Dosing of Remifentanil to Prevent Movement During Craniotomy in the Absence of Neuromuscular Blockade Marco A

CLINICAL INVESTIGATION

Dosing of Remifentanil to Prevent Movement During Craniotomy in the Absence of Neuromuscular Blockade Marco A. Maurtua, MD,*w Anupa Deogaonkar, MD,z Mohamed H. Bakri, MD, PhD,y Edward Mascha, PhD,J Jie Na, MS,# Joseph Foss, MD,* Daniel I. Sessler, MD,y Michelle Lotto, MD,*w Zeyd Ebrahim, MD,* and Armin Schubert, MD, MBA*w

Adjunctive therapy is needed to ablate movement reliably, and Background: In neuroanesthesia practice, muscle relaxants may to counteract the hypotensive effect of remifentanil. These at times need to be avoided to facilitate intraoperative motor findings may be helpful for clinicians administering remifentanil pathway monitoring. Our study’s objective was to determine the and isoflurane during procedures, where muscle relaxants may optimal dose of remifentanil required to prevent movement after not be desirable. neurosurgical stimulation. Key Words: remifentanil, depth of anesthesia, immobility, head Methods: After Institutional Review Board approval and pins, neurosurgery, craniotomy written informed consent, 132 patients undergoing elective craniotomy randomly received one of 12 remifentanil dose (J Neurosurg Anesthesiol 2008;20:221–225) regimens (0.10 to 0.21 mg/kg/min). Remifentanil was started before induction with propofol and succinylcholine. Anesthesia was maintained with isoflurane (0.6% end-tidal) in air/oxygen. he goals of a general anesthetic are to achieve During the study, movement was assessed on predetermined Thypnosis, amnesia, analgesia, control of autonomic criteria by the anesthesiology, nursing, and neurosurgical teams. responses, and muscle relaxation.1 In clinical practice it Heart rate and blood pressure were recorded every 5 minutes. We can be challenging to achieve complete immobility when assessed the relationship between movement, hypotension, brady- the use of muscle relaxants are unnecessary, restricted, or cardia, and dose using probit analysis and logistic regression. contraindicated, such as may occur during neurosurgical Results: Sixty-five percent of the patients moved in response to procedures requiring assessment of motor-evoked poten- surgical stimuli [95% confidence interval (CI): 49%-79%] at a tials and/or electromyography. It may also be difficult to remifentanil infusion rate of 0.10 mg/kg/min, and movement achieve reliable immobility in patients on anticonvulsant decreased to 21% (95% CI: 11-35) at 0.21 mg/kg/min. The drugs, which shorten the half-life of muscle relaxants. probability of movement was 50% at an infusion rate (95% CI) Muscle relaxants are not required in every surgical of 0.13 (0.10 to 0.15) mg/kg/min remifentanil and decreased to procedure and their avoidance may prevent adverse 25% at an infusion rate of 0.19 (0.17 to 0.29) mg/kg/min. The effects such as inadequate recovery of normal neuromus- probability of hypotension and bradycardia was 50% at 0.13 cular function and consequent postoperative respiratory (0.10 to 0.15) mg/kg/min and 0.17 (0.15 to 0.21) mg/kg/min, failure.2 Patients at high risk for these complications respectively. include those with certain neuromuscular diseases and preexisting respiratory impairment.2 Finally, avoidance Conclusions: Higher doses of remifentanil lessen the risk of of neuromuscular block may aid in the prevention of movement in the absence of muscle relaxants with surgical awareness under anesthesia as movement will alert the stimulation for elective craniotomy. Hypotension and brady- practitioner to light anesthetic conditions.2,3 For these cardia were common at higher doses. Even at the maximum reasons, an anesthetic adjunct that reduces or abolishes dose (0.21 mcg/kg/min) there was a 20% chance of movement. patient movement in the absence of neuromuscular blockade would represent a substantive advantage to Received for publication January 18, 2008; accepted May 20, 2008. clinicians. From the Departments of *General Anesthesiology; yOutcomes The purpose of pain is to signal acute injury and Research; JQuantitative Health Sciences and Outcomes Research; prevent further tissue