Original Contribution

Hemodynamics after intraosseous administration of hydroxocobalamin or normal saline in a goat model^?,??

Stephen W. Borron MD, MS ^a,?, Juan C. Arias MD ^a, Charles R. Bauer MD ^a, Michael Sanchez MD ^a, Miguel Fernandez MD ^a, Inkyung Jung PhD ^b

^aDepartment of Surgery, Division of Emergency Medicine and the South Texas Poison Center,

University of Texas Health Science Center, San Antonio, TX 78229-3900, USA

^bDepartment of Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA

Received 6 August 2008; accepted 15 August 2008

Abstract

Study Objective: Hydroxocobalamin may be lifesaving in cyanide (CN) poisoning, but Personal protective equipment wear, rescue, and decontamination may delay intravenous administration. Intraosseous lines may be rapidly placed even when wearing PPE. We assessed the hemodynamics of hydroxocobalamin (OHCo) and normal saline by the IO route.

Keywords: Cyanide; Hydroxocobalamin;

Intraosseous infusion; Hazardous materials;

Personal protective equipment

Methods: Twelve anesthetized Spanish goats underwent Arterial line catheterization. Operators in PPE placed IO lines. After placement confirmation by fluoroscopy, animals randomly received hydroxocobalamin 75 mg/kg (3 mL/kg) (n = 6) or normal saline (NS) 3 mL/kg (n = 6) IO over approximately 7.5 minutes. Blood pressures and heart rates were monitored for 240 minutes after infusion initiation.

Results: In the OHCo group, mean systolic and diastolic pressures peaked at 120 minutes, with mean increases of 14% and 17%, respectively, relative to infusion start, returning to near preinfusion values at 240 minutes. Heart rate changes were virtually nil. In the NS group, mean systolic pressures peaked at 60 minutes, with a mean increase of 36%, whereas diastolic pressures peaked at about 110 minutes, increasing 42%, returning to near preinfusion values at 240 minutes. Heart rate changes were minimal. Conclusion: hemodynamic effects of OHCo given by the IO route in non-CN-poisoned goats are mild and well tolerated. Increases in mean blood pressure at peak after baseline were greater in the NS group, but the mean values over time were not significantly different from those observed in the OHCo group. Hemodynamic effects would likely differ somewhat in a CN-poisoned goat. Intraosseous OHCo administration warrants additional investigation.

(C) 2009

^? This study was funded by Merck Sante, Lyon, France, manufacturer of Cyanokit (hydroxocobalamin), and by VidaCare Corporation, San Antonio, Tex, manufacturer of the EZ-IO intraosseous needle system.

^?? Dr Borron has received research funding, consulting fees, and speaker fees from Merck Sante (Lyon, France) and Dey, LP (which manufacture and

distribute hydroxocobalamin, respectively).

* Corresponding author. Department of Surgery - Division of Emergency Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA. Tel.: +1 210 567 5762; fax: +1 210 579 6599.

E-mail address: [email protected] (S.W. Borron).

0735-6757/$ - see front matter (C) 2009 doi:10.1016/j.ajem.2008.08.021

Introduction

Background

The wearing of Personal protective equipment in hazardous materials (hazmat) events limits efficient medical care of contaminated victims. If definitive medical care and antidote administration are delayed until decontamination is complete, some victims may die or have persistent injuries. Development of methods for earlier provision of emer- gency medical care for chemical weapons victims is a desirable goal.

Hydroxocobalamin (OHCo) is a rapid, safe, and effective cyanide antidote that must be administered via direct vascular access because of a relatively large administration volume. Intravenous (IV) administration of medications is essentially impossible in a zone of contamination and very difficult to perform while wearing PPE during decontamination. A viable alternative, intraoss- eous (IO) access has been used since World War II and is becoming a standard of care for emergency vascular access in both prehospital [1-5] and emergency department environments [6-8]. We demonstrated that intraosseous lines may be placed using the EZ-IO device (VidaCare Corporation, San Antonio, Tex) in an animal model by hazmat First responders and receivers wearing task- appropriate levels of PPE, (Borron et al, in preparation) confirming previous mannequin and ex vivo studies [9-13]. An earlier study has shown that the EZ-IO may be placed faster than intravenous lines by operators in PPE [12]. These data suggest that an opportunity exists to deliver antidotes in a timelier manner to hazmat victims. The concept of administering antidotes in the “hot zone” has previously been proposed [14] and appears logical given the current delays to treatment in chemical incidents.

