William E. Hoffman

Lipid Emulsion Infusion Rescues Dogs From Bupivacaine-Induced Cardiac Toxicity

Background and Objectives We previously demonstrated in rats that intravenous infusion of a lipid emulsion increases survival in resuscitation from severe bupivacaine cardiac toxicity. The present studies were undertaken to determine if this method is similarly effective in a non-rodent model using a larger animal. Methods Bupivacaine, 10 mg/kg, was administered intravenously over 10 seconds to fasted dogs under isoflurane general anesthesia. Resuscitation included 10 minutes of internal cardiac massage followed with either saline or 20% lipid infusion, administered as a 4-mL/kg bolus followed by continuous infusion at 0.5 mL/kg/min for 10 minutes. Electrocardiogram (EKG), arterial blood pressure (BP), and myocardial pH (pHm) and pO2 (pmO2) were continuously measured. Results Survival after 10 minutes of unsuccessful cardiac massage was successful for all lipid-treated dogs (n = 6), but with no survivors in the saline controls (n = 6) (P < .01). Hemodynamics, PmO2, and pHm were improved during resuscitation with lipid compared with saline treatment in which dogs did not recover. Conclusions We found that infusing a lipid emulsion during resuscitation from bupivacaine-induced cardiac toxicity substantially improved hemodynamics, pmO2, and pHm and increased survival in dogs.

Dexmedetomidine Improves Neurologic Outcome from Incomplete Ischemia in the Rat Reversal by the α2-Adrenergic Antagonist Atipamezole

Dexmedetomidine is an alpha 2-adrenergic agonist that decreases central sympathetic activity and reduces the anesthetic requirement for halothane. We evaluated the effect of dexmedetomidine on neurologic and histopathologic outcome from incomplete cerebral ischemia in the rat. Anesthesia was maintained with a 25-micrograms.kg-1.h-1 fentanyl infusion combined with 70% nitrous oxide. Incomplete ischemia was produced by unilateral carotid artery ligation combined with hemorrhagic hypotension to 35 mmHg for 30 min. Arterial blood gas tensions, pH, and head temperature were maintained at normal levels during the experiment. Four ischemic groups were tested: group 1 (n = 15) received an intraperitoneal (ip) saline injection (control); group 2 (n = 10) received an ip injection of 10 micrograms/kg dexmedetomidine 30 min before ischemia; group 3 (n = 10) received 100 micrograms/kg dexmedetomidine; and group 4 (n = 10) received 100 micrograms/kg dexmedetomidine plus 1 mg/kg atipamezole (an alpha 2-adrenergic antagonist). Neurologic outcome was evaluated for 3 days using a graded deficit score. Histopathology was evaluated in coronal section in caudate and hippocampal tissue segments. Dexmedetomidine (10 and 100 micrograms/kg) significantly decreased plasma catecholamines and improved neurologic and histopathologic outcome in a dose-dependent manner compared to control rats (P less than 0.05). Atipamezole abolished the decrease in catecholamines and the improvement in outcome seen with dexmedetomidine, confirming that these effects were mediated by alpha 2-adrenergic receptors. It is concluded that alpha 2-adrenoreceptor stimulation decreases sympathetic activity and decreases ischemic injury in a model of incomplete cerebral ischemia.

Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart.

Background and Objectives: Infusion of a lipid emulsion has been advocated for treatment of severe bupivacaine cardiac toxicity. The mechanism of lipid rescue is unknown. These studies address the possibility that lipid infusion reduces cardiac bupivacaine content in the context of cardiac toxicity. Methods: We compared the effects of a 1% lipid emulsion with standard Krebs buffer after inducing asystole in isolated rat heart with 500 μmol/L bupivacaine. We compared times to first heart beat and recovery of 90% of baseline rate pressure product (RPP = heart rate × [left ventricular systolic pressure − left ventricular diastolic pressure]) between controls and hearts receiving 1% lipid immediately after bupivacaine. We also used minibiopsies to compare control bupivacaine tissue content with hearts getting lipid immediately after an infusion of radiolabeled bupivacaine. We then compared bupivacaine efflux from hearts with and without lipid infusion started 75 seconds after radiolabeled bupivacaine was administered. Results: Infusion of lipid resulted in more rapid return of spontaneous contractions and full recovery of cardiac function. Average (± SEM) times to first beat and to 90% recovery of rate pressure product were 44.6 ± 3.5 versus 63.8 ± 4.3 seconds (P < .01) and 124.7 ± 12.4 versus 219.8 ± 25.6 seconds (P < .01) for lipid and controls, respectively. Lipid treatment resulted in more rapid loss of bupivacaine from heart tissue (P < .0016). Late lipid infusion, 75 seconds after bupivacaine infusion ended, increased the release of bupivacaine measured in effluent for the first 15-second interval compared with controls (183 vs. 121 nmol, n = 5 for both groups, P < .008). Conclusions: Lipid emulsion speeds loss of bupivacaine from cardiac tissue while accelerating recovery from bupivacaine-induced asystole. These findings are consistent with the hypothesis that bupivacaine partitions into the emulsion and supports the concept of a “lipid sink.” However, the data do not exclude other possible mechanisms of action.

