Determination of the median effective dose of propofol in combination with different doses of ketamine during gastro-duodenoscopy in children: a randomised controlled trial.

BACKGROUND: Propofol is used to induce deep sedation or general anaesthesia for procedures in children. Adjuvants, such as ketamine, are routinely added to reduce the dose of propofol required and propofol-related adverse events. We conducted a randomised controlled trial to determine the effective bolus dose of propofol in combination with ketamine that induces adequate depth of anaesthesia in 50% of children (ED50) undergoing gastro-duodenoscopy. METHODS: Children were randomised to one of four doses of ketamine: 0 (control), 0.25, 0.5, and 1 mg kg-1, followed by a dose of propofol according to Dixon's up-and-down methodology. Excessive movement, coughing, gagging, or airway obstruction that prevented endoscope insertion was considered a failure. RESULTS: The ED50 of propofol (median, 95% CI) was greater in the ketamine 0, 0.25, and 0.5 mg kg-1 groups compared with the ketamine 1 mg kg-1 group (6.1, 4.1-8.1; 4.5, 2.9-6; 4.7, 3.1-6.2 mg kg-1vs 1.1, 0.5-1.8 mg kg-1, respectively, P<0.008). Total dose of propofol administered during the procedure was reduced with ketamine 1 mg kg-1. The mean arterial pressure was lower in the ketamine 0 mg kg-1 group compared with the 1 mg kg-1 group during and immediately after the procedure. The ketamine 1 mg kg-1 group experienced a higher incidence of nausea and visual disturbances. CONCLUSIONS: Ketamine at 0.5-1 mg kg-1 reduces the dose of propofol required to provide general anaesthesia for gastro-duodenoscopy in children and may reduce the incidence of propofol-related changes in haemodynamics. CLINICAL TRIAL REGISTRATION: NCT 02295553.

Effect of aspirin in vascular surgery in patients from a randomized clinical trial (POISE-2).

BACKGROUND: In the POISE-2 (PeriOperative ISchemic Evaluation 2) trial, perioperative aspirin did not reduce cardiovascular events, but increased major bleeding. There remains uncertainty regarding the effect of perioperative aspirin in patients undergoing vascular surgery. The aim of this substudy was to determine whether there is a subgroup effect of initiating or continuing aspirin in patients undergoing vascular surgery. METHODS: POISE-2 was a blinded, randomized trial of patients having non-cardiac surgery. Patients were assigned to perioperative aspirin or placebo. The primary outcome was a composite of death or myocardial infarction at 30 days. Secondary outcomes included: vascular occlusive complications (a composite of amputation and peripheral arterial thrombosis) and major or life-threatening bleeding. RESULTS: Of 10 010 patients in POISE-2, 603 underwent vascular surgery, 319 in the continuation and 284 in the initiation stratum. Some 272 patients had vascular surgery for occlusive disease and 265 had aneurysm surgery. The primary outcome occurred in 13·7 per cent of patients having aneurysm repair allocated to aspirin and 9·0 per cent who had placebo (hazard ratio (HR) 1·48, 95 per cent c.i. 0·71 to 3·09). Among patients who had surgery for occlusive vascular disease, 15·8 per cent allocated to aspirin and 13·6 per cent on placebo had the primary outcome (HR 1·16, 0·62 to 2·17). There was no interaction with the primary outcome for type of surgery (P = 0·294) or aspirin stratum (P = 0·623). There was no interaction for vascular occlusive complications (P = 0·413) or bleeding (P = 0·900) for vascular compared with non-vascular surgery. CONCLUSION: This study suggests that the overall POISE-2 results apply to vascular surgery. Perioperative withdrawal of chronic aspirin therapy did not increase cardiovascular or vascular occlusive complications. Registration number: NCT01082874 ( http://www.clinicaltrials.gov).

L-type calcium channel blockade modifies anesthetic actions on aged hippocampal neurons.

