Neuroprotection by anaesthetics in rodent models of traumatic brain injury: a systematic review and network meta-analysis.

BACKGROUND: Anaesthetic neuroprotection in the setting of traumatic brain injury (TBI) remains unproved and is based upon the results in preclinical experiments. Here, we sought to synthesise the results in rodent models of TBI, and to evaluate the effects of publication bias, experimental manipulation, and poor study quality on the effect estimates. METHODS: After a systematic review, we used pairwise meta-analysis to estimate the effect of anaesthetics, opioids, and sedative-hypnotics on neurological outcome, and network meta-analysis to compare their relative efficacy. We sought evidence of bias related to selective publication, experimental manipulation, and study quality. RESULTS: Sixteen studies, involving 32 comparisons, were included (546 animals). The treatment improved the neurological outcomes by 35%; 95% confidence interval: 26-44%; P<0.001. The statistical heterogeneity was small (12%), but the 95% prediction interval for the estimate was wide (15-56%). The statistical power was low: 61% (90% confidence interval: 22-86%). The small sample size in the studies was a serious shortcoming reducing the statistical heterogeneity and obscuring differences in outcome between drugs and between experimental conditions. CONCLUSIONS: Anaesthetics do provide neuroprotection in rodent models of TBI. The effect-size estimates do not appear to be exaggerated by selective publication, experimental manipulation, or study design. The main shortcoming of the included studies were small sample sizes leading to low power and imprecision, which precluded the network meta-analysis from providing a meaningful ranking for efficacy amongst the drugs. Reliable preclinical investigations of neuroprotection by anaesthetics will require larger sample sizes.

The effect of pentobarbital and isoflurane on glucose metabolism in thermally injured rat brain.

The effect of pentobarbital and isoflurane on cerebral glucose metabolism (CMRglc) was studied in thermally injured rat brain using quantitative autoradiography. In awake lesioned animals, CMRglc in cortical regions ipsilateral to the injury was reduced to 50% of normal while little if any decrease was observed in contralateral cortical regions and subcortical regions bilaterally. Treatment of lesioned animals with pentobarbital or isoflurane further reduced CMRglc, but more in the hemisphere contralateral to the injury than on the injured side. Thus, the side-to-side difference in cortical CMRglc present in the awake lesioned animals was abolished by the anesthetics. The results support the hypothesis that CMRglc depression associated with a focal cold injury is functional in nature. Reduction of metabolism by anesthetics in functionally depressed brain is limited by the decrease in CMRglc associated with the injury.

Effects of rapid mannitol infusion on cerebral blood volume. A positron emission tomographic study in dogs and man.

Positron emission tomography was used to study the effect of a rapid infusion of mannitol on cerebral blood volume (CBV) in five dogs and in three human subjects. The ability of mannitol to reduce intracranial pressure (ICP) has always been attributed to its osmotic dehydrating effect. The effects of mannitol infusion include increased osmolality, total blood volume, central venous pressure (CVP), and cerebral blood flow, and decreased hematocrit, hemoglobin concentration, serum sodium level, and viscosity. Mannitol's ability to dilate the cerebral vasculature, either directly or indirectly, and thus to transiently increase ICP, is a subject of controversy. By in vivo labeling of red cells with carbon-11, the authors were able to demonstrate an early increase in CBV in dogs of 20%, 27%, and 23% (mean increase, p less than 0.05) at 1, 2, and 3 minutes, respectively, after an infusion of 20% mannitol (2 gm/kg over a 3-minute period). The animals' muscle blood volume increased by 27% (mean increase, p less than 0.05) 2 minutes after infusion. In the human subjects, lower doses and a longer duration of infusion (1 gm/kg over 4 minutes) resulted in an increase in CBV of 8%, 14% (p less than 0.05), and 10% at 1, 2, and 3 minutes, respectively, after infusion. In dogs, ICP increased by 4 mm Hg (mean increase, p less than 0.05) 1 minute after the infusion, before decreasing sharply. The ICP was not measured in the human subjects. Hematocrit, hemoglobin, sodium, potassium, osmolality, heart rate, mean arterial pressure (MAP), and CVP were measured serially. Results of these measurements, as well as the significant decrease in MAP that occurred after mannitol infusion, are discussed. This study demonstrated that rapid mannitol infusion increases CBV and ICP. The increase in muscle blood volume, in the presence of a decreased MAP and an adequate CVP, suggests that mannitol may have caused vasodilation in these experiments.

