Brain expression of inducible cyclooxygenase 2 messenger RNA in rats undergoing cardiopulmonary bypass.

BACKGROUND: We hypothesized that systemic proinflammatory cytokines or endotoxemia, or both, associated with cardiopulmonary bypass (CPB) would increase expression of inducible cyclooxygenase (COX-2) or inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), or both, in brain. METHODS: Isoflurane-anesthetized Sprague-Dawley rats were randomly selected for CPB (n = 6) or sham surgery (n = 6). All animals underwent tracheotomy and controlled ventilation, arterial and venous pressure monitoring, insertion of a jugular venous outflow catheter, insertion of a subclavian arterial inflow catheter, systemic anticoagulation (500 U/kg heparin) and, except during CPB, servoregulation of pericranial temperature at 37.5 degrees C. Animals selected for CPB underwent 1 h of CPB at 165 ml x kg(-1) x min(-1) (31.8 +/- 0.2 degrees C), whereas animals having sham surgery underwent no intervention during this interval. Thereafter, all animals were given protamine and remained anesthetized for 4 more h. Brain and liver COX-2 and iNOS mRNA expression were determined by a ribonuclease protection assay with ribosomal L32 mRNA as a loading control. Arterial blood was analyzed for interleukin 1beta, interleukin 6, and endotoxin concentrations. RESULTS: Endotoxin concentrations did not increase above baseline values in either group. At 4 h after the CPB interval, interleukin 6 concentrations were significantly greater in CPB animals (101 +/- 45 pg/ml) versus sham animals (44 +/- 17 pg/ml) (P = 0.025). Brain COX-2 expression was significantly greater in CPB animals (0.36 +/- 0.11) versus shams (0.19 +/- 0.08) (P = 0.013). Brain COX-2 expression correlated with interleukin 6 concentration 4 h after CPB (r = 0.91; P = 5 x 10(-5)). In brain, iNOS mRNA was not detected in any animal. Cardiopulmonary bypass animals had only trace COX-2 and iNOS mRNA induction in liver. CONCLUSIONS: Cardiopulmonary bypass was associated with increased systemic interleukin 6 concentrations and increased brain COX-2 expression.

Brain injury after cerebral arterial air embolism in the rabbit as determined by triphenyltetrazolium staining.

BACKGROUND: Microscopic cerebral arterial air embolism (CAAE) occurs commonly during cardiac surgery and causes acute and chronic nonfocal neurologic dysfunction. Nevertheless, most neuroimaging studies do not detect brain injury after cardiac surgery. Using a rabbit model, the authors hypothesized they could detect and quantitate severe brain injury and infarction 24 h after microscopic CAAE using the vital stain triphenyltetrazolium chloride. METHODS: Experiments were conducted in methohexital anesthetized New Zealand white rabbits. Surgical shams (n = 5) underwent surgery but had no neurologic insult. Positive controls (n = 3) received 200 microl/kg of intracarotid air. Other animals were randomized to receive either 50 microl/kg intracarotid air, which produces microscopic CAAE (n = 18), or 300 microl intracarotid saline (control, n = 18). Outcomes included somatosensory evoked potential amplitude at 90 min, neurologic impairment score at 4 and 24 h (0 [normal] to 99 [coma]), and percentage of nonstaining brain at 24 h using color-discrimination image analysis. Severely injured or infarcted brain does not stain with triphenyltetrazolium chloride. RESULTS: Surgical shams had little neurologic impairment and a small amount of nonstaining brain at 24 h (5.2 +/- 2.4%; mean +/- SD). Positive controls had profound neurologic impairment and large amounts of nonstaining brain (40-97%). Ninety-minute somatosensory evoked potential amplitude was less in animals receiving 50 microl/kg air versus saline: 38 +/- 28% versus 102 +/- 32%, respectively, P < 1 x 10(-7). Neurologic impairment scores were greater in animals receiving 50 microl/kg air versus saline: at 4 h, 43 +/- 16 versus 23 +/- 9, P < 1 x 10(-7); at 24 h, 24 +/- 12 versus 15 +/- 8, P = 0.013. Nevertheless, there was no difference between 50 microl/kg air and saline in nonstaining brain: 5.5 +/- 2.9% versus 6.8 +/- 5.4%, P = 0.83. CONCLUSIONS: Neurologic injury after CAAE is dose-dependent. Although microscopic CAAE causes somatosensory evoked potential abnormalities and neurologic dysfunction, severe cerebral injury or infarction is not present at 24 h. The author's findings are consistent with clinical imaging studies that suggest microscopic CAAE causes neurologic dysfunction even though overt infarction is absent.

