Recombinant Human Activated Protein C in Sepsis

Bahar Mjos, DO

 

Evaluating the use of recombinant human activated protein C in adult severe sepsis: Results of the Surviving Sepsis Campaign*

Casserly, Brian MD; Gerlach, Herwig MD, PhD; Phillips, Gary S. MAS; Marshall, John C. MD; Lemeshow, Stanley PhD; Levy, Mitchell M. MD

After the PROWESS-SHOCK trial and Cochrane review in 2012, it appeared that the controversy related to efficacy of activated protein C and its role in sever sepsis had been resolved. However, this month in the journal of Critical Care Medicine, revisited this topic.

It has been shown that after adjusting for multiple confounders, patients who received rhAPC had statistically significantly lower in-hospital mortality. “Propensity score matching was used to validate the risk adjusted multivariate regression model, and the results were similar. Patients with thrombocytopenia and coagulopathy also were found to have lower, and statistically significant, adjusted risks of hospital mortality”.

As of October 2011 Xigris (activated protein C) has been withdrawn from the market.

“While further discussions about rhAPC might be considered moot, it is worth noting that previous rigorously conducted clinical trials occasionally have yielded discordant results compared to observational, “real-life” investigations. The recent moratorium on the use of rhAPC appears to represent yet another failure of immunomodulatory agents to impact outcomes for critically ill patients with sepsis; however, the infrequent use of rhAPC, in selected populations, was found to be associated with a significant improvement in adjusted hospital mortality in this study.”

Early vs Late TPN in ICU Patients, Dr. Mjos

Bahar Mjos, DO
PGY-4 Resident at RCRMC who will do a Critical Care Fellowship at John's Hopkins University on graduation

Early versus Late Parenteral Nutrition in Critically Ill Adults

Prior data on early vs. late feeding in critically ill patients have been difficult to interpret. *A metaanalysis of 15 studies examining early enteral nutrition (containing 753 subjects) suggested that early enteral nutrition was associated with a significantly lower incidence of infections (RR 0.45; p =.00006) and a reduced hospital stay (mean 2.2 days; p =.004), however there were no significant differences in mortality* or noninfectious complications. The results of this meta-analysis must be interpreted with some caution because of the *significant heterogeneity between studies.*

More recently, seven Belgian ICUs performed *The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) Study *, a prospective, randomized, controlled, parallel-group, multicenter investigator-initiated trial (partially funded by Baxter) in which 4640 nutritionally at-risk patients were randomized to early (within 48 hours) vs. late (at least 8 days) initiation of parenteral nutrition (2007 to 2010). While the early nutrition group clearly received more nutrition (both in terms of total energy and percentage of target), *the late group was discharged from the ICU one day earlier (p = 0.04), had a lower

incidence of hypoglycemia (p = 0.001), fewer infections (22.8% vs. 26.2%, p = 0.008), and a reduction in total healthcare costs of ~ $1600 (€1,110)*. Mortality was the same. Importantly, mean units of insulin and average glucose in the early and late groups were 58U/107 mg/dL and 31U/102 mg/dL, respectively.

Meta-Analysis of Fluid Management Strategies, Dr. Mjos

Bahar Mjos, DO

Perioperative Fluid Management Strategies in Major Surgery: A Stratified Meta-Analysis

This article reviewed the outcome of goal directed fluid therapy versus liberal fluid therapy intraoperative. Many previous studies focus on perioperative fluid therapy. However, the optimal strategy remains controversial and uncertain. Most current studies center around the type of fluids administered (colloid versus crystalloid), the total volume administered (restrictive versus liberal [LVR]), and whether the administration of fluids should be guided by hemodynamic goals (goal directed [GD] versus not goal directed. In this paper it was hypothesized that liberal use of perioperative fluid therapy without hemodynamic goals is not equivalent to GD fluid therapy, and a meta-analysis was conducted to compare these 2 approaches of managing perioperative fluid therapy and how they many have different end results. 

Studies were grouped into 2 strata, standard therapy with hemodynamic goals versus GD and liberal versus restrictive in this meta-analysis. The primary outcome was postoperative mortality. Secondary outcomes were organ-specific complications, recovery of bowel function (time to first flatus, time to first bowel movement, and return to oral diet), and length of hospital stay.

The findings:

1)    “ GD fluid therapy reduced renal complications, pneumonia, time to first bowel movement, resumption of normal diet and length of stay compared to non-GD therapy”

2)    “Restrictive fluid strategy reduced the incidence of pulmonary edema and pneumonia, time to first bowel movement, and the length of stay compared to liberal fluid therapy without using hemodynamic goals”

3)    “Both patients randomized to have GD fluid strategy and liberal fluid therapy without hemodynamic goals received more perioperative fluid than those managed with non-GD therapy and a restrictive fluid strategy, respectively.”

4)     “Although both GD and liberal fluid therapy both used a large amount of perioperative fluid, their effects on perioperative outcomes were different; patients in the GD groups had a shorter length of stay, time to recovery of gastrointestinal function, and a lower incidence of pneumonia compared to those in the liberal groups;

5)     “No specific fluid management strategy was associated with an improvement in mortality”

6)     “Significant heterogeneity in continuous outcome was observed, but publication bias was not apparent.”

This study showed that both methods of GD fluid therapy and liberal use of fluid w/o hemodynamics goals ended up using a large amount of fluid intraop. But the end outcomes still favored the use of hemodynamic monitoring. With the limited data available, significant uncertainty remains concerning the relative benefits of GD and restrictive fluid strategies, or the superiority of one modality of hemodynamic monitoring over another.