Immunol 2001; 166:6952–63
35. Hotchkiss RS, Tinsley KW, Swanson PE, Grayson MH, Osborne DF, Wagner TH, Cobb JP, Coopersmith C, Karl IE: Depletion of dendritic cells, but not macrophages, in patients with sepsis. J Immunol 2002; 168:2493–500
36. Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA: Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol 2005; 174:3765–72
37. Toti P, De Felice C, Occhini R, Schuerfeld K, Stumpo M, Epistolato MC, Vatti R, Buonocore G: Spleen depletion in neonatal sepsis and chorioamnionitis. Am J Clin Pathol 2004; 122:765–71
38. Green DR, Beere HM: Apoptosis. Gone but not forgotten. Nature 2000; 405:28–9
39. Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I: Immunosuppressive effects of apoptotic cells. Nature 1997; 390:350–1
40. Hershman MJ, Cheadle WG, Wellhausen SR, Davidson PF, Polk HC Jr: Monocyte HLA-DR antigen expression characterizes clinical outcome in the trauma patient. Br J Surg 1990; 77:204–7
41. Landelle C, Lepape A, Voirin N, Tognet E, Venet F, Bohé J, Vanhems P, Monneret G: Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med 2010; 36:1859–66
42. Huang X, Venet F, Wang YL, Lepape A, Yuan Z, Chen Y, Swan R, Kherouf H, Monneret G, Chung CS, Ayala A: PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A 2009; 106:6303–8
43. Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS: Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol 2010; 88:233–40
44. Venet F, Chung CS, Monneret G, Huang X, Horner B, Garber M, Ayala A: Regulatory T cell populations in sepsis and trauma. J Leukoc Biol 2008; 83:523–35
45. Inoue S, Bo L, Bian J, Unsinger J, Chang K, Hotchkiss RS: Dose-dependent effect of anti-CTLA-4 on survival in sepsis. Shock 2011; 36:38–44
46. Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, O'Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, Ramphal R, Gabrilovich DI, Reeves WH, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL: MyD88-dependent expansion of an immature GR-1(+)CD11b(+) population induces T cell suppression and Th2 polarization in sepsis. J Exp Med 2007; 204:1463–74
47. Pober JS, Sessa WC: Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 2007; 7:803–15
48. Stanciu LA, Bellettato CM, Laza-Stanca V, Coyle AJ, Papi A, Johnston SL: Expression of programmed death-1 ligand (PD-L) 1, PD-L2, B7–H3, and inducible costimulator ligand on human respiratory tract epithelial cells and regulation by respiratory syncytial virus and type 1 and 2 cytokines. J Infect Dis 2006; 193:404–12
49. Torgersen C, Moser P, Luckner G, Mayr V, Jochberger S, Hasibeder WR, Dünser MW: Macroscopic postmortem findings in 235 surgical intensive care patients with sepsis. Anesth Analg 2009; 108:1841–7
50. Kollef KE, Schramm GE, Wills AR, Reichley RM, Micek ST, Kollef MH: Predictors of 30-day mortality and hospital costs in patients with ventilator-associated pneumonia attributed to potentially antibiotic-resistant gram-negative bacteria. Chest 2008; 134:281–7
51. Luyt CE, Combes A, Deback C, Aubriot-Lorton MH, Nieszkowska A, Trouillet JL, Capron F, Agut H, Gibert C, Chastre J: Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care Med 2007; 175:935–42
52. Limaye AP, Kirby KA, Rubenfeld GD, Leisenring WM, Bulger EM, Neff MJ, Gibran NS, Huang ML, Santo Hayes TK, Corey L, Boeckh M: Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008; 300:413–22
53. Meisel C, Schefold JC, Pschowski R, Baumann T, Hetzger K, Gregor J, Weber-Carstens S, Hasper D, Keh D, Zuckermann H, Reinke P, Volk HD: Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: A double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med 2009; 180:640–8
54. Hall MW, Knatz NL, Vetterly C, Tomarello S, Wewers MD, Volk HD, Carcillo JA: Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med 2011; 37:525–32
55. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL, International Surviving Sepsis Campaign Guidelines Committee, American Association of Critical-Care Nurses, American College of Chest Physicians, American College of Emergency Physicians, Canadian Critical Care Society, European Society of Clinical Microbiology and Infectious Diseases, European Society of Intensive Care Medicine, European Respiratory Society, International Sepsis Forum, Japanese Association for Acute Medicine, Japanese Society of Intensive Care Medicine, Society of Critical Care Medicine, Society of Hospital Medicine, Surgical Infection Society, World Federation of Societies of Intensive and Critical Care Medicine: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36:296–327
56. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr C, Artigas A, Ramsay G, Beale R, Parker MM, Gerlach H, Reinhart K, Silva E, Harvey M, Regan S, Angus DC: The Surviving Sepsis Campaign: Results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Med 2010; 36:222–31
57. Ferrer R, Artigas A, Levy MM, Blanco J, González-Díaz G, Garnacho-Montero J, Ibáñez J, Palencia E, Quintana M, de la Torre-Prados MV, Edusepsis Study Group: Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA 2008; 299:2294–303
58. Micek ST, Roubinian N, Heuring T, Bode M, Williams J, Harrison C, Murphy T, Prentice D, Ruoff BE, Kollef MH: Before-after study of a standardized hospital order set for the management of septic shock. Crit Care Med 2006; 34:2707–13
59. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, Suppes R, Feinstein D, Zanotti S, Taiberg L, Gurka D, Kumar A, Cheang M: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 2006; 34:1589–96
60. Shorr AF, Micek ST, Welch EC, Doherty JA, Reichley RM, Kollef MH: Inappropriate antibiotic therapy in Gram-negative sepsis increases hospital length of stay. Crit Care Med 2011; 39:46–51
61. Zilberberg MD, Shorr AF, Micek ST, Chen J, Ramsey AM, Hoban AP, Pham V, Doherty JA, Mody SH, Kollef MH: Hospitalizations with healthcare-associated complicated skin and skin structure infections: Impact of inappropriate empiric therapy on outcomes. J Hosp Med 2010; 5:535–40
62. Micek ST, Welch EC, Khan J, Pervez M, Doherty JA, Reichley RM, Kollef MH: Empiric combination antibiotic therapy is associated with improved outcome against sepsis due to Gram-negative bacteria: A retrospective analysis. Antimicrob Agents Chemother 2010; 54:1742–8
63. Schramm GE, Johnson JA, Doherty JA, Micek ST, Kollef MH: Methicillin-resistant Staphylococcus aureus sterile-site infection: The importance of appropriate initial antimicrobial treatment. Crit Care Med 2006; 34:2069–74
64. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C: Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med 2003; 31:2742–51
65. Kollef MH, Sherman G, Ward S, Fraser VJ: Inadequate antimicrobial treatment of infections: A risk factor for hospital mortality among critically ill patients. Chest 1999; 115:462–74
66. Bhat S, Fujitani S, Potoski BA, Capitano B, Linden PK, Shutt K, Paterson DL: Pseudomonas aeruginosa infections in the Intensive Care Unit: Can the adequacy of empirical beta-lactam antibiotic therapy be improved? Int J Antimicrob Agents 2007; 30:458–62
67. El Amari EB, Chamot E, Auckenthaler R, Pechère JC, Van Delden C: Influence of previous exposure to antibiotic therapy on the susceptibility pattern of Pseudomonas aeruginosa bacteremic isolates. Clin Infect Dis 2001; 33:1859–64
68. Micek ST, Kollef KE, Reichley RM, Roubinian N, Kollef MH: Health care-associated pneumonia and community-acquired pneumonia: A single-center experience. Antimicrob Agents Chemother 2007; 51:3568–73
69. Kollef MH, Napolitano LM, Solomkin JS, Wunderink RG, Bae IG, Fowler VG, Balk RA, Stevens DL, Rahal JJ, Shorr AF, Linden PK, Micek ST: Health care-associated infection (HAI): A critical appraisal of the emerging threat-proceedings of the HAI Summit. Clin Infect Dis 2008; 47(Suppl 2):S55–99
70. Beardsley JR, Williamson JC, Johnson JW, Ohl CA, Karchmer TB, Bowton DL: Using local microbiologic data to develop institution-specific guidelines for the treatment of hospital-acquired pneumonia. Chest 2006; 130:787–93
71. Lancaster JW, Lawrence KR, Fong JJ, Doron SI, Garpestad E, Nasraway SA, Devlin JW: Impact of an institution-specific hospital-acquired pneumonia protocol on the appropriateness of antibiotic therapy and patient outcomes. Pharmacotherapy 2008; 28:852–62
72. Aarts MA, Hancock JN, Heyland D, McLeod RS, Marshall JC: Empiric antibiotic therapy for suspected ventilator-associated pneumonia: A systematic review and meta-analysis of randomized trials. Crit Care Med 2008; 36:108–17
73. Paul M, Benuri-Silbiger I, Soares-Weiser K, Leibovici L: Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: Systematic review and meta-analysis of randomised trials. BMJ 2004; 328:668
74. Heyland DK, Dodek P, Muscedere J, Day A, Cook D, Canadian Critical Care Trials Group: Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia. Crit Care Med 2008; 36:737–44
