William L. Lanier

Temperature Changes of greater or equal to 1 degree Celsius Alter Functional Neurologic Outcome and Histopathology in a Canine Model of Complete Cerebral Ischemia

Background Changes in basal temperature of greater or equal to 1 degree Celsius (e.g., fever-induced hyperthermia or anesthesia-related hypothermia) are a common occurrence in neurologically impaired patients. The current study tested the hypothesis that temperature changes as small as 1 degree Celsius or 2 degrees Celsius would significantly alter post-ischemic functional neurologic outcome and cerebral histopathology. The hypothesis was tested in a canine model of transient, complete cerebral ischemia.

Glucose Modulation of Ischemic Brain Injury: Review and Clinical Recommendations

Ischemic brain injury is the third-leading cause of death among Americans and the leading cause of serious disability. Based on studies of animal models, a substantial amount of experimental evidence shows that hyperglycemia at the onset of brain ischemia worsens postischemic neurologic outcome. Consistent with these observations, hyperglycemia also is associated with a worsening of postischemic brain injury in humans. In humans, however, data are often difficult to interpret because of problems in determining the timing of hyperglycemia relative to a critical ischemic event and in elucidating the effect of coexisting pathophysiologic processes (for example, a stress response) on outcome. Glucose modulation of neurologic injury is observed when ischemia is either global (for example, that accompanying cardiac arrest or severe systemic hypotension) or focal (for example, that accompanying thrombotic or embolic stroke). Toxicity is probably the result of an intracellular lactic acidosis. Specifically, the associated hydrogen ions are injurious to neurons and glia. On the basis of these factors, we recommend diligent monitoring of blood glucose concentrations in patients who are at increased risk for new-onset, ongoing, or recurring cerebral ischemia. In such patients, the use of fluid infusions, corticosteroid drugs, and insulin, as well as stress management, should be tailored to treat preexisting hyperglycemia and prevent new-onset hyperglycemia. Maintenance of normoglycemia is recommended. When one attempts to treat preexisting hyperglycemia, care should be taken to avoid rapid fluid shifts, electrolyte abnormalities, and hypoglycemia, all of which can be detrimental to the brain.

Nimodipine Improves Outcome when Given after Complete Cerebral Ischemia in Primates

Twenty-seven pigtailed monkeys (Macaca nemestrina) were subjected to 17 min of complete cerebral ischemia followed by 96 h of intensive care treatment. Fourteen of the monkeys were assigned randomly to the treatment group and received nimodipine 10 μg·kg−1 5 min postischemia followed by 1 μg·kg−1·min−1 for 10 h. Six monkeys (three treated) failed to meet preestablished protocol criteria and were excluded. The remaining treated and untreated monkeys were well matched for age, sex, and other physiologic variables. Neurologic outcome at 96 h postischemia was significantly better in the nimodipine-treated monkeys than in the controls. Eight of the 11 treated animals had an apparent normal level of consciousness; four of these had no detectable neurologic deficits and a fifth had only a slight motor apraxia. Only two of the 10 untreated animals had an apparent normal level of consciousness, and all had major neurologic deficits. Histopathologic examination showed variable ischemic neuronal change and infarction to involve gray matter in distal arterial perfusion zones. Significant white matter changes were not observed. A histopathologic scoring system yielded a significantly better mean score for the treated group than for the untreated group, and there was significant correlation between neurologic function and histopathologic findings. The authors conclude that nimodipine improves the neurologic outcome when given after an episode of complete cerebral ischemia in primates, and they recommend controlled clinical trials in patients resuscitated after cardiac arrest.

The effects of dextrose infusion and head position on neurologic outcome after complete cerebral ischemia in primates: examination of a model.

