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Neurol Med Chir (Tokyo) 50, 622¿626, 2010 Intravenous Methylprednisolone Reduces the Risk of Propofol-Induced Adverse Effects During Wada Testing Nobuhiro MIKUNI, Youhei YOKOYAMA, Atsuhito MATSUMOTO, Takayuki KIKUCHI, Shigeki YAMADA, Nobuo HASHIMOTO*, Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto; *National Cerebral and Cardiovascular Center, Suita, Osaka The adverse effects and risks associated with intracarotid propofol injection during Wada testing wereretrospectively compared in two groups of patients with (n = 75) and without (n = 58) intravenousmethylprednisolone administered before intracarotid propofol injection. The incidences of all adverseeffects were decreased in the methylprednisolone group. In particular, severe adverse effects such as in-creased muscle tone with twitching and rhythmic movements or tonic posture, which could adverselyaffect Wada test results, were seen in one patient in the methylprednisolone group and seven patients inthe control group, indicating 92% risk reduction. This study suggests that Wada testing using in-travenous methylprednisolone administration prior to propofol injection is a safe approach to thepreoperative evaluation of brain tumors, epilepsy, and arteriovenous malformations.
The Wada test, a direct intracarotid amobarbital in- jection that induces transient anesthesia in a singlecerebral hemisphere,11) has been the gold standard The clinical records were retrospectively examined for lateralization of hemispheric speech and memo- of all 75 patients (44 men and 31 women), aged 10 to ry dominance. Although amobarbital has been com- 74 years, who underwent the Wada test from 2006 to monly used for this purpose, its limited availability 2008 as part of a preoperative examination. The due to worldwide shortages has led to the explora- population included 43 patients with brain tumors, tion of alternative agents such as propofol,10) metho- 18 patients with temporal or frontal lobe epilepsy, hexital,2) and etomidate.6) We have previously report- and 14 patients with arteriovenous malformations ed the clinical utility of an intracarotid propofol test (AVMs). Fifty-eight patients who underwent the for speech and memory dominance with a moderate- Wada test from 2001 to 2005 using intracarotid ly high risk of adverse effects.8) Previous research has suggested that propofol infusion is likely to formed the control group in this study. Adverse ef- cause a considerably high incidence of adverse ef- fects of the control group were reported previously.8) fects, although no data on adverse effects for None of the patients had received steroids before the amobarbital equivalents has been provided.5) The present study evaluated the efficacy of The methylprednisolone group received an in- methylprednisolone for improving the safety of travenous bolus injection of 500 mg (or 250 mg for propofol administration during the Wada test by children 15 years of age and younger) methylpred- comparing outcome measures of 75 patients who nisolone at most 5 minutes prior to propofol ad- received methylprednisolone (methylprednisolone ministration. The Wada test was then performed group) to those of 58 patients who did not (control using the propofol-based protocol reported previous-ly.8,10) Propofol was administered as a 10 ml saline suspension at a concentration of 1 mg/ml. If this dose did not induce contralateral hemiplegia, addi- Intravenous Methylprednisolone During Wada Testing tional propofol was injected immediately, up to a eye version. Grade 3 adverse effects included in- maximum dose of 15 mg in one side. All patients in creased muscle tone with twitching and rhythmic both groups received equal total propofol injection movements or tonic posture. To evaluate the poten- volumes bilaterally except for one patient in the con- tial risks of propofol injection, the odds ratios and trol group who suffered strong adverse effect after 95% confidence intervals (CIs) associated with vari- the first propofol dose, and so did not receive a sec- ous demographic variables were calculated, such as ond injection. Total propofol injection volume (me- sex, age, history of convulsions, lesion type, lesion an ± standard deviation) was 22.7 ± 3.8 mg in the laterality, laterality of language function, relation- methylprednisolone group and 20.8 ± 3.7 mg in the ship between the laterality of the lesion and the lan- guage center, and injection volume (total, first injec- Clinical characteristics of the two groups were tion, and second injection), using SAS version 8.2 compared using the x2 test at a significance level of p software (SAS Institute, Cary, N.C., U.S.A.). P values º 0.05. The results showed no significant difference less than 0.05 were considered to be statistically sig- in underlying disease, sex, history of epilepsy, lesion nificant in each analysis, whereas p values equal to laterality, speech dominance, or mean age, indicat- 0.05 were considered to indicate marginal risks.
ing the control group was appropriate (Table 1).
The adverse effects following propofol injection were grouped into three categories as previouslymentioned.8) Grade 1 adverse effects included eye In the methylprednisolone group, 9 of 75 patients ex- pain, shivering, face contortion and lacrimation, perienced adverse effects, all of which were ob- laughing, or apathy. Grade 2 adverse effects consist- served immediately after propofol injection. In all of ed of confusion, involuntary movement, or head and these patients, symptoms disappeared within 5minutes of injection, and were mild enough to allowcontinuation of the Wada test as usual. In the control group, 19 of 58 patients had adverse effects. The in- cidence in the methylprednisolone group was sig- nificantly lower, with an odds ratio of 0.280 (95% CI: 0.115–0.679, p = 0.0036), yielding a 72% risk reduc- Analysis of the incidence of individual signs and symptoms found that the methylprednisolone group included 1 epilepsy patient with tonic posture (con- trol group 3 patients) and no patients with increased tone with twitching (control group 4 patients) (Fig.
