INFECTIOUS DISEASES COHEN, CHAPTER 44.

SEPSIS, UPDATE JAN 2011

MANAGEMENT Mortality from sepsis and multiorgan failure remains high but by early recognition and prompt therapeutic intervention patients can be prevented from progressing down this path. There is no complete consensus on how best to manage severe sepsis and few randomized trial data dealing with optimal treatment. An approach to therapy is encapsulated in the Surviving Sepsis Campaign guidelines first produced in 2004 and updated in 2008.[5,][52] These guidelines have not met with universal approval, mainly because severe sepsis is not a homogeneous condition and a generalized approach to treatment can be criticized. However, they do provide a logical and structured approach to the septic patient. The key principles in the management of severe sepsis are: treat infection with prompt and effective antimicrobial therapy and, where indicated, source control; maintain tissue perfusion/oxygenation and preserve organ function; and prevent complications during/following the episode of severe sepsis. Antibiotic chemotherapy Incorrect empiric antibiotic choice is strongly associated with a higher mortality in severe sepsis.[18,][53] Furthermore, delay in administration of antibiotics worsens survival. Kumar et al. reviewed 2154 patients with septic shock and found that only 50% had received antibiotics within 1 hour of the onset of shock.[14] In this study the mortality rate was 20.1% if antibiotics were administered within the first hour after the onset of hypotension and rose by 7.6% per hour of delay, becoming statistically significant if antibiotics were delayed more than 2 hours. It is not possible to provide specific antimicrobial guidelines for severe sepsis as there are many local variables that must be taken into consideration such as local resistance patterns and risks of C. difficile. An overview of the principles underpinning antibiotic choice in severe sepsis is provided in Table 44.6. There are few outcome data on duration of antibiotic therapy in severe sepsis and a course of 710 days is frequently recommended, although shorter courses may be given to selected patients and helps to reduce resistance.

Table 44.6 -- Principles of antibiotic administration and selection of antimicrobial agents in severe sepsis Antibiotic administration Intravenous high dose therapy within 1h of the recognition of severe sepsis Broad-spectrum choice to include one or more drugs active against the

Antibiotic administration likely infecting pathogen Chosen antibiotic should penetrate the likely site of infection Review antibiotic choice every 24 h in the light of clinical response and microbiology results Consider combination therapy for known or suspected Pseudomonas infection or in neutropenic sepsis Selection of antimicrobial agent Clinical syndrome/likely microbiology Site of infection Risk of resistance based on local and national data Host factors including immunocompromised state Co-morbidities including organ function and drug allergy Risk of Clostridium difficile and other hospital-acquired infections based on local epidemiology Antibiotic-induced endotoxin release In experimental models, and some limited situations in humans, release of endotoxin from bacteria has been shown to increase the inflammatory response.[54] Thus, a school of thought has developed that antibiotics should be chosen on the basis of their potential to cause endotoxin release.[55] However, beyond a handful of small studies there are few clinical data to support a major role for this hypothesis in severe sepsis. Antibiotics should be selected on the basis of efficacy for the specific clinical picture, rather than on the risk of endotoxin release. Source control detection and removal of infected material It is essential to drain/remove all possible infective foci as these are often the cause for treatment failure (see Fig. 44.13). Thus, abscesses should be drained, dead tissue resected and infected foreign material, such as an infected central venous catheter, removed. Guidance suggests that source control should occur as early as possible after initial resuscitation and is ideally performed within 6 hours of the onset of severe sepsis.[5] One exception to early intervention is severe necrotic pancreatitis where current practice is to defer percutaneous drainage due to the high complication rate and secondary infective risk.[56] The critically ill patient on intensive care may have repeated episodes of sepsis; locating the underlying focus often requires considerable determination, repeated radiologic investigation and sometimes persistent discussions with surgical colleagues. Supportive therapy The goal of supportive therapy is to try to maintain tissue oxygen delivery, a concept advanced by Shoemaker and others throughout the 1970s.[57] The potential benefit of early aggressive supportive therapy is shown in a study by Rivers et al.[58] in which 263 patients with severe

sepsis were randomized to receive standard therapy or goal-directed therapy where cardiac preload, afterload and contractility were actively managed to try to balance oxygen delivery with demand prior to admission to the ICU. In-hospital mortality was reduced from 46.5% in the standard group to 30.5% in the goal-directed group (p <0.009). Goal-directed therapy appears to improve outcome during initial resuscitation when patients first develop severe sepsis and the applicability of this approach to all comers with sepsis has been questioned. However, the Rivers study establishes the importance of paying attention to prompt and effective resuscitation in severe sepsis. Ideally, patients who have sepsis should be closely monitored in an intensive therapy or highdependency unit. Indeed a review of 41 patients who had septic shock revealed increased mortality when patients were managed outside of the intensive therapy unit, 70% versus 39%, even though the patients had less severe illness.[59] Minimal requirements for safe management include facilities for measurement of blood pressure, cardiac monitoring, central venous pressure recording, arterial blood gas analysis, oxygen and facilities for assisted/mechanical ventilation or dialysis when required. Invasive monitoring is useful in excluding other causes of shock and in directing therapy. However, invasive monitoring is not a substitute for repeated examination and clinical assessment of the patient. Many factors such as cardiovascular disease, hypovolemia or inotropic drugs can confound such data; results must be interpreted in the context of the clinical situation. Normal values and the typical ranges for hemodynamic parameters in severe sepsis are given in Table 44.7.