The hypothesis that iv dextrose infusion prior to--and head position during--cerebral ischemia would influence the severity and pattern of neurologic injury was tested in primates. Fifteen pigtail monkeys weighing 3.3 +/- 0.2 kg (mean +/- SE) were subjected to 17 min complete cerebral ischemia followed by 24 h intensive care treatment and neurologic assessment for an additional 72 h. Monkeys were given 50 ml iv infusions of either dextrose 5% in 0.45% saline solution (n = 8) or lactated Ringers solution (n = 7) during the preparatory period. This volume corresponds to approximately 1 1/70 kg individual. These same monkeys were placed in either the lateral (n = 3), prone (n = 5), or supine (n = 7) position during the ischemic period. Two monkeys failed to meet preestablished protocol criteria and were excluded from data analysis. Blood glucose immediately preischemia in the dextrose-treated group (181 +/- 19 mg X dl-1) was not significantly greater than in the group given lactated Ringers solution (140 +/- 6 mg X dl-1; P = 0.07). Dextrose infusion resulted in significantly greater cerebral injury at 96 h postischemia when comparing both neurologic (P less than 0.05) and histopathology (P less than 0.05) scores. Specifically, dextrose administration resulted in the greatest injury to the insular cortex, thalamus, Purkinje cells, and substantia nigra. Although blood glucose was less than 250 mg X dl-1 in all monkeys at the time of complete cerebral ischemia, there was a high correlation between blood glucose rank and neurologic function rank (rs = 0.76; P less than 0.005). The authors were unable to note any effect of head position on the distribution of histopathologic lesions. Prior to removing the brain for histopathologic studies, four monkeys were given repeat infusions of 50 ml dextrose 5% in 0.45% saline solution over 11 +/- 1 min. These infusions produced increases in blood glucose from 56.7 +/- 7.6 to 244 +/- 24.9 mg X dl-1 (P less than 0.01) and increases in brain glucose from 1.64 +/- 0.22 to 5.11 +/- 0.48 mumol X g-1 (P less than 0.01).

Occurrence of Potentially Detrimental Temperature Alterations in Hospitalized Patients at Risk for Brain Injury

OBJECTIVE To ascertain the incidence and timing of fever in patients at risk for temperature modulation of brain injury resulting from ischemia or trauma. DESIGN We retrospectively reviewed the medical records of patients admitted between January 1991 and December 1994. MATERIAL AND METHODS We investigated three groups of hospitalized patients considered at risk for ongoing brain injury resulting from a prior cerebral insult: successful resuscitation from out-of-hospital cardiac arrest (CA), subarachnoid hemorrhage (SAH), or traumatic closed-head injury (CHI). Forty patients per condition were randomly selected from those who survived for more than 24 hours after hospital admission. RESULTS During the initial 72 hours of hospitalization, temperature increases to 38 degrees C or more (that is, temperatures previously reported to worsen neurologic outcome after brain injury) were noted in 83% of patients with CA, 70% of those with SAH, and 68% of those with CHI. Within the cohort of febrile patients, 18 to 44% of all temperature measurements were 38 degrees C or higher, and the febrile episodes occurred randomly throughout the study interval. Fewer than one-eighth of the febrile patients received drugs possessing antipyretic properties (such as aspirin or acetaminophen) in a dose appropriate to treat fever. No other method of temperature control (for example, physical means) was used in any patient. The fractions of patients who were dismissed from the hospital with permanent neurologic injury were as follows: CA, 20%; SAH, 45%; and CHI, 43%. CONCLUSION In these hospitalized patients at risk for ongoing brain injury, the incidence of temperature increases within the range reported to worsen neurologic outcome (elevations of 1.0 degree C or more) was very high. The characterization of these potentially injurious, randomly occurring, and traditionally undertreated temperature increases may have implications for the design of future protocols aimed at providing cerebral protection.

The Effects of Dizocilpine Maleate (MK-801), an Antagonist of the N-Methyl-D-Aspartate Receptor, on Neurologic Recovery and Histopathology Following Complete Cerebral Ischemia in Primates

