Advances in pathogenesis and management of sepsis Ismail Cinel and R. Phillip Dellinger

Purpose of review The rationale for therapeutic targets in sepsis has arisen from the concept of pathogenesis. This review focuses on recent advances in pathogenesis of sepsis that can aid in management of sepsis patients. Recent findings Cellular survival in sepsis is related to the magnitude of the stimulus, the stage of the cell cycle and the type of microbe. While phenotypic modification of the endothelium (procoagulant and proadhesive properties, increased endothelial permeability, endothelial apoptosis and changes in vasomotor properties) leads to vasoplegia as a direct correlate to septic shock mortality, phenotypic changes in the epithelium cause activation of the virulence of the opportunistic pathogens and loss of mucosal barrier function, the latter causing a vicious circle in severe sepsis. Early identification of sepsis with protocolized screening, triggering evidence-based protocolized care, is anticipated to reduce sepsis morbidity and mortality. Current treatment of sepsis includes early antibiotic therapy, early aggressive goal-directed resuscitation targeting tissue hypoperfusion, steroids (for refractory shock), activated protein C (for high risk of death) and maintaining support of organ systems. Summary A better understanding of pathogenesis of sepsis has led to specific proven management tools that are likely to improve clinical outcome once incorporated into protocolized care. Keywords lactate, pathogenesis of sepsis, protocolized care, severe sepsis, steroids, Surviving Sepsis Campaign Curr Opin Infect Dis 20:345–352. ß 2007 Lippincott Williams & Wilkins. Robert Wood Johnson School of Medicine, University of Medicine and Dentistry of New Jersey, Department of Critical Care Medicine, Cooper University Hospital, Camden, New Jersey, USA Correspondence to R. Phillip Dellinger, MD, Head, Department of Critical Care Medicine, Cooper University Hospital, One Cooper Plaza, 393 Dorrance, Camden, NJ 08103, USA Tel: +1 856 342 2657; fax: +1 856 968 8306; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:345–352

Abbreviations CRP CVP MAP PAMP PARP PPR rhAPC RIG-I ROS/RNS SSC TLR ScvO2 SvO2

C-reactive protein central venous pressure mean arterial pressure pathogen-associated molecular patterns poly(ADP-ribose) polymerase pattern recognition receptor recombinant human activated protein C retinoic-acid-inducible gene I reactive oxygen and/or reactive nitrogen species Surviving Sepsis Campaign toll-like receptor central venous oxygen saturation mixed venous oxygen saturation

ß 2007 Lippincott Williams & Wilkins 0951-7375

Introduction Sepsis is the systemic maladaptive response of the host organism to the invasion of normally sterile tissue, fluid or body cavity by pathogenic or potentially pathogenic microorganisms. The culmination of complex interactions between the infecting microorganism and the host immune, inflammatory and coagulation responses influences the outcome in sepsis. Until recently, sepsis was regarded as a condition of hyperinflammation and hypercoagulation resulting in cellular damage and macrocirculation/microcirculation derangement. Dysregulation of the immune response favoring a shift to an antiinflammatory phenotype and phenotypic modulations of cells which can activate the virulence of the opportunistic pathogens, however, may be equally important [1,2
]. Phenotypic modification of the endothelium including changes in procoagulant and proadhesive properties, increased endothelial permeability, endothelial cell apoptosis and changes in vasomotor properties leads to vasoplegia, which is directly related to septic shock mortality.

Pathogenesis of sepsis The innate immune system is an evolutionally conserved host defense mechanism against pathogens [3]. Innate immune responses are initiated by pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Pattern-recognition receptors and pathogen-associated molecular patterns

The initiation of the response during sepsis or in response to sterile tissue injury involves three families of PRRs [4]: toll-like receptors (TLRs), nucleotide-oligomerization domain (NOD) leucine-rich repeat proteins and retinoic345

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346 Nosocomial and hospital-related infections

Figure 1 Pathogenic mechanisms leading to organ dysfunction

PRRs. Organ dysfunctions in severe sepsis can be seen as the clinical manifestation of a TLR-mediated dysregulation of the immune response to pathogens.

