Nerve tissue protein S-100 and neurone-specific enolase concentrations in cerebrospinal fluid and blood during carotid endarterectomy.

Nerve tissue protein S-100 and neurone-specific enolase levels in serum were studied in 10 patients before, during and for 2 days after elective carotid endarterectomy performed under general anaesthesia and using a Javid Shunt. In six patients, simultaneous cerebrospinal fluid samples were also obtained. Serum nerve tissue protein S-100 was normal throughout the operation, but in one patient with severe hypertension, levels increased to 1.38 microg. l-1 at 1 h postoperatively. Two patients showed an increase in cerebrospinal fluid nerve tissue protein S-100 during clamping: these patients also had neurological deficits at 6 months. Serum neurone-specific enolase increased from 5.8 to 9.3 microg.l-1 during shunting while cerebrospinal fluid neurone-specific enolase did not change. Uncomplicated carotid endarterectomy does not produce cerebral damage as measured by serum nerve tissue protein S-100; cerebrospinal fluid nerve tissue protein S-100 may be more sensitive for minor cerebral damage. Neurone-specific enolase appeared to be nonspecific. The lack of correlation between the neuroproteins may need to be explained before relying on these simple assays as diagnostic indicators of cerebral ischaemia.

Sex and oestrous cycle differences in visceromotor responses and vasopressin release in response to colonic distension in male and female rats anaesthetized with halothane.

Visceromotor responses and vasopressin release before and after colonic visceral distension were compared between male (n=5 (n=4 for vasopressin)) and female rats and between females during the oestrous cycle (proestrus n=6, oestrus n=5, metestrus n=5, diestrus n=6) at a controlled depth of anaesthesia. Pre-stimulation vasopressin and blood pressures demonstrated oestrous cycle variability. The mean (SEM) colonic balloon pressure triggering visceromotor responses was significantly higher in males (64 (4) mm Hg) than females (41 (1) mm Hg), P=0.002 and within females, proestrus rats had the lowest thresholds, (29 (1) mm Hg, P<0.01). Post-stimulation, vasopressin concentrations increased significantly in all groups (males 1.34 (0.39) to 2.24 (0.74) pmol litre(-1); females 1.54 (0.24) to 2.88 (0.58) pmol litre(-1); P=0.002). Within groups statistically significant differences were measured in proestrus 2.06 (0.56) to 3.42 (1.12) and oestrus 1.16 (0.38) to 2.76 (0.60) pmol litre(-1) (P<0.05). High vasopressin concentrations coupled with low-pressure stimulation during proestrus shows sex-hormone dependent integration of the neuroendocrine response to noxious visceral stimulation.

Time course of neurone-specific enolase and S-100 protein release during and after coronary artery bypass grafting.

Serum neurone-specific enolase (NSE) and S-100 protein are well established as markers of cerebral injury, and have been used as markers of neuronal and glial cell damage, respectively, after cardiac surgery with cardiopulmonary bypass (CPB), but the speed of their increase during CPB has not been studied. Therefore, we have investigated the time course of NSE and S-100 release during and after CPB. We studied 18 adult patients undergoing elective coronary artery bypass grafting (CABG). Standard hypothermic (32 degrees C) pulsatile bypass with membrane oxygenation was used. Blood samples were obtained at induction, before bypass, before rewarming, at the end of rewarming, 10 min, 1 h and 8 h after bypass and 1, 2 and 3 days after surgery. NSE and S-100 were assayed using immunoradiometric assay kits (Sangtec Medical). NSE and S-100 release followed similar time courses. Both increased sharply during bypass, reached peak concentrations at the end of rewarming (mean 25.55 (SEM 2.79) and 1.65 (0.23) microgram litre-1, respectively), had decreased significantly by the end of operation and returned to pre-bypass concentrations by the second day after surgery. No patient developed a major neurological deficit. When using NSE and S-100 assays to study cerebral dysfunction in relation to CPB, postoperative samples miss peak (end-bypass) concentrations, and studies should be designed to include intraoperative samples.

Arterial to inspired partial pressure ratio of halothane, isoflurane, sevoflurane and desflurane in rats.

