In 1991, Kapur called postoperative nausea and vomiting (PONV) ‘the big little problem’ of postanaesthesia care.1 Frequently considered a minor postoperative complication, this side effect can have a major impact on affected patients, with hours of distress as well as possible severe sequelae such as tension on suture lines, wound bleeding, increased intracranial pressure, dehydration, electrolyte imbalance and pulmonary aspiration. Although a plethora of antiemetic drugs are available, and the introduction of serotonin (5HT3) receptor antagonists has undoubtedly led to improvements in prophylaxis and treatment, still some 20 to 40% of patients suffer from PONV, with incidences of up to 70 to 80% in high-risk patients.2 This most unpleasant side effect of anaesthesia can prolong the stay in the post-anaesthesia care unit, is a leading cause of unanticipated readmissions following ambulatory surgery, and increases costs.3
Risk factors for PONV such as female sex, nonsmoking status, PONV after previous surgery or motion sickness, and the use of opioids have all been well described.2,4,5 As heritability is underlined by respective family histories and varying PONV rates in cohorts of different ethnicities, more recent studies have focused on the genetic background of patients.2,5–7
Multiple neurotransmitters such as serotonin, dopamine, acetylcholine and histamine are involved, with their genes being possible candidates for analysing PONV susceptibility. Polymorphisms of the serotonin receptors subunit A (HTR3A) and B (HTR3B) as well as the dopamine receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) have been associated with nausea and vomiting before, whereas information on the serotonin transporter (5HTT; SLC6A4 gene) is scarce.8–12 As sample sizes in these trials were mostly small, validation of previous findings in larger cohorts was recommended.9,11–14
As the relevance of biomarkers for current approaches in precision medicine is often questioned, we wanted to investigate both the classical patient-related and clinical risk factors as well as polymorphisms of candidate genes and their association with PONV in routine clinical settings. We hypothesised that in patients undergoing general anaesthesia for major surgery in addition to the classical risk factors known for many years, there are genetic variants associated with PONV. The primary endpoint of this study was the frequency of candidate gene alleles in the three phenotypes: No PONV, Intermediate PONV and Severe PONV.
Materials and methods
The study was designed as a prospective genetic association study focusing on PONV within a project addressing the risk of peri-operative adverse events, and was performed in two independent cohorts from different hospitals. Approval of the study was obtained from the Ethik-Kommission University Hospital of Bonn (Chairperson Prof. K. Racké: No. 028/07, 12 April 2007) and the Kantonale Ethikkommission Bern (Chairperson: Prof. N. Tüller, No. 041/09, 19/5/2009, amendment 21/7/2011). This manuscript conforms to the applicable STROBE/STREGA guidelines. Nonrelated patients of European origin, aged at least 18 years were consecutively recruited during their presurgery evaluation between 2008 and 2010 (Cohort A) and between 2011 and 2016 (Cohort B). Inclusion criteria consisted of patients’ written informed consent, major elective general surgery (abdominal, thoracic), urological, gynaecological or orthopaedic surgery under general anaesthesia, and patients’ ability to understand the purpose of the study and to fill in a postoperative questionnaire. Exclusion criteria were a regional anaesthetic technique during or after surgery, bariatric surgery, a history of vomiting from any organic aetiology, pregnancy, cognitive impairment, drug dependence, psychiatric diseases, preoperative use of antiemetics or chemotherapeutics. Secondary exclusion criteria were the need for prolonged postoperative mechanical ventilation, repeat surgery within 24 h, lacking or insufficient blood sampling, missing genotypes or incomplete clinical data.
Clinical study protocol
General anaesthesia with tracheal intubation and postoperative analgesia were performed according to departmental standards. Propofol, cis-atracurium and fentanyl were used for induction. Anaesthesia was maintained with isoflurane 0.5 to 1.0 (MAC) along with either fentanyl, fentanyl and remifentanil or remifentanil alone, and with cis-atracurium for neuromuscular relaxation. Antiemetic prophylaxis was administered in both hospitals as a single dose or a combination of two or three drugs depending on a patient's risk score (Cohort A: dimenhydrinate, ondansetron and/or metoclopramide; Cohort B: dexamethasone, ondansetron and/or metoclopramide).
Opioid loading doses for postoperative analgesia were given about half an hour before emergence from anaesthesia [piritramide, hydromorphone, morphine or fentanyl intravenous (i.v.)]. Patients were transferred to the PACU wherein antiemetics (ondansetron, dimenhydrinate, droperidol, metoclopramide) and analgesics were administered by the PACU staff as needed. Patients reporting pain scores at least 4 on the numeric rating scale (NRS, 0 to 10) were given opioids either via PCA (bolus dose 1.5 mg morphine equivalent doses, lock-out time 8 min), as an i.v. bolus dose, or as a short infusion, depending on the type of surgery and the patient's pain intensity. In addition, all patients received nonopioids i.v. (dipyrone 5 g day−1, or in case of contraindications, acetaminophen 4 g day−1 or ketorolac 60 mg day−1). Occurrence of PONV was documented by the research team on an hourly basis up to 8 h postsurgery and at 12, 18 and 24 h.
In both sites, patients completed a validated outcome questionnaire 28 to 36 h after surgery.15,16 Peri-operative opioid doses and electronic PCA protocols were used to calculate morphine-equivalent doses. Conversion factors for calculating intravenous morphine equivalents were 100, 5 and 0.6 for morphine versus fentanyl, hydromorphone and piritramide, respectively.17
The aim of this analysis was to compare the frequency of genetic variants as well as clinical variables between three phenotypes: Severe PONV (=clinically relevant PONV considering severity, need for treatment and duration), Intermediate PONV and No PONV. The basis for allocation to one of these groups were the clinical data documented by the research team up to 12 h after surgery, the need for antiemetics administered in the PACU and on the ward, and the results of a validated patient-reported outcome questionnaire.15,16 In this questionnaire highlighting the patients’ perspective of PONV, the subjective severity of nausea was considered as in previous publications.18,19 Patients assessed nausea using a NRS (0 = no nausea, 10 = nausea as bad as it could be). For vomiting, how many times a patient vomited/retched was counted (none, once, twice, three, four times or more). On the basis of these two questions, a composite score was calculated (sum of nausea NRS score + counts of vomiting/retching).
The definition of phenotypes was as follows:
- No-PONV group: Neither nausea nor vomiting was documented by the research team, no antiemetic therapy; neither nausea nor vomiting reported in the patient questionnaire (PONV score = 0).
- Severe PONV group: Nausea and/or vomiting was documented by the research team at least twice; antiemetic therapy was given in the PACU and/or on the ward; the patient reported nausea and/or vomiting in the patient questionnaire (PONV score ≥7).
- Intermediate PONV group: Nausea and/or vomiting was documented once by the research team; no antiemetic or a single antiemetic dose was administered after surgery; the patient reported nausea and/or vomiting of less severity in the questionnaire (composite score < 7). This group also encompassed patients with inconsistent answers, for example PONV documented by the research team and antiemetics received, but no PONV indicated in the patient questionnaire.We choose this three-group model in order to clearly define two extreme groups (No PONV versus Severe PONV), as these are likely to be the most promising for detecting possible associations between genetic variants and clinical phenotypes. Clinical practise demonstrates that many patients only suffer from mild emetic symptoms or even cannot remember the early postoperative period and whether they had PONV or not. Thus, the Intermediate PONV group was introduced as a divider between the two extreme groups.
Blood sampling and genotyping
Blood samples were obtained into EDTA at induction of anaesthesia and stored at -20°C until DNA extraction (QiaAmp DNA Blood Mini Kit; Qiagen, Hilden, Germany). Genotyping was performed in 96-well plates (92 samples from patients, three positive controls, one negative control (LightCycler 480II; Roche Diagnostics, Basel, Switzerland) or as conventional PCR (Thermocycler: TProfessional Standard Gradient 96, Biometra, Jena, Germany) followed by agarose gel electrophoresis, analysing a maximum of 86 samples/batch in the molecular laboratory of the Department of Anaesthesiology and Pain Medicine, University of Bern. Call rates were 100%: replicates of 10% of the samples genotyped showed an error rate of 0.5%.
Thirteen genetic variants within seven candidate genes were analysed: serotonin receptors 3A (HTR3A; rs1176713) and 3B (HTR3B, rs1176744, rs1672717), serotonin transporter (5HTT, SLC6A4 gene; rs4795541, rs25531, STin2), dopamine receptor (DRD2; rs1800497), muscarinic acetylcholine receptor 3 subtype (CHRM3; rs2355230), catecholamine-O-transferase (COMT; rs4633, rs4680, rs6269, rs4818) and the μ-opioid receptor (OPMR1; rs1799971). Details of genotyping and sequences of specific primers and probes appear in Supplemental Digital Content 1, http://links.lww.com/EJA/A204.20–23
The χ2-goodness of fit test was applied to assess Hardy--Weinberg equilibrium for each single nucleotide polymorphism. PONV was treated as an ordinal three-stage factor with the categories No PONV, Intermediate PONV and Severe PONV. Cohen's w was used as the effect size measure for power and sample size estimation.24 In the case of a 1 : 1 allocation between two groups, w values of 0.1, 0.3 and 0.5 represented small, medium and large effect sizes, corresponding to odds ratios (ORs) of 1.22, 1.86 and 3.00, respectively. When testing for association between the categorical variables PONV (none, intermediate, severe) and genotype (wildtype coded as 11, heterozygous as 12, homozygous variant as 22), each with three mutually exclusive categories, and an assumed type I error probability of 0.05 and a power of 80%, a total of 1194 cases are needed to detect a small effect size (w = 0.1) using a contingency test with 4 degrees of freedom. For an effect size of 0.2, only 299 cases are needed. The study was powered to detect small to medium effects.
