Effects of nalmefene, CG3703, tirilazad, or dopamine on cerebral blood flow, oxygen delivery, and electroencephalographic activity after traumatic brain injury and hemorrhage.

Hemorrhage after traumatic brain injury (TBI) in cats produces significant decreases in cerebral oxygen delivery (DcereO2) and electroencephalographic (EEG) activity. To determine whether effective treatments for the separate insults of TBI and hemorrhagic shock would also prove effective after the clinically relevant combination of the two, we measured the effects of a kappa-opiate antagonist (nalmefene), an inhibitor of lipid peroxidation (tirilazad), a thyrotropin-releasing hormone analog (CG3703), a clinically useful pressor agent (dopamine) or a saline placebo on cerebral blood flow (CBF), and EEG activity after TBI and mild hemorrhagic hypotension. Cats (n = 40, 8 per group) were anesthetized with 1.6% isoflurane in N2O:O2 (70:30) and prepared for fluid-percussion TBI and microsphere measurements of CBF. Cats were randomized to receive nalmefene (1 mg/kg), tirilazad (5 mg/kg), CG3703 (2 mg/kg), dopamine (20 microg x kg(-1) x min[-1]) or a saline placebo (2 ml, 0.9% NaCl). Animals were injured (2.2 atm), hemorrhaged to 70% of preinjury blood volume, treated as just described and resuscitated with a volume of 10% hydroxyethyl starch equal to shed blood. CBF was determined and EEG activity recorded before injury, after hemorrhage, and 0, 60, and 120 min after resuscitation (R0, R60, and R120). CBF increased significantly after resuscitation (R0) in the nalmefene- and CG3703-treated groups. CBF did not differ significantly from baseline in any group at R60 or R120. DcereO2 was significantly less than baseline in the saline-, dopamine-, and tirilazad-treated groups at R60 and in the dopamine-, tirilazad-, and CG3703-treated groups at R120. EEG activity remained unchanged in the nalmefene-treated group but deteriorated significantly at R60 or R120 compared to baseline in the other groups. Nalmefene and CG3703 preserved the hyperemic response to hemodilution (otherwise antagonized by TBI), and nalmefene prevented the deterioration in DcereO2 and EEG activity that occurs after TBI and hemorrhage.

Hypertonic saline does not improve cerebral oxygen delivery after head injury and mild hemorrhage in cats.

OBJECTIVES: To investigate the effects of hypertonic saline for resuscitation after mild hemorrhagic hypotension combined with fluid-percussion traumatic brain injury. Specifically, the effects of hypertonic saline on intracranial pressure, cerebral blood flow (radioactive microsphere method), cerebral oxygen delivery (cerebral oxygen delivery = cerebral blood flow x arterial oxygen content), and electroencephalographic activity were studied. DESIGN: Randomized, controlled, intervention trial. SETTING: University laboratory. SUBJECTS: Thirty-four mongrel cats of either sex, anesthetized with 1.0% to 1.5% isoflurane in nitrous oxide/oxygen (70:30). INTERVENTIONS: Anesthetized (isoflurane) cats were prepared for traumatic brain injury, and then randomly assigned to the following groups: moderate traumatic brain injury only (2.7 +/- 0.2 atmospheres [atm], group 1); mild hemorrhage (18 mL/kg) only, followed immediately by resuscitation with 10% hydroxyethyl starch in 0.9% saline in a volume equal to shed blood (group 2); or both traumatic brain injury (2.7 +/- 0.1 atm) and mild hemorrhage, followed immediately by replacement of a volume equal to shed blood of 10% hydroxyethyl starch in 0.9% saline (group 3); or 3.0% saline (group 4). MEASUREMENTS AND MAIN RESULTS: Data were collected at baseline, at the end of hemorrhage, and at 0, 60, and 120 mins after resuscitation (or at comparable time points in group 1). Intracranial pressure in group 1 was significantly increased by traumatic brain injury at the end of hemorrhage, immediately after resuscitation, and 60 mins after resuscitation (p < .02 vs. baseline). In group 2, intracranial pressure increased significantly only immediately after resuscitation (p < .0001 vs. baseline). Groups 3 and 4 exhibited higher, although statistically insignificant, intracranial pressure increases at 60 and 120 mins after resuscitation. During resuscitation, cerebral blood flow increased significantly (p < .02 vs. baseline) in the uninjured cats. In contrast, cerebral blood flow failed to increase during resuscitation in the cats subjected to traumatic brain injury before hemorrhage and resuscitation. Although cerebral oxygen delivery in group 2 decreased significantly immediately, 60 mins, and 120 mins after resuscitation (p < .001 vs. baseline) both groups 3 and 4 had significantly lower cerebral oxygen delivery at 60 and 120 mins after resuscitation (p < .01 and p < .005, respectively, vs. group 1 at 60 mins after resuscitation, and p < .01 and p < .01, respectively, vs. group 1 at 120 mins after resuscitation). CONCLUSIONS: After a combination of hemorrhage and traumatic brain injury, neither 10% hydroxyethyl starch nor 3.0% hypertonic saline restored cerebral oxygen delivery. Although neither trauma alone nor hemorrhage alone altered electroencephalographic activity, the combination produced significant decreases in electroencephalographic activity at 60 and 120 mins after resuscitation in groups 3 and 4, suggesting that cerebral oxygen delivery is inadequately restored by either resuscitation fluid. Therefore, traumatic brain injury abolished compensatory cerebral blood flow increases to hemodilution, and neither hydroxyethyl starch nor 3.0% hypertonic saline restored cerebral blood flow, cerebral oxygen delivery, or electroencephalographic activity after hemorrhagic hypotension after traumatic brain injury.

