AMBULATORY ANESTHESIA Section Editor Patricia A. Kapur
A Comparison of the Effects of Propofol and Nitrous Oxide on the Electroencephalogram in Epileptic Patients During Conscious Sedation for Dental Procedures Vivian L. B. Oei-Lim, m, Cor J. Kalkman, MD, PhD, Elinor C. M. Bouvy-Berends, DDS, Eelco F. Posthumus Meyjes, MD, PhD, Peter c. Makkes, DDS, PhD, Doreen M. E. Vermeulen-Cranch, MD, FFARCS, Joseph A. Odoom, MD, PhD, Harry B. van Wezel, MD, PhD, and James G. Bovill, MD, PhD, FFARCSI Departments of Anesthesiology and Clinical Neurophysiology, University of Amsterdam, Amsterdam; Department of Special Care Dentistry, Craeyenburch, Nootdorp; and Department of Anesthesiology, University of Leiden, Leiden, The Netherlands
The influence of sedative doses of propofol or nitrous oxide on the electroencephalogramwas studied in 11 mentally handicapped patients with treated epilepsy undergoing dental procedures. At one session, propofol was titrated to achieve conscious sedation. The mean ( ~ s D )dose requirements were 5.5 k 1.1 m g kg-'.h-'. In six patients, the electroencephalogram was unchanged during propofol administration. In three patients, there was a decreasein epilepticactivity, and in two patients, paroxysmal discharges disappeared. At another session, nitrous oxide was admin-
P
ropofol is the latest intravenous anesthetic to be introduced into clinical practice. It has been used for sedation in subanesthetic doses for short periods to supplement regional anesthesia (1,2) and for longer periods in patients in intensive care units (3,4). Discontinuation of propofol infusion results in rapid recovery because of its favorable pharmacokinetic profile (5). In a previous study, we administered propofol by continuous infusion for conscious sedation in mentally and physically handicapped patients undergoing dental procedures in whom nitrous oxide sedation had failed or was not possible to administer (6). However, there are conflicting data with respect to the proconvulsive or anticonvulsive properties of propofol(7-17). Because epilepsy is a common additional disorder in the handicapped patient, it is important to know whether Supported by a grant from ICI Farma, Ridderkerk, The Netherlands. Accepted for publication June 16, 1992. Address correspondence to Dr. Oei-Lim, Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
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istered by nasal mask. The mean ( ~ S D concentration ) of nitrous oxide needed was 43.6% ? 4.8%. The electroencephalogram did not change in nine patients, whereas in two patients epileptic activity decreased. There were no clinical epileptoid or other adverse manifestations during any treatment or up to 48 h thereafter. The results of the present study suggest that propofol or nitrous oxide can be administered in subanesthetic doses for conscious sedation in mentally handicapped patients with treated epilepsy. (Anesth Analg 1992;75:708-14)
intravenous sedation with propofol might provoke seizures or enhance interictal electroencephalographic (EEG) manifestations. The present study was designed to investigate the effects of propofol and nitrous oxide, titrated to achieve conscious sedation, on the EEG in epileptic patients undergoing dental procedures.
Methods Eleven mentally handicapped patients with epilepsy who required dental treatment under sedation were prospectively studied. Pregnant patients and patients with a history of allergy to propofol or its vehicle were excluded from the study. Written, informed consent was obtained from the parents of the patients, and the study protocol was approved by the institutional ethics committee. A medical history was obtained from all patients. Weight, height, and arterial blood pressure were measured, and a physical examination was carried out. All preoperative medication was recorded and continued up to the time of the procedure. 01992 by the International Anesthesia Research Society 0003-2999/92/$5.00
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All patients were known to have primary or secondary epilepsy. The diagnosis of epilepsy was based on the presence of clinical seizures and confirmed by EEG demonstration of seizure activity. Epilepsy was adequately controlled with medication in all patients. Patients were randomly assigned to receive either propofol or nitrous oxideloxygen for their first treatment and the alternative sedative regimen for the second treatment. Each patient was thus studied twice on different days. Patients for the morning sessions fasted; patients who were treated in the afternoon were allowed a light breakfast. No premedication was administered. At each session, the initial procedures were performed without sedation. These involved explanation, adaptation to the surroundings, and oral examination where possible (step 1).Then either propofol or nitrous oxide sedation was introduced, and the following dental procedures were performed: removal of calculus and taking intraoral radiographs if indicated (step 2). The next stage included sealing of fissures, cavity preparation, and restoration and extraction if necessary (step 3). If the patient did not tolerate procedures during step 1, sedation was started. Articaine HC1 was administered for local analgesia if necessary. The same dental surgeon performed the treatment in all patients. The EEG was continuously monitored and recorded with a 12-channel Siemens-Elema recorder at a paper speed of 3 c d s and with a time constant of 0.3, 0.6, or 1.2 s, according to the degree of restlessness of the patient. The gain was 70 or 100 pV/cm. The scalp electrodes were placed at F F,, T,, T,, C,, C,, 01,and 0, (International 10-26 System). The electrode impedance was 1 5 kfl. A bipolar montage was used. All events and changes of dosages were manually marked, with indication of the time. The EEG was recorded continuously throughout the dental procedure, starting with a 5-min baseline recording. The EEG recordings were continued for 15 min after discontinuation of sedation. The EEG was visually assessed for epileptic activity by a clinical neurophysiologist who was unaware of the sedative regimen used. Spikes, spike waves, and sharp waves with local or diffuse distribution were considered epileptic discharges. A continuous infusion of propofol was started at an T initial rate of 3.5 mg.kg-l-h-l via a Braun Secura I syringe pump (B. Braun, Melsungen AG, Germany), and a loading dose of propofol (0.5-1 mgkg) was administered by slow intravenous injection until sedation score 3 was reached (Table 1). Thereafter, the infusion rate was adjusted as necessary to maintain sedafion score 3, avoiding unconsciousness (sedation score 5). Nitrous oxide sedation was administered by the
