Attenuation of brain free fatty acid liberation during global ischemia: a model for screening potential therapies for efficacy?

Whole brain free fatty acids (FFA) continue to rise appreciably even 1 h after decapitation, which may reflect the evolution of ischemic brain injury at least during global ischemia. If so, the attenuation of FFA liberation by various drugs may reflect their efficacy in ischemic brain injury. Rats were pretreated with either 0.9% NaCl (controls), ketamine, halothane, lofentanil, etomidate, Y-9179, R41-468, Innovar-Vet, pentobarbital, thiopental, or phenytoin and decapitated 15 to 30 min thereafter. The brains were kept normothermic for 10 min until they were frozen in liquid nitrogen. Whole brain FFAs were quantitated gy gas-liquid chromatography. After 10 min of ischemia in controls, total FFAs and arachidonic, stearic, oleic, and palmitic acids increased by 8- to 10-fold. The drugs, in order of decreasing effectiveness in attenuating FFA liberation, fell into the following three groups: (1) phenytoin, thiopental, pentobarbital, and Innovar-Vet; (2) R41-468, Y-9179, and etomidate; and (3) lofentanil, halothane and ketamine. The three groups reduced total FFAs by about 23%, 13%, and 8%, respectively. The effectiveness of drugs in attenuating FFA liberation appears to correlate with their efficacy in ischemic brain injury. However, a cause and effect relationship between FAA liberation and the evolution of ischemic brain injury must be established before accurate predictions of efficacy can be made by this method. The limitations of the proposed method of evaluation are discussed.

Mechanisms of cerebrovascular dilation by ether in monkeys.

We hypothesized that when the depth of ether anesthesia is increased from 2 to 5%, cerebral vessels dilate secondary to circulating catecholamine stimulation of cerebral metabolism. Cerebral blood flow (CBF) by 133Xe clearance and cerebral metabolic rate for oxygen (CMRO2) were measured on 2% and then 5% ether in air in two groups of seven monkeys each during mechanical ventilation. Propranolol, 0.5 mg/kg i.v., was infused over 5 min in one group, and the other received saline. All measurements were repeated on 5% and 2% ether. Cerebrovascular resistance (CVR) fell by 30%, from 2.28 +/- 0.61 (mean +/- SD) to 1.51 +/- 0.28 mm Hg ml-1 100 g-1 min-1 (p less than 0.01), with the increase in ether from 2 to 5%. CBF and CMRO2 were unaltered from values of about 45 ml 100 g-1 min-1 and 2.3 ml 100 g-1 min-1, respectively. During 5% ether anesthesia, propranolol had no effect on CBF, CMRO2, or CVR. On 2% ether, it increased CVR twofold, from 1.5 +/- 0.30 to 3.0 +/- 1.0 mm Hg ml-1 100 g-1 min-1, and decreased CBF by 33%, from 48 +/- 8 to 32 +/- 10 ml 100 g-1 min-1. Plasma epinephrine was two-fold higher on 2% compared to 5% ether, both before and after saline or propranolol infusion. In monkeys, cerebrovascular dilation by ether at 5% compared to 2% is not secondary to catecholamine stimulation of CMRO2. It may result from a direct effect of either plasma catecholamines or ether on the cerebrovasculature.

Rehabilitation of the crippled larynx: application of the Tucker technique for muscle-nerve reinnervation.