Pathogenic mechanisms leading to organ dysfunction TNF-α HMGB-1

IL-1

Protease activation

Insult

Heparan sulfate Hyaluronic acid Fibronectin Heat shock proteins Fibrinogen Surfactant A

24 hr

LPS, LTA, PGN, Flagellin

PAMPs

PMN, Monocyte, Lymphocyte, Dendritic cells

PRRs R

e el

as

fT eo

LR

n tio bi hi in

Endogenous activators

Endothelium, Epithelium, VSMCs

NOD-LRRs

TLRs

RBCs

RLHs

Caspase-1

NF-kβ

Inflammasome

Proinflammatory cytokines Adhesion molecules

RAGE expr.

ROCK expr.

Potential imbalances between Capillary perm. Ischemia/Reperfusion MPT, Cyt C release

NADPH oxidase Myeloperoxidase iNOS COX-2

Anti-inflammatory cytokines Enzymes

Cell signaling with cytokines and ROS/RNS

Vasodilation

Platelets

PARP-1 expr.

PPAR Expr.

Inflammation vs Anti-inflammation Coagulation vs Anti-coagulation Oxidant vs Anti-oxidant Apoptotic vs Anti-apoptotic

Edema

RBC deformability

Hypoxia/Reoxygenation

Mitochondrial dysfunction

Bcl-2

O2 Delivery/Consumption mismatch

Mitoptosis + Apoptosis + Necrosis Endothelial dysfunction

The lipopolysaccharide of Gram-negative bacilli binds to lipopolysaccharide-binding protein, CD14 complex. The peptidoglycan of Gram-positive bacteria and the lipopolysaccharide of Gram-negative bacteria bind to TLR-2 and TLR-4, respectively. Binding of TLRs activates intracellular signal-transduction pathways that lead to the activation of cytosolic nuclear factor-kb (NF-kb). Activated NF-kb moves from the cytoplasm to the nucleus, binds to transcription sites and induces activation of a set of genes, as well as enzymatic activation of a cellular protease. TLRs induce pro-interleukin-1b production and prime NOD-like receptor-containing multiprotein complexes, termed ‘inflammasomes’, to respond to bacterial products and products of damaged cells [3]. This results in caspase-1 activation and the subsequent processing of pro-interleukin-1b to its active form. Negative regulation of TLRs and TLR-induced programmed cell death have also taken place [5].

Epithelial dysfunction

Microcirculatory failure Multiorgan failure

Pathogenic mechanisms during sepsis or in response to sterile tissue injury can lead to multiorgan failure. COX-2, cyclooxygenase; Cyt C, cytochrome C release; HMGB-1, high mobility group box-1; IL-1, interleukin 1; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharide; LTA, lipoteichoic acid; MPT, mitochondrial permeability; NOD-LRR, nucleotide-oligomerization domain leucine-rich repeat protein receptors; PARP-1, poly(ADP ribose) polymerase-1; PGN, peptidoglycan; PPAR, peroxisome proliferator-activated receptor; PRRs, pattern recognition receptors; RAGE, receptor for advanced glycation end-products; RBC, red blood cell; RIG-I-like helicases, retinoic-acid-inducible gene I (RIG-I)like helicases; ROCK, RhoA/Rho kinase; ROS/RNS, reactive oxygen and nitrogen species; TLRs, toll-like receptors; TNF-a, tumor necrosis factor a; VSMCs, vascular smooth muscle cells.

acid-inducible gene I (RIG-I)-like helicases, as shown in Fig. 1. TLRs with 13 distinct receptors are capable of sensing organisms ranging from bacteria to fungi, protozoa and viruses, and play a major role in human innate immunity [5]. Gram-positive and Gram-negative bacteria, viruses and fungi have unique cell-wall molecules known as pathogen-associated molecular patterns (PAMPs), also termed ‘microbial-associated molecular patterns’. These molecules are common to pathogenic, nonpathogenic and commensal bacteria [6]. PAMPs bind to PRRs, that is TLRs, on the surface of immune cells. Cytoplasmic PRRs have, however, been identified to detect pathogens that have invaded cytosols [5]. Observations suggest that specific host immune response to each pathogen is mediated by various sets of PAMPs and

