Emergency management of severe sepsis and septic shock

REVIEW C URRENT OPINION Emergency management of severe sepsis and septic shock Michael A. Puskarich Purpose of review Numerous implementation studies have demonstrated the benefit of bundled care in the initial treatment of patients with severe sepsis and septic shock, but the relative value of each component of these bundles remains uncertain. Recent studies have attempted to further define the optimal supportive and adjunctive treatments for these patients. Recent findings The choice of optimal intravenous resuscitation fluid for the emergency treatment of severe sepsis remains uncertain. Albumin appears safe, although safety concerns have arisen regarding the use of hydroxyethyl starch. Norepinephrine and vasopressin appear superior to dopamine as vasopressors of choice. Several studies have successfully incorporated lactate clearance into resuscitation strategies, albeit with differing protocols. Although corticosteroids may hasten improvement, there does not appear to be a mortality benefit in heterogeneous patients with sepsis, leaving their role uncertain. Summary Recent negative studies have questioned the role of previously promising adjunctive treatments. However, recent clinical trials and meta-analytic data continue to refine the relative importance of various components of sepsis bundles. Keywords albumin, lactate clearance, resuscitation, sepsis, vasopressor INTRODUCTION Although septic shock has been recognized since the earliest days of organized medicine, the importance of early recognition and treatment for sepsis have undergone a major shift over the last several decades. The recognition that early, aggressive resuscitation in the hours immediately following hospital presentation leads to improved patient outcomes has moved the initial resuscitation of patients with septic shock into the emergency department, similar to other time-sensitive diseases [1,2]. Data from over 10 years ago highlighted the fact that over 750 000 patients are treated annually in the United States for severe sepsis [3], a number that has almost certainly increased given changing demographics. As over two-thirds of these patients present annually to US emergency departments [4], it is imperative that emergency physicians as well as intensivists are familiar with recent advances in order to provide optimal care to individual patients in the critical hours following initial presentation. This article will attempt to summarize and highlight the most recent literature regarding the emergency management of septic shock, focusing on recent clinical trials applicable to the initial hours of resuscitation. CONSTRUCTING AND DECONSTRUCTING BUNDLED CARE Bundled care refers to the use of a group of strategies en masse to improve the care for patients with a particular disease or condition. Not only are bundles summations of the effects of multiple interventions, but they also comprise interactions between interventions. However, it can be unclear which components of the bundle, if any, truly impact patient outcome. As a result, considerable time and effort may be directed toward potentially fruitless efforts, Department of Emergency Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA Correspondence to Michael A. Puskarich, MD, Department of Emergency Medicine, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA. E-mail: mpuskarich@umc.edu Curr Opin Crit Care 2012, 18:295 300 DOI:10.1097/MCC.0b013e328354dc16 1070-5295 ß 2012 Wolters Kluwer Health Lippincott Williams Wilkins www.co-criticalcare.com

Emergencies not an insignificant consideration in a resource-limited environment such as an emergency department or ICU. Considerable effort, therefore, has recently been directed at better understanding and deconstructing bundles in order to maximize efficiency while maintaining optimal outcomes for patients. Following the work of Rivers et al. [1], numerous implementation studies of a before-and-after study design were published demonstrating the benefit of bundled care implementation [5 10]. Meta-analytic data from such studies suggest quantitative strategies only demonstrate benefit when initiated early and are potentially harmful when initiated late [2], emphasizing the importance of early recognition and initiation of treatment. Although implementation of sepsis bundles is associated with decreased mortality and decreased time to antibiotics, other components of the bundle display more heterogeneous adoption without clear differences in patient-centered outcomes, suggesting that some components are less critical than others [11 ]. All of these studies are limited by their beforeand-after design, and the study by Rivers et al. [1] remains the only randomized control trial comparing bundled with standard care to date. Three large, multicenter randomized control trials are currently enrolling patients: ProCESS (NCT00510835), ARISE (NCT00975793), and ProMISE (ISRCTN36307479) [12,13]. Although the shift in the standard of care in early septic shock over the past 10 years may impact the interpretation of these studies, the varied study locations and large number of patients will provide a wealth of data that will certainly influence the care of patients with sepsis in the coming decade. HEMODYNAMIC RESUSCITATION The current paradigm of sepsis resuscitation is based upon the hypothesis that the fundamental flaw in septic shock is a deficiency in oxygen supply compared with demand. A graduated, stepwise resuscitation strategy involving serial assessments and interventions targeting