Increased brain oxygenation during intubation-related stress.

BACKGROUND AND OBJECTIVES: The purpose of this study was to determine whether brain oxyhaemoglobin-deoxyhaemoglobin coupling was altered by anaesthesia or intubation-induced stress. METHODS: This was a prospective observational study in the operating room. Thirteen patients (ASA I and II) undergoing spinal or peripheral nerve procedures were recruited. They were stabilized before surgery with mask ventilation of 100% oxygen. Anaesthesia was induced with 2 microg kg(-1) fentanyl and 3 mg kg(-1) thiopental. Laryngoscopy and intubation were performed 4 min later. After intubation, desflurane anaesthesia (FiO2=1.0) was adjusted to maintain response entropy of the electroencephalogram at 40-45 for 20 min. Prefrontal cortex oxyhaemoglobin and deoxyhaemoglobin were determined every 2 s using frequency domain near-infrared spectroscopy. Blood pressure, heart rate and response entropy were collected every 10 s. RESULTS: Awake oxyhaemoglobin and deoxyhaemoglobin were 18.9 +/- 2.3 micromol (mean +/- SD) and 12.7 +/- 0.8 micromol, respectively, and neither changed significantly during induction. Intubation increased oxyhaemoglobin by 37% (P < 0.05) and decreased deoxyhaemoglobin by 16% (P < 0.05), and both measures returned to baseline within 20 min of desflurane anaesthesia. Blood pressure, heart rate and electroencephalogram response entropy increased during intubation, and the increase in heart rate correlated with the increase in brain oxygen saturation (r = 0.48, P < 0.05). CONCLUSIONS: Intubation-related stress increased oxyhaemoglobin related to electroencephalogram and autonomic activation. Stress-induced brain stimulation may be monitored during anaesthesia using frequency domain near-infrared spectroscopy.

Nascent EDHF-mediated cerebral vasodilation in ovariectomized rats is not induced by eNOS dysfunction.

In estrogen-depleted [i.e., ovariectomized (Ovx)] animals, an endothelium-derived hyperpolarizing factor (EDHF)-like mechanism may arise to, at least partially, replace endothelial nitric oxide (NO) synthase (eNOS)-derived NO in modulating cerebral arteriolar tone. Additional findings show that eNOS expression and function is restored in estrogen-treated Ovx female rats, while the nascent EDHF-like activity disappears. Because NO has been linked to repression of EDHF activity in the periphery, the current study was undertaken to examine whether the nascent EDHF role in cerebral vessels of Ovx females relates to a chronically repressed eNOS-derived NO-generating function. We compared the effects of chronic NOS inhibition with Nomega-nitro-L-arginine-methyl ester (L-NAME; 100 mg. kg-1. day-1 for 3 wk) on EDHF-mediated pial arteriolar vasodilation in anesthetized intact, Ovx, and 17beta-estradiol-treated (0.1 mg. kg-1. day-1 ip, 1 wk) Ovx (OVE) female rats as well as in male rats that were prepared with closed cranial windows. In the chronic NOS inhibition groups, pial arteriolar responses were monitored in the absence (all groups) and presence (females only) of indomethacin (Indo; 10 mg/kg iv). Finally, the gap junction inhibitory peptide Gap 27 (300 muM) was applied to block EDHF-related vasodilation. NO donor (S-nitroso-N-acetyl-penicillamine) responses were similar in all rats studied. Acetylcholine (ACh) reactivity was virtually absent in control Ovx rats and chronically NOS-inhibited intact female, OVE, and male rats. However, a partial recovery of ACh reactivity was seen in L-NAME-treated Ovx females. In addition, in the presence of L-NAME, a normal CO2 reactivity was observed in all females, whereas a 50% reduction in CO2 reactivity was seen in males. In intact and OVE rats, both chronic and acute (NG-nitro-L-arginine suffusion) NOS inhibition, combined with Indo, depressed ADP-induced dilation by > or =50%, and subsequent application of Gap 27 had no further effect on ADP-induced vasodilation. ADP reactivity was retained in Ovx rats after combined chronic NOS inhibition and acute Indo, but was attenuated significantly by Gap 27. In males, Gap 27 had no effect on arteriolar reactivity. Taken together, our data demonstrate that in the cerebral microcirculation, NO does not have an inhibitory effect on EDHF production or action. The increased EDHF-like function in chronic estrogen-depleted animals is not due to eNOS deficiency, suggesting a more direct effect of estrogen in modulating EDHF-mediated cerebral vasodilation.

