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.

Small-dose pentobarbital enhances synaptic transmission in rat hippocampus.

UNLABELLED: We investigated the contribution of bicarbonate ion, gamma-aminobutyric acid-A (GABA(A)) receptors, and N-methyl-D-aspartate (NMDA) receptors to pentobarbital-induced enhancement of excitatory synaptic transmission in the hippocampal slice. Transverse hippocampal slices (400 microm thick) were prepared from 20- to 30-day-old Sprague-Dawley rats and maintained in an interface chamber perfused with warmed (35 degrees C) oxygenated artificial cerebrospinal fluid. Extracellular field potentials, evoked by orthodromic paired-pulse stimulation of the Schaffer collateral CA1 pathway, were analyzed for the population spike (PS) amplitude. Pentobarbital had a concentration-dependent, biphasic effect on PS amplitudes, which were increased approximately twofold (P < 0.001) when the slice was exposed to pentobarbital concentrations of 1 and 5 microM and depressed at drug concentrations larger than 10 microM. Pentobarbital (5 microM) did not increase the PS amplitude when stimulation was stopped during exposure to the drug. The enhancement of PS amplitude was suppressed in the presence of 10 microM acetazolamide, a nonselective carbonic anhydrase inhibitor, and when the slice was bathed in CO(2)/HCO(3)(-)-free artificial cerebrospinal fluid. Pretreatment with 1 microM picrotoxin, a GABA(A) receptor antagonist, or 5 microM 2-amino-5-phosphopentanoic acid, a specific NMDA receptor antagonist, also suppressed enhancement of PS amplitude by 5 microM pentobarbital. The results suggest that small concentrations of pentobarbital (1 and 5 microM) enhance synaptic transmission through mechanisms involving GABA(A) and NMDA receptors and the HCO(3)(-) ion. IMPLICATIONS: Enhanced hippocampal synaptic transmission after exposure to subanesthetic concentrations of pentobarbital persists during drug washout. This finding may help to explain why some patients experience excitation and enhanced pain during emergence from anesthesia.

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.

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 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.

[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.

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.

Nocifensive reflex thresholds in rats: measures of central nervous system effects of barbiturates.

PURPOSE: To characterize the pharmacodynamic relationships between plasma pentobarbitone and thiopentone concentrations and nocifensive reflexes during emergence from anaesthesia. METHODS: Forty-nine rats were studied. Plasma barbiturate concentrations were measured with high performance liquid chromatography. Nocifensive reflexes were assessed with the hindlimb withdrawal latency (WL) to heat and the somatic motor response threshold (SMRT) to tail pressure. In Protocol I, SMRT, WL, sedation, and the presence of paw-licking and the righting reflex were assessed in unrestrained rats before and every 10 min for two hours after an intraperitoneal injection of pentobarbitone (30 mg.kg-1). Plasma pentobarbitone kinetics were determined in a separate group of rats. In Protocol II, SMRT and drug concentrations were measured concurrently in partially restrained animals before and for 35 min after a computer-controlled i.v. bolus of thiopentone. In Protocol III the SMRT-plasma thiopentone relationship was determined during increasing and decreasing plasma thiopentone concentrations. RESULTS: Enhancement of both nocifensive reflexes was observed in the unrestrained animals. Enhancement of SMRT was maximal [175% (153-197) of control values] at a mean plasma thiopentone concentration of 11 (9-13) micrograms.ml-1. The SMRT-plasma thiopentone curve showed a mean efflux-influx difference in plasma thiopentone concentration of 4(2.3-5.7) micrograms.ml-1. CONCLUSIONS: Barbiturate-associated nocifensive reflex enhancement occurs in unrestrained animals with both thermal and pressure stimuli. The SMRT-plasma thiopentone concentration relationship during emergence from anaesthesia was similar to that observed previously during induction. The thiopentone plasma concentration-SMRT plot showed an equilibrium delay similar to that previously described by others for thiopentone at an electroencephalographic effect site.

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.