1). These results indicated a significant reduction in Grade 3 adverse effects in the methylprednisolone group, with an odds ratio of 0.084 (95% CI: 0.010–0.712, p = 0.0052) and a 92% risk reduction (Table 2). The methylprednisolone group included no patients with involuntary movements and 1 with head and eye version, demonstrating a marked *Excludes one patient who stopped the examination and reduction in Grade 2 adverse effects compared with the control group, in which 2 patients showed in- malformation, SD: standard deviation.
voluntary movements and 5 exhibited head and eye Adverse effects of intracarotid propofol injection into the brachial artery has been reported, suggest-ing particulate embolization or chemical incom-patibility with the blood could be the cause of thedecrease in vascular supply following propofol ar-terial injection.1) The significant decrease in Grade 3adverse effects seen in methylprednisolone-treatedpatients could have involved methylprednisolone ef-fects such as improvement of vascular supply andanti-allergic action, which reduced ischemia-in-duced trophysiological or imaging studies during in-tracarotid propofol injection are needed to elucidatethe mechanism of reduction of these severe adverse Comparison of the number of patients with in- dividual adverse effects between the groups with (shadedcolumns) and without (closed columns) methylpredniso- Methohexital2) and etomidate6) have been reported lone injection prior to propofol administration.
as equivalent to amobarbital in terms of the efficacyin the Wada test. However, methohexital was soshort-acting that two successive injections wereneeded for each hemisphere, and no detailed version (Fig. 1). The number of patients experienc- description of adverse effects was provided. In- ing confusion in the methylprednisolone group was half that in the control group (3 patients versus 6).
shivering-like tremors in approximately half of the Statistical analysis found no significant difference patients, and either evidence of contralateral elec- in the effect of methylprednisolone on the incidence troencephalography slowing following most injec- of Grade 1 or Grade 2 adverse effects (odds ratio: tions, or an increase in interictal spike activity in the 0.394, 95% CI: 0.105–1.483, p = 0.1570) (Table 2).
hemisphere ipsilateral to injection.6) Moreover,etomidate infusion may be a major risk factor for the development of relative adrenocortical insufficiencyin critically ill patients.7) Future reports of adverse Our previous study showed that intracarotid effects in a large number of patients undergoing propofol injection is associated with a moderately neurosurgery will provide useful information.
high risk of side effects. The present study found The only adverse effects observed in two or more that intravenous administration of methylpredniso- patients in the methylprednisolone group were con- lone followed by intracarotid propofol injection sig- fusion (3 patients) and eye pain (2 patients), but the nificantly reduced the incidence of severe (Grade 3) incidences were approximately half those in the con- trol group. Confusion is a condition arising from Grade 3 adverse effects, which are comparatively suppression of frontal lobe function and is indepen- rare after amobarbital administration, may result in dent of the type of anesthesia used. Confusion was incompletion or inaccuracy of the Wada test.8) These observed with at least one other adverse effect in 5 of adverse effects may be caused by propofol-induced 7 control patients that experienced Grade 3 adverse cerebral hyperexcitation.4) A recent systemic review effects; no patients in this group experienced only confusion. On the other hand, confusion was ob- served as the only adverse effect in 3 methylpred- phenomena were correlated with sudden increases nisolone-treated patients. These results suggest that in the cerebral concentrations of propofol, not sei- infusion of methylprednisolone suppressed the oc- zure history.12) In our previous study, no electroen- currence of serious adverse effects. Further studies cephalographic seizures or increasing epileptiform are needed to clarify the mechanism reducing these discharges were recorded before, during, and after moderate adverse events with methylprednisolone.
the onset of clinical symptoms.8) Propofol induces Methylprednisolone did not reduce the incidence of contractions at low concentrations and relaxation at eye pain, a Grade 1 adverse effect, presumably be- high concentrations in the perfused cerebral artery cause it does not influence the direct effect of of the dog,9) but no in vivo action on cerebral perfu- sion after intraarterial injection has been described.
In our previous study, the risk factors for Grade 3 Transient decrease in arterial blood flow immedi- adverse effects (increased tone with twitching, tonic ately after inadvertent injection of 10 ml propofol posture) included age of 55 years or greater, AVM, Intravenous Methylprednisolone During Wada Testing High-grade adverse effects of intracarotid propofol injection among 113 patients *Excludes 4 patients with Grade 1 and 4 patients with Grade 2 adverse effects. AVM: arteriovenous malformation, CIs:confidence intervals.
and total propofol injection dose greater than 20 mg.
