The effect of hair colour on anaesthetic requirements and recovery time after surgery.
Natural hair colour is genetically determined, due to variation in the amount, type, and packaging of melanin produced by melanocytes (4-7). Melanin is the substance that gives skin, hair and eyes their colour, dependent on the relative amounts of the two forms of melanin, eumelanin and pheomelanin. People who produce mostly eumelanin tend to have brown or black hair; those who produce mostly pheomelanin tend to have red or blond hair (4,5). There is a natural range of skin and hair colour, which is controlled by multiple pigmentation genes in a complex manner. Not all of these genes are as yet known, but several key genes have been characterised (4,8). In humans the 'red hair colour' (RHC) phenotype is associated with allelic variants of the MC1R gene (5). Mutations within this gene that reduce the function of the MC1R switch melanin synthesis to favour pheomelanin (4,8). Valherde et al5 found at least one variant allele in 82% of individuals with red hair, 33% of those with blond/fair hair, and less than 20% of those with brown/black hair; changes in both alleles were exclusively associated with RHC (29%). Subsequent association, familial and functional studies have supported the role of mutations that significantly impair the function of the MC1R in the RHC phenotype in caucasians (8-11).
The MC1R is a member of a group of melanocortin receptors that are active in cells involved in adrenocortical steroidogenesis, and the body's immune and inflammatory responses, hypothalamic regulation of food intake, body weight, exocrine gland function and thermoregulation (12,13). A few previous studies have found that red hair may indicate a reduced sensitivity to general anaesthetics1 and/or an altered pain response (13-16). In view of the limited data available we set out to examine the effects of hair colour on requirements and response to general anaesthesia, and on recovery from anaesthesia, in a cohort study in adults undergoing general anaesthesia for elective surgery.
MATERIALS AND METHODS
After ethics committee approval (approval number 02015/D) and informed consent, 468 of 500 adult patients enrolled in a concurrent study investigating the effects of sex on recovery after elective non-cardiac surgery with general anaesthesia (17) were enrolled in this planned prospective cohort study. Patient enrolment occurred from 2003 to May 2007. Patients were included in the study if they were aged between 18 and 70 years, were American Society of Anesthesiologists physical status I or II, and were undergoing elective general, orthopaedic, urology, plastic or ear, nose or throat surgery. They were excluded if they did not receive an inhalational general anaesthetic, were undergoing sex-specific (gynaecology or prostatic surgery), emergency or high-risk surgery, were being treated with a major tranquilliser or lithium, or had a neurological condition.
All preoperative demographic and perioperative characteristics, details of medical and surgical history, smoking status and current medications were recorded. In addition, we specifically asked patients to describe their natural hair colour as either black, brown, blond or red, irrespective of their current appearance. Operative data including type and dose of anaesthetic drugs used, airway management, adverse intraoperative events, type and extent of surgery (minor, intermediate, major) and duration of anaesthesia were recorded. Postoperative sequelae including recovery room stay, adverse events and pain scores using a 10-point numerical rating scale were recorded.
Most aspects of anaesthetic and perioperative management were left to the discretion of the anaesthetist, but all relevant data were collected on a study case report form. General anaesthesia was induced with propofol (in all but two patients who received thiopentone) titrated to loss of consciousness and maintained using volatile anaesthesia (isoflurane, sevoflurane or desflurane) with or without nitrous oxide. Non-depolarising muscle relaxants, when used, were reversed with neostigmine and atropine. End-tidal inhalational agent concentration was monitored using the Datex-Ohmeda Aisys Carestation[R] (GE Healthcare, Helsinki, Finland), which has an accuracy or [+ or -] 0.2%. Bispectral index (BIS) monitoring was used to measure the hypnotic component of depth of anaesthesia though administration of anaesthesia was not titrated to BIS. BIS measurements were made every five minutes for the first hour and then every 10 minutes for every subsequent hour. A time-averaged mean BIS score was then calculated for the duration of general anaesthesia. Intraoperative age-adjusted minimum alveolar concentration (MAC) was determined using an established nomogram (18). We did not collect individual anti-emetic data, but for the vast majority the anti-emetic administered was ondansetron and/or dexamethasone.
