The surviving sepsis campaign: 2013 and beyond

The 2012 revision of the Surviving Sepsis Campaign: International Guideless for Management of Severe Sepsis and Septic Shock was recently published (February 2013) in Critical Care Medicine and Intensive Care Medicine.1,2 The effort to create this document occurred over two years and likely represents the most comprehensive buy-in of any international medical guidelines to date with 30 sponsoring organizations. Included in this list of sponsoring organizations is the Chinese Society of Critical Care Medicine-China Medical Association and the Chinese Society of Critical Care Medicine. The evidence based medicine (EBM) grading system continues to evolve under the leadership of the Grades of Recommendation Assessment Development and Evaluation Group (GRADE Group), based in Canada.3 Each recommendation is graded based on quality of evidence and strength of recommendation. The quality of evidence is defined by the source material for making the recommendation with higher quality being “A”, descending to lower quality at “D”. For the first time in this edition of the guidelines some recommendations are “ungraded” based on being nonconducive to EBM. The strength of the recommendation is considered most important with a grade “1” being a strong recommendation and a grade “2” being a weak recommendation. The factors determining strength include quality of evidence, relative importance of outcomes, risk, cost, and absolute magnitude and precision of effect. The early administration of antibiotics in suspected or known severe sepsis remains a high priority in the guidelines, recommending intravenous antibiotic therapy be administered as early as possible and ideally within the first hour of recognition of severe sepsis with or without septic shock. The guidelines also recognize that this is not currently medical practice but is a goal that should be aspired to. There have been considerable changes since 2008 in the recommendations as to the choice of fluid for resuscitation. Crystalloids are now recommended as the initial fluid of choice for resuscitation of severe sepsis (1B) with a suggestion that albumin be added when patients require substantial amounts of crystalloids (2C). The SAFE study published in the New England Journal of Medicine in 2004 demonstrated equivalence of albumin and crystalloids in fluid resuscitation of ICU patients and crystalloids are cheaper than albumin.4 A subgroup analysis in the SAFE study showed better outcome in patients with severe sepsis who received albumin; however, this was not the a priori endpoint and even if it had been would not have quite reached statistical significance. Meta-analysis have suggested the potential of albumin to be a better fluid choice but no head-to-head study versus crystalloid has proven this.5 Albumin is more expensive. The guidelines recommend against the use of hydroxylethyl starches (1B) based on the composite results of the VISEP, CRYSTMAS, 6S and CHEST trials.6-9 The recently completed CRYSTAL study was not considered and could lead to re-evaluation and refinement of recommendations in this area. There have also been significant changes in the guidelines as to vasopressor recommendations. In septic shock, following adequate fluid resuscitation, the continued presence of hypotension signifies some combination of depression of cardiac contractility and arteriolar vasodilatation as the cause of hypotension. These facts support the use of combined inotrope/vasopressor drugs for maintaining adequate blood pressure following adequate fluid resuscitation. There are three combined inotrope/vasopressor agents: norepinephrine, dopamine, and epinephrine. A 2010 study, although not achieving statistical significance, showed better outcome with norepinephrine as opposed to dopamine in all forms of shock, with a concerning occurrence of lifethreatening arrhythmias with dopamine.10 A 2012 metaanalysis also supports norepinephrine as a preferred agent when compared to dopamine.11 The guidelines therefore recommend norepinephrine as the first choice vasopressor (1B) and suggest dopamine as an alternative vasopressor agent only in highly selected patients with very low risk of tachyarrhythmias and with relative or absolute bradycardia (2C). In patients who fail to achieve mean arterial pressure target of 65 mmHg with norepinephrine, the two options for achieving this goal are the addition of epinephrine (2B) or low dose vasopressin, 0.03 units/minute (ungraded). The guidelines recommend against the empiric use of phenylephrine in septic shock as it is a pure vasopressor and will decrease stroke volume. Phenylephrine may be considered in certain circumstances such as (a) serious tachyarrhythmias with use with norepinephrine, (b) cardiac output known to be high and blood pressure is persistently low despite high dose norepinephrine or (c) as salvage therapy when combination therapy of norepinephrine, epinephrine, and low dose vasopressin have failed to achieve MAP target (1C). In sepsis induced tissue hypoperfusion (requirement for vasopressors after fluid challenge or initial lactate ≥4 mg/dl) quantitative resuscitation is recommended and protocolized