Previous pharmacokinetic studies comparing IO and IV administration demonstrate their equivalence [15-19]. Drugs usually given IV may be given by the IO route [8]. Intraosseous antidote administration is not new, but reports are few [20]. To our knowledge, OHCo has been administered IO in humans only once (JL Fortin, personal communication). We studied IO placement by protected rescuers in a goat model, with subsequent administration of OHCo or saline to determine whether IO antidote administration might be feasible in hazmat incident response involving cyanides. The administration of OHCo or saline via the IO route and subsequent hemodynamic monitoring are the subjects of

this article.

Materials and methods

This study was approved by the UTHSCSA Institutional Animal Care Unit Committee (protocol no. 08027-71-01- B2). All experimentation was performed in compliance

with existing USDA regulations regarding the humane treatment of animals. A veterinarian assessed the health of the animals and supervised the administration of anesthesia and experimentation.

Selection of participants

Fire department paramedics from the San Antonio Fire Department EMS Medical Special Operations Unit and physicians, physician assistants, and nurses from our hospital served as volunteer operators for the study.

Study design

Spanish goats weighing between 15.5 and 35.1 kg (mean, 24.1 +- 6.4 kg) on the days of experimentation were obtained for the study from 5R Farms, Floresville, TX. The animals arrived in the animal care unit no less than 4 days before experimentation and underwent veterinary examination, including deworming and complete blood count. They were fed normal goat chow and water ad libitum until the evening before the procedure when they were fasted. Water was allowed up until experimentation. Anesthesia was induced with ketamine 10 mg/kg IM and xylazine 0.2 mg/kg IM, then maintained with isoflurane 1.5% to 2.0% in 100% oxygen via endotracheal tube. Mechanical ventilation was maintained throughout the experiment. A carotid arterial line was placed for monitoring of vital signs. Sixteen goats were used for the experiments and randomized to practice (n = 4), OHCo (n = 6), or normal saline (NS, n = 6) groups. Animals were sacrificed at the end of experimentation using sodium pentobarbital.

Participants donned various levels of PPE and placed IO lines in the goats (Borron et al, manuscript in preparation). The EZ-IO was used for all IO placements. Adult and pediatric human needles were variably used for the purpose at the discretion of the operator. Hydroxocobalamin (Cyanokit) was manufactured by Merck Sante (Lyon, France) and supplied by Dey, LP (Napa, Calif).

Interventions

Operators were randomized to a particular experimental animal and to order of PPE wear before arrival. Intraosseous needles were placed in 4 assigned anatomical locations in the goat (right or left forelimb, right or left hindlimb). Animals were randomized to receive an infusion of either OHCo 75 mg/kg (3 mL/kg) or NS (3 mL/kg) over approximately 7.5 minutes via the last IO placement site. Correct placement of this site was verified by fluoroscopy. The dose of OHCo used is approximately equivalent on a weight basis to the initial recommended human dose of 5 g. The rate of administration is approximately double that used in humans (5 g/15 minutes).

