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.

Pharmacokinetics of intraosseous and central venous drug delivery during cardiopulmonary resuscitation.

UNLABELLED: We compared the pharmacokinetics of intraosseous (IO) drug delivery via tibia or sternum, with central venous (CV) drug delivery during cardiopulmonary resuscitation (CPR). METHODS: CPR of anesthetized KCl arrest swine was initiated 8 min post arrest. Evans blue and indocyanine green, each were simultaneously injected as a bolus with adrenaline through IO sternal and tibial needles, respectively, n=7. In second group (n=6) simultaneous IO sternal and IV central venous (CV) injections were made. RESULTS: Peak arterial blood concentrations were achieved faster for sternal IO vs. tibial IO administration (53±11 s vs. 107±27 s, p=0.03). Tibial IO dose delivered was 65% of sternal administration (p=0.003). Time to peak blood concentration was similar for sternal IO and CV administration (97±17 s vs. 70±12 s, respectively; p=0.17) with total dose delivered of sternal being 86% of the dose delivered via CV (p=0.22). CONCLUSIONS: IO drug administrations via either the sternum or tibia were effective during CPR in anesthetized swine. However, IO drug administration via the sternum was significantly faster and delivered a larger dose.

Viral interaction: a possible contributing factor in head and neck cancer progression.

CONCLUSION: Human herpesvirus-8 could potentiate the effects of human papillomavirus (HPV)-16 on cell cycle dysregulation by up-regulating the transcription of HPV-16 E7, which can lead to malignant transformation of normal epithelial cells. OBJECTIVES: High-risk HPV-16 is known for its association with development of head and neck carcinoma, leading to considerable morbidity and mortality worldwide. HPV-16 produces two early proteins, E6 and E7, that can disrupt the cell cycle and transform cells. Other viruses may potentiate dysregulation of the cell cycle by HPV-16. Herpes viruses are known to produce replication transcription activators, which may contribute to the malignant transformation of normal cells. This study aimed to determine if the ORF50/Rta protein of HHV-8 binds to genomic regions within HPV-16 and alters the transcription and/or translation of E6 and E7 in HPV-infected cells. MATERIALS AND METHODS: Protein shift assays determined the binding potential of ORF50 to various HPV-16 genomic regions. A real-time polymerase chain reaction (PCR) assay quantified the effect of ORF50 on the transcription of E6 and E7 within these cells. Finally, immunofluorescent confocal microscopy was used to quantify E6 and E7 protein levels within transfected cells and study their localization patterns. RESULTS: The results reveal potential ORF50/Rta binding sites within HPV-16 and a significant up-regulation of E7 transcription in ORF50 transfected cells.

Hypertonic 15% sodium pyruvate offers no initial resuscitation advantage compared with 8% hypertonic NACl in sheep with multiple hemorrhages.

Initial fluid resuscitation of hemorrhagic shock might be enhanced by the infusion of monocarboxylate-energy substrates. We evaluated hemodynamics, metabolism, and fluid dynamics for initial resuscitation of hemorrhage using small volume 15% sodium pyruvate solution (HPY) compared with osmotically matched 8% hypertonic saline (HS). Instrumented conscious sheep were hemorrhaged 25 mL/kg at time zero through 15 min (T0-T15) and 5 mL/kg for 5 min at T50 to T55 and T70 to T75. Fluid resuscitation from T30 to T180 was performed by a computer-controlled closed-loop system, which titrated infusion rate to a mean arterial pressure of 90 mmHg. Initial infusion was 4 mL/kg of either HPY or HS, followed by the administration of lactated Ringer. Both HPY and HS restored cardiac index similarly. The lactate/pyruvate ratio was used to assess metabolic debt and was significantly higher (T180), whereas oxygen delivery was significantly lower (T120) with HPY versus HS. Total fluid administered was similar, with 43.7 +/- 6.2 mL/kg for HPY and 39.4 +/- 6.8 mL/kg for HS. Plasma volume was similarly increased and approached baseline values for both groups. Initial resuscitation with small volume HPY offered no hemodynamic or metabolic advantage compared with small volume HS when the fluids were infused to an end point pressure.

Closed-loop resuscitation of burn shock.

Fluid therapy for burn shock is adjusted to establish a target level of urinary output. However, the means for adjusting infusion rate are not defined. Our objective was to compare the performance of automated computer-controlled resuscitation with manual control for burn resuscitation. Sheep with a 40% TBSA full-thickness burn, administered under halothane anesthesia, were resuscitated to restore and maintain normal sheep urinary outputs in a target range of 1 to 2 ml/kg per hour over the course of 48 hours using closed-loop resuscitation (n = 10) or manual hourly adjustment of infusion rate (n = 11). The automated closed-loop resuscitation system is based on a proportional-integral-derivative algorithm, which adjusted infusion rate based on continuous monitoring and changes in urinary output. Mean urinary outputs over the course of 48 hours were in target range and were virtually identical at 1.9 +/- 0.5 ml/kg per hour for the closed-loop group and 2.0 +/- 0.7 ml/kg per hour for the technician group. Mean infusion rates and infused volumes also were similar. The closed-loop group exhibited significantly lower hourly variation for both urinary output and infusion rate compared hourly control. Hourly targets were achieved in 41% of the measurements in technician group compared with 48% for the closed-loop group (P = .23). Hourly urinary output in the technician group was undertarget by 25% as opposed to 16% with the closed-loop group (P = .02). Automated closed-loop control of infusion rates after burn injury produced urinary outputs in target ranges with less variation and less under target values than manual hourly adjustments. Closed-loop resuscitation may provide an improvement over current resuscitation regimens.