Mild hypothermia as a protective therapy during intracranial aneurysm surgery: a randomized prospective pilot trial.

OBJECTIVE: To conduct a pilot trial of mild intraoperative hypothermia during cerebral aneurysm surgery. METHODS: One hundred fourteen patients undergoing cerebral aneurysm clipping with (n = 52) (World Federation of Neurological Surgeons score < or =III) and without (n = 62) acute aneurysmal subarachnoid hemorrhage (SAH) were randomized to normothermic (target esophageal temperature at clip application of 36.5 degrees C) and hypothermic (target temperature of 33.5 degrees C) groups. Neurological status was prospectively evaluated before surgery, 24 and 72 hours postoperatively (National Institutes of Health Stroke Scale), and 3 to 6 months after surgery (Glasgow Outcome Scale). Secondary outcomes included postoperative critical care requirements, respiratory and cardiovascular complications, duration of hospitalization, and discharge disposition. RESULTS: Seven hypothermic patients (12%) could not be cooled to within 1 degrees C of target temperature; three of the seven were obese. Patients randomized to the hypothermic group more frequently required intubation and rewarming for the first 2 hours after surgery. Although not achieving statistical significance, patients with SAH randomized to the hypothermic group, when compared with patients in the normothermic group, had the following: 1) a lower frequency of neurological deterioration at 24 and 72 hours after surgery (21 versus 37-41%), 2) a greater frequency of discharge to home (75 versus 57%), and 3) a greater incidence of good long-term outcomes (71 versus 57%). For patients without acute SAH, there were no outcome differences between the temperature groups. There was no suggestion that hypothermia was associated with excess morbidity or mortality. CONCLUSION: Mild hypothermia during cerebral aneurysm surgery is feasible in nonobese patients and is well tolerated. Our results indicate that a multicenter trial enrolling 300 to 900 patients with acute aneurysmal SAH will be required to demonstrate a statistically significant benefit with mild intraoperative hypothermia.

Cerebrovascular relaxation responses to endothelium-dependent and -independent vasodilators after normothermic and hypothermic cardiopulmonary bypass in the rabbit.

BACKGROUND: Cardiopulmonary bypass causes activation of leukocytes and increased concentrations of proinflammatory mediators, which may result in endothelial dysfunction. Because hypothermia attenuates many inflammatory processes, the authors hypothesized that hypothermic cardiopulmonary bypass would be associated with better endothelial function than normothermic cardiopulmonary bypass. METHODS: Isoflurane-anesthetized New Zealand White rabbits were randomized to undergo 90 min of either normothermic (37 degrees C, n=9) or hypothermic (27 degrees C, n=9) cardiopulmonary bypass with terminal rewarming. A third group served as anesthetized normothermic non-cardiopulmonary bypass surgical controls (n=8). Basilar artery and descending thoracic aorta were isolated from each animal. In vitro vessel relaxation responses to increasing concentrations of acetylcholine (which induces endothelial release of nitric oxide) and nitroprusside (which provides exogenous nitric oxide) were measured in phenylephrine-precontracted vessel rings. RESULTS: There were no differences in vessel relaxation responses between normothermic and hypothermic cardiopulmonary bypass groups in basilar artery or aorta. In contrast, basilar arteries from non-cardiopulmonary bypass controls had increased relaxation responses to both acetylcholine (P=0.004) and nitroprusside (P=0.031) compared with the pooled cardiopulmonary bypass animal data. CONCLUSIONS: The authors observed no differences in endothelial or vascular smooth muscle function between normothermic and hypothermic cardiopulmonary bypass groups. Compared with non-cardiopulmonary bypass controls, cardiopulmonary bypass appeared to decrease basilar artery smooth muscle relaxation in response to endogenous and exogenous nitric oxide.