preload, perfusion pressure, and oxygen delivery form the scaffold of current quantitative resuscitative protocols. Although other factors, such as microcirculatory shunting and mitochondrial dysfunction also likely play a role in the pathogenesis of septic shock, targeted therapies have not been sufficiently studied in large clinical trials to recommend standardized interventions at this time. The interested reader is referred to review articles on the state of the art on these topics [14 16]. Assessing and optimizing preload Patients with septic shock frequently present intravascularly depleted [17]. This occurs for a variety of reasons including decreased oral intake, increased sensible and insensible losses, and increased vascular permeability. Due to the adverse effects of interventions such as vasopressors, inotropes, and packed red blood cells, accurate assessment and timely treatment of intravascular depletion represents the backbone of the initial management of septic shock. During the initial evaluation of the hemodynamically unstable patient with undifferentiated hypotension, an empiric fluid bolus is typically warranted while the differential diagnosis is being refined. Once a clinician suspects septic shock, further attempts should be made at determining volume responsiveness. The concept of volume responsiveness refers to the principle illustrated by the Frank-Starling curve, which demonstrates that increases in left ventricular end diastolic volume lead to increased stroke volume and to cardiac output, until a plateau. The goal of the clinician is to determine where on this curve the patient lies. If the patient lies on the steep portion of the curve rather than the plateau, a fluid bolus may be beneficial. In general, methods of assessing volume responsiveness are divided into two categories, static and dynamic. Traditionally, assessments of volume status are made using static, surrogate measures of left ventricular end diastolic pressure, namely pulmonary artery occlusion pressure and central venous pressure (CVP). The use of these static measurements requires a number of assumptions, many of which may be violated in the critically ill septic patient. For these and a variety of other reasons, pulmonary artery catheter use is decreasing [18]. Meanwhile, CVP has been demonstrated to correlate poorly with volume responsiveness [19]. As a result, clinicians are beginning to decrease their reliance on static in favor of dynamic measures of fluid responsiveness. There are several dynamic measures of fluid responsiveness and a comprehensive summary is beyond the scope of this article, but a brief overview is provided. A caveat should be applied to all of the studies cited in this section, as they have been predominantly conducted in hemodynamically stable patients in the ICU outside the acute resuscitation window. The simplest of dynamic measures are small (500 ml), serial empiric fluid boluses with attention paid to the exhibited hemodynamic response. This method is time intensive and carries the risk of excessive fluid administration. Dynamic measures of echocardiographic function may be useful to advanced practitioners with specialized training [20], but is beyond the scope of most emergency physicians. In intubated patients on a control mode of ventilation with invasive blood pressure 296 www.co-criticalcare.com Volume 18 Number 4 August 2012

Emergency management of severe sepsis and septic shock Puskarich monitoring, arterial waveform variation provides a reliable measure of volume responsiveness [21], although access to this monitoring is typically unavailable during the initial resuscitation. Perhaps the most useful dynamic assessment available to emergency physicians, therefore, is the passive straight leg raise (SLR) test. This method provides an increase in passive venous return to the heart by mechanically raising the patient s leg, and monitoring for changes in various measures of cardiac output or pulse pressure. The details of the performance and accuracy of such measurements can be found in a systematic review, but in general, SLR correlates well with exogenous fluid challenge compared with other static and dynamic measurements [22 ]. Sepsis bundles have been slow to adopt such dynamic measures of assessing preload in place of CVP, although such a substitution may be warranted given the current state of evidence. Once a clinician has determined a patient to be volume responsive, one must select the preferred intravenous (i.v.) fluid [17]. Several recent articles on this topic deserve attention. A recent metaanalysis by Delaney et al. [23 ] examined albumin versus other i.v. fluids in sepsis. This study differed from previous systematic reviews on the topic, only including studies with a definable subgroup of patients with sepsis. The results of the study suggest benefit to albumin versus other fluids, although the observed effect lost statistical significance in random effects modeling. Furthermore, predefined subgroup analysis of patients with sepsis failed to demonstrate clear benefit. It remains uncertain whether these results are due to underpowered studies, or whether albumin truly possesses no unique benefit as a resuscitation fluid in sepsis. When considering the totality of evidence, it is worth noting that the largest randomized control trial on the topic to date, the SAFE study [24], demonstrated no adverse effects of albumin on organ failure compared with isotonic saline (0.9% NaCl), but did suggest a potential mortality benefit in the subgroup of patients with sepsis [25 ]. Combined, these