The inspired partial pressure of an anaesthetic is often used as an index of arterial partial pressure in small animal experiments. We have investigated the influence of anaesthetic solubility on the ratio of arterial to inspired partial pressure in 24 rats, allocated randomly to receive halothane, isoflurane or desflurane at four different inspired concentrations. The arterial partial pressure of the volatile agent was measured by two-stage headspace analysis using a gas chromatograph calibrated with the same gas used to calibrate the Datex Capnomac that measured the inspired concentration. Mean values of arterial to inspired ratio at the lowest concentrations were 0.60 (95% confidence intervals 0.50, 0.71) for 0.8% halothane, 0.54 (0.38, 0.69) for 0.8% isoflurane, 0.72 (0.59, 0.86) for 1.5% sevoflurane and 0.71 (0.54, 0.87) for 4% desflurane. Analysis of variance showed a significant effect of anaesthetic agent (P = 0.008) on the arterial to inspired ratio. Thus volatile anaesthetic agents do not demonstrate a fixed arterial to inspired ratio in rats.

A comparison of anaesthetic tensions in arterial blood and oxygenator exhaust gas during cardiopulmonary bypass.

This study evaluates the usefulness of the analysis of gas sampled from the exhaust port of a membrane oxygenator in the estimation of anaesthetic tension in arterial blood. Sixty-seven arterial blood samples were drawn from patients undergoing hypothermic cardiopulmonary bypass with anaesthesia maintained by either isoflurane or desflurane. Anaesthetic tensions in the oxygenator exhaust gas were measured using an infrared analyser and in arterial blood using a two-stage headspace technique with a gas chromatograph. Both measurement systems were calibrated with the same standard gas mixtures. There was no difference in anaesthetic tension measured in arterial blood and gas leaving the oxygenator exhaust (isoflurane: n = 29, range: 0.3-0.8%, 95% limits of agreement: -0.08% to 0.09%; desflurane: n = 38, range: 1.5-5.4%; 95% limits of agreement -0.65% to 0.58%). We conclude that anaesthetic tensions in arterial blood can be accurately monitored by analysis of the gas emerging from the exhaust port of a membrane oxygenator.

Synergistic antinociceptive interaction between sevoflurane and intrathecal fentanyl in dogs.

This study determined the nature of the antinociceptive interaction between sevoflurane and intrathecal fentanyl on somatosympathetic reflexes in anaesthetized dogs. Afferent A delta- and C-fibre-mediated somatosympathetic reflexes, evoked by supramaximal electrical stimulation of tibial nerves, were recorded from renal sympathetic nerves. The effect of fentanyl alone, administered intrathecally (i.t.) in incremental doses from 2 to 64 micrograms, was compared with the effect of the same doses during the administration of 1.5% sevoflurane. The mean ED50s for the depressant effect of fentanyl (i.t.) on A delta and C reflexes were 35.6 micrograms and 14.2 micrograms while 1.5% sevoflurane, when administered alone, depressed them by 15.5% (P < 0.05) and 27.5% (P < 0.01) respectively. During the administration of 1.5% sevoflurane, the mean ED50s of fentanyl (i.t.) for the depression of A delta and C reflexes were reduced by 76% and 75%, to 8.5 micrograms and 3.5 micrograms respectively. The combined antinociceptive effects of sevoflurane and intrathecal fentanyl were not additive but exhibited a high degree of synergistic interaction.

Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits.

BACKGROUND: It has been shown that the depressive effects of both propofol and midazolam on consciousness are synergistic with opioids, but the nature of their interactions on other physiological systems, e.g. respiration, has not been fully investigated. The present study examined the effect of propofol and midazolam alone and in combination with fentanyl on phrenic nerve activity (PNA) and whether such interactions are additive or synergistic. METHODS: PNA was recorded in 27 anaesthetised and artificially ventilated rabbits. In three groups, propofol, fentanyl and midazolam were administered intravenously in incremental doses to construct dose-response curves for the depressant effects of each one on PNA. In another two groups, the effect of pretreatment with either fentanyl 1 microgram.kg-1 i.v. or midazolam 0.05 mg.kg-1 i.v. on the effects of propofol and fentanyl respectively on PNA were studied. RESULTS: Propofol and fentanyl caused a dose-dependent depression of PNA with complete abolition at the highest total doses of 16 mg.kg-1 i.v. and 32 micrograms.kg-1 i.v., respectively. In contrast, midazolam in incremental doses to a total of 0.8 mg.kg-1 reduced mean PNA by 63%, but approximately 12% of PNA remained at a total dose as high as 6.4 mg.kg-1. The mean ED50s, calculated from dose-response curves, were 5.4 mg.kg-1, 3.9 micrograms.kg-1 and 0.4 mg.kg-1 for propofol, fentanyl and midazolam, respectively. Initial doses of either fentanyl 1 microgram.kg-1 i.v. or midazolam 0.05 mg.kg-1 i.v. acted synergistically with subsequent doses of either propofol or fentanyl to abolish PNA at total doses of 8 mg.kg-1 and 8 micrograms.kg-1, respectively. CONCLUSION: Fentanyl has a synergistic interaction with both propofol and midazolam on PNA and hence potentially on respiration.

