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Canadian Journal of Anesthesia 51:25-30 (2004)
© Canadian Anesthesiologists' Society, 2004
General Anesthesia

Midazolam causes less sedation in volunteers with red hair

[Le midazolam cause moins de sédation chez des volontaires aux cheveux roux]

Marlene V. Chua, MD, Kentaro Tsueda, MD and Anthony G. Doufas, MD PhD

From the Department of Anesthesiology and the Outcomes ResearchTM Institute, University of Louisville School of Medicine, Louisville, Kentucky, USA.

Address correspondence to: Dr. Kentaro Tsueda, Department of Anesthesiology, University of Louisville School of Medicine, Louisville, KY 40292, USA. Phone: 502-852-5851; Fax: 502-852-6056; E-mail: agdoufas{at}louisville.edu


   Abstract
TOP
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: We studied sedation, cognition, and mood during midazolam infusion in volunteers with red and non-red (blond or brown) hair, to test the hypothesis that patients with red hair may require more drugs to attain desired levels of sedation.

Methods: Twenty red and 19 non-red hair subjects were studied in a randomized, placebo-controlled cross-over design. Subjects were studied during placebo and midazolam at 30 ng•mL-1 target effect site concentration. Sedation was assessed using the observer’s assessment of alertness/sedation (OAA/S) scale, the drowsiness visual analogue scale (VAS), and the bispectral index; cognition was assessed using the Repeatable Battery for Assessment of Neuropsychological Status; and mood was assessed using the bipolar form of the Profile of Mood States (POMS).

Results: Red hair volunteers showed significantly higher OAA/S (P < 0.01) and lower drowsiness VAS (P < 0.05) scores compared to non-red hair subjects during midazolam infusion. Visuospatial score was significantly higher in subjects with red compared to non-red hair during placebo and midazolam trials. Delayed memory score was significantly higher during midazolam infusion in subjects with red compared to non-red hair. There were no group differences in POMS during either trials.

Conclusion: Midazolam appears to cause significantly less sedation and cognitive impairment in red haired subjects.


   Introduction
TOP
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
ANECDOTAL descriptions exist that subjects with red hair may faint easily and are difficult to anesthetize.1 A mail survey of anesthesiologistsA has shown that red-haired patients are perceived to have a propensity for drug hypersensitivity, airway difficulties, hemodynamic instability, dysrrhythmias, combativeness and confusion at anesthesia emergence, nausea/vomiting, and bleeding. Our clinical observations suggest that patients with red hair may also require more drugs to attain desired levels of sedation.

We therefore evaluated the hypothesis that subjects with red hair are more resistant to sedative drugs than are subjects with non-red hair. To this end, sedation, cognition, and mood were studied at a light sedation with midazolam in healthy volunteers with red and non-red hair.


   Methods
TOP
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval by the Human Studies Committee of the University of Louisville and written informed consent, we studied 40 healthy volunteers of both genders with red (n = 20) and non-red hair (blond or brown, n = 20) using a randomized, placebo-controlled, and crossover design. Both investigators and volunteers were blinded with respect to the treatment but not to hair colour. Exclusion criteria were: 1) hair dyed red; 2) age less than 18 and more than 40 yr; 3) education less than eight years; 4) vulnerability to psychosis (screened by the Bell Realty Testing Inventory);2 5) history of psychological counselling; 6) psychiatric disease; 7) chemical substance abuse; 8) use of drugs that affect central nervous system function; 9) chronic pain; 10) obesity defined by a body mass index >= 30.0, and/or 11) presence of acute or chronic diseases.

Sample size
Sample size was based on two primary end-points, observer’s assessment of alertness/sedation (OAA/S)3 and the bispectral index (BIS) of the electroencephalogram (EEG). We assumed baseline values of OAA/S and BIS to be 5 and 95 to 99, respectively and a 20% reduction in these values to be clinically meaningful. From the data in our previous study,4 sample size was 18 for OAA/S and 20 for BIS with {alpha} = 0.25 (two tests) and a power of 0.9.

Protocol
Each subject was tested twice approximately two weeks apart. Subjects were randomly assigned to computer generated numbers to receive either midazolam or placebo during the first trial and the alternative treatment during the second trial. All trials were scheduled to begin at 9:00 a.m. A Harvard pump 22TM (Harvard Apparatus, Holliston MA, USA) was used to target a midazolam effect site concentration of 30 ng•mL-1. The pump was controlled by version 4/98 of the Stanpump program (Steven L. Shafer, M.D., Stanford University) using the pharmacokinetic data of Greenblatt et al.5 For placebo, normal saline was infused with the pump similarly set. Volunteers sat in a reclining chair in a quiet study room for approximately 15 min. An antecubital vein was cannulated with a 20-gauge catheter for the drug infusion. Electrocardiogram, heart rate (HR), respiratory rate (RR), and arterial oxygen saturation (SaO2) were monitored continuously. Blood pressure (BP) was monitored every 15 min. Sedation, cognition, and mood were assessed before (baseline) and 20 min after the beginning of the infusion.

Measurements
A detailed medical/surgical history was taken with a particular focus on any unusual perianesthetic event. BP, HR, RR, and SaO2 were recorded every 15 min. RR was measured using a nasal cannula (Salter StyleTM Salter Labs, Arvin, CA, USA) and a capnograph.

Sedation was assessed using the OAA/S, the drowsiness visual analogue scale (VAS, 0–100), and the BIS using a Monitor Model A-2000TM (Aspect Medical Systems, Inc., Natick, MA, USA). The mean values of 60 epochs recorded immediately before assessment of OAA/S and the drowsiness VAS scores were used for analysis.

Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANSTM Randolph C: RBANS manual; Psychological Corporation, San Antonio, Harcourt Brace & Co., 1998).6 Each of the five domains of RBANS consists of two to four subtests. Immediate memory was assessed by a ten-word list (range, 0–40) and story memory (0–24). Visuospatial/constructional ability was assessed by a figure copy (0–20) and line orientation (0–20). Language was assessed by picture naming (0–10) and semantic fluency (0–40). Attention was evaluated by digit span (0–16) and digit-symbol substitution (0–89). Delayed memory was evaluated by a ten-word list recall (0–10), the list recognition (0–20), a story recall (0–12), and figure recall (0–12). The subtest score was converted by z-score transformation. An index score for a domain was obtained by transforming the sum of subtest z-scores to a scale with a mean (SD) of 100 (15). The total scale of index scores (i.e., global assessment of cognitive function) was obtained similarly by transforming the sum of index scores that contribute to the total composite to a scale with a mean ± SD, of 100 ± 15 (40–160).

Mood was assessed using the bipolar form of the Profile of Mood States (McNair DM, Lorr M, Doppleman LF. EdITS manual for the profile of mood states; San Diego: Educational and Industrial Testing Service, 1992).7 Each of the six mood states in the test (i.e., composed-anxious, agreeable-hostile, elated-depressed, confident-unsure, energetic-tired, and clearheaded-confused) is composed of 12 adjective scales, of which one pole represents the positive aspect of the dimension while the other pole refers to the negative aspect. Each adjective was rated by a four-point scale. The total score (i.e., the sum of positive items and negative items plus a constant of 18 for each of the mood states; 0–36) was transformed into a T-scale with a mean ± SD value of 50 ± 10.

Data analysis
Two-factor analysis of covariance was used for between-groups analysis of vital signs, RBANS scores, and mood scores. Analysis of covariance adjusted for any disparity between groups at baseline. Red hair subjects were compared with non-red hair subjects at baseline and infusion, during the placebo and midazolam trial. Differences between baseline and infusion during midazolam infusion were analyzed by paired t- test with Sidak adjustment for multiple comparisons. The OAA/S score, drowsiness VAS, and BIS were analyzed using the Mann-Whitney test. Data are presented as means ± standard deviations, unless otherwise indicated. P < 0.05 was considered to be statistically significant. Post hoc power analysis for comparisons between groups during midazolam infusion was performed on cognitive and mood data.


   Results
TOP
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Demographic and morphometric data are summarized in Table IGo. One woman with red hair who fainted at vein cannulation withdrew from the study. One more volunteer was recruited for the red-hair group. One subject with non-red hair failed to appear for the second session. The study was completed in 20 red-haired subjects and 19 non-red haired subjects (i.e., two with blond hair, 16 with brown hair, and one with black hair). Age, gender, body height, body weight, body mass index, racial composition, and education level were comparable between the groups.


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  		TABLE I Demographics and morphometrics in volunteers with red and non-red hair
 
Anesthetic history showed that 15 red-haired volunteers had 28 previous surgical procedures. Ten of these subjects had 18 general anesthetics, and ten subjects had 11 maxillary and/or mandibular nerve blocks for dental procedures. Three red-haired subjects experienced intraoperative awareness, and four other subjects required repeated injections of local anesthetics for dental extraction (resistance to loco-regional anesthesia). Fourteen non-red haired volunteers had 29 surgical procedures. Eleven of these subjects had 24 general anesthetics, and five had five regional blocks for dental procedures, without experiencing any unusual event. Thus, the incidence of unusual perianesthetic events was significantly higher in subjects with red hair. Five red-haired subjects fainted on puncture of an antecubital vein (vasovagal reaction). One subject with non-red hair fainted. The incidence of fainting was not different between the groups.

Data for the OAA/S, drowsiness VAS, and BIS scores were not normally distributed and are presented as medians with interquartile ranges (Table IIGo). The OAA/S score was significantly higher in subjects with red hair during midazolam infusion (P < 0.005). The drowsiness VAS score was significantly lower in subjects with red hair (P < 0.05). BIS values were not different between groups.


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  		TABLE II Sedation during placebo and midazolam in red and non-red hair subjects
 
Midazolam significantly impaired total RBANS score, immediate and delayed memory, visuospatial activity, and attention in both groups (P < 0.05; Table IIIGo). The visuospatial score was significantly higher in subjects with red compared to non-red hair both during placebo and midazolam. Delayed memory and total RBANS scores were significantly higher in red hair compared to non-red hair subjects during midazolam infusion.


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  		TABLE III Cognitive function in red and non-red hair subjects
 
There were no significant differences between the groups in mood states during the placebo or midazolam trials. Post-hoc analysis demonstrated a power between 0.05 and 0.26 (Table IVGo).


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  		TABLE IV Mood in red and non-red hair subjects
 

   Discussion
TOP
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We found that the OAA/S score was significantly higher and the VAS score for drowsiness was significantly lower in subjects with red compared to non-red hair during midazolam infusion. The midazolam concentration used in this study was equivalent to that expected approximately 30 min after a bolus injection of 2 mg midazolam in a 70-kg subject.4 Sedation in non-red haired volunteers was similar to that previously observed by our group at the plasma concentration of 30 ng•mL-1.8 Drowsiness was moderate to severe, and response to name calling was lethargic during the midazolam infusion, while, in red-haired volunteers, drowsiness was less (i.e., mild to moderate), and response to name calling during the infusion was brisk.

Proopiomelanocortin (POMC) is synthesized and cleaved into peptides that include {alpha}-melanocyte-stimulating hormone ({alpha}-MSH), adrenal corticotrophic hormone (ACTH), and ß-endorphine in the pituitary gland, gastrointestinal tract, gonads, placenta, and skin.9 Neuropeptides, ACTH and {alpha}-MSH, are potent modulators of cognitive function and neurobehavioural activities in animals and humans.10,11 The peptides consistently enhance selective attention and stimulus processing with a visual (but not an auditory) discrimination learning procedure. The peptides produce higher EEG frequencies in humans that are consistent with a generalized arousal response and a disinhibition of central nervous system-activating mechanisms.12,13 The EEG signs of focusing attention have been reported in occipital leads overlying the primary visual cortex, and visual evoked potentials are consistent with increased attention.14 Human subjects, when treated with these peptides, performed significantly better than control subjects in visual memory, digit-symbol substitution test (i.e., visual-motor learning), and continuous performance task.15 Sandman et al.16 reported that, although the peptides actually raised perceptual threshold of stimuli, once these stimuli were perceived, visual discrimination was significantly facilitated. Thus, it has been postulated that ACTH/{alpha}-MSH exert their predominant effect on attention rather than memory processes (attentional hypothesis).16,17 However, reported effects of those peptides on human attention have been inconsistent and at best marginal.18,19

The mechanism for the significant resistance to sedation observed in our red-haird volunteers during midazolam infusion is not clear. MSH and ACTH equipotently act on melanocortin receptor-1 (MC1-R), initiating melanogenesis.9 Of the allelic variants of the MC1-R gene identified in humans, three particular variants, Arg 151Cys, Arg160Trp, and Asp294His, are the most frequently encountered loss of function mutations.20 These variants result in an increase in the pheomelanin/eumelanin ratio in the skin and hair, and are associated with red hair, fair skin, and poor tanning ability.9 The mechanisms controlling production of {alpha}-MSH have not been clarified, but most pituitary functions are controlled by negative feedback systems. End-organ failure (e.g., loss of function mutations) leads to an increase in the level of hormones. Thus, it may be assumed that MC1-R dysfunction may activate a putative feedback system and increase central {alpha}-MSH levels, conferring resistance to midazolam-induced sedation.

Midazolam impaired cognitive function and affected mood, as it has been reported previously.4,8,10,21 Interestingly, visuospatial/constructional ability was significantly higher in subjects with red compared to non-red hair at all phases (i.e., baseline and infusion) of the study both during placebo and midazolam trials. The heightened visuospatial activity observed in this study is comparable to the enhanced selective attention and stimulus processing with visual learning procedure shown in subjects treated with {alpha}-MSH and ACTH.12–17 We also found that delayed memory score was less impaired in subjects with red compared to non-red hair. This finding is also consistent with the previous results16 showing heightened attention and subsequent facilitation of visual discrimination in subjects receiving {alpha}-MSH and ACTH. It is, thus, possible that the significant differences found in visuospatial activity and delayed memory between groups might be due to higher central levels of {alpha}-MSH in red-haired subjects.

The incidence of fainting spells at cannulation of a vein in the sitting position was higher in red (5/21) than in non-red haired volunteers (1/19). The incidence appears to be consistent with perceived vascular instability during anesthesiaA and the view that subjects with red hair tend to faint easily.1 The effects of melanocortins on cardiovascular function have recently been reviewed.22 A putative change in the dynamics of central {alpha}-MSH activity may be the underlying mechanism for the perceived association between red hair colour and vascular instability or fainting spells in red hair subjects.A Unusual perianesthetic events (i.e., awareness during general anesthesia and resistance to maxillary and mandibular block for dental procedures) were more frequent in subjects with red than non-red hair. These events appear to be consistent with the observations that subjects with red hair may require more inhaled anesthetics for a given level of anesthetics23 and subjects with red hair are more sensitive to noxious stimuli.24

The amount of midazolam used during the study was comparable between subjects with red and non-red hair. However, since plasma levels of midazolam were not measured, a possibility that our findings were due to phamacokinetic differences between subjects with red and non-red hair could not be excluded. The investigators were not blinded with respect to hair colour. Even though efforts had been made to blind the study by covering subjects’ hair, the investigators were still able to identify red hair subjects from the skin appearance. The OAA/S and drowsiness VAS scores used in this study are fairly subjective tools for assessment of sedation/sleepiness and the existence of bias can not be excluded.

The results of the study suggest that red haired subjects appear to be less sedated than are those with non-red hair for a given plasma concentration of midazolam. Change in the melanocortin system may be a part of the mechanism for the apparent resistance to the sedative effect of midazolam observed in red-haired subjects.


   Acknowledgments
 
We are grateful to Dr. D.I. Sessler for his advice in preparation of the manuscript and Dr. R. L. Vogel for help with the statistical analysis.


   Footnotes
 
Accepted for publication June 2, 2003. Revision accepted October 20, 2003.

A Algarra NN, Foust JA, Green SM, Hardy AE, Hendrix SR. Perception of certified registered nurse anesthetists in Georgia regarding anesthesia morbidity in patients with red hair. Houston: University of Texas Health Science Center, School of Nursing, 1994: 1–5. Back


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 Methods
 Results
 Discussion
 References
 
1 Loefler IJ. Pigmentation, melanocortins and red hair (Letter). QJM 1999; 92: 418–9.[Free Full Text]

2 Bell MD, Billington RJ, Becker B. Scale for the assessment of reality testing: reliability, validity, and factorial invariance. J Consult Clin Psychol 1985; 53: 506–11.[Medline]

3 Chernik DA, Gillings D, Laine H, et al. Validity and reliability of the Observer’s Assessment of Alertness/Sedation scale: study with intravenous midazolam. J Clin Psychopharmacol 1990; 10: 244–51.[Medline]

4 Suzuki M, Tsueda K, Lansing PS, et al. Midazolam attenuates ketamine-induced abnormal perception and thought process but not mood changes. Can J Anesth 2000; 47: 866–74.[Abstract/Free Full Text]

5 Greenblatt DJ, Ehrenberg BL, Gunderman J, et al. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo. Clin Pharmacol Ther 1989; 45: 356–65.[Medline]

6 Randolph C, Tierney MC, Mohr E, Chase TN. The repeatable battery for the assessment of neuropsychological status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol 1998; 20: 310–9.[Medline]

7 Tsueda K, Mosca PJ, Heine MF, et al. Mood during epidural patient-controlled analgesia with morphine or fentanyl. Anesthesiology 1998; 88: 885–91.[Medline]

8 Dundee JW, Wilson DB. Amnesic action of midazolam. Anaesthesia 1980; 35: 459–61.[Medline]

9 Schaffer JV, Bolognia JL. The melanocortin-1 receptor. Red hair and beyond. Arch Dermatol 2001; 137: 1477–85.[Abstract/Free Full Text]

10 Ghoneim MM, Mewaldt SP. Benzodiazepines and human memory: a review. Anesthesiology 1990; 72: 926–38.[Medline]

11 Datta PC, King MG. {alpha}-Melanocyte-stimulating hormone and behavior. Neurosci Biobehav Rev 1982; 6: 297–310.[Medline]

12 Zager EL, Black PM. Neuropeptides in human memory and learning processes. Neurosurgery 1985; 17: 355–69.[Medline]

13 Endroczi E, Lissak K, Fekete T, De Wind D. Effects of ACTH on EEG habituation in human subjects. Progr Brain Res 1970; 32: 254–62.[Medline]

14 Miller LH, Kastin AJ, Sandman CA, Fink M, Van Veen WJ. Polypeptide influences on attention, memory and anxiety in man. Pharmacol Biochem Behav 1974; 2: 663–8.[Medline]

15 Miller LH, Harris LC, Van Riezen H, Kastin AJ. Neuroheptapeptide influence on attention and memory in man. Pharmacol Biochem Behav 1976; 5(Suppl 1): 17–21.[Medline]

16 Sandman CA, George JM, Nolan JD, Van Riezen H, Kastin AJ. Enhancement of attention in man with ACTH/MSH 4-10. Physiol Behav 1975; 15: 427–31.[Medline]

17 Ward MM, Sandman CA, George J, Shulman H. MSH/ACTH 4-10 in men and women: effects upon performance of an attention and memory task. Physiol Behav 1979; 22: 669–73.[Medline]

18 Gaillard AW, Sanders AF. Some effects of an ACTH 4-10 on performance during a serial reaction task. Psychopharmacologia (Berlin) 1975; 42: 201–8.

19 Gaillard AW, Varey CA. Some effects of an ACTH 4-9 analog (ORG 2766) on human performance. Physiol Behav 1979; 23: 79–84.[Medline]

20 Schioth HB, Phillips SR, Rudzish R, Birch-Machin MA, Wikberg JE, Rees JL. Loss of function mutations of the human melanocortin 1 receptor are common and are associated with red hair. Biochem Biophys Res Commun 1999; 260: 488–91.[Medline]

21 Reves JG, Fragen RJ, Vinik HR, Greenblatt DJ. Midazolam: pharmacology and uses. Anesthesiology 1985; 62: 310–24.[Medline]

22 Versteeg DH, Van Bergen P, Adan RA, De Wildt DJ. Melanocortins and cardiovascular regulation. Eur J Pharmacol 1998; 360: 1–14.[Medline]

23 Liem EB, Lin CM, Suleman MI, Doufas AG, Akça O, Sessler DI. Increased anesthetic requirement in subjects with naturally red hair. Anesthesiology 2002; 96: 77 (abstract).

24 Vrinten DH, Adan RA, Groen GJ, Gispen WH. Chronic blockade of melanocortin receptors alleviates allodynia in rats with neuropathic pain. Anesth Analg 2001; 93: 1572–7.[Abstract/Free Full Text]




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