Previous studies in our laboratory demonstrated a reversal of anesthetic actions on aged neurons by decreasing extracellular [Ca(2+)] in hippocampal slices. Such maneuver indirectly attenuated Ca(2+) influx, hence decreased exogenous intraneuronal Ca(2+) loads during neuronal activity and consequently improved intracellular Ca(2+) concentration homeostasis. Therefore, in the present study we hypothesized that decreasing exogenous Ca(2+) loads by blocking voltage-gated calcium influx in aged neurons would oppose isoflurane actions. Conversely, increasing endogenous Ca(2+) loads by suppressing calcium efflux during forced reversal of Na(+)/Ca(2+) exchanger function would enhance anesthetic effects. Hippocampal slices were prepared from young (2-4 months) and old (24-26 months) Fischer 344 rats. Isoflurane depressed the evoked dendritic field excitatory postsynaptic potentials by approximately 45% in slices taken from old animals. However, application of isoflurane in addition with CoCl(2) or nifedipine opposed the anesthetic actions, which then depressed the evoked dendritic field postsynaptic potentials by only 15%. Selective blockade of the N-type and P/Q-type calcium channels with omega-conotoxin GVIA and omega-conotoxin MVIIC respectively caused rapid but partial depression of synaptic transmission in slices taken from old Fischer 344 rats. However, isoflurane actions in these aged slices were not affected compared with slices perfused only with normal artificial cerebrospinal fluid. Young and aged slices were then exposed to a low sodium perfusate that forces the Na(+)/Ca(2+) exchanger protein into a reverse mode, thus increasing intracellular Ca(2+) concentration. Isoflurane actions under such conditions were profoundly potentiated in aged slices but were not altered in young hippocampi. The current results show that in aged central neurons, selectively blocking L-type calcium channels opposes anesthetic-induced depression of excitatory synaptic transmission. On the contrary, increasing calcium loads in aged neurons potentiates these actions.

Isocapnic hyperpnoea accelerates recovery from isoflurane anaesthesia.

BACKGROUND: Hyperventilation should speed up elimination of volatile anaesthetic agents from the body, but hyperventilation usually results in hypocapnia. We compared recovery from isoflurane anaesthesia in patients allowed to recover with assisted spontaneous ventilation (control) and those treated with isocapnic hyperpnoea. METHODS: Fourteen patients were studied after approximately 1 h of anaesthesia with isoflurane. Control patients were allowed to recover in the routine way. Isocapnic hyperpnoea patients received 2-3 times their intraoperative ventilation using a system to maintain end tidal PCO(2) at 45-50 mm Hg. We measured time to removal of the airway and rate of change of bispectral index (BIS) during recovery. RESULTS: With isocapnic hyperpnoea, the time to removal of the airway was markedly less (median and interquartile range values of 3.6 (2.7-3.7) vs 12.1 (6.8-17.2) min, P<0.001); mean (SD) BIS slopes during recovery were 11.8 (4.4) vs 4.3 (2.7) min(-1) (P<0.01) for isocapnic hyperpnoea and control groups, respectively. Isocapnic hyperpnoea was easily applied in the operating room. CONCLUSIONS: Isocapnic hyperpnoea at the end of surgery results in shorter and less variable time to removal of the airway after anaesthesia with isoflurane and nitrous oxide.

Activation of electrocorticographic activity with remifentanil and alfentanil during neurosurgical excision of epileptogenic focus.