Cessation of administration of general anaesthesia was timed for the patient to emerge from anaesthesia after final wound closure. Emergence from anaesthesia was timed from completion of wound dressing (= time 0) and included time to spontaneous eye-opening, time to obeying commands and the time spent in the recovery room (until eligible for discharge to the surgical ward). Quality of recovery was assessed on each of the first three days after surgery using the 40-item quality of recovery score (19).
The primary outcome of the study was speed of recovery, using time to eye-opening, time to obeying commands and time spent in the recovery room. Secondary outcomes included pain scores (measured with an 11-point verbal rating scale) and quality of recovery (measured with the 40-item quality of recovery score).
Sample size calculation and statistical analysis
The sample size was based on our previous data for recovery times after intermediate surgery (20), using a 15% reduction of a mean (SD) time to eye opening of 9 (4) minutes. With a type I error of 0.05 and a type II error of 0.2, we needed to enrol at least 170 patients per group. We expected to include over 400 patients in the study, allowing us to perform subgroup and adjusted analyses. Descriptive statistics are expressed as number (%) or mean (SD). Differences between groups were examined using analysis of variance, Student's t-test, Mann Whitney U test, or chi-square test, as appropriate. We adjusted for sex imbalance using the Mantel Haenzsel common odds ratio (OR) estimate. All analyses were performed using SPSS for Windows version 19.0. A P value of less than 0.05 was considered statistically significant.
Patient demographic and perioperative characteristics are reported in Table 1. Black or brown hair colour was more common in males and so we undertook subgroup and adjusted analyses to account for the known effect of sex on anaesthetic drug responses (17,21,22). Anaesthetic technique and drug administration were mostly comparable across the hair colour groups, with the exception of anti-emetic prophylaxis and avoidance of nitrous oxide, which were used more commonly in those with red hair, who were more likely to be female (Table 2). The apparent increased incidence of previous postoperative nausea and vomiting was not significant after accounting for the sex imbalance, Mantel-Haenzsel OR 1.7 (95% confidence interval: 0.71-4.2); P=0.33. There was no increased risk of postoperative nausea and vomiting after accounting for the sex imbalance, Mantel-Haenzsel OR 0.47 (95% confidence interval: 0.1-3.8); P=0.75.
The average BIS score during surgery, at wound closure and at the time of eye opening were comparable for each hair colour group (Tables 2 and 3). Patients with black hair, who were mostly male, had longer recovery times (Table 2), but this apparent difference disappeared after adjusting for patient sex, age and duration of surgery (Table 4). We explored this probable confounding further by undertaking subgroup analysis of males and females separately (Table 5), comparing those with dark (black or brown) versus red hair and could not identify any evidence of increased speed of recovery in the latter group. Nor was there any evidence of increased anaesthetic requirement in redheads, age-adjusted MAC 1.28 (0.27) vs 1.31 (0.34), P=0.46. This lack of difference was confirmed when stratified by patient sex (Table 5).
There were no differences in intraoperative morphine administration, postoperative pain scores, nausea and vomiting, or overall quality of recovery as measured by the 40-item quality of recovery score (Table 3).
We found no evidence that redheads had increased anaesthetic requirement or faster speed of recovery after surgery. Nor was there any evidence of a difference in pain response (as measured by morphine requirement), pain intensity (as measured by a numerical rating scale) or other adverse effects after anaesthesia and surgery.
