Harry Scheinin

Effects of Sevoflurane, Propofol, and Adjunct Nitrous Oxide on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans

Background Anesthetic agents, especially volatile anesthetics and nitrous oxide (N2O), are suspected to perturb cerebral homeostasis and vascular reactivity. The authors quantified the effects of sevoflurane and propofol as sole anesthetics and in combination with N2O on regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV) in the living human brain using positron emission tomography. Methods 15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine rCBF, rCMRO2 and rCBV, respectively, in eight healthy male subjects during the awake state (baseline) and at four different anesthetic regimens: (1) sevoflurane alone, (2) sevoflurane plus 70% N2O (S+N), (3) propofol alone, and (4) propofol plus 70% N2O (P+N). Sevoflurane and propofol were titrated to keep a constant hypnotic depth (Bispectral Index 40) throughout anesthesia. End-tidal carbon dioxide was strictly kept at preinduction level. Results The mean ± SD end-tidal concentration of sevoflurane was 1.5 ± 0.3% during sevoflurane alone and 1.2 ± 0.3% during S+N (P < 0.001). The measured propofol concentration was 3.7 ± 0.7 &mgr;g/ml during propofol alone and 3.5 ± 0.7 &mgr;g/ml during P+N (not significant). Sevoflurane alone decreased rCBF in some (to 73–80% of baseline, P < 0.01), and propofol in all brain structures (to 53–70%, P < 0.001). Only propofol reduced also rCBV (in the cortex and cerebellum to 83–86% of baseline, P < 0.05). Both sevoflurane and propofol similarly reduced rCMRO2 in all brain areas to 56–70% and 50–68% of baseline, respectively (P < 0.05). The adjunct N2O counteracted some of the rCMRO2 and rCBF reductions caused by drugs alone, and especially during S+N, a widespread reduction (P < 0.05 for all cortex and cerebellum vs. awake) in the oxygen extraction fraction was seen. Adding of N2O did not alter the rCBV effects of sevoflurane and propofol alone. Conclusions Propofol reduced rCBF and rCMRO2 comparably. Sevoflurane reduced rCBF less than propofol but rCMRO2 to an extent similar to propofol. These reductions in flow and metabolism were partly attenuated by adjunct N2O. S+N especially reduced the oxygen extraction fraction, suggesting disturbed flow–activity coupling in humans at a moderate depth of anesthesia.

Effects of surgical levels of propofol and sevoflurane anesthesia on cerebral blood flow in healthy subjects studied with positron emission tomography.

Background The authors report a positron emission tomography (PET) study on humans with parallel exploration of the dose-dependent effects of an intravenous (propofol) and a volatile (sevoflurane) anesthetic agent on regional cerebral blood flow (rCBF) using quantitative and relative (Statistical Parametric Mapping [SPM]) analysis. Methods Using H215O, rCBF was assessed in 16 healthy (American Society of Anesthesiologists [ASA] physical status I) volunteers awake and at three escalating drug concentrations: 1, 1.5, and 2 MAC/EC50, or specifically, at either 2, 3, and 4% end-tidal sevoflurane (n = 8), or 6, 9, and 12 &mgr;g/ml plasma concentration of propofol (n = 8). Rocuronium was used for muscle relaxation. Results Both drugs decreased the bispectral index and blood pressure dose-dependently. Comparison between adjacent levels showed that sevoflurane initially (0 vs. 1 MAC) reduced absolute rCBF by 36–53% in all areas, then (1 vs. 1.5 MAC) increased rCBF in the frontal cortex, thalamus, and cerebellum (7–16%), and finally (1.5 vs. 2 MAC) caused a dual effect with a 23% frontal reduction and a 38% cerebellar increase. In the propofol group, flow was also initially reduced by 62–70%, with minor further effects. In the SPM analysis of the “awake to 1 MAC/EC50” step, both anesthetic agents reduced relative rCBF in the cuneus, precuneus, posterior limbic system, and the thalamus or midbrain; additionally, propofol reduced relative rCBF in the parietal and frontal cortices. Conclusions Both anesthetic agents caused a global reduction of rCBF (propofol > sevoflurane) at the 1 MAC/EC50 level. The effect was maintained at higher propofol concentrations, whereas 2 MAC sevoflurane caused noticeable flow redistribution. Despite the marked global changes, SPM analysis enabled detailed localization of regions with the greatest relative decreases.

Effects of dexmedetomidine, a selective α2‐adrenoceptor agonist, on hemodynamic control mechanisms

Dexmedetomidine, a selective α2‐adrenoceptor agonist, was administered to five healthy male volunteers in single intravenous doses of 12.5, 25, 50, and 75 µg as part of a placebo‐controlled study. The drug caused dose‐dependent decreases in systolic and diastolic blood pressure. A small initial hypertensive response was observed after injection of the two highest doses. Heart rate was decreased. The concentration of norepinephrine in plasma was decreased significantly (by up to 92%), and the decrease was dose‐dependent. No significant drug‐induced alterations were observed in plasma renin activity or in the concentrations of atrial natriuretic peptide and arginine vasopressin in plasma. Other drug effects included dose‐dependent impairment of vigilance and stimulation of growth hormone secretion. Plasma Cortisol levels were unaffected. Dexmedetomidine is a potentially useful tool for studies of the physiology and pharmacology of α2‐adrenoceptors in human beings and may have therapeutic applications in clinical conditions in which sedative and sympatholytic effects are considered beneficial, such as premedication for anesthesia and surgery.