Cell signaling with reactive oxygen and/or nitrogen species

Reactive oxygen and/or reactive nitrogen species (ROS/ RNS) exert several beneficial physiological cellular functions such as intracellular signaling (several cytokines, growth factors and hormones use them as second messengers) and redox regulation. ROS/RNS are produced by the nicotinamide adenine dinucleotide phosphateoxidase complex, and represent a defense mechanism against invading microorganisms. Despite their importance in innate immunity as a defense mechanism against invading pathogens, an overwhelming production of ROS/RNS or a deficit in antioxidant systems can result in oxidative/nitrosative stress, which is the key element in the cascade of deleterious processes in sepsis [7]. Superoxide anion (O2) and peroxynitrite (ONOO) play key roles in the pathogenesis of hemodynamic instability and organ dysfunction during septic shock. ONOO can cause DNA strand breakage, triggering the activation of poly(ADP-ribose) polymerase (PARP). PARP plays a role in the repair of strand breaks in DNA, and its activation results in a substantial depletion of nicotinamide adenine dinucleotide, thus leading to cell dysfunction. It has been shown that PARP inhibitors have beneficial effects against oxidative and nitrosative stress-induced organ dysfunctions in endotoxemia [8,9]. Recently, the potential role of PARP activation has been demonstrated in the pathogenesis of myocardial contractile dysfunction associated with human septic shock [10]. Several important antioxidant defense systems are based around glutathione, which in the reduced form is the most important intracellular antioxidant within human

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Pathogenesis and management of sepsis Cinel and Dellinger 347

cells. Replacement of glutathione stores with glutamine in sepsis has been demonstrated to exert a beneficial effect in the prevention of organ damage [11]. Another element of the defense system is formed by chaperones or heat shock proteins. It has recently been demonstrated that glutamine’s protection against sepsis is dependent on HSP70 expression [12]. Coagulation and inflammation

Sepsis is characterized by exacerbated coagulation, impaired anticoagulation and decreased fibrin removal. With systemic inflammation, interleukin-6 release triggers tissue factor upregulation and tumor necrosis factora suppresses the natural anticoagulants, combining to produce a tendency towards coagulation activation in sepsis [13]. These derangements are implicated in the generation of microcirculation thrombosis, with deposition of microclots and obstruction of microcirculation, impairing blood flow and contributing to tissue hypoperfusion and organ dysfunction. The consumption of protein C in sepsis may play a pivotal role in the association of inflammation and coagulation. Baseline protein C levels are an independent predictor of sepsis outcome, and day 1 changes in protein C, regardless of baseline levels, are also a predictor of outcome [14].

various microparticle formations in oxido-inflammatory states may participate in the mechanism of vascular endothelial injury and resultant organ dysfunction. Evidence is emerging that microparticles defined as deleterious partners in sepsis play an important role in coagulation, inflammation and endothelial dysfunction [19]. Levels of microparticles and their interactions with leukocytes have however been shown to negatively correlate with organ dysfunction in severe sepsis [20]. Mitochondrial dysfunction

Although microvascular blood flow abnormalities have been described in experimental and human sepsis, it is unlikely that these alone explain the pathogenesis of organ dysfunctions seen in severe sepsis [21]. The concept of sepsis-induced abnormalities in oxygen utilization at the mitochondrial level is supported by findings of elevated tissue oxygen tension and decreased oxygen consumption, together with functional and biochemical derangements associated with minimal cell death in sepsis and septic shock [22,23]. Growing evidence suggests that perturbations of key mitochondrial functions, including mitochondrial permeability transition, play a critical role in septic organ dysfunction [24

]. In humans, skeletal muscle mitochondrial dysfunction has been demonstrated to relate to severity of sepsis and poor outcome [25].