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Table 1. Sedation Scores 1 2 3 4 5
Fully awake and oriented Drowsy Eyes closed, responds promptly to verbal commands Eyes closed, arousable on mild physical stimulation Eyes closed, unarousable on mild physical stimulation
dental surgeon with the Porter MXR machine (Porter Instrument Co., Heatfield, Pa.) equipped with a Dameca scavenging system (Dameca, Copenhagen, Denmark) and a nasal mask (Dameca). The initial nitrous oxide concentration was 40% in oxygen. Nitrous oxide was administered and titrated to the same clinical endpoints of sedation as propofol (sedation score 3). In addition to EEG monitoring, the level of consciousness was constantly assessed using the sedation score. Continuous verbal and nonverbal communication with the patient was maintained. Nonverbal communication was maintained with those patients for whom verbal communication was difficult or impossible. Their hands were squeezed to assess their response. Any excitatory effects, such as spontaneous movements, twitching, or tremor, were noted. Electrocardiogram, heart rate, noninvasive arterial bIood pressure, pulse oximetry (Spo,), and end-tidal carbon dioxide concentration (PETCO~) were continuously monitored using Hewlett Packard 78352A (Boblingen, Germany) and Ohmeda 4700 Oxicap (Englewood, Colo.) monitors. Ten minutes after the dental procedure was completed, the patients returned to their ward. The patients were observed by their personal attendants during the whole procedure and until 48 h after sedation for any side effects and complications. The possibility of determining propofol blood concentration became available only at the end of the study. Therefore, propofol concentration was measured in the last three patients. Blood samples of 5 mL were obtained from the contralateral antecubital vein on ending the propofol infusion. Samples were collected in tubes containing potassium oxalate and stored at 4°C until assay of blood concentration of propofol by the combination of high-pressure liquid chromatography and fluorescence detection method (18).
A repeated measures analysis of variance was performed for each physiologic variable (arterial blood pressure, heart rate, oxygen saturation [Spo,], and PETCO~) using the statistical package BMDP (BMDP Statistical Software, Berkeley, Calif.). Differences between time trends in both sedation groups were tested. Results are expressed as mean 2 SD. A value of P < 0.05 was considered to be statistically significant.
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Table 2. Clinical Characteristics of Eleven Mentally Handicapped Patients With Epilepsy Undergoing Dental Treatment Under Sedation Pt No./ Gender
Age (yr)
Wt (kg)
Diagnosis
l/M
25
43
Mental retardation, epilepsy
Focal ep act
2/M 3/F
24 25
59 52
4lF
18
59
5/F
19
41
6iM
17
57
Mental retardation, epilepsy Mental retardation, epilepsy, deaf Mental retardation, epilepsy, spastic tetraparesis Mental retardation, epilepsy, spastic tetraparesis Mental retardation, epilepsy, spastic tetraparesis
Multifocal ep act Focal and generalized ep act Generalized ep act during HV Multifocal and generalized ep act Diffuse slow frequencies without ep act
71M
30
105
Mental retardation, epilepsy
8/F
21
40
91F
18
40
10lF
26
52
lllF
19
48
Mental retardation, epilepsy, spastic tetraparesis, blind Mental retardation, epilepsy, hydrocephalus Mental retardation, epilepsy, spastic tetraparesis Tuberous sclerosis, mental retardation, epilepsy
Generalized ep act during HV Multifocal and generalized ep act Normal
Previous EEG
~~
Medication
Epileptic attacks
Carbamazepine; valproic acid Carbamazepine Valproic acid; carbamazepine Valproic acid; diazepam Valproic acid Valproic acid; carbamazepine Valproic acid Carbamazepine
Multifocal ep act Focal and generalized e p act
Phenobarbital; valproic acid Carbamazepine; phenobarbital Phenytoin; carbamazepine
1 Seizure in 7 mo
Seizure free Twice a day Once a day Seizure free 1-2 Petit mal/wk; 1 seizure in 6 mo 2-3 Seizures in 2 wk 3 Seizures in 1 wk
Seizure free Once a day 1 Petit mallday; 1
seizurelday
Pt, patient; EEG, electroencephalogram; M, male; F, female; ep act, epileptic activity; HV, hyperventilation.
Table 3. Electroencephalographic Data Before and During Sedation in t h e Eleven Study Patients EEG data Before sedation Pt No. 1
2 3 4 5 6 7 8 9
10 11
Drug N (45%) p (5) N (40%) P (4.4) N (50%) P (4.8) N (40%) P (6.4) N (40%) P (5.7) N (40%) P (5.4) N (45%) p (3.7) N (35%) P (4.4) N (45%) P (7.3) N (50%) P (6.6) N (50%)
P (6.5)
Normal
Diffuse slow
Focal
Paroxysmal dischargeb 3 in 15 min 11 in 16 min
X X
X X X
X
X
X
Some sharp waves Some sharp waves Spikes, spike waves Spikes, spike waves
X X X
X
X
X X
X
X
X
X
X
X
X
Spikes 1-3/10 s Spikes 1-3/10 s Rare sharp waves
X
X
X
14 in 19 min Some spikes Some spikes Some sharp waves Some sharp waves Some sharp waves Some sharp waves 25 in 15 min
X
X
75 in 24 min
X
X
X X X
EEG, electroencephalographic; N, nitrous oxide; , ' l propofol; Pt, patient. "Numbers in parentheses are nitrous oxide concentrations (7%) or propofol dose (bolus dose "Epilepticactivity including spikes, spike waves, and sharp waves.
During sedation 9 Paroxysmal discharges in 68 min None No change No change No change No change No change No change No change No change No change No change No change None No change Decrease of spikes No change No change No change Decrease of sharp waves 22 Paroxysmal discharges in 35 min 22 in 5 min postsedation 13 Paroxysmal discharges in 50 min 50 in 15 min postsedation
+ total cumulative dose) (mg,kg-'.h-').