BACKGROUND: Opioids are known to stimulate surface electroencephalographic activity in patients with temporal lobe epilepsy. The objective of the current study was to compare the electrocorticographic activation effects of the newer short-acting opioid remifentanil with those of alfentanil during epilepsy surgery under general anaesthesia. METHODS: Thirteen patients undergoing temporal lobe epilepsy surgery under general anaesthesia received alfentanil 30 microg kg(-1) and remifentanil 1 microg kg(-1) as i.v. boluses in sequence. The design was a randomized double-blind cross-over study. After opening the dura, electrocorticogram (ECoG) electrode contact strips were placed over the temporal and supratemporal neocortex and depth electrodes were inserted in the amygdala and hippocampus. Alfentanil 30 microg kg(-1) or remifentanil 1 microg kg(-1) were administered randomly in a blinded fashion. The ECoG was recorded continuously before and after the injection of each drug. The interictal epileptiform activity (spikes and sharp waves) above baseline was analysed. RESULTS: Both drugs increased epileptiform activity especially that recorded from depth electrodes in the temporal limbic structures. No epileptiform activity was recorded from the electrodes overlying the supratemporal neocortex before or after drug administration. The more potent activator was alfentanil, which caused an increase in activation from baseline of 99.8% compared with 67.4% for remifentanil. In addition, alfentanil activated the epileptiform activity in 3 patients in which remifentanil had no effect. There were no changes in heart rate after the opioid boluses. Both remifentanil and alfentanil caused significant reductions in blood pressure at 3 and 5 min after administration. CONCLUSION: We conclude that at the doses used in this study, alfentanil is the better opioid for intraoperative activation of the ECoG in neurosurgical patients undergoing resection of a temporal lobe epileptic focus. This pharmacological activation of epileptiform activity assists in localizing and confirming the site of surgical excision. Neither alfentanil nor remifentanil activated epileptiform activity in non-epileptic brain tissue.

Loss of the airway during tracheostomy: rescue oxygenation and re-establishment of the airway.

PURPOSE: To describe loss of the airway during tracheostomy and suggest a method for re-establishment of the airway and providing rescue oxygenation. CLINICAL FEATURES: A 22-yr-old female diagnosed with encephalomyelopathy was admitted to the intensive care unit with a progressively deteriorating level of consciousness and respiratory failure requiring intubation and ventilation. Several weeks later, an elective tracheostomy was performed under anesthesia. The surgeon made an anterior tracheal wall incision and inserted a cuffed #6 Shiley tracheostomy tube. No end-tidal CO(2) was detected and the patient could not be ventilated. After another failed attempt at insertion of a second tracheostomy tube, the diagnosis was made of a false passage within the trachea. The Shiley tracheostomy tube was removed and a #6 regular endotracheal tube was introduced in the trachea through the tracheostomy incision. The patient now could be ventilated with difficulty and low readings of end-tidal CO(2) were noted. Despite all efforts to further ventilate the patient, the arterial oxygen saturation never recovered, resulting in cardiac arrest. CONCLUSION: To restore a lost airway during tracheostomy, we recommend that a jet ventilation airway exchange catheter (JVAE) be inserted in the endotracheal tube through a bronchoscope port attachment prior to surgical entry into the trachea. The JVAE will also ensure continued ability to oxygenate the patient.

A submersion method to induce hypoxic damage in organotypic hippocampal cultures.

Organotypic brain slices cultured on semi-porous membranes is an increasingly popular in vitro preparation for studying mechanisms of ischemic brain damage. To model in vivo hypoxia, cultured brain slices are exposed to anaerobic atmosphere by placing them into a special incubator. This requirement limits the use of in vitro ischemic models to highly specialized laboratories. Here, we describe a simple method that reproduces hypoxic injury, where cultured hippocampal slices are submerged into glucose-free deoxygenated medium for 1 h. The extent and distribution of hippocampal neuronal loss obtained with this treatment resembled that caused by hypoxia in living tissue in situ, i.e. CA1 pyramidal cell layer was most vulnerable and dentate granular cell layer was least susceptible to hypoxia as measured with fluorescence of the viability marker propidium iodide (PI). Electrophysiologic functional impairment determined by field recordings of CA1 pyramidal neurones temporally coincided with the extent of neuronal death. In addition, known neuroprotective treatments, such as hypothermia and phenytoin application ameliorated neuronal damage in a pattern similar to previously published reports. Therefore, the present in vitro model of ischemia is simple, reliable and of low cost. It is well suited for short and long-term studies of the mechanisms of hypoxic brain damage.

Pott's disease with unstable cervical spine, retropharyngeal cold abscess and progressive airway obstruction.