Endothelial dysfunction and microparticles

Vascular endothelium plays an important role in regulating immune and inflammatory responses to pathogens. Endothelium dysfunction and impaired microvascular function in sepsis are increasingly recognized as key characteristics contributing to organ dysfunction and death. Sepsis induces phenotypic modulations of the endothelium through direct or indirect interaction between the endothelial layer and components of the bacterial wall, inducing various host-derived factors from endothelial cells. On the molecular level, endothelial dysfunction is caused by reduced nitric oxide bioavailability, which is, in turn, regulated by genes such as nitric oxide synthase, phosphatidylinositol 3-kinase and AKT [15]. On the cellular level, endothelial dysfunction is based on a progressive loss of endothelial cells determined by the degree of apoptosis of endothelial cells [16]. The microvasculature contributes to inflammation through altered leukocyte recruitment and impaired perfusion [17]. It has been demonstrated that early microcirculatory perfusion indices in severe sepsis and septic shock are more impaired in nonsurvivors compared with survivors [18

]. Microparticles shed during cell activation or apoptosis have procoagulant and proinflammatory properties. Microparticles can be derived from circulating cells (platelets, leukocytes and erythrocytes) as well as cells that compose the vessel wall, mainly endothelial cells, macrophages and smooth muscle cells. The orchestration of

Apoptosis

Apoptosis (programmed cell death) of immune effector cells is a hallmark of sepsis. Sepsis induces extensive lymphocyte and dendritic cell apoptosis that alters immune responsiveness, resulting in decreased clearance of invading organisms [1,26]. The profound decrease in the numbers of T and B cells impairs the adaptive immune response. The loss of cells of the adaptive immune system also impairs the innate immune response because of the important cross-talk between the innate and adaptive immune system. Additionally, the uptake of apoptotic cells has an anti-inflammatory/immunosuppressive effect through the induction of anergy and T-helper2 cell responses on surviving immune cells. Three independent autopsy studies of adult, pediatric and neonatal patients who died of sepsis showed profound apoptosis-induced depletion of CD4þ T cells and B cells [23,27,28]. These findings were similar to animal studies showing increased lymphocyte and epithelial cell apoptosis [29,30]. Moreover, clinical studies of patients with sepsis demonstrate that the degree of apoptosis of circulating lymphocytes correlates with sepsis severity and predicted fatal outcome in septic shock patients, suggesting the importance of apoptosis as a biomarker [29,31,32
].

Management of sepsis Early identification of sepsis with the help of protocolized screening, triggering evidence-based protocolized care, is

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348 Nosocomial and hospital-related infections

anticipated to reduce sepsis morbidity and mortality. The evidence for best clinical practice for resuscitation, management of infection and intensive care unit supportive care has been synthesized by the Surviving Sepsis Campaign (SSC), and published as evidence-based guidelines for the management of severe sepsis and septic shock [33]. Protocolized screening

Efforts have been made to reduce the time needed to diagnose sepsis in order to reduce mortality from sepsisrelated multiple organ dysfunction. Protocolized screening is very important, especially in the early phase of sepsis, and can also help to identify critically-ill patients who are at a high risk of mortality [34
]. One such approach is that recommended by the SSC using the sepsis bundle performance improvement program, which is based on selected recommendations from the SSC bundles for the management of severe sepsis and septic shock [33]. Bundles represent performance indicators which, when achieved in a timely manner, are anticipated to improve clinical outcome. Protocolized screening should be employed throughout the hospital and should not be delayed pending intensive care unit admission. Lactate

The conventional view in severe sepsis or septic shock is that most of the lactate that accumulates in the circulation is due to cellular hypoxia and the onset of anaerobic glycolysis. There is increasing evidence that sepsis is accompanied by a hypermetabolic state, with enhanced glycolysis and hyperlactatemia [35]. This should not be rigorously interpreted as an indication of hypoxia. The link between Naþ/Kþ-ATPase pump activity and muscle lactate formation has been shown in human septic shock [36]. Although serum lactate concentrations may lack precision as a measure of tissue metabolic status, levels equal to or greater than 4.0 mEq/l support aggressive resuscitation. Persistence of an elevated lactate level can be due to consistent overproduction related to a persistence of the initiator mechanism as well as lowering of lactate clearance due to hepatic dysfunction. In septic shock, hyperlactatemia is mainly related to increased production with lactate clearance similar to healthy subjects [37]. Irrespective of its mechanism of formation, hyperlactatemia remains an excellent prognostic marker in sepsis. Future role of biomarkers

