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The Gly16 Allele of the Gly16Arg Single-Nucleotide Polymorphism in the ß2-Adrenergic Receptor Gene Augments Perioperative Use of Vasopressors: A Retrospective Cohort Study

Nielsen, Morten MD; Staalsoe, Jonatan M. MD, PhD; Ullum, Henrik MD, PhD; Secher, Niels H. MD, PhD; Nielsen, Henning B. MD, PhD; Olsen, Niels V. MD, PhD

doi: 10.1213/ANE.0000000000001167
Anesthetic Pharmacology: Research Report

BACKGROUND: Arterial hypotension is frequent in patients undergoing anesthesia and may aggravate the outcome. Common genetic variations may influence the cardiovascular response to anesthesia. In this retrospective cohort study, we tested whether variation in the gene encoding the β2-adrenergic receptor (ADRB2) influences perioperative arterial blood pressure and consequently the use of vasopressors.

METHODS: Five hundred seventy-one Danish Caucasians undergoing neurosurgery were genotyped for 5 marker single-nucleotide polymorphisms (SNPs) within ADRB2 (Gly16Arg, Gln27Glu, Thr164Ile, Arg175Arg, and Gly351Gly). A pairwise tagging principle was used to identify ADRB2 haplotypes. Mean arterial blood pressure (MAP) was recorded in the supine awake state and, together with administration of vasopressors (ephedrine and/or phenylephrine), for 30 minutes after induction of general anesthesia (sevoflurane/remifentanil or propofol/remifentanil).

RESULTS: Four hundred thirteen (72%) patients received ephedrine and/or phenylephrine. Only baseline MAP (P < 0.001) and the Arg175Arg SNP (P = 0.01) were associated with nadir perioperative MAP. The Gly16Arg SNP but no other SNPs showed a trend toward an association with the amount of vasopressors used during anesthesia with Arg16 homozygotes receiving less ephedrine equivalents. The Arg16-Gln27-Thr164-Arg175-Gly351 haplotype was associated with approximately 13% lower vasopressor requirements than the most common Gly16-Glu27-Thr164-Arg175-Gly351 haplotype (P = 0.01).

CONCLUSIONS: Gly16 carriers received larger amounts of vasopressor compared with Arg16 homozygotes. This corresponds to previous studies demonstrating that the Gly16 allele in ADRB2 is associated with vasodilation and high cardiac output.

Published ahead of print January 14, 2016

From the *Department of Neuroanesthesia, The Neuroscience Centre, Department of Clinical Immunology, Centre of Clinical Investigation, and Department of Anesthesia, The Abdominal Centre, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark; and §Department of Neuroscience and Pharmacology, The Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.

Accepted for publication December 15, 2015.

Published ahead of print January 14, 2016

Funding: This work was supported by The Research Board of Copenhagen University Hospital (Rigshospitalet).

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Niels V. Olsen, MD, PhD, Department of Neuroanaesthesia 3042, The Neuroscience Centre, Copenhagen University Hospital (Rigshospitalet), 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. Address e-mail to nvolsen@sund.ku.dk.

Arterial hypotension is a frequent adverse effect of most anesthetic drugs1,2 and may aggravate outcome.3 Perioperative hypotension has been shown to correlate with postoperative morbidity and mortality.4,5 A decrease in arterial blood pressure after induction of anesthesia varies among patients and may depend on variation in the gene encoding the β2-adrenergic receptor (ADRB2).6 In healthy subjects, the Gly16 allele of the Gly16Arg single-nucleotide polymorphism (SNP) in ADRB2 is associated with larger cardiac output at rest and during exercise compared with the Arg16 allele.7–12 There is controversy, however, as to the effect of other SNPs in ADRB2 on cardiovascular regulation, especially the Gln27Glu SNP.8,9,13–15 Frey et al.16 evaluated the effect of ADRB2 variation on the arterial blood pressure response to thoracic epidural and general anesthesia and reported that both the Gly16 and the Gln27 alleles are associated with increased perioperative requirements for vasopressors. However, of the 2 ADRB2 SNPs, the Gln27 appeared to be most important.16