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Pre Propofol
711
1s
100 IvI-
Figure 1. Representative EEG segments from a 19-yr-old patient (patient 11) with treated epilepsy before and during conscious sedation with propofol and nitrous oxide. Note absence of spike-and-wave complexes during propofol sedation.
Results Demographic and clinical details of the patients (7 women, 4 men) are shown in Table 2. Eight of the 11 patients had multiple handicaps. Five patients were severely mentally retarded, two were moderately retarded, and four were mildly retarded. Apart from their mental disorder and physical handicap, all patients were in good health. All but one patient (patient 9) had EEG evidence of epileptic activity. The EEG activity data before and during sedation are shown in Table 3. During propofol sedation, EEG activity did not change in six patients. Paroxysmal discharges disappeared in two patients (patients 1 and 7) and were decreased in three (patients 8, 10, and 11)(Figure 1).In three patients (patients 4,6,and 8), there was an increase in fast activity in the beta band (13-30 Hz). During nitrous oxide sedation, the EEG did not change in nine patients. In two patients (patients 1and ll),a decrease in epileptic activity was evident. Neither form of sedation was associated with any adverse effects. Specifically, there was no increase in the frequency or intensity of clinical epileptic manifestations during the 48 h after treatment. The mean duration of sedation was 40.0 ? 9.6 min
(range 27-62) for propofol and 41.5 ? 10.3 min (range 31-68) for nitrous oxide. The mean dose require1.1 mg.kg-'.h-l (range 3.7-6.6) ments were 5.5 for propofol and 43.6% ? 4.8% (range 35%-50%) for nitrous oxide. Figure 2 shows mean ( ~ s D ) values for arterial blood pressure, heart rate, Spo,, and PETCO~ during propofol and nitrous oxide sedation. Arterial blood pressure did not change significantly in the nitrous oxide group, whereas there was a significant decrease in the patients sedated with propofol. Compared with presedation values, heart rate decreased significantly in both groups (by 9 beatdmin). The Spo, remained above 95% in the propofol group and remained above 98% in the nitrous oxide group. The PETCO~ was slightly higher ( P < 0.05) in the propofol group (40 vs 35 mm Hg in the nitrous oxide group). The level of consciousness during propofol or nitrous oxide sedation did not exceed sedation score 3 except in one patient, who reached sedation score 4 at the end of the propofol sedation. At that time, a short period of airway obstruction occurred that was immediately detected and corrected. Table 4 shows the blood concentrations of propofol in three patients at the end of sedation.
*
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1992;75708-14
1
90 loo
Heart rate (BPM)
systolic Pressure (mm Hg)
Figure 2. Mean ( ~ s D )hemodynamic and resuiratorv variables during urouofol and nitious oxide sedation. "Solid' symbols, propofol; open symbols, nitrous oxide. Spo,, oxygen saturation; BPM, beats/&; etCO, end-tidal C 0 2 concentration.
Diastolic Pressure (mrn Hg)
'
40
etC02 (mm Hg) 30
-5
10 20 Time (minutes)
0
30
40
Table 4. Plasma Concentration of Propofol at the End of the Infusion in Three Study Patients
Pt No. 8 9 11
Duration of infusion (min) 62
41 50
Bolus dose Infusion rate ( m g W (mg.kg-'.h-') 0.8 0.7
0.8
3.7 6.2 5.7
Blood conc (Plw-) 0.6 1.0 1.1
Conc, concentration; Pt, patient.
Discussion The provision of quality dental care to patients who are severely mentally and physically handicapped is a challenge. Behavior management combined with conscious sedation using nitrous oxide/oxygen has become an established technique for dental treatment in this group of patients. However, a small proportion of these patients cannot be adequately managed by this technique alone, because of restricted coping resources and the inability to carry out continuous nasal breathing, essential for nitrous oxide administration by nasal mask. In a previous study, we demonstrated that propofol by continuous intrave-
nous infusion can be a suitable alternative to nitrous oxide for conscious sedation in dentistry or oral surgery. Sedation with propofol infusion is comparable to nitrous oxide/oxygen inhaled sedation in that recovery is rapid without side effects (6). However, there are conflicting data with respect to the proconvulsive or anticonvulsive properties of propofol. The results of the present study suggest that propofol administered in sedative doses neither provokes seizures nor enhances interictal EEG manifestations in patients with treated epilepsy. Dystonic reactions have been reported to occur immediately after induction with propofol administered as the sole anesthetic agent in children (7). Opisthotonus and tonic-clonic seizures have been described after emergence from anesthesia with propofol and additional anesthetics (alfentanil and enflurane) (8) and after the use of propofol for sedation in the intensive care unit (9). This involved patients without a history of epilepsy. The EEG, recorded with surface electrodes after the acute states, demonstrated no evidence of epileptic activity. Two studies reported the effects of propofol administration during general anesthesia on the EEG recorded with chronically implanted subdural elec-
ANESTH ANALG 19!22;75:70%14
trodes in epileptic patients. Hodkinson et al. (10) recorded discharges of epileptiform activity from the previously mapped epileptogenic foci during propofol infusion. They also observed new epileptic activity in other areas of the cortex that had showed no epileptic activity before the injection of propofol. Hufnagel et al. (11)observed maximal suppression of brain activity in the epileptogenic brain area in 12 of 20 patients and also suppression of spontaneous interictal activity present before the onset of anesthesia in 10 of 20 patients; in 5 of 20 patients, there was induction of epileptiform activity. In one patient, a seizure occurred. Our patients were conscious during propofol administration. The EEG recorded from surface electrodes did not show any evidence of increased epileptic activity. There is also considerable evidence that propofol may have anticonvulsive properties. Protection against epileptiform seizures induced by electroshock and pentylenetetrazol in mice was assessed by Lowson et al. (12). They concluded that intraperitoneal administration of propofol (50 mgkg) has a strong anticonvulsant effect. Several studies comparing propofol and methohexitone in patients receiving electroconvulsive therapy have shown a shorter duration of seizure activity with propofol(l3-15). Others have reported the successful use of propofol infusions in the control of intractable status epilepticus, resistant to conventional therapy (16,17). We conclude that the available data are inconclusive with respect to whether propofol administration is associated with enhancement of epileptic activity. In a review of proconvulsant and anticonvulsant properties of anesthetic drugs, Modica et al. (19,20) concluded that the available evidence with regard to the cerebral stimulatory effects of nitrous oxide suggests that its epileptogenic potential is extremely low. In our study, the EEG was unchanged during nitrous oxide sedation in nine patients, whereas in two patients the frequency of paroxysmal discharges decreased. This suggests that nitrous oxide can be administered safely to patients with treated epilepsy. In a previous study, we administered propofol for conscious sedation in nonepileptic patients (6). The mean infusion rate of propofol was 3.6 mg-kg-'-h-' (range 2.55.4). In the present study, all patients had long-term treatment for epilepsy. Using the same sedation scoring system and titrating propofol to identical endpoints (sedation score 3), the mean infusion rate was 5.5 mg.kg-*.h-' (range 3.7-6.6) in the epileptic patients. It is conceivable that this higher dose requirement is a result of hepatic enzyme induction, as a consequence of long-term antiepileptic medication (21,22).
