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.
Division of Pediatric Critical Care, Oregon Health and Science University, Portland, OR, USA.
Brahm
B
Goldstein
Simon
S
Nadel
Mark
M
Peters
Roger
R
Barton
Flavia
F
Machado
Howard
H
Levy
Douglas J
DJ
Haney
Barbara
B
Utterback
Mark D
MD
Williams
Brett P
BP
Giroir
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