Enhancement of CNS activity by thiopentone: comparison of nocifensive reflexes with hippocampal EEG.

1. This study tested the hypothesis that the nociceptive effects of thiopentone, are pharmacodynamically distinct from EEG effects. 2. We concurrently examined the effects of thiopentone on nocifensive reflex thresholds and on the power spectrum of the hippocampal electroencephalogram (hEEG) in chronically instrumented rats. 3. Pharmacodynamic descriptors were derived to characterize the biphasic (enhancement followed by depression) relationship between plasma thiopentone concentrations and the CNS effects. 4. Peak facilitation of nocifensive reflexes occurred at 13 (10-16) microg/ml whereas maximal enhancement of hEEG was observed at 16 (12-20) microg/ml. 5. The enhancement produced by low concentrations of thiopentone on nocifensive reflexes appear to pharmacodynamically distinct from the hEEG excitation produced within a similar range of thiopentone concentrations.

[Physiopathological consequences of blood-brain barrier involvement]. / Conséquences physiopathologiques d'une atteinte de la barrière hématoencéphalique.

Most of the adverse effects of cerebral injury derive result from the formation of cerebral oedema, which causes brain swelling, brain shift and intracranial hypertension. The mechanisms of cerebral oedema are specific of the type of cerebral injury and the effectiveness of treatments such as corticosteroids depend on the type of cerebral oedema. Recent magnetic resonance imaging studies of the brain in patients with acute intracranial injury have confirmed that anatomical brain shifts accompany the clinical syndromes of brain herniation. In particular, specific neurological syndromes can effectively identify rostro-caudal herniation, both transtentorially (uncal and central syndrome) and through the foramen magnum. Signs of upward transtentorial herniation are less specific. Early detection of these syndromes is essential if therapeutic measures to reduce intracranial pressure are to be taken before secondary neurological injury occurs.

[Role of blood-brain barrier in cerebral homeostasis]. / Rôle de la barrière hématoencéphalique dans l'homéostasie cérébrale.

By a variety of mechanisms, the cerebral endothelium isolates the extracellular fluid space in the central nervous system from the plasma. The combination of physical and enzymatic mechanisms which prevent macromolecules, polar solutes, neurotransmitters, peptides, and electrolytes from passively entering the brain has been termed the blood-brain barrier (BBB). Specific mechanisms provide facilitated transport across the BBB and active secretion of extracellular fluid and CSF maintain homeostasis for nutrients and for cation and H+ respectively. Consequently, interstitial fluid volume in the CNS does not increase when the total extracellular fluid volume is increased. Total tissue volume is sensitive to osmotic forces, while oncotic forces are relatively unimportant. Most anaesthetic drugs are sufficiently lipid soluble that they enter the CNS easily by passive diffusion. Differences in the rates of CNS penetration between drugs can be predicted from their lipid solubility. Anaesthetic drugs have little effect on BBB permeability and their effects on brain oedema formation derive principally from their haemodynamics effects.

[Perioperative effects of the prone position: anesthesiologic aspects]. / Effets peropératoires de la position ventrale: aspects anesthésiques.

The prone position is commonly used for surgery of the spine and the posterior fossa, and is well tolerated by the majority of patients. As long as the abdomen is not compressed, the physiologic impact of this position on cardiorespiratory function is minor, in some cases even less than with the supine position. However extremes of position, particularly of the head and neck, are poorly tolerated and may lead to a variety of severe neurological complications. In addition, several specific forms of pre-existing pathology may predispose the prone patient to major cardiorespiratory complications. In this paper we have systematically reviewed the English and French literature from 1991 to 1997 using Medline Search of peer reviewed journals for the search terms "prone position" and "prone position and venous air embolism". The 330 collected references were reviewed for quality. In combination with review of current standard textbooks these references form the basis for the current report.

[Use of mannitol in neuroanesthesia and neurointensive care]. / Utilisation du mannitol en neuroanesthésie et neuroréanimation.