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With both sedative regimens there were no untoward changes in hemodynamic and respiratory variables. In all patients, Spo, remained above 95% and was higher during nitrous oxide sedation, as a result of a higher fraction of inspired oxygen. The higher PETCO~ and slightly lower Spo, values during propofol infusion indicate that close supervision of the airway and respiration is necessary. It is especially important not to exceed sedation score 3. In conclusion, the results of the present study suggest that propofol and nitrous oxide can be administered in subanesthetic doses for conscious sedation in mentally and physically handicapped patients with treated epilepsy undergoing dental procedures. More EEG studies are needed to determine the epileptogenic potential of propofol. We thank M. de Groot-Venema, MD, and Marjan van de Werken, EEG technician, Craeyenburch, for screening the patients and recording the EEGs; C. Romijn, AMC, for technical assistance and support; and Dr. J. Oosting, Department of Medical Physics and Statistics, Academic Medical Center, for performing the statistical analysis of the measurements.
References 1. Mackenzie N, Grant IS. Propofol for intravenous sedation. Anaesthesia 1987;42:3-6. 2. Wilson E, Mackenzie N, Grant IS. A comparison of propofol and midazolam by infusion to provide sedation in patients who receive spinal anaesthesia. Anaesthesia 1988;43:914. 3. Newman LH, McDonald JC, Wallace PGM, Ledingham IM. Propofol infusion for sedation in intensive care. Anaesthesia 1987;42:929-37. 4. Hams CE, Grounds RM, Murray AM, Lumley J, Royston D, Morgan M. Propofol for long-term sedation in the intensive care unit. Anaesthesia 1990;45:366-72. 5. Skues MA, Prys-Roberts C. The pharmacology of propofol. J Clin Anesth 1989;1:387400. 6. Oei-Lim LB, Vermeulen-Cranch DME, Bouvy-Berends ECM. Conscious sedation with propofol in dentistry. Br Dental J 1991;17O:MO-2. 7. Borgeat A, Dessibourg C, Popovic V, Meier D, Blanchard M, Schwander D. Propofol and spontaneous movements: an EEG study. Anesthesiology 1991;74:24-7. 8. Saunders PRI, Hams MNE. Opisthotonos and other unusual neurological sequelae after outpatient anaesthesia. Anaesthesia 1990;45:552-7. 9. Au J, Walker WS, Scott DHT. Withdrawal syndrome after propofol infusion. Anaesthesia 1990;45:741-2. 10. Hodkinson BP, Frith RW, Mee EW. Propofol and the electroencephalogram. Lancet 1987;2:1518. 11. Hufnagel A, Elger CE, Nadstawek J, Stoeckel H, Boker DK. Specific response of the epileptic focus to anesthesia with propofol. J Epilepsy 1990;3:3745. 12. Lowson S, Gent JP, Goodchild CS. Anticonvulsant properties of propofol and thiopentone: comparison using two tests in laboratory mice. Br J Anaesth 1990;64:59-63. 13. Bone ME, Wilkins CJ, Lew JK. A comparison of propofol and methohexitone as anaesthetic agents for electroconvulsive therapy. Eur J Anaesthesiol 1988;5:279-86. 14. Rampton AJ, Griffin RM, Stuart CS, Duncan JJ, Huddy NC,
n4
15. 16.
17. 18.
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Abbott MA. Comparison of methohexital and propofol for electroconvulsive therapy: effects on hemodynamic responses and seizure duration. Anesthesiology 1989;70:412-7. Boey WK, Lai FO. Comparison of propofol and thiopentone as anesthetic agents for electroconvulsive therapy. Anaesthesia 1990;45:623-8. Wood PR, Browne GPR, Pugh S. Propofol infusion for the treatment of status epilepticus. Lancet 1988;1:4€%1. Mackenzie SJ, Kapada F, Grant IS. Propofol infusion for control of status epilepticus. Anaesthesia 1990;45:1043-5. Plummer GF. Improved method for the determination of
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19. 20. 21.
22.
propofol in blood by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987;421:171-6. Modica PA, Tempelhoff R, White PF. Pro and anticonvulsant effects of anesthetics (Part I). Anesth Analg 1990;70305-15. Modica PA, Tempelhoff R, White PF. Pro and anticonvulsant effects of anesthetics (Part 11). Anesth Analg 1990;70433-44. Maze M. Hepatic physiology. In: Miller RD, ed. Anesthesia. 3rd ed. New York Churchill Livingstone, 1990:588-92. Perucca E, Richens A. General principles, biotransformation. In: Levy RH, ed. Antiepileptic drugs. New York: Raven, 1989:3540.