damage by withdrawal from w #Quantitative Health Sciences; zAnesthesia Institute; and Cleve- noxious stimuli.4 Remifentanil, through its m-receptor land Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH. agonist effect and ability to potentiate volatile anesthetics Support: Institutional Funding. like isoflurane, has been shown to prevent withdrawal Current address: Mohamed H. Bakri, MD, PhD, Assiut University, movement during surgical stimulation.5 Studies have Asiut, Egypt. shown remifentanil’s synergistic effects, with induction Reprints: Marco Maurtua, MD, Department of General Anesthesiol- 5–7 ogy/E31, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH drugs such as propofol and volatile anesthetics. 44195 (e-mail: [email protected]). Remifentanil decreases isoflurane’s minimum alveolar Copyright r 2008 by Lippincott Williams & Wilkins concentration (MAC),6 but the dosing requirements to

J Neurosurg Anesthesiol Volume 20, Number 4, October 2008 221 Maurtua et al J Neurosurg Anesthesiol Volume 20, Number 4, October 2008 produce immobility have not been established with allowed head pinning to occur 15 minutes after the certainty. remifentanil infusion was started. No local anesthetic was The main objective of this study was to determine administered to the patient’s scalp before head pinning, the dose-response relationship of remifentanil, when used which is standard practice at our institution. in combination with 0.6% isoflurane, in reducing patient Demographic data including age, height, weight, movement during surgical head pinning and incision for and sex were obtained, as were heart rate, mean arterial craniotomy. Head pinning and incision are used as pressure, systolic and diastolic blood pressure, and end- surrogates for intraoperative stimuli, to achieve a tidal isoflurane concentration. Blood pressure was mea- standard, highly potent degree of stimulation in each sured via an automated blood pressure cuff. These patient, and to achieve our results early in the procedure measurements were recorded immediately before remi- and therefore decrease unnecessary movement risks fentanil infusion, 5 minutes after remifentanil infusion during surgical brain manipulation. A secondary objec- was started, immediately after head pinning, 5 minutes tive was to determine the frequency with which different after pinning, at skin incision, and 5 minutes after remifentanil infusion doses produce hypotension and/or incision. bradycardia. Patient movement was defined as either gross purposeful movement, such as reaching for the endo- tracheal tube or the head pins, coughing or bucking, MATERIALS AND METHODS chewing, swallowing, or grimacing, or minor limb move- This study was approved by the Institutional ments, including movement distal to the elbow or the Review Board of the Cleveland Clinic and written knees. Patient reactions were observed continuously by informed consent was obtained from each patient. Our the anesthesiologist, operating room nurse, and research study setting was in the neurosurgical operating room coordinator. Although efforts were made to keep during elective craniotomy; patients were enrolled over a observers blinded to the dose of remifentanil, it became 2-year period. This was a prospective, randomized, apparent during the first portion of the study that clinical trial of 12 remifentanil infusion doses ranging blinding was incomplete. Thereafter, blinding procedures from 0.10 to 0.21 m/kg/min to assess optimal dosing to were tightened further. prevent movement response to surgical stimulation. Any patient movement resulted in termination of Computer-generated random numbers were used for the study and immediate intervention to increase the group assignment. depth of anesthesia. Hypotension was considered to occur The study excluded patients who were pregnant or if mean arterial pressure decreased to <60 mm Hg.9 nursing, had a Glasgow coma score <15, had contra- Bradycardia was defined as <60 beats/min.10 The treat- indications to succinylcholine, underwent cerebral aneur- ment of bradycardia and hypotension, once diagnosed, ysm clipping, were morbidly obese (body mass index was left to the discretion