Mannitol, the osmotic diuretic used in neuroanaesthesia and neurointensive care, has, in addition to its osmotic properties, various effects upon haemodynamics, cerebral blood flow and cerebral blood volume. Three factors are proposed to contribute to mannitol's capacity to lower intracranial pressure and to improve cerebral compliance: cerebral dehydration, and two forms of autoregulation-mediated vasoconstriction. In the case of viscosity autoregulation, it is admitted that changes in blood viscosity after mannitol result in reflex vasoconstriction to maintain cerebral blood flow constant. It has also been proposed that when mannitol administration results in increased cerebral perfusion pressure, vasoconstriction may occur in vascular beds in which autoregulation to perfusion pressure is preserved. On the basis of its effects on cerebral blood flow and free radical scavenging properties, mannitol has recently been investigated as a cerebral protective agent, with the capacity to reduce or prevent damage due to cerebral ischaemia. Finally, mannitol may be injected into a carotid or a vertebral artery to produce blood-brain barrier breakdown, thus improving the brain penetration of chemotherapeutic agents.

[Enhancement of cardiac performance for prevention and treatment of delayed cerebral ischemia caused by vasospasm]. / Augmentation de la performance cardiaque pour la prévention et le traitement de l'ischémie cérébrale retardée par vasospasme.

Following subarachnoid haemorrhage, delayed cerebral ischaemia from cerebral vasospasm remains the most important cause of mortality and morbidity in patients with surgically secured aneurysms. Therapy with haemodilution, hypertension and volume expansion has been recommended to prevent and treat delayed cerebral ischaemia in these patients on the basis of uncontrolled clinical series (level of evidence III to V, grade C recommendation). Despite the lack of controlled studies, the maintenance of a cardiac index > 3.5 L.min-1.m-2 and a systolic arterial pressure between 120 and 150 mmHg before clipping and 160 to 200 mmHg thereafter is recommended as a prophylactic or therapeutic measure for vasospasm. Close monitoring of neurological and cardiorespiratory status is important to avoid neurologic and systemic complications.

[The effect of position on intracranial pressure]. / Effet de la position sur la pression intracrânienne.

The question as to whether the head and trunk of neurosurgery patients should be elevated remains controversial. This question is particularly important when intracranial hypertension is present. Head up position may have beneficial effects on intracranial pressure (ICP) via changes in mean arterial pressure (MAP), airway pressure, central venous pressure and cerebro spinal fluid displacement. However, in some circumstances, head up position may decrease MAP which in turn will result in a paradoxical rise in ICP through autoregulation mechanisms. Therefore, the degree of head elevation has to be titrated by evaluating the most adequate cerebral perfusion pressure (CPP) for each patient by means of transcranial Doppler or measurement of jugular venous blood oxygen saturation. Head elevation above 30 degrees should be avoided in all cases. In most patients with intracranial hypertension, head and trunk elevation up to 30 degrees is useful in helping to decrease ICP, providing that a safe CPP of at least 70 mmHg or even 80 mmHg is maintained. Patients in poor haemodynamic conditions are best nursed flat. CPP is thus the most important factor in assessment and monitoring when considering head elevation in patients with increased ICP.

[Treatment of hypovolemia in brain injured patients]. / Traitement de l'hypovolémie chez le traumatisé craniocérébral.

The appropriate administration of intravenous fluids in neurosurgical patients remains an area of disagreement between neurosurgeons and anaesthetists. Fluid restriction has long been advocated by the former and is widely believed to reduce or prevent the formation of cerebral oedema. However, such restriction can lead to hypovolaemia which in turn can result in haemodynamic instability. Thus, brain homeostasis should be aimed for through adequate fluid administration and normal or slightly elevated mean arterial pressure. The properties of the endothelium differ between the brain and the remainder of the body. In most non CNS tissues the size of the junctions between endothelial cells averages 65 A. Proteins do not cross these gaps while sodium does. In the brain, the junction size is only 7 A, which is too small to allow crossing by sodium. Investigations with changes in osmotic and oncotic pressure have demonstrated that: 1) reducing osmolality results in oedema formation in all tissues including normal brain; 2) a decrease in oncotic pressure is only associated with peripheral oedema but not in the brain; 3) in case of brain injury, a decrease in osmolality elicits oedema in the part of brain which remained normal; 4) similarly, a decrease in oncotic pressure does not cause an increase in brain oedema in the injured part of the brain. Thus, a major reduction in oncotic pressure is unimportant for the brain, whereas changes in total osmolality are the dominant driving force at this level. To conclude, in a hypovolaemic patient with severe head injury, the crystalloid of choice is NaCl 0.9% and the colloid of choice is hydroxyethylstarch, both with an osmolality > 300 mosm.kg-1. Ringer-lactate is hypoosmotic (255 mosm.kg-1) and may cause or increase cerebral oedema. Mean arterial pressure should be maintained above 80 mmHg.