Table 44.7 -- Hemodynamic changes in severe sepsis Parameter Normal range Heart rate (HR) 7288 beats/min Mean arterial pressure (MAP) 70105 mmHg Cardiac output (CO) Systemic vascular resistance (SVR) Oxygen delivery (Do2) Oxygen consumption (Vo2) 48 l/min 8001500 dyne/s/cm2 520720 ml/min/m2

Changes in severe sepsis

Sinus tachycardia Hypotension <60 mmHg Increased but not enough to compensate for low SVR Reduced (<600 if no pressor agents) Decreased

100180 Typically increased ml/min/m2 CO = SV HR; SVR = (MAP CVP)/CO 79.92 Do2 = Cl arterial oxygen 10; Vo2 = Cl (arterial venous oxygen) 10 CI, cardiac index (CO/m[2] surface area); CVP, central venous pressure; SV, stroke volume.

Severe sepsis is a heterogeneous condition and it is not possible to be didactic about the management of individual patients. Patients should be monitored closely during resuscitation and interventions tailored to physiologic measurements of organ function/perfusion. Improvement in acidosis and reduction in serum lactate is a reliable guide to improved tissue perfusion and oxygenation. A stepwise approach to initial resuscitation is provided by the Surviving Sepsis Campaign guidelines:[5] Begin resuscitation immediately in patients with hypotension or serum lactate >4.0 mmol/l. Do not delay pending ICU admission. Resuscitation goals: CVP 812 mmHg Mean arterial pressure >65 mmHg Urine output >0.5 ml/kg/h Central venous oxygen saturation >70%.

Intravenous fluid therapy Fluid resuscitation is critical and should precede any pharmacologic agents. Crystalloid or colloids can be used as there are no clear data supporting one over the other.[5] Concerns over the safety of human albumin have been decreased by the SAFE study which showed equal efficacy and safety when albumin was used in comparison to saline in ICU patients.[60] One recent study has found an unexplained increase in adverse events in patients who were resuscitated with pentastarch compared to Ringer's lactate.[61] This finding requires further investigation before a definitive recommendation can be made about colloid solutions based on starch derivatives. In hypotensive or hypovolemic adults, an initial fluid challenge of 1000 ml crystalloid or 300500 ml colloid should be administered over 30 minutes. Fluid filling should be continued as long as patients have evidence of hypovolemia and impaired organ perfusion. Patients must be monitored closely as cardiac filling pressures increase to avoid cardiac failure. Vasopressors Pharmacologic intervention is indicated if evidence of hypoperfusion persistent hypotension or acidosis persists despite fluid filling. Initial treatment is with noradrenaline (norepinephrine) or dopamine. There is no evidence that one agent is superior to the other. In refractory cases vasopressin or terlipressin may also be considered but large trial data on these agents are lacking.[62] The dose of pressor agents is titrated to maintain an arterial pressure of 65 mmHg or greater with improved organ perfusion. Patients receiving pressor agents require continuous arterial pressure monitoring and close attention to peripheral perfusion as ischemia of the extremities may complicate their use. There is no role for renal dose dopamine in the management of severe sepsis. Inotropes Substantial experimental and clinical data indicate that myocardial function is impaired in severe sepsis. Inotropes increase cardiac contractility and can increase cardiac output and tissue

perfusion in severe sepsis. Adrenaline (epinephrine) or dobutamine can fulfill this role and there is no evidence that either agent is superior. Inotropes are indicated where there is evidence of a persistent low cardiac output despite fluid resuscitation and treatment with pressor agents. Inotropes should not be given to patients who are still hypovolemic. Some researchers have used inotropes to try to achieve supranormal oxygen delivery in severe sepsis but there is no evidence that this strategy improves clinical outcome and it is potentially deleterious.[63] Insulin therapy in severe sepsis Assiduous control of the blood glucose level is essential in diabetic patients with severe sepsis. Several studies had previously indicated a benefit from tight glycemic control with intensive insulin therapy in nondiabetic patients with critical illness, including those with severe sepsis.[64] However, a large multicenter randomized study reported in 2008 has shown no overall benefit from insulin therapy in sepsis and a significant increase in hypoglycemic events.[61] Therefore, at this time, insulin should only be used in septic patients with hyperglycemia until more data are available. Blood products in severe sepsis There is some controversy around red cell transfusions in patients with severe sepsis. Early goaldirected therapy suggests transfusion of red cells to maintain a hematocrit >30% in patients with a superior vena cava oxygen saturation of <70% after fluid resuscitation. In contrast, the Transfusion Requirements in Critical Care trial suggests that there is no benefit in transfusing above a threshold hemoglobin of 7 g/dl in patients in ICU.[65] Thrombocytopenia is common in severe sepsis. Platelet transfusion should be considered if the absolute platelet count is less than 5 10[9]/l in the absence of bleeding or less than 30 10[9]/l in the presence of bleeding. Replacement of coagulation factors with fresh frozen plasma or cryoprecipitate may be required to combat bleeding. Plasma also contains potentially proinflammatory components such as complement and replacing these may increase inflammation. Other supportive treatments Patients with severe sepsis should receive thromboprophylaxis unless there is a specific contraindication. Stress ulcer prophylaxis is indicated with an H2 blocker or a proton pump inhibitor. Nutrition should be maintained, preferably by the enteral route. In renal impairment or severe acidosis early consideration should be given to hemofiltration. In the intubated and ventilated patient a reduced risk of ARDS and improved clinical outcome can be achieved using a volume and pressure limited strategy and, where necessary, permissive hypercapnia.[5] Update: New Content Added Date Added: 28 January 2011 Endotoxin removal in the treatment of sepsis Jonathan Cargan, MD, W. Powderly, MD, FRCPI, Editor Summary

