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Physostigmine Does Not Antagonize Sevoflurane Anesthesia Assessed by Bispectral Index or Enhances Recovery

Paraskeva, Adia, MD*; Papilas, Konstantinos, MD, DEAA*; Fassoulaki, Argyro, MD, PhD, DEAA; Melemeni, Aikaterini, MD*; Papadopoulos, Georgios, MD, PhD

doi: 10.1097/00000539-200203000-00017
Ambulatory Anesthesia: Research Report

In this double-blinded study, we investigated the effect of physostigmine on sevoflurane anesthesia and recovery. Forty female patients scheduled for breast biopsy were randomly assigned to receive either physostigmine 2 mg IV or an equal volume of normal saline after skin closure. Anesthesia was induced and maintained with sevoflurane in oxygen. After skin closure, a steady state of 0.6% inspired and end-tidal sevoflurane concentration was obtained, heart rate, blood pressure, and Bispectral index (BIS) baseline values were recorded, and physostigmine or normal saline was administered. Hemodynamics and BIS values were also recorded 5, 8, and 10 min after treatments. Anesthesia was discontinued, and orientation, sedation, sitting ability, and “picking up matches” scores were recorded immediately after extubation and 15 and 30 min later. No differences were found between the two groups in BIS (69, 70, 70, and 71 in the Physostigmine group versus 70, 74, 75, and 76 in the Control group) or blood pressure. Only heart rate was increased 8 min after physostigmine (P < 0.05 versus the control). Scores assessing early recovery were similar in the two groups at all time points. We conclude that physostigmine does not change BIS or enhance recovery after sevoflurane anesthesia.

*Department of Anesthesiology, St Savas Hospital, Athens; †Department of Anesthesiology, Aretaieion Hospital, Athens; and ‡Medical School, University of Ioannina

November 6, 2001

Address correspondence and reprint requests to Argyro Fassoulaki, Department of Anesthesiology, Aretaieion Hospital, 57-59 Raftopoulou St., 11744 Athens, Greece. Address e-mail to

Increases in acetylcholine may affect cortical arousal and shift the level of consciousness from non-rapid eye movement (REM) to REM sleep and from REM sleep to awake states (1). On the other hand, volatile anesthetics may suppress cholinergic pathways in the central nervous system (CNS) (2). Physostigmine has been used to reverse the central anticholinergic syndrome (3,4). There are also indications that physostigmine antagonizes the depressant effects of propofol (5). The aim of the present study was to determine whether physostigmine alters sevoflurane anesthesia monitored by Bispectral index (BIS), enhances recovery, or both.

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The Local Ethics Committee approved this prospective, randomized, and double-blinded study, and written informed consent was obtained from all patients. Forty female unpremedicated patients, ASA physical status I or II, scheduled for breast biopsy were studied. Exclusion criteria were hepatic, renal, pulmonary, thyroid or ischemic heart disease, alcoholism, drug abuse, possible pregnancy, and obesity.

Before the operation, each patient was reminded of the present day and date and performed the “picking up matches” test. The patient picked up with the dominant hand seven matches spread on a 0.5-m2 wooden quadrant, and the time of completion was recorded. In the operating room, a 20-gauge IV catheter was inserted in the nondominant hand.

The standard monitoring was used, as well as the inspired and end-tidal sevoflurane concentrations (Capnomac Ultima™, Datex-Ohmeda, Helsinki, Finland). The electroencephalogram signal was obtained from Zipprep™ electrodes (Aspect Medical Systems Inc, Newton, MA) applied to the forehead and temple.

All patients received IV metoclopramide 10 mg and droperidol 0.25 mg and were preoxygenated for 5 min from a separate oxygen source. The anesthetic system was primed with 8% sevoflurane in oxygen at 6 L/min. Anesthesia was induced with a vital capacity breath technique with 8% inspired sevoflurane concentration. When the BIS value was 70, 0.6 mg/kg of rocuronium was given IV, and the trachea was intubated. Sevoflurane concentrations were adjusted during the operation to maintain the BIS value at 30–40.

After skin closure, sevoflurane was adjusted to obtain 0.6% inspired and end-tidal concentration at equilibrium. Then the patients received randomly 2 mg of physostigmine or an equal volume of normal saline by an anesthesiologist who did not participate in anesthesia or data analysis. BIS was recorded before and 5, 8, and 10 min after treatment, and sevoflurane was discontinued. All patients received IV 40 mg of methylprednisolone as an antiemetic, and the residual neuromuscular block was antagonized with 2.5 mg of neostigmine and 1.2 mg of atropine. The criterion for tracheal extubation was coughing and an inability to tolerate the tracheal tube. The time to extubation, which was defined as the interval elapsed from sevoflurane discontinuation to coughing and an inability of the patient to tolerate the tracheal tube, BIS, and end-tidal sevoflurane were recorded.

