Manish S. Lavhale

Endothelin modulates the cardiovascular effects of clonidine in the rat.

Clonidine decreases mean arterial pressure (MAP) by acting as an α(2)-adrenergic receptor (AR) agonist in the central nervous system; it also acts on peripheral α-ARs to produce vasoconstriction. Endothelin (ET) has been shown to modulate the action of ARs. The present study was conducted to determine the involvement of ET in cardiovascular effects of clonidine. Intravenous administration of clonidine (10, 30 and 90μgkg(-1)) produced a dose-dependent decrease in MAP and heart rate (HR). Treatment with ET-1 (100, 300 and 900ngkg(-1)) significantly attenuated clonidine (10μgkg(-1)) induced fall in MAP and HR. Rats treated with ET-1 (900ngkg(-1)) showed an increase in MAP and HR after clonidine administration compared to untreated rats, while ET(A/B) antagonist, TAK-044 (1mgkg(-1)) and ET(A) antagonist, BMS-182874 (9mgkg(-1)) potentiated the hypotensive effect of clonidine. ET(B) receptor agonist, IRL-1620 (5μgkg(-1)) produced significant attenuation of clonidine induced fall in MAP and HR, while ET(B) receptor antagonist, BQ-788 (0.3mgkg(-1)), potentiated the hypotensive effect of clonidine. Prazosin (0.1mgkg(-1)) completely blocked ET-1 induced changes in cardiovascular effects of clonidine. Clonidine-induced contraction of rat abdominal aortic ring was potentiated by ET-1, which was completely blocked by prazosin. Clonidine produced an increase in ET(A) receptor expression in the brain and abdominal aorta while ET(B) receptors were not affected. It is concluded that ET enhances the responsiveness of vascular ARs to the constrictor effect of clonidine and ET antagonists potentiate the hypotensive effect of clonidine suggesting that a combination of ET antagonist with clonidine may be a useful option to treat hypertension.

Resuscitative effect of centhaquin after hemorrhagic shock in rats

BACKGROUND Centhaquin is a cardiovascular active agent that significantly reduced blood lactate levels and enhanced resuscitative effect of hypertonic saline. The present study was carried out to determine the resuscitative effect of centhaquin and compare that with large-volume lactated Ringer (LR) solution in hemorrhaged rats. MATERIALS AND METHODS Male, adult Sprague-Dawley rats were anesthetized with urethane, and a pressure catheter SPR-320 was placed in the left femoral artery; another pressure-volume catheter SPR-869 was placed into the left ventricle through carotid artery. Hemorrhage was induced by withdrawing blood from the right femoral artery, and the mean arterial pressure (MAP) was maintained at 35 mm Hg for 30 minutes after which resuscitation was performed using LR solution (LR-100) (100% shed blood volume), centhaquin (0.017, 0.05, and 0.15 mg/kg) dissolved in LR (100% shed blood volume), or LR-300 (300% shed blood volume). Arterial blood gases and cardiovascular parameters were determined before the induction of hemorrhage and at various times after hemorrhage. RESULTS It was found that survival time after resuscitation with LR-100 was 78 ± 10 min. Centhaquin in doses of 0.017 and 0.05 mg/kg significantly improved survival time to 291 ± 57 and 387 ± 39 min, respectively. Blood lactate levels (millimoles per liter) increased from 7.22 ± 0.67 at hemorrhage to 10.20 ± 0.61 at 60 min after resuscitation with LR-100. On the other hand, blood lactate levels significantly decreased to 3.55 ± 0.07 and 4.08 ± 0.28 at 60 min after resuscitation with 0.017 and 0.05 mg/kg doses of centhaquin, respectively. Centhaquin in these doses produced a 55% and 59% increase in MAP, respectively, compared with a 29% decrease by LR-100. A decrease in systemic vascular resistance of 57% and 41% was observed with 0.017 and 0.05 mg/kg doses of centhaquin, respectively, compared with a 6% decrease by LR-100. LR-100 decreased cardiac output (CO) by 28%, whereas 0.017 and 0.05 mg/kg doses of centhaquin increased it by 260% and 180%, respectively. LR-300 commonly used for resuscitation was found to increase MAP and CO. Compared with LR-300, centhaquin (0.05 mg/kg) significantly improved survival time, increased CO, and was effective in resuscitation of hemorrhaged rats. CONCLUSIONS Centhaquin was found to be more effective than LR-300 as an effective resuscitative agent for the treatment of hemorrhagic shock in rat.

