Sepsis is a commonly encountered clinical entity of

Transcription

1 MUMJ Clinical Review 3 CLINICAL REVIEW Sepsis: A Review of Pathophysiology and Management Katarzyna Czarnecka-Kujawa, BSc Fady Saleh, MD ABSTRACT Sepsis is a common clinical syndrome associated with significant morbidity and mortality. Early diagnosis and the rapid initiation of therapy are critical in the management of the septic patient. This review discusses the pathophysiology and management of sepsis. The importance of heightened suspicion for the early recognition of sepsis is emphasized. A large focus of the review is placed on the approach to the treatment of sepsis, including new avant-garde adjuvant therapies which are gaining prominence in the treatment of severe sepsis and septic shock. INTRODUCTION Sepsis is a commonly encountered clinical entity of altered organ perfusion resulting from a systemic response to infection. It remains a major challenge to diagnose and is associated with significant morbidity and mortality.1 One prospective observational study estimated that sepsis occurs in 1-3% of admissions to a tertiary care center, with an associated mortality of 34% at 28 days and 45% at five months.1 Absolute values of the mortality rate from sepsis rival deaths after acute myocardial infarction on a population level.2 Sepsis is not just a disease of the intensive care unit (ICU), and approximately half of cases are diagnosed in the emergency department and on wards throughout the hospital.1,2 Although males seem to have a higher age-specific incidence of sepsis, the overall incidence of sepsis in males and females appears equal.1-3 Given that sepsis accounts for 2% of all hospital admissions, it is inevitable that all medical personnel will encounter a septic patient.1-3 It is of the utmost importance that practitioners are able to recognize this clinical entity promptly. The first few hours of resuscitation of the septic patient are known as the Golden Hour of sepsis because early recognition and treatment of sepsis leads to improved survival outcomes.4 Although the details of resuscitating the septic patient may be more limited to the walls of the ICU, first line physicians have essential roles in the rapid recognition of sepsis and the initiation of treatment. DEFINITIONS Sepsis is the presence of infection in the setting of a systemic inflammatory process, more formally termed systemic inflammatory response syndrome (SIRS). As its name implies, SIRS occurs in a wide range of inflammatory states in addition to infection, such as burns and surgery (Table 1).5 The diagnosis of SIRS requires alterations in two of the following four parameters, including temperature, heart rate, respiratory rate and white blood cell count (WBC) (Table 2). When SIRS is the result of a confirmed infectious etiology, the clinical scenario is termed sepsis. This is distinct from the confusing term septicemia which is used without a clear definition and probably has little place in academic circles.5

2 4 Clinical Review Volume 4 No. 1, 2007 Table 1. Causes of SIRS 5 Causes of SIRS Pancreatitis Ischemia Multiple trauma Hemorrhagic shock Immune-mediated organ injury Exogenous inflammatory mediators (TNF-α) Systemic infection Table 2. Definitions 5-7 Definitions of Sepsis and Related Terms Infection Microbial phenomenon characterized by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by those organisms Bacteremia The presence of viable bacteria in the blood Systemic Inflammatory Response Syndrome (SIRS) Two or more of the following criteria present: 1) Temperature of > 38ºC OR < 36ºC 2) Heart rate > 90 beats per minute* 3) Respiratory Rate > 20 breaths per minute OR a PaCO 2 < 32 mm Hg OR mechanically ventillated 4) Leukocyte count > 12,000/µL OR < 4,000/µL OR > 10% immature bands Sepsis SIRS in the presence or presumed presence of an infection Severe Sepsis Sepsis plus organ hypoperfusion AND/OR organ dysfunction Septic Shock Sepsis with either: 1) Refractory hypotension as defined by: a) Systolic blood pressure < 90 mm Hg OR a mean arterial pressure of < 65 mm Hg OR a 40 mm Hg drop in systolic blood pressure below patient s baseline b) Pressure unresponsive to a fluid challenge of ml/kg 2) Vasopressor dependency after adequate fluid resuscitation * Criteria fails if the patient is rate controlled (such as with beta-blockers or calcium-channel blockers) or the heart is paced. 