Synergism between sevoflurane and intravenous fentanyl on A delta and C somatosympathetic reflexes in dogs.

UNLABELLED: In this study, we defined the nature of the interactions between sevoflurane and fentanyl on spontaneous and reflex-evoked sympathetic activity, resting heart rate (HR), and mean arterial pressure (MAP). Spontaneous renal sympathetic nerve activity (RSNA) and A delta- and C-fiber-mediated somatosympathetic reflexes, evoked by electrical stimulation of radial nerves, and HR and MAP were recorded in anesthetized dogs. In one group, the effects of incremental doses of 2-64 micrograms/kg fentanyl i.v. were observed. It had a greater inhibitory effect on C than on A delta reflexes, which were abolished by mean cumulative doses of 64 micrograms/kg and approximately 128 micrograms/kg, respectively. Although 1.5% sevoflurane reduced C reflexes by 28% and A delta reflexes by only 12%, it reduced the total doses of fentanyl required for their abolition to 32 micrograms/kg and 64 micrograms/kg, respectively. Mean RSNA, HR, and MAP values were reduced by 46%, 54%, and 30%, respectively, by fentanyl alone and by 23%, 11%, and 17%, respectively, in response to 1.5% sevoflurane. The combination of fentanyl and sevoflurane caused reductions of 44%, 54%, and 41%, respectively, which indicates a less than additive effect. These results indicate that sevoflurane interacts synergistically with fentanyl to depress A delta and C somatosympathetic reflexes, whereas for RSNA, HR, and MAP, their effects were less than the additive. IMPLICATIONS: Although fentanyl caused a greater depression of C than of A delta reflexes to the point of abolition, the maximal depression of spontaneous sympathetic activity, heart rate, and arterial pressure occurred at smaller doses. The combined depressant effects of sevoflurane and fentanyl were synergistic on somatosympathetic reflexes but were less than additive on spontaneous sympathetic activity, heart rate, and arterial pressure.

Effect of sevoflurane on spontaneous sympathetic activity and baroreflexes in rabbits.

Sevoflurane causes a decrease in mean arterial pressure (MAP). We have studied in anaesthetized rabbits its interactive effects on MAP, the autonomic nervous system and baroreflexes. During sevoflurane administration changes in renal sympathetic nerve activity (RSNA) and heart rate (HR) were observed: (1) when the normal decrease in MAP occurred; (2) when this was prevented by angiotensin II; (3) during a similar decrease in MAP induced by infusion of sodium nitroprusside (SNP) without sevoflurane administration; and (4) during pressor and depressor responses to phenylephrine and SNP. There was a reduction in MAP from 80 to 40 mm Hg after 1-4% sevoflurane without changes in HR, while RSNA remained unchanged only up to concentrations of 3% and was depressed by 37% (P < 0.05) with 4% sevoflurane. When MAP was maintained constant with angiotensin II, both HR and RSNA decreased, by 12% and 69%, respectively, after 4% sevoflurane (P < 0.05). A decrease in MAP of 40 mm Hg during infusion of SNP increased HR and RSNA by 22% (P < 0.05) and 150% (P < 0.01), respectively. At 2% sevoflurane, baroreflex sensitivity (i.e. delta RSNA/delta MAP and delta HR/delta MAP) was depressed by 36% and 57%, respectively, for the pressor effects of pherylephrine, and by 89% and 81%, respectively, for the depressor effects of SNP. We conclude that the baroreflexes continued to compensate for the effects of sevoflurane on sympathetic and cardiomotor activity with concentrations up to 3% and 4%, respectively.

Effect of temperature on the solubility of desflurane, sevoflurane, enflurane and halothane in blood.

We have investigated the effect of temperature on the blood-gas solubility of desflurane, sevoflurane, enflurane and halothane. Blood was equilibrated with gas mixtures of known composition in open cuvette or closed flask tonometers over a temperature range of 29-39 degrees C, and the concentration of each anaesthetic in blood was measured at 37 degrees C by repeated headspace analysis using a gas chromatograph. Solubility increased by 5.4% of the solubility at 37 degrees C for each degree that equilibration temperature was reduced. This result was true for all anaesthetics in all blood samples, and is in keeping with results for other volatile anaesthetics.