Postischemic therapy with MK-801 (dizocilpine) in a primate model of transient focal brain ischemia.

The purpose of this study was to develop a primate model for assessing EEG, behavior and histology, and to test the effect of NMDA receptor blockade in transient focal ischemia. Squirrel monkeys (Saimiri sciureus) under halothane anesthesia were subjected to 110 min of transient focal ischemia (n = 15) by temporary clip occlusion of the MCA. An eight-lead EEG was recorded. Neurobehavioral testing was done in a subgroup of animals (n = 6). Brain temperature (37.5 degrees C) was monitored and controlled to avoid hypothermia or intergroup temperature differences, and blood pressure was regulated to 60 mmHg. The entire brain was subserially sectioned, and 52 standardized coronal sections encompassing the infarct were examined histologically 2 wk after the ischemia. Animals were randomized to receive either (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) 1 mg/kg of maleate salt or carrier solution, 20 min and again at 12 h after the onset of ischemia. Cingulate and retrosplenial cortex were examined for NMDA-antagonist-induced neuronal necrosis. No reduction, or trend toward reduction of neurobehavioral deficit was seen with MK-801. MCA occulsion reduced EEG power over the ischemic hemisphere. MK-801 appeared to cause brain activation, and globally increased power at several frequencies. MK-801 did not reduce infarction in either neocortex (p > 0.05) or striatum (p > 0.05). No selective neuronal necrosis was seen in the cingulate or retrosplenial cortex. We conclude that MK-801 given 20 min after the onset of transient ischemia offers no significant neuroprotective effect against either neurobehavioral deficit or ischemic infarction in this model of transient focal ischemia. Further experiments in unanesthetized animals are necessary to determine if MK-801-induced necrosis exists in the gyrencephalic brain, but the enhancement of primate brain electrical activity by MK-801 suggests that brain activation occurs in primates as it does in rodents.

Thiopentone induced enhancement of somatic motor responses to noxious stimulation: influence of GABAA receptor modulation.

PURPOSE: This study was conducted to determine whether hyperalgesic effects of subanaesthetic concentrations of thiopentone could be attributed to GABAA receptor effects. METHODS: All studies were performed on 50 rats in a prospective, randomized, blinded fashion using saline-injected animals as controls. Using a modified Randall-Selitto technique, the motor behavior stimulated by noxious stimulation was quantified by determining the lowest tail pressure required to provoke a withdrawal response (somatic motor response threshold, SMRT). In the first protocol (21 rats), we studied the effects of 0.5, 1.5 and 5 mg.kg-1 i.v. of the GABAA agonist, muscimol, on SMRT. In the second protocol (20 rats), the effects of administration of saline, muscimol 0.5 mg.kg-1, or the competitive GABAA antagonist, bicuculline 0.25 mg.kg-1, upon the SMRT-reducing effects of a standardized thiopentone infusion were observed. RESULTS: No dose of muscimol produced hyperalgesia. The highest dose of muscimol used (5 mg.kg-1) produced pronounced analgesic effects, raising the SMRT above 750 g. No change in SMRT was detected with the smaller doses of muscimol. Given in combination with muscimol (0.5 mg.kg-1), thiopentone produced analgesia, as shown by an increase in SMRT (P = 0.009). In the bicuculline treated animals, SMRT decreased linearly with increasing plasma thiopentone concentrations (P < 0.001). The slope of the relationship in the bicuculine group was not significantly different from that observed in the saline-treated group, indicating that bicuculline did not block the hyperalgesic effects of thiopentone. CONCLUSION: The results of these studies suggest that hyperalgesia associated with thiopentone is not mediated primarily by GABAA receptors.

[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.

Laryngeal mask airway with mouth opening less than 20 mm.