A Comparison of the Effects of Propofol and Nitrous Oxide on the Electroencephalogram in Epileptic Patients During Conscious Sedation for Dental Procedures Vivian L. B. Oei-Lim, m, Cor J. Kalkman, MD, PhD, Elinor C. M. Bouvy-Berends, DDS, Eelco F. Posthumus Meyjes, MD, PhD, Peter c. Makkes, DDS, PhD, Doreen M. E. Vermeulen-Cranch, MD, FFARCS, Joseph A. Odoom, MD, PhD, Harry B. van Wezel, MD, PhD, and James G. Bovill, MD, PhD, FFARCSI Departments of Anesthesiology and Clinical Neurophysiology, University of Amsterdam, Amsterdam; Department of Special Care Dentistry, Craeyenburch, Nootdorp; and Department of Anesthesiology, University of Leiden, Leiden, The Netherlands
The influence of sedative doses of propofol or nitrous oxide on the electroencephalogramwas studied in 11 mentally handicapped patients with treated epilepsy undergoing dental procedures. At one session, propofol was titrated to achieve conscious sedation. The mean ( ~ s D )dose requirements were 5.5 k 1.1 m g kg-'.h-'. In six patients, the electroencephalogram was unchanged during propofol administration. In three patients, there was a decreasein epilepticactivity, and in two patients, paroxysmal discharges disappeared. At another session, nitrous oxide was admin-
P
ropofol is the latest intravenous anesthetic to be introduced into clinical practice. It has been used for sedation in subanesthetic doses for short periods to supplement regional anesthesia (1,2) and for longer periods in patients in intensive care units (3,4). Discontinuation of propofol infusion results in rapid recovery because of its favorable pharmacokinetic profile (5). In a previous study, we administered propofol by continuous infusion for conscious sedation in mentally and physically handicapped patients undergoing dental procedures in whom nitrous oxide sedation had failed or was not possible to administer (6). However, there are conflicting data with respect to the proconvulsive or anticonvulsive properties of propofol(7-17). Because epilepsy is a common additional disorder in the handicapped patient, it is important to know whether Supported by a grant from ICI Farma, Ridderkerk, The Netherlands. Accepted for publication June 16, 1992. Address correspondence to Dr. Oei-Lim, Department of Anesthesiology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
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istered by nasal mask. The mean ( ~ S D concentration ) of nitrous oxide needed was 43.6% ? 4.8%. The electroencephalogram did not change in nine patients, whereas in two patients epileptic activity decreased. There were no clinical epileptoid or other adverse manifestations during any treatment or up to 48 h thereafter. The results of the present study suggest that propofol or nitrous oxide can be administered in subanesthetic doses for conscious sedation in mentally handicapped patients with treated epilepsy. (Anesth Analg 1992;75:708-14)
intravenous sedation with propofol might provoke seizures or enhance interictal electroencephalographic (EEG) manifestations. The present study was designed to investigate the effects of propofol and nitrous oxide, titrated to achieve conscious sedation, on the EEG in epileptic patients undergoing dental procedures.
Methods Eleven mentally handicapped patients with epilepsy who required dental treatment under sedation were prospectively studied. Pregnant patients and patients with a history of allergy to propofol or its vehicle were excluded from the study. Written, informed consent was obtained from the parents of the patients, and the study protocol was approved by the institutional ethics committee. A medical history was obtained from all patients. Weight, height, and arterial blood pressure were measured, and a physical examination was carried out. All preoperative medication was recorded and continued up to the time of the procedure. 01992 by the International Anesthesia Research Society 0003-2999/92/$5.00
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All patients were known to have primary or secondary epilepsy. The diagnosis of epilepsy was based on the presence of clinical seizures and confirmed by EEG demonstration of seizure activity. Epilepsy was adequately controlled with medication in all patients. Patients were randomly assigned to receive either propofol or nitrous oxideloxygen for their first treatment and the alternative sedative regimen for the second treatment. Each patient was thus studied twice on different days. Patients for the morning sessions fasted; patients who were treated in the afternoon were allowed a light breakfast. No premedication was administered. At each session, the initial procedures were performed without sedation. These involved explanation, adaptation to the surroundings, and oral examination where possible (step 1).Then either propofol or nitrous oxide sedation was introduced, and the following dental procedures were performed: removal of calculus and taking intraoral radiographs if indicated (step 2). The next stage included sealing of fissures, cavity preparation, and restoration and extraction if necessary (step 3). If the patient did not tolerate procedures during step 1, sedation was started. Articaine HC1 was administered for local analgesia if necessary. The same dental surgeon performed the treatment in all patients. The EEG was continuously monitored and recorded with a 12-channel Siemens-Elema recorder at a paper speed of 3 c d s and with a time constant of 0.3, 0.6, or 1.2 s, according to the degree of restlessness of the patient. The gain was 70 or 100 pV/cm. The scalp electrodes were placed at F F,, T,, T,, C,, C,, 01,and 0, (International 10-26 System). The electrode impedance was 1 5 kfl. A bipolar montage was used. All events and changes of dosages were manually marked, with indication of the time. The EEG was recorded continuously throughout the dental procedure, starting with a 5-min baseline recording. The EEG recordings were continued for 15 min after discontinuation of sedation. The EEG was visually assessed for epileptic activity by a clinical neurophysiologist who was unaware of the sedative regimen used. Spikes, spike waves, and sharp waves with local or diffuse distribution were considered epileptic discharges. A continuous infusion of propofol was started at an T initial rate of 3.5 mg.kg-l-h-l via a Braun Secura I syringe pump (B. Braun, Melsungen AG, Germany), and a loading dose of propofol (0.5-1 mgkg) was administered by slow intravenous injection until sedation score 3 was reached (Table 1). Thereafter, the infusion rate was adjusted as necessary to maintain sedafion score 3, avoiding unconsciousness (sedation score 5). Nitrous oxide sedation was administered by the
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Table 1. Sedation Scores 1 2 3 4 5
Fully awake and oriented Drowsy Eyes closed, responds promptly to verbal commands Eyes closed, arousable on mild physical stimulation Eyes closed, unarousable on mild physical stimulation
dental surgeon with the Porter MXR machine (Porter Instrument Co., Heatfield, Pa.) equipped with a Dameca scavenging system (Dameca, Copenhagen, Denmark) and a nasal mask (Dameca). The initial nitrous oxide concentration was 40% in oxygen. Nitrous oxide was administered and titrated to the same clinical endpoints of sedation as propofol (sedation score 3). In addition to EEG monitoring, the level of consciousness was constantly assessed using the sedation score. Continuous verbal and nonverbal communication with the patient was maintained. Nonverbal communication was maintained with those patients for whom verbal communication was difficult or impossible. Their hands were squeezed to assess their response. Any excitatory effects, such as spontaneous movements, twitching, or tremor, were noted. Electrocardiogram, heart rate, noninvasive arterial bIood pressure, pulse oximetry (Spo,), and end-tidal carbon dioxide concentration (PETCO~) were continuously monitored using Hewlett Packard 78352A (Boblingen, Germany) and Ohmeda 4700 Oxicap (Englewood, Colo.) monitors. Ten minutes after the dental procedure was completed, the patients returned to their ward. The patients were observed by their personal attendants during the whole procedure and until 48 h after sedation for any side effects and complications. The possibility of determining propofol blood concentration became available only at the end of the study. Therefore, propofol concentration was measured in the last three patients. Blood samples of 5 mL were obtained from the contralateral antecubital vein on ending the propofol infusion. Samples were collected in tubes containing potassium oxalate and stored at 4°C until assay of blood concentration of propofol by the combination of high-pressure liquid chromatography and fluorescence detection method (18).