ADP-induced pial arteriolar dilation in ovariectomized rats involves gap junctional communication.

It was previously shown that, despite the loss of nitric oxide (NO) dependence, ADP-induced pial arteriolar dilation was not attenuated in estrogen-depleted [i.e., ovariectomized (Ovx)] rats. Additional evidence suggested that the NO was replaced by an endothelium-dependent hyperpolarizing factor (EDHF)-like mechanism. To further characterize the nascent EDHF role in Ovx females, the current study was undertaken to test whether, in Ovx rats, ADP-induced pial arteriolar dilation retained its endothelial dependence and whether gap junctions are involved in that response. A closed cranial window and intravital microscopy system was used to monitor pial arteriolar diameter changes in anesthetized rats. The endothelial portion of the ADP-induced dilation was evaluated using light dye endothelial injury (L/D). The study was organized around three experimental approaches. First, the responses of pial arterioles to ADP before and after L/D exposure in intact and Ovx female rats were tested. L/D reduced the ADP response by 50-70% in both groups, thereby indicating that the endothelium dependence of ADP-induced vasodilation is not altered by chronic estrogen depletion. Second, the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA) and the prostanoid synthesis inhibitor indomethacin (Indo) were coapplied. In intact females, L-NNA-Indo attenuated the response to ADP by 50%, with no further changes upon the addition of L/D. On the other hand, L-NNA-Indo did not affect ADP reactivity in Ovx rats, but subsequent L/D exposure reduced the ADP response by >50%. The NO-prostanoid-independent, but endothelium-dependent, nature of the response in Ovx females is a hallmark of EDHF participation. Third, gap junctional inhibition strategies were applied. A selective inhibitor of gap junctional function, Gap 27, did not affect ADP reactivity in intact females but reduced the the ADP response by 50% in Ovx females. A similar result was obtained following application of a connexin43 antisense oligonucleotide. These findings suggest that the nascent EDHF dependency of ADP-induced pial arteriolar dilation in Ovx females involves connexin43-related gap junctional communication.

The key role of caveolin-1 in estrogen-mediated regulation of endothelial nitric oxide synthase function in cerebral arterioles in vivo.

The marked impairment in cerebrovascular endothelial nitric oxide synthase (eNOS) function that develops after ovariectomy may relate to the observation that the abundance of cerebral vascular eNOS and its endogenous inhibitor, caveolin-1, vary in opposite directions with chronic changes in estrogen status. The authors endeavored, therefore, to establish a link between these correlative findings by independently manipulating, in ovariectomized female rats, eNOS and caveolin-1 expression, while monitoring agonist (acetylcholine)-stimulated eNOS functional activity. In the current study, the authors showed that individually neither the up-regulation of eNOS (through simvastatin treatment), nor the down-regulation of caveolin-1 (through antisense oligonucleotide administration) is capable of restoring eNOS function in pial arterioles in vivo in these estrogen-depleted rats. Only when eNOS up-regulation and caveolin-1 down-regulation are combined is activity normalized. These results establish a mechanistic link between the estrogen-associated divergent changes in the abundance of caveolin-1 and eNOS protein and eNOS functional activity in cerebral arterioles.

Relative contributions from neuronal and endothelial nitric oxide synthases to regional cerebral blood flow changes during forebrain ischemia in rats.