Computer simulation of microscopic cerebral air emboli absorption during cardiac surgery.

Microscopic cerebral arterial air emboli (MCAAE) cause neurologic injury during cardiac surgery. We used a mathematical model of gas absorption to gain a preliminary assessment of what physical or physiologic parameters affect MCAAE absorption in the setting of cardiac surgery with its unique set of normal values. Simulated MCAAE of radii 50 and 200 microns have absorption times of 2 and 32 min, respectively. Predicted absorption times depend dramatically on PaN2. MCAAE are predicted to be absorbed twice as quickly at a PaN2 of 0 vs. 380 mmHg (FiO2 approximately equal to 0.50). Moderate hypothermia (27 degrees C) is predicted to cause only small decreases in absorption time. Changes in cerebral blood flow (for example, as affected by hemoglobin concentration, PaCO2, PaO2, collateral circulation, anesthetics, or cerebral metabolism) probably have only small effects on absorption time. Intravascular perfluorocarbons are predicted to cause small-to-moderate decreases in absorption time. In conclusion, there is probably only one important determinant of MCAAE absorption time during normothermic or moderately hypothermic CPB: arterial nitrogen partial pressure.

Recovery of evoked potential amplitude after cerebral arterial air embolism in the rabbit: a comparison of the effect of cardiopulmonary bypass with normal circulation.

BACKGROUND: Cerebral arterial air embolism (CAAE) may cause neurologic injury during cardiac surgery. It is not known whether cardiopulmonary bypass (CPB) increases or decreases brain injury from CAAE compared with the normal circulation. METHODS: A model of CAAE was produced by injection of 50 microl/kg air into the internal carotid artery of methohexital-anesthetized New Zealand white rabbits. Somatosensory-evoked potential (SSEP) amplitude was measured serially as a marker of neurologic recovery. In experiment A, saline rather than air was injected to control for surgical manipulation and time in CPB (n = 4) and nonheparinized non-CPB (n = 4) animals. In experiment B, 50 microl/kg air was injected in CPB (n = 11) and nonheparinized non-CPB (n = 11) animals. In experiment C, non-CPB animals (n = 6) were given heparin according to the same protocol as for CPB. RESULTS: In experiment A, SSEP latencies and amplitudes did not differ between CPB and non-CPB conditions. In experiment B, there was no SSEP recovery 5 min after CAAE in either CPB or non-CPB animals. Thereafter, SSEP recovery was less in CPB animals than in non-CPB animals at 30 min (9 +/- 12% vs. 29 +/- 20%; P = 0.009) and 60 min (18 +/- 15% vs. 39 +/- 22%; P = 0.030) after CAAE. Ninety-minute SSEP recovery did not differ between CPB and non-CPB groups (at 24 +/- 19% vs. 39 +/- 24%, respectively; P = 0.146). In experiment C (heparinized non-CPB), SSEP recovery 5, 30, 60, and 90 min after CAAE was 67 +/- 48%, 72 +/- 47%, 80 +/- 35%, and 77 +/- 35%, respectively. CONCLUSIONS: Somatosensory-evoked potential recovery after CAAE is no better (and is probably worse) during CPB than during normal circulation. The adverse effect of CPB occurs despite heparinization, which, under non-CPB conditions, appears to be protective. Therapies in addition to heparin are needed during CPB to reduce neurologic injury from CAAE.

Effect of haemoglobin concentration on brain oxygenation in focal stroke: a mathematical modelling study.

Acute perioperative anaemia may affect neurological injury from permanent focal ischaemic insults. We modelled the opposing effects of haemodilution (increasing cerebral blood flow, decreasing arterial oxygen content) on oxygen availability and uptake in the ischaemic penumbra. First, we validated a mathematical model of regional cerebral oxygen uptake by using published arterial oxygen content and cerebral blood flow values from normal rabbits with progressive anaemia. Then we applied the model to the problem of interest (i.e. the ischaemic penumbra of a focal embolic stroke). We re-analysed published experimental data giving the cerebral blood flow response to anaemia in the ischaemic penumbra. Penumbral extraction reserves were nearly exhausted at a haemoglobin concentration of approximately 10g 100ml-1. Oxygen uptake in the ischaemic penumbra decreased progressively when haemoglobin concentrations decreased to less than 10g 100ml-1. We conclude that, given the available clinical and experimental literature, and until a suitable randomized clinical study has been performed, a haemoglobin concentration of 10 g 100 ml-1 is the rational transfusion "trigger" for the acutely anaemic stroke patient.