Brain tissue oxygen, carbon dioxide, and pH in neurosurgical patients at risk for ischemia.

A sensor that measures oxygen pressure (PO2), carbon dioxide pressure (PCO2), and pH was evaluated in brain tissue of patients at risk for ischemia.The sensor is 0.5 mm in diameter and was inserted into cortex tissue in 14 patients undergoing craniotomy for cerebrovascular surgery. A compromised cerebral circulation was identified in 8 of 14 patients by single photon emission computed tomography (SPECT) scan, cerebral angiography, and transient ischemic episodes before surgery. Under baseline conditions with isoflurane anesthesia and normal blood gases, tissue PO2 was lower in the eight compromised compared to six noncompromised patients (noncompromised 37 +/- 12 mm Hg, compromised 10 +/- 5 mm Hg; P < 0.05), PCO2 was increased (noncompromised 49 +/- 5 mm Hg, compromised 72 +/- 23 mm Hg; P < 0.05), and pH was decreased (noncompromised 7.16 +/- 0.08, compromised 6.82 +/- 0.21; P < 0.05). Critical tissue values for the identification of ischemia were a PO2 of 20 mm Hg, PCO2 of 60 mm Hg, and a pH of 7.0. These results suggest that brain tissue measures of PO2, PCO2, and pH provide information on the adequacy of cerebral perfusion in neurosurgical patients. (Anesth Analg 1996;82:582-6)

The Effects of Propofol on Brain Electrical Activity, Neurologic Outcome, and Neuronal Damage Following Incomplete Ischemia in Rats

This study compares the effects of propofol and fentanyl/N2O on spontaneous brain electrical activity, neurologic outcome, and neuronal damage due to incomplete cerebral ischemia in rats. Thirty Sprague-Dawley rats were assigned to one of three groups: group 1 (n = 10) received 70% N2O in O2 plus fentanyl (bolus 10 micrograms.kg-1, infusion 25 micrograms.kg-1.h-1); group 2 (n = 10) received 70% N2 in O2 and propofol (infusion 0.8-1.2 mg.kg-1.min-1) adjusted to maintain EEG burst suppression during ischemia; group 3 (n = 10) was anesthetized with propofol and received 6 ml.kg-1 10% glucose intraperitoneally 15 min before the start of ischemia. Incomplete cerebral ischemia was produced by right common carotid artery occlusion combined with hemorrhagic hypotension (35 mmHg) for 30 min. Arterial blood gases, pH, and rectal temperature were kept constant in all groups. Plasma glucose was lower during ischemia in propofol-anesthetized rats compared to that in fentanyl/N2O- (P = 0.009) and glucose-loaded propofol-treated rats (P = 0.008). Neurologic outcome and brain tissue injury were significantly better in propofol-anesthetized compared to fentanyl/N2O-anesthetized rats (P less than 0.05). Elevated plasma glucose in propofol-treated rats resulted in similar neurologic outcome and histopathologic injury as seen in propofol-anesthetized rats given no glucose. Recovery of EEG theta-alpha activity after ischemia was inversely correlated to neurologic deficit (fentanyl/N2O: r = -0.71; propofol: r = -0.83; P less than 0.01). These results show that propofol improves neurologic outcome and decreases neuronal damage from incomplete cerebral ischemia when compared to fentanyl/N2O. This effect is not dependent on plasma glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurologic Outcome in Rats Following Incomplete Cerebral Ischemia during Halothane, Isoflurane, or N2O