75. Kumar A, Zarychanski R, Light B, Parrillo J, Maki D, Simon D, Laporta D, Lapinsky S, Ellis P, Mirzanejad Y, Martinka G, Keenan S, Wood G, Arabi Y, Feinstein D, Kumar A, Dodek P, Kravetsky L, Doucette S, Cooperative Antimicrobial Therapy of Septic Shock (CATSS) Database Research Group: Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: A propensity-matched analysis. Crit Care Med 2010; 38:1773–85
76. Labelle AJ, Micek ST, Roubinian N, Kollef MH: Treatment-related risk factors for hospital mortality in Candida bloodstream infections. Crit Care Med 2008; 36:2967–72
77. Haque NZ, Zuniga LC, Peyrani P, Reyes K, Lamerato L, Moore CL, Patel S, Allen M, Peterson E, Wiemken T, Cano E, Mangino JE, Kett DH, Ramirez JA, Zervos MJ, Improving Medicine through Pathway Assessment of Critical Therapy of Hospital-Acquired Pneumonia (IMPACT-HAP) Investigators: Relationship of vancomycin minimum inhibitory concentration to mortality in patients with methicillin-resistant Staphylococcus aureus hospital-acquired, ventilator-associated, or health-care-associated pneumonia. Chest 2010; 138:1356–62
78. Lodise TP, Graves J, Evans A, Graffunder E, Helmecke M, Lomaestro BM, Stellrecht K: Relationship between vancomycin MIC and failure among patients with methicillin-resistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother 2008; 52:3315–20
79. Soriano A, Marco F, Martínez JA, Pisos E, Almela M, Dimova VP, Alamo D, Ortega M, Lopez J, Mensa J: Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis 2008; 46:193–200
80. Bhat SV, Peleg AY, Lodise TP Jr, Shutt KA, Capitano B, Potoski BA, Paterson DL: Failure of current cefepime breakpoints to predict clinical outcomes of bacteremia caused by gram-negative organisms. Antimicrob Agents Chemother 2007; 51:4390–5
81. Tam VH, Gamez EA, Weston JS, Gerard LN, Larocco MT, Caeiro JP, Gentry LO, Garey KW: Outcomes of bacteremia due to Pseudomonas aeruginosa with reduced susceptibility to piperacillin-tazobactam: Implications on the appropriateness of the resistance breakpoint. Clin Infect Dis 2008; 46:862–7
82. Roberts JA, Kirkpatrick CM, Roberts MS, Dalley AJ, Lipman J: First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis. Int J Antimicrob Agents 2010; 35:156–63
83. Nicasio AM, Ariano RE, Zelenitsky SA, Kim A, Crandon JL, Kuti JL, Nicolau DP: Population pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically ill patients with ventilator-associated pneumonia. Antimicrob Agents Chemother 2009; 53:1476–81
84. Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, Lipman J: Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: Intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother 2009; 64:142–50
85. Lodise TP Jr, Lomaestro B, Drusano GL: Piperacillin-tazobactam for Pseudomonas aeruginosa infection: Clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 2007; 44:357–63
86. Lorente L, Jiménez A, Martín MM, Iribarren JL, Jiménez JJ, Mora ML: Clinical cure of ventilator-associated pneumonia treated with piperacillin/tazobactam administered by continuous or intermittent infusion. Int J Antimicrob Agents 2009; 33:464–8
87. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M, Early Goal-Directed Therapy Collaborative Group: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368–77
88. Rivers EP: Point: Adherence to early goal-directed therapy: Does it really matter? Yes. After a decade, the scientific proof speaks for itself. Chest 2010; 138:476–80; discussion 484–5
89. Schmidt GA: Counterpoint: Adherence to early goal-directed therapy: Does it really matter? No. Both risks and benefits require further study. Chest 2010; 138:480–3; discussion 483–4
90. Annane D, Vignon P, Renault A, Bollaert PE, Charpentier C, Martin C, Troché G, Ricard JD, Nitenberg G, Papazian L, Azoulay E, Bellissant E, CATS Study Group: Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: A randomised trial. Lancet 2007; 370:676–84
91. Sakr Y, Reinhart K, Vincent JL, Sprung CL, Moreno R, Ranieri VM, De Backer D, Payen D: Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med 2006; 34:589–97
92. De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL, SOAP II Investigators: Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010; 362:779–89
93. Patel GP, Grahe JS, Sperry M, Singla S, Elpern E, Lateef O, Balk RA: Efficacy and safety of dopamine versus norepinephrine in the management of septic shock. Shock 2010; 33:375–80
94. Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, Holmes CL, Mehta S, Granton JT, Storms MM, Cook DJ, Presneill JJ, Ayers D, VASST Investigators: Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877–87
95. Leone M, Boyle WA: Decreased vasopressin responsiveness in vasodilatory septic shock-like conditions. Crit Care Med 2006; 34:1126–30
96. Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arlt W, Keh D, Briegel J, Beishuizen A, Dimopoulou I, Tsagarakis S, Singer M, Chrousos GP, Zaloga G, Bokhari F, Vogeser M, American College of Critical Care Medicine: Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med 2008; 36:1937–49
97. Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud P, Bellissant E: Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288:862–71
98. Sprung CL, Annane D, Keh D, Moreno R, Singer M, Freivogel K, Weiss YG, Benbenishty J, Kalenka A, Forst H, Laterre PF, Reinhart K, Cuthbertson BH, Payen D, Briegel J, CORTICUS Study Group: Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008; 358:111–24
99. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr, Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001; 344:699–709
100. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Brückmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL, Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group: Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005; 353:1332–41
101. Nadel S, Goldstein B, Williams MD, Dalton H, Peters M, Macias WL, Abd-Allah SA, Levy H, Angle R, Wang D, Sundin DP, Giroir B, REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE) study group: Drotrecogin alfa (activated) in children with severe sepsis: A multicentre phase III randomised controlled trial. Lancet 2007; 369:836–43
102. Martí-Carvajal A, Salanti G, Cardona AF: Human recombinant activated protein C for severe sepsis. Cochrane Database of Systematic Reviews 2008, CD004388
103. Unsinger J, McGlynn M, Kasten KR, Hoekzema AS, Watanabe E, Muenzer JT, McDonough JS, Tschoep J, Ferguson TA, McDunn JE, Morre M, Hildeman DA, Caldwell CC, Hotchkiss RS: IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol 2010; 184:3768–79
104. Sportès C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, Fleisher TA, Krumlauf MC, Babb RR, Chow CK, Fry TJ, Engels J, Buffet R, Morre M, Amato RJ, Venzon DJ, Korngold R, Pecora A, Gress RE, Mackall CL: Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 2008; 205:1701–14
105. Levy Y, Lacabaratz C, Weiss L, Viard JP, Goujard C, Lelièvre JD, Boué F, Molina JM, Rouzioux C, Avettand-Fénoêl V, Croughs T, Beq S, Thiébaut R, Chêne G, Morre M, Delfraissy JF: Enhanced T cell recovery in HIV-1-infected adults through IL-7 treatment. J Clin Invest 2009; 119:997–1007
106. Patel A, Patel J, Ikwuagwu J: A case of progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia. J Antimicrob Chemother 2010; 65:2697–8
107. Pellegrini M, Calzascia T, Toe JG, Preston SP, Lin AE, Elford AR, Shahinian A, Lang PA, Lang KS, Morre M, Assouline B, Lahl K, Sparwasser T, Tedder TF, Paik JH, DePinho RA, Basta S, Ohashi PS, Mak TW: IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell 2011; 144:601–13
108. Mueller SN, Vanguri VK, Ha SJ, West EE, Keir ME, Glickman JN, Sharpe AH, Ahmed R: PD-L1 has distinct functions in hematopoietic and nonhematopoietic cells in regulating T cell responses during chronic infection in mice. J Clin Invest 2010; 120:2508–15
109. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL: Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010; 28:3167–75
110. Lázár-Molnár E, Gácser A, Freeman GJ, Almo SC, Nathenson SG, Nosanchuk JD: The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl Acad Sci U S A 2008; 105:2658–63
111. Nakada TA, Oda S, Matsuda K, Sadahiro T, Nakamura M, Abe R, Hirasawa H: Continuous hemodiafiltration with PMMA Hemofilter in the treatment of patients with septic shock. Mol Med 2008; 14:257–63
112. Payen D, Mateo J, Cavaillon JM, Fraisse F, Floriot C, Vicaut E, Hemofiltration and Sepsis Group of the Collège National de Réanimation et de Médecine d'Urgence des Hôpitaux extra-Universitaires: Impact of continuous venovenous hemofiltration on organ failure during the early phase of severe sepsis: A randomized controlled trial. Crit Care Med 2009; 37:803–10
© 2011 American Society of Anesthesiologists, Inc.