A repeated measures analysis of variance was performed for each physiologic variable (arterial blood pressure, heart rate, oxygen saturation [Spo,], and PETCO~) using the statistical package BMDP (BMDP Statistical Software, Berkeley, Calif.). Differences between time trends in both sedation groups were tested. Results are expressed as mean 2 SD. A value of P < 0.05 was considered to be statistically significant.
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Table 2. Clinical Characteristics of Eleven Mentally Handicapped Patients With Epilepsy Undergoing Dental Treatment Under Sedation Pt No./ Gender
Age (yr)
Wt (kg)
Diagnosis
l/M
25
43
Mental retardation, epilepsy
Focal ep act
2/M 3/F
24 25
59 52
4lF
18
59
5/F
19
41
6iM
17
57
Mental retardation, epilepsy Mental retardation, epilepsy, deaf Mental retardation, epilepsy, spastic tetraparesis Mental retardation, epilepsy, spastic tetraparesis Mental retardation, epilepsy, spastic tetraparesis
Multifocal ep act Focal and generalized ep act Generalized ep act during HV Multifocal and generalized ep act Diffuse slow frequencies without ep act
71M
30
105
Mental retardation, epilepsy
8/F
21
40
91F
18
40
10lF
26
52
lllF
19
48
Mental retardation, epilepsy, spastic tetraparesis, blind Mental retardation, epilepsy, hydrocephalus Mental retardation, epilepsy, spastic tetraparesis Tuberous sclerosis, mental retardation, epilepsy
Generalized ep act during HV Multifocal and generalized ep act Normal
Previous EEG
~~
Medication
Epileptic attacks
Carbamazepine; valproic acid Carbamazepine Valproic acid; carbamazepine Valproic acid; diazepam Valproic acid Valproic acid; carbamazepine Valproic acid Carbamazepine
Multifocal ep act Focal and generalized e p act
Phenobarbital; valproic acid Carbamazepine; phenobarbital Phenytoin; carbamazepine
1 Seizure in 7 mo
Seizure free Twice a day Once a day Seizure free 1-2 Petit mal/wk; 1 seizure in 6 mo 2-3 Seizures in 2 wk 3 Seizures in 1 wk
Seizure free Once a day 1 Petit mallday; 1
seizurelday
Pt, patient; EEG, electroencephalogram; M, male; F, female; ep act, epileptic activity; HV, hyperventilation.
Table 3. Electroencephalographic Data Before and During Sedation in t h e Eleven Study Patients EEG data Before sedation Pt No. 1
2 3 4 5 6 7 8 9
10 11
Drug N (45%) p (5) N (40%) P (4.4) N (50%) P (4.8) N (40%) P (6.4) N (40%) P (5.7) N (40%) P (5.4) N (45%) p (3.7) N (35%) P (4.4) N (45%) P (7.3) N (50%) P (6.6) N (50%)
P (6.5)
Normal
Diffuse slow
Focal
Paroxysmal dischargeb 3 in 15 min 11 in 16 min
X X
X X X
X
X
X
Some sharp waves Some sharp waves Spikes, spike waves Spikes, spike waves
X X X
X
X
X X
X
X
X
X
X
X
X
Spikes 1-3/10 s Spikes 1-3/10 s Rare sharp waves
X
X
X
14 in 19 min Some spikes Some spikes Some sharp waves Some sharp waves Some sharp waves Some sharp waves 25 in 15 min
X
X
75 in 24 min
X
X
X X X
EEG, electroencephalographic; N, nitrous oxide; , ' l propofol; Pt, patient. "Numbers in parentheses are nitrous oxide concentrations (7%) or propofol dose (bolus dose "Epilepticactivity including spikes, spike waves, and sharp waves.
During sedation 9 Paroxysmal discharges in 68 min None No change No change No change No change No change No change No change No change No change No change No change None No change Decrease of spikes No change No change No change Decrease of sharp waves 22 Paroxysmal discharges in 35 min 22 in 5 min postsedation 13 Paroxysmal discharges in 50 min 50 in 15 min postsedation
+ total cumulative dose) (mg,kg-'.h-').
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AMBULATORY ANESTHESIA OEI-LIM ET AL. PROPOFOL, N,O, EPILEPSY, AND CONSCIOUS SEDATION
Pre Propofol
711
1s
100 IvI-
Figure 1. Representative EEG segments from a 19-yr-old patient (patient 11) with treated epilepsy before and during conscious sedation with propofol and nitrous oxide. Note absence of spike-and-wave complexes during propofol sedation.