PURPOSE: Retropharyngeal abscess formation has the potential for acute respiratory compromise from obstruction or secondarily from rupture. The initial attempt to secure the airway is of paramount importance. We describe a patient with an unstable cervical spine secondary to Pott's disease who developed progressively obstructing retropharyngeal cold abscess. CLINICAL FEATURES: A 33-yr-old man with an unstable C-spine in halo traction presented with progressive airway obstruction secondary to retropharyngeal abscess extending from the cervical to the mid-thoracic vertebrae. After review of computerized tomography (CT) and magnetic resonance (MR) studies, preparations were made to secure the airway through fibreoptic assisted intubation. A conservative approach was chosen to secure the airway before surgical airway control as a first line approach. Following local and topical anesthesia, awake endoscopy was performed to assess the extent of obstruction and possibility of intubation without abscess rupture. A narrow tract along the lateral pharynx was identified to continue inferiorly to the epiglottis, from which point the cords were visualized. Extensive edema and abscess formation otherwise distorted the normal anatomy and prevented visualization from other directions. The airway was successfully secured without trauma with a well-lubricated 7.0 mm ID endotracheal tube. CONCLUSION: This report suggests that selected cases of tense obstructing retropharyngeal abscesses can be effectively managed with fibreoptic endoscopy for assessment and subsequent intubation before requiring surgical airway control as a first line strategy.

Intraoperative localization of an epileptogenic focus with alfentanil and fentanyl.

UNLABELLED: We evaluated the effectiveness of alfentanil and fentanyl in stimulating epileptogenic activity during surgery for intractable temporal lobe epilepsy under general anesthesia. Ten patients received a standardized anesthetic induction with i.v. fentanyl 5 microg/kg, propofol 3-5 mg/kg, and atracurium 0.5 mg/kg. Maintenance was with isoflurane, 70% N2O/30% O2, and an atracurium infusion. After dural opening, droperidol 0.02 mg/kg was administered i.v.. Both inhaled anesthetics were discontinued and verified to be at 0 end-tidal concentration before the study. Baseline electrocorticography over the surface of the temporal lobe and depth electrode recordings in the amygdala and hippocampus were obtained, followed by 10 min of recording before and after the i.v. administration of both alfentanil 50 microg/kg and fentanyl 10 microg/kg. Any changes in cardiovascular variables were documented. The number of interictal epileptiform spikes at the most active site for each patient was tabulated before and after the administration of each drug. Both alfentanil and fentanyl induced an increase in spike activity in all patients. Alfentanil was more potent, increasing the median number of spikes per epoch from 18 to 58, compared with fentanyl (20 to 42 spikes) (P < 0.05). Alfentanil had a shorter duration of action (4.9+/-1.3 min) compared with fentanyl (8.5+/-2 min) (P < 0.009). In nine patients, the most active site was the hippocampus or amygdala. There was a decrease in mean blood pressure, but only after the administration of alfentanil (P < 0.05). Two patients had electrographic evidence of seizure activity. These opioids can be used to assist in the localization of the epileptogenic focus during surgery. IMPLICATIONS: Both alfentanil and fentanyl activate epileptiform activity in patients with temporal lobe epilepsy. These opioids can be used to assist in the localization of the epileptogenic focus during surgery.

Complete upper airway obstruction during awake fibreoptic intubation in patients with unstable cervical spine fractures.