Table 1

Table 1

A haplotype is a combination of alleles at multiple loci that tend to be inherited together within a block of an individual chromosome (Table 1). The bronchodilator response to β2-agonist inhalation17 and body mass index (BMI)18 are associated with specific ADRB2 haplotypes but not with any individual SNP. Along with studies of isolated SNPs, the use of haplotype analysis may add information about the effects caused by interaction of multiple SNPs.19 The aim of this retrospective study was to investigate a possible association of common genetic variation within the ADRB2 with the arterial blood pressure response to anesthesia with propofol/remifentanil or sevoflurane with either remifentanil or fentanyl and thus the vasopressor requirement. A pairwise tagging principle was used to select 5 marker SNPs within ADRB2 [Gly16Arg (46G>A), Gln27Glu (79C>G), Thr164Ile (491C>T), Glu175Glu (523C>A), and Arg351Arg (1053G>C)] for the analysis of both individual SNPs and haplotypes.7,18

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METHODS

Study Population

Five hundred seventy-one unrelated Caucasian patients (at least second-generation Scandinavians) undergoing elective neurosurgery and who had volunteered to donate a blood sample for inclusion in an institutional database were included in this retrospective study. The study was approved by the Regional Ethical Committee of Copenhagen Region (J. nr. H-4-2014-020), and written informed consent was obtained from all patients. To reach a statistical power of 0.80 and an overall 2-sided significance level of 0.05, approximately 600 patients were considered to be included. This is based on an assumption that anesthesia with propofol/remifentanil or sevoflurane with either remifentanil or fentanyl induces hypotension (mean arterial blood pressure [MAP] <60 mm Hg) in 40% of the patients unexposed to the candidate minor allele, an estimated relative risk of hypotension of 1.5 by carriage of at least 1 copy of the minor allele, and an estimated frequency of minor alleles of 10%.20

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Anesthesia

All patients were anesthetized according to a protocol for each type of elective surgery. Two types of general anesthesia were used: total IV anesthesia with propofol and remifentanil for spinal surgery, and sevoflurane combined with remifentanil or fentanyl for intracranial surgery.

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Propofol/Remifentanil

Propofol (10 mg/mL) was used both as a bolus dose (2 mg/kg) and for infusion (5 mg/kg/h). Remifentanil (60 μg/mL) was used for infusion (30 μg/kg/h). With loss of the ciliary reflex and apnea and free passive movement of the lower jaw, tracheal intubation was performed without the use of muscle relaxants.

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Sevoflurane/Remifentanil

At the time of induction of anesthesia, infusion of remifentanil (20 μg/kg/h) was started and bolus thiopental (5 mg/kg) administered. A free airway was secured after neuromuscular blockade by cisatracurium (0.15 mg/kg). The patients were intubated after at least 2 minutes preceded by a supplementation dose of thiopental (1 mg/kg).

The inspired oxygen fraction was 80%, and minute ventilation was 400 to 600 mL tidal volume, frequency 12 and adjusted to maintain a PCO2 between 4 and 4.5 kPa. O2 saturation was at all times between 98% and 100%. Isotonic saline, plasma expanders, fresh frozen plasma, platelets, and packed red blood cells were provided on indication, independent of study protocol. According to guidelines, ephedrine (EP) or phenylephrine (PE) was administered if MAP was reduced by >25% or decreased <60 mm Hg. The timing and the type of any treatment procedure were at the discretion of an anesthesiologist who was not an investigator. Only MAP values recorded before administration of EP and/or PE were used for analyses in the present study.

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Arterial Blood Pressure, Vasopressor Dosage, and Clinical Covariates

MAP was measured by a Hewlett Packard M1094B monitor (Palo Alto, CA). In patients scheduled for intracranial surgery, a radial artery catheter was introduced after induction of anesthesia and the MAP was measured (Hewlett Packard M1094B). MAP values and the total amount of EP and/or PE administered for 30 minutes after induction of anesthesia were extracted from each anesthesia chart. MAP measured in the awake patient immediately before the induction of anesthesia served as baseline. As a measure of the degree of hypotension, we used both nadir of MAP and percentage decrease in MAP as primary end points. Obviously, however, both these are directly affected by administration of vasoactive agents. Doses of PE were recalculated to EP dose equivalents (EE) as: EE = EP + 81.2 × PE.21 We also analyzed the influence of age, sex, alcohol abuse (self-reported intake of >21 standard drinks per week), BMI, arterial hypertension (subjects receiving antihypertensive treatment at the time of admission), smoking, type of anesthesia, type of surgery, and MAP before anesthetic induction.