data suggest albumin should at least be considered by clinicians alongside crystalloids as potential first-line agents during the initial phase of sepsis resuscitation, although ongoing and recently completed clinical trials may help to provide more definitive guidance on the topic (NCT00707122 and NCT00327704) [12]. Finally, given study [26] and growing safety concerns regarding the effects of artificial colloids such as hydroxyethyl starch (HES) on renal function [27 ], it is difficult to recommend their routine use at the current time when other options such as albumin or crystalloid are available, until more rigorous safety data are published. Maintaining perfusion pressure If a patient remains persistently hypotensive after optimization of preload, the subsequent goal of quantitative resuscitation protocols is the maintenance of perfusion pressure through the use of vasopressors. A recent meta-analysis of dopamine versus norepinephrine in sepsis suggests significantly more arrhythmias in patients who received dopamine [28 ]. More importantly, patients assigned to dopamine compared with norepinephrine in randomized control trials demonstrated significantly higher mortality. These data suggest that norepinephrine is superior to dopamine in the routine care of patients with septic shock. As for other vasopressors, the Vasopressin versus Norepinephrine infusion in Patients with Septic Shock study of lowdose vasopressin versus norepinephrine in septic shock failed to demonstrate superiority of vasopressin [29]. However, given similar adverse event rates, vasopressin may also be considered a first-line therapy at doses 0.03 U/min or less along with norepinephrine. The role of phenylephrine has not been thoroughly studied in clinical trials, leaving its role uncertain. Matching oxygen supply and demand Once preload and perfusion pressure have been optimized, current bundles suggest an assessment of global oxygen supply versus demand. The most commonly used method of assessment in the emergency treatment of patients with septic shock is via central venous oxygen saturation (ScvO 2 ). ScvO 2 monitoring has undergone criticism for several reasons. First, implementation trials have consistently demonstrated less abnormal ScvO 2 values than observed in the Rivers trial [6,7,9,10]. ScvO 2 also represents a rudimentary measure of oxygen supply and demand with inherent limitations. Evidence from several studies suggests that high ScvO 2 levels in sepsis are associated with poor outcomes as much as low levels [30,31], suggesting that an ideal normal ScvO 2 exists. It remains unresolved in current protocols whether and how to address very high ScvO 2 levels, representing a potential area for future investigations. Given these limitations, ongoing validation studies should further clarify the role of ScvO 2 as a resuscitation goal [12,13]. A second method of assessing metabolic supply and demand is via the use of lactate clearance, or change in lactate, over time. The prognostic value of lactate clearance is established in sepsis [32,33], although its use as a goal of resuscitation has only recently been evaluated. Despite its value as a prognostic tool, the use of lactate clearance as a 1070-5295 ß 2012 Wolters Kluwer Health Lippincott Williams Wilkins www.co-criticalcare.com 297

Emergencies resuscitation goal carries some of the same shortcomings of ScvO 2. Several processes may influence lactate production [34] and clearance in addition to alterations in oxygen delivery, and the interested reader is referred to a review article on the topic [35]. The main advantage of lactate clearance is that it does not require specialized equipment as is necessary in the case of continuous ScvO 2 monitoring. Recently, two groups have published randomized control trials incorporating lactate clearance into resuscitation strategies for septic shock, both of which met the primary outcome for the intervention group. These groups had different clinical questions in mind when the studies were designed, and as a result, each developed a unique protocol making direct comparisons between the studies difficult. When taken together, however, these studies suggest that lactate clearance should be included as an early sepsis resuscitation goal. The most optimal, feasible, and externally valid method of doing so remains contentious and the optimal method of therapeutically addressing a suboptimal lactate clearance remains uncertain. The more easily interpreted study incorporating lactate clearance was conducted by Jones et al. [36 ], a multicenter study attempting to address barriers in the adoption and translation of quantitative resuscitation strategies into clinical practice. Data suggest that numerous barriers exists in US emergency departments to the utilization of any quantitative resuscitation protocol, including inability to provide invasive monitoring [37,38]. Beginning to address these barriers, the authors developed a resuscitation strategy utilizing lactate clearance in place of ScvO 2 as the final goal of early sepsis resuscitation, with the hypothesis that lactate clearance was noninferior, or no worse and potentially better than ScvO 2. Patients assigned to the two treatment arms underwent the same treatment except that clinicians were provided either ScvO 2 or lactate clearance data, but not both. Clinicians chose to initialize dobutamine or packed red blood cell transfusion based primarily on this piece of data. This study demonstrated a mortality difference of 6% (confidence interval 3 to 15%) in favor of the lactate clearance