Maria G Castaneda

Intravenous Cobinamide Versus Hydroxocobalamin for Acute Treatment of Severe Cyanide Poisoning in a Swine (Sus scrofa) Model

STUDY OBJECTIVE Hydroxocobalamin is a Food and Drug Administration-approved antidote for cyanide poisoning. Cobinamide is a potential antidote that contains 2 cyanide-binding sites. To our knowledge, no study has directly compared hydroxocobalamin with cobinamide in a severe, cyanide-toxic large-animal model. Our objective is to compare the time to return of spontaneous breathing in swine with acute cyanide-induced apnea treated with intravenous hydroxocobalamin, intravenous cobinamide, or saline solution (control). METHODS Thirty-three swine (45 to 55 kg) were intubated, anesthetized, and instrumented (continuous mean arterial pressure and cardiac output monitoring). Anesthesia was adjusted to allow spontaneous breathing with FiO2 of 21% during the experiment. Cyanide was continuously infused intravenously until apnea occurred and lasted for 1 minute (time zero). Animals were then randomly assigned to receive intravenous hydroxocobalamin (65 mg/kg), cobinamide (12.5 mg/kg), or saline solution and monitored for 60 minutes. A sample size of 11 animals per group was selected according to obtaining a power of 80%, an α of .05, and an SD of 0.17 in mean time to detect a 20% difference in time to spontaneous breathing. We assessed differences in time to death among groups, using Kaplan-Meier estimation methods, and compared serum lactate, blood pH, cardiac output, mean arterial pressure, respiratory rate, and minute ventilation time curves with repeated-measures ANOVA. RESULTS Baseline weights and vital signs were similar among groups. The time to apnea and cyanide dose required to achieve apnea were similar. At time zero, mean cyanide blood and lactate concentrations and reduction in mean arterial pressure from baseline were similar. In the saline solution group, 2 of 11 animals survived compared with 10 of 11 in the hydroxocobalamin and cobinamide groups (P<.001 between the 2 treated groups and the saline solution group). Time to return of spontaneous breathing after antidote was similar between hydroxocobalamin and cobinamide (1 minute 48 seconds versus 1 minute 49 seconds, respectively). Blood cyanide concentrations became undetectable at the end of the study in both antidote-treated groups, and no statistically significant differences were detected between the 2 groups for mean arterial pressure, cardiac output, respiratory rate, lactate, or pH. CONCLUSION Both hydroxocobalamin and cobinamide rescued severely cyanide-poisoned swine from apnea in the absence of assisted ventilation. The dose of cobinamide was one fifth that of hydroxocobalamin.

Intravenous Lipid Emulsion Therapy Does Not Improve Hypotension Compared to Sodium Bicarbonate for Tricyclic Antidepressant Toxicity: A Randomized, Controlled Pilot Study in a Swine Model

OBJECTIVES Tricyclic antidepressants (TCAs) are highly lipophilic medications used to treat posttraumatic stress disorder and chronic pain. Intravenous lipid emulsion (ILE) is a recent antidote for lipophilic drug overdose with unclear effectiveness. ILE has been studied in TCA overdose in small animals, and cases are reported in humans, but controlled studies in a larger animal model are lacking. Given the high lipophilicity of amitriptyline, a TCA, the hypothesis was that ILE would be more effective than the standard antidote sodium bicarbonate in improving amitriptyline-induced hypotension. The objective was to determine if ILE improved hypotension (defined by a mean arterial pressure [MAP] < 60% baseline) compared to sodium bicarbonate for amitriptyline overdose in a critically ill porcine model. METHODS In this prospective, randomized, controlled trial, 24 female Sus scrofa swine weighing 45 to 55 kg were infused with amitriptyline at 0.5 mg/kg/min until the MAP reached 60% of baseline values. Animals were randomized to the experimental treatment group (ILE 7 mL/kg bolus, then 0.25 mL/kg/min) or the standard treatment group (sodium bicarbonate 2 mEq/kg plus an equal volume of saline). The primary outcome was a 50% improvement in MAP after ILE administration. We continuously monitored heart rate (HR), systolic blood pressure (sBP), MAP, and cardiac output. Electrocardiograms were recorded every 15 minutes. Serum pH, pCO2 , bicarbonate, lactate, and electrolytes were measured. Amitriptyline levels were measured by liquid chromatography/tandem mass spectrometry. Statistical methods used to detect a difference in MAP between the two treatment groups included repeated-measures analysis of variance, adjusted for treatment, time, and the interaction of treatment by time. A sample size of 12 animals per group provided a power of 0.8 and an alpha of 0.05 to detect a 50% difference in MAP. RESULTS There was no difference at baseline between ILE and sodium bicarbonate groups in mean HR, sBP, MAP, or cardiac output. Mean amounts of amitriptyline to reach hypotension and time to hypotension were similar between groups. After hypotension there was no difference between groups for mean HR, sBP, MAP, or cardiac output. The median time from hypotension to death was greater for the sodium bicarbonate group (10 minutes [IQR = 6 to 61 minutes] vs. 5 minutes [IQR = 4.5 to 6 minutes] for the ILE group; p = 0.003), but overall survival was not different. One ILE and four sodium bicarbonate pigs survived. Additionally, no difference was detected in QRS intervals between the two groups. The mean (±SD) amitriptyline level in the lipid layer was 3.34 (±2.12) μg/mL, and in the aqueous layer, 4.69 (±2.44) μg/mL. The ILE fatty layer contained 38.2% of total measurable amitriptyline, while the aqueous layer contained 53.6%. CONCLUSIONS Intravenous lipid emulsion treatment failed to improve amitriptyline-induced hypotension when compared to the standard treatment of sodium bicarbonate in a large animal model of severe TCA overdose. Larger groups with better survival may yield different results from the high mortality observed in this pilot study. Similar amounts of amitriptyline were found in the aqueous and lipid layers. These conclusions are limited to a single ILE regimen.