Effects of two dihydropyridine calcium channel blockers on cerebral metabolism and blood flow in traumatized rat brain.

The effect of two dihydropyridine calcium (Ca) channel blocking drugs on cerebral glucose metabolism (LCGU), blood flow (LCBF), and blood flow-metabolism coupling were studied in thermally injured rat brain using quantitative radioautographic techniques. No reversal of the previously noted LCGU depression caused by the freezing lesion (Pappius, 1981) was detected following treatment with either PY-108-068 (PY) or nimodipine (NIM). These results therefore provided no support for the role of Ca in the mechanism of functional disturbances induced by cold injury (Pappius and Wolfe, 1983b), though they do not rule out its involvement. Treatment with PY, but not NIM, reestablished the normal LCBF-LCGU relationship in cortical areas, which has been shown to be disturbed by the freezing lesion and in subcortical and brainstem structures, in which the alteration caused by the injury was not as pronounced. The results suggest that the mechanism that apparently uncouples LCBF from LCGU in injured brain is altered in the presence of PY. However, since NIM did not have the same effect on LCBF, it is not clear whether the effects of PY relate to blockade of Ca channels or some other effect of PY.

Pharmacodynamics of thiopentone: nocifensive reflex threshold changes correlate with hippocampal electroencephalography.

The electroencephalographic (EEG) effects of thiopentone have been used extensively in the pharmacodynamic and pharmacokinetic modelling of drug effects in the central nervous system (CNS). Thiopentone has a biphasic (enhancement followed by inhibition) effect on nocifensive reflexes that occurs in a dose range similar to that which activates the EEG. In this study we have used rats chronically instrumented with hippocampal EEG (hEEG) electrodes to simultaneously characterize the effects of thiopentone on the hEEG and nocifensive reflex thresholds. Enhancement of these two measures of CNS effect correlated well with plasma thiopentone concentrations of 10-30 micrograms ml-1 (35-75 mumol litre-1) but maximal reflex enhancement occurred at concentrations of 3 micrograms ml-1 (11 mumol litre-1) less than the peak hEEG effect. The results validate the usefulness of nocifensive reflex thresholds for measurement of the CNS effects of thiopentone at subanaesthetic concentrations.

Acetazolamide and amiloride inhibit pentobarbital-induced facilitation of nocifensive reflexes.

BACKGROUND: Neuronal excitation may result from stimulation of gamma-aminobutyric acid A (GABA(A)) receptors that prolong the channel opening, depolarizing the postsynaptic membrane. Drugs such as acetazolamide or amiloride can block GABA depolarization. Barbiturates facilitate nociceptive reflexes and also prolong the GABA(A) channel open-time. To evaluate the possible mechanism, the authors studied the impact of acetazolamide and amiloride on pentobarbital-induced nocifensive reflex facilitation. Because nitric oxide (NO) is a mediator of reflex facilitation, the authors evaluated the effects of NO synthase inhibition. METHODS: Nocifensive reflex thresholds were quantified with the hind paw withdrawal latency from radiant heat (HPW latency) in the rat. Nocifensive reflexes were facilitated with intraperitoneal injection of pentobarbital (30 mg/kg). The authors tested the roles of GABA-mediated depolarization and NO in reflex facilitation by pretreatment with acetazolamide and amiloride and inhibition of NO synthase with L-NAME and 7-NI, respectively. Sedative effects of pentobarbital were evaluated with the righting reflex, the response to vibrissal stimulation, and plasma drug concentrations. RESULTS: Pentobarbital decreased the hind paw withdrawal latency from 11.2+/-1 to 8.3+/-1 s (P < 0.001). Pretreatment with each of the four test drugs limited the reduction in reflex facilitation after pentobarbital to 1.3 s or less, similar to the reduction seen after saline injection, without altering sedation. L-NAME increased plasma pentobarbital concentrations by 10% without changing the concentration associated with return of responsiveness. CONCLUSIONS: Pentobarbital-induced nocifensive reflex facilitation was inhibited by all four tested drugs without evidence of increased sedation. The results are consistent with a role for GABA(A) receptor-mediated depolarization in barbiturate-induced hyper-reflexia.

The influence of cryogenic brain injury on nociception in the rat.