The principal aim of this study was to examine the relative contributions from the neuronal and endothelial isoforms of nitric oxide synthase (nNOS and eNOS, respectively) in their capacity to modulate intra-ischemic cerebral blood flow (CBF) changes, in the ischemically vulnerable hippocampus and striatum. CBF changes were monitored, using laser-Doppler flowmetry, in rats subjected to 30 min of forebrain ischemia (right common carotid occlusion+hemorrhagic hypotension). Rats were pretreated with a selective nNOS inhibitor (ARR 17477), a NOS inhibitor that blocks both eNOS and nNOS (N(G)-nitro-L-arginine; L-NNA), or saline (control). In initial experiments, where ischemic MABP was targeted to exactly 30 mmHg, NOS inhibition reduced intra-ischemic cortical CBF from the control level of approximately 20% of baseline to 3% (L-NNA) or 6% (ARR 17477) of baseline. The statistically similar effects of the two NOS inhibitors confirmed that nNOS is the predominant NO source supporting intra-ischemic vasodilation in the cortex. In subsequent experiments, CBF was measured in the right hippocampus, and striatum, as well as the cortex, and, to reduce data variability, blood withdrawal was adjusted to achieve an intra-ischemic cortical CBF of 20% (controls) or 5% (NOS inhibited rats) of baseline. In those groups, mean ischemic MABP levels ranged from 28 to 32 mmHg. In controls, intra-ischemic CBF fell to 20%, 45%, and 47% of baseline in the cortex, hippocampus, and striatum, respectively. With nNOS inhibition, intra-ischemic CBF was further reduced to 5%, 15%, and 18% of baseline, respectively. However, with combined eNOS/nNOS inhibition, the CBF values were 5%, 37%, and 21%, respectively. These results suggest that the nNOS contribution to intra-ischemic vasodilation in vulnerable regions is substantially greater than eNOS. The significantly higher intra-ischemic CBF level in the hippocampus in combined eNOS/nNOS vs nNOS-inhibited rats may relate, in contrast to other regions, to a low eNOS influence on vascular function in that structure and CBF redistribution to the hippocampus when eNOS activity is blocked globally.

Efficacy of repeat intravenous dosing of ondansetron in controlling postoperative nausea and vomiting: a randomized, double-blind, placebo-controlled multicenter trial.

STUDY OBJECTIVES: To compare repeat intravenous (i.v.) dosing of ondansetron 4 mg with placebo for the treatment of postoperative nausea and vomiting (PONV) in patients for whom prophylactic, preoperative ondansetron 4 mg i.v. was inadequate DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Ten outpatient surgical centers in the United States. PATIENTS: 2,199 male and female ASA physical status I, II, and III patients > or = 12 years old scheduled to undergo outpatient surgical procedures and receive nitrous oxide-based general anesthesia. INTERVENTIONS: Ondansetron 4 mg i.v. was administered to all patients before induction of general anesthesia. Patients who experienced PONV or requested antiemetic therapy within 2 hours after discontinuation of inhaled anesthesia were randomized (1:1) to either a repeat i.v. ondansetron 4 mg dose or placebo. MEASUREMENTS AND MAIN RESULTS: Of the 2,199 patients prophylactically treated with ondansetron 4 mg before anesthesia induction, 1,771 (80.5%) did not experience PONV or request antiemetic therapy during the 2 hours following discontinuation of anesthesia. Of the 428 patients who experienced PONV or requested antiemetic therapy during the same period, and were randomized to additional treatment (214 randomized to ondansetron, 214 randomized to placebo), the incidence of complete response (no emesis, no rescue medication, no study withdrawal) was similar for both ondansetron-randomized and placebo-randomized groups for the 2-hour (34% and 43%, respectively, p = 0.074) and 24-hour (28% and 32%, respectively, p = 0.342) postrandomization study periods. Repeat ondansetron dosing was not more effective than placebo in controlling either postoperative emesis or the severity/duration of postoperative nausea. The administration of an additional dose of ondansetron 4 mg postoperatively did not result in an increased incidence of adverse effects. CONCLUSIONS: In patients for whom preoperative prophylaxis with ondansetron 4 mg i.v. is not successful, a repeat dose of ondansetron 4 mg i.v. in the postanesthesia care unit does not appear to offer additional control of PONV.

Estrogen provides neuroprotection in transient forebrain ischemia through perfusion-independent mechanisms in rats.

BACKGROUND AND PURPOSE: Estrogen-related neuroprotection in association with animal models of transient forebrain and focal ischemia has been documented in several recent reports. Some of those studies indicated that part of that benefit was a function of improved intraischemic vasodilating capacity. In the present study we examined whether chronic estrogen depletion and repletion affected ischemic neuropathology through perfusion-independent mechanisms. METHODS: Normal, ovariectomized (OVX), and OVX female rats treated with 17beta-estradiol (E2) were subjected to 30 minutes of transient forebrain ischemia (right common carotid occlusion plus hemorrhagic hypotension) and reperfusion. Neurological function and brain histopathology were assessed over the 72-hour recovery period. In all rats, preischemic and intraischemic cortical cerebral blood flow (CBF) levels were monitored with laser-Doppler flowmetry. In additional rats, CBF changes in the striatum and hippocampus were also monitored with laser-Doppler flowmetry probes and radiolabeled microspheres. In each experiment, the level of ischemia was targeted to a 75% to 80% reduction in cortical CBF. RESULTS: The similarity in ischemic severity among groups was supported by measurements of comparable patterns of electroencephalographic power changes during the ischemic period. Compared with normal females, OVX rats showed diminished neurological outcomes and more severe histopathology in the hippocampus and striatum. Two-week treatment of OVX rats with E2 was accompanied by postischemic neuropathological changes similar to those seen in normal females. Intraischemic CBF reductions in the hippocampus and striatum were similar in all groups (to 35% to 50% of the preischemic value) but significantly less than the cortical CBF reductions. CONCLUSIONS: These findings indicate that estrogen provides ischemic neuroprotection through mechanisms unrelated to improvement of intraischemic cerebral perfusion.

Cerebral vasodilating capacity during forebrain ischemia: effects of chronic estrogen depletion and repletion and the role of neuronal nitric oxide synthase.

The effects of chronic 17beta-estradiol (E2) depletion, via ovariectomy (OVX), and its repletion, on cortical cerebral blood flow (CBF) and EEG activities during forebrain ischemia, as well as post-ischemic recovery and neuropathology, were assessed and compared with results obtained in normal female rats. We also examined whether neuronal nitric oxide synthase (nNOS) activity is affected by OVX and E2 replacement and whether NOS-derived NO supports vasodilation during ischemia. OVX females displayed a significantly lower CBF during ischemia (10% of baseline) than did normal females (23% of baseline). In OVX rats, given chronic low-dose E2 treatment (0.1 mg kg(-1) day(-1)), intra-ischemic CBF was similar to normal females (25% of baseline). However, at supraphysiologic E2 doses (> or = 0.5 mg kg(-1) day(-1)), that benefit was diminished or lost. Intra-ischemic EEG power reductions and post-ischemic survival rates, neurological dysfunction, and histopathology displayed similar relative differences among groups as the CBF findings. Intra-ischemic CBF was reduced by nNOS inhibition, with ARL 17477, in normal and low-dose E2-treated OVX rats (4-8% baseline). The repressed intra-ischemic vasodilating function in OVX rats may be due to reductions in nNOS activity, because untreated OVX rats showed a 50% lower cortical nNOS activity than that in normal rats and in rats treated with low or high dose (5 mg kg(-1) day(-1)) E2. However, the inability to restore vasodilating function despite normalization of nNOS activity indicates that another mechanism is responsible for the repression of vasodilatory function in the high-dose group. These findings suggest that E2, at levels within the physiological range, promotes ischemic neuroprotection via improving vasodilating capacity. One possible mechanism may relate to E2 enhancing brain nNOS expression and activity.

