Key points

Introduction

Sepsis is a common and deadly disease, in which many survivors are burdened with life altering effects. In order to deliver current evidence-based treatment and avoid unnecessary, costly, and harmful therapy, it is imperative that emergency and acute care providers be knowledgeable about current treatments that affect outcomes in septic patients. In 2001, a landmark trial by Rivers and colleagues was published, which showed that an early and aggressive treatment approach to patients with sepsis was associated with a significant mortality benefit. In the period following this study, along with the efforts of the Surviving Sepsis Campaign (SSC), there was the emergence of protocolized, evidence-based care for patients with sepsis and septic shock. Although the SSC provided an evidence-based approach, the largest impact from this work is likely the increased awareness for early identification of septic patients.

So-called usual’ sepsis care has evolved over the past 3 decades as knowledge of the disease and its treatment has been refined. The term usual care (UC), represents a consensus of what is needed to effectively combat this syndrome. Early goal-directed therapy (EGDT), as described in the Rivers and colleagues study and the Surviving Sepsis Guidelines from the SSC, can be especially taxing in resource-limited settings. Further, additional literature over the past several years has questioned whether all components are necessary or even harmful, prompting the ProCESS (A Protocolized Care for Early Septic Shock), ARISE (The Australasian Resuscitation in Sepsis Evaluation) and ProMISe (A Protocolised Management in Sepsis) trials. These studies evaluated the various elements of EGDT, and it is anticipated that these data will further refine the components that should be routinely applied in the care of septic patients. This article discusses the landmark sepsis trials that have been published over the past several decades and offers recommendations on what should currently be considered UC.

Introduction

Sepsis is a common and deadly disease, in which many survivors are burdened with life altering effects. In order to deliver current evidence-based treatment and avoid unnecessary, costly, and harmful therapy, it is imperative that emergency and acute care providers be knowledgeable about current treatments that affect outcomes in septic patients. In 2001, a landmark trial by Rivers and colleagues was published, which showed that an early and aggressive treatment approach to patients with sepsis was associated with a significant mortality benefit. In the period following this study, along with the efforts of the Surviving Sepsis Campaign (SSC), there was the emergence of protocolized, evidence-based care for patients with sepsis and septic shock. Although the SSC provided an evidence-based approach, the largest impact from this work is likely the increased awareness for early identification of septic patients.

So-called usual’ sepsis care has evolved over the past 3 decades as knowledge of the disease and its treatment has been refined. The term usual care (UC), represents a consensus of what is needed to effectively combat this syndrome. Early goal-directed therapy (EGDT), as described in the Rivers and colleagues study and the Surviving Sepsis Guidelines from the SSC, can be especially taxing in resource-limited settings. Further, additional literature over the past several years has questioned whether all components are necessary or even harmful, prompting the ProCESS (A Protocolized Care for Early Septic Shock), ARISE (The Australasian Resuscitation in Sepsis Evaluation) and ProMISe (A Protocolised Management in Sepsis) trials. These studies evaluated the various elements of EGDT, and it is anticipated that these data will further refine the components that should be routinely applied in the care of septic patients. This article discusses the landmark sepsis trials that have been published over the past several decades and offers recommendations on what should currently be considered UC.

Mortality in the era before early goal-directed therapy

In the roughly 35 years leading up to the introduction of the SSC, the overall mortality for patients with sepsis was 49.7%. Most publications over that time reported mortalities between 40% and 80%. Although there had been some improvements in mortality, the trend was small. Although it is easy to assume that this was the result of outdated treatments, the therapies delivered then were similar to modern interventions. Despite this, recent studies have suggested dramatic improvements in survival, with current mortalities ranging from 20% to 35%. Note that just as sepsis care has changed, its definition has changed as well. As a result, this can present some challenges to interpreting current and historical data. Regardless of which definition is used, mortality has clearly improved.