7 As organ hypoperfusion and organ dysfunction develop, severe sepsis ensues. This may manifest clinically as altered mental status or oliguria, with accompanying laboratory results like lactic acidosis (Table 3).5 Septic shock occurs when there is a drop in systolic or mean arterial blood pressure despite adequate volume resuscitation. Shock, in general, is defined as an abnormality of the circulatory system that results in inadequate organ perfusion and tissue oxygenation.8 There are several causes of shock in addition to sepsis, including hypovolemia and cardiac, but a thorough review is beyond the scope of the text (see Clinical Highlight). Though it is clinically relevant to differentiate between the different causes of shock, in reality they are essentially stages along a continuum.9 While SIRS may be self-limiting in the setting of sepsis, it may progress to concomitant organ hypoperfusion and dysfunction. When cardiovascular collapse occurs, septic shock results from hypotension. Clinical Highlight S: Septic, Spinal/Neurogenic H: Hypovolemic/Hemorrhagic O: Obstructive C: Cardiac K: anaphylactik E: Endocrine PATHOPHYSIOLOGY The pathogenesis of sepsis is complex and this article only touches on some basic points. The inflammatory cascade begins with an insult to the host, such as burns and infection. The mounted inflammatory response is meant to protect the host from tissue damage, but many inflammatory mediators have the potential to harm the host as well. The prevailing, although debated theory, is that sepsis occurs when the host response overwhelms the protective mechanisms in place, resulting in a superimposing insult to the patient in addition to the infection initially triggered this response.10,11 In sepsis, the systemic inflammatory response is due to an infectious insult. In a review by Rivers et al, the host response is described to be due to three factors: humoral, cellular and neuroendrocrine reactions.7 Inflammatory cells such as neutrophils, monocytes, macrophages, basophils and platelets interact with endothelial cells via cell mediators that further amplify the inflammatory response. Microvascular blood flow may eventually be affected with the activation of the coagulation and complement systems, resulting in local ischemia, which impairs cellular respiration. The end result is global tissue hypoxia in which the systemic oxygen delivery is insufficient to meet the oxygen demands of the body.7 This leads to decreased myocardial contractility, decreased systemic vascular resistance, hypotension, metabolic acidosis, hyperglycemia and ultimately, multiorgan dysfunction syndrome and death.12 DIAGNOSIS Early diagnosis and initiation of treatment are key principles in the management of the septic patient, resulting in improved survival outcomes.4 Due to the high morbidity and mortality associated with sepsis, much research has been devoted to finding biomarkers that can efficiently

3 MUMJ Clinical Review 5 diagnose sepsis.13 However, presently no gold standard to diagnose sepsis exists.6 It is fundamental to identify the signs of systemic inflammation, such as fever and leukocytosis, which may be the result of an infection process. Importantly, inflammation and infection are two distinct entities (Figure 1).10 The astute clinician must have a heightened suspicion to first recognize the presence of SIRS and then a source of infection. Investigations such as a complete blood count (CBC), urinalysis, blood cultures, chest X-ray as well as more sophisticated imaging modalities may assist in finding the source of infection. Additional clinical and laboratory variables may be used to assess the severity of sepsis, organ dysfunction and organ hypoperfusion (Table 3). Currently, there is much promising work being done to validate biochemical markers that may be adopted as gold standards for the diagnosis of sepsis Clinical Highlight Inflammation and infection are two distinct entities Figure 1. The interrelationship between SIRS, Sepsis and Infection (adapted from Chest 1992; 101: ) 5 Table 3. Clinical and Laboratory Manifestations of Severe Sepsis 7 Organ Hypoperfusion Elevated blood lactate level Oliguria Poor peripheral circulation Altered mental state Organ Dysfunction Hematologic: DIC, thrombocytosis Respiratory: ARDS Renal: ARF GI: Hepatic dysfunction CNS: Delirium CRF: Capillary Refill; DIC: Disseminated Intravascular Coagulopathy; ARDS: Acute Respiratory Distress Syndrome; ARF: Acute Renal Failure; GI: Gastrointestinal System; CNS: Central Nervous System Lactate Production When oxygen demand is no longer sustained by oxygen delivery, lactate levels increase in the serum as a result of anaerobic cellular respiration.7,16 Briefly, glucose, the primary energy source of cells, is converted to two molecules of pyruvate in the series of reactions which comprise glycolysis. In the absence of oxygen, the production of large quantities of ATP cannot occur via oxidative phosphorylation. Anaerobic respiration is the process whereby cells convert pyruvate to lactate in a reversible reaction catalyzed by lactate dehydrogenase: Pyruvate + NADH Lactate + NAD + + H + Conversion of pyruvate to lactate allows the replenishment of the coenzyme NAD + which is needed for glycolysis to continue Lactate levels in the setting of SIRS have been shown to significantly affect ICU mortality. Lactate is routinely measured in patients with suspected and established organ hypoperfusion. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock.16 TREATMENT OF SEVERE SEPSIS AND SEPTIC SHOCK Rivers et al introduced the concept of early goal-directed therapy (EGDT) for patients with severe sepsis and septic shock.4 EGDT highlights the importance of aggressive therapy in the first six hours after a prompt diagnosis of sepsis is made, as well as the identification of high-risk patients with evidence of global tissue hypoxia. Protocols for the management of severe sepsis and septic shock have been developed with this in mind (Figure 2). In 2004, the Surviving Sepsis Campaign (SCC) established guidelines for the management of severe sepsis and septic shock.19 Rangel-Frausto summarized the principles of treatment in a review in 2005, which include: controlling the source of infection as well as prompt initiation of antibiotics; resuscitation and hemodynamic support; organ support; sedation and analgesia as necessary; nutritional support; and other adjuvant treatments.12 Antimicrobial Therapy Bloodwork and cultures should be collected prior to the initiation of antibiotics. Broad-spectrum antibiotics targeting likely organisms should be administered without delay (within 1 hour of recognition of severe sepsis). A study by Kumar et al29 demonstrated that delay in initiation of antimicrobial therapy timed from the onset of hypotension was associated with increased mortality. Initiation of effective antimicrobial therapy within an hour of the onset of hypotension was associated with 79.9% survival by hospital discharge. A drastic drop of 7.6% in patient survival was observed per hour of delay following the onset of hypotension. A delay of 9-12 hours in the initiation of

4 6 Clinical Review Volume 4 No. 1, 2007 antimicrobial therapy was associated with a survival rate of 25.5%. The mortality benefit applies to all major patient subgroups irrespective of isolation of pathogenic bacteria, presence or absence of bacteremia, clinical site of infection, or epidemiologic factors.29 Despite clear evidence for the benefit of early initiation of antimicrobial therapy in septic patients, on average only about 50% of patients receive this therapy in a timely manner within six hours of the onset of hypotension.29 Early empiric, broad-spectrum antimicrobial therapy should be an intrinsic component of the early resuscitation in septic shock. It is likewise important to initiate source control to eliminate the cause of sepsis, such as an abdominal abscess or perforation, if possible. As with the usage of antibiotics in general, attempts to narrow coverage should be attempted within hours and duration of therapy should follow the usual 7-10 day course guided by the clinical response.19 Clinical Highlight Mortality increases with every hour of delay in initiation of antimicrobial therapy Resuscitation and Hemodynamic Support Hemodynamic optimization aims to restore the balance of oxygen supply and demand. A central venous line should be obtained to measure central venous pressure (CVP) or preload. CVP should be maintained at 8-12 mmhg using crystalloid and colloid intravenous fluids.4,7 Mean arterial pressure (MAP), or afterload, should also be monitored using an arterial line. MAP should be maintained at mmhg using vasoactive agents such as dopamine or norepinephrine.4,7 Cardiac