Diagnosis of infection is difficult in critically-ill patients. Markers of inflammation such as C-reactive protein (CRP) and white blood cell count have proved less than ideal in identifying critically-ill patients who need antimicrobial therapy, as sensitivity and specificity for bacterial infection is low. Patients with liver dysfunction may not mount an adequate CRP response to infection [38].

Patients may develop fever, leukocytosis or elevated CRP without infection. Measurement of procalcitonin has been shown to be superior to CRP in detecting significant infection compared with clinical signs [39

]. Several studies have underscored the value of procalcitonin in identifying infectious processes, characterizing the severity of the underlying illness [39

], guiding therapy [40] and risk stratification [41]. It has been reported that procalcitonin increase for 1 day (1.0 ng/ml) is an independent predictor of 90-day survival [42]. Optimizing antimicrobial dosing, especially avoiding underdosing, is an important goal to achieve effectiveness of therapy and prevent the risk of development of resistant microbial side effects and treatment costs. A reduced use of antimicrobial therapy has been demonstrated when treatment was guided by procalcitonin in patients with suspected lower respiratory tract infection without affecting outcome [40]. Antibiotic therapy

Selecting initial antibiotics that cover the infecting organism is a high priority in sepsis. It has been demonstrated that administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was associated with a survival rate of 79.9%, and each hour of delay in antimicrobial administration over the ensuing 6 h was associated with an average decrease in survival of 7.6% [43

]. In multivariate analysis [including Acute Physiology and Chronic Health Evaluation (APACHE) II score and therapeutic variables], time to initiation of effective antimicrobial therapy has been shown to be the single strongest predictor of outcome. After appropriate cultures have been obtained, intravenous antibiotic therapy should be started within the first hour of recognition of severe sepsis. Establishing a supply of premixed antibiotics in an emergency department or critical care unit for such urgent situations is an appropriate strategy for enhancing the likelihood that antimicrobial agents will be infused promptly. Cycling or rotating antibiotics has been advocated to reduce the risk of emergence and selection of bacterial resistance, although the frequency of cycles is unclear [44]. Early aggressive goal directed resuscitation targeting tissue hypoperfusion

Aggressive resuscitation of a patient with sepsis-induced tissue hypoperfusion (hypotension persisting after initial fluid challenge or serum lactate of at least 4 mmol/dl) should begin as soon as recognized [33,34
,45]. Data from the Sepsis Occurrence in Acutely Ill Patients (SOAP) study showed that fluid balance was the most important predictor of mortality [46]. Assessing fluid responsiveness, however, is complicated. A fundamental component of the fluid challenge technique is the monitoring of cardiac filling pressures, as hydrostatic pressures are

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Pathogenesis and management of sepsis Cinel and Dellinger 349

