Christopher T. Privalle

Pyridoxalated hemoglobin polyoxyethylene: a nitric oxide scavenger with antioxidant activity for the treatment of nitric oxide-induced shock.

Hemoglobins modified for therapeutic use as either hemoglobin-based oxygen carriers or scavengers of nitric oxide are currently being evaluated in clinical trials. One such product, pyridoxalated hemoglobin polyoxyethylene conjugate (PHP), is a human-derived and chemically modified hemoglobin that has yielded promising results in Phase II clinical trials, and is entering a pivotal Phase III clinical trial for the treatment of shock associated with systemic inflammatory response syndrome (SIRS). Shock associated with SIRS is a NO-induced shock. PHP, a new mechanism-based therapy, has been demonstrated in clinical trials to have the expected hemodynamic activity of raising blood pressure and reducing catecholamine use, consistent with its mechanism of action as a NO scavenger. PHP is conjugated with polyoxyethylene, which results in a surface-decorated molecule with enhanced circulation time and stability as well as in attachment of soluble red blood cell enzymes, including catalase and superoxide dismutase. PHP thus contains an antioxidant profile similar to the intact red blood cell and is therefore resistant to both initial oxidative modification by oxidants such as hydrogen peroxide and subsequent ferrylhemoglobin formation. These studies suggest both that the redox activity of modified hemoglobins can be attenuated and that modified hemoglobins containing endogenous antioxidants, such as PHP, may have reduced pro-oxidant potential. These antioxidant properties, in addition to the NO-scavenging properties, may allow the use of PHP in other indications in which excess NO, superoxide, or hydrogen peroxide is involved, including ischemia-reperfusion injury and hemorrhagic shock.

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. Design:Phase II multicenter, randomized (1:1), placebo-controlled study. Setting:Fifteen intensive care units in North America. Patients:Sixty-two patients with distributive shock, ≥2 systemic inflammatory response syndrome criteria, and persistent catecholamine dependence despite adequate fluid resuscitation (pulmonary capillary wedge pressure ≥12). Interventions: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. Measurements and Main 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.

Multicenter, randomized, placebo-controlled phase III study of pyridoxalated hemoglobin polyoxyethylene in distributive shock (PHOENIX).

Objective:To compare the effectiveness and safety of the hemoglobin-based nitric oxide scavenger, pyridoxalated hemoglobin polyoxyethylene, against placebo in patients with vasopressor-dependent distributive shock. Design:Multicenter, randomized, placebo-controlled, open-label study. Setting:Sixty-one participating ICUs in six European countries (Austria, Belgium, Germany, the Netherlands, Spain, and United Kingdom). Patients:All patients admitted with distributive shock, defined as the presence of at least two systemic inflammatory response syndrome criteria, persisting norepinephrine dependence and evidence of organ dysfunction/hypoperfusion despite adequate fluid resuscitation. Interventions:Patients were randomized to receive 0.25 mL/kg/hr pyridoxalated hemoglobin polyoxyethylene (20 mg Hb/kg/hr) or an equal volume of placebo, infused for up to 150 hours, in addition to conventional vasopressor therapy. Measurements and Main Results:The study was stopped after interim analysis showed higher mortality in the pyridoxalated hemoglobin polyoxyethylene group and an increased prevalence of adverse events. At this time, 377 patients had been randomized to pyridoxalated hemoglobin polyoxyethylene (n = 183) or placebo (n = 194). Age, gender, type of patient (medical/surgical), and Acute Physiology and Chronic Health Evaluation II scores were similar between groups. Twenty-eight–day mortality rate was 44.3% in the pyridoxalated hemoglobin polyoxyethylene group versus 37.6% in the placebo group (OR, 1.29; 95% CI, 0.85–1.95; p = 0.227). In patients with higher organ dysfunction scores (Sepsis-related Organ Failure Assessment > 13), mortality rates were significantly higher in the pyridoxalated hemoglobin polyoxyethylene group when compared with those in placebo-treated patients (60.9% vs 39.2%; p = 0.014). Survivors who received pyridoxalated hemoglobin polyoxyethylene had a longer vasopressor-free time (21.3 vs 19.7 d; p = 0.035). Conclusions:In this randomized, controlled phase III trial in patients with vasopressor-dependent distributive shock, administration of a pyridoxalated hemoglobin solution decreased the need for vasopressors but was associated with a trend to increased mortality.