Neurone-specific enolase and Sangtec 100 assays during cardiac surgery: Part I--The effects of heparin, protamine and propofol.

Neurone-specific enolase (NSE) and Sangtec 100 (S-100) (Sangtec Medical, Sweden) assays are designed for clotted samples, but when studying cerebral damage following cardiac surgery, perioperative samples will contain heparin and/or protamine. The lipid emulsion propofol is also frequently used during cardiac surgery and could affect the assays. We, therefore, studied the effects of heparin, protamine and propofol on the accuracy of NSE and S-100 assays in five healthy patients. Blood samples were taken and divided into four groups: normal saline was added to group A; heparin to group B; heparin followed by protamine to group C; and propofol to group D. NSE and S-100 concentrations were measured for all samples. Neither heparin, protamine nor propofol affected the accuracy of S-100 and NSE assays; therefore, samples can be taken throughout operations involving cardiopulmonary bypass without influencing the results.

Neurone-specific enolase and Sangtec 100 assays during cardiac surgery: Part II--Must samples be spun within 30 min?

Sangtec 100 (S-100) (Sangtec Medical, Sweden) and neurone-specific enolase (NSE) assays are showing promise in the assessment of cerebral damage following cardiopulmonary bypass (CBP). The manufacturer's instructions state, however, that samples must be spun and frozen within 30 min, which is inconvenient for serial studies. We, therefore, investigated whether strong blood samples at room temperature (RT) or 4 degrees C for up to 48 h affected the measured levels. Blood samples were taken before and after CBP in six patients and stored for 15 min, 4, 8, 24 or 48 h at RT or 4 degrees C. S-100 and NSE levels did not alter in either 'before surgery' or CPB samples when stored for up to 48 h at 4 degrees C. There was a small, nonsignificant rise when stored at RT. Samples may, therefore, be collected throughout long operations or stored overnight without affecting NSE or S-100 plasma levels.

Neurone-specific enolase and Sangtec 100 assays during cardiac surgery: Part III--Dose haemolysis affect their accuracy?

Neurone-specific enolase (NSE) and Sangtec 100 (S-100) are useful for detecting cerebral damage during cardiopulmonary bypass (CPB). However, red cells contain NSE, and the haemolysis frequently caused by CPB could produce a false rise in NSE; S-100 is not found in red cells and should not be affected. We, therefore, compared the effects of haemolysis on NSE and S-100 to see if correction was necessary and possible. From seven patients, serial dilutions of haemolysed red cells were added to plasma (1/64-1/2048), measured for absorption at 540 nm and assayed for NSE and S-100. S-100 concentrations showed no change with haemolysis. Measured NSE increased significantly with haemolysis > 1/512 (an increase of 6.6 micrograms/ml): a correction formula is presented. In 39/48 patients after CPB, mean haemolysis was < 1/256 and would not need any correction. NSE and S-100 assay can, therefore, be used throughout CPB, which allows both glial and neuronal damage to be studied.

A new method for measurement of anaesthetic partial pressure in blood.

We have developed a simple, reliable method for rapid analysis of the partial pressure of volatile anaesthetic agents, based on a two-stage, head-space analysis. It is designed to solve the problems associated with reduced solubility of modern anaesthetics. After equilibration and analysis of a 2-ml sample of blood at 37 degrees C, 1 ml is transferred to another vial for a second equilibration. This ensures that there is no vapour in the headspace before the second equilibration. Measurements were performed on human blood samples equilibrated with 1% sevoflurane, 2.5% isoflurane or 3% desflurane in a tonometer. The mean error in the sample measurements was -2.3% of the tonometer reading and the 95% confidence interval for an individual measurement was +/- 8.5%. Blood samples may be stored overnight without any significant change in the results.

Magnetic resonance spectroscopy of isoflurane kinetics in humans. Part I: Elimination from the head.

We describe the first human experiments to demonstrate wash-out of isoflurane using fluorine magnetic resonance spectroscopy. Using a surface receive coil, we found two-compartment kinetics within the head with decay half-times of 9.5 and 130 min, but the signal was too weak to localize the compartments. If the fast compartment is assumed to be the brain then our results match the predictions of the classical perfusion-limited pharmacokinetic model of inhalation anaesthesia.