the primary determinant of edema formation. End-diastolic volumes represent ventricular preload better than filling pressures. The goal of a fluid challenge must be a clinically relevant end point, such as an increase in arterial pressure, a decrease in heart rate, or an improvement in peripheral perfusion. Rate of fluid administration needs reduction with rising filling pressures and no improvement in tissue perfusion. The validity of central venous pressure (CVP) measurements in patients with sepsis is widely debated. It is commonly accepted that a very low CVP is indicative of low intravascular volumes and supports the administration of fluids (crystalloids or colloids) for volume expansion and improvement in tissue hypoperfusion. An elevated CVP does not however always correlate with adequate intravascular volume. Despite these limitations, CVP measurement in conjunction with other measurements is often utilized to assess and guide resuscitation in patients with sepsis as more sophisticated monitoring tools are usually not available during the critical early hours of resuscitation. In mechanically ventilated patients or patients with known preexisting decreased ventricular compliance, a higher target CVP of 12–15 mmHg is recommended to account for the impediment to filling (Fig. 2). Similar consideration may be warranted in circumstances of increased abdominal pressure. The pulmonary artery catheter allows measurements of intracardiac pressures, determination of cardiac output (through thermodilution), and mixed venous oxygen saturation (SvO2) which can be useful in diagnosing different causes of shock as well as monitoring disease progression and response to therapeutic interventions. Studies randomizing critically-ill patients to treatment with or without pulmonary artery catheter have not shown any significant difference in outcome [47,48]. The determinants of SvO2 include cardiac output, oxygen demand, hemoglobin and arterial oxygen saturation. Normal SvO2 is 70–75%. Following resuscitation of sepsis, SvO2 may be elevated secondary to maldistribution of flow defined as blood returning to the venous circulation without opportunity for oxygen transfer. Patients with sepsis, however, frequently present with a low SvO2. Although a normal or high SvO2 does not always indicate adequate resuscitation, a low SvO2 should trigger aggressive interventions to increase oxygen delivery to the tissues and minimize sepsis-induced tissue hypoperfusion. An association between good clinical outcome in septic shock and mean arterial pressure (MAP) of at least 65 mmHg as well as SvO2 no less than 70% have been demonstrated [49]. Recently, it has also been shown that SvO2 runs 5–7% lower than central venous oxygen saturation (ScvO2) in shock [50]. MAP is not necessarily a marker of adequate resuscitation. Some patients, despite a normal MAP, have low ScvO2 levels and are clearly

under-resuscitated. Without a measurement of central venous oxygenation, these subjects may be mistriaged. In reference to the correlation between ScvO2 and SvO2, the relationship seems strong (with a correlation coefficient of 0.8 in several studies) [51]. The Saline versus Albumin Fluid Evaluation (SAFE) trial showed no benefit of albumin over crystalloid resuscitations [52]. There are, however, multiple types of colloids (e.g. gelatins and dextrans), and it is not clear whether the results of the study can be extrapolated to all these compounds. Source control

Source control is defined as therapy targeting a focus of infection that is unlikely to be cleared with antibiotics alone. Source control is an essential component of the early management of severe sepsis. When a focus of infection that requires source control is identified, source control measures should be instituted as soon as possible following initial resuscitation. Steroids for refractory shock

The CORTICUS study, which is an international, multicenter, randomized trial of corticosteroids in sepsis (n ¼ 499 analyzable patients), showed no benefit in intent to treat mortality or shock reversal [53]. Steroids did produce earlier reversal of shock which was unrelated to adrenocorticotropic hormone stimulation test results. Superinfection and new sepsis/septic shock occurred more frequently in the steroid group. Steroids were not associated with increased incidence of polyneuropathy. These results suggest that hydrocortisone therapy cannot be recommended as routine adjuvant therapy for septic shock. If systolic blood pressure remains less than 90 mmHg despite appropriate fluid and vasopressor therapy, hydrocortisone at 200 mg/day for 7 days in four divided doses or by continuous infusion should be considered [54]. Activated protein C for high risk of death

Realization of the links between the coagulation system and the immune response to sepsis led to the development of recombinant human activated protein C (rhAPC) [55]. After the rhAPC Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the Food and Drug Administration (FDA) approved rhAPC for adults who had severe sepsis and a high risk of death (such as an APACHE II score  25) in November 2001. The Administration of Drotrecogin alpha (activated) in Early Stage Severe Sepsis (ADDRESS) trial, designed with the purpose of prospectively studying the effect of rhAPC in severe sepsis patients with a clinical assessment of low risk of death, supported the FDA labeling that rhAPC was not of utility in severe sepsis patients with a clinical assessment of low risk of death (defined by an APACHE II score

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350 Nosocomial and hospital-related infections Figure 2 Resuscitation protocol for severe sepsis

SEPSIS-INDUCED HYPOPERFUSION Clinical picture of sepsis PLUS: SBP < 90 mmHg or MAP < 65 mmHg OR Lactate >4 mmol/l Supplemental O2 ± ETI with mechanical ventilation (if necessary). Target SaO2 of>95%