Regional cerebrovascular responses to progressive hypotension after traumatic brain injury in cats.

We investigated the effects of hypotension on cerebral blood flow (CBF) after traumatic brain injury (TBI) in cats. Isoflurane-anesthetized cats were prepared for TBI and for microsphere measurements of total (T) and regional (r) CBF. Four groups were studied: sham injury (group I, n = 6); TBI (group II, n = 6); isoflurane anesthesia, no TBI or hypotension (group III, n = 4); and isoflurane and TBI, no hypotension (group IV, n = 8). After TBI or sham trauma, mean arterial pressure (MAP) was reduced to 80, 60, and 40 mmHg by hemorrhage. Group I TCBF did not change significantly from baseline until MAP reached 40 mmHg, but rCBF was more dependent on MAP in anterior hemispheric than in brain stem regions. Group II TCBF was significantly lower than baseline, and group I TCBF at all levels of hypotension and autoregulation was impaired at higher MAP levels in anterior than in posterior brain regions. Groups III and IV indicated that decreases in TCBF were not due to duration of the preparation or to TBI in the absence of hemorrhagic hypotension. We conclude that global and regional autoregulation are absent in response to hemorrhagic hypotension after TBI.

Cerebral hemodynamic effects of fluid resuscitation in the presence of an experimental intracranial mass.

We addressed the impact on intracranial pressure (ICP) of posthemorrhage fluid resuscitation with a protocol in which additional fluid was infused to maintain a stable cardiac output after an initial bolus of fluid was infused. Anesthetized, mechanically ventilated mongrel dogs (n = 27) underwent a 30-minute interval of hemorrhagic shock (mean arterial pressure = 55 mm Hg) during which inflation of a subdural balloon maintained ICP at 15 mm Hg. After shock, animals were resuscitated with one of four randomly assigned fluids: (1) slightly hypotonic crystalloid (Na+, 125 mEq.L-1; designated Na-125); (2) hypertonic crystalloid (Na+, 250 mEq.L-1; designated Na-250); (3) slightly hypotonic crystalloid plus 10% pentastarch (Na-125P); or (4) hypertonic crystalloid plus 10% pentastarch (Na-250P). Supplemental fluid was administered as needed to maintain cardiac output comparable to baseline values. ICP increased progressively in all fluid groups during resuscitation. Cerebral blood flow, measured by the cerebral venous outflow method, increased immediately after resuscitation and then declined steadily over time in all groups. Fluids containing pentastarch maintained hemodynamic stability with minimal supplementation throughout most of the postresuscitation period, compared with crystalloid alone, which required substantial additional volume. If decreased intracranial compliance and hemorrhage are combined, ongoing resuscitation is associated with significantly increased ICP and significantly decreased cerebral blood flow, independent of the tonicity and oncotic pressure of the infused fluid.