artery. Anaesth Intensive Care 22: 291–292, 1994 In our current study, 113 subjects were selected by Buchtel H, Passaro E, Selwa L, Deveikis J, Gomez- eliminating 10 patients with Grade 1 adverse effects Hassan D: Sodium methohexital (Brevital) as an and 10 with Grade 2 adverse effects. Analysis con- anesthetic in the Wada test. Epilepsia 43: 1056–1061, ducted on these 113 patients confirmed that risk fac- tors for Grade 3 adverse effects were age of 55 years Chyatte D, Fode NC, Nichols DA, Sundt TM Jr: Preli-minary report: effects of high dose methylpredniso- or greater, AVM, and total propofol injection dose lone on delayed cerebral ischemia in patients at high greater than 20 mg (Table 3). Other factors (sex, risk for vasospasm after aneurysmal subarachnoid history of epilepsy, lesion laterality, and speech hemorrhage. Neurosurgery 21: 157–160, 1987 dominance) did not reach statistical significance. To Collier C, Kelly K: Propofol and convulsions: the evi- further clarify the effects of the methylprednisolone, dence mounts. Anaesth Intensive Care 19: 573–575, subgroup analysis was performed on 67 patients selected by excluding 4 patients with Grade 1 ad- Grote CL, Meador K: Has amobarbital expired? Con- verse effects and 4 with Grade 2 adverse effects from sidering the future of the Wada. Neurology 65: the methylprednisolone group. The results showed that none of the 3 factors mentioned above sig- Jones-Gotman M, Sziklas V, Djordjevic J, Dubeau F,Gotman J, Angle M, Tampieri D, Olivier A, Ander- nificantly affected the risk of Grade 3 adverse effects mann F: Etomidate speech and memory test (eSAM): a new drug and improved intracarotid procedure.
This study suggests that Wada testing using in- travenous methylprednisolone administration prior Malerba G, Romano-Girard F, Cravoisy A, Dousset B, to propofol injection is a safe approach to the Nace L, L áevy B, Bollaert PE: Risk factors of relative preoperative evaluation of brain tumors, epilepsy, adrenocortical deficiency in ICU patients needing and AVMs. Further studies in a large number of mechanical ventilation. Intensive Care Med 31: patients are needed to compare the adverse effects associated with intracarotid methohexital and etomidate injection during Wada testing.
Hayashi N, Nishida N, Taki J, Enatsu R, Ikeda A,Miyamoto S, Hashimoto H: Evaluation of adverse ef- fects in intracarotid propofol injection for Wada test.
Neurology 65: 1813–1816, 2005 Nakamura K, Hatano Y, Hirakata H, Nishiwada M, Supported by Grants-in-Aid for Scientific Research Toda H, Mori K: Direct vasoconstrictor and vasodila- 2059713 from the Japan Society for the Promotion of tor effects of propofol in isolated dog arteries. Br J Takayama M, Miyamoto S, Ikeda A, Mikuni N, Taka- hashi JB, Usui K, Satow T, Yamamoto J, MatsuhashiM, Matsumoto R, Nagamine T, Shibasaki H, Brimacombe J, Gandini D, Bashford L: Transient Hashimoto N: Intracarotid propofol test for speech decrease in arm blood flow following accidental in- and memory dominance in man. Neurology 63: tra-arterial injection of propofol into the left brachial Wada J, Rasmussen T: Intracarotid injection of sodi- The current study is a retrospective comparison of um amytal for the lateralization of cerebral speech 75 patients who underwent a Wada test from 2006 to dominance: experimental and clinical observations. J 2008 using intracarotid propofol with intravenous methylprednisolone and 58 patients who underwent Walder B, Tramer MR, Seeck M: Seizure-like the Wada test from 2001 to 2005 using intracarotid phenomena and propofol: a systematic review. Neu- propofol without methylprednisolone. The compari- son was performed to determine if the use of in-travenous methylprednisolone decreased the inci-dence of adverse effects associated with the arterial Address reprint requests to: Nobuhiro Mikuni, M.D., injection of propofol. The analysis demonstrated that Ph.D., Department of Neurosurgery, Kyoto Univer- the methylprednisolone group had fewer adverse ef- sity Graduate School of Medicine, 54 Kawahara–cho, fects, including a significantly lower incidence of Shogoin, Sakyo–ku, Kyoto 606–8507, Japan.
Although the study is retrospective, the two groups were well matched with regard to demographics, un- derlying disease and propofol dosage. This study sug-gests the use of intravenous methylprednisolone may Mikuni and his colleagues previously reported ad- reduce the incidence of adverse effects associated with verse effects associated with the intracarotid injection the use of intracarotid injections of propofol for Wada of propofol for Wada testing. These adverse effects testing. What this retrospective, non-randomized were divided into three grades: Grade 1 includes eye study does not address is any change in the manufac- pain, shivering, face contortion and lacrimation, turing of propofol over the time period of the study laughing or apathy. Grade 2 includes confusion, in- that may account for the reduced incidence of side ef- voluntary movement, or head and eye version. Grade 3 includes increased muscle tone with twitching and rhythmic movements or tonic posture. Grade 3 ad- verse effects are the most clinically relevant since they may result in incompletion or inaccuracy of the Wada



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