Our findings failed to support those of previous studies (1,2). Liem and co-workers investigated healthy female volunteers with natural bright red (n=10) or dark (n=10) hair (1). They specifically excluded women with chemical hair treatment and utilised spectrophotometric hair analysis to confirm the pheomelanin proportion. They also genotyped each participant using single nucleoptide poly morphism analysis of MC1R alleles. Anaesthesia was maintained with desflurane and a noxious electrical stimulus was used to ascertain anaesthetic requirement. They found that desflurane requirement in redheads was significantly greater than in dark-haired women, 6.2% (95% confidence interval: 5.9-6.5) vs 5.2% (95% confidence interval: 4.9-5.5), P=0.0004. Nine of the 10 redheads were either homozygous or compound heterozygotes for mutations on the MC1R associated with RHC. In another study mice with an MC1R mutation with no receptor function and yellow coats were found to have slightly increased MAC when compared to controls (2). In our study comparable BIS scores at equivalent levels of general anaesthesia suggests that redheads have similar sensitivity to the hypnotic effects of anaesthesia. This demonstrates that laboratory animal and human models may not replicate surgical stimulation, and they certainly do not replicate real world surgical practice. Our findings should alleviate any concern that RHC is a risk factor for awareness.
An Australian study of twins and their siblings measured the strength of the relationship between allelic variants of MC1R and RHC (23). There is a strong association (OR=63) between four common alleles and a weaker association (OR=5.1) with three other alleles. The strength of the association is such that in a cohort of 196 individuals two RHC mutations were present in 96% of individuals with self-described red hair (24). A grouping of 'red' hair typically includes shades such as carrot red, strawberry blond and auburn. For this reason we did exploratory subgroup analyses to exclude those with blond hair and merge those with black or brown hair to simplify the analyses and interpretation, and increase study power.
MC1R is minimally expressed in brain tissue (13,25), and laboratory studies in mice and humans indicate a link between MC1R variants, pain tolerance and enhanced response to opioid analgesia (13,16). Further studies support these findings and suggest a role of MC1R in acute pain and pain of inflammatory origin rather neuropathic pain (15). Liem and coworkers (14) found that redhead volunteers were more sensitive to cold pain (perception and tolerance) and demonstrated significantly less subcutaneous lignocaine efficacy when compared to dark-haired volunteers. This would suggest that analgesic requirements should be greater in redheads. In our study we found no difference in pain scores and opioid requirement in redheads. However, larger genetic association studies would be required to demonstrate a role of the MC1R in surgical pain.
We and others have found that women appear to be less sensitive to hypnotic drugs, as assessed by the doses required to achieve a similar hypnotic depth (17), and faster recovery times following cessation of anaesthetic drug delivery (21,22). It is for this reason that we chose to undertake stratified and adjusted analyses in order to account for the overt confounding effect of patient sex.
There are limitations to our study. We excluded patients who received total intravenous anaesthesia. We did not use spectrophotometric analysis to establish RHC phenotype or undertake genetic analyses to look for mutations affecting the MC1R. However, the exclusion of blond hair from the subgroup combined with the evidence supporting the strong association between RHC and common MC1R variants would imply, although not establish, that the common MC1R mutations that impair receptor function would be highly likely to be present in the redheads in our study. Liem and co-workers acknowledged a similar assumption in their analysis of responses to thermal pain and lignocaine efficacy (14).
In summary, we could find no evidence that a patient's natural hair colour meaningfully affects anaesthetic requirement, speed or quality of recovery times after surgery. That is, there is no evidence that redheads are at higher risk of awareness during anaesthesia.
The study was funded by an Australian and New Zealand College of Anaesthetists project grant (02/014). Dr Frank Buchanan was supported by an Australian and New Zealand College of Anaesthetists scholarship. Professor Paul Myles is supported by an Australian National Health and Medical Council Practitioner fellowship.
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(2.) Xing Y, Sonner JM, Eger EI, Cascio M, Sessler DI. Mice with a melanocortin 1 receptor mutation have a slightly greater minimum alveolar concentration than control mice. Anesthesiology 2004; 101:544-546.
(3.) Cunningham AL, Jones CP, Ansell J, Barry JD. Red for danger: the effects of red hair in surgical practice. BMJ 2010; 341:c6931.
(4.) Rees JL. Genetics of hair and skin color. Annu Rev Genet 2003; 37:67-90.
(5.) Valverde P, Healy E, Jackson I, Rees JL, Thody AJ. Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet 1995; 11:328-330.
(6.) Healy E, Jordan SA, Budd PS, Suffolk R, Rees JL, Jackson IJ. Functional variation of MC1R alleles from red-haired individuals. Hum Mol Genet 2001; 10:2397-2402.