Lidocaine in the endotracheal tube cuff reduces postoperative sore throat.

STUDY OBJECTIVES: To test the hypothesis that continuous application of local anesthesia at the contact area between the endotracheal tube cuff and trachea would reduce both the incidence and severity of postoperative sore throat by blocking the tracheal pain receptors with local anesthetic delivered via endotracheal tube (ETT) cuff. DESIGN: Double-blind randomized study. SETTING: University affiliate hospital. PATIENTS: 106 ASA physical status I and II patients. INTERVENTIONS: Patients' ETT cuffs were inflated with either air or lidocaine. The cuffs of the lidocaine group were prefilled with lidocaine for 90 minutes prior to intubation to saturate the cuff membrane. One hour and 24 hours following extubation, patients were asked about the presence and severity of postoperative sore throat. MEASUREMENTS AND MAIN RESULTS: There was no difference between groups in demographics or anesthetic management. The incidence of sore throat was significantly different at the 24-hour evaluation (59% air vs. 32% lidocaine, p = 0.01). Severity of sore throat was significantly worse with air at both evaluation periods (1 hour = 18.7 +/- 27.0 air vs. 7.90 +/- 18.1 lidocaine, p = 0.02; 24 hours = 25.6 +/- 27.5 air vs. 14.5 +/- 24.8 lidocaine, p = 0.03). CONCLUSIONS: Using lidocaine to inflate the ETT cuff decreases the severity of postoperative sore throat at one hour, and both the incidence and severity at 24 hours.

NO synthase inhibition modulates NMDA-induced changes in cerebral blood flow and EEG activity.

The effects of nitric oxide synthase (NOS) inhibition on the cerebral blood flow (CBF) and electroencephalographic (EEG) changes accompanying intravenous administration of the excitatory amino acid receptor agonist, N-methyl-D-aspartate (NMDA), were examined in anesthetized rats. Two NOS inhibition strategies were used: chronic N omega-nitro-L-arginine (L-NNA) administration (100 mg.kg-1.day-1 ip, over 4 days) and acute L-NNA administration (100 mg/kg iv infused over 1 h). In both cases, cortical CBF was continuously monitored on study days using laser-Doppler flowmetry, and EEG was recorded, along with measurements of total EEG power. In all rats, the NMDA was given as a 1-min intravenous infusion (20 mg/kg). During all experiments, arterial pressure was controlled within the autoregulatory range. We compared the results from rats treated chronically with L-NNA or its enantiomer. N omega-nitro-D-arginine. In the acute treatment group, two NMDA infusions were given, separated by 90 min, interposed by a 1-h L-NNA infusion. Control rats received saline in place of the L-NNA. Both L-NNA treatment protocols significantly increased the duration of NMDA-induced alterations in EEG activity, relative to controls. NMDA induced a transient 40-100% increase in cortical CBF that was blocked by acute but not chronic L-NNA administration. These results indicate that 1) under normal circumstances nitric oxide is the principal mediator of NMDA-induced cerebrovasodilation; 2) with chronic NOS inhibition, NMDA-induced vasodilation returns to normal, implying replacement of nitric oxide by other factors; and 3) nitric oxide acts as a negative feedback modulator of NMDA-induced changes in brain activity.

The role of neuronal nitric oxide synthase in regulation of cerebral blood flow in normocapnia and hypercapnia in rats.