Group		Time	n	Mean (SD)		SEM	Median	Min, Max	Contrast (95% CI)	SE	P a
SBP	NS	Baseline	5	70.6	(18)	8.1	79	46, 90
		240	5	74.6	(16.9)	7.6	81	49, 92
		240 - baseline b	5	4	(2.9)	1.3	3	2, 9
		Baseline to 240 c	130	87.2	(15.3)	1.3	90	46, 120
	OHCo	Baseline	6	68	(7.1)	2.9	68	56, 76	- 2.6 (-20.6, 15.4)	7.94	0.75 d
		240	6	78.8	(20.6)	8.4	85	42, 95
		240 - baseline b	6	10.8	(23.4)	9.6	13.5	-24, 39
		Baseline to 240 c	156	85	(19.3)	1.5	85	39, 118	-1.2 (-15.2, 12.8)	6.18	0.85 e
SBP indicate systolic blood pressure; CI, confidence interval a Repeated-measures linear model in terms of subject (goat), drug group (NS, OHCo), and time. b Value at time 240 minutes minus value at baseline. c Value between baseline and time 240. d Group contrast at baseline. e Group contrast across all times.

Methods of measurement

Table 1 Systolic blood pressure comparison between NS and OHCo at baseline and end of study (time = 240)

Blood pressure was measured continuously via carotid arterial catheter and transducer using a Datascope Passport 2 (Montvale, NJ) monitor. An electrocardiogram tracing was likewise monitored continuously. Baseline measurements were obtained shortly after completion of the arterial line placement. Initial preinfusion measurements were obtained just before administration of the infusion of OHCo or NS. Measurements were recorded every 10 minutes for a total of 240 minutes after initiation of drug infusions.

Primary data analysis

Power calculations were performed to determine the study’s ability to detect clinically important hemodynamic changes. With 6 animals in each group, our study had 80% power to detect a difference (either an increase or decrease) of 25% in the treated group’s mean systolic blood pressure relative to the baseline control group mean, using baseline data reported in Table 1. The study had a power of 80% to

Table 2 DBP comparison between NS and OHCo at baseline and end of study (time = 240 minutes)

Baseline to 240 ^c

DBP indicates diastolic blood pressure.

^a Repeated-Measures linear model in terms of subject (goat), drug group (NS, OHCo), and time.

^b Value at time 240 minutes minus value at baseline.

^c Value between baseline and time 240 minutes.

^d Group contrast at baseline.

^e Group contrast across all times.

156

64.7 (19.3)

1.5

62

24, 109

0.2 (-12.6, 13)

5.64 0.97 ^e

detect an 11% mean difference in diastolic blood pressure and a 24% difference in mean heart rates between the treated and control groups based on data in Tables 2 and 3. Serial simple randomization was used for determination of order of PPE, operator to animal assignment, and animal to antidote assignment.

The significance of group differences with regard to mean changes in hemodynamics over time was assessed with a repeated-measures linear model in terms of group, time, and the group by time interaction. Time by group interaction was not significant in any model (P N .10), and this term was dropped from the model in every analysis. All statistical testing was 2-sided with a significance level of 5%, and all data analyses were performed using SAS Version 9.1 for Windows (SAS Institute, Cary, NC).

Results

Baseline blood pressures were obtained shortly after completion of anesthesia and arterial line placement (first

Group		Time	n	Mean (SD)	SEM	Median	Min, Max	Contrast (95% CI)	SE	P a
DBP	NS	Baseline	5	41.6 (7.7)	3.4	43	29, 49
		240	5	54 (9.8)	4.4	56	43, 66
		240 - baseline b	5	12.4 (8.7)	3.9	14	-1, 23
		Baseline to 240 c	130	63.8 (14.7)	1.3	66	29, 104
	OHCo	Baseline	6	38.2 (4.4)	1.8	39	33, 44	10.7 (-15.2, 36.5)	11.42	0.37 d
		240	6	54.8 (16.1)	6.6	51.5	35, 82
		240 - baseline b	6	16.7 (14)	5.7	14	2, 43