Begin fluid resuscitation (initial bolus of at least 20 ml/kg crystalloid or colloid equivalent)†

SBP remains <90 mmHg or MAP remains <65 mmHg or initial lactate >4 mmol/l

Boluses crystalloid or colloid equivalent

CVP <8 mm Hg

Insert CVP catheter CVP 8--12 mmHg CVP 12 -- 15 (if mechanically ventilated)

MAP <65

Vasopressors (norepinephrine or dopamine preferred)

MAP

MAP >65

• Administer stress dose steroids • Consider for drotrecogin α

< 70%

Transfuse if HCT <30

ScvO2†† YES

Dobutamine

> 70%

• Consider for drotrecogin α

MAP> 65 mmHg and vasopressors still required?

YES

NO

MAP < 65 mmHg and vasopressors still required?

YES NO Resuscitation complete. Establish re-evaluation intervals. †In ††If

Achieve ALL goals?

NO

circumstances where MAP is judged to be critically low, vasopressors may be started at any point in this algorithm. pulmonary artery catheter is used, a mixed venous O2 saturation is an acceptable surrogate and 65% would be the target.

Cooper University Hospital Protocol for initial resuscitation of sepsis-induced tissue hypoperfusion (targets adapted from Rivers’ [45] early goal directed therapy and Surviving Sepsis Campaign bundles performance improvement program). CVP, central venous pressure; ETI, endotracheal intubation; HCT, hematocrit; MAP, mean arterial pressure; SBP, systolic blood pressure.

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Pathogenesis and management of sepsis Cinel and Dellinger 351

below 25 or single-organ failure) [56]. A decline in protein C levels in patients with severe sepsis and septic shock has been recently proposed as a population at high risk for death [14]. High risk of death due to sepsis-induced organ dysfunction determined at the bedside by a seasoned critical care clinician with an understanding and knowledge of severe sepsis and rhAPC clinical results, while weighing risk/benefit ratio in that patient, however, is the optimal method for determining need for rhAPC administration [57,58]. Genetically-engineered variants of APC have been also designed with greater antiapoptotic activity and reduced anticoagulant activity relative to wild-type APC [59

]. Sustained support of organ system dysfunction

Maintaining support of organ systems in severe sepsis is important. Recommendations to achieve this goal include: glycemic control; semi-recumbent position to prevent ventilator-associated pneumonia; use of daily spontaneous breathing trial to evaluate for ventilation discontinuation and a standardized weaning protocol; use of sedation protocols; use of sedation scores and retitrate daily to the minimum necessary dose; avoidance of neuromuscular blockers if at all possible and, if necessary, intermittent dosing preferred; and use of deep vein thrombosis prophylaxis. In addition, although adequate nutrition has not been demonstrated in clinical trials to alter outcome in septic patients, it is generally considered worthy of achieving [34
].

Surviving Sepsis Campaign performance improvement program The use of standardized decision support tools assists in standardizing assessment and interventions in a specific patient population [60]. The SSC has developed performance improvement bundles with associated database software and educational tools in order to integrate the SSC guidelines into clinical practice and measure performance [61]. Improvement in process of care should lead to better outcomes. Evaluation of process change requires consistent data collection, measurement of the indicators and feedback in order to facilitate the continuous path to performance improvement. Ongoing educational sessions provide feedback of indicator compliance and can help identify areas for additional performance improvement efforts. Implementation of the SSC performance improvement program has provided a mechanism to produce and measure improved clinical performance effectively [62,63].

Conclusion Mortality rates remain high in severe sepsis, and despite recent therapeutic breakthroughs much remains to be done to advance our understanding and treatment of sepsis. Early correction of tissue hypoperfusion and hypoxia, as well as modulation of oxidative/nitrosative

and apoptotic stress, may afford protection for the vicious circle leading to severe sepsis. The SSC guidelines have been an important advance in promoting optimal care. Protocolized care is very important, especially in the early phase of severe sepsis. Large trials studying the effects of interventions based on molecular knowledge are most likely to lead to the development of effective treatment strategies in sepsis.

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