of the clinician, and the use of >40), and had an American Society of Anesthesiologists vasopressor, and their doses were recorded. physical status (ASA score) >3. Movement was continuously assessed according to predetermined criteria by Statistical Methods the research investigator, as well as the neurosurgical, The relationships between remifentanil dose, move- nursing, and anesthesiology teams, until 5 minutes after ment, hypotension, or bradycardia were analyzed using scalp incision at which time the study ended. logistic regression models and summarized by odds ratios No premedication was given before induction of and 95% confidence intervals (CIs). Probit analysis was anesthesia. The administration of fluids was left to the used to estimate the dose and 95% fiducial limits discretion of the attending anesthesiologist, our standard (analogous to CIs) corresponding to a given probability practice calling for approximately 10 to 15 mL/kg crystal- of having the outcome. The significance level was 0.05 for loid during induction and positioning. all hypotheses. Standard statistical software (SAS, Cary, Remifentanil infusion was started 2 to 4 minutes NC) was used. before induction, which was accomplished with lidocaine Sample size calculations indicated that 132 patients (10 to 20 mg to prevent pain after propofol administra- would be required with 11 patients for each of the 12 dosing tion), propofol (2 to 4 mg/kg), and succinylcholine steps. This number was chosen to be able to estimate the (1 to 2 mg/kg) to facilitate tracheal intubation. Non- probability of movement with sufficient precision. Specifi- depolarizing muscle relaxants were avoided and the end- cally, we planned to have a sufficiently narrow CI tidal isoflurane concentration was kept at 0.6% in air/ (width = 0.16, corresponding to a standard error of oxygen throughout the study period. 0.041) from a logistic regression analysis for the probability After induction and tracheal intubation, an arterial of movement at a dose of 0.15 mg/kg/min assuming a true line was placed and a second peripheral IV was started. probability of movement of 0.20 at that dose. Train-of-4 stimulation of the ulnar nerve was performed before head pinning to assure recovery from succinylcho- RESULTS line’s neuromuscular blocking effect. As remifentanil Of 132 randomized patients, only 131 were available plasma concentrations are reported to reach a steady for analysis because of an infusion pump malfunction in 1 state within 10 minutes of beginning an infusion,8 we patient. Table 1 gives a summary of baseline factors such

222 r 2008 Lippincott Williams & Wilkins J Neurosurg Anesthesiol Volume 20, Number 4, October 2008 Remifentanil to Prevent Movement During Craniotomy

TABLE 1. Summary of Demographic Information Age Body Mass Index Sex N (%) ASA N (%) Remifentanil Dose lg/kg/min N Mean (SD) Mean (SD) Male I II III 0.10 10 44 (21) 24 (5) 3 (30) 1 (13) 7 (88) 0 (0) 0.11 11 51 (10) 25 (3) 5 (46) 1 (9) 9 (82) 1 (9) 0.12 10 45 (14) 30 (8) 5 (50) 0 (0) 10 (100) 0 (0) 0.13 11 53 (15) 25 (4) 4 (40) 1 (9) 8 (73) 2 (18) 0.14 11 52 (11) 29 (6) 3 (27) 0 (0) 10 (100) 0 (0) 0.15 11 48 (11) 26 (5) 5 (46) 2 (18) 8 (73) 1 (9) 0.16 11 38 (12) 29 (7) 3 (27) 0 (0) 9 (90) 1 (10) 0.17 11 43 (15) 29 (5) 5 (46) 1 (9) 8 (73) 2 (18) 0.18 11 42 (18) 30 (5) 4 (36) 0 (0) 9 (82) 2 (18) 0.19 11 41 (22) 29 (6) 7 (64) 0 (0) 10 (91) 1 (9) 0.20 11 41 (13) 29 (7) 6 (55) 1 (9) 9 (88) 1 (9) 0.21 12 42 (16) 28 (7) 8 (67) 0 (0) 11 (92) 1 (83) All 131 45 (15) 28 (6) 58 (44) 7 (6) 108 (85) 12 (10) as age, body mass index, sex, and ASA score by dose. All study, we included a phase variable (patients 1 to 93 vs. 94 randomized patients had elective surgery for either brain onwards) in assessing confounders of the dose-movement tumor resection or brain biopsy. relationship. No significant association was found be- A total of 53 patients moved. All except 2 moved tween movement and phase (early vs. late) of the study, during head pinning. One moved before head pinning and no interaction between phase or any other variable with ventilator setting changes; the other moved during and dose was found (Table 3). head positioning. The