contractility is maximized by using inotropes like dobutamine, however it is important to avoid tachycardia. Central venous oxygen saturation (ScvO 2 ) is measured to assess tissue hypoxia. Packed red blood cells to maintain a hematocrit >30% should be used in order to maintain the ScvO 2 > 70%.4,7 r-apc Activated protein C (APC) is an endogenous, vitamin K-dependent protein that is converted from its inactive precursor, protein C, by thrombin coupled to thrombomodulin.20 APC regulates thrombosis by inactivating factors Va and VIIIa, and promotes fibrinolysis by limiting the generation of thrombin. APC also has anti-inflammatory properties by inhibiting thrombin-induced production of pro-inflammatory cytokines by monocytes.30 Activation of protein C may be impaired in sepsis due to the downregulation of thrombomodulin.20 Indeed, reduced levels of protein C are found in patients with sepsis. Decreased levels of APC may contribute to a hypercoagulable environment in sepsis, resulting in microvascular thrombosis and compromised tissue perfusion. Figure 2. Treatment Protocol for the Septic Patient (Adapted from CMAJ. 2005; 107(9): with permission of E. Rivers) The PROWESS trial demonstrated a decreased 28 day all-cause mortality in patients with severe sepsis and a low risk of bleeding treated with recombinant human APC (rhapc) compared to placebo (RRR 19.4%).30 However, a 57% relative risk of serious bleeds was also observed in the treatment arm. Based on the results of the PROWESS trial, rhapc was approved by the FDA in 2001 for use in severely septic patients.30 Additional randomized controlled trials, including ADDRESS, have failed to replicate the benefit conferred by rhapc in patients with severe sepsis (defined as two or more criteria of organ dysfunction and APACHE II score 25). Both ADDRESS and PROWESS demonstrated an increased all-cause mortality in the low risk septic patient population (defined as one criteria of organ dysfunction, recent surgery, and APACHE II score <25) treated with the rhapc compared to placebo.1,21,31 A meta-analysis has raised doubts about the therapeutic utility of rhapc in the severe sepsis population of patients.31 Another properly

5 MUMJ Clinical Review 7 designed clinical trial is needed to quantify the benefit of rhapc in sepsis. At present in Canada, the indication for APC use is the presence of septic shock in a patient with an APACHEscore >25. In most European countries, the presence of 2 or more organ failures is considered an indication. Contraindications to APC include: active internal bleeding; recent hemorrhagic stroke (within 3 months); recent intracranial or intraspinal surgery or severe head trauma (within 2 months); trauma with an increased risk of lifethreatening bleeding; presence of an epidural catheter; intracranial neoplasm or mass lesion or evidence of cerebral herniation. There are specific protocols for delivering the drug around the time of surgery or invasive intention (like central line placement). Tight Glycemic Control Hyperglycemia and insulin resistance are common in the critically ill, septic patient Previously serum glucose level was a widely ignored variable.25 In 2001, Van Den Berghe et al presented a randomized unblinded study of tight glycemic control in a population of mostly surgical ICU patients.23 This study demonstrated that intensive insulin therapy to maintain a blood glucose level between 4.4 and 6.1 mmol/l was associated with a nearly 50% decrease in mortality and a significant reduction in morbidity in the treatment group. Interestingly, the biggest effect was seen in patients with multi-organ failure with a septic focus.23 The same research group has recently published a similar study focusing on tight-glycemic control in the medical ICU, however the results were less impressive.24 The study demonstrated reduced morbidity in all subsets, although mortality was not overall reduced in the treatment group with intensive insulin therapy to maintain tight glycemic control.24 A number of ongoing studies will hopefully shed light on the best approach to glucose management in the septic patient.25 The current opinion of the SCC is to keep glucose levels below 8.3 mmol/l, which reduces the likelihood of a hypoglycemic episode.19 Low-dose Corticosteroids Cortisol is the primary glucocorticoid and is produced in the adrenal cortex. It is a major stress response