Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77.
There was no standardized approach to the early management of severe sepsis and septic shock until the turn of the century, with relatively high mortality, ranging between 40–50%. By then, an expeditious, systems-based approach had already been well-established and demonstrated to improve outcomes following acute myocardial infarction, stroke, and trauma. There was a compelling need for early recognition and targeted interventions directed towards improving outcomes following sepsis. Rivers et al. conceptualized a goal-directed approach for the optimization of oxygen delivery by targeting the preload, afterload, and myocardial contractility during the initial “golden hours” of sepsis and embarked upon a ground-breaking randomized controlled trial between 1997–2000 (1).
Early studies on optimized oxygen delivery in the critically ill
The concept of optimization of oxygen delivery in critically ill patients was not new. In an observational study, survivors of high-risk surgical procedures had higher cardiac index, oxygen delivery, and oxygen consumption compared to non-survivors (2). Based on this observation, Shoemaker et al. tested the efficacy of therapeutic interventions aimed at supranormal values of cardiac index (>4.5 L/m2), oxygen delivery, and oxygen consumption among high-risk surgical patients. They found that supranormal values led to a lower incidence of postoperative mortality, complications, and reduced length of stay in the ICU and hospital (3).
Yet another randomized controlled trial (RCT), published 5 years later, seemed to corroborate these findings. High-risk surgical patients were managed according to a protocol targeting an oxygen delivery index of >600 mL/min/m2 using dopexamine, a D1 and β2 agonist that was popular during that period. This strategy of a protocolized increase in oxygen delivery resulted in a lower 28-d mortality and a fewer complications compared with a standard care group (4).
However, there was conflicting evidence behind targeted oxygen delivery in general critically ill patients. Gattinoni et al. tested the hypothesis in an RCT whether aiming for supranormal levels of cardiac index (>4.5 L/m2) or normal mixed venous oxygen saturation (SvO2) levels (≥70 percent) would improve outcomes compared with targeting normal cardiac index (control group) among critically ill patients (5). They could achieve a supranormal cardiac index in only 44.9%, and normal SvO2 levels in 66.7% of patients. In the control group, 94.3% of patients achieved a normal cardiac index. Survival to ICU discharge and at 6 months did not differ between the three groups. The incidence of organ dysfunction and length of ICU stay was also similar in all three groups.
Background to the trial
Early goal-directed therapy (EGDT), as proposed by Rivers et al., was based on the paradigm of an imbalance between oxygen delivery and demand in sepsis. They hypothesized that global tissue hypoxia occurs in sepsis due to the failure of oxygen delivery to match up with the increased demand triggered by the hypermetabolic state, intravascular volume depletion, vasoplegia, and myocardial depression. They proposed that the tools commonly used for hemodynamic assessment, including blood pressure, central venous pressure, and urine output often fail to identify tissue hypoxia. More sensitive indicators may include SVO2, serum lactate levels, and the degree of metabolic acidosis. As the measurement of mixed venous oxygen saturation required the insertion of a pulmonary artery catheter, the central venous oxygen saturation (ScvO2) was considered a reasonable surrogate based on the evidence available at that time (6).
The emphasis was on early intervention in septic patients to forestall a catastrophic decline in the clinical status. Time to intervention is crucial in septic patients; previous studies on goal-directed therapies may have failed to improve outcomes as therapeutic interventions were delayed until organ failure had already set in. This concept was rooted in sepsis being a time-sensitive disease process, akin to acute myocardial infarction and stroke, where early intervention profoundly influences outcomes. ICU care was often delayed due to logistical reasons, and a standardized approach toward the septic patient was yet to evolve. The EGDT investigators conceptualized a bundled approach toward the early management of the septic patient, focusing on the key principles of early identification, risk stratification, antibiotic administration, source control, and optimization of the hemodynamic status. The hemodynamic components of EGDT included augmentation of preload with early aggressive fluid resuscitation, optimization of contractility, and vasopressor therapy based on pre-specified targets.