type of movement observed was Hypotension occurred in 50% of patients receiving chewing and swallowing in 3 patients (5.6%), minor limb remifentanil at a rate of 0.13 mg/kg/min and in 75% of the movement in 5 patients (9.4%), major purposeful limb patients receiving 0.20 mg/kg/min. CIs for estimated dose movement in 6 patients (11.3%), coughing and bucking at a given probability of hypotension were not available plus limb movement in 11 patients (20.7%), and coughing due mainly to an outlier response at dosage 0.20 mg/kg/ and bucking alone in 28 patients (52.8%). min, where only 1/11 patients was hypotensive (Table 4, Movement in response to surgical stimuli was Fig. 1). observed in 65% (95% CI: 49%-79%) of patients at a A similar trend was observed for bradycardia, remifentanil infusion rate of 0.10 mg/kg/min, and pro- which was experienced by 22 (95% CI: 12%-38%) gressively decreased to 21% (95% CI: 11%-35%) as the patients at an infusion rate of 0.10 mg/kg/min remifenta- infusion rate increased to 0.21 mg/kg/min (Table 2). nil, and increased to 68 (95% CI: 52%-81%) patients at Besides remifentanil dose, patient age was the only 0.21 mg/kg/min remifentanil. Similarly, the probability of factor significantly associated with movement in response bradycardia was 25% at a remifentanil infusion rate of to surgical stimuli (P = 0.02). Higher age was associated 0.12 (0.08 to 0.13) mg/kg/min and increased to 50% at 0.17 with less movement, regardless of dosage. Specifically, a (0.15 to 0.21) mg/kg/min remifentanil (Table 5, Fig. 2). difference of 10 years of age was associated with a 36% (5% to 44%) less chance of movement (odds ratio 0.74, 95% CI: 0.56-0.95) (Table 3). To assess the impact of TABLE 3. Models Assessing Potential Confounders of improved blinding procedures from early and late in the Relationship Between Dosage and Movement Main Effect Interaction With Dosage Odds Ratio TABLE 2. Estimated Probability of Movement at Each Dose PCF (95% CI) P* Parameter (SE) Pw Probability of 95% Confidence Age (10 y)y 0.73 (0.56, 0.96) 0.02 0.005 (0.039) 0.89 Dose (lg/kg/min) Movement (%)* Limits BMI (5 U)J 0.79 (0.57, 1.10) 0.16 0.040 (0.051) 0.43 0.10 65.4 (48.6, 79.0) ASA class (per 1.02 (0.38, 2.7) 0.97 0.155(0.169) 0.36 0.11 61.2 (46.4, 74.2) level) 0.12 56.9 (44.0, 68.6) First 93 patients 0.74 (0.32, 1.7) 0.47 0.081(0.127) 0.52 0.13 52.4 (41.3, 63.3) vs. restz 0.14 47.9 (38.3, 57.7) 0.15 43.5 (34.7, 52.7) Odds ratio = odds of movement in risk group versus reference (eg, patients age 0.16 39.1 (30.6, 48.3) 30 vs. 20, or ASA 2 vs. 1). *Model includes dosage (P<0.05 in each model) and PCF. 0.17 34.9 (26.2, 44.8) wModel includes dosage, PCF and interaction of dose, and PCF. 0.18 31.0 (21.9, 41.9) zThe incidence of movement in the first 93 patients was 39.8% and 45.7% in 0.19 27.3 (17.8, 39.4) the following 35 patients. 0.20 23.9 (14.2, 37.1) yPer 10 y of age. 0.21 20.7 (11.2, 35.1) JPer 5 BMI units. ASA indicates American Society of Anesthesiologists; BMI, body mass index; *Logistic regression results. PCF, potentially confounding factor; SE, standard error. r 2008 Lippincott Williams & Wilkins 223 Maurtua et al J Neurosurg Anesthesiol Volume 20, Number 4, October 2008

TABLE 4. Estimated Remifentanil Dose at Selected TABLE 5. Estimated Probability of Bradycardia at Each Dose of Hypotension and Bradycardia Probabilities Remifentanil Probability of 95% Fiducial Probability of 95% Confidence Hypotension (%) lg/kg/min Limits (lg/kg/min) Bradycardia (%) Limits 25 0.08 NA 0.10 22.5 (12.2, 37.8) 50 0.13 NA 0.11 25.8 (15.4, 39.8) 75 0.20 NA 0.12 29.4 (19.2, 42.1) Probability of bradycardia 0.13 33.2 (23.5, 44.6) 25 0.12 (0.08, 0.13) 0.14 37.4 (28.2, 47.6) 50 0.17 (0.15, 0.21) 0.15 41.6 (32.8, 51.1) 75 0.25 (0.20, 0.47) 0.16 46.1 (37.1, 55.3) 0.17 50.6 (40.9, 60.2) NA, no fiducial limits available for hypotension due to outlier dose 0.20 mg/kg/ 0.18 55.1 (44.1, 65.5) min (Fig. 2). 