hormone with numerous metabolic, catabolic, anti-inflammatory and vasoactive functions.26 By facilitating catecholamineinduced vasoconstriction, cortisol contributes to the maintenance of peripheral vasomotor tone.26,27 In severe sepsis, inflammatory mediators may lead to relative adrenal insufficiency or systemic inflammationinduced glucocorticoid resistance.28 This prompted Annane et al to study the effect of low dose steroids in severely septic patients.27 Improved survival was found in patients with relative adrenal insufficiency confirmed by a corticotropin test, in which patients are given a low dose of adrenocorticotropic hormone (ACTH) and cortisol is subsequently measured. Relative adrenal insufficiency was defined as cortisol levels of 9 µg/dl after ACTH administration.27 Again, ongoing studies will likely add to our understanding of the role of corticosteroids in severe sepsis. CONCLUSIONS While many conditions lead to the non-specific syndrome of SIRS, inflammation may be the only clue available for the astute clinician to diagnosis sepsis. If left unrecognized, severe sepsis or septic shock may intervene and eventually lead to death. Prompt initiation of early goal-directed therapy using target goals has been shown to significantly decrease morbidity and mortality. Once antibiotics have been administered and aggressive hemodynamic optimization is underway, more experienced personnel will have the opportunity to assist in critical aspects of patient management, like pursuing source control (for example, draining of abscesses), as well as a consideration of adjuvant therapies such as r-apc, corticosteroids and tight glycemic control in a monitored setting. In a concerted effort, through evidence-based practice and continued research, the future may promise improved outcomes for patients with sepsis. REFERENCES 1. 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6 8 Clinical Review Volume 4 No. 1, 2007 tious systemic inflammatory response syndrome. Clinica Chimica Acta 2005;351(1-2): Nguyen HB, Rivers EP, Knoblich BP, Jacobsen G, Muzzin A, Ressler JA, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Critical Care Medicine 2004;32(8): Baker RR. PDQ Biochemistry. Hamilton: BC Decker Inc; Vander A, Sherman J, Luciano D. Human physiology: the mechanisms of body function. 7 ed: McGraw-Hill; Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, et al. Surviving Sepsis: Campaign guidelines for management of severe sepsis and septic shock. Critical Care Medicine 2004;32(3): [erratum appears in Crit Care Med Jun;32(6):1448 Note: Correction of dosage error in text]. 20. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez- Rodriguez A, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. New England Journal of Medicine 2001;344(10): Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. New England Journal of Medicine 2005;353(13): Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Critical Care Medicine 1985;13(10): Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. New England Journal of Medicine 2001;345(19): Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive insulin therapy in the medical ICU. New England Journal of Medicine 2006;354(5): Malhotra A. Intensive insulin in intensive care. New England Journal of Medicine 2006;354(5): Rivers EP, Gaspari M, Saad GA, Mlynarek M, Fath J, Horst HM, et al. Adrenal insufficiency in high-risk surgical ICU patients. Chest 2001;119(3): Axelrod L. Perioperative management of patients treated with glucocorticoids. Endocrinology & Metabolism Clinics of North America 2003;32(2): Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288(7): Kumar A, Roberts D, Kenneth E, Wood DO, Light B, Porrillo 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 severity in human septic shock. Critical Care Medicine 2006;34(6) Rice TW and Bernard GR. Therapeutic intervention and Targets for Sepsis. Annual Review of Medicine 2005; 56: Wiedermann CJ and Kaneider NC. A meta-analysis of controlled trials of recombinant human activated protein C therapy in patients with sepsis. BMJ Emergency Medicine 2005; 5:7. Author Biographies Katarzyna Czarnecka-Kujawa earned her BSc from the University of Toronto and is presently a final year medical student at McMaster University. Fady Saleh studied medicine at the University of Toronto and is currently a General Surgery resident at McMaster University.