saline group (n = 5)”>Group		Time	n	Mean (SD)	SEM	Median	Min, Max	Contrast (95% CI)	SE	P a
HR	NS	Baseline	5	80.8 (16.4)	7.3	91	56, 94
		240	5	85 (11.7)	5.2	82	70, 100
		240 - baseline b	5	4.2 (12.8)	5.7	-1	-9, 24
		Baseline to 240 c	130	84 (12.4)	1.1	81.5	56, 120
	OHCo	Baseline	6	83.7 (9.2)	3.7	84.5	72, 95	2.9 (-14.8, 20.5)	7.8	0.72 d
		240	6	94.2 (11.9)	4.9	96	79, 112
		240 - baseline b	6	10.5 (8.9)	3.6	11	-2, 21
		Baseline to 240 c	156	85.6 (12.8)	1	85	60, 112	3.7 (-9, 16.4)	5.6	0.53 e
HR indicates heart rate. a Repeated-measures linear model in terms of subject (goat), drug group (NS, OHCo), and time. b Value at time 240 minutes minus value at baseline. c Value between baseline and time 240 minutes. d Group contrast at baseline. e Group contrast across all times.

point in Figs. 1-3). The second point represents vital signs taken just before administration of OHCo or NS (preinfusion). Measurements for 1 animal in the NS group were interrupted because of technical problems, so that animal is excluded from the values seen here. As shown by Figs. 1 and 2, blood pressure changes were mild to moderate in general for both groups. Heart rate changes (Fig. 3) were minimal in both groups. Mean values and other descriptive statistics are presented in Tables 1-3.

Table 3 Heart rate comparison between NS and OHCo at baseline and end of study (time = 240 minutes)

Hydroxocobalamin group (n = 6)

In the OHCo group, mean systolic and diastolic pressures peaked at 120 minutes, with mean increases of 14% and 17%, respectively, relative to infusion start. Values returned to near preinfusion values at about 240 minutes, similar to

Fig. 1 Systolic blood pressures after administration of OHCo or NS via the IO route.

the time to return to preinfusion pressure values noted in healthy volunteers [21]. Changes in heart rates were virtually nil over the 240-minute period.

Normal saline group (n = 5)

In the NS group, the mean of systolic pressures peaked at 60 minutes, with a mean change of 36%, whereas the mean of the diastolic pressures peaked at about 110 minutes, with a change of 42%. Values returned to near preinfusion values at 240 minutes. Heart rate changes were minimal.

Group comparison

As seen in Tables 1-3, the mean values of both systolic and diastolic blood pressures and heart rates over

Fig. 2 Diastolic blood pressures after administration of OHCo or NS via the IO route.

Fig. 3 Heart rates after administration of OHCo or NS via the IO route.

time were not statistically significantly different between the 2 groups.

Discussion

This study demonstrates that OHCo can be safely administered via the intraosseous route in a goat model. The hemodynamic changes encountered were expected and were mild. Increases in blood pressure routinely occur after administration of OHCo in both poisoned [22] and nonpoisoned animals [23] and in healthy volunteers [21,24] and Fire victims [25,26]. The basis for the increase in blood pressures in nonPoisoned patients appears to be the capture of nitric oxide by OHCo as nitrosocobalamin [27,28]. In poisoned animals and humans, the mechanisms likely involve both capture of cyanide (which may lower blood pressures) and nitric oxide. Thus, OHCo pharma- cokinetics and pharmacodynamics are likely to differ somewhat in a CN-poisoned goat, where binding of cyanide and nitric oxide, rather than nitric oxide alone, would be expected.

Hydroxocobalamin has been shown safe and effective for Cyanide poisoning [21,25,29] offering significant advantages over other available antidotes. It has been safely administered in smoke inhalation-related cyanide poisoning [25,26,30] and in pure cyanide poisoning [29]. Unlike amyl and sodium nitrite, parts of the so-called Taylor kit, OHCo does not induce methemoglobinemia or interfere with oxygen utilization or transport. Although the formation of methemoglobin may be beneficial in cyanide poisoning because of cyanide’s partial conversion to biologically inert cyanmethemoglobin [31], it should be recalled that neither methemoglobin nor cyanmethemoglo- bin carry oxygen. In the setting of hazmat events, the