Doxycycline reduces early neurologic impairment after cerebral arterial air embolism in the rabbit.

BACKGROUND: Previous studies indicate leukocytes play a role in the pathogenesis of cerebral arterial air embolism. Because doxycycline inhibits numerous leukocyte activities, the authors hypothesized doxycycline would decrease neurologic impairment after cerebral arterial air embolism. METHODS: New Zealand White rabbits anesthetized with methohexital received either intravenous saline (n = 7) or 10 mg/kg doxycycline (n = 7) 1 h before administration of 100 microl/kg of air into the internal carotid artery. Somatosensory-evoked potentials (SSEPs) were recorded at 30-min intervals for the next 2 h. After the final recording, the anesthetic was discontinued, and animals recovered. Animals were neurologically evaluated 4 h after air embolism on a scale of 0 (normal) to 99 (coma) points. RESULTS: At 4 h, doxycycline animals had lesser neurologic impairment (46 +/- 23; median, 41) than animals that received saline (77 +/- 20; median, 81); P = 0.007. SSEP amplitude was greater in the doxycycline group at 60, 90, and 120 min after air embolism; P = 0.001, 0.006, 0.026, respectively. SSEP amplitudes at 30, 60, 90, and 120 min inversely correlated with 4 h neurologic impairment; tau = -0.43, -0.75, -0.85, -0.79, respectively. CONCLUSIONS: Doxycycline decreased electrophysiologic and neurologic abnormalities after cerebral air embolism. Because groups could be distinguished electrophysiologically as soon as 1 h after air embolism and because SSEP amplitude inversely correlated with neurologic impairment, doxycycline appears to inhibit a key early (approximately 1 h) process in the pathophysiology of cerebral air embolism.

Recommendations for hyperbaric oxygen therapy of cerebral air embolism based on a mathematical model of bubble absorption.

Transcranial doppler studies show that microscopic cerebral artery air emboli (CAAE) are present in virtually all patients undergoing cardiac surgery. Massive cerebral arterial air embolism is rare. If it occurs, hyperbaric oxygen therapy (HBO) is recommended as soon as surgery is completed. We used a mathematical model to predict the absorption time of CAAE, assuming that the volumes of clinically relevant CAAE vary from 10(-7) to at least 10(-1) mL. Absorption times are predicted to be at least 40 h during oxygenation using breathing gas mixtures of fraction of inspired oxygen approximately equal to 40%. When CAAE are large enough to be detected by computerized tomography, absorption times are calculated to be at least 15 h. Decreases in cerebral blood flow caused by the CAAE would make the absorption even slower. Our analysis suggests that if the diagnosis of massive CAAE is suspected, computerized tomography should be performed, and consideration should be given to HBO therapy if the CAAE are large enough to be visualized, even if patient transfer to a HBO facility will require several hours.

The brain uses mostly dissolved oxygen during profoundly hypothermic cardiopulmonary bypass.

BACKGROUND: During profoundly hypothermic cardiopulmonary bypass, cerebral venous oxygen saturation increases (eg, to 98% at 15 degrees C). We reanalyzed results of clinical studies to learn why. METHODS: One hundred sixty-eight cerebral oxygen transport measurements were available from 96 infants and children undergoing profoundly hypothermic cardiopulmonary bypass during repair of congenital heart defects. RESULTS: Dissolved oxygen accounted for 2% to 17% of arterial oxygen content, depending on the arterial oxygen partial pressure and hemoglobin concentration. The fraction of the cerebral metabolic rate for oxygen obtained from dissolved oxygen depended on pump flow, temperature, hemoglobin concentration, and arterial oxygen partial pressure (all p < 10(-3)). For "full-flow" cardiopulmonary bypass, temperatures less than 18 degrees C, and arterial oxygen partial pressure measurements more than 180 mm Hg, the mean +/- standard deviation of the fraction of cerebral metabolic rate for oxygen obtained from dissolved oxygen equaled 77% +/- 19%. CONCLUSIONS: Dissolved oxygen satisfies most of the brain's oxygen requirements during profound hypothermic cardiopulmonary bypass. This result reflects four properties of profound hypothermic cardiopulmonary bypass: (1) increases in hemoglobin's oxygen affinity due to profound hypothermia (which impairs oxygen transfer from hemoglobin to cerebral tissue), (2) use of hemodilution, (3) use of high arterial oxygen partial pressure, and (4) low cerebral metabolic rate of oxygen.