(7.) Raimondi S, Sera F, Gandini S, Iodice S, Caini S, Maisonneuve P et al. MC1R variants, melanoma and red hair color pheno type: a meta-analysis. Int J Cancer 2008; 122:2753-2760.
(8.) Beaumont KA, Shekar SN, Newton RA, James MR, Stow JL, Duffy DL et al. Receptor function, dominant negative activity and phenotype correlations for MC1R variant alleles. Hum Mol Genet 2007; 16:2249-2260.
(9.) Flanagan N, Healy E, Ray A, Philips S, Todd C, Jackson IJ et al. Pleiotropic effects of the melanocortin 1 receptor (MC1R) gene on human pigmentation. Hum Mol Genet 2000; 9:25312537.
(10.) Sulem P, Gudbjartsson DF, Stacey SN, Helgason A, Rafnar T, Magnusson KP et al. Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 2007; 39:14431452.
(11.) 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; 260:488-491.
(12.) Schaffer JV, Bologna JL. The melanocortin-1 receptor; red hair and beyond. Arch Dermatol 2001; 137:1477-1485.
(13.) Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV, Lariviere WR et al. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc Natl Acad Sci USA 2003; 100:4867-4872.
(14.) Liem EB, Joiner TV, Tsued AK, Sessler DI. Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads. Anesthesiology 2005; 102:509-514.
(15.) Delaney A, Keighren M, Fleetwood-Walker SM, Jackson IJ. Involvement of the melanocortin-1 receptor in acute pain and pain of inflammatory but not neuropathic origin. PLoS One 2010; 5:e12498.
(16.) Mogil JS, Ritchie J, Smith SB, Strasburg K, Kaplan L, Wallace MR et al. Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans. J Med Genet 2005; 42:583-587.
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(18.) Mapleson WW. Effect of age on MAC in humans: a meta analysis. Br J Anaesth 1996; 76:179-185.
(19.) Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Validity and reliability of a postoperative quality of recovery score: the QoR-40. Br J Anaesth 2000; 84:11-15.
(20.) Myles PS, Hunt JO, Fletcher H, Smart J, Jackson T. Propofol, thiopental, sevoflurane and isoflurane: a randomized controlled trial of effectiveness. Anesth Analg 2000; 91:1163-1169.
(21.) Gan TJ, Glass PS, Sigl J, Sebel P, Payne F, Rosow C et al. Women emerge from general anaesthesia with propofol/ alfentanil/nitrous oxide faster than men. Anesthesiology 1999; 90:1283-1287.
(22.) Myles PS, McLeod A, Hunt JO, Fletcher H. Sex differences in speed of emergence differences in speed of emergence and quality of recovery after anaesthesia: cohort study. BMJ 2001; 322:710-711.
(23.) Sturm RA, Duffy DL, Box NF, Chen W, Smit DJ, Brown DL et al. The role of melanocortin-1 receptor polymorphism in skin cancer risk phenotypes. Pigment Cell Res 2003; 16:266-272.
(24.) Grimes EA, Noake PJ, Dixon L, Urquhart A. Sequence polymorphism in the human melanocortin 1 receptor gene as an indicator of the red hair phenotype. Forensic Sci Int 2001; 122:124-129.
(25.) Xia Y, Wikberg JE, Chhajlani V. Expression of melanocortin 1 receptor in periaqueductal gray matter. Neuroreport 1995; 6:2193-2196.
Accepted for publication on April 13, 2012.
P.S. MYLES *, F.F. BUCHANAN ([dagger]), C. R. BAIN ([double dagger])
Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Melbourne, Victoria, Australia
* MB, BS, MPH, MD, FCARCSI, FANZCA Director, Department of Anaesthesia and Perioperative Medicine, Alfred Hospital and Academic Board of Anaesthesia and Perioperative Medicine, Monash University.
([dagger]) MB, BS, FANZCA, Consultant Anaesthetist.
([double dagger]) MB, BS, FANZCA, Consultant Anaesthetist, Department of Anaesthesia and Perioperative Medicine, Alfred Hospital and Adjunct Senior Lecturer, Academic Board of Anaesthesia and Perioperative Medicine, Monash University.
Address for correspondence: Professor P. S. Myles, Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Commercial Road, Melbourne, Vic., 3004, Australia. Email: email@example.com
Table 1 Patient characteristics and clinical details for each hair colour group Black Brown Blond Red Variable (n=56) (n=265) (n=115) (n=32) P value Patient sex <0.0005 Male 73 56 40 28 Female 27 44 60 72 Age, y 41 (13) 40 (14) 38 (13) 40 (15) 0.70 Weight, kg 78 (17) 78 (15) 73 (15) 78 (17) 0.020 ASA physical status 0.92 I 75 78 75 78 II 25 22 25 22 Type of surgery 0.24 General 39 41 33 44 Orthopaedic 45 40 39 31 Urological 5.4 3.1 1.7 6.3 ENT 3.6 4.3 11 0 Plastics 7.1 9.0 12 16 Other 0 3.1 2.6 3.1 Extent of surgery 0.012 Minor 18 24 20 3.1 Intermediate 82 69 75 97 Major 0 7.0 5.2 0 Previous PONV 0.5 13 22 28 0.005 Previous motion 5.4 11 7.0 6.3 0.46 sickness Smoking status 0.34 Non-smoker 50 56 52 69 Smoker 16 20 17 9.4 Ex-smoker 34 24 31 22 Alcohol use 0.63 Non-drinker 16 9.4 11 16 Social 82 86 83 81 Heavy 21.8 5.1 6.1 3.1 Values are mean (SD) or %. ASA=American Society of Anesthesiologists, ENT=ear, nose and throat, PONV=postoperative nausea and vomiting. Table 2 Intraoperative characteristics Black Brown Blond Variable (n=56) (n=265) (n=115) Airway Laryngeal mask 63 59 64 Endotracheal tube 37 41 36 Induction dose of 2.5 (0.5) 2.5 (0.5) 2.6 (0.5) propofol, mg/kg Muscle relaxant 38 42 37 Volatile agent Isoflurane 11 7.4 10 Sevoflurane 77 72 70 Desflurane 13 21 19 Nitrous oxide 64 48 44 Age-adjusted MAC 1.3 (0.2) 1.0 (0.3) 1.8 (0.6) Average BIS 38 (9.9) 37 (7.6) 36 (7.0) Fentanyl, mg/kg 1.2 (0.5) 1.2 (0.4) 1.3 (0.5) % of cases 36 47 53 Morphine, mg/kg 0.13 (0.04) 0.13 (0.04) 0.12 (0.04) Anti-emetic prophylaxis 45 53 66 Duration of surgery, min 70 (46) 69 (42) 70 (49) Red Variable (n=32) P value Airway 0.52 Laryngeal mask 50 Endotracheal tube 50 Induction dose of 2.5 (0.5) 0.13 propofol, mg/kg Muscle relaxant 53 0.39 Volatile agent 0.38 Isoflurane 3.1 Sevoflurane 66 Desflurane 31 Nitrous oxide 19 0.001 Age-adjusted MAC 1.3 (0.3) 0.31 Average BIS 38 (8.8) 0.40 Fentanyl, mg/kg 1.5 (0.3) 0.012 % of cases 50 Morphine, mg/kg 0.13 (0.04) 0.62 Anti-emetic prophylaxis 84 <0.0005 Duration of surgery, min 84 (36) 0.38 Values are number (%) or mean (SD). MAC=minimum alveolar concentration, BIS=bispectral index. Table 3 Recovery characteristics Black Brown Blond Characteristic (n=56) (n=265) (n=115) BIS score at wound closure 52 (9.1) 52 (10) 50 (9.4) Time to eye-opening, min 8.4 (4.0) 6.0 (3.5) 6.5 (4.3) BIS score at eye-opening 79 (3.0) 78 (7.6) 78 (4.5) Time to obeying commands, min 9.4 (5.0) 7.0 (6.8) 7.6 (6.4) Recovery room stay, min 36 (13) 36 (13) 36 (13) Shivering 7.1 12 15 Nausea 1.8 4.3 6.2 Vomiting 0 1.2 2.6 Pain score in recovery room 2.1 (2.4) 2.8 (2.8) 3.0 (3.0) Discharge