Centhaquin improves resuscitative effect of hypertonic saline in hemorrhaged rats

BACKGROUND We observed that centhaquin, a cardiovascular active agent, reduces blood lactate levels. Because blood lactate is an important indicator of end-organ perfusion, we determined the resuscitative effect of centhaquin in hemorrhaged rats. MATERIALS AND METHODS Male, adult Sprague-Dawley rats (Harlan, Indianapolis, IN) were anesthetized with urethane, and a pressure catheter SPR-320 was placed in the left femoral artery, and a pressure-volume catheter SPR-869 was placed into the left ventricle through carotid artery. Hemorrhage was induced by withdrawing blood from the right femoral artery, and mean arterial pressure was maintained between 35 and 40 mm Hg for 30 min after which resuscitation was performed using normal saline (control), 3% hypertonic saline, or centhaquin dissolved in 3% hypertonic saline. Arterial blood pH, pO(2), pCO(2), lactate, hematocrit, and cardiovascular parameters were measured before the induction of hemorrhage (baseline), 30 min after induction of hemorrhagic shock, and every 60 min thereafter until the animal expired. RESULTS Hypertonic saline was effective in reducing blood lactate levels and improving cardiac output (CO) of hemorrhaged rats. Centhaquin dissolved in hypertonic saline produced a significantly greater decrease in blood lactate and increase in mean arterial pressure and CO compared with hypertonic saline in hemorrhaged rats. Fraction survival at 250 min was 0 when resuscitated with hypertonic saline, whereas it was 0.8 with centhaquin. CONCLUSIONS Centhaquin significantly improved the resuscitative effect of hypertonic saline by increasing CO, reducing blood lactate, and improving survival time of hemorrhaged rats.

Pharmacokinetics of centhaquin citrate in a dog model

Centhaquin citrate is a novel agent that is being developed for use in the resuscitation of patients with haemorrhagic shock. While pharmacokinetics have been described in small animal models, the pharmacokinetic parameters of centhaquin citrate in large mammals have yet to be described.

Efficacy of centhaquin as a small volume resuscitative agent in severely hemorrhaged rats

Centhaquin has been reported to be an effective resuscitative agent. The present study was carried out to determine resuscitative effect of centhaquin when administered using a small volume of 3% hypertonic saline (HS) to hemorrhaged rats. Sprague-Dawley rats were anesthetized with urethane, and a pressure catheter SPR-320 was placed in the left femoral artery; another pressure-volume catheter SPR-869 was placed into the left ventricle. Hemorrhage was induced by withdrawing blood and mean arterial pressure (MAP) was maintained at 35 mm Hg for 30 minutes after which resuscitation was performed. Animals were divided in 2 groups: group A received HS and group B received centhaquin (0.05 mg/kg) dissolved in HS. The time by which MAP fell back to 35 mm Hg was observed at that time all animals were administered fresh blood. It was found that centhaquin significantly reduced blood lactate and improved cardiac output and MAP of hemorrhaged rats compared with HS. The time by which MAP fell back to 35 mm Hg in rats treated with HS was 55 ± 6 minutes, whereas it was 161 ± 14 minutes in centhaquin treated rats. Survival time following administration of fresh blood was 79 ± 7 minutes in vehicle-treated group, whereas it was 105 ± 9 minutes in centhaquin-treated rats. The total time of survival of rats treated with HS or centhaquin was 134 ± 12 minutes and 266 ± 16 minutes, respectively. Centhaquin, in small volume, maintained MAP of hemorrhaged rats for a considerable long time and improved the survival time.

345: EFFECT OF CENTHAQUIN ON ENDOTHELIN RECEPTORS FOLLOWING RESUSCITATION OF HEMORRHAGED RAT

Crit Care Med 2016 • Volume 44 • Number 12 (Suppl.) that multiple CPR events during a single hospitalization are associated with significantly higher risk of in-hospital mortality. Methods: We performed a retrospective analysis of the Nationwide Inpatient Sample, the largest all-payer inpatient care database in the USA, for the years 2012 and 2013. All patients aged<18 years who had a CPR performed following hospitalization were included. The outcome was in-hospital mortality (IHM) and primary independent variable is number of CPRs performed during the same hospitalization. Multivariable logistic regression analysis was used to examine the impact of number of CPRs on IHM. Patient and hospital level characteristics were adjusted in regression model. Results: During the study period, a total of 11,270 children had a CPR. Of these, 10,955 had one CPR and 315 had more than one CPR. Mean age was 1.5 years. 55% were males. Medicaid(55%) was the predominant payer. 45.9% where Whites, rest included Blacks(22.5%), Hispanics(18.3%), Asian/Pacific Islanders (4.8%), Native Americans(0.8%), and other races(7.7%). 4,520 children(40.1%) died in hospitals. IHM rate was 39.7% in those who had one CPR (compared to 55.5% in those who had more than one CPR). Following adjustment of patient and hospital level factors, those who had more than one CPR were associated with significantly higher odds for IHM (OR=1.92, 95% CI=1.11-3.32, p=0.02). Conclusions: Following a CPR event, nearly 1 in 35 children are at risk of subsequent cardiac arrest requiring CPR. Recipients of multiple in-hospital CPR attempts are at an incrementally higher risk of in-hospital mortality. This information could be helpful in optimizing care to prevent such repeat events or in discussing end of life care issues with parents.