Results Demographic and clinical details of the patients (7 women, 4 men) are shown in Table 2. Eight of the 11 patients had multiple handicaps. Five patients were severely mentally retarded, two were moderately retarded, and four were mildly retarded. Apart from their mental disorder and physical handicap, all patients were in good health. All but one patient (patient 9) had EEG evidence of epileptic activity. The EEG activity data before and during sedation are shown in Table 3. During propofol sedation, EEG activity did not change in six patients. Paroxysmal discharges disappeared in two patients (patients 1 and 7) and were decreased in three (patients 8, 10, and 11)(Figure 1).In three patients (patients 4,6,and 8), there was an increase in fast activity in the beta band (13-30 Hz). During nitrous oxide sedation, the EEG did not change in nine patients. In two patients (patients 1and ll),a decrease in epileptic activity was evident. Neither form of sedation was associated with any adverse effects. Specifically, there was no increase in the frequency or intensity of clinical epileptic manifestations during the 48 h after treatment. The mean duration of sedation was 40.0 ? 9.6 min
(range 27-62) for propofol and 41.5 ? 10.3 min (range 31-68) for nitrous oxide. The mean dose require1.1 mg.kg-'.h-l (range 3.7-6.6) ments were 5.5 for propofol and 43.6% ? 4.8% (range 35%-50%) for nitrous oxide. Figure 2 shows mean ( ~ s D ) values for arterial blood pressure, heart rate, Spo,, and PETCO~ during propofol and nitrous oxide sedation. Arterial blood pressure did not change significantly in the nitrous oxide group, whereas there was a significant decrease in the patients sedated with propofol. Compared with presedation values, heart rate decreased significantly in both groups (by 9 beatdmin). The Spo, remained above 95% in the propofol group and remained above 98% in the nitrous oxide group. The PETCO~ was slightly higher ( P < 0.05) in the propofol group (40 vs 35 mm Hg in the nitrous oxide group). The level of consciousness during propofol or nitrous oxide sedation did not exceed sedation score 3 except in one patient, who reached sedation score 4 at the end of the propofol sedation. At that time, a short period of airway obstruction occurred that was immediately detected and corrected. Table 4 shows the blood concentrations of propofol in three patients at the end of sedation.
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1992;75708-14
1
90 loo
Heart rate (BPM)
systolic Pressure (mm Hg)
Figure 2. Mean ( ~ s D )hemodynamic and resuiratorv variables during urouofol and nitious oxide sedation. "Solid' symbols, propofol; open symbols, nitrous oxide. Spo,, oxygen saturation; BPM, beats/&; etCO, end-tidal C 0 2 concentration.
Diastolic Pressure (mrn Hg)
'
40
etC02 (mm Hg) 30
-5
10 20 Time (minutes)
0
30
40
Table 4. Plasma Concentration of Propofol at the End of the Infusion in Three Study Patients
Pt No. 8 9 11
Duration of infusion (min) 62
41 50
Bolus dose Infusion rate ( m g W (mg.kg-'.h-') 0.8 0.7
0.8
3.7 6.2 5.7
Blood conc (Plw-) 0.6 1.0 1.1
Conc, concentration; Pt, patient.
Discussion The provision of quality dental care to patients who are severely mentally and physically handicapped is a challenge. Behavior management combined with conscious sedation using nitrous oxide/oxygen has become an established technique for dental treatment in this group of patients. However, a small proportion of these patients cannot be adequately managed by this technique alone, because of restricted coping resources and the inability to carry out continuous nasal breathing, essential for nitrous oxide administration by nasal mask. In a previous study, we demonstrated that propofol by continuous intrave-
nous infusion can be a suitable alternative to nitrous oxide for conscious sedation in dentistry or oral surgery. Sedation with propofol infusion is comparable to nitrous oxide/oxygen inhaled sedation in that recovery is rapid without side effects (6). However, there are conflicting data with respect to the proconvulsive or anticonvulsive properties of propofol. The results of the present study suggest that propofol administered in sedative doses neither provokes seizures nor enhances interictal EEG manifestations in patients with treated epilepsy. Dystonic reactions have been reported to occur immediately after induction with propofol administered as the sole anesthetic agent in children (7). Opisthotonus and tonic-clonic seizures have been described after emergence from anesthesia with propofol and additional anesthetics (alfentanil and enflurane) (8) and after the use of propofol for sedation in the intensive care unit (9). This involved patients without a history of epilepsy. The EEG, recorded with surface electrodes after the acute states, demonstrated no evidence of epileptic activity. Two studies reported the effects of propofol administration during general anesthesia on the EEG recorded with chronically implanted subdural elec-
ANESTH ANALG 19!22;75:70%14
trodes in epileptic patients. Hodkinson et al. (10) recorded discharges of epileptiform activity from the previously mapped epileptogenic foci during propofol infusion. They also observed new epileptic activity in other areas of the cortex that had showed no epileptic activity before the injection of propofol. Hufnagel et al. (11)observed maximal suppression of brain activity in the epileptogenic brain area in 12 of 20 patients and also suppression of spontaneous interictal activity present before the onset of anesthesia in 10 of 20 patients; in 5 of 20 patients, there was induction of epileptiform activity. In one patient, a seizure occurred. Our patients were conscious during propofol administration. The EEG recorded from surface electrodes did not show any evidence of increased epileptic activity. There is also considerable evidence that propofol may have anticonvulsive properties. Protection against epileptiform seizures induced by electroshock and pentylenetetrazol in mice was assessed by Lowson et al. (12). They concluded that intraperitoneal administration of propofol (50 mgkg) has a strong anticonvulsant effect. Several studies comparing propofol and methohexitone in patients receiving electroconvulsive therapy have shown a shorter duration of seizure activity with propofol(l3-15). Others have reported the successful use of propofol infusions in the control of intractable status epilepticus, resistant to conventional therapy (16,17). We conclude that the available data are inconclusive with respect to whether propofol administration is associated with enhancement of epileptic activity. In a review of proconvulsant and anticonvulsant properties of anesthetic drugs, Modica et al. (19,20) concluded that the available evidence with regard to the cerebral stimulatory effects of nitrous oxide suggests that its epileptogenic potential is extremely low. In our study, the EEG was unchanged during nitrous oxide sedation in nine patients, whereas in two patients the frequency of paroxysmal discharges decreased. This suggests that nitrous oxide can be administered safely to patients with treated epilepsy. In a previous study, we administered propofol for conscious sedation in nonepileptic patients (6). The mean infusion rate of propofol was 3.6 mg-kg-'-h-' (range 2.55.4). In the present study, all patients had long-term treatment for epilepsy. Using the same sedation scoring system and titrating propofol to identical endpoints (sedation score 3), the mean infusion rate was 5.5 mg.kg-*.h-' (range 3.7-6.6) in the epileptic patients. It is conceivable that this higher dose requirement is a result of hepatic enzyme induction, as a consequence of long-term antiepileptic medication (21,22).
