Anesth Analg 2002;94:1298-1303
© 2002 International Anesthesia Research Society
NEUROSURGICAL ANESTHESIA
Mild Core Hypothermia and Anesthetic Requirement for Loss of Responsiveness During Propofol Anesthesia for Craniotomy
Kate Leslie, MD FANZCA,
Andrew R. Bjorksten, BSc PhD,
Antony Ugoni, BSc(Hons), MSciStat, and
Peter Mitchell, MB BS, FRANZCR
Outcomes ResearchTM Group, Department of Anaesthesia and Pain Management, and the Department of Radiology, Royal Melbourne Hospital, Melbourne, Australia
Address correspondence to Kate Leslie, Department of Anaesthesia and Pain Management, Royal Melbourne Hospital, Parkville, VIC, 3050, Australia. Address e-mail to kate.leslie{at}mh.org.au No reprints will be available from the authors.
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Abstract
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Mild hypothermia may be induced during neurosurgery for brain protection. However, its effect on propofol requirement has not been defined. Accordingly, we tested the hypothesis that 3°C of core hypothermia decreases the propofol blood concentration at which patients respond to command (CP50-awake) in neurosurgical patients. Forty patients were anesthetized with alfentanil 50 µg/kg IV, nitrous oxide, propofol target-controlled infusion, and rocuronium. The bispectral index (version 3.12) was monitored continuously. Patients were randomized to a core temperature of 34°C or 37°C. At the end of surgery, neuromuscular blockade was reversed, nitrous oxide was ceased, and propofol was infused to achieve a blood target determined by the previous patient’s response. Responsiveness to command was assessed 15 min later. Results were analyzed with logistic regression models; P < 0.05 was considered statistically significant. The CP50-awake of propofol was 3.05 µg/mL (95% confidence interval, 2.34–3.66). Propofol concentration, but not core temperature, predicted loss of response to command (odds ratio, 11.76; 95% confidence interval, 2.40–57.63; P < 0.01). Core temperature did not alter the relationship between bispectral index and response to command. Propofol infusion regimens may not require adjustment during mild hypothermia.
IMPLICATIONS: Neurosurgical patients may be allowed to become mildly hypothermic during anesthesia in an effort to provide brain protection. Propofol maintenance infusion doses may not require adjustment in these patients.
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Introduction
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Mild hypothermia may be induced during neurosurgery in an effort to provide brain protection, despite limited evidence of benefit in humans (1,2). However, mild hypothermia may result in prolonged recovery from anesthesia (3). In neurosurgical patients this may obscure surgical complications. The anesthesiologist therefore must satisfy two conflicting aims: to provide potential brain protection and to facilitate rapid recovery.
Propofol is used widely as an anesthetic during neurosurgery. However, mild hypothermia increases propofol blood concentrations achieved by a constant-rate infusion (4). In addition, the potency of propofol may increase with decreasing core temperature, like the potency of volatile anesthetics (5), although this has not been reported previously. The combination of these pharmacokinetic and pharmacodynamic effects makes relative overdose theoretically possible if propofol is given at a standard rate to hypothermic patients. Accordingly, we tested the hypothesis that 3°C of core hypothermia decreases the propofol blood concentration at which patients respond to command (CP50-awake) in patients undergoing intracranial tumor surgery. We also assessed the effect of core temperature on the ability of the bispectral index (BIS; a multivariate electroencephalographic index) (6) to predict response to command during propofol anesthesia.
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Methods
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With approval from the Institutional Ethics Committee and written, informed consent, 40 patients, aged 18–60 yr and of ASA status I–III, scheduled for intracranial tumor surgery, were studied. Patients were excluded if they had any contraindication to the induction of core hypothermia or were taking any drug affecting anesthetic requirement.
Responsiveness to command was assessed at the end of the operation (Fig. 1). Anesthetic management during surgery was as follows: IV infusion of 0.9% NaCl was commenced at 120 mL/h, and a radial arterial cannula was inserted for arterial blood pressure monitoring and blood sampling. Routine anesthetic monitoring and BIS monitoring were commenced. The patient then breathed 100% oxygen, and alfentanil 50 µg/kg IV was administered. Anesthesia then was induced with a target-controlled infusion (TCI) of propofol titrated to maintain a BIS of 40–60 during surgery. Neuromuscular blockade was induced and maintained with rocuronium. The trachea was intubated and the lungs ventilated with 30% oxygen and 70% nitrous oxide. No other anesthetics or analgesics were given.