At each time point, we recorded three consecutive BIS values and averaged them. When the trachea was extubated and 15 and 30 min later, patients were assessed for orientation, sedation, sitting ability, and the “picking up matches” test.

Questions for orientation included: (a) Where are you? (b) What is the day today? (c) What is the date? (d) What is your date of birth? For each correct answer, the patient was given one point. Sedation was accredited with one point if the patient was asleep, two points if sleepy but arousable, and three points if spontaneously awake. Then the patient was asked to sit up without help and perform the “picking up matches” test. In the recovery room, all patients were observed for nausea and vomiting and received IM 75 mg of dextropropoxyphene and 600 mg of paracetamol as analgesics.

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Demographics and end-tidal sevoflurane concentrations between the groups at extubation were compared with the Student’s t-tests. BIS values at extubation in each group, assessed by the Kolmogorov-Smirnov test did not follow normal distributions (Physostigmine group P = 0.02, Control group P = 0.00001). For this reason, we used nonparametric statistics, the Mann-Whitney U-test. Orientation, sedation, and sitting ability scores were compared with the χ2 test or Fisher’s exact test when appropriate. The time (in seconds) required to pick up seven matches and the BIS values at 0, 5, 8, and 10 min after physostigmine or normal saline were compared with repeated-measures analysis of variance.

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The Physostigmine and Control groups were similar regarding age (29 ± 6 versus 29 ± 7 yr), body weight (59 ± 9 versus 59 ± 7 kg), height (165 ± 6 versus 167 ± 7 cm), and duration of anesthesia (43 ± 10 versus 40 ± 8 min), respectively.

BIS at 0, 5, 8, and 10 min and after extubation (Fig. 1), time from sevoflurane discontinuation to extubation (4.4 ± 2.8 min versus 5.2 ± 2.5 min), and end-tidal sevoflurane at extubation (0.18% ± 0.06% versus 0.16% ± 0.05%) in the Physostigmine versus Control group, respectively, did not differ. Hemodynamics are shown in Table 1. We found no difference in the orientation, sedation, sitting ability, and the “picking up matches” test scores (Table 2, Fig. 2) between the two groups. During the 30 min in the recovery room, only one patient vomited in each group treated with 4 mg of ondansetron IV.

Figure 1

Figure 1

Table 1

Table 1

Table 2

Table 2

Figure 2

Figure 2

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Physostigmine did not alter the state of anesthesia produced by 0.6% sevoflurane in oxygen nor enhance immediate recovery. We used sevoflurane as a single anesthetic to avoid influences caused by other CNS depressants. We studied patients undergoing excision of a breast lump, as this procedure is associated with mild intra- and postoperative pain. To avoid contamination of BIS by the patient’s movements or interference from surgical stimuli, we administered a muscle relaxant and started recording after skin closure. The degree of neuromuscular block was not monitored during the period after skin closure because this might interfere with the BIS values or tolerance to the endotracheal tube, as well as the responses to various tests assessing recovery at zero time.

The dose of 2 mg of physostigmine was based on previous studies (4,5). Stimulation of muscarinic receptors in the nucleus solitarius has been implicated in the physiology of vomiting. We administered a multimodal antiemetic treatment to both groups to prevent vomiting and minimize bias factors. The tachycardia recorded in the Physostigmine group did not compromise the blinding of the study, because in this group we expected a slower heart rate compared with the Control group.

A light state of 0.6% end-tidal sevoflurane anesthesia could easily be maintained, and at this level, the BIS correlates well to the depth of sevoflurane sedation and hypnosis (6,7).

The orientation assessment was used because this cognitive function is restored soon after awaking. The sitting ability without aid also evaluates early recovery. The “picking up matches” test provides a reliable baseline score, is easily performed, and assesses coordination, manual dexterity, and concentration of the subjects.

Volatile anesthetics interfere with nicotinic acetylcholine receptors, inhibiting the α4β2 subtypes (8). They also inhibit acetylcholine release in the CNS (9). Our results are in accordance with previous studies where physostigmine did not enhance recovery after methohexital (10). Nor did it enhance recovery or reduce the occurrence of emergence phenomena after ketamine (11).

On the other hand, physostigmine reverses the somnolence after induction of anesthesia with halothane (12), ketamine (13), or propofol (14). Also, physostigmine increases propofol requirements to induce anesthesia (5). These controversial results may imply different sites of action of anesthetics in the CNS and different actions of physostigmine depending on the dose, timing of administration, and state of consciousness. In conclusion, physostigmine has no effect on light sevoflurane anesthesia nor does it enhance recovery.

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