Interruption of laryngeal innervation may partially or totally impair respiration, deglutition and phonation--the three basic laryngeal functions. Tucker has developed a principle of muscle-nerve pedicle transfer for laryngeal reinnervation to relieve airway obstruction following bilateral recurrent laryngeal nerve injury. We have applied the principle of reinnervation proposed by Tucker to treat patients not only with airway obstruction, but also with aspiration and impaired phonation due to interruption of laryngeal innervation. There were 23 patients in this study. The functional defects included: voice alteration in 10 patients, airway obstruction in 8 and aspiration, as well as a voice change, in 5. The causes of injury were surgery in 9 patients, trauma in 5, tumor in 3, polio in 1 and a birth defect in 1 patient. No cause of nerve injury could be determined in 4 patients. The technique employed involved selective reinnervation of the laryngeal nerve branches to one or more laryngeal muscle groups; the muscle groups reinnervated were selected so as to overcome the functional defect of each particular patient. The patients have been followed for 6 mo. or longer. The results have been independently evaluated by a speech pathologist and documented by indirect and direct endoscopic observations, as well as by audio and audio-video recordings. In some cases, there was further documentation by cine-fluoro-audio tape recordings, laryngo-pharyngography, laryngeal tomography and pulmonary function studies. The muscle-pedicle transfer technique described by Tucker was found to be useful to correct laryngeal dysfunction in carefully selected cases.

Reflex sympathetic dystrophy. Objective clinical signs in diagnosis and treatment.

Diagnosis and follow-up treatment of reflex sympathetic dystrophy is difficult because of the subjective, nonspecific nature of its primary symptom, burning pain. Early diagnosis and aggressive treatment of reflex sympathetic dystrophy with epidural nerve blocks improves clinical resolution. Temperature difference between extremities and dependent cyanosis are reliable objective signs for clinical diagnosis and the evaluation of progress for treatment for reflex sympathetic dystrophy.

Case report: increased myocardial irritability with halothane and aminophylline.

Increased cardiac sensitivity to epinephrine during halothane anesthesia has been well documented; however, there are few reports of increased cardiac irritability due to interaction between halothane anesthesia and aminophylline. The following case report is suggestive of such an interaction resulting in ventricular tachycardia.

Reflex sympathetic dystrophy involving the foot.

Reflex sympathetic dystrophy often presents with the subjective chief symptom of pain. This paper demonstrates that careful study of the subtle and often cyclical objective signs can be used to assess the state of the disease. It may also evaluate progress of treatment.

Anesthetic considerations for the oral surgery patient with hemophilia.

Hemophiliac patients undergoing oral surgical procedures can be a challenge for both dental and medical personnel involved in their care and treatment. Anesthetic management of hemophiliac patients may be safely attained by various pain control techniques including local anesthesia. Possible complications resulting from administration of anesthesia must be kept in mind at all times. Preparation, caution, and gentleness are necessities for administration of safe and effective anesthesia to the hemophiliac patient.

Comparison of the effects of succinylcholine and atracurium on intracranial pressure in monkeys with intracranial hypertension.

The effects of succinylcholine (1.5 mg X kg-1 IV) administered five minutes after a defasciculating dose of curare (0.05 mg X kg-1 IV), were compared with the effects of atracurium (0.5 mg X kg-1 IV) on intracranial pressure (ICP) in 13 cynomolgus monkeys with intracranial hypertension (ICP approximately 25 mmHg). Neither succinylcholine nor atracurium increased ICP during general anaesthesia with 60 per cent N2O/O2, 0.5-1 per cent halothane. During a rapid sequence induction and intubation with thiopentone 5 mg X kg-1 IV, ICP increased equally with intubation following both atracurium (25 +/- 1 to 32 +/- 2 mmHg) and succinylcholine (25 +/- 1 to 31 +/- 2 mmHg) (p less than 0.05). Intubation was also associated with significant increases in PaCO2, CVP and MAP. We conclude that in this primate model of intracranial hypertension, neither atracurium nor succinylcholine (when given following a defasciculating dose of curare) elevates ICP. In terms of the elevation of ICP associated with intubation, atracurium was found to offer no advantage over succinylcholine.

Brain blood flow autoregulation and metabolism during halothane anesthesia in monkeys.