Early goal-directed therapy

In 2001, Rivers and colleagues published a landmark article that challenged contemporary sepsis care. The investigators theorized that if patients could be treated in a timely and targeted manner to correct the imbalance between oxygen delivery and demand, the progression to multiorgan failure and death could be halted. They did this by targeting specific central hemodynamic end points during the initial 6 hours of treatment of severe sepsis (defined by the presence of 2 systemic inflammatory response syndrome criteria and end-organ damage) and septic shock (defined by a lack of blood pressure response to adequate fluid resuscitation).

The study randomized 263 patients to 2 study arms. Those in the standard therapy (ST) arm were treated at physician discretion according to a protocol for hemodynamic support. This treatment included placement of central venous and arterial catheters. Patients randomized to the EGDT arm were resuscitated according to a protocol that designated preset hemodynamic end points. This protocol included placement of a central venous catheter capable of continuous central venous oxygen saturation (Scv o ₂ ) monitoring.

Importantly, treatments in the 2 arms varied. The EGDT group used prespecified hemodynamic targets to assess success of resuscitation and as triggers for additional interventions. The first hemodynamic variable targeted was a central venous pressure (CVP) of 8 to 12 mm Hg. In order to achieve this, patients were given 500 mL of a crystalloid every 30 minutes until this target was reached. If the mean arterial pressure (MAP) remained less than 65 mm Hg despite a CVP of 8 to 12 mm Hg, vasopressor therapy was initiated to achieve this goal. If, despite achieving a goal CVP and MAP, the Scv o ₂ was less than 70%, the patient was transfused red blood cells to a hematocrit of 30%. If, despite transfusion, the Scv o ₂ remained less than the target, inotropic therapy was initiated with dobutamine. In addition, if the Scv o ₂ goal was still not achieved in a nonventilated patient, the patient was intubated and sedative agents were administered.

The results of this study suggested that a timely, targeted approach conferred a significant mortality benefit, because the EGDT group had statistically significant improvements in in-hospital, 28-day, and 60-day mortalities. Some of the significant differences between the treatment arms included fluid administration, continuous Scv o ₂ monitoring, vasopressor use, inotropic support, and blood transfusions ( Table 1 ). The total amount of fluids at 72 hours administered to both groups was not statistically significant. However, the amount that the EGDT group received in the first 6 hours was significant, compared with patients in the ST arm. Also, during the initial 6 hours, the EGDT group received continuous Scv o ₂ monitoring, and significantly more inotropic medications and red blood cell transfusions.

The investigators of this study postulated that the improved mortality seen in the EGDT group was caused by improved matching of oxygen delivery to oxygen demand during the earliest stages of sepsis and septic shock. This improved matching was accomplished with improved preload via volume resuscitation and increased oxygen carrying capacity from blood transfusions and inotropy. Patients in the ST group, after the 6-hour intervention period, received more fluids, required more vasopressors, and were mechanically ventilated at higher rates. This finding suggested that providers may have missed an opportunity for hemodynamic optimization during the essential early phase of resuscitation. There were no measurements of time-to-antibiotic administration in each group. However, more patients received antibiotic therapy in the first 6 hours in the ST group than in the EGDT group.

A shift in sepsis care

After publication of the Rivers and colleagues trial, EGDT was viewed as cornerstone to successful sepsis management. In 2002, EGDT was suggested as a guideline for care by an expert sepsis panel. In 2004, the SSC, a committee composed of critical care and infectious disease experts representing 11 international organizations, recommended the following EGDT hemodynamic targets with grade B evidence: CVP of 8 to 12 mm Hg, MAP greater than or equal to 65 mm Hg, central venous or mixed venous oxygen saturation of greater than 70% via the use of fluids, red blood cells, and dobutamine to achieve these goals.

The SSC guidelines established goals of care across various therapeutic modalities for sepsis. These guidelines were expansive and included recommendations on initial resuscitation; diagnostic goals; timing and regimens of antibiotic administration; vasopressor and inotropic use; corticosteroids; sedation strategies; ventilation strategies; blood product administration; and preventive measures against ventilator-acquired pneumonia, stress ulcers, and deep vein thrombosis (DVT).

