ENHANCE: results of a global open-label trial of drotrecogin alfa (activated) in children with severe sepsis.
OBJECTIVE
To gather additional 28-day all-cause mortality data and safety information for pediatric patients with severe sepsis who received drotrecogin alfa (activated) (DrotAA).


METHODS
Single-arm, open-label, multicentered study conducted in 59 study sites in 15 countries.


METHODS
One-hundred eighty-eight children (term newborn to <18 yrs old) with severe sepsis were consecutively enrolled in the study.


METHODS
Administration of DrotAA, 24 microg/kg/hr for 96 hrs.


METHODS
Four-day and 28-day all-cause mortality, safety information, and protein C levels.


RESULTS
: One-hundred eighty-seven patients completed the study. The 4-day mortality rate was 7.0%, and the 28-day mortality rate was 13.4%. At baseline, 57.6% of patients were severely deficient in protein C (a level < or = 40% of normal). There was a statistically significant association between increased 28-day mortality and decreased end-of-infusion protein C levels (p < .001), greater number of baseline organ dysfunctions (p < .001), and greater baseline ventilator use (p = .03). Bleeding was the most significant complication observed. Serious bleeding events (including anemia without a bleeding source) were experienced by 27.7% of patients (n = 52). Six of the serious bleeding events (3.2%) were considered related to administration of DrotAA. During infusion, serious bleeding events with an identified source of bleeding were experienced by 5.9% of patients (n = 11). Central nervous system bleeding was experienced by 2.7% (n = 5). Two of the intracranial hemorrhages were fatal and occurred postinfusion.


CONCLUSIONS
Without a placebo control, no efficacy conclusions are possible. Subgroups at higher risk of death were identified, and the change in protein C level from baseline was predictive of survival. The most significant complication observed was bleeding. Risk factors for serious bleeding appear to be multiple organ failure, thrombocytopenia, and coagulopathy.
Goldstein
Brahm
B
Division of Pediatric Critical Care, Oregon Health and Science University, Portland, OR, USA.
Nadel
Simon
S
Peters
Mark
M
Barton
Roger
R
Machado
Flavia
F
Levy
Howard
H
Haney
Douglas J
DJ
Utterback
Barbara
B
Williams
Mark D
MD
Giroir
Brett P
BP
D000293:Adolescent; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D008297:Male; D011486:Protein C / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D018709:Statistics, Nonparametric; D015996:Survival Rate; D016896:Treatment Outcome
D000890:Anti-Infective Agents; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated