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© 2001 International Anesthesia Research Society
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Abstract |
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Differences in sensitivity to anesthetic drugs have already been described among races. This study was designed to comparatively investigate the anesthetic requirements of two different ethnic groups: Caucasians and African blacks. Forty-five Caucasians from Italy and 45 African blacks from Senegal, who underwent general IV anesthesia with propofol and remifentanil, were comparatively evaluated for anesthetic depth and time lapsed before recovery. We used an electroencephalographic-derived index of depth of anesthesia, the bispectral index (BIS), and evaluation of clinical variables to assess the depth of anesthesia and the recovery trend. Mean BIS values from Caucasians after propofol dis- continuation returned to baseline (92–100) in approximately 8 min, whereas in African blacks BIS values remained <80 for some 30 min. Time to eye opening was 10.6 ± 4.8 min in Caucasians versus 16.9 ± 8.8 min in African blacks (P < 0.001). Time to respond to loud verbal commands was 14.8 ± 9.1 min in African blacks versus 9.1 ± 4.2 min in Caucasians (P < 0.01). During anesthetic induction, the mean arterial pressure decreased by 20% in Caucasians and by only 10% in African blacks. We conclude that the recovery from general anesthesia with propofol was slower in African blacks compared with Caucasian patients.
IMPLICATIONS: This study demonstrates statistically significant differences between Caucasians and African blacks in the arousal time from IV anesthesia with propofol and remifentanil. The authors conclude that the recovery from general anesthesia was slower in African blacks compared with Caucasian patients.
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Introduction |
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Different patients may need variable doses of anesthetics to reach and maintain a surgical level of anesthesia. Sleep may be prolonged in patients with increased central nervous system responses to depressant drugs or in those with pathologies affecting redistribution and metabolism of drugs. Sex may be a potential variable in recovery from general anesthesia, with females awakening faster than males (1). An inverse relationship between age and anesthetic or hypnotic requirements occurs for both volatile and IV anesthetics (2,3). There are findings of differences in pharmacokinetics and pharmacodynamics of some drugs among human races; these differences are relevant for anesthesiologists (4–6).
Race differences need accurate investigation for scientists to design general models for anesthesia, such as target-controlled infusion, to be used in a multiracial society. The differential pharmacokinetics and pharmacodynamics of anesthetics between African blacks and Caucasians have not been investigated.
There is growing interest among anesthesiologists in optimizing models for drug infusion in their patients. This study was designed to evaluate the effects of ethnicity on hypnotic requirements through an electroencephalographic index, the bispectral index (BIS), which is highly indicative of the brain concentration of anesthetics (7) and correlates well with hypnotic or sedative end points (8). Subjects from two populations were studied: Caucasians from Italy and black Africans from Senegal. To quantify racial differences in sensitivity to propofol, we chose to give patients fixed amounts per kilogram per hour of the drug and to evaluate the behavior of the different races according to the values of the BIS and recovery variables.
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Methods |
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The study was performed in two hospitals: Policlinico Careggi in Florence, Italy, and Hopital Le Dantec in Dakar, Senegal. After obtaining Institutional Ethics Committee approval both in Florence and in Dakar and written, informed consent, Caucasian patients and black African patients who were nonsmokers within normal arterial blood pressure range were enrolled. The African blacks examined belonged to seven different tribes from Senegal (Wolof, Diola, Peul, Serere, Toucouleur, Mandingue, and Soninke). Neither Caucasian nor Asiatic subjects were present in their pedigree. The Caucasians were all Italians, with no African or Asian subjects in their pedigree.
The patients considered were of both sexes, were aged between 20 and 55 yr, and had weight between 60 and 75 kg, height between 1.65 and 1.75 m, and body mass index between 20 and 25. They were ASA physical status I and had no associated pathologies. These subjects underwent general lower abdominal surgery lasting from 60 to 90 min. Heart rate, noninvasive blood pressure, and arterial oxygen saturation were recorded during anesthesia. Exclusion criteria were history of pulmonary or renal disease, drug or alcohol use, body mass index <19 or >26, presence of anemia, and hemoglobin sickle cell disease. Patients were enrolled until 45 patients of each race were successfully included in the study.
Patients received lactated Ringer’s solution 10 mL/kg and 0.5 mg of atropine 30 min before the induction of anesthesia. Anesthesia was induced by using a total IV technique, including the infusion of remifentanil 15 µg · kg-1 · h-1, no initial bolus; propofol 1.5 mg/kg (initial bolus) and 10 mg · kg-1 · h-1; and vecuronium 0.05 mg/kg.
Patients were tracheally intubated and ventilated with oxygen and air (fraction of inspired oxygen = 0.4). Propofol and remifentanil were delivered by infusion pumps. All patients received 800 mL/h of saline solution during surgery. If there was a need to reduce or increase the amount of both drugs according to the patient’s requirements during anesthesia, the patient was excluded from the trial. Propofol and remifentanil administration was suspended 10 and 5 min, respectively, before the expected end of surgery (patient regaining consciousness).
Mean arterial blood pressure, heart rate, blood oxygenation, common clinical variables, and BIS were used to evaluate the depth of anesthesia. Evaluation of the level of consciousness through eye opening, response to verbal stimuli, and BIS were used to evaluate wake-up differences between the groups. Patients with a decrease of arterial blood pressure of >30% of the basal (10 in the Caucasian group, 2 in the African black group) were not considered.
The BIS was monitored from two fronto-parietal electroencephalogram (EEG) signals with an Aspect A-1000 EEG monitor (Aspect Medical Systems, Natick, MA). EEG signals were picked up with four Zipprep self-sticking frontal surface electrodes placed on both sides of the outer malar bone (At1 and At2), with Fpz as reference and Fp1 as the ground. All data were automatically sent through a serial RS232 interface to a computer at 5-s intervals by using self-designed software. Mean BIS values for each patient were calculated from 5 min of data before the anesthesia induction (B0), starting from 20 and 40 min after induction (B1 and B2), and then from 3-min data starting 3 min (B3) and 6 min (B4) after propofol discontinuation. The mean values B1 and B2 were considered as intraoperative BIS, B3 as prerecovery BIS, and B4 as recovery BIS. B3 and B4 were used to evaluate wake-up behavior.
To assess the recovery time, verbal stimuli were applied at 30-s intervals starting from discontinuation of propofol infusion. Spontaneous eye-opening time and movements both spontaneous and under loud verbal command were recorded.
End-point values were tested for normality by using the Kolmogorov-Smirnov statistic. Because they were normally distributed (P > 0.10), Student’s t-test for unpaired data were used to compare the values. Welch correction was applied when data did not show equal variances. Statistical significance was defined as a P value <0.05.
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Results |
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Demographic data of the patients that completed the trial and details about surgery of both groups are summarized in Table 1. The trial profile is described in Figure 1. Table 2 outlines patients withdrawn from the trial and reasons for their withdrawal.
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Figure 2 shows mean BIS values calculated in African blacks and Caucasians from 5-min data at times B1 (20 min after anesthesia induction) and B2 (40 min after anesthesia induction) and from 3-min data at times B3 (3 min after propofol discontinuation) and B4 (6 min after propofol discontinuation). No differences were found between the groups either in basal values, B0 (P = 0.89), or in intraoperative values, B1 (P = 0.88) and B2 (P = 0.64).
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BIS values were significantly different during the wake-up. B3 values (prerecovery values) were 26% larger in African blacks compared with Caucasians (P < 0.001). However, B4 values (recovery BIS values) were 14% smaller in African blacks compared with those of Caucasians (P < 0.01). The BIS values of African black patients remained smaller than basal values for up to 30 min after propofol discontinuation.
The time from discontinuation of propofol infusion to eye opening was 16.9 ± 8.8 min in African blacks versus 10.6 ± 4.8 min in Caucasians (P < 0.001). Time to respond to loud-speaking verbal commands was 14.8 ± 9.1 min in African blacks versus 9.1 ± 4.2 min in Caucasians (P < 0.01). Figure 3 shows the mean BIS awakening profile after propofol and remifentanil administration had been discontinued.
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Table 3 shows the behavior of clinical variables during the trial. There were no significant variations in SpO2 and heart rate during our experiment conducted with fixed ventilation variables (10 breaths/min, expiratory ventilation volume 120 mL · kg-1 · min-1), but mean arterial pressure differences were observed within the two groups 10 min after anesthesia induction.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The different sensitivity toward drugs may be caused both by genetic factors and by life habits (health, nutrition, enzymatic induction, physical exercise, etc.). For instance, West Africans show reduced metabolic activation of paracetamol (9) and increased sensitivity to alcohol, possibly because polymorphism of human alcohol dehydrogenase (10). It is clear that most of the genetic or environmental variables between African blacks and Caucasians are still unknown, and the effects of known variables still have to be established.
The enrolling criteria of our sample were very narrow. Overweight patients were excluded (because of considerations of possibly different redistribution of the drug in these patients). Care was taken to include equal numbers of men and women and to represent the same kind of surgery in the two groups. Also, we excluded from our trial patients who drank alcohol, smoked, or took drugs on a regular basis. The idea was to reduce bias caused by the development in some subjects of a kind of enzymatic induction.
The main question is this: are the differences found in the two groups caused primarily by genetic factors, or are they caused, at least partly, by differences in feeding habits? It is difficult to find an answer; we have data neither from Caucasian subjects who have eating habits similar to those of African blacks from Senegal nor from African blacks elsewhere. There are huge differences in the eating habits of the two examined groups which may account for differences in body composition between Caucasians and African blacks and which may play a role in the distribution and elimination of administered drugs.
If we consider the genetic point of view, polymorphisms of plasma proteins have been observed in different races, indicating the presence of different gene constellation in tissues (11). This may account for differences in mean arterial pressure and time of arousal. Differences in fat distribution (12), skeletal muscle fiber type proportions (13), and serum plasma lipoproteins (14) may play some role.
So, although our observations are very indicative for a pharmacokinetic and pharmacodynamic difference between the two groups, any attempt to find a key to interpret these differences, or eventually to find an "African gene" that may account for the differences (15), is left to further research effort.
In conclusion, statistically significant differences have been found between Caucasians and African blacks in the arousal from IV anesthesia with propofol and remifentanil. These findings should be compared with the ones from other African, Asian, and South American countries to obtain a map of the differential sensitivity of different peoples to anesthesia. This information is of great importance in preparing and trimming models for automated infusion systems that have been established only for Caucasians.
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Acknowledgments |
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Supported by public funds from the University of Florence. The Aspect A-1000 EEG Monitor was provided by Astra Zeneca Italia, Palazzo Volta, Via F.Sforza, Basiglio (MI) Italy.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- Gan TJ, Glass PS, Sigl J, et al. Women emerge from general anesthesia with propofol/alfentanil/nitrous oxide faster than men. Anesthesiology 1999; 90: 1283–7.[Web of Science][Medline]
- Gold MI, Abello D, Herrington C. Minimum alveolar concentration of desflurane in patients older than 65 yr. Anesthesiology 1993; 79: 710–4.[Web of Science][Medline]
- Minto CF, Schnider TW, Egan TD, et al. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997; 86: 10–23.[Web of Science][Medline]
- Houghton IT, Chan K, Wong YC, et al. Pethidine pharmacokinetics after intramuscular dose: a comparison in Caucasian, Chinese and Nepalese patients. Methods Find Exp Clin Pharmacol 1992; 14: 451–8.[Web of Science][Medline]
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Short TG, Aun CST, Tan H. Prospective evaluation of pharmacokinetic model-controlled infusion of propofol in paediatric patients. Br J Anaesth 1994; 72: 302–30.
[Abstract/Free Full Text] - Chan A, Nickoll E, Thornton C, et al. Spontaneous movement after injection of propofol. Anesthesia 1996; 51: 663–6.[Web of Science][Medline]
- Rampil IJ. A primer for EEG signal processing in anesthesia. Anesthesiology 1998; 89: 980–1002.[Web of Science][Medline]
- Gan TJ, Glass PS, Windsor A, et al. Bispectral index monitoring allows faster emergence and improved recovery from propofol, alfentanil, and nitrous oxide anesthesia. BIS Utility Study Group. Anesthesiology 1997; 87: 808–15.[Web of Science][Medline]
- Critchley JA, Nimmo GR, Gregson CA, et al. Intersubject and ethnic differences in paracetamol metabolism. Br J Clin Pharmacol 1986; 22: 649–57.[Web of Science][Medline]
- Iron A, Groppi A, Fleury B, et al. Polymorphism of class I alcohol-dehydrogenase in French, Vietnamese and Niger populations: genotyping by PCR amplification and RFLP analysis of dried blood spot. Ann Genet 1992; 35: 152–6.[Web of Science][Medline]
- Corbo RM, Scacchi R, Cossu G, et al. Genetic studies on the Senegal population. II. Polymorphism of the plasma proteins F13A, F13B, ORM1, AHSG, C6, C7 and APOC2. Hum Biol 1994; 66: 885–903.[Web of Science][Medline]
- Ama PF, Poehlman ET, Simoneau JA, et al. Fat distribution and adipose tissue metabolism in non-obese male black African and Caucasian subjects. Int J Obes 1986; 10: 503–10.[Web of Science][Medline]
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Ama PF, Simoneau JA, Boulay MR, et al. Skeletal muscle characteristics in sedentary black and Caucasian males. J Appl Physiol 1986; 61: 1758–61.
[Abstract/Free Full Text] -
Fontana P, Mooser V, Bouet P, et al. Dose dependent inverse relationship between alcohol consumption and serum Lp(a) levels in black American males. Arterioscler Thromb Vasc Biol 1999; 19: 1075–82.
[Abstract/Free Full Text] - Moskowitz DW. Hypertension, thermotolerance and the "African gene": an hypothesis. Clin Exp Hypertens 1996; 18: 1–19.
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