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Figure 1. Response to command was determined at the end of surgery. The target propofol concentration was reset at the end of surgery to a target determined by the response of the previous patient (the Dixon up-and-down method). Arterial blood samples for propofol and alfentanil assay were taken during the final 15 min of propofol infusion.
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Arterial hypotension was treated with IV fluid boluses and metaraminol. Arterial hypertension and tachycardia were treated with increases in the target propofol concentration and hydralazine. Patients received cephalothin, dexamethasone, furosemide, phenytoin, and mannitol, as requested by the neurosurgeon.
Before induction, patients were randomized to a core temperature of 34°C or 37°C by use of random number tables. Randomization results were concealed in sealed opaque envelopes. Forced-air warming was commenced immediately after induction in patients randomized to normothermia. Patients randomized to hypothermia initially were allowed to cool passively. Those in whom the core temperature did not decrease rapidly enough were cooled with forced-air cooling.
At the end of surgery, the patients’ lungs were ventilated with 100% oxygen, and neuromuscular blockade was reversed. If coughing occurred, the trachea was extubated immediately, and 100% oxygen was administered with assisted ventilation as required. Cutaneous forced-air warming was commenced or recommenced in all patients to prevent shivering and improve blinding of the observer. Propofol infusion was continued. At this time, the target propofol blood concentration in the first patient in each group was set to 3 µg/mL. Subsequent target concentrations were increased or decreased by 0.5 µg/mL, on the basis of the response of the previous patient in the same group (7). Time was allowed for effect-site concentration to equal target blood concentration. Fifteen minutes later, the patient’s response to command was tested by an observer who was blinded to the patient’s core temperature and target propofol concentration. A positive response was recorded if the patient opened his or her eyes after any of three requests made within 15 s. At this time, the study was complete. Hypothermic patients were warmed with forced-air warming, and meperidine 25 mg IV was administered to prevent shivering.
Core temperature was measured in the distal esophagus. Routine anesthetic variables were monitored continuously and recorded regularly. The electrocardiogram was acquired with Zip-prepTM (Aspect Medical Systems, Newtown, MA) electrodes (At1, At2; reference, Fpz; ground, Fp1 or 2). After confirming that all impedances were <5000 
, the BIS (A1000, version 3.12; Aspect Medical Systems, Newtown, MA) was calculated, displayed, and recorded. The BIS value just before assessment for responsiveness to command was recorded for use in the analyses.
Arterial blood samples for propofol were collected at 10 and 15 min of the final 15 min of propofol infusion. The samples were stored at 4°C for up to 10 wk: propofol concentrations decrease at <0.2%/wk at 4°C. They were analyzed with a high-performance liquid chromatography assay modified from the method of Plummer (8). This assay is linear to at least 20 µg/mL, and it has a detection limit of 0.025 µg/mL and a coefficient of variation of 4.1% at 2 µg/mL.
An arterial blood sample for alfentanil assay was collected at 15 min of the final 15 min of propofol infusion. The samples were frozen and subsequently analyzed with a gas chromatography assay modified from the method of Bjorkman and Stanski (9). This method is linear to at least 10 µg/mL and has a detection limit of 0.1 ng/mL and a coefficient of variation of 5.4% at 20 ng/mL.
Brain tumor size was established from the most recent magnetic resonance imaging scan, by a neuroradiologist who was blinded to the randomization and who categorized tumors as large or small according to previously published criteria (10,11). Tumor types, intraoperative medications, tumor size, numbers of positive responses to command, and numbers of extubated patients were compared by using two-sided Fisher’s exact tests. All other patient variables at baseline and at assessment of responsiveness (Tables 1, 2), as well as the median performance error and median absolute performance error of the TCI device, were compared by using two-sample Kolmogorov-Smirnov tests.
Core temperature group, rather than actual core temperature, was used (intention-to-treat analysis). Core temperature group, measured propofol and alfentanil concentrations at 15 min, brain tumor size, and intraoperative phenytoin administration were included as independent variables in the analyses; the outcome variable was response to command. Results were analyzed with logistic regression and are presented as odds ratios. The relationship between BIS and response to command was explored with a similar model. Confidence intervals (CI) for the estimates of CP50 and BIS50 (BUS value at response to command in 50% of patients) were derived by using bootstrapping. The relationship between BIS and measured propofol concentration, and target and measured concentrations, for each group, were determined by use of generalized linear models with log links and Gaussian error distribution. For target versus measured concentration, equality of agreement between the groups also was assessed by bootstrapping the difference in intercepts and slopes between the groups. All statistical analyses were performed with Stata 6.0 (Stata Corp., College Station, TX). P < 0.05 was considered statistically significant.