Comparison of remifentanil and fentanyl in patients undergoing craniotomy for supratentorial space-occupying lesions.

BACKGROUND: Remifentanil hydrochloride is an ultra-short-acting, esterase-metabolized mu-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions. METHODS: Sixty-three adults gave written informed consent for this prospective, randomized, double-blind, multiple-center trial. Anesthesia was induced with thiopental, pancuronium, nitrous oxide/oxygen, and fentanyl (n = 32; 2 micrograms.kg.-1. min-1) or remifentanil (n = 31; 1 mu.kg-1.min-1). After tracheal intubation, infusion rates were reduced to 0.03 microgram.kg-1.min-1 (fentanyl) or 0.2 microgram.kg-1.min-1 (remifentanil) and then adjusted to maintain anesthesia and stable hemodynamics. Isoflurane was given only after specified infusion rate increases had occurred. At the time of the first burr hole, intracranial pressure was measured in a subset of patients. At bone flap replacement either saline (fentanyl group) or remifentanil (approximately 0.2 microgram.kg-1.min-1) were infused until dressing completion. Hemodynamics and time to recovery were monitored for 60 min. Analgesic requirements and nausea and vomiting were observed for 24 h. Neurological examinations were performed before operation and on postoperative days 1 and 7. RESULTS: Induction hemodynamics were similar. Systolic blood pressure was greater in the patients receiving fentanyl after tracheal intubation (fentanyl = 127 +/- 18 mmHg; remifentanil = 113 +/- 18 mmHg; P = 0.004). Intracranial pressure (fentanyl = 14 +/- 13 mmHg; remifentanil = 13 +/- 10 mmHg) and cerebral perfusion pressure (fentanyl = 76 +/- 19 mmHg; remifentanil = 78 +/- 14 mmHg) were similar. Isoflurane use was greater in the patients who received fentanyl. Median time to tracheal extubation was similar (fentanyl = 4 min: range = -1 to 40 min; remifentanil = 5 min: range = 1 to 15 min). Seven patients receiving fentanyl and none receiving remifentanil required naloxone. Postoperative systolic blood pressure was greater (fentanyl = 134 +/- 16 mmHg; remifentanil = 147 +/- 15 mmHg; P = 0.001) and analgesics were required earlier in patients receiving remifentanil. Incidences of nausea and vomiting were similar. CONCLUSIONS: Remifentanil appears to be a reasonable alternative to fentanyl during elective supratentorial craniotomy.

Estimate of the maximum absorption rate of microscopic arterial air emboli after entry into the arterial circulation during cardiac surgery.

Some clinicians place patients in the Trendelenburg position during aortic unclamping to decrease the incidence of microscopic cerebral air embolism. Experimental studies have shown that use of the Trendelenburg position does not prevent air emboli from reaching the brain. Nevertheless, the position can decrease the velocity at which bubbles approach the brain, giving more time for nitrogen in the bubbles to be absorbed. We applied a validated mathematical model to estimate that the maximum rate of absorption of microscopic air emboli in blood during and after cardiopulmonary bypass (CPB) equals 1.57 microns/s. This rate is very small, since clinically relevant microbubbles have radii 50-1500 microns, and travel from the aorta to the brain within seconds. The result holds for all usual conditions of CPB. We conclude that absorption does not affect the disposition of air introduced into the arterial circulation. Use of the Trendelenburg position cannot decrease neurologic injury from cerebral air embolism by permitting greater bubble absorption.