The present study was designed to determine if the noncompetitive excitatory amino acid antagonist, dizocilpine maleate, when administered after a 17 min period of complete cerebral ischemia in primates, would improve postischemic neurologic function and hippocampal histopathologic outcome when compared to placebo-treated animals. Ten pigtail monkeys were anesthetized and subjected to complete cerebral ischemia using an established neck tourniquet model. Five minutes postischemia, five monkeys received dizocilpine 300 μg/kg i.v. over 5 min, followed by an infusion of 150 μg/kg/h for 10 h. This produced plasma levels of the drug in excess of 30 ng/ml for the duration of the infusion. An additional five monkeys were treated with an identical volume of saline placebo. All monkeys received intensive care for the initial 24 to 48 h postischemia. At 96 h postischemia, there was no significant difference in neurologic function between the two groups (p = 0.53, with the placebo group having the numerically better outcome). There also was no significant difference between hippocampal histopathology scores between dizocilpine and placebo-treated monkeys. The authors conclude that dizocilpine is not an efficacious therapy in the treatment of neurologic injury that occurs following complete cerebral ischemia in this primate model.

The Cerebral and Systemic Effects of Movement in Response to a Noxious Stimulus in Lightly Anesthetized Dogs Possible Modulation of Cerebral Function by Muscle Afferents

BackgroundAfferentation theory predicts that agents or maneuvers that stimulate muscle stretch receptors (i.e., muscle afferents) will produce cerebral stimulation. From this theory it follows that, regardless of the source (e.g., drug effect, active muscle movement), increases in stretch receptor activity should result in a similar effect on the brain. The present study tested the hypothesis that active muscle movement in lightly anesthetized subjects would result in cerebral stimulation. MethodsStudies were conducted in six dogs who were lightly anesthetized with halothane (0.70% end-expired). The following physiologic variables were quantified before and for 6 min after the initiation of a standardized (1-min duration) noxious stimulus to the trachea and the skin overlying the hind limb: cerebral blood flow, cerebral metabolic rate for oxygen (CMRO2), cerebral perfusion pressure, cerebral vascular resistance, electroencephalogram activity, electromyogram activity, arterial carbon dioxide partial pressure (PaCO2), central venous pressure, and serum epinephrine and norepincphrine concentrations. Response to stimulation was evaluated initially in unparalyzed dogs and later was evaluated in the same dogs after they were paralyzed with intravenous pancuronium (0.2 mg/kg). ResultsIn unparalyzed dogs, stimulation produced episodes of coughing plus head and limb movement during the 6-min study period. Accompanying the movement was activation of the electromyogram, an increase in electroencephalogram frequency, and a reduction in electroencephalogram amplitude. There also was a 35% increase in cerebral blood flow, a 25% decrease in cerebral vascular resistance, and a 7% increase in CMRO2 versus the baseline values for each variable. There were no significant increases in either cerebral perfusion pressure, central venous pressure, PaCO2, or serum norepinephrine concentration to account for the cerebral effects; however, serum epinephrine concentrations increased by 61%. In pancuronium-paralyzed dogs, noxious stimulation resulted in a 5% increase in cerebral blood flow, a 7% decrease in cerebral vascular resistance, and an 5% increase in CMRO2 versus baseline levels. Electroencephalogram frequency was increased, but amplitude was unchanged. Central venous pressure, electromyogram activity, and serum norepinephrine concentration were unaffected. The serum epinephrine response was similar to that observed when the dogs were not paralyzed. ConclusionsThese data support the hypothesis that active muscle movement in lightly anesthetized subjects has an effect on the brain that is mediated in part by muscle afferent receptors. This cerebral response was manifested as electroencephalogram activation, cerebral vasodilation unrelated to central venous pressure changes, and an increase in cerebral blood flow greater than that required to meet metabolic demands. Paralysis with pancuronium abolished movement induced by stimulation (and, thus, the muscle afferent response) and also attenuated the cerebral blood flow, cerebral vascular resistance, and electroencephalogram responses.

Glucose management during cardiopulmonary bypass: cardiovascular and neurologic implications.