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Results
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One patient had an anaphylactic reaction to rocuronium and was replaced in the study. No significant differences were present between Hypothermic and Normothermic patients at baseline (Table 1). At testing for responsiveness, target propofol concentrations were significantly larger and BIS values were significantly smaller in the Normothermic group compared with the Hypothermic group (Table 2).
Measured propofol concentration was a significant predictor of response to command (OR, 11.76; 95% CI, 2.40–57.63; P < 0.01). Core temperature group, measured alfentanil concentration, brain tumor size, and phenytoin administration were not significant predictors of response to command (Table 3). Core temperature did not change the effect of propofol concentration on the likelihood of response to command (interaction P value = 0.27). The CP50-awake of propofol was 3.05 µg/mL (95% CI, 2.34–3.66) for all patients, 2.65 µg/mL (95% CI, 1.88–3.64) in the Hypothermic group, and 3.41 µg/mL (95% CI, 1.77–4.52) in the Normothermic group (Fig. 2).
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Figure 2. Probability of nonresponsiveness to command versus measured propofol concentration. Raw data for nonresponders are displayed above and for responders are displayed below. The 95% confidence intervals are offset for clarity. Core temperature did not have a significant effect on the relationship between measured propofol concentration and response to command. The relationship between measured propofol concentration and responsiveness was defined by this equation: log[p/(1 - p)] = a + b x [propofol]. For all patients, a = -5.16 (95% CI, -8.41 to 1.92; P = 0.002) and b = 1.69 (95% CI, 0.69–2.70; P = 0.001). For Hypothermic patients, a = -8.36 (95% CI, -15.40 to 1.31; P = 0.02) and b = 3.15 (95% CI, 0.49–5.83; P = 0.02). For Normothermic patients, a = -5.07 (95% CI, -9.92 to 0.22; P = 0.04) and b = 1.49 (95% CI, 0.18–2.79; P = 0.02).
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BIS was a significant predictor of response to command in a univariate model, but not in a multivariate model including measured propofol concentration or all predictor variables. Core temperature did not alter the relationship between BIS and response to command (Table 4). The BIS50-awake was 84 (95% CI, 70.04–102.87) for all patients, 91 (95% CI, 65.24–113.58) in the Hypothermic group, and 75 (95% CI, 55.11–99.88) in the Normothermic group (Fig. 3).
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Figure 3. Probability of nonresponsiveness to command versus bispectral index (BIS). Raw data for nonresponders are displayed above and for responders are displayed below. The 95% confidence intervals are offset for clarity. Core temperature did not have a significant effect on the relationship between BIS and response to command. The relationship between BIS and responsiveness was defined by this equation: log[p/(1 - p)] = a + b x BIS. For all patients, a = 5.52 (95% CI, 1.29–9.74; P < 0.01) and b = -0.07 (95% CI, -0.02 to 0.12; P < 0.01). For Hypothermic patients, a = 9.71 (95% CI, -1.07 to 20.50; P = 0.08) and b = -0.11 (95% CI, -0.01 to 0.22; P = 0.07). For Normothermic patients, a = 6.97 (95% CI, 0.73–13.21; P = 0.03) and b = 0.09 (95% CI, -0.18 to 0.01; P = 0.03).
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Measured propofol concentration (P = 0.03), but not core temperature (P = 0.85), was a significant predictor of BIS. An apparent effect of core temperature on BIS was caused by confounding by measured propofol concentration: that is, patients in the Hypothermic group had smaller measured propofol concentrations and larger BIS values than patients in the Normothermic group (Fig. 4).
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Figure 4. Bispectral index (BIS) versus measured propofol concentrations at 15 min. The relationship between BIS and measured propofol concentration is defined by this equation: BIS = a + b x [propofol], where a = 108 (95% CI, 96–120; P = 0.001) and b = -8.93 (95% CI, -12.26 to 5.61; P = 0.001). Core temperature did not affect the relationship between measured propofol concentration and BIS.