Somatosensory evoked potentials correlate with neurological outcome in rabbits undergoing cerebral air embolism.

BACKGROUND AND PURPOSE: Somatosensory evoked potentials (SSEPs) have been used as an outcome measure in models of cerebral air embolism despite the lack of studies correlating SSEPs with other measures of neurological injury. We examined the relationship between SSEPs and neurological impairment in the setting of cerebral air embolism. METHODS: Anesthetized New Zealand White rabbits received either 0, 50, 100, or 150 microL/kg of air into the internal carotid artery. SSEPs were recorded at intervals for the subsequent 2 hours. After the final recording the anesthetic was discontinued, and the animals recovered. Animals were neurologically evaluated at 3 and 24 hours after cerebral air embolism on a scale of zero (normal) to 97 (coma) points. RESULTS: There was a clear relationship between the dose of air and 2-hour SSEP amplitude (P = .00003). SSEP amplitudes at 2 hours were inversely correlated with neurological impairment scores at 3 hours (r = -0.71, P < .0001). SSEP amplitudes at 2 hours were less in animals that died (11 +/- 16%; n = 9) than in those that survived to 24 hours (53 +/- 20%; n = 9) (P = .0008). CONCLUSIONS: These results support SSEPs as an index of neurological impairment in this model of cerebral air embolism.

Intracranial pressure and hemodynamic effects of remifentanil versus alfentanil in patients undergoing supratentorial craniotomy.

Remifentanil hydrochloride is an ultra-short-acting esterase metabolized mu-opioid receptor agonist. The purpose of this study was to provide preliminary information regarding the effects of this drug on intracranial pressure (ICP) and mean arterial pressure (MAP) in patients scheduled for craniotomy. Twenty-six patients undergoing excision of supratentorial space-occupying lesions were anesthetized with 0.3-0.8 vol% isoflurane in a 2:1 mixture of nitrous oxide:oxygen. Ventilation was adjusted to provide a Paco2 of < 30 mm Hg. After the first burr hole was drilled, patients (n = 5-6 per group) were administered an intravenous infusion of study drug (placebo, remifentanil 0.5 micrograms/kg or 1.0 micrograms/kg, or alfentanil 10 micrograms/kg or 20 micrograms/kg) over 1 min. Epidural ICP and MAP values were recorded at baseline, at completion of infusion, and every minute for the next 10 min. Blood study drug concentrations were measured immediately after completion of infusion. Neither opioid caused a significant increase in ICP. Both drugs were associated with a dose-dependent decrease in MAP. Remifentanil was 31 times more potent than alfentanil for effects on MAP. We conclude that remifentanil produces similar cerebral perfusion pressure effects as does alfentanil.

Rapid rewarming causes an increase in the cerebral metabolic rate for oxygen that is temporarily unmatched by cerebral blood flow. A study during cardiopulmonary bypass in rabbits.

BACKGROUND: Jugular venous hemoglobin desaturation during the rewarming phase of cardiopulmonary bypass is associated with adverse neuropsychologic outcome and may indicate a pathologic mismatch between cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). In some studies, rapid rewarming from hypothermic cardiopulmonary bypass results in greater jugular venous hemoglobin desaturation. The authors wished to determine if rewarming rate influences the temperature dependence of CBF and CMRO2. METHODS: Anesthetized New Zealand white rabbits, cooled to 25 degrees C on cardiopulmonary bypass, were randomized to one of two rewarming groups. In the fast group (n = 9), aortic blood temperature was made normothermic within 4 min. In the slow group (n = 9), aortic blood temperature was made normothermic over 25 min. Cerebral blood flow (microspheres) and CMRO2 (Fick) were determined at baseline (25 degrees C), and at brain temperatures of 28 degrees, 31 degrees, 34 degrees, and 37 degrees C during rewarming. RESULTS: Systemic physiologic variables appeared similar between groups. At a brain temperature of 28 degrees C, CMRO2 was 47% greater in the fast rewarming group than in the slow group (2.2 +/- 0.5 vs. 1.5 +/- 0.2 ml O2.100 g-1. min-1, respectively; P = 0.01), whereas CBF did not differ (48 +/- 18 vs. 49 +/- 8 ml.100 g-1.min-1, respectively; P = 0.47). Throughout rewarming, CBF increased as a function of brain temperature but was indistinguishable between groups. Cerebral metabolic rate for oxygen differences between groups decreased as brain temperatures increased. CONCLUSIONS: Cerebral venous hemoglobin desaturation with rapid rewarming is caused by an increase in CMRO2 that is temporarily greater than the increase in CBF. This mismatch may indicate a transient abnormality in flow-metabolism coupling, or the effect of temperature gradients on oxygen transfer from hemoglobin to brain.

