Intramuscular versus Intraosseous Delivery of Nerve Agent Antidote Pralidoxime Chloride in Swine.

OBJECTIVE: Exposure to nerve agents requires prompt treatment. We hypothesized that intraosseous (IO) injections of drug antidotes into the vascularized bone marrow will provide a more rapid and effective means to treat exposure to nerve agents than standard intramuscular (IM) injections. We compared the pharmacokinetics of IM and IO administration of pralidoxime chloride (2-PAM Cl) during normovolemia and hypovolemia, as well as their combined administration during normovolemia in swine. METHODS: Ten normovolemic swine were randomly administered 2 mL, 660 mg 2-PAM Cl via the IM or IO route and monitored for 180 minutes. IM versus IO also was compared in 8 hypovolemic swine bled to a mean arterial pressure of 50 mmHg. In a combined group, an IO injection was administered followed by an IM injection 60 minutes later. Blood samples were collected at times over a 180-minute period to calculate standard pharmacokinetic variables to compare the 2 routes of administration. RESULTS: In the normovolemic swine, IM injection achieved therapeutic levels (4 µg/mL) in 2 minutes, whereas IO infusion achieved these levels in less than 15 seconds. 2-PAM-Cl concentrations fell below these levels at 60 minutes post-injection in both groups. In the hypovolemic swine, IM injection achieved therapeutic levels in 4 minutes compared to less than 15 seconds in the IO group. 2-PAM-Cl concentrations fell below therapeutic levels at 12 and 90 minutes post-injection in the IM and IO groups, respectively. In the combined IO-IM treatment, plasma levels remained above therapeutic levels for the entire experiment and had two concentration peaks that corresponded to IO and IM injections. CONCLUSIONS: The IO route for the delivery of 2-PAM Cl provides a significant time and high initial blood concentrations advantage compared to the IM route for the prehospital treatment of nerve agent exposure even under hypovolemic conditions. The initial concentration peak associated with IO, but not IM, may provide greater initial therapy at the most critical time.

Issues of concern regarding the use of hypertonic/hyperoncotic fluid resuscitation of hemorrhagic hypotension.

Small volume resuscitation fluids continue to be of interest to the military and limited volume resuscitation is becoming more common in the treatment of hemorrhage in the civilian community. With renewed interest to undertake a large US-Canada multi-center clinical trial of hypertonic saline alone or combined with dextran (HSD) possibly in 2006, concerns related to the safe use of this product continue to surface. This review addresses the use of these products in uncontrolled hemorrhage models, in dehydration and addresses perceived risks associated with hypernatremia, dextran-associated anaphylactoid reactions and effects on coagulation and renal function.

Benefit of slow infusion of hypertonic saline/dextran in swine with uncontrolled aortotomy hemorrhage.

In laboratory models of uncontrolled hemorrhage, immediate resuscitation from hemorrhage is associated with high mortality. However, in clinical practice, resuscitation is often delayed and the rate of fluid administration is limited. We hypothesized that a slow rate of infusion after delayed resuscitation, reflecting the clinical environment, might improve survival in the presence of uncontrolled hemorrhage. To investigate the rate of administration in the presence of delayed resuscitation, we subjected anesthetized swine weighing 35 to 45 kg to wire suture abdominal aortotomy that resulted in an uncontrolled hemorrhage. After a 30-min delay, hemorrhaged swine were infused i.v. with 4 mL/kg hypertonic saline/Dextran solution (7.5% saline in 6% Dextran 70) administered as a bolus over 1 min or as a slow infusion over 12 min (the time period to administer a similar volume to a human with a gravity feed i.v. and an 18-gauge needle) and were then monitored for another 90 min. Survival increased to 78% (seven of nine) in the slow infusion group compared with a survival rate of 56% (five of nine) in the bolus group and 50% (7/14) in the untreated controls. Blood loss was significantly higher in the bolus group (926 +/- 77 mL) compared with the slow infusion (714 +/- 83 mL) and control groups (604 +/- 46 mL). Hypertonic saline/Dextran administered slowly significantly increased cardiac output and blood pressure. Taken together, these results are consistent with the hypothesis that resuscitation solutions can be effective for treatment of uncontrolled hemorrhage when administered at a slow infusion rate 30 min after the insult.