initial identification of the Toxic compound(s) at cause is often tentative at best [32]. A recent example is that of a mass arsenic poisoning in Japan. Local investigators initially believed that cyanide was at cause (Dr Alan Hall, personal communication). Although methemoglobi- nemia may be tolerated to a certain extent in cyanide poisoning (the actual amount of methemoglobin formed is almost never known), it may not be well tolerated in other forms of poisoning, particularly those in which other causes of hypoxemia or hypoxia are in play (carbon monoxide, respiratory irritant gases, or other asphyxiant poisonings). This doubt appears to offer a significant safety advantage of OHCo over other currently available cyanide antidotes [33,34]. One perceived disadvantage of OHCo in the hazmat setting has been the requirement for direct vascular access. Intraosseous infusion of OHCo could theoretically be rapidly initiated, alleviating this inconve- nience. Additional data regarding the pharmacokinetics, systemic adverse effects, consequences of extravasation, and specific effects on bone marrow histology after IO administration are needed. In addition, studies need to be done to see if it may be safely administered as a bolus in extreme cases, such as the setting of multiple chemical casualties. Our research program anticipates further evalua- tion of the feasibility of use of IO placement for the purpose of OHCo administration.

The relatively larger increases in blood pressures in the NS group warrant reflexion, as these were unanticipated. There are several possible explanations. First, our sample size was small, thus the differences may be simply random. Our choice of anesthetic may also have played a role in the measured differences. Hydroxocobalamin’s effect on blood pressure in nonpoisoned animals appears to be mediated by nitric oxide [27]. Alva and colleagues [35] have recently demonstrated that ketamine leads to increased plasmatic NO levels. Thus, the effect of OHCo on blood pressure may have been somewhat “buffered” by ketamine-induced NO pro- duction. Parenthetically, Fernandez and colleagues [36] have demonstrated that NO is important in the regulation of vascular tone in the goat and that its inhibition by L-NAME causes increases in mean arterial pressure. That said, little is known of OHCo pharmacodynamics in the goat. Other pharmacokinetic (exposure) and pharmacodynamic factors may have played some role in limiting the blood pressure rise after OHCo.

Limitations

Our study suffers from several limitations. Because of an equipment failure, one NS animal had to be excluded from evaluation. An intent-to-treat analysis, replacing immeasur- able values by the last available measurement (“last- observation-carried-forward” method) did not alter the conclusions. Although the goat appears an acceptable model for IO needle placement, differences in physiology make extrapolation to humans problematic. Because of the

desire to limit the number of animals used, we did not study an IV control group.

Conclusion

Hemodynamic effects of OHCo given by the IO route in non-CN-poisoned goats are mild and well tolerated. Increases in mean blood pressure at peak after baseline were greater in the NS group, but the mean values over time were not significantly different from those seen in the OHCo group. Hemodynamic effects would likely differ somewhat in a CN-poisoned goat. Intraosseous OHCo administration warrants additional investigation. Intraoss- eous administration of OHCo may find a role in the settings of individual patients with cyanide-induced Cardiovascular collapse or mass cyanide casualties.

Acknowledgments

The authors would like to thank Merck Sante, Lyon, France, and VidaCare, San Antonio, Tex, for their financial support of this project. Particular thanks go to Dr Larry Miller of VidaCare for logistical and equipment assistance. The study would not have been possible without the generous support of the San Antonio Fire Department EMS Medical Special Operations Unit, its Medical Director, Dr Donald J. Gordon, and, in particular, Terry Eaton, EMT-P, who recruited the medics and assisted with PPE. We would like to thank paramedics Brian D. Worley, Robert W. Dugie, Emmett Guzman, and Michael Pierce and 2 other medics who preferred to remain unnamed, who acted as first responders, and Dr Claudio Zeballos, Dr Ricardo Hernandez, Jr, Dr George Layton, Patti Hass, RN, MSN, Diana Montez, RN, BSN, and PA-Cs Wayne Lawson and Terry Henrie, who (in addition to the authors) acted as first receivers in the study.

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