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Selection of SNPs in ADRB2

Figure 1

Figure 1

Selection of tagging SNPs for the ADRB2 genes was done using the information in HapMap (www.HapMap.org), and the SNP genotype data from Caucasians analyzed in Haploview 4.0 (www.broadinstitute.org/haploview). The tagging SNPs were selected by pairwise tagging in Haploview with default setting (r2 ≥ 0.8; mean maximum r2 = 0.967). The haplotype blocks, as shown in haploview with default setting, are covered with the selected SNPs (Fig. 1). The 5 selected SNPs in ADRB2 were likewise presumed to determine the major haplotypes with a frequency >1% in Caucasians.17,22

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Isolation of Genomic DNA and Genotype/Haplotype Analysis

Whole-blood samples were collected perioperatively in EDTA vacuum tubes for isolation of genomic DNA. Genomic DNA was purified from 200-μL frozen whole blood by the magnetic bead–based MagneSil® Blood Genomic, Max Yield System (Promega, Madison, WI). Genotyping of the 5 SNPs was performed using predeveloped TaqMan Genotyping Assays (Thermo Fisher Scientific, Inc., Waltham, MA), and analyses were made using real-time polymerase chain reaction by an Applied Biosystem 7500 Fast Real-Time Polymerase Chain Reaction Device according to the instructions given by the manufacturer (Applied Biosystem, Lincoln, CA). Twelve samples within each 96-well plate were randomly chosen for repeated genotyping of each SNP. The agreement was 100%.

Assigning of haplotypes from the unphased genotype data was estimated using a Bayesian approach implemented with PHASE version 2.1.23,24 Positions of polymorphisms in each gene were given as the contig position numbers obtained from www.ncbi.nlm.nih.gov and used in the input file of PHASE for computation of haplotypes. The software program estimates the haplotype frequencies in the sample population, the confidence interval, and the haplotype pair for each individual (http://www.stat.washinton.edu/stephens/sofware.html).

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Statistical Methodology

Statistical analysis was performed using R 3.0.3 (R Core Team, Vienna, Austria). Statistical significance was accepted at the 5% level using 2-sided tests. Haplotype analysis was performed using the haplo.stats R package (Sinnwell JP and Schaid DJ, 2013, version 1.6.8, http://CRAN.R-project.org/package=haplo.stats). This package uses an expectation-maximization procedure to estimate haplotype frequencies and also provides options for analyzing these in context with generalized linear models. Deviations from Hardy-Weinberg equilibrium were tested using the exact test.

Association between genetic variants and MAP was tested using a linear model with baseline MAP and genetic group as predictor variables with dominant, recessive, and additive effects (analysis of covariance). The model allows for testing of a potential difference in perioperative MAP between genotypes in individuals with identical baseline MAP. Other potential covariates were included in initial models and eliminated stepwise. Normality assumptions were checked with various plots of model residuals. P = 0.11 for Shapiro-Wilk normality test of standardized residuals.

The analysis of vasopressor doses was complicated by the fact that a part of the population did not receive vasopressor and that vasopressor dosage tends to have a digit bias (only administrated in increments of 5 mg). Vasopressor doses were highly skewed, thus violating normality assumptions (Fig. 2). Therefore, we used a 2-step strategy. First, we analyzed the probability (risk ratio) of receiving vasopressor with a modified Poisson regression approach.25 Second, we analyzed the log-transformed vasopressor doses with parametric linear models to achieve estimates of the differences between groups and with nonparametric models (Kruskal-Wallis test) to assess the reliability of the P values of the parametric models. The Bartlett test for homogeneity of variances on the log-transformed doses between genotypes was P = 0.55. Furthermore, residual analysis revealed no signs of variance heterogeneity on the log-transformed scale, which could potentially lead to bias in the backtransformed estimates.26 Estimates of differences between groups were achieved by taking the exponential function of the linear regression estimates and confidence intervals of the log-transformed vasopressor doses versus predictors.

Figure 2

Figure 2

To correlate for multiple comparisons, we considered P < 0.01 as significant according to recommendations described by Johnson.27

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RESULTS

Genotypes

Table 2

Table 2

Table 3

Table 3

Characteristics of the study population are listed in Table 2, and the allelic distribution of the 5 ADRB2 polymorphisms is given in Table 3. Genotype data were missing in <1% of the material. All polymorphisms were in Hardy-Weinberg equilibrium. Age, alcohol abuse, BMI, antihypertensive treatment, baseline MAP, smoking, sex, type of surgery, or type of anesthesia was not associated with distribution of the polymorphisms.