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Measured propofol concentrations varied by -1% ± 7% (range, -17% to 13%) from 10 to 15 min of the final infusion. The median performance error of the TCI device was +24% (-1% to 30%), and the median absolute performance error was 26% (19%–34%) for all patients. The performance of the TCI device was not significantly different in Hypothermic versus Normothermic patients (median performance error, 9% [-1% to 81%] vs 25% [-6% to 34%]; P = 0.87) (median absolute performance error, 19% [6%–81%] vs 28% [24%–35%]; P = 0.34).
Targeted propofol concentration (P = 0.02), but not core temperature (P = 0.51), was a significant predictor of measured propofol concentration. The relationship between measured propofol concentration and target propofol concentration was defined by this equation: [measured propofol] = a + b x [target propofol]. For all patients, a = 0.79 (95% CI, -0.59 to 2.18; P = 0.25) and b = 0.95 (95% CI, 0.47–1.43; P = 0.0001). For Hypothermic patients, a = 0.22 (95% CI, -2.02 to 2.46; P = 0.84) and b = 1.12 (95% CI, 0.26–2.14; P = 0.01). For Normothermic patients, a = 1.34 (95% CI, -1.49 to 4.18; P = 0.33) and b = 0.78 (95% CI, -0.08 to 1.64; P = 0.07). The 95% CI for the difference in intercepts were -4.21818 to 1.91241, and for the difference in slopes they were -0.67809 to 1.45053, indicating lack of evidence to reject the hypothesis that the regressions are the same.
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Discussion
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Measured propofol concentration predicted response to command in this study. The CP50-awake (3.05 µg/mL) was consistent with previous reports when propofol was infused alone or with alfentanil (12–14). Core temperature was not a predictor of response to command, even when known confounders, including pharmacokinetic factors (4), brain tumor size (10,11), and the coadministration of alfentanil (14), were taken into account. Propofol infusion regimens therefore may not require adjustment when mild hypothermia is induced in neurosurgical patients.
Our result is surprising given that hypothermia possesses anesthetic properties of its own (15) and that the volatile anesthetic requirement decreases 5%/°C in animals (5). The difference may be due to wider variability in responsiveness in surgical patients and a narrower range of core temperatures. Median propofol concentrations at assessment were larger in the Normothermic group than the Hypothermic group, even though the numbers of responders and nonresponders were similar. However, the difference in the CP50-awake values of the two groups (
0.76 µg/mL), which was calculated with logistic regression, was not statistically significant. Logistic regression properly relates propofol blood concentration with the likelihood of response. Even if this difference were significant, it is not clinically important, especially if interindividual variability in propofol requirement is taken into account.
Core temperature did not alter the ability of BIS to predict response to command. An apparent effect of core temperature on BIS values was caused by confounding by measured propofol concentration, because BIS values were greater and propofol concentrations were less in Hypothermic compared with Normothermic patients. These data support our previous report that core temperatures between 35°C and 38°C have no significant effect on BIS during pseudo-steady-state concentrations of propofol (16). Others have reported that BIS decreases 1.9/°C during cardiac surgery (17,18). However, an effect of hypothermia or cardiopulmonary bypass on propofol concentration cannot be excluded in these studies. We conclude that core temperature does not complicate the interpretation of BIS values in the mild hypothermic range.
The BIS predicted responsiveness in this study via its ability to predict measured propofol concentration (6,16,19–21). The BIS50-awake (84) was greater than in previous reports. Alfentanil (20) and nitrous oxide (19) both increase BIS50-awake values, but residual concentrations in our patients were too small to exert a significant influence. Electromyographic activity may falsely increase BIS (particularly versions earlier than 3.2) (22). However, gross shivering was not seen in our patients. Finally, neurological disease may have affected BIS, although little is published on this subject (22).
In conclusion, responsiveness to command in this group of neurosurgical patients was predicted by measured propofol concentration, but not by core temperature. Propofol infusion regimens therefore may not need adjustment during neuroanesthesia when hypothermia is induced or reversed. BIS reflected the pharmacodynamic effects of propofol and was not affected by mild hypothermia.
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Acknowledgments
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Supported by grants from the Australian and New Zealand College of Anaesthetists, Aspect Medical Systems, Inc., and AstraZeneca Pharmaceuticals Pty Ltd.
We wish to thank the neurosurgeons and operating room staff of the Royal Melbourne Hospital for their cooperation and encouragement.
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Accepted for publication December 17, 2001.
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Abstract
Introduction
