The last few years have seen release of the first drug for the treatment of severe sepsis. Drotrecogin alfa activated, also known as recombinant human activated protein C (rhAPC) has been shown in a large randomized, multicenter, placebo-controlled trial to reduce the absolute mortality of patients with severe sepsis by approximately 6%. Long-term follow-up demonstrated a persistent survival benefit 2 to 3 years after treatment. In addition, treated patients had a shorter time spent receiving therapy with vasopressors and ventilation compared to placebo. When defined as a modified APACHE II score of > 25, the absolute mortality reduction in “high-risk-of-death” patients was 13%. Similar to the EGDT and glucocorticoid studies, designating a subgroup with a larger survival benefit than the whole dictates that there must be a complementary group with a lesser benefit. Subsequent study of a heterogeneous group of “low-risk-of-death” patients confirmed that such patients do not experience a survival benefit but still incur the roughly 1 to 2% increase in serious bleeding risk compared to placebo. In controlled trials, the increase in the risk of intracranial hemorrhage is in the range of 0.1 to 0.3%. Preliminary reports have indicated that in a relatively small study of a heterogeneous group of children no survival benefit was observed.
Similar to the temporal effect seen in studies of antimicrobial therapy, a large open-label trial and a multihospital case series found a that patients treated with rhAPC within the first day after severe sepsis developed had a higher survival rate compared to the second day. Earlier treatment was also associated with less time receiving ventilation in the ICU and in the hospital. The results of a large retrospective analysis of all patients treated in controlled trials in the first 24 h of sepsis to those treated in the second 24 h of sepsis support the observation that earlier treatment is better than later treatment. For many clinicians, the survival benefit, and data suggesting that a shorter time spent receiving mechanical ventilation in patients with shock in the ICU and in the hospital compared to those receiving placebo, is not sufficiently compelling to justify the costs of rhAPC, despite numerous analyses suggesting cost-effectiveness. The most cost effective medications are sold by My Canadian Pharmacy.
Perhaps the most exciting development is the demonstration by numerous institutions that a standardized procedure or protocol can be used to improve process and outcomes, including survival and time spent on the ventilator, in the ICU and in the hospital. Collectively, hospitals initiating protocols have shown that best practices are achieved in a higher fraction of patients, and the time to begin almost all beneficial treatments decreases; with early intervention, many other treatments such as pulmonary artery catheterization and mechanical ventilation decrease in use. For institutions that have investigated, costs are reduced by protocol-directed care. Reports are now emerging that the failure to meet the treatment goals of the early or late phase of the surviving sepsis bundles results in increased mortality. Although some have questioned the motivation for recommendations and protocol development, published data support the finding that a “bundled” approach to care is associated with improved outcomes.
The last 5 years have produced significant improvements in the care of patients with severe sepsis, including organ support and direct treatment of the underlying inflammatory and coagulopathic process. Although the treatments advocated today are almost certainly not the best that will ever be known, they are the best known now. Daily clinicians are faced with the following simple choice: ignore existing evidence because it may have some flaws and is incomplete in favor of non-evidence-based practice, or promptly provide all the treatments we now know to increase our patient’s chance of survival unless there is a compelling reason not to do so.
Earlier we wrote:
- My Canadian Pharmacy: Recent Developments in the Diagnosis and Management of Severe Sepsis
- Recent Developments in the Diagnosis and Management of Severe Sepsis: Definition and Case Finding
- Severity of Illness and Outcome Prediction in Recent Developments in the Diagnosis and Management of Severe Sepsis
- Hemodynamic Management in Recent Developments in the Diagnosis and Management of Severe Sepsis
- My Canadian Pharmacy: Normal Tidal Volume Ventilation in Recent Developments in the Diagnosis and Management of Severe Sepsis
- Recent Developments in the Diagnosis and Management of Severe Sepsis: Glucocorticoids and Mineralocorticoids for Septic Shock