Heparin reduces neurological impairment after cerebral arterial air embolism in the rabbit.

BACKGROUND AND PURPOSE: Neurological injury after cerebral air embolism may be due to thromboinflammatory responses at sites of air-injured endothelium. Because heparin inhibits multiple thromboinflammatory processes, we hypothesized that heparin would decrease neurological impairment after cerebral air embolism. METHODS: To first establish a dose of air that would cause unequivocal neurological injury, anesthetized New Zealand White rabbits received either 0, 50, 100, or 150 microL/kg of air into the internal carotid artery (n = 5 in each group). One hour later, anesthesia was discontinued. Animals were neurologically evaluated at 24 hours with the use of a scale ranging from 0 (normal) to 97 (coma) points. In a subsequent experiment, anesthetized rabbits received either heparin (n = 17) or saline (n = 15) 5 minutes before air injection (150 microL/kg). Heparin was given as a 200-IU/kg bolus and followed by a constant infusion of 75 IU.kg-1.h-1 for 2 hours. Equal volumes of saline were given to control rabbits. Two hours later, anesthesia was discontinued. Animals were neurologically evaluated 24 hours after air embolism. RESULTS: There was a monotonic relationship between dose of air and severity of neurological impairment at 24 hours (P = 1.1 x 10(-7)). Animals receiving 150 microL/kg of air were unequivocally injured (score, 60 +/- 16). In the second experiment, heparin animals had significantly less neurological impairment at 24 hours (34 +/- 14) than saline controls (52 +/- 8) (P = .0013). CONCLUSIONS: When given prophylactically, heparin decreases neurological impairment caused by severe cerebral arterial air embolism.

Marked hemodilution increases neurologic injury after focal cerebral ischemia in rabbits.

Moderate hemodilution (hematocrit approximately 30%) reduces neurologic injury after focal cerebral ischemia. In contrast, both clinical and experimental studies suggest that marked hemodilution (hematocrit < 30%) may exacerbate neurologic injury. We compared the effect of marked versus minimal hemodilution on cerebral infarct volume after focal cerebral ischemia in rabbits. Anesthetized New Zealand White rabbits underwent hemodilution by exchange of arterial blood with 6% high molecular weight hydroxyethyl starch. In the marked hemodilution group (n = 15) the target hemoglobin concentration was 6 g/100 mL. In the minimal hemodilution group (n = 15) the target hemoglobin concentration was 11 g/100 mL. After hemodilution, middle cerebral artery occlusion was achieved by embolizing an autologous blood clot via the internal carotid artery. Four hours after embolization, the animals were killed and their brains removed. Brains were sectioned, stained with 2,3,5-triphenyltetrazolium chloride, and infarct volumes determined via quantitative image analysis. Systemic physiologic variables were similar between groups, except for arterial hemoglobin concentration. The percentage of hemispheric infarct was significantly larger in the marked hemodilution group as compared to the minimal hemodilution group, 70% +/- 19% vs 51% +/- 23%, respectively (mean +/- SD); P = 0.02. Similarly, the percentage of infarct was greater in the hemodilution group as compared to the minimal hemodilution group in both cortex (73% +/- 18% vs 54% +/- 23%, respectively; P = 0.02) and subcortex (62% +/- 25% vs 44% +/- 23%, respectively; P = 0.04). These findings indicate that marked hemodilution exacerbates neurologic injury resulting from permanent focal ischemia. Although some degree of hemodilution may improve neurologic outcome, the advantage is lost at an extreme level of therapy.