Clearly, more integrated care for sepsis developed from the EGDT trial. However, despite the mortality benefit noted in this study population, there were concerns that certain elements of the EGDT protocol may be unnecessary, or potentially harmful. For instance, restrictive transfusion protocols have shown improved mortality, whereas other literature has simply shown noninferiority. This finding suggests that transfusing to a goal hematocrit of 30% to improve the Scv o ₂ and oxygen delivery did not confer the observed benefit seen in the River and colleagues EGDT algorithm. In addition, CVP and other static cardiac filling pressures can be poor predictors of fluid responsiveness. Further, there are some retrospective data that suggested increased mortality in patients who are over-resuscitated because of implementation of EGDT. In addition, placement of central venous catheters is not completely benign and carries inherent risks of mechanical complications and infection. When catheter-related infections do occur, they increase morbidity and mortality, length of stay, and health care cost.

There were also criticisms of the external validity of the EGDT study, because this was a single-center trial. Although mortality of the control group for this single-center study was 48.3%, control arms of multicenter, randomized controlled trials conducted in a similar time period were only 30% to 35%, highlighting a possible overestimation of treatment benefit with EGDT. These patients may also have been sicker or arrived to the emergency room in later stages of disease, creating results that may, at best, only translate to a small and specific subset of septic patients.

In addition, there are many barriers to implementation of EGDT. A survey of medical directors and nurse managers from high-volume, urban hospitals in the United States found common barriers to be nursing staff requirements, monitoring CVP in the emergency department, and identification of septic patients. Regarding the use of continuous Scv o ₂ , not all settings are equipped to use these catheters, and further study found lactate trends to be a noninferior surrogate. Other barriers to EGDT that have been reported include reluctance of physicians, availability of and training for new technology, and the extensive time and resources needed to implement the protocol.

The ProCESS, ARISE, and ProMISe trials

Given the criticisms, 3 multicenter, randomized, independent but collaborative trials were conducted in the United States (ProCESS), Australia (ARISE), and United Kingdom (ProMISe) to evaluate the benefits of EGDT. Each trial used the definitions of severe sepsis and septic shock used in the original EGDT trial. However, the definition of refractory hypotension was changed from unresponsive to 20 to 30 mL/kg over 30 minutes (as in the original EGDT trial) to unresponsive to a 1-L fluid bolus over 30 to 60 minutes. In contrast with the original EGDT trial, it was specified that antibiotics should be administered before randomization in the ARISE and ProMISe trials. Each center selected in these trials lacked routine protocolized emergency department sepsis care. Investigators in each trial chose leading academic and regional centers that were thought to follow best evidence for sepsis care in order to maximize the likelihood of best current practice in the UC arms. The EGDT arms of each study required a central venous catheter with Scv o ₂ monitoring, administration of fluids, use of vasopressors, and red blood cells targeting CVP, MAP, and Scv o ₂ goals in the same fashion as the original EGDT study. The ProCESS trial included a third arm, protocolized standard care (PSC), which used a 6-hour protocol but did not require central venous catheters, inotropes, or blood products. Volume status decisions were based on clinical signs of perfusion, in contrast with triggered fluid administration of the EGDT arm, and used a systolic blood pressure goal of 100 mm Hg rather than the MAP.

In total 1351, 1600, and 1260 patients underwent randomization in the ProCESS, ARISE, and ProMISe trials, respectively. The primary outcome of the ProCESS trial was 60-day mortality. The primary outcomes for the ARISE and ProMISe trials were 90-day mortality. The secondary outcomes of all 3 trials included the use of mechanical ventilation, dialysis, prolonged vasopressor or cardiac support, and the duration of intensive care unit (ICU) and hospital stay.

The key results of the 3 trials are included in Tables 2 and 3 . There were no significant differences in mortality between arms in any of the 3 trials. There were no differences in the need for mechanical ventilation and dialysis between groups, except for the PSC group in the ProCESS trial, in which more patients received dialysis (see Table 3 ). With the exception of a shorter ICU stay in the UC arm of the ProMISe trial, there were otherwise no differences in ICU or hospital length of stay. There was more use of vasopressors and advanced cardiovascular support, fluids, central venous catheters, dobutamine, and red blood cell transfusions in the EGDT arms of all 3 trials.

Table 2

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