Population and design
Patients who presented to the emergency department of the Henry Ford Hospital, Detroit, with severe sepsis, septic shock, or the sepsis syndrome over a 3-year period between 1997–2000 were screened for inclusion in the study. Patients with 2 of 4 systemic inflammatory response criteria (SIRS), a systolic blood pressure ≤90 mm Hg after crystalloid administration of 20–30 ml/kg over 30 minutes, and a serum lactate level of ≥4 mmol/L were included. Among those excluded were patients with acute stroke, acute coronary syndrome, acute pulmonary edema, gastrointestinal bleed, requirement expeditious surgical intervention, and do-not-resuscitate status. Patients were randomly assigned to receive protocolized EGDT or to a control group that received standard therapy.
The EGDT protocol
Patients received a series of protocolized interventions as part of EGDT for at least six hours in the emergency department before being transferred out for continued inpatient care. The stepwise protocol commenced with fluid boluses for a target CVP of 8–12 mm Hg. If the mean arterial pressure (MAP) remained <65 mmHg after fluid resuscitation, vasopressors were initiated aiming for a target MAP of 65–90 mm Hg. If the MAP exceeded 90 mm Hg, vasodilators were administered. ScvO2 was continuously monitored using a specially devised central venous catheter. If the ScvO2 remained <70% after attaining the target MAP, red cell transfusions were administered for a hematocrit level of 30%. If the ScvO2 was persistently <70%, dobutamine was titrated to a maximum dose of 20 mcg/kg/min, aiming to increase the cardiac output. The dobutamine infusion rate was reduced or ceased if the MAP was <65 mm Hg or if the heart rate exceeded 120/min. If the protocol targets could not be attained with these measures, mechanical ventilation with sedatives and neuromuscular blockers was carried out with a view to reducing oxygen consumption.
Invasive monitoring lines, including arterial and central venous catheters, were placed. Therapeutic interventions were based on clinician judgment, targeting a CVP ≥ 8–12 mmHg, MAP ≥ 65 mmHg, and urine output ≥ 0.5 ml/kg/h. Supplemental oxygen and mechanical ventilation were carried out as appropriate.
Patients in both groups were administered antibiotics after blood, urine, and other samples were collected for culture.
Sample size calculation
In-hospital mortality was the primary endpoint of the study. Assuming a 15% reduction in mortality with EGDT compared with standard care, the authors calculated a sample size of 260 patients for a two-sided type I error of 5%, and 80% power, after allowing for a 10% dropout rate.
Two hundred and eighty-eight patients were screened; 25 patients were either excluded or refused to participate and the remaining 263 patients were randomized to the EGDT or standard therapy arm. Among these, 236 patients completed the stipulated 6-h study period in the emergency department. Twenty-seven patients did not complete the 6-h study period – 13 in the EGDT and 14 in the standard therapy group.
Pneumonia was the most common etiology of sepsis, followed by urosepsis and intrabdominal infections. Hemodynamic parameters, the degree of organ dysfunction, and the severity of illness based on the APACHE II and SAPS II scores were comparable at baseline. The time to administration of the first dose of antibiotic, its adequacy, and the duration of therapy were similar in both groups.
Hemodynamic parameters and organ function
The combined CVP, MAP, and urine output targets were attained in significantly more patients in the EGDT compared with the standard care arm (99.2% vs.86.1%). The target ScvO2 level of ≥70% was also achieved in significantly more patients in the EGDT group (94.9% vs. 60.2%). During the 7–72 h period after randomization, the APACHE II and SAPS II scores were significantly higher in the standard care arm.
The volume of fluid administered was higher in the EGDT group in the first 6 hours; however, from 7–72 hours, more fluids were administered in the standard care arm. Thus, at the end of the first 72 hours after randomization, the total volume of fluid administered was similar in both groups. In the first 6 hours, 64.1% of patients received red cell transfusion compared with 18.5% in the standard therapy group. Dobutamine infusion as inotropic therapy was used more often in the EGDT group. The mean duration of vasopressor therapy, mechanical ventilation, and hospital length of stay was similar in the two groups. Overall, the data suggested a more aggressive level of support with EGDT during the first 6 hours of treatment.
Among patients who received standard therapy, hospital mortality, the primary outcome, was significantly higher compared to the EGDT group [59/133 (46.5%) vs. 38/130 (30.5%), p = 0.009]. The mortality difference was most pronounced in patients with septic shock (56.8% vs. 42.3%, p = 0.04). The 28-d mortality was also significantly higher in the standard therapy group (49.2% 33.3%, p = 0.01). At 60 days, 56.9% of patients in the standard therapy group had died, compared with 44.3% in the EGDT arm (p = 0.03).