The nitric oxide synthase (NOS) inhibitors, nitro-L-arginine, its methyl ester, and N-monomethyl-L-arginine, have been shown to attenuate resting CBF and hypercapnia-induced cerebrovasodilation. Those agents nonspecifically inhibit the endothelial and neuronal NOS (eNOS and nNOS). In the present study, we used a novel nNOS inhibitor, 7-nitroindazole (7-NI) to examine the role of nNOS in CBF during normocapnia and hypercapnia in fentanyl/N2O-anesthetized rats. CBF was monitored using laser-Doppler flowmetry. Administration of 7-NI (80 mg kg-1 i.p.) reduced cortical brain NOS activity by 57%, the resting CBF by 19-27%, and the CBF response to hypercapnia by 60%. The 60% reduction was similar in magnitude to the CBF reductions observed in previous studies in which nonspecific NOS inhibitors were used. In the present study, 7-NI did not increase the MABP. Furthermore, the CBF response to oxotremorine, a blood-brain barrier permeant muscarinic agonist that induces cerebrovasodilation via endothelium-derived NO, was unaffected by 7-NI. These results confirmed that 7-NI does not influence eNOS; they also indicated that the effects of 7-NI on the resting CBF and on the CBF response to hypercapnia in this study were solely related to its inhibitory action on nNOS. The results further suggest that the NO synthesized by the action of nNOS participates in regulation of basal CBF and is the major, if not the only, category of NO contributing to the hypercapnic CBF response.

The role of nitric oxide in modulating brain activity and blood flow during seizure.

The role played by nitric oxide (NO) in modulating seizure activity and cerebral blood flow (CBF) during seizures was investigated in rats. Seizures were induced with bicuculline (a GABA antagonist, 1.2 mg kg-1, i.v.). Each animal was subjected to an initial bicuculline-induced seizure followed by treatment with either L-nitroarginine (L-NA, a NO synthase inhibitor) or its less active enantiomer D-NA as a 50 mg kg-1 bolus followed by an infusion of 1 mg kg-1 min-1. The animals then received a second bicuculline treatment. Seizure duration was monitored using EEG and CBF was measured with laser-Doppler. There was no difference in seizure duration before or after D-NA administration. Seizure duration doubled from (6 +/- 1 to 12 +/- 2 min p < 0.05) following inhibition of NO synthase with L-NA. The increase in CBF that accompanied the seizure activity paralleled the seizure duration. Our data support the concept that (1) NO acts as an endogenous anticonvulsant, with seizure duration doubling when NO synthase is acutely inhibited, and (2) that NO is not the messenger that couples CBF to metabolism during bicuculline-induced seizures.

Comparative pharmacokinetics of oral versus sublingual clonidine.

STUDY OBJECTIVE: To compare the pharmacokinetic and pharmacodynamic profile of orally versus sublingually administered clonidine. DESIGN: Randomized, crossover, nonblinded, open-label study. SETTING: University tertiary-care center. PATIENTS: 10 healthy male and female volunteers aged 20 to 42 years. INTERVENTIONS: A heparinized catheter was placed intravenously for blood-sampling purposes. An automatic sphygmomanometer was placed on the volunteers' left upper arm to obtain systolic and diastolic blood pressure, and a pulse oximeter was placed on the right index finger to measure heart rate (HR). MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected throughout the 24-hour study period to determine clonidine concentrations. The effect of clonidine on blood pressure (BP) and HR also was measured. The half-life, area under the curve, maximum concentration, and time to reach maximum concentration were similar for both the sublingual and oral routes. BP and HR changes were similar for both sublingual and oral clonidine. CONCLUSION: Both routes of administration resulted in similar pharmacokinetic and pharmacodynamic profiles. Attempts to shorten clonidine's latency with sublingual administration were unsuccessful. Our study shows that a single dose of clonidine 0.3 mg has the same pharmacokinetic and dynamic profile when administered orally or sublingually. Therefore, the sublingual route can be predictably used in fasting patients, those having difficulty swallowing, or those who are unable to absorb drugs through the gastrointestinal tract; the sublingual dose is the same as the oral dose.

Nitric oxide (NO) is an endogenous anticonvulsant but not a mediator of the increase in cerebral blood flow accompanying bicuculline-induced seizures in rats.