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Haplotype Structure

Table 4

Table 4

The 5 SNPs in the ADRB2 gene were organized into 9 distinct haplotypes (Table 4). Four haplotypes had frequencies higher than 10% and accounted for 91% of the total number of haplotypes. The present haplotypes correspond closely to those described in Danish Caucasians.7,22

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MAP and Vasopressor Requirements

Immediately before anesthesia, MAP was 99 ± 14 mm Hg (baseline, mean ± SD). The nadir in MAP after anesthetic induction was 57 ± 8 mm Hg, and the decrease in MAP was 41 ± 15 mm Hg or a decrease by 41% ± 11%. There was no correlation between baseline MAP and vasopressor requirement (Spearmans ρ = 0.07; P = 0.1). Baseline MAP was 5 mm Hg higher in men than in women (P < 0.001; CI99, 2–8 mm Hg). Four hundred thirteen (72%) patients received EP and/or PE. The one patient anesthetized with propfol/fentanyl was pooled with the propofol/remifentanil group in the following analysis. The distribution of vasopressor doses was highly skewed (Fig. 2).

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Clinical Covariates

Patients anesthetized with sevoflurane/remifentanil required vasopressors in 81% of cases compared with 69% in the propofol/remifentanil group and 71% in the sevoflurane/fentanyl group (PFisher = 0.008). Thus, the risk ratio for requiring vasopressors with sevoflurane/remifentanil versus propofol/remifentanil was 1.16 (CI99, 1.02–1.32, PPoisson = 0.004). Also, the sevoflurane/remifentanil group received more EP equivalents than patients anesthetized with propofol/remifentanil or sevoflurane/fentanyl (median: 20 mg versus 10 and 15 mg, respectively; PKruskal-Wallis < 0.001). Analyzing the log-transformed vasopressor doses (to comply with normality assumptions) in patients receiving vasopressors showed an approximately 21% increased vasopressor requirement on average in patients anaesthetized with sevoflurane versus propofol CI99, 1%–44%, Pt test = 0.006). In summary, patients anesthetized with sevoflurane/remifentanil were more likely to receive vasopressors and when so, they were treated with dosages approximately 20% larger than with the other anesthetic regimen.

The probability of receiving vasopressors increased with age (PPoisson < 0.001) corresponding to a risk ratio of 1.17 (CI99, 1.11–1.23) per decade. Also, the amount of vasopressor (EE) increased by approximately 13% (CI99, 6%–20%) per decade (P < 0.001). Of those patients with arterial hypertension, 83% received vasopressors compared with 69% in the normotensive group (risk ratio 1.21; CI99, 1.06–1.38; PPoisson < 0.001). Also patients with arterial hypertension were administered approximately 45% higher doses of vasopressor than normotensive patients (CI99, 19%–75%; P < 0.001).

Sex, BMI, type of surgery, or smoking was not associated with a decrease in MAP or vasopressor requirement. None of the covariates was associated with nadir MAP in univariate regression models adjusted for baseline MAP. The nadir MAP was associated with the administration of vasopressors such that patients receiving vasopressors had a nadir MAP 4 mm Hg lower than those that did not receive vasopressors (CI99, 2–6 mm Hg; P < 0.001). Baseline MAP was associated with the nadir of MAP after induction of anesthesia (MAPnadir = 47 mm Hg + 0.1 × MAPbaseline; P < 0.001).

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MAP and ADRB2

The Arg175Arg (C523A) genotype was associated with nadir MAP adjusted for baseline MAP (PANOVA = 0.01). Within the Arg175Arg (C523A) genotype, nadir MAP was 6 mm Hg lower in the A523A homozygotes than in C523C homozygotes (P = 0.003; CI99, 1–11 mm Hg). None of the other SNPs showed a significant association with nadir MAP after induction of anesthesia. Haplotype 7 (Gly16-Glu27-Thr164-Arg175-Gly351) was trending toward an association with the degree of hypotension with a nadir MAP of 6 mm Hg lower than that of the most common haplotype 1 (Gly16-Glu27-Thr164-Arg175-Gly351; P = 0.03; CI99, −1 to 12 mm Hg, dominant model). These results, however, were not significant when correlating for multiple comparisons. None of the other haplotypes differed in nadir MAP compared with the most common haplotype.

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Vasopressor Administration and ADRB2

Figure 3

Figure 3

However, not statistically significant, when correlating for multiple comparisons (as described in the Methods section), there was a trend toward an association between the Gly16Arg polymorphism and the vasopressor dosage (PANOVA = 0.015), with the Arg16 homozygotes receiving approximately 24% less EE than the Gly16 homozygotes (P = 0.01; CI99, 0%–42%). None of the other 3 ADRB2 polymorphisms showed any trend toward association with vasopressor dosage. The Arg16-Gln27-Thr164-Arg175-Gly351 haplotype was associated with an approximately 13% lower vasopressor requirement than the most common Gly16-Glu27-Thr164-Arg175-Gly351 haplotype (P = 0.01). None of the other haplotypes was significantly different from the most common haplotype with regard to vasopressor requirement (Fig. 3).

