Biomarker response to drotrecogin alfa (activated) in children with severe sepsis: results from the RESOLVE clinical trial*.
OBJECTIVE
REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE), a phase III trial of drotrecogin alfa (activated) in pediatric severe sepsis, examined biomarker changes in inflammation and coagulation. This report describes biomarker profiles in early severe sepsis and the pharmacodynamic assessment of drotrecogin alfa (activated) in RESOLVE.


METHODS
Serial measurements of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tissue necrosis factor-α, procalcitonin, D-dimer, and thrombin-antithrombin complex were performed at baseline and daily over the first five study days. Protein C levels were performed at baseline and at the end of the 96-hr study drug infusion. Analysis of variance-based log-transformed data compared the treatment groups for each measured variable.


METHODS
: One hundred four pediatric intensive care units in 18 countries.


METHODS
Four hundred seventy-seven children between 38 wks corrected gestational age and 17 yrs with sepsis-induced cardiovascular and respiratory dysfunction.


METHODS
Drotrecogin alfa (activated).


RESULTS
Pharmacodynamic activity of drotrecogin alfa (activated) compared with placebo was observed with reduction of D-dimer on day 1 (p < .01) and thrombin-antithrombin complex on days 1-4 (p < .05). There were no significant changes by treatment in multiple cytokines or procalcitonin. In the overall population, a median protein C difference was not observed (p > .05) with drotrecogin alfa (activated) administration compared with placebo, although a difference (median percentage change from baseline) in favor of drotrecogin alfa (activated) was observed in patients >1 yr old (p = .0449).


CONCLUSIONS
While children in the RESOLVE trial were similar to adults in that they showed a relationship between severity of coagulation and inflammation abnormalities and mortality, their pharmacodynamic response to drotrecogin alfa (activated) differed with respect to changes in protein C activity and systemic inflammation.
Division of Critical Care Medicine, Phoenix Children's Hospital, Phoenix, AZ, USA. hdalton@phoenixchildrens.com
Heidi J
HJ
Dalton
Joseph A
JA
Carcillo
D Bradley
DB
Woodward
Mary A
MA
Short
Mark D
MD
Williams
D000293:Adolescent; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D000990:Antithrombin III; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000378:metabolism*; D002116:Calcitonin / Q000097:blood*; D015740:Calcitonin Gene-Related Peptide; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood*; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000209:etiology / Q000503:physiopathology; D004311:Double-Blind Method; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D010447:Peptide Hydrolases / Q000097:blood; D011486:Protein C / Q000378:metabolism / Q000627:therapeutic use*; D011498:Protein Precursors / Q000097:blood*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012131:Respiratory Insufficiency / Q000209:etiology; D018805:Sepsis / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D016019:Survival Analysis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000890:Anti-Infective Agents; D015415:Biomarkers; D001798:Blood Proteins; C000606589:CALCA protein, human; D016207:Cytokines; D005338:Fibrin Fibrinogen Degradation Products; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D011486:Protein C; D011498:Protein Precursors; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; D016753:Interleukin-10; D000990:Antithrombin III; D002116:Calcitonin; D010447:Peptide Hydrolases; C421124:drotrecogin alfa activated; D015740:Calcitonin Gene-Related Peptide