Magnetic resonance spectroscopy of isoflurane kinetics in humans. Part II: Functional localization.

We describe the first experiments to relate the cerebral kinetics of isoflurane (determined by fluorine magnetic resonance spectroscopy) to cerebral function. Using a surface receive coil we found two-compartment kinetics within the head with equilibrium half-times of 3.5 min and approximately 1 h with respect to expired isoflurane concentrations. Using critical fusion flicker frequency as an objective measure of the cerebral effect of isoflurane, we found evidence to identify the fast component as the brain. Responsiveness to command was lost at a brain partial pressure of 0.3% isoflurane. We conclude that the measured cerebral kinetics of isoflurane exactly matched the predictions of the classical perfusion-limited model.

Estrous cycle phase variations in visceromotor and cardiovascular responses to colonic distension in the anesthetized rat.

Visceromotor and cardiovascular responses to colonic distension were measured in female rats, anesthetized with halothane in oxygen, in the proestrus, estrus, metestrus and diestrus phases of the estrous cycle. Ten rats were studied in each group and responses were measured at 5-min intervals for 60 min. A mixed model analysis of variance showed that there was no real change in either the visceral or cardiovascular response with time. There was a highly significant difference in visceromotor responses between the phases of the estrous cycle (P < 0.001). During the phase of proestrus the balloon pressure at which a response was triggered was much lower, with a mean value (95% confidence interval) of 18.7 (16.1, 21.8) mmHg, than the other phases with mean values (95% confidence interval) of 31.9 (27.4, 37.2) mmHg for estrus, 28.1 (24.2, 32.8) mmHg for metestrus, and 31.1 (26.7, 36.3) mmHg for diestrus. The mean arterial blood pressure increased in all groups (range 3.2, 5.4%) as a response to the stimulus, but there was no associated heart rate variability and no significant differences in cardiovascular changes between the groups (P = 0.6). The visceromotor responses measured during the phase of proestrus occurred at a significantly lower threshold than in the other phases of estrous.

Metabolic and hormonal responses to induced hypotension for middle ear surgery.

We have investigated in 30 patients the metabolic and hormonal responses to middle ear surgery using induced hypotension to a mean arterial pressure of 55 mm Hg. A standardized anaesthetic technique of propranolol, thiopentone-vecuronium-isoflurane was used in all patients and hypotension induced with sodium nitroprusside, trimetaphan camsylate or additional isoflurane. All patients showed a classic stress response with an increase in circulating blood glucose, cortisol and growth hormone concentrations. Blood lactate and plasma uric acid concentrations changed little during operation, suggesting that tissue oxygenation was adequate. However, the former declined after operation, possibly as a result of the concomitant use of propranolol. There were no significant differences between the three hypotensive techniques in their effects on the hormonal and metabolic response, although the increase in blood glucose concentration in the trimetaphan group was obtunded. We conclude that induced hypotension for middle ear surgery induced an endocrine and metabolic response of small magnitude and short duration.

Metabolic control of non-insulin-dependent diabetic patients undergoing cataract surgery: comparison of local and general anaesthesia.

We studied 40 elderly patients undergoing cataract surgery. Ten non-insulin-dependent diabetes mellitus (NIDDM) patients received standardized general anaesthesia, 10 NIDDM patients received local anaesthesia using retrobulbar block, 10 non-diabetic control patients received general anaesthesia and 10 non-diabetic controls received retrobulbar block. We measured sequential changes in blood glucose, lactate and beta-hydroxybutyrate, serum cortisol and insulin, and plasma non-esterified fatty acid concentrations until 4 h after operation. The results showed that in both general anaesthesia groups, NIDDM and control, blood glucose and serum cortisol concentrations increased significantly during surgery, before returning to normal by 4 h after operation; in both local anaesthesia groups, glucose and cortisol concentrations changed little during surgery. Serum insulin concentrations increased 30 min after operation to coincide with the peak of the glucose increase in the non-diabetic patients who received general anaesthesia, but no insulin response was seen in the diabetic general anaesthesia patients. Blood glucose and insulin concentrations increased in patients who received local anaesthesia (NIDDM and controls) when they ate after operation. The results show that cataract surgery under local anaesthesia provides improved metabolic control for the diabetic patient. Its use maintains glucose homeostasis, prevents the increases in cortisol and glucose which are seen under general anaesthesia and obviates the need for postoperative starvation.