Left Ventricular Compressions Improve Hemodynamics in a Swine Model of Out-of-Hospital Cardiac Arrest

ABSTRACT Introduction: We hypothesized that chest compressions located directly over the left ventricle (LV) would improve hemodynamics, including coronary perfusion pressure (CPP), and return of spontaneous circulation (ROSC) in a swine model of cardiac arrest. Methods: Transthoracic echocardiography (echo) was used to mark the location of the aortic root and the center of the left ventricle on animals (n = 26) which were randomized to receive chest compressions in one of the two locations. After a period of ten minutes of ventricular fibrillation, basic life support (BLS) with mechanical cardiopulmonary resuscitation (CPR) was initiated and performed for ten minutes followed by advanced cardiac life support (ACLS) for an additional ten minutes. During BLS the area of maximal compression was verified using transesophageal echo. CPP and other hemodynamic variables were averaged every two minutes. Results: Mean CPP was not significantly higher in the LV group during all time intervals of resuscitation; mean CPP was significantly higher in the LV group during the 12–14 minute interval of BLS and during minutes 22–30 of ACLS (p < 0.05). Aortic systolic and diastolic pressures, right atrial systolic pressures, and end-tidal CO2 (ETCO2) were higher in the LV group during all time intervals of resuscitation (p < 0.05). Nine of the left ventricle group (69%) achieved ROSC and survived to 60 minutes compared to zero of the aortic root group (p < 0.001). Conclusions: In our swine model of cardiac arrest, chest compressions over the left ventricle improved hemodynamics and resulted in a greater proportion of animals with ROSC and survival to 60 minutes.

Intravenous Lipid Emulsion Therapy for Severe Diphenhydramine Toxicity: A Randomized, Controlled Pilot Study in a Swine Model

STUDY OBJECTIVE Diphenhydramine is a moderately lipophilic antihistamine with sodium channel blockade properties. It is consumed recreationally for mild hallucinogenic and hypnotic effects and causes dysrhythmias, seizures, and death with overdose. Intravenous lipid emulsion is a novel agent used to treat lipophilic drug overdose. Two case reports describe clinical improvement with intravenous lipid emulsion after diphenhydramine toxicity, but no prospective studies have been reported. Our objective is to determine whether intravenous lipid emulsion improved hypotension compared with sodium bicarbonate for severe diphenhydramine toxicity in a model of critically ill swine. METHODS Twenty-four swine weighing 45 to 55 kg were infused with diphenhydramine at 1 mg/kg per minute until the mean arterial pressure reached 60% of baseline. Subjects were randomized to receive intravenous lipid emulsion (bolus of 7 mL/kg and then 0.25 mL/kg per minute) or sodium bicarbonate (2 mEq/kg plus an equal volume of normal saline solution). We measured pulse rate, systolic blood pressure, mean arterial pressure, cardiac output, QRS interval, and serum diphenhydramine level. Twelve animals per group provided a power of 0.8 and α of .05 to detect a 50% difference in mean arterial pressure. We assessed differences between groups with a repeated-measures linear model (MIXED) and Kaplan-Meier estimation methods. We compared systolic blood pressure, mean arterial pressure, and cardiac output with repeated measures ANOVA. RESULTS Baseline weight, hemodynamic parameters, QRS interval, time to hypotension, and diphenhydramine dose required to achieve hypotension were similar between groups. After hypotension was reached, there was no overall difference between intravenous lipid emulsion and sodium bicarbonate groups for cardiac output or QRS intervals; however, there were transient differences in mean arterial pressure and systolic blood pressure, favoring intravenous lipid emulsion (difference: mean arterial pressure, sodium bicarbonate versus intravenous lipid emulsion -20.7 [95% confidence interval -31.6 to -9.8]; systolic blood pressure, sodium bicarbonate versus intravenous lipid emulsion -24.8 [95% confidence interval -37.6 to -12.1]). Time to death was similar. One intravenous lipid emulsion and 2 sodium bicarbonate pigs survived. End-of-study mean total serum diphenhydramine levels were similar. The mean lipid layer diphenhydramine level was 6.8 μg/mL (SD 3.1 μg/mL) and mean aqueous layer level 8.6 μg/mL (SD 5.5 μg/mL). CONCLUSION In our study of diphenhydramine-induced hypotensive swine, we found no difference in hypotension, QRS widening, or diphenhydramine levels in aqueous layers between intravenous lipid emulsion and sodium bicarbonate.