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Multivariate Regression Model of Vasopressor Dosage

Table 5

Table 5

A multiple regression model of log-transformed vasopressor doses was build including gly16gly genotype, type of anesthesia, age, BMI, sex, smoking, and arterial hypertension with all 2-way interactions as covariates. Stepwise backward regression based on the Akaike information criterion was applied to arrive at a final model. The model had interaction between sevoflurane anesthesia and the Gly16Gly genotype, indicating that patients with both effects were given approximately 33% (CI99, −7% to 90%) more EP equivalents than would be predicted for the individual effects of genotype and type of anesthesia. This contrasts to the approximately 5% (CI99, −16% to 32%) increased vasopressor dose in Gly16Gly homozygotes subjected to propofol anesthesia (Table 5).

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DISCUSSION

This retrospective study suggests that genetic variation in the gene encoding the ADRB2 is important for the regulation of perioperative hemodynamics after induction of general anesthesia. Besides ADRB2 variation, also type of anesthesia, age, and presence of arterial hypertension in neurosurgical patients predicted perioperative requirements of vasopressors. Carriers of the Gly16 allele of the ADRB2 Gly16Arg polymorphism received higher doses of EP equivalents compared with Arg16 allele carriers; however, these findings were not statistically significant when correlating for multiple comparisons. Similar findings were also observed in patients anesthetized for abdominal surgery with a combination of thoracic epidural analgesia and general anesthesia (thiopental, rocuronium, fentanyl, and isoflurane).16 In patients anesthetized by spinal blockade, the Gly16 allele was predictive of perioperative hypotension, along with preexisting bradycardia and concomitant use of spinal clonidine.28

In contrast to the study by Frey et al.16 but in accordance with Zaugg et al.,28 we did not find an effect of the Gln27Glu polymorphism. The current analysis of ADRB2 haplotypes showed that the presence of both the Gly16 and the Glu27 alleles in haplotype 1 (Table 4) was linked with higher doses of vasopressor compared with possession of Arg16 and Gln27 in haplotype 2. However, vasopressor requirement was not altered by haplotype variation of the Gln27Glu SNP, and, taken together, the present data may suggest that the Gly16Arg SNP is the main contributor to the effect of ADRB2 variation on perioperative dosage of vasopressor.

The current results are consistent with findings in healthy subjects, indicating that the presence of the Gly16 allele is associated with greater cardiac output and β2-mediated vasodilatation.7,9–12,29 Compared with Arg16 homozygotes, subjects homozygous for Gly16 showed more systemic vasodilatation in response to β2-adrenergic agonists29 and had an augmented forearm blood flow response to β2-adrenergic agonists30,31 and mental stress and handgrip.15 The effect of Gly16 on peripheral vessels is, in part, mediated via the endothelial nitric oxide system.30 The difference in functional response among Gly16Arg genotypes is compatible with analyses in isolated human lymphocytes showing increased density of β2-adrenergic receptors in Gly16 homozygotes compared with Arg16 homozygotes.29 This agrees with the study of Drysdale et al.17 reporting increased ADRB2 density and mRNA expression in human embryonic kidney cells transfected with haplotypes containing the Gly16 allele. Further downstream, the mechanisms may involve reduced agonist-mediated desensitization and degradation of Gly16 receptor isoforms compared with Arg16 isoforms.32,33

Results from studies assessing the functional impact of ADRB2 polymorphisms are not unanimous. In healthy subjects, normotensive Caucasians possession of the Gly16 allele was associated with attenuated vasodilatation after systemic infusion of β2-adrenergic agonists.34,35 Upon adrenaline infusion in healthy subjects, more vasoconstriction was observed in Gly16 homozygotes compared with Arg16 genotypes.36 Likewise, asthmatic Caucasians with the Arg16-Gln27 haplotype exhibited a greater decrease in diastolic blood pressure after inhalation of salbutamol compared with the Gly16-Glu27 haplotype.37 In line with such functional effects of the Gly16Arg SNP, but in contrast with the present study and other studies,16,28 Smiley et al.38 in a cohort of mixed ethnicities reported that both the Gly16 and the Glu27 alleles were linked with decreased use of vasopressor during spinal anesthesia. In Chinese women, the ADRB2 genotype did not affect the requirements for EP during spinal anesthesia for cesarean delivery.39 Disagreement between studies may be caused by ethnic inhomogeneity because there are marked differences in haplotype patterns among Asians, African Americans, and North-European Caucasians.17,20,22 It is also noteworthy that environmental factors such as the dietary sodium intake may modulate the cardiovascular effects of ADRB2 variation.40