arm, meeting the primary hypothesis of noninferiority. However, one cannot rule out that ScvO 2 and lactate clearance may provide complementary data, particularly in patients with a normal initial lactate and abnormal ScvO 2, and, therefore, may both have a role in early sepsis resuscitation. With that consideration in mind, an interesting strategy incorporating lactate clearance into early sepsis resuscitation was studied by Jansen et al. [39 ]. Both treatment arms underwent a similar resuscitation strategy, but clinicians caring for patients in the intervention arm were provided with data regarding ongoing lactate clearance. The resuscitation protocol is complex, but the unique component of this study was the conceptual use of lactate clearance as a marker of microcirculatory dysfunction and shunting. If other parameters were optimized, microcirculatory dysfunction was targeted utilizing nitroglycerin. Although the use of a vasodilator in the setting of a condition traditionally presented as the archetype of vasodilatory shock may seem counterintuitive, its use in this situation is an attempt to achieve microcirculatory vasodilatation. The study found that patients assigned to the intervention arm received more i.v. fluids and more nitroglycerin than patients assigned to the control arm. The intervention arm demonstrated a mortality benefit in an adjusted analysis, but lactate clearance did not differ between the groups. Recently, a pilot randomized control trial failed to demonstrate beneficial effect of nitroglycerin infusion on the microcirculation, with a concerning trend toward poorer clinical outcomes in patients treated with nitroglycerin [40 ]. Taken together, these data suggest that the Jansen protocol may have provided benefit in some manner independent of enhanced lactate clearance, and likely not due to improvements in microcirculation. One might hypothesize that increased awareness on the part of physicians regarding patients with a poor prognosis as evidenced by lack of lactate clearance led to changes in the overall care of those patients, and it was this change that subsequently led to improved outcomes. However, this interpretation is open to debate. The major value of this study at this point is the suggestion that knowledge of lactate clearance may improve clinical decision making. Adjuvant therapies: corticosteroids The CORTICUS study was a large randomized control trial of hydrocortisone treatment for heterogeneous patients with septic shock [41]. Although the study demonstrated a faster improvement in organ failure scores among the intervention arm, no mortality benefit was observed. Meta-analytic data suggest faster resolution of shock, although no mortality benefit of steroid treatment [42]. As a result, the role of corticosteroids in the initial management of septic shock is unclear, but decision can likely be deferred in the emergency department. However, stress dose steroids should still be administered to patients undergoing chronic steroid treatment and those with an abnormal hypothalamic pituitary adrenal axis (such as Cushing s syndrome), 298 www.co-criticalcare.com Volume 18 Number 4 August 2012

Emergency management of severe sepsis and septic shock Puskarich and may be considered for those with vasopressorresistant shock [43], although clear clinical trials supporting these practices are lacking. Conclusion Hemodynamic resuscitation forms the backbone for the care of the emergency department patient with septic shock. Advances have been made in defining the relative importance of various components of bundled care. Dynamic measures of fluid responsiveness are gaining support, and evidence suggests dopamine should not be utilized as the vasopressor of choice in sepsis. Lactate clearance should be considered an additional goal of early sepsis resuscitation, although the ideal clearance goal and method of attaining it remains unclear. Previously encouraging adjunctive treatments, such as lowdose corticosteroids, have failed to demonstrate a mortality benefit in clinical trials and their role remains uncertain. Acknowledgements None. Conflicts of interest M.A.P. has received research support from the American Heart Association, grant 10POST3560001. He has no conflicts of interest to report. REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 399). 1. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368 1677. 2. Jones AE, Brown MD, Trzeciak S, et al. The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis. Crit Care Med 2008; 36:2734 2739. 3. Angus D, Linde-Zwirble W, Lidicker J, et al. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. 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This meta-analysis found dopamine was associated with more arrhythmias and higher mortality than norepinephrine in the treatment of septic shock. 29. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877 887. 30. Pope J, Jones AE, Gaieski D, et al. Multi-center study of central venous oxygen saturation (ScvO2) as a predictor of mortality in patients with sepsis. Ann Emerg Med 2010; 55:40 46. 31. Textoris J, Fouche L, Wiramus S, et al. High central venous oxygen saturation in the latter stages of septic shock is associated with increased mortality. Crit Care 2011; 15:1 6. 32. Nguyen H, Rivers E, Knoblich B, et al. Early lactate clearance is associated with improved outcome in severe sepsis and septic shock. Crit Care Med 2004; 32:1637 1642. 1070-5295 ß 2012 Wolters Kluwer Health Lippincott Williams Wilkins www.co-criticalcare.com 299

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