Septic Shock: Null Trial Results May Point the Way

Laurie Barclay, MD

March 19, 2014

Two protocols for the resuscitation of patients with septic shock diagnosed in the emergency department did not improve outcomes compared with standard care, according to a randomized controlled trial published online March 18 in the New England Journal of Medicine.

Despite the lack of benefit with either of the protocols, the trial results may point out important elements of care for septic shock. "The...trial identifies early recognition of sepsis, early administration of antibiotics, early adequate volume resuscitation, and clinical assessment of the adequacy of circulation as the elements we should focus on to save lives," writes Craig M. Lilly, MD, from the Division of Pulmonary, Allergy and Critical Care Medicine, University of Massachusetts Medical School in Worcester, in an accompanying editorial.

"In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care," write Donald M. Yealy, MD, from the University of Pittsburgh, Pennsylvania, and colleagues from the Protocolized Care for Early Septic Shock (ProCESS) study. "We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary."

The current study took place at 31 US tertiary care emergency departments. Patients with septic shock were randomly assigned to 1 of 3 groups for 6 hours of resuscitation: protocol-based EGDT, standard therapy based on a similar but less aggressive protocol, or usual care.

Protocol Components

The EGDT protocol included central venous catheterization to monitor central venous pressure and central venous oxygen saturation as a guide to the use of intravenous fluids, vasopressors, packed red cell transfusions, and dobutamine to reach prespecified physiological targets.

Protocol-based standard therapy also used a team approach with 6-hour resuscitation instructions, but with less aggressive components than those in the EGDT protocol. Central venous catheter placement was required only if peripheral venous access was insufficient. Hourly monitoring of systolic blood pressure, shock index (the ratio of heart rate to systolic blood pressure), fluid status, and hypoperfusion determined fluid administration (until the team leader decided that patient's fluids were replete. Unlike the EGDT protocol, the standard therapy protocol recommended packed red cell transfusion only if the hemoglobin level was less than 7.5 g/dL.

Neither protocol required an arterial catheter for blood pressure monitoring or specified types of resuscitation fluid or vasopressors, and in both protocols, all aspects of care other than resuscitation were at the discretion of the treating physician.

In the usual-care group, the bedside providers directed all care; the study coordinator collected data but did not prompt any actions.

Study goals were to compare outcomes for protocol-based care (EGDT and standard-therapy groups combined) vs usual care and for protocol-based EGDT vs protocol-based standard therapy. Sixty-day in-hospital mortality was the main study outcome, and longer-term mortality and the need for organ support were secondary outcomes.

Mortality Similar in All Groups

Of 1341 patients, 439 received protocol-based EGDT, 446 received protocol-based standard therapy, and 456 received usual care. Central venous pressure monitoring, oxygen monitoring, and use of intravenous fluids, vasopressors, inotropes, and blood transfusions differed significantly among groups.

However, the groups did not differ significantly in 90-day mortality, 1-year mortality, or the need for organ support.

In the protocol-based EGDT group, 92 people (21.0%) died by 60 days compared with 81 (18.2%) in the protocol-based standard-therapy group and 86 (18.9%) in the usual-care group. Relative risk (RR) for 60-day mortality with protocol-based therapy vs usual care was 1.04 (95% confidence interval [CI], 0.82 - 1.31; P = .83), and RR with protocol-based EGDT vs protocol-based standard therapy was 1.15 (95% CI, 0.88 - 1.51; P = .31).

Protocol-based resuscitation was associated with a small but transient improvement in blood pressure by the end of the resuscitation period, but also with a greater requirement for intensive care and renal replacement therapy.

"In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes," the study authors write.

Limitations of this study include the inability to ensure close adherence to all elements of the resuscitation protocols, lack of generalizability to patients in whom septic shock is not recognized promptly, inability to control for possible differences in care before randomization, and limited power to compare the efficacy of particular strategies in specific subgroups. In addition, varying practices regarding the withdrawal of care strongly affects in-hospital mortality among patients requiring life support, and this could have influenced the findings.

"[I]n our multicenter, randomized trial, in which patients were identified early in the emergency department as having septic shock and received antibiotics and other nonresuscitation aspects of care promptly, we found no significant advantage, with respect to mortality or morbidity, of protocol-based resuscitation over bedside care that was provided according to the treating physician's judgment," the study authors conclude. "We also found no significant benefit of the mandated use of central venous catheterization and central hemodynamic monitoring in all patients."

New Era of Sepsis Management

In the editorial, Dr. Lilly describes "a new era of sepsis management" made possible by early recognition of sepsis. In the ProCESS trial, early administration of intravenous antibiotics and other best practices were associated with rates of survival that were higher than projected or predicted.

He suggests that similar outcomes among groups may have resulted from the prompting, serum lactate screening, and assessment of systemic inflammatory response syndrome criteria required in all groups. These could be applied in clinical practice to ensure early diagnosis and treatment for all patients with septic shock.

"State legislation and clinical guidelines, including those endorsed by the National Quality Forum, should be updated to remove the requirement for central hemodynamic monitoring and to focus on less costly, lower-risk, and equally effective alternatives," Dr. Lilly writes.

"The ProCESS trial allows refinement of the EGDT approach to fluid administration by defining lower boundaries that are associated with equivalent outcomes and setting limits that are needed to avoid the twin problems of renal failure from too little fluid and pulmonary dysfunction from fluid overload," he adds.

The National Institute of General Medical Sciences, National Institutes of Health, funded this study. Two of the study authors reported receiving consulting fees from Thermo Fisher Scientific, Cumberland Pharmaceuticals, Rapid Pathogen Screening, Cheetah Medical, Astute Medical. MedImmune, Ferring Pharmaceuticals, Roche Diagnostics, Pfizer, Eli Lilly, and/or Eisai. Full conflict-of-interest information is available on the journal's Web site.

N Engl J Med. Published online March 18, 2014. Article full text, Editorial full text

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