pain score from 3.8 (2.1) 3.8 (2.2) 4.0 (2.3) recovery room Postoperative day 1 pain score 1.5 (1.8) 2.0 (2.2) 2.0 (2.1) QoR-40 score, day 1 184 (18) 186 (15) 185 (16) Red Characteristic (n=32) P value BIS score at wound closure 51 (10) 0.15 Time to eye-opening, min 6.5 (3.3) <0.0005 BIS score at eye-opening 78 (4.8) 0.92 Time to obeying commands, min 7.4 (4.1) <0.0005 Recovery room stay, min 33 (9.3) 0.73 Shivering 6.3 0.37 Nausea 3.1 0.59 Vomiting 3.1 0.47 Pain score in recovery room 2.4 (3.1) 0.24 Discharge pain score from 4.1 (2.1) 0.21 recovery room Postoperative day 1 pain score 1.9 92.1) 0.67 QoR-40 score, day 1 183 (19) 0.74 Values are mean (SD), number (%) or median (IQR). * Pain scores using a verbal rating scale of 0 (no pain) to 10 (worst pain imaginable). BIS=bispectral index, PONV= postoperative nausea and vomiting, QoR-40= 40-item quality of recovery score (maximum score 200), IQR= interquartile range. Table 4 The effect of red hair colour on time to eye-opening and obeying commands, adjusted for age, sex, ASA and duration of surgery Eye-opening recovery ratio (95% CI) * P value Red hair [dagger] 0.82 (0.57-1.19) 0.30 Age 1.0 (0.99-1.01) 0.56 Female sex 2.04 (1.64-2.56) <0.001 Duration of surgery 1.002 (1.000-1.005) 0.096 [double dagger] Obeying commands P value recovery ratio (95% CI) * Red hair [dagger] 1.01 (0.69-1.47) 0.96 Age 1.00 (0.99-1.01) 0.92 Female sex 1.45 (1.16-1.82) 0.001 Duration of surgery 0.999 (0.996-1.002) 0.49 [double dagger] * Derived from the hazard ratio, where a value greater than 1.0 indicates an increased likelihood of faster recovery time. [dagger] Using black or brown hair colour as a reference. [double dagger] Per minute of surgery. ASA=American Society of Anesthesiologists physical status, CI=confidence interval. Table 5a Inhalational anaesthetic and recovery characteristics according to hair colour and patient sex for males Characteristic Black or brown Red (n = 185) (n = 8) P value Age-adjusted MAC 1.29 (0.27) 1.42 (0.34) 0.19 BIS score at wound 52 (9.1) 52 (11) 0.95 closure Time to eye-opening, 7.5 (3.7) 8.7 (4.0) 0.42 min BIS score at eye- 80 (14) 76 (5.5) 0.20 opening Time to obeying 7.9 (4.1) 9.4 (4.3) 0.26 commands, min Values are mean (SD). MAC=minimum alveolar concentration, BIS= bispectral index. Table 5b Inhalational anaesthetic and recovery characteristics according to hair colour and patient sex for females Black or brown Red Characteristic (n = 127) (n = 127) P value Age-adjusted MAC 1.25 (0.26) 1.27 (0.33) 0.73 BIS score at wound 52 (11) 51 (9.5) 0.60 closure Time to eye-opening, 4.9 (3.0) 5.7 (2.7) 0.24 min BIS score at 77 (8.8) 78 (5.6) 0.44 eye-opening Time to obeying commands, 6.9 (9.0) 6.7 (3.8) 0.89 min Values are mean (SD). MAC=minimum alveolar concentration, BIS= bispectral index.
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|Author:||Myles, P.S.; Buchanan, F.F.; Bain, C.R.|
|Publication:||Anaesthesia and Intensive Care|
|Date:||Jul 1, 2012|
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