We describe the use of a laryngeal mask airway in three adult patients whose mouth opening varied from 12 mm to 18 mm. The first patient's incisal opening was 12 mm. His airway was otherwise normal and the standard laryngeal mask was used as the definitive airway for the 90 min revision of facial scars and bone graft to mandible. The second patient, who had an incisal opening of 18 mm, was scheduled for posterior fossa craniotomy. She adamantly refused awake fibreoptic tracheal intubation. Following induction of general anaesthesia, a standard laryngeal mask was inserted and, through this, fibreoptic intubation was performed. The third patient, in addition to a mouth opening of only 18 mm, had limited neck movement from previous flap reconstruction following mandibulectomy, hemiglossectomy and radical neck dissection. For three more reconstructive head and neck procedures that ranged from 90 min to nine hours, the flexible reinforced laryngeal mask was inserted under topical anaesthesia and its correct position confirmed by fibreoptic laryngoscopy before induction of general anaesthesia. Maintenance of anaesthesia in all cases was uneventful and there were no postoperative complications.

Local cerebral glucose utilization in stimulated rats sedated with thiopental.

BACKGROUND: Recent studies have suggested that supraspinal structures are involved in barbiturate-induced enhancement of nociceptive processing. The goal of the study was to determine whether cortical and subcortical regions involved in nociception were relatively activated or depressed by noxious stimulation during infusion of small doses of thiopental. METHODS: Local cerebral glucose utilization (LCGU) was measured with the 14C-2-deoxyglucose radioautographic technique in 14 rats. During the LCGU experiment, pressure was applied to the tail every 2 min, and the somatic motor response threshold was recorded. Seven animals received thiopental infusions to produce a steady-state plasma concentration (target concentrations of 10 micrograms/ml), and seven untreated animals served as controls. RESULTS: A steady-state plasma thiopental concentration (11.1 +/- 1.8 to 13.0 +/- 2.1 micrograms/ml) was accompanied by a decrease in the somatic motor response threshold from 277 +/- 32 g (before thiopental) to 215 +/- 41 g (P < 0.001). The somatic motor response threshold remained unchanged in the control group. Average LCGU was 29% less in the thiopental-treated animals than in the untreated controls (P < 0.001). In cortical regions associated with nociception, LCGU was relatively increased (+3% +/- 14%) during the thiopental infusion in comparison to the visual and auditory cortices (-18% +/- 13%; P < 0.001). Individual structures that showed relative changes during thiopental infusion included the nucleus accumbens (+17%, P < 0.05) and the habenula (-17%, P < 0.05). Heterogenous relative changes (P < 0.05) in LCGU were observed in the auditory system: auditory cortex (-22%), medial geniculate (-16%), lateral lemniscus (+26%), superior olive (+38%). CONCLUSIONS: Noxious stimulation during low-dose thiopental infusions relatively increased LCGU in cortical regions postulated to be responsible for processing of noxious stimuli. Nuclei in the descending pain modulating system were not relatively depressed.

Hyperalgesia during sedation: effects of barbiturates and propofol in the rat.

Subhypnotic doses of thiopentone are considered to possess antianalgesic or hyperalgesic properties. In this study, we have tested the hypothesis that the coincidence of sedation and hyperalgesia is a property of both barbiturate and non-barbiturate anaesthetic agents. In a randomized, prospective, blinded study, the effects of slow (20 min) iv infusions of thiopentone, pentobarbitone, methohexitone or propofol on nociceptive threshold were measured in rats by tail pressure analgesimetry and compared with saline-infused control animals. Nociceptive thresholds were correlated with measurements of plasma drug concentrations and behavioural assessments. Comparison of pre-infusion nociceptive threshold with the lowest threshold obtained during drug infusion revealed decreases in all four treatment groups. As a percentage of the pre-infusion values, the decreases were: thiopentone: 42.5% (P < 0.001), pentobarbitone: 27.8% (P = 0.014), methohexitone: 24.9% (P = 0.013), propofol: 21.6% (P = 0.006). There were no changes in nociceptive threshold in the control groups. The relationship between nociceptive threshold and plasma drug concentration was usually characterized by an initial decline followed by a rise in nociceptive threshold as the plasma concentration and degree of sedation increased. The results support the hypothesis that hyperalgesia is a property of different anaesthetic agents when administered at sub-hynotic concentrations.

[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.