In contrast to previous prospective studies,16,28 we did not observe an association between the Gly16Arg and Gln27Glu SNPs and perioperative MAP. Unexpectedly, however, the synonymous Arg175Arg (C523A) SNP in ADRB2 showed a trend toward an association with the nadir MAP. This may reflect linkage disequilibrium with other SNPs, but the functional significance, if any, remains unknown. The current data revealed that the nadir value of MAP after anesthetic induction is consistent (i.e., 55–60 mm Hg in average) regardless of ADRB2 genotype and clinical covariables (type of anesthesia, age, and antihypertensive medication). The only significant clinical covariable associated with the perioperative nadir of MAP was the preoperative MAP. The use of potent anesthetic drugs, especially remifentanil, is prone to cause marked hypotension that is likely to blunt the contribution of more subtle factors. Thus, the amount of vasopressor used perioperatively to sustain an acceptable MAP may better reflect the inherent cardiovascular status.

Perioperative hypotension and requirement for vasopressors can be viewed as an intermediate physiologic trait that may predict the occurrence of more distant and complex phenotypes including cardiovascular adverse effects and mortality.8,16 There is some evidence to suggest that ADRB2 genetic variation has an impact on cardiovascular health.8,41 In patients with heart failure, the Arg16 allele either alone or combined with the Gln27 allele was associated with an increased risk of adverse outcome.42,43 Survival in a large cohort of patients with acute coronary syndrome was enhanced by the Gly16 allele in the subgroup of African Americans.44 Others, however, report a lack of association between adrenergic receptor genotypes and survival among heart failure patients treated with β-blockers.45 Cardiovascular complications are the main cause of mortality in surgical patients within the first postoperative year,3 and further studies are needed to explore the potential impact of genetic variation.

The immediate clinical implications of this study are sparse. Although our data suggest that there is in fact an association between genetic variations in ADBR2 and perioperative hemodynamics, these effects are easily manageable by using vasopressors.

There are several limitations of this study, and the conclusions should be regarded with caution. MAP measurements were routine evaluations and later retrieved. The retrospective study design undoubtedly resulted in some inaccuracy and imprecision. First, administration of anesthesia and vasopressors was uncontrolled, and the presence of different anesthetics and operation types confound the interpretation. Second, a radial artery catheter for continuous MAP monitoring was used only in patients scheduled for intracranial surgery; moreover, it was inserted after induction of anesthesia, whereas baseline measurements of MAP in all patients were obtained noninvasively. However, all recordings were performed in a double-blinded manner, and measurement was not affected by knowledge of the patients’ genotypes. We also acknowledge as a limitation that pooling patients receiving EP and patients receiving PE could never be completely accurate because there is no true “EP equivalent” for PE. Furthermore, regression analysis was used to assess the significance of each variable and also the large number of subjects in the study population tended to diminish the bias. This study was exploratory, and the statistical models introduced the risk of spurious associations, because there is not yet a strong underlying biological rationale for any genetical trait model with regard to the ADRB2 polymorphisms.

In conclusion, this retrospective study suggests that the ADRB2 Gly16Arg polymorphism is predictive of perioperative vasopressor requirements in patients anesthetized for elective neurosurgery, along with type of anesthesia, age, and concurrent arterial hypertension. Patients with the Gly16 allele received larger amounts of vasopressor, thus indicating a more severe level of perioperative hypotension compared with Arg16 allele carriers. This corresponds to studies describing the Gly16 allele being associated with higher cardiac output and vasodilation.

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DISCLOSURES

Name: Morten Nielsen, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Morten Nielsen has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jonatan M. Staalsoe, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Jonatan M. Staalsoe has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Henrik Ullum, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Henrik Ullum has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Niels H. Secher, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Niels H. Secher has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Henning B. Nielsen, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Henning B. Nielsen has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Niels V. Olsen, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Niels V. Olsen has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

This manuscript was handled by: Ken B. Johnson, MD.

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ACKNOWLEDGMENTS

The authors thank biotechnician Birgit Heine Hansen for skillful laboratory assistance.

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