BACKGROUND: Previous studies have suggested that focal cryogenic brain lesions that cause functional cerebral depression may increase anesthetic potency. To determine whether this effect was caused by changes in nociception, this study prospectively evaluated the influence of an experimental focal brain injury on the analgesic effects of the opioids, fentanyl and alfentanil, in rats. METHODS: The cortical freezing lesion was made with a brass probe cooled to -50 degrees C, applied through a craniotomy to the intact dura for 5 s. The analgesic effects of the opioids were quantified by tail-flick latency 3 days after the injury. The prolongation of tail-flick latency by infusions of each opioid in animals injured with a standardized cortical freezing lesion was compared with the results obtained from sham-operated control animals. RESULTS: At the endpoint of the experiment, prolongation of the tail-flick latency to 10 s, the mean serum concentrations (EC50) of both fentanyl and alfentanil were approximately 25% less in the brain-injured animals than in the controls (EC50 fentanyl; injured: 10.2 +/- 2.6 ng/ml, controls: 13.6 +/- 5.2 ng/ml [P < 0.02]; EC50 alfentanil; injured: 54.7 +/- 9.2 ng/ml, controls: 74.3 +/- 18.4 ng/ml [P < 0.02]). For alfentanil, no significant differences in pharmacokinetics between injured and control animals were observed. CONCLUSIONS: These results support the hypothesis that reductions in anesthetic requirements in this animal model of brain injury may be caused, in part, by alterations in nociception.

Successful management of venous air embolism with inotropic support.

PURPOSE: Since venous air embolism may occur during many different types of surgery, management of this clinical emergency can be required in patients who do not have a previously established central venous access for aspiration of air. Recent reviews suggest that management of right heart syndromes in patients with embolism is critical in improving outcome. CLINICAL FEATURES: Abrupt decreases in oxygen saturation (from 98% to 40%) and end-tidal carbon dioxide tension (from 24 to 6 mm Hg), compatible with venous air embolism were observed in a 73-yr-old woman during craniotomy for meningioma in the supine position. Since no access for aspiration of air was readily available, therapy was directed at inotropic support of the right heart using a bolus of ephedrine. Cardiorespiratory variables rapidly returned to normal, and the patient recovered from anesthesia and surgery without sequelae. CONCLUSIONS: Venous air embolism places an acute load on the right ventricle and may provoke right heart failure, even in the absence of total cardiovascular collapse. Treatment that supports right heart function may allow sufficient time for redistribution of embolized air and produce a good outcome when access for central aspiration of air is not available.

Pentobarbital induces nocifensive yhyperreflexia, not hyperalgesia in rats.

PURPOSE: To seek behavioural, reflexive and histochemical evidence of long-lasting changes in nociceptive stimulus transmission induced by exposure to doses of pentobarbital that induce nocifensive hyperreflexia. METHODS: Nocifensive hyperreflexia was induced in 12 rats with 30 mg x kg(-1) pentobarbital ip. Reflex latency times for withdrawal of the hind paw from noxious radiant heat were measured with an automated electronic timer. Subjective responses to noxious stimulation (licking or biting of the stimulated hindpaw) and the level of sedation were recorded. Histological sections of lumbar spinal cord were stained for immunoreactivity of the immediate-early-gene (IEG), c-fos, in three rats that received repeated threshold noxious radiant heat stimulation during the period of nocifensive hyperreflexia induced by 30 mg x kg(-1) pentobarbital ip. RESULTS: Reflex withdrawal latency decreased by 32 +/- 8% of control values (P < 0.001 ) following pentobarbital injection and returned to control values 120 min after drug injection. Once fully alert, pentobarbital-treated animals did not show any increase in nociceptive behaviour relative to saline-injected controls (P = 0.41). Sustained noxious stimulation to the hindpaw in halothane-anesthetized animals was associated with an increase in c-fos immunoreactivity in the dorsal horn of the lumbar spinal cord ipsilateral to the stimulation (P < 0.001). Threshold stimulation in the pentobarbital-treated animals was not associated with any increase in c-fos expression. CONCLUSIONS: During pentobarbital-induced hyperreflexia, rats did not show any reflexive, behavioural, or histochemical evidence of long-lasting enhancement of nocifensive signal transmission. The results are consistent with previous observations that, in the absence of tissue injury, nocifensive hyperreflexia induced by barbiturates is a short-lived pharmacological effect.