care should be available to guide this resuscitation.12,13 Quantitative resuscitation is defined as a structured (protocolized) cardiovascular intervention targeting pre-defined hemodynamic endpoints. This quantitative resuscitation should include a MAP target of 65 mmHg and a urine output of 0.5 ml·kg−1·h−1 (1C). The recommended initial fluid challenge in sepsis induced tissue hypoperfusion is a minimum of 30 ml/kg of crystalloids (a portion of this may be albumin equivalent), recognizing that more rapid administration and greater amounts of fluids may be needed in some patients (1B). In patients with sepsis induced tissue hypoperfusion a central venous catheter should be inserted in the neck or chest and central venous pressure measured in the superior vena cava with the target of 8-12 mmHg (higher with altered ventricular compliance or increased intrathoracic pressure). An ScvO2 saturation (SVC) ≥70% (again in superior vena cava) is also a target (1C). If achievement of CVP target and MAP target do not elevate ScvO2 to ≥70%, the alternatives to achieve this goal include empiric dobutamine, transfusion of packed red blood cells (if hematocrit is <30%) or additional fluid resuscitation. The committee recognized that there are some limitations of using a right sided pressure measurement to predict fluid responsiveness of the left ventricle since the Starling Principle as it applies to responsiveness of fluid resuscitation in shock relate better to volume of the left ventricle than to right heart pressure. Recognizing this fact, the committee also encourages the use of dynamic variables to judge adequacy of fluid administration such as delta pulse pressure and stroke volume variation. Measurement of flow is also a logical variable to track and this can be done with arterial pressure pulse contour analysis, pulmonary artery catheter or esophageal Doppler measurement of flow. Ultrasound also offers an alternative to guide fluid therapy with visualization of inferior vena cava or left ventricular size. Unfortunately, these latter variables are not typically available during the critical first six hours of resuscitation making insertion of a central venous catheter to monitor fluid therapy a more viable early option at most institutions. The potential role of lactate clearance to judge adequacy of quantitative resuscitation is also recognized by the committee.14,15 In patients with elevated lactate levels, the committee recommends targeting quantitative resuscitation to normalize lactate as rapidly as possible (2C). The use of steroids in septic shock remains controversial with contrasting study results.16,17 The committee continues to de-emphasize the use of steroids in adult septic shock and recommends against the use of intravenous steroids in septic shock if adequate fluid resuscitation and vasopressor therapy restore hemodynamic stability. If used 200 mg/24 hours intravenous hydrocortisone given by continuous infusion is recommended. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage or lactic acidosis, red blood cell transfusion is recommended only when hemoglobin falls below 7.0 g/dl (IB). ARDSnet ventilator strategy continues to be recommended for ventilation of acute respiratory distress syndrome (ARDS) to include 6 ml/kg per predicted body weight tidal volume and limitation of plateau pressure to ≤30 cmH2O. New suggestions for management of ARDS in the 2012 guidelines include (a) higher range positive end expiratory pressure (PEEP) for moderate and severe ARDS (PaO2/FiO2 ratio ≤200 mmH2O) (2C), using the ALVEOLI trial higher PEEP table (b) recruitment maneuvers in severe refractory hypoxemia (2B) and (c) prone positioning in severe ARDS (PaO2/FIO2 <100) despite recruitment maneuvers and PEEP setting (2C). Concerning glucose control, continuous infusion insulin is recommended when two consecutive blood glucose levels are >180 mg/dl, targeting glucose maintenance ≤180 mg/dl (1A). The changes in the guidelines in 2012 have lead to a revision in the SSC sepsis performance improvement bundles with elimination of the 24-hour bundle. Currently the bundle consists of seven quality indicator targets, four to be completed within the first three hours and the remainder within the first six hours (Table 1). It is important to remember that guidelines are an excellent reference source of evidence based knowledge, but are unlikely to affect a significant bedside change in physician behavior. Protocols should be developed that guide physicians to accomplish the quality indicators in the sepsis bundles with formal performance improvement programs that include, most importantly, audit and feedback. Audit and feedback of performance scores to physicians are essential for improving outcomes in severe sepsis.Table 1: Surviving sepsis campaign bundlesWith the revision of the guidelines and new sepsis bundles, the SSC website has been updated with new information and new educational tools to facilitate start-up of the SSC sepsis performance improvement program (www.survivingsepsis.org). A new revision of the free software for the performance improvement program will be available later this year.

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