Evaluation of Extremity Tissue and Bone Injury after Intraosseous Hypertonic Saline Infusion in Proximal Tibia and Proximal Humerus in Adult Swine

Abstract Background. Hypertonic saline (HTS) has been reported as a treatment for sever traumatic brain injury and hemorrhagic shock and current clinical guidelines recommend it. Intraosseous (IO) infusion is often needed in the pre-hospital and combat settings to administer life-saving treatments. However, the safety of IO HTS infusion is not clear. The aim of our study was to evaluate the clinical and histological outcome of HTS IO infusion into the extremity of a large animal model. Methods. We conducted a randomized comparative study of adult pigs that were infused intraosseously with one of the following solutions: 7.5% HTS, 3% HTS or normal 0.9% isotonic saline. The animals were observed daily for infection, necrosis and gait (5 point Tarlov score) up to 5 days. Five days after infusion, necropsy and histological analysis was performed using a validated scale of tissue necrosis. Results. The mean Tarlov gait scores were similar in all arms and all animals showed a score of 4 (normal ambulation) by day 5. During the 5 day observation period, there were no signs of infection or tissue abnormalities. Histological examinations showed no indication of necrosis, or abnormal bone and muscle healing (p < 0.05). Conclusion. We observed regular tissue morphology and normal gait scores over the 5 day observation period. There was an absence of gross tissue necrosis and microscopic ischemia post IO HTS infusion in this swine model. This data confirms the clinical safety of IO HTS infusion and highlights its use as an alternative lifesaving treatment.

Intraosseous hydroxocobalamin versus intravenous hydroxocobalamin compared to intraosseous whole blood or no treatment for hemorrhagic shock in a swine model

OBJECTIVE To determine if intraosseous (IO) hydroxocobalamin can improve systolic blood pressure (SBP) in a swine model after severe hemorrhagic shock. METHODS Thirty six swine (45-55 kg) were anesthetized, intubated, and instrumented with continuous femoral and pulmonary artery pressure monitoring and then hemorrhaged such that 30 percent of their blood volume was extracted over 20 minutes. Five minutes later, animals were randomly assigned to receive 500 mL IO whole blood, 150 mg/kg IO or intravenous (IV) hydroxocobalamin in 180 mL of saline, or no treatment and then monitored for 60 minutes. A sample size of eight animals per group was based on a power of 80 percent, an alpha of 0.05, and a small effect size to detect a difference in SBP between groups. Outcome data were analyzed using repeated measures analysis of variance (RMANOVA). RESULTS RMANOVA outcome analysis detected a significant difference between groups (p < 0.05). IO whole blood, IO hydroxocobalamin, and IV hydroxocobalamin groups were similar to each other, but significantly different compared to controls regarding SBP, mean arterial pressure (MAP), systemic vascular resistance, and heart rate. Differences in SBP and MAP were sustained throughout the experiment. At 60 minutes, the comparison among the groups, IO whole blood, IO hydroxocobalamin, IV hydroxocobalamin, and control, was the following: SBP 78.2 versus 83.7 versus 75.1 versus 55.3 mm Hg; MAP 62.7 versus 65 versus 60 versus 43 mm Hg. There was a significant interaction by time in lactate values (p < 0.01) such that control animal lactate values increased over time (3.3 mmol/L) compared to IO whole blood, IO or IV hydroxocobalamin treated animals (1.1, 1.6, 1.3 mmol/L). CONCLUSIONS IO hydroxocobalamin improved SBP, MAP, compared to no treatment and was similar to IO whole blood and IV hydroxocobalamin in this animal model of severe hemorrhage. Moreover, whereas serum lactate was improving in all treated groups, it was deteriorating in the control group.