Neurons synthesize NO, which may act as a retrograde messenger, involved in either potentiating or depressing neuronal excitability. NO may also play a role in the cerebral vasodilatory response to increased neuronal activity (i.e., seizures). In this study, two questions were asked: (1) is NO an endogenous anticonvulsant or proconvulsant substance? and (2) is the cerebral blood flow (CBF) increase accompanying bicuculline (BC)-induced seizures mediated by NO? The experiments were performed in 300-400-g Wistar rats anesthetized with 0.6% halothane and 70% N2O/30% O2. CBF was measured using the intracarotid 133Xe clearance method or laser-Doppler flowmetry. EEG activity was recorded. Chronic treatment (4 days) with nitro-L-arginine (L-NA), a potent NO synthase (NOS) inhibitor (400 mg/kg total), suppressed brain NOS by > 97% and prolonged seizure duration from 6 +/- 1 (saline-treated controls) to 12 +/- 2 min. In the L-NA-treated group, the CBF increase was sustained as long as seizure activity remained, indicating that CBF was still tightly coupled to seizure activity. Interestingly, the supposed inactive enantiomer of L-NA, D-NA, also showed an inhibition of brain NOS activity, ranging from 87 to 100%. The duration of seizures in this group (average 8 +/- 2 min) corresponded directly to the magnitude of reduction in NOS activity (r = 0.83, P < 0.05). Specifically, the D-NA results indicated that NOS inhibition had to exceed 95% before any effect on seizure duration could be seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction of catecholamines and nitrous oxide ventilation during incomplete brain ischemia in rats.

The interaction of plasma catecholamines and nitrous oxide (N2O) ventilation was examined during brain ischemia in rats. Group 1 (n = 19) was anesthetized with 50 micrograms.kg-1 x h-1 of fentanyl and ventilated with 70% nitrogen in oxygen. Group 2 (n = 19) was anesthetized with intravenous fentanyl (25 micrograms.kg-1 x h-1) and 70% N2O ventilation in oxygen. Group 3 (n = 10) received 25 micrograms.kg-1 x h-1 of fentanyl and 70% N2O ventilation and 100 micrograms/kg of dexmedetomidine, an alpha 2-adrenergic receptor agonist that decreases sympathetic activity. Incomplete brain ischemia was produced by right carotid ligation combined with hemorrhagic hypotension to 30 mm Hg for 30 min. Plasma catecholamines were measured during ischemia. Cerebral blood flow (CBF) was evaluated by using laser Doppler. Neurologic outcome was evaluated for 3 days after ischemia. Plasma epinephrine and norepinephrine and were decreased 20% and neurologic outcome was significantly worse in Group 2 ventilated with N2O compared with fentanyl-anesthetized controls (P < 0.05). Dexmedetomidine-treated rats had lower plasma catecholamines (20% of control) and larger decreases in CBF during ischemia compared with controls. Dexmedetomidine (Group 3) improved outcome from ischemia in comparison to both Groups 1 and 2 (P < 0.05). These results suggest that catecholamines play a major role in worsening ischemic outcome. N2O ventilation may increase neuronal injury by enhancing the sympathetic response to ischemia.

The effects of midazolam and sufentanil sedation on middle cerebral artery blood flow velocity in awake patients.

Midazolam and sufentanil are commonly used for sedation. Cerebrovascular effects of low-dose midazolam have not been studied previously, and cerebrovascular effects of sufentanil remain controversial. Forty ASA I and II patients were studied preoperatively. These patients were given midazolam (20 or 40 micrograms/kg) or sufentanil (0.1 or 0.2 micrograms/kg) i.v. Transcranial Doppler recordings of middle cerebral artery mean blood flow velocity (Vm) were recorded before administration of the study drug and for the 5-min investigation period. Mean arterial pressure, heart rate, and end-tidal CO2 remained constant during the investigation and did not vary between treatment groups. Vm decreased 17 to 21% with both midazolam doses (p < 0.05), returning to baseline within 5 min. Vm did not change with either sufentanil dose. These results suggest that midazolam decreases cerebral blood flow (CBF) by increasing cerebral vascular resistance (CVR). The low sedative doses of sufentanil used in this study did not affect Vm over 5 min in unanesthetized patients.