PURPOSE: To describe the presentation and management of complete upper airway obstruction with life threatening arterial oxygen desaturation that occurred during attempted awake fibreoptic intubation in two patients presenting with unstable C-spine injury. CLINICAL FEATURE: Complete upper airway obstruction occurred during awake fibreoptic intubation of two men (ASA II; 68 & 55 yr old) presenting with unstable C-spine fractures. In both cases, bag and mask ventilation with CPAP failed to relieve the progressive hypoxemia. A surgical airway was established urgently to oxygenate the two patients who were suffering progressive life-threatening oxygen desaturation. One patient had trans-cricothyroid jet ventilation performed through a 16G intravenous cannula prior to an urgent tracheostomy. In the other patient, an emergency tracheostomy was inserted. Interestingly, both patients had been sedated in the Neurosurgical Intensive Care Unit with morphine and benzodiazepines before their scheduled surgeries. The most likely etiology for the complete upper airway obstruction was laryngospasm due to inadequate topicalization of the airway and additional sedation given in the operating room. Neither patients suffered any new neurological deficits following these events. They went on to have uneventful surgeries. CONCLUSION: This case report suggest that prior to awake fibreoptic intubation, oxygenation, adequate topicalization with testing to verify the lack of pharyngeal and laryngeal responses and careful assessment of sedation levels in the operating room are prudent for a safe endoscopic intubation.

Early postoperative complications following neurosurgical procedures.

PURPOSE: To assess the incidence and characteristics of early postoperative complications in patients following neurosurgical procedures. METHODS: All patients undergoing neurosurgery during a four month period were followed postoperatively for up to four hours in the post anesthetic care unit or intensive care unit. Patient information and all complications were documented by the investigators on a standardized form. Complications were classified as respiratory, cardiovascular, nausea and vomiting, shivering and other. Risk factors analyzed for the occurrence of complications included age, sex, ASA status, type of surgery, elective or emergency surgery and postoperative placement. RESULTS: Four hundred eighty six adult patients were followed, but in 55 patients the trachea remained intubated during the four hour study period and they were eliminated from the analysis of postoperative complications. At least one complication occurred in 54.5% of the remaining 431 patients. Respiratory problems occurred in 2.8%, trauma to the airway in 4.4%, cardiovascular complications in 6.7%, neurological in 5.7% and nausea and/or vomiting in 38%. The highest incidence of patients with complications was during spine (65%) and vascular (66%) surgery, compared with tumour (47%) and other (43%) surgery, P < 0.05. Other risk factors included age < 70 yr for nausea and vomiting (P < 0.02), and elective surgery for spine and vascular surgery (P < 0.001). CONCLUSION: There was a high incidence of early postoperative complications in neurosurgical patients. The most common problem was nausea and vomiting especially in the younger patient undergoing elective spine surgery.

Enhanced isoflurane suppression of excitatory synaptic transmission in the aged rat hippocampus.

1. The effects of the volatile anaesthetic, isoflurane, were investigated on evoked dendritic field excitatory postsynaptic potentials (f.e.p.s.p.) and antidromic and orthodromic population spikes recorded extracellularly in the CA1 cell layer region in the in vitro hippocampal slice taken from young mature (2-3 months) and old (24-27 months) Fisher 344 rats. 2. Isoflurane depressed the f.e.p.s.ps and the orthodromically-evoked population spikes in both old and young hippocampi. However, the magnitude of the anaesthetic-induced depression was greater in slices taken from old rats compared to those taken from young rats during the application of different isoflurane concentrations (0.5-5%). 3. In the presence of the GABA(A) antagonist, bicuculline methiodide (15 microM), isoflurane suppressed the f.e.p.s.ps to the same extent as was observed in the absence of the GABA(A) antagonist. 4. Orthodromically evoked population spikes were suppressed by isoflurane in a manner quantitatively similar to the suppression of the f.e.p.s.ps. However, antidromic population spikes and presynaptic volleys evoked in young and old slices were resistant to anaesthetic action. In addition, paired pulse facilitation ratio of the evoked dendritic f.e.p.s.ps was not affected in both young and old slices during the application of isoflurane. 5. When slices were exposed to low Ca2+/high Mg2+ solution, isoflurane (1 and 3%) depressed the f.e.p.s.ps in aged slices to the same extent as in young slices. 6. The augmented anaesthetic depression of f.e.p.s.ps in old compared to young hippocampi in the absence and presence of bicuculline, and the lack of anaesthetic effects on antidromic population spikes and presynaptic volleys in old and young slices, suggest that the increased sensitivity of anaesthetic actions in old hippocampi is due to age-induced attenuation of synaptic excitation rather than potentiation of synaptic inhibition. Furthermore, elimination of the increased sensitivity of old slices to anaesthetic actions when the slices were perfused with low Ca2+/high Mg2+ medium, which presumably would decrease intracellular [Ca2+], suggests that the enhanced anaesthetic effects in aged neurones might be related to increased intraneuronal [Ca2+] in the synaptic terminal.

Indomethacin and ketorolac given preoperatively are equally effective in reducing early postoperative pain after laparoscopic cholecystectomy.

OBJECTIVE: To evaluate the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) on pain after laparoscopic cholecystectomy. DESIGN: A prospective, randomized, placebo-controlled, double-blind study. SETTING: A university hospital. PATIENTS: Fifty-two patients with cholelithiasis but without known allergy to one of the study drugs, history of bleeding, peptic ulcer disease, known cardiac, lung or renal disease, abnormal liver function or use of opiates or NSAIDs within 2 weeks before operation. Patients were assigned to one of three groups and treatment was randomized by placing the drugs in sealed, numbered envelopes. INTERVENTION: Administration of the NSAIDs ketorolac, intramuscularly, or indomethacin, rectally, before laparoscopic cholecystectomy. MAIN OUTCOME MEASURES: Postoperative pain scored on a a visual analogue scale and by nurse assessment, total dose of fentanyl citrate given, and nausea or emesis. RESULTS: Patients in the placebo group reported significantly more pain than either NSAID group (p<0.05) and were reported as having significantly more pain by the nurses (P<0.05). These patients were subsequently treated with a higher mean postoperative dose of fentanyl citrate than either NSAID group (p<0.05). Furthermore, the placebo group reported more nausea and emesis (p<0.05). There was no significant difference in any of the parameters measured between the ketorolac or indomethacin group. CONCLUSIONS: The data demonstrate that the NSAIDs ketorolac and indomethacin, administered preoperatively, decrease early postoperative pain and nausea after laparoscopic cholecystectomy and are equally efficacious in producing these results.

Ageing potentiates anaesthetic-induced synaptic depression in hippocampal slices.

The effects of the volatile anaesthetic isoflurane on dendritic field excitatory postsynaptic potentials (fEPSP) were compared in hippocampal slices taken from young mature and old Fisher 344 rats. Application of isoflurane (1% v/v) to young brain slices produced minimal effects on the recorded fEPSPs. On the contrary, the same anaesthetic concentration depressed field responses obtained from old hippocampal slices by 42 +/- 6.8% compared with baseline values. Such increased sensitivity to anaesthetic action in the old slices was consistently observed with administration of higher isoflurane concentrations. The presynaptic afferent volley was unaffected by application of low or high anaesthetic concentration, suggesting that age-induced changes in nerve fibre conduction and probably nerve ending excitability are not involved in the increased vulnerability of old synapses to anaesthetic action. Other synaptic sites are probably involved in the mechanisms of age-dependent potentiation of anaesthetic suppression of synaptic transmission.

Prophylaxis against the systemic hypotension induced by propofol during rapid-sequence intubation.

The objective of this study was to determine the effectiveness of two prophylactic approaches against the anticipated hypotension induced by propofol during rapid-sequence intubation. Thirty-six male or female nonpremedicated ASA class I-II patients aged 21-60 yr undergoing elective outpatient surgery were included in the study. Patients were randomly allocated to receive pre-induction ephedrine sulphate (70 micrograms x kg(-1)iv), pre-induction volume loading (12 ml x kg(-1) Ringer's lactate) or no treatment. Rapid-sequence intubation with cricoid pressure was then performed with propofol (2.5 mg. x kg(-1)) and succinylcholine (1.5 mg x kg(-1). The lungs were subsequently ventilated with 0.25-0.5% isoflurane in a 2:1 N2O/O2 mixture. Vecuronium was given once neuromuscular function had recovered from the succinylcholine. Heart rate and systemic arterial blood pressure were measured non-invasively before induction, after propofol administration and every minute for ten minutes after intubation. Pre-induction volume loading prevented the hypotension observed before surgical stimulation in control and ephedrine groups. Moreover, pre-induction volume loading was not associated with increases in heart rate after intubation as was ephedrine administration. The intubating conditions were excellent to satisfactory in most patients and the overall incidence of adverse events during intubation was mainly due to pain during injection of propofol. The present study showed that preoperative volume loading is more efficacious than pre-induction administration of ephedrine sulphate in maintaining haemodynamic stability during rapid-sequence induction with propofol and succinylcholine. In addition, propofol in combination with succinylcholine provides excellent conditions for rapid-sequence intubation.

Correlation of anoxic neuronal responses and calbindin-D28k localization in stratum pyramidale of rat hippocampus.

Immunohistochemical staining for the calcium-binding protein calbindin-D28k (CaBP) was combined with Lucifer Yellow (LY) identification and intracellular recording of changes in membrane parameters of pyramidal neurons in CA2, CA1, and the subiculum of rat hippocampal slices during brief exposure (4.0 +/- 0.19 min) to N2. Anoxia evoked either a depolarization or hyperpolarization of membrane potential (VM) (+21.5 +/- 2.79 mV above VM = -70.5 +/- 1.50 mV, n = 30 and -7.2 +/- 0.72 mV below VM = -68.2 +/- 1.34 mV, n = 24, respectively) and a fall in membrane resistance of approximately 20%. Differences in the response could be correlated with the presence or absence of CaBP and the localization of neurons in different layers of stratum pyramidale and sectors of the hippocampus. For neurons immunopositive for calbindin (CaBP(+)), depolarization was observed more frequently (83%) than hyperpolarization (17%); in contrast, 44% of responses of calbindin-negative (CaBP(-)) neurons were depolarizing and 56% were hyperpolarizing. Depolarizations of CaBP(+) neurons were more gradual in slope, and more rapidly reached a plateau in comparison with those recorded in CaBP(-) neurons. Responses of neurons in the superficial layer of stratum pyramidale (in which 79% of CaBP(+) pyramidal neurons were situated) were mainly depolarizing (91%), while for those in the deep layer (which contained 89% of the CaBP(-) cells) such responses were observed less often (45%). Depolarization was also more common than hyperpolarization for cells located in CA2/CA1c/CA1b (63%) than in the CA1a/subicular region (37%). The depolarizing response of the majority of pyramidal neurons which are CaBP(+), superficial, and closer to CA3 may reflect an efficient buffering of intracellular Ca2+, which maintains a low [Ca2+]i, steep gradient for Ca2+ influx and may facilitate the movement of Ca2+ away from points of entry. The neurons which are CaBP(-), deep, and closer to subiculum and in which N2 evokes hyperpolarization, on the other hand, may have a sustained elevation/accumulation of cytosolic Ca2+ which could activate K+ conductance, inhibit Ca2+ influx, and stabilize the membrane potential. These experiments provide a functional correlate for CaBP and suggest that it may have a significant role in Ca2+ homeostasis and the determination of selective neuronal vulnerability.

Effect of hypoxia on glutamate efflux and synaptic transmission in the guinea pig hippocampus.

Simultaneous assessment of synaptic activity and glutamate efflux in guinea pig hippocampal brain slices was made before, during and after a 10-min period of hypoxia. Spontaneous glutamate efflux was assessed by determining glutamate concentration in the superfusion medium at discrete times using high performance liquid chromatography (HPLC). Synaptic activity was assessed using extracellular recording of the evoked population spike in the CA1 region following stimulation of the Schaffer collateral pathway. Hypoxia decreased (P < 0.05) the amplitude of the population spike by 3 min and abolished it by 5 min. This was accompanied by an increase (P < 0.05) in glutamate concentration in the superfusate at 10 min. Following re oxygenation, the population spike returned to baseline amplitude by 5 min and was greater (P < 0.05) than baseline at 10 and 20 min of recovery. Glutamate concentration returned to baseline levels by 1 min of recovery. This experimental preparation can be used to explore the temporal relationship between glutamate efflux and synaptic activity during hypoxia. The results of this study indicate that, in the hippocampal CA1 region, post-synaptic elements are more sensitive than their presynaptic counterparts to hypoxia.