0.19 59.5 (46.9, 70.9) 0.20 63.7 (49.4, 76.0) 0.21 67.8 (51.7, 80.5) Thus, both hypotension and bradycardia increased at higher remifentanil infusion rates. The observed data for movement in the study at elective craniotomy. The probability of preventing move- doses of 0.10, 0.15, and 0.21 mg/kg/min, respectively, ment increased with remifentanil dose. On the basis of resulted in CI widths of 0.30, 0.18, and 0.24. Logistic our observations, the remifentanil dose estimates for 50% regression CIs are naturally narrowest at the middle of and 75% reduction of the probability of movement were the predictor (ie, the dose). Our observed CI width at 0.13 and 0.19 mg/kg/min, respectively with 0.5 MAC 0.15 mg/kg/min is slightly wider than planned because the isoflurane. observed movement at that dose was larger than planned It is important to note that the probability of (44% vs. 20%), resulting in larger variance in the bradycardia was 33% at a remifentanil dose of 0.13 mg/ estimated probability of movement. kg/min and almost doubled at 0.19 mg/kg/min. Similarly, patients dosed at 0.13 mg/kg/min had a 25% probability of hypotension, which increased to 50% at 0.19 mg/kg/ DISCUSSION min. The hemodynamic instability induced by remifenta- The results of our study demonstrate that higher nil is especially concerning because it was common at the doses of remifentanil lessen the risk of movement in the doses required to reliably produce immobility. Our absence of muscle relaxants with surgical stimulation for hemodynamic findings are consistent with the findings

FIGURE 1. Relationship between remifentanil dose and FIGURE 2. Relationship between remifentanil dose and hypotension. Circles indicate the proportion of patients with bradycardia. Circles indicate the proportion of patients with observed hypotension at each randomized dose. The solid line observed bradycardia at each randomized dose. The solid line is the predicted proportion with hypotension at a certain dose. is the predicted proportion with bradycardia at a certain dose. Dotted lines are 95% confidence intervals around the Dotted lines are 95% confidence intervals around the predicted proportion with hypotension. predicted proportion with bradycardia.

224 r 2008 Lippincott Williams & Wilkins J Neurosurg Anesthesiol Volume 20, Number 4, October 2008 Remifentanil to Prevent Movement During Craniotomy of Bilgin et al11 who while using a low-dose remifentanil relationships.6,12 Second, the dose range studied extended (0.05 mcg/kg/min) combined with midazolam for con- only from 0.10 to 0.21 mcg/kg/min. It was not possible to scious sedation during stereotactic brain biopsy found a find a dose within this range at which all patients were low incidence of hypotension, similar to our findings immobile. It is therefore unknown whether this dose while using low-dose remifentanil and Morgan et al5 after indeed exists. Third, we did not measure plasma the administration of a remifentanil bolus of 1.25 mcg/kg remifentanil concentrations so we cannot say for certain in combination with an induction dose of propofol for that the infusion doses employed truly resulted in a intubation found a higher incidence of bradycardia and progressively higher plasma effect. Nevertheless, the hypotension when compared with the administration of remifentanil dose is clinically thought of as an infusion propofol and suxamethonium, also similar to our findings dose and therefore our findings should be relevant to at greater doses of remifentanil.5,11 Clinicians intending to clinical practice. employ remifentanil at a dose of 0.2 mcg/kg/min or higher Our results suggest that higher doses of remifentanil to take advantage of the 80% probability of immobility substantially lessen the risk of movement with potent should expect to have to support blood pressure surgical stimulation in the absence of neuromuscular pharmacologically. blockade. Clinicians should bear in mind that, even at our Our results are also consistent with the findings of maximum dose of remifentanil (0.21 mcg/kg/min) a 20% Lang et al,6 who described the reduction of isoflurane chance of movement was observed. Adjunctive therapy is MAC by remifentanil. These authors randomly assigned needed to ablate movement reliably, and to counteract different remifentanil plasma concentrations (achieved via the hypotensive effect of remifentanil. Further studies are a computer-assisted continuous infusion device) to iso- required to determine the optimal combination of flurane-anesthetized patients. Movement was strictly remifentanil and isoflurane to ablate any movement. defined as only gross purposeful muscular movement of the head and extremities following the criteria used for MAC determination by Quasha et al.12 Lang et al showed that a remifentanil target plasma concentration of REFERENCES 1.37 ng/mL resulted in a 50% reduction in isoflurane 1. Woodbridge PD. Changing concepts concerning depth of anesthe- 6 sia. Anesthesiology. 