Effects of remifentanil, a new short-acting opioid, on cerebral blood flow, brain electrical activity, and intracranial pressure in dogs anesthetized with isoflurane and nitrous oxide.

BACKGROUND: A new short-acting opioid, remifentanil, is metabolized by esterase activity in blood and tissue. It is important to know whether remifentanil may decrease the time to recovery of opioid-induced cardiovascular and cerebral effects compared to that of other short-acting agents such as alfentanil. METHODS: Baseline measures were made during 1% end-tidal isoflurane and 50% N2O in oxygen in dogs. Approximately equipotent low- and high-dose remifentanil (0.5 and 1.0 micrograms.kg-1.min-1) or alfentanil (1.6 and 3.2 micrograms.kg-1.min-1) were infused for 30 min each (total infusion time 60 min) followed by a 30-min recovery period. Blood pressure, heart rate, and intracranial pressure were recorded continuously. Electroencephalogram measurements were made using aperiodic analysis, and regional cerebral blood flow using radioactive microspheres. RESULTS: Both remifentanil and alfentanil decreased blood pressure and heart rate 25-30%. Cortex, hippocampus, and caudate blood flow decreased 40-50% during opioid infusion, but flow changes in lower brain regions were modest or absent. The electroencephalogram showed a shift from low-amplitude, high-frequency activity during baseline to high-amplitude, low-frequency activity during opioid infusion. During a 30-min recovery period, heart rate, electroencephalogram, and regional cerebral blood flow recovered to baseline levels in remifentanil--but not in alfentanil--treated dogs. Blood pressure and intracranial pressure decreased during opioid infusion and increased above baseline levels during the recovery period in remifentanil-treated dogs. CONCLUSIONS: These results show that the cardiovascular and cerebral effects of remifentanil and alfentanil are similar but that recovery of these parameters occurs sooner following remifentanil.

Oral clonidine blunts the hemodynamic responses to brief but not prolonged laryngoscopy.

STUDY OBJECTIVE: To determine whether a 300 micrograms dose of oral clonidine given 90 minutes prior to laryngoscopy and intubation provides hemodynamic protection from the stress of a brief (15-second) and/or a prolonged (45-second) laryngoscopy. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Inpatients and outpatients scheduled for general anesthesia with intubation at a university-affiliated medical center. PATIENTS: Forty patients who gave informed, written consent to receive either an oral placebo or clonidine 5 micrograms/kg (up to a maximum dose of 300 micrograms) 90 minutes prior to induction of anesthesia and to undergo either brief or prolonged laryngoscopy prior to intubation. INTERVENTIONS: The patients underwent a standardized induction sequence that included d-tubocurarine 3 mg, thiopental sodium 5 mg/kg, and succinylcholine 1.5 mg/kg. The four treatment groups (each n = 10) included (1) placebo with 15-second laryngoscopy, (2) placebo with 45-second laryngoscopy, (3) clonidine with 15-second laryngoscopy, and (4) clonidine with 45-second laryngoscopy. Heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were mechanically obtained and recorded at 1-minute intervals for 12 minutes. MEASUREMENTS AND MAIN RESULTS: There were no differences between groups in the premedication hemodynamic measurements. Within each group, maximal hemodynamic variables increased significantly over the corresponding baseline values for that group. In the 15-second, but not the 45-second, laryngoscopy, clonidine successfully blunted the maximum SBP and DBP obtained when compared with the corresponding control group. In both the 15- and 45-second clonidine groups, maximum HR was significantly lower than in the corresponding placebo groups. CONCLUSIONS: Oral clonidine, when used as a preoperative medication, affords hemodynamic protection to patients undergoing a 15-second laryngoscopy. However, the stress of a 45-second laryngoscopy may be too great or the 300 micrograms dose of clonidine too low to provide hemodynamic protection for patients in this group.