Slow progress in advancement of the treatment of sepsis has revived interest in alternative treatments for sepsis, including endotoxin removal. Although this approach is used widely only in Japan, ongoing research is examining the potential utility of devices for endotoxin removal. Davies and Cohen[1] summarize the history of endotoxin removal, evidence for various approaches, and current research in the field. Lipopolysaccharide (LPS) is a bacterial endotoxin with a key role in sepsis. It is found in the membranes of gram-negative bacteria and includes a highly conserved lipid A component, which is released during bacterial cell destruction. Lipid A activates host immunity, including cytokines, complement, and the coagulation cascade. Administration of LPS in low doses can produce signs and symptoms of sepsis. Endotoxin levels in septic patients have been correlated with higher mortality, making endotoxin removal a feasible strategy for treatment. Endotoxin removal may also secondarily reduce cytokine levels and, in some cases, may directly remove endogenous cannabinoids, which may have hemodynamic benefits. Polymixins are a group of compounds that bind endotoxin. The only members of the group in clinical use are polymixin B and colistin, both of which are limited in use by nephrotoxicity and neurotoxicity. It is unclear whether chemical modification would reduce toxicity while retaining the ability to bind LPS. Polymixin binds LPS strongly, and polymixin B was shown many years ago in animal models to neutralize the effects of LPS. Clinical utility of these data was limited by toxicity in humans. One approach to circumventing toxicity has been the development of polymixin columns for filtration of blood, which is complicated by the difficulty of separating endotoxin from protein. Comparison of these columns with control columns showed a protective effect against signs and consequences of sepsis in animals. Only a few human clinical trials have been done, and they have been inconclusive regarding benefit, although results of a phase 2 Japanese trial were encouraging (2-week survival 54 percent in treated patients vs. 36.4 percent in controls; P less than .05). Phase 3 trials were not designed to focus on clinical outcome, however. Polymixin columns have been in wide use in Japan since the mid-1990s. A small European randomized controlled trial in patients with intraabdominal sepsis failed to show significant differences in 28-day mortality or endotoxin concentrations, but the study was not powered to assess mortality difference. More recently, an Italian trial (Early Use of Polymixin-B Hemoperfusion in Abdominal Sepsis [EUPHAS]) examined hemodynamic endpoints and organ dysfunction and 28-day mortality.[2] The trial showed improvement in hemodynamics, organ dysfunction, and mortality, but the statistical methods of the trial have been criticized.[3],[4] In addition, an ethics committee stopped the trial early because of clinical benefit with treatment, but the investigators were not in agreement with the conclusions of the committee. Additional trials are now being conducted in the U.S. and Italy. Columns containing other compounds have also been investigated for endotoxin removal. Albumin has been tested, but phase 2 trial results were unfavorable. CTR is another potential compound for endotoxin removal. The Alteco LPS Absorber (Alteco Medical, Sweden) uses a polypeptide for LPS removal, and limited human data have been collected. Although safety of

the device has been shown, small trials in sepsis have produced mixed results. Diethylaminoethyl cellulose is another potential agent for endotoxin removal and has shown some initial promise. Although interest in endotoxin removal is experiencing a revival, limited and conflicting data concerning efficacy hinder widespread use. Ongoing trials in the U.S. and Europe may help to clarify the role of endotoxin removal in the treatment of sepsis. References 1. Davies B, Cohen J: Endotoxin removal devices for the treatment of sepsis and septic shock. Lancet Infect Dis 2011; 11(1):65-71. 2. Cruz DN, Antonelli M, Fumagalli R, et al: Early use of polymyxin B hemoperfusion in abdominal septic shock: The EUPHAS randomized controlled trial. JAMA 2009; 301(23):24452452. 3. Vincent JL: Polymyxin B hemoperfusion and mortality in abdominal septic shock. JAMA 2009; 302(18):1968-1968; author reply 1969-1970. 4. Amaral AC: Polymyxin B hemoperfusion and mortality in abdominal septic shock. JAMA 2009; 302(18):1968-1969; author reply 1969-1970.