The acute and chronic effects of nitrendipine on plasma catecholamines in hypertensive patients.

OBJECTIVE: To investigate the acute and chronic effects of nitrendipine on plasma catecholamines in hypertensive patients. DESIGN: The variations in level of plasma noradrenaline and adrenaline were measured in the supine and standing positions before and after the initial dose, and after 12 weeks of nitrendipine therapy. Following a washout placebo period, treatment was initiated by a single 20 mg dose of nitrendipine. This was followed by a double-blind randomization into two groups: one receiving 10 mg nitrendipine twice daily, the other receiving 20 mg once daily. SETTING: Clinical investigation unit, University Hospital (University of British Columbia site), Vancouver, British Columbia. PATIENTS: Sixteen patients (seven males and nine females), mean age 51 years (range 27 to 63), with mild to moderate, uncomplicated hypertension. RESULTS: Two hours after administration of the initial 20 mg nitrendipine dose to all patients, there was a significant fall in the supine and standing systolic and diastolic blood pressure - from 164 +/- 3/102 +/- 1 to 139 +/- 2/87 +/- 2 mmHg, and from 153 +/- 4/105 +/- 1 to 139 +/- 3/90 +/- 1 mmHg, respectively. The supine and standing heart rates were unchanged. After 12 weeks of nitrendipine therapy, blood pressure was reduced (2 h after the dose) to a similar extent as that seen after the initial dose. Acute and chronic nitrendipine administration significantly increased supine and standing noradrenaline, but not adrenaline. Two hours after the initial 20 mg dose, supine noradrenaline increased from 3404 +/- 585 to 4005 +/- 644 pmol/L and standing noradrenaline increased from 3769 +/- 609 to 5821 +/- 615 pmol/L. At the end of the 12 weeks of therapy, similar dose-dependent effects were observed 2 h after the dose, but not 12 or 24 h after the dose, in both groups. The percentage increase in noradrenaline produced by nitrendipine in the standing position was consistently greater than in the supine position. CONCLUSIONS: Chronic nitrendipine therapy results in a daily increase in plasma noradrenaline (2 h after the dose), and the effect is greater in the standing position.

Anesthetic effects on glutamate-stimulated increase in intraneuronal calcium.

The aim of these investigations was to examine directly with fura-2 microspectrofluorimetry, the effects of general anesthetics on the resting level and glutamate-stimulated increase of intraneuronal free calcium ([Ca++]i) in cultured hippocampal neurons. Media were chosen for the preferential activation by glutamate of either the quisqualate (QUIS media) or N-methyl-D-aspartate (NMDA media) receptor subtypes. Continuous perfusion (20 min) of either media that had been saturated with isoflurane (0.5-4%) or, in some cases halothane (3-4%), produced only small and inconsistent changes in resting [Ca++]i. The rise in [Ca++]i induced by glutamate (or in some cases, NMDA) that was applied in the mainstream of QUIS or NMDA media was attenuated greatly during such applications of isoflurane or halothane for 6 to 20 min. Analysis of concentration-response relationships revealed that the EC50 values for the isoflurane-depressions were 1.7% for the Ca response to glutamate in QUIS media and 1.2% in NMDA media. Application of isoflurane blunted the peak increases in [Ca++]i produced by brief (1 min) applications of 50 mM K. Verapamil (25 microM) did not reduce the resting [Ca++]i and had long-lasting depressant effects on glutamate-stimulated increases in [Ca++]i in NMDA media. The effects of 2% isoflurane and verapamil were approximately additive. These investigations provided evidence that isoflurane reduced the increase in [Ca++]i which resulted from Ca influx linked directly to receptors for glutamate in addition to Ca entry due to activation of voltage-gated Ca channels.