AMBULATORY ANESTHESIA OEI-LIM ET AL. PROPOFOL, N20, EPILEPSY, AND CONSCIOUS SEDATION
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With both sedative regimens there were no untoward changes in hemodynamic and respiratory variables. In all patients, Spo, remained above 95% and was higher during nitrous oxide sedation, as a result of a higher fraction of inspired oxygen. The higher PETCO~ and slightly lower Spo, values during propofol infusion indicate that close supervision of the airway and respiration is necessary. It is especially important not to exceed sedation score 3. In conclusion, the results of the present study suggest that propofol and nitrous oxide can be administered in subanesthetic doses for conscious sedation in mentally and physically handicapped patients with treated epilepsy undergoing dental procedures. More EEG studies are needed to determine the epileptogenic potential of propofol. We thank M. de Groot-Venema, MD, and Marjan van de Werken, EEG technician, Craeyenburch, for screening the patients and recording the EEGs; C. Romijn, AMC, for technical assistance and support; and Dr. J. Oosting, Department of Medical Physics and Statistics, Academic Medical Center, for performing the statistical analysis of the measurements.
References 1. Mackenzie N, Grant IS. Propofol for intravenous sedation. Anaesthesia 1987;42:3-6. 2. Wilson E, Mackenzie N, Grant IS. A comparison of propofol and midazolam by infusion to provide sedation in patients who receive spinal anaesthesia. Anaesthesia 1988;43:914. 3. Newman LH, McDonald JC, Wallace PGM, Ledingham IM. Propofol infusion for sedation in intensive care. Anaesthesia 1987;42:929-37. 4. Hams CE, Grounds RM, Murray AM, Lumley J, Royston D, Morgan M. Propofol for long-term sedation in the intensive care unit. Anaesthesia 1990;45:366-72. 5. Skues MA, Prys-Roberts C. The pharmacology of propofol. J Clin Anesth 1989;1:387400. 6. Oei-Lim LB, Vermeulen-Cranch DME, Bouvy-Berends ECM. Conscious sedation with propofol in dentistry. Br Dental J 1991;17O:MO-2. 7. Borgeat A, Dessibourg C, Popovic V, Meier D, Blanchard M, Schwander D. Propofol and spontaneous movements: an EEG study. Anesthesiology 1991;74:24-7. 8. Saunders PRI, Hams MNE. Opisthotonos and other unusual neurological sequelae after outpatient anaesthesia. Anaesthesia 1990;45:552-7. 9. Au J, Walker WS, Scott DHT. Withdrawal syndrome after propofol infusion. Anaesthesia 1990;45:741-2. 10. Hodkinson BP, Frith RW, Mee EW. Propofol and the electroencephalogram. Lancet 1987;2:1518. 11. Hufnagel A, Elger CE, Nadstawek J, Stoeckel H, Boker DK. Specific response of the epileptic focus to anesthesia with propofol. J Epilepsy 1990;3:3745. 12. Lowson S, Gent JP, Goodchild CS. Anticonvulsant properties of propofol and thiopentone: comparison using two tests in laboratory mice. Br J Anaesth 1990;64:59-63. 13. Bone ME, Wilkins CJ, Lew JK. A comparison of propofol and methohexitone as anaesthetic agents for electroconvulsive therapy. Eur J Anaesthesiol 1988;5:279-86. 14. Rampton AJ, Griffin RM, Stuart CS, Duncan JJ, Huddy NC,
n4
15. 16.
17. 18.
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Abbott MA. Comparison of methohexital and propofol for electroconvulsive therapy: effects on hemodynamic responses and seizure duration. Anesthesiology 1989;70:412-7. Boey WK, Lai FO. Comparison of propofol and thiopentone as anesthetic agents for electroconvulsive therapy. Anaesthesia 1990;45:623-8. Wood PR, Browne GPR, Pugh S. Propofol infusion for the treatment of status epilepticus. Lancet 1988;1:4€%1. Mackenzie SJ, Kapada F, Grant IS. Propofol infusion for control of status epilepticus. Anaesthesia 1990;45:1043-5. Plummer GF. Improved method for the determination of
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19. 20. 21.
22.
propofol in blood by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987;421:171-6. Modica PA, Tempelhoff R, White PF. Pro and anticonvulsant effects of anesthetics (Part I). Anesth Analg 1990;70305-15. Modica PA, Tempelhoff R, White PF. Pro and anticonvulsant effects of anesthetics (Part 11). Anesth Analg 1990;70433-44. Maze M. Hepatic physiology. In: Miller RD, ed. Anesthesia. 3rd ed. New York Churchill Livingstone, 1990:588-92. Perucca E, Richens A. General principles, biotransformation. In: Levy RH, ed. Antiepileptic drugs. New York: Raven, 1989:3540.