Past studies suggest that halothane causes cerebrovascular dilatation and increased cerebral blood flow (CBF); these properties may be relevant to its use for neurosurgical procedures. We studied CBF autoregulation in monkeys during anesthesia with 66% N2O/33% O2 and with 0.5%, 1.0%, and 2.0% inspired halothane at various cerebral perfusion pressures (CPP) achieved by infusion of trimethaphan camsylate or phenylephrine. CBF was measured by monitoring brain xenon-133 clearance after intra-arterial injection of the isotope in saline. CBF autoregulation was intact during N2O/O2 and during 0.5% halothane/N2O/O2 anesthesia at CPPs ranging from 50 to 100 mmHg, but began to fail at 1.0% halothane. Complete loss of autoregulation occurred during 2% halothane/N2O/O2 anesthesia. Estimated brain O2 consumption fell by 30%, 40%, and 50% during 0.5%, 1.0%, and 2.0% halothane anesthesia, respectively, compared to O2 consumption during N2O/O2 anesthesia (100%).

Inadvertent endobronchial intubation with nasogastric tube. Occurrence after head and neck surgery.

Inadvertent endobronchial intubation with nasogastric tubes is hazardous. Massive aspiration can be fatal after nasogastric feeding. In this study, methods of blind nasogastric tube insertion and conventional techniques of confirming the site of the tube are discussed. We stress that direct laryngoscopy either during or immediately after placement or a chest roentgenogram should be considered in the case of nasogastric feeding after major head and neck surgery.

Free fatty acid accumulation in the pathogenesis and therapy of ischemic-anoxic brain injury.

Energy depletion and lactate are at plateau levels within five minutes of complete ischemic-anoxia in the brain; however, irreversible brain injury has not occurred in this time. Brain free fatty acids (FFA) rise sharply during the first five minutes of ischemic-anoxia, but then continue to rise during the following hour without plateauing. Barbiturate anesthesia preischemia attenuates the FFA rise. Other agents which also attenuate the FFA increase include, among others, phenytoin and Innovar. The Ca2+ antagonists flunarizine and gallopamil also attenuated FFA rise, but were not as effective as pentobarbital during ischemia. Protective effects of Ca2+ antagonists may be more important during recirculation than during ischemia.

Postoperative venous air embolism after removal of neck drains.

Venous air embolism has been known to be a major hazard during diagnostic, therapeutic, and surgical procedures. An acute massive venous air embolism can cause obstruction of the pulmonary outflow tract and subsequently result in cardiac standstill. Sudden cardiopulmonary instability occurred in a patient after removal of neck drains. Various methods of diagnosis and treatment can be used to manage this complication. An awareness of this potential complication and early diagnosis with prompt management are critical.

Absence of beta-adrenergic receptor involvement in cerebrovascular dilation by halothane in monkeys.

We determined, in monkeys, whether halothane-induced cerebrovascular dilation is mediated by beta-adrenergic receptors and whether cerebrovascular tone progressively returns to baseline values during prolonged halothane anesthesia. Total cerebral blood flow (CBF), cerebral perfusion pressure, plasma halothane concentration, and arterial blood gas tensions and pH were measured in 14 rhesus monkeys mechanically ventilated with 0.5% (inspired) halothane, 33% O2 and balance N2O. Halothane was increased to 2.0% and the measurements repeated 30 and 60 min later. Then either 0.9% NaCl (controls n = 6) or propranolol (n = 8), 1.0 mg/kg was infused intravenously over 10 min, and the measurements repeated at 70, 90, 120, and 150 min. After 30 min at 2.0% halothane, CBF increased in the controls by 50% (P less than 0.05) from 92 +/- 8 (mean +/- SD) to 137 +/- 39 ml X 100 g-1 X min-1 and in the propranolol group by 30% (P less than 0.05) from 106 +/- 33 to 137 +/- 28 ml X 100 g-1 X min-1. After 2.5 hr of 2.0% halothane anesthesia, CBF remained elevated above baseline levels, but by only 28 and 23% in the control and propranolol groups, respectively. Cerebrovascular resistance was identical in both groups (0.55 +/- 0.33 vs 0.53 +/- 0.13 mm Hg X ml-1 X 100 g 1 X min 1). The results show that there is only a 10-20% return of CBF toward baseline levels after up to 2.5 hr of 2% halothane anesthesia. The results also indicate that halothane-induced cerebrovascular dilation is not mediated by beta-adrenergic receptors.

Global brain ischemia: a reproducible monkey model.

We developed a monkey model of 16 minutes global brain ischemia (GBI) resulting in reproducible, severe, permanent functional neurologic deficit with long term (7 days) postischemic (PI) survival made possible by standardized intensive care with 24 hour coverage by trained personnel. Quantitated neurologic deficit (ND) and brain histopathological examinations were developed. Fifteen minutes GBI resulted in rapid recovery within12--24 hours PI without residual neurologic sequelae. Twenty minutes GBI caused severe neurologic deficit and within 4 days PI, a delayed Cushing response eventually leading to cardiac arrest. Sixteen minutes GBI resulted in severe neurologic deficit (monkeys unable to sit, stand, walk, or feed themselves), but with long term survival. Brain histopathological analyses revealed a combination of cortical and brainstem lesions. Severest changes were observed in the occipital (calcarine) cortex with less severe damage in the frontal and temporal regions. Oculomotor nuclei and medial longitudinal fasciculus in the midbrain were regularly affected. With this model we can test the efficacy of promising therapies in terms of clinically relevant variables.

[Pathogenesis and treatment of anoxic encephalopathy. Definition and importance of experimental animal models (author's transl)]. / Pathogénie et traitement de l'encéphalopathie anoxique. Définition et utilité des modèles expérimentaux animaux.

A reproducible noninvasive monkey model for global brain ischemia with exact insult (no flow x 16 min) to the brain, with survival and with standardized preischemic, ischemic and postischemic variables is described. This model allowed us to demonstrate for the first time: 1) that a substantial part of brain damage early postischemia is reversible and amenable especially to barbiturate treatment; 2) that the postischemic brain shows increased vulnerability for additional insults. Optimal postischemic intensive monitoring and immobilization for 24-48 hours is important for improved outcome; 3) that immediate postischemic reperfusion pressure (MAP 110-150 mm Hg) significantly improves the outcome; 4) that heparinisation during ischemia has no protective effect and 5) that postischemic heparinisation and intravenous hemodilution does not ameliorate the outcome. The protective effect of trimetaphan against neurogenic pulmonary edema can be explained by the prevention of pulmonary hypertension but its protective effect on the development of secondary cerebral edema has to be elucidated.

Augmentation of postischemic brain damage by severe intermittent hypertension.

The neurological recovery and histological changes were studied in monkeys after intermittent postischemic arterial hypertension after 16 min of global brain ischemia. Ischemia was produced with a high pressure (1500 mm Hg) neck tourniquet and systemic arterial hypotension. Intensive care and life support, including monitoring of physiological variables, were provided for 7 days. Postischemia all monkeys were immobilized; ventilation was controlled and mean arterial pressure was maintained between 85--115 mm Hg for the first 48 hours. Immediately postischemia in four monkeys, intermittent arterial hypertension (i.e., 150--190 mm Hg) was induced by norepinephrine infusion for 3--5 min. Hypertensive episodes were repeated at 15, 30, 60, and 120 min postischemia, once every hour for the first 24 hours and once every 2 hours between 24 and 48 hours. Thereafter, the monkeys were allowed to breathe spontaneously. Four control monkeys were similarly treated except that arterial hypertension was not induced. Neurological recovery was evaluated by EEG, intracranial pressure, neurological deficit scoring, and histological examination of the brain after killing on day 7 postischemia. The neurological deficit score (100 % = brain death; 50% = vegetative state; 0% = normal) in control monkeys on day 7 was 17.8 +/- 1.8 (SEM) % compared to 46.3 +/- 6.5% (p less than 0.05) in the hypertension group. EEG recovery was delayed and the postischemic increase in intracranial pressure was prolonged in the hypertension group. Histological damage scores in the brain correlated with neurological deficit scores. Severe intermittent hypertension has a deleterious effect on neurological recovery after global brain ischemia.