Dexmedetomidine, an α2-Adrenoceptor Agonist, Reduces Anesthetic Requirements for Patients Undergoing Minor Gynecologic Surgery

The effects of dexmedetomidine, an alpha 2-adrenoceptor agonist, on vigilance, thiopental anesthetic requirements, and the hemodynamic, catecholamine, and hormonal responses to surgery were investigated in healthy (ASA physical status 1) women scheduled for dilatation and curettage (D & C) of the uterus. Fifteen minutes before induction they received single iv doses of either dexmedetomidine (0.5 micrograms/kg; n = 19) or saline (n = 20) in a double-blind fashion. Anesthesia was induced with thiopental and maintained with N2O/O2 (70/30%) and thiopental. Dexmedetomidine was well tolerated and no serious drug-related subjective side-effects or adverse events were observed. The most prominent subjective effects were fatigue and decreased salivation. The total amount of thiopental needed to perform D & C of the uterus was reduced approximately 30% (from 456 +/- 141 mg [mean +/- SD] after saline to 316 +/- 79 mg after dexmedetomidine). This was mostly due to a smaller induction dose in the group receiving dexmedetomidine. Dexmedetomidine appeared to improve the recovery from anesthesia as measured by visual analogue scales (VAS) on fatigue and nausea. The plasma concentration of norepinephrine was decreased by 56% after dexmedetomidine implying decreased sympathetic nervous activity. Systolic and diastolic blood pressure were moderately reduced after dexmedetomidine administration. The authors conclude that dexmedetomidine preanesthetic medication decreases thiopental anesthetic requirements and improves the recuperation from anesthesia with no serious hemodynamic or other adverse effects. Further studies in patients undergoing more stressful surgery are indicated.

Effects of Subanesthetic Doses of Ketamine on Regional Cerebral Blood Flow, Oxygen Consumption, and Blood Volume in Humans

Background Animal experiments have demonstrated neuroprotection by ketamine. However, because of its propensity to increase cerebral blood flow, metabolism, and intracranial pressure, its use in neurosurgery or trauma patients has been questioned. Methods 15O-labeled water, oxygen, and carbon monoxide were used as positron emission tomography tracers to determine quantitative regional cerebral blood flow (rCBF), metabolic rate of oxygen (rCMRO2), and blood volume (rCBV), respectively, on selected regions of interest of nine healthy male volunteers at baseline and during three escalating concentrations of ketamine (targeted to 30, 100, and 300 ng/ml). In addition, voxel-based analysis for relative changes in rCBF and rCMRO2 was performed using statistical parametric mapping. Results The mean ± SD measured ketamine serum concentrations were 37 ± 8, 132 ± 19, and 411 ± 71 ng/ml. Mean arterial pressure was slightly elevated (maximally by 15.3%, P < 0.001) during ketamine infusion. Ketamine increased rCBF in a concentration-dependent manner. In the region-of-interest analysis, the greatest absolute changes were detected at the highest ketamine concentration level in the anterior cingulate (38.2% increase from baseline, P < 0.001), thalamus (28.5%, P < 0.001), putamen (26.8%, P < 0.001), and frontal cortex (25.4%, P < 0.001). Voxel-based analysis revealed marked relative rCBF increases in the anterior cingulate, frontal cortex, and insula. Although absolute rCMRO2 was not changed in the region-of-interest analysis, subtle relative increases in the frontal, parietal, and occipital cortices and decreases predominantly in the cerebellum were detected in the voxel-based analysis. rCBV increased only in the frontal cortex (4%, P = 0.022). Conclusions Subanesthetic doses of ketamine induced a global increase in rCBF but no changes in rCMRO2. Consequently, the regional oxygen extraction fraction was decreased. Disturbed coupling of cerebral blood flow and metabolism is, however, considered unlikely because ketamine has been previously shown to increase cerebral glucose metabolism. Only a minor increase in rCBV was detected. Interestingly, the most profound changes in rCBF were observed in structures related to pain processing.