Using rats in which incomplete cerebral ischemia was induced, the authors evaluated the effects of halothane (H) and isoflurane (I) on neurologic outcome compared to nitrous oxide (N2O) controls. Incomplete cerebral ischemia was produced by right carotid artery occlusion combined with hemorrhagic hypotension. Neurologic outcome was evaluated using a graded deficit score from 0 to 5 (0 = normal, 5 = death associated with stroke). Two levels of cerebral ischemia were tested. At moderate ischemia with hypotension of 30 mmHg, an FIO2 of 0.3, and ischemic periods of 30 or 45 min, N2O produced a deficit of 4.7–5.0 and a mortality rate of 90–100%. In contrast, halothane (1 MAC) and isoflurane (1 MAC) resulted in similar deficit scores (H = 1.1–1.8, I = 1.4–1.6) and mortality rates (H = 17–30%, I = 17–20%). Cerebral blood flow (CBF) measured with radioactive microspheres showed a 60–65% decrease in the ischemic hemisphere at this level of hypotension. With severe ischemia with hypotension = 25 mmHg, FIO2 = 0.2, and a 30-min period of ischemia, deficit scores increased to 3.0 and 3.9 with 1 MAC halothane and 1 MAC isoflurane, respectively. Morality rates also increased to 40% with halothane and 70% with isoflurane. Increasing the concentration of halothane or isoflurane to 2 MAC did not significantly improve outcome. Brain histology demonstrated extensive neuronal damage in striatal, hippocampal, and neocortical regions of N2O control treated rats, and less damage with little difference between H-and I-treated rats at each level of ischemia. Using this model of incomplete cerebral ischemia, halothane and isoflurane provided significantly better neurologic and histologic outcomes when compared to N2O controls, with little difference between the two volatile anesthetics.

Effects of Remifentanil, a New Short-acting Opioid, on Cerebral Blood Flow, Brain Electrical Activity, and Intracranial Pressure in Dogs Anesthetized with Isoflurane and Nitrous Oxide

BackgroundA new short-acting opioid, remifentanil, is metabolized by esterase activity in blood and tissue. It is important to know whether remifentanil may decrease the time to recovery of opioid-induced cardiovascular and cerebral effects compared to that of other short-acting agents such as alfentanil. MethodsBaseline measures were made during 1% end-tidal isoflurane and 50% N2O in oxygen in dogs. Approximately equipotent low- and high-dose remifentanil (0.5 and 1.0

Effects of Sufentanil on Cerebral Hemodynamics and Intracranial Pressure in Patients with Brain Injury

mUg. kg−1. min−1) or alfentanil (1.6 and 3.2

Cerebral autoregulation in awake versus isoflurane-anesthetized rats

mUg. kg−1. min−1) were infused for 30 min each (total infusion time 60 min) followed by a 30-min recovery period. Blood pressure, heart rate, and intracranial pressure were recorded continuously. Electroencephalogram measurements were made using aperiodic analysis, and regional cerebral blood flow using radioactive microspheres. ResultsBoth remifentanil and alfentanil decreased blood pressure and heart rate 25–30%. Cortex, hippocampus, and caudate blood flow decreased 40–50% during opioid infusion, but flow changes in lower brain regions were modest or absent. The electroencephalogram showed a shift from low-amplitude, high-frequency activity during baseline to high-amplitude, low-frequency activity during opioid infusion. During a 30-min recovery period, heart rate, electroencephalogram, and regional cerebral blood flow recovered to baseline levels in remifentanil- but not in alfentanil-treated dogs. Blood pressure and intracranial pressure decreased during opioid infusion and increased above baseline levels during the recovery period in remifentanil-treated dogs. ConclusionsThese results show that the cardiovascular and cerebral effects of remifentanil and alfentanil are similar but that recovery of these parameters occurs sooner following remifentanil.

Nitrous oxide markedly increases cerebral cortical metabolic rate and blood flow in the goat

Background The current study investigates the effects of sufentanil on cerebral blood flow velocity and intracranial pressure (ICP) in 30 patients with intracranial hypertension after severe brain trauma (Glasgow coma scale < 6).