1957;18:536–550. MAC. In our study, the administration of remifentanil at 2. Bevan DR, Donati F. Muscle relaxants. In: Barash P, Cullen BF, 0.13 mg/kg/min produced immobility in 50% of the Stoelting RK, eds. Clinical Anesthesia. Philadelphia: Lippincott patients when combined with 0.6% isoflurane. However, Williams & Wilkins; 2001:419–469. it is worth noting that the definition of movement in 3. Ghoneim MM. Awareness during anesthesia. Anesthesiology. 2000; our study included both gross purposeful muscular 92:597–602. 4. Stein C. Morphine—A ‘‘Local Analgesic’’ [Pain Clinical Updates movement, as well as minor limb movement, coughing, web site] March 1995;3:1-8. Available at: http://www.iasppain.org/ swallowing, chewing, and grimacing. Because any move- AM/Template.cfm?Section = Home§ion = Pain_Clinical_Updates1 ment during head-pin placement is undesirable and is &template = /CM/ContentDisplay.cfm&ContentFileID = 215. likely a sign of inadequate anesthesia, we believe our 5. Morgan JM, Barker I, Peacock JE, et al. A comparison of intuba- ting conditions in children following induction of anaesthesia with definition of movement and study results to have superior propofol and suxamethonium or propofol and remifentanil. relevance to clinical practice. Anaesthesia. 2007;62:135–139. Our study had several limitations which should be 6. Lang E, Kapila A, Shlugman D, et al. Reduction of isoflurane considered when interpreting our results. First, although minimal alveolar concentration by remifentanil. Anesthesiology. the response to surgical stimulation was assessed using 1996;85:721–728. 7. van Delden PG, Houweling PL, Bencini AF, et al. Remifentanil- criteria established at the beginning of the study, it was sevoflurane anaesthesia for laparoscopic cholecystectomy: compar- not always possible to keep the observer blinded to the ison of three dose regimens. Anaesthesia. 2002;57:212–217. dosing group assignment. This could have introduced 8. Stoelting RK. Opioid agonists and antagonists. In: Stoelting RK, bias in the interpretation of the patient’s movement ed. Pharmacology and Physiology in Anesthetic Practice. Philadel- phia: Lippincott-Raven; 1999:77–112. response. In our multivariable statistical model, we 9. LeDoux D, Astiz ME, Carpati CM, et al. Effects of perfusion assessed whether the relationship between movement pressure on tissue perfusion in septic shock. Crit Care Med. 2000;28: and dose was different for the first 93 patients compared 2729–2732. with the last 39 (ie, those with tighter blinding) and it was 10. Josephson ME, Zimetbaum MA. The bradyarrhythmias: disorders not. Although this does not prove absence of bias from of sinus node function and AV conduction disturbances. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrison’s Principles of unblinding, it is unlikely that our results were affected in a Internal Medicine. New York: McGraw-Hill, Medical Pub. Division; major way. We believe this to be the case in part because 2005:1333–1341. our definition of movement required no clinical judgment 11. Bilgin H, Basag˘ an Mog˘ ol E, Bekar A, et al. A comparison of effects over what constituted movement, as all movement was of alfentanil, fentanyl, and remifentanil on hemodynamic and respiratory parameters during stereotactic brain biopsy. J Neurosurg scored as a positive response. Furthermore, previous Anesthesiol. 2006;18:179–184. investigators did not consider blinding procedures neces- 12. Quasha AL, Eger EI, Tinker JH. Determination and applications of sary to make valid conclusions about dose-response MAC. Anesthesiology. 1980;53:315–334.

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