Striatal dopamine D1 and D2 receptors in burning mouth syndrome

&NA; Animal studies have indicated that the nigrostriatal dopaminergic system is involved in central pain modulation. In a recent positron emission tomography (PET) study, we demonstrated presynaptic dysfunction of the nigrostriatal dopaminergic pathway in burning mouth syndrome, which is a chronic pain state. The objective of the present study was to examine striatal dopamine D1 and D2 receptors in these patients. We used 11C‐NNC 756 and 11C‐raclopride to study D1 and D2 receptor binding in a PET study in ten burning mouth patients and 11 healthy controls. Patients underwent a structured psychiatric evaluation and an electrophysiological test for the excitability of the blink reflex. The striatal uptake of 11C‐NNC 756 did not differ between patients and controls. In a voxel‐level analysis, the uptake of 11C‐raclopride was statistically significantly higher in the left putamen in burning mouth patients (corrected P‐value 0.038 at cluster‐level). In the region of interest analysis, the D1/D2 ratio was 7.7% lower in the right putamen (0.64±0.04 vs. 0.69±0.04, P=0.01) and 6.4 % lower in the left putamen (0.65±0.05 vs. 0.70±0.05, P=0.05) when compared to controls. Increased 11C‐raclopride uptake and the subsequent decrease in the D1/D2 ratio may indicate a decline in endogenous dopamine levels in the putamen in burning mouth patients.

The analgesic action of dexmedetomidine — a novel α2-adrenoceptor agonist — in healthy volunteers

&NA; The analgesic efficacy of dexmedetomidine (DEX) — a novel &agr;2‐adrenoceptor agonist — was studied in man. Single intravenous doses of fentanyl (FEN; 2 &mgr;g/kg), DEX (0.25, 0.50 and 1.0&mgr;g/kg) and placebo were administered to 5 healthy male volunteers in a double‐blind, crossover study in randomized order. The analgesic effect of the different treatments was measured by determining the time course of pain threshold with dental dolorimetry and by quantitating subjective pain induced by a standard ischemic pain stimulus on the upper arm using a visual analogue scale (VAS). The drugs were generally well tolerated. FEN and DEX both had analgesic effects on ischemic pain, which was seen as a statistically significant decrease in subjective VAS ratings. FEN appeared to be more effective than DEX; the difference was not, however, statistically significant. Neither of the drugs affected the pain threshold measurements.

Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep

Background: Dexmedetomidine, a selective α2‐adrenoceptor agonist, induces a unique, sleep‐like state of sedation. The objective of the present work was to study human electroencephalogram (EEG) sleep spindles during dexmedetomidine sedation and compare them with spindles during normal physiological sleep, to test the hypothesis that dexmedetomidine exerts its effects via normal sleep‐promoting pathways.

Altered dopamine D2 receptor binding in atypical facial pain.

&NA; Animal studies suggest that the dopaminergic system plays a role in central pain modulation. We have previously demonstrated with positron emission tomography (PET) that striatal dopaminergic hypofunction may be involved in the burning mouth syndrome. The aim of the present study was to evaluate the nigrostriatal dopaminergic system in patients with atypical facial pain using PET. In seven patients with atypical facial pain, striatal presynaptic dopaminergic function was assessed with [18F]FDOPA and dopamine D1 and D2 receptor availabilities with [11C]NNC 756 and [11C]raclopride, respectively. The results were compared with those of healthy controls. A quantitative region‐of‐interest analysis showed that the uptakes of [18F]FDOPA and [11C]NNC 756 did not differ between patients and controls. There was a tendency of increased D2 receptor availability in the left putamen (P=0.056), and the D1/D2 ratio in the putamen was decreased bilaterally by 7.7% (P=0.002) in patients when compared to controls. In a voxel‐based analysis, the uptake of [11C]raclopride was increased in the left putamen (P=0.025). In conclusion, the increase in D2 receptor availability in the left putamen and the decrease in D1/D2 ratio imply that alterations in the striatal dopaminergic system as evaluated by PET may be involved in chronic orofacial pain conditions.

Effect of intravenously administered dexmedetomidine on pain after laparoscopic tubal ligation

Ninety-six women undergoing laparoscopic tubal ligation were randomized to receive intravenously either 0.2 or 0.4 microgram/kg of dexmedetomidine, 60 micrograms/kg of oxycodone, or 250 micrograms/kg of diclofenac for postoperative pain in a double-blind study design. The study drugs were administered in the recovery room for moderate or severe pain and were repeated until pain subsided or disappeared. In the group receiving diclofenac, 83% of the patients required analgesic supplementation with morphine. This contrasted (P less than 0.01) with 33% of the patients receiving either oxycodone or the higher dose of dexmedetomidine. After the first dose of oxycodone was injected, the visual analogue scale for pain (0%-100%) was reduced from 58% to 33%, whereas corresponding pain relief was only achieved after the third injection of 0.4 microgram/kg of dexmedetomidine. Repeated doses of 0.2 microgram/kg of diclofenac or dexmedetomidine did not reduce the visual analogue scale value by more than 17%. More sedation was seen with the higher dose of dexmedetomidine than with either diclofenac or oxycodone (P less than 0.001). Both doses of dexmedetomidine decreased heart rate when compared with diclofenac (P less than 0.001). In the group given 0.4 microgram/kg of dexmedetomidine, 33% of the patients required atropine for bradycardia. The authors conclude that after laparoscopic tubal ligation, intravenously administered dexmedetomidine relieves pain and reduces opioid drug requirement but is attended by sedation and a high incidence of bradycardia.