Multicenter, randomized, placebo-controlled study of the nitric oxide scavenger pyridoxalated hemoglobin polyoxyethylene in distributive shock.
OBJECTIVE
To assess the safety and efficacy of the hemoglobin-based nitric oxide scavenger, pyridoxalated hemoglobin polyoxyethylene (PHP), in patients with distributive shock.


METHODS
Phase II multicenter, randomized (1:1), placebo-controlled study.


METHODS
Fifteen intensive care units in North America.


METHODS
Sixty-two patients with distributive shock, > or = 2 systemic inflammatory response syndrome criteria, and persistent catecholamine dependence despite adequate fluid resuscitation (pulmonary capillary wedge pressure > or = 12).


METHODS
Patients were randomized to PHP at 0.25 mL/kg/hr (20 mg/kg/hr), or an equal volume of placebo, infused for up to 100 hrs, in addition to conventional vasopressor therapy. Because treatment could not be blinded, vasopressors and ventilatory support were weaned by protocol.


RESULTS
Sixty-two patients were randomized to PHP (n = 33) or placebo (n = 29). Age, sex, etiology of shock (sepsis in 94%), and Acute Physiology and Chronic Health Evaluation II scores (33.1 +/- 8.3 vs. 30 +/- 7) were similar in PHP and placebo patients, respectively. Baseline plasma nitrite and nitrate levels were markedly elevated in both groups. PHP infusion increased systemic blood pressure within minutes. Overall 28-day mortality was similar (58% PHP vs. 59% placebo), but PHP survivors were weaned off vasopressors faster (13.7 +/- 8.2 vs. 26.3 +/- 21.4 hrs; p = .07) and spent less time on mechanical ventilation (10.4 +/- 10.2 vs. 17.4 +/- 9.9 days; p = .21). The risk ratio (PHP/placebo) for mortality was .79 (95% confidence interval, .39-1.59) when adjusted for age, sex, Acute Physiology and Chronic Health Evaluation II score, and etiology of sepsis. No excess medical interventions were noted with PHP use. PHP survivors left the intensive care unit earlier (13.6 +/- 8.6 vs. 17.9 +/- 8.2 days; p = .21) and more were discharged by day 28 (57.1 vs. 41.7%).


CONCLUSIONS
PHP is a hemodynamically active nitric oxide scavenger. The role of PHP in distributive shock remains to be determined.
University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Gary-kinasewitz@ouhsc.edu
Gary T
GT
Kinasewitz
Christopher T
CT
Privalle
Amy
A
Imm
Jay S
JS
Steingrub
John T
JT
Malcynski
Robert A
RA
Balk
Joseph
J
DeAngelo
D018806:APACHE; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D012769:Shock / Q000145:classification / Q000188:drug therapy* / Q000401:mortality; D016019:Survival Analysis
D006454:Hemoglobins; C050907:pyridoxalated-hemoglobin-polyethylene glycol conjugate; D011092:Polyethylene Glycols