Metz and Keats (1) report in the present issue on the relationship between glucose-containing priming solutions in the cardiopulmonary bypass (CPB) circuit and perioperative cardiac and neurologic function. Their conclusions are twofold: first, glucose solutions in the CPB circuit reduce intraoperative fluid requirements and improve perioperative fluid balance; and, second, glucose does not increase postoperative neurologic injury. When reduced to its essence, the study by Metz and Keats had a single positive finding: glucose-treated subjects had a more favorable perioperative fluid balance. The use of glucose was associated with increased urine output, but it did not alter inotrope use, diuretic requirement, or hospital course. The greatest difference in fluid requirement occurred during the CPB period: glucose-treated subjects received one-eighth the amount of crystalloid given to non-glucose-treated patients (144 * 270 vs 1147 * 1149 mL; mean ? SD; P < 0.001). The decision to give fluid during CPB was based on the status of the CPB-reservoir volume, and flexibility was permitted ”depending on (the) stage of operation.” The process was not blinded. The second conclusion of the study by Metz and Keats was that glucose administration during CPB and coronary artery bypass grafting (CABG) does not adversely affect postoperative neurologic function. This conclusion, based on data from their study and from their interpretation of the related literature, deserves comment. The study by Metz and Keats evaluated 107 patients undergoing CABG. They reported only two

Ten Common Questions (and Their Answers) About Off-label Drug Use

The term off-label drug use (OLDU) is used extensively in the medical literature, continuing medical education exercises, and the media. Yet, we propose that many health care professionals have an underappreciation of its definition, prevalence, and implications. This article introduces and answers 10 questions regarding OLDU in an effort to clarify the practices meaning, breadth of application, acceptance, and liabilities. Off-label drug use involves prescribing medications for indications, or using a dosage or dosage form, that have not been approved by the US Food and Drug Administration. Since the Food and Drug Administration does not regulate the practice of medicine, OLDU has become common. It occurs in every specialty of medicine, but it may be more common in areas of medicine in which the patient population is less likely to be included in clinical trials (eg, pediatric, pregnant, or psychiatric patients). Pharmaceutical companies are not allowed to promote their medications for an off-label use, which has lead to several large settlements for illegal marketing. To limit liability, physicians should prescribe medications only for indications that they believe are in the best interest of the patient. In addition, health care professionals should educate themselves about OLDU to weigh the risks and benefits and provide the best possible care for their patients.

Cerebral Stimulation Following Succinylcholine in Dogs

The effects of iv succinylcholine (SCh) on the electroencephalogram (EEG), cerebral blood flow (CBF), cerebral metabolic rate (CMRo2), intracranial pressure (ICP), central venous pressure (CVP), and mean arterial pressure (MAP) were tested in halothane-anesthetized dogs. Six dogs were maintained at 0.87 ‡ 0.00% (mean ‡ SE) expired halothane (1.0 MAC) and received both SCh 1.0 mg. kg−1and lactated Ringers solution placebo 0.05 ml. kg−1. Fasciculations began 24 ‡ 4 s after iv SCh. Fasciculations were followed by immediate EEG arousal in five of six dogs and increases in CBF in all six. Average CBF was 151 ‡ 14% of control for the 0–15 min measurement period and 127 ‡ 7% of control for the 15–30 min period. Both were significantly greater than pre-SCh control values and placebo group values. Peak CBF of 177 ‡ 19% of control occurred 3 min after iv SCh and was accompanied by a peak ICP of 435 ‡ 131% of control. ICP values were significantly different between SCh and placebo treatments only during the periods of greatest CBF (1 to 5 min after iv SCh). Average Paco2 values after iv SCh were significantly greater than pre-SCh control values and placebo values during each 15-min measurement interval. Average Paco2 was 116 ± 2% of control during the 0–15 min measurement period, 114 ± 2% of control during the 15–30 min period, and 109 ± 1% of control during the 30–45 min period. CVP, MAP, and CMRo2 did not significantly change after iv SCh. In two dogs maintained at 1.32 ± 0.01% expired halothane (1.5 MAC), SCh 1.0 mg. kg−1produced Paco2 changes comparable with those in dogs maintained at 1.0 MAC halothane without comparable changes in CBF, ICP, or EEG. In an additional two dogs receiving pancuronium 0.2 mg.kg−1and 1.0 MAC halothane, SCh had no meaningful effect on any variable measured. The authors conclude that iv SCh increased ICP in the dog secondary to increases in CBF. They hypothesize that the CBF increases are related primarily to SCh-induced increases in afferent muscle spindle activity and secondarily to increases in Paco2.