Relevance of this landmark study
Rivers et al. embarked upon a protocolized model of care in sepsis during an era when a systematic approach was not in vogue. The need for a methodical approach was especially felt during the “golden hours” of sepsis when many patients were still being managed in the emergency department or on the floors. The bundled approach was rooted in sound physiological principles, facilitating early recognition of sepsis, risk stratification, antibiotic administration, and a time-honored approach toward hemodynamic optimization. The presumed benefits of many of the individual components of the bundle have since been challenged; however, EGDT radically changed our approach toward the management of the early phase of sepsis at the turn of the century, emphasizing the importance of expeditious therapeutic interventions during this crucial phase.
The EGDT trial revealed a 16% reduction in hospital mortality through the adoption of a stepwise protocol. However, several limitations and criticisms arose soon after its publication. The study was confined to the emergency department of a single center at the Henry Ford Hospital, Detroit, with doubtful generalizability. The clinicians in the emergency department involved in the study were unblinded to the study arm, which could have led to bias. However, the treating clinicians were unaware of the study arm once patients were transferred to the ICU. The impact of individual elements of the bundle also remained unclear. CVP levels have been shown to be an insensitive index of fluid responsiveness (7). A lower transfusion threshold was equally effective compared to the target hematocrit of 30% employed in the Transfusion Requirements In Septic Shock (TRISS) study. The use of dobutamine to improve cardiac output and oxygen delivery in critically ill patients may also be associated with adverse outcomes, including increased mortality (8).
In the standard care group, although CVP, MAP, and urine output targets were defined, no specific guidelines were provided on how these could be achieved. The mortality in the control group was relatively high (46.5%), even considering the relatively higher mortality from severe sepsis during the period when the study was conducted. The lead investigator, Emmanuel Rivers, had a conflict of interest and received consultation fees from the company that manufactured the central venous catheters that measured ScvO2.
PROMISE, PROCESS, and ARISE: the trilogy that challenged EGDT
Following its publication, the key interventions of the EGDT trial were included in the early iterations of sepsis management guidelines by the Surviving Sepsis Campaign (9). However, questions remained regarding the relevance of individual components of the bundle, especially, monitoring of ScvO2 using specialized catheters. Continued interest in a bundled approach to the care of the septic patient led to three RCTs that were published between 2014–2015. The Protocolized Care for Early Septic Shock (ProCESS) (10), the Australasian Resuscitation in Sepsis Evaluation (ARISE) (11), and the Protocolised Management in Sepsis (ProMISe) (12) compared the EGDT protocol with standard care. The ProMISe and the ARISE trials randomized patients to EGDT or usual care; the PROCESS trial compared three strategies – EGDT, usual care, or a protocolized standard therapy. These three trials reported all-time low mortality in sepsis; there was no improvement in survival noted with the EGDT protocol. ARISE, from Australia and New Zealand, reported a 90-d mortality of 18.6% with EGDT vs. 18.8% in the usual care arm, and ProMISe, from the UK, reported 29.5% vs. 29.2%. The 60-day mortality in the PROCESS trial from the US was 21.0%, 18.9%, and 18.2%, and in the EGDT, usual care, and protocolized standard therapy arms, respectively.
An individual-patient data meta-analysis of these three trials confirmed similar 90-day between EGDT and usual care (24.9% vs 25.4%; adjusted odds ratio: 0.97, 95% CI 0.82-1.14). (13).
It was abundantly clear from the findings of these trials that improved survival in severe sepsis, and septic shock could not be attributed to the individual elements of the EGDT bundle as proposed by Rivers et al. Resuscitation guided by CVP and ScvO2 or the use of dobutamine to augment cardiac output and oxygen delivery may not hold the key to improved survival. However, the EGDT trial emphasized the importance of early recognition of sepsis, expeditious resuscitation, antibiotic administration, and source control. Although the efficacy of EGDT-specific interventions may have been refuted, early recognition and targeted interventions remain important cornerstones in the management of sepsis, as espoused by Rivers et al. more than two decades ago.
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