A Prospective, Randomized Trial of Intravenous Hydroxocobalamin Versus Whole Blood Transfusion Compared to No Treatment for Class III Hemorrhagic Shock Resuscitation in a Prehospital Swine Model

Abstract

Objectives: The objective was to compare systolic blood pressure (sBP) over time in swine that have had 30% of their blood volume removed (Class III shock) and treated with intravenous (IV) whole blood or IV hydroxocobalamin, compared to nontreated control animals.Methods: Thirty swine (45 to 55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring. Animals were hemorrhaged a total of 20 mL/kg over a 20-minute period. Five minutes after hemorrhage, animals were randomly assigned to receive 150 mg/ kg IV hydroxocobalamin solubilized in 180 mL of saline, 500 mL of whole blood, or no treatment. Animals were monitored for 60 minutes thereafter. A sample size of 10 animals per group was determined based on a power of 80% and an alpha of 0.05 to detect an effect size of at least a 0.25 difference (>1 standard deviation) in mean sBP between groups. sBP values were analyzed using repeated-measures analysis of variance (RANOVA). Secondary outcome data were analyzed using repeated-measures multivariate analysis of variance (RMANOVA).Results: There were no significant differences between hemodynamic parameters of IV hydroxocobalamin versus whole blood versus control group at baseline (MANOVA; Wilks' lambda; p = 0.868) or immediately posthemorrhage (mean sBP = 47 mm Hg vs. 41 mm Hg vs. 37 mm Hg; mean arterial pressure = 39 mm Hg vs. 28 mm Hg vs. 34 mm Hg; mean serum lactate = 1.2 mmol/L vs. 1.4 mmol/L vs. 1.4 mmol/L; MANOVA; Wilks' lambda; p = 0.348). The outcome RANOVA model detected a significant difference by time between groups (p < 0.001). Specifically, 10 minutes after treatment, treated animals showed a significant increase in mean sBP compared to nontreated animals (mean sBP = 76.3 mm Hg vs. 85.7 mm Hg vs. 51.1 mm Hg; p < 0.001). RMANOVA modeling of the secondary data detected a significant difference in mean arterial pressure, heart rate, and serum lactate (p < 0.001). Similar to sBP, 10 minutes after treatment, treated animals showed a significant increase in mean arterial pressure compared to nontreated animals (mean arterial pressure = 67.7 mm Hg vs. 61.4 mm Hg vs. 40.5 mm Hg). By 10 minutes, mean heart rate was significantly slower in treated animals compared to nontreated animals (mean heart rate = 97.3 beats/min vs. 95.2 beats/min vs. 129.5 beats/min; p < 0.05). Serum lactate, an early predictor of shock, continued to rise in the control group, whereas it did not in treated animals. Thirty minutes after treatment, serum lactate values of treated animals were significantly lower compared to nontreated animals (p < 0.05). This trend continued throughout the 60-minute observation period such that 60-minute values for lactate were 1.4 mmol/L versus 1.1 mmol/L versus 3.8 mmol/L. IV hydroxocobalamin produced a statistically significant increase in systemic vascular resistance compared to control, but not whole blood, with a concomitant decrease in cardiac output.

Looking back to inform the future: a review of published paramedicine research

“…Four articles were on triage [ 140 – 143 ], four were on trauma system assessment or design [ 144 – 147 ], and one was on prehospital levels of care [ 148 ]. Of the eight articles in the Hemorrhage theme, four articles focused on hemostatic dressings [ 149 – 152 ], and one each on tourniquets [ 153 ], IV infusion strategies [ 154 ], blood transfusion [ 155 ], and triage [ 156 ]. Of the six articles in the Immobilization theme, four focused on spinal immobilization [ 157 – 160 ], one on pelvis [ 161 ] and one on neck of femur fractures [ 162 ].…”

“…Of the eight articles in the Hemorrhage theme, four articles focused on hemostatic dressings [ 149 – 152 ], and one each on tourniquets [ 153 ], IV infusion strategies [ 154 ], blood transfusion [ 155 ], and triage [ 156 ].…”

Efficacy of Intravenous Hydroxocobalamin for Treatment of Sodium Methanethiolate Exposure in a Swine Model (Sus scrofa) of Severe Methanethiol Toxicity

“…Following animal stabilization, baseline blood samples were collected for serum biochemical analysis. Baseline biochemical measurements included oxygen saturation, PaO 2 , PaCO 2 , hemoglobin (Hgb), pH, bicarbonate, base excess, and lactate, which were collected in a manner reported in prior publications (ABL 800 Flex blood gas analyzer, Radiometer America, Westlake, OH) [11,[21][22][23][24].…”

A prospective, randomized trial of intravenous hydroxocobalamin versus noradrenaline or saline for treatment of lipopolysaccharide‐induced hypotension in a swine model

“…While noradrenaline (NA) is currently the vasopressor of choice when treating sepsis‐induced hypotension that is not fluid responsive, it is predominantly an alpha 1 receptor agonist and has no activity against nitric oxide synthase . Hydroxocobalamin (HOC) is both a nitric oxide scavenger and has been suggested to modulate nitric oxide synthase in a tissue dependent manner . In vivo, in a rodent LPS‐induced septic model, HOC demonstrated an organ dependent promotion/inhibition of NOS, such that the balance between endothelial nitric oxide synthase (eNOS or NOS‐3), the constitutive local regulator of vascular tone, with inducible nitric oxide synthase (iNOS) was improved .…”

“…We speculated that HOC, unlike specific NOS inhibitors, may be more effective in treating sepsis‐induced hypotension by modulating expression of nitric oxide synthase and scavenging NO and may produce a more beneficial response to NO induced vasodilation compared to NA in the early treatment of sepsis. Because our previous findings suggest that HOC supports mean arterial pressure in other models of hypotension, we undertook this experiment to examine the efficacy of HOC to sustain mean arterial pressure (MAP) and thus decrease mortality from hypotension in LPS‐induced endotoxaemia.…”