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.

The role of organic osmolytes in the response of cultured astrocytes to hyperosmolarity.

Idiogenic osmoles are volume-regulatory organic solutes that accumulate within a cell in response to hyperosmolar conditions such as those found in diabetic ketoacidosis or hypernatremic dehydration in infants. Intracellular metabolites known to play this role include certain amino acids and taurine, polyols, and trimethylamines. In this study, in vitro astrocyte cultures prepared from the cerebral cortices of 1-day-old Sprague-Dawley rats were exposed to graded conditions of hypernatremia (325-375 mOsm/kg), a range that can be observed in vivo, for 24, 48, and 72 hours. Cell survival and generation of idiogenic osmoles were determined. Next, we assessed the ability of selected exogenous osmoles to protect the cultured cells from the effects of hypernatremia. Significant cell loss occurred after 48 to 72 hours of exposure and was proportional to the degree of hyperosmolarity. Addition of myoinositol (1 mM) to the cultures reduced cell loss resulting from hypernatremia by approximately 50%. In agreement with previous studies, intracellular levels of myoinositol and taurine correlated with the degree of in vitro hypernatremic exposure and play a significant role in increasing survival of astrocytes subjected to hypertonic insult.

Neuroprotective Effect of IRL-1620, an Endothelin B Receptor Agonist, on a Pediatric Rat Model of Middle Cerebral Artery Occlusion.

Objective: The purpose of this study was to determine the potential neuroprotective effect of endothelin B (ETB) receptor agonist IRL-1620 treatment in a pediatric model of ischemic stroke. Design: A prospective, animal model study. Setting: An experimental laboratory. Subjects: Three-month-old male Wistar Han rats. Interventions: The rats underwent permanent middle cerebral artery occlusion (MCAO). At 2, 4, and 6 h post MCAO, they were treated with saline, IRL-1620 (5 µg/kg, IV), and/or ETB antagonist BQ788 (1 mg/kg, IV). Measurements and Main Results: The rats were evaluated over the course of 7 days for neurological and motor deficit, cerebral blood flow (CBF), and infarct volume. Young rats treated with IRL-1620 following MCAO improved significantly in neurological and motor assessments as compared to the vehicle-treated group, as measured by neurological score (P = 0.00188), grip test (P < 0.0001), and foot-fault error (P = 0.0075). CBF in the infarcted hemisphere decreased by 45-50% in all groups immediately following MCAO. After 7 days, CBF in the infarcted hemisphere of the IRL-1620 group increased significantly (P = 0.0007) when compared to the vehicle-treated group (+2.3 ± 23.3 vs. -45.4 ± 10.2%). Additionally, infarct volume was significantly reduced in IRL-1620-treated rats as compared to vehicle-treated rats (P = 0.0035, 41.4 ± 35.4 vs. 115.4 ± 40.9 mm3). Treatment with BQ788 blocked the effects of IRL-1620. Conclusions: IRL-1620 significantly reduced neurological and motor deficit as well as infarct volume while increasing CBF in a pediatric rat model of cerebral ischemia. These results indicate that selective ETB receptor stimulation may provide a novel therapeutic strategy in the treatment of pediatric ischemic stroke as has been demonstrated in adult ischemic stroke.

Energy expenditure in children with severe head injury: lack of agreement between measured and estimated energy expenditure.

BACKGROUND: The purpose of this study was to test the hypotheses that estimates of resting energy expenditure (REE) vary significantly from measured energy expenditure in a population of head-injured children and are not accurate for use in determining nutrition needs in this population. METHODS: This is a retrospective study of 30 children with severe head injury, with Glasgow Coma Scale (GCS) score of <8 and needing mechanical ventilation. Measured REE was obtained using indirect calorimetry. Estimated REEs were calculated using Harris-Benedict, World Health Organization (WHO), Schofield, and White formulas. Severity of illness was calculated using Pediatric Risk of Mortality (PRISM) score. Agreement between measured REE and estimated REE was tested using the Bland-Altman method. Correlation coefficient between PRISM score and measured REE was calculated using Spearman test. RESULTS: More than half of the estimates of REE differed from measured REE by >10%. Significant disagreement between estimated REE and measured REE was demonstrated using the Bland-Altman method. There was no correlation between severity of illness and measured REE to explain the inaccuracies of REE estimates. CONCLUSION: Energy expenditure in critically ill children cannot be estimated accurately; hence, nutrition for critically ill children with head injury should be provided according to measurement of REE to avoid the consequences of overfeeding or malnutrition.