Ordinal regression analysis with stepwise variable selection using PONV as the outcome variable was set up for each cohort to investigate the association of genetic variants and nongenetic variables with PONV. The modelling was based on the assumption that the categories of PONV were ordered from No PONV to Severe PONV and satisfied the proportional odds assumption. PONV prophylaxis was introduced as a confounding variable. A history of PONV and/or motion sickness was not entered in the model, as it may mask any observed genetic effect, as genetic variants would predispose to PONV in prior surgeries as well.25,26 The effects of the most important genetic and nongenetic factors were reported as ORs with 95% confidence intervals [OR, (95% CI)] to indicate the risk of the predictors. In a second step, association of variables with PONV was investigated separately for males and females.
For an overview, clinical and genetic variables were tested separately for association with the primary endpoint PONV. Normally distributed values were compared by analysis of variance (ANOVA), frequencies by the χ2-test. The Jonckheere–Terpstra trend test or the general independence test (in case of the multicategorical dependent variable PONV) was applied to test for a linear trend in proportions with respect to genotypes, assuming an additive genetic model. All P values were reported on the nominal level, especially the P values of the bivariate statistics between PONV and the single genetic factors. Taking into account that 13 genetic variants were tested – three of them twice (both for a recessive and a dominant genetic model) – a conservative estimate of the overall significance level would be an α = 0.003. Statistical analyses were performed using R v3.2.5 with the libraries genetics v220.127.116.11, coin v1.0–23 and multcomp v1.3–6.
Patient characteristics and surgery-related data
Of the 984 and 1789 patients who gave written informed consent, data from 918 and 1663 could be analysed in Cohorts A and B, respectively (Fig. 1). One hundred and eighty-eight individuals were excluded due to cancellation or postponement of surgery, missing or inconsistent clinical data, missing questionnaires (n = 159), blood samples (25) or genotypes (four). Demographic and anaesthesia-related data are displayed in Table 1. In Cohort A, mainly urological and major general (abdominal) surgery were included, whereas in Cohort B predominantly patients undergoing orthopaedic and general surgery were enrolled. Abdominal surgery was more frequently open surgery in Cohort A, whereas in Cohort B more laparoscopic procedures were included. The high numbers of urological surgery in Cohort A contributed to 66.3% of the patients being male, in contrast to 41.7% in Cohort B.
Postoperative nausea and vomiting and clinical variables
In Cohort A, 10.2% of the patients were allocated to the group Severe PONV, whereas in Cohort B, it was 16.9% (P < 0.001; Fig. 1). This difference was partly due to a higher proportion of women in Cohort B and the known elevated PONV rates in women compared with men. PONV rates were especially high in patients undergoing laparoscopic surgery, which was mainly performed in Cohort B. As expected, the risk factors being female, nonsmoking, younger age and a history of previous PONV and/or motion sickness were associated with PONV (Supplemental Digital Content 2, Table S2, http://links.lww.com/EJA/A204). Opioid doses for postoperative analgesia were significantly higher in the Severe PONV group. Use of intra-operative fentanyl did not differ between phenotypes.
Genetic variables and postoperative nausea and vomiting
Of the patients, 29 had to be excluded due to missing or insufficient blood samples or failed genotyping (Fig. 1). The allele frequencies of the genetic variants and Hardy--Weinberg equilibrium are displayed in Supplemental Digital Content 3, Table S3, http://links.lww.com/EJA/A204. There were no significant differences in genotype distribution between men and women. Bivariate association analyses of genotypes with the phenotype No, Intermediate and Severe PONV revealed an association for genetic variants within the serotonin transporter linked polymorphic region 5-HTTLPR in both cohorts (Table 2 and Supplemental Digital Content 4, Table S4, http://links.lww.com/EJA/A204). The percentage of SS-carriers in the promoter region of 5-HTTLPR was higher in the group Severe PONV (Cohort A: 28.7%; Cohort B: 28.1%, significant at the conservative Bonferroni-adjusted significance level for Cohort B) compared with the Intermediate PONV and No PONV groups. In addition, carriers of 12/12 repeats in STin2 of 5HTT suffered more frequently from PONV in Cohort B than carriers of other genotypes (Table 2).
A comparison of opioid consumption between the different 5-HTTLPR genotypes revealed no difference in intra-operative fentanyl requirements, consumption of morphine equivalents up to 2 h after surgery or total amount of opioids administered in the PACU and on the ward (Supplemental digital content 5, Table S5, http://links.lww.com/EJA/A204).
Ordinal logistic regression analyses
In the separate regression models of the two cohorts, the following variables were positively associated with PONV (Table 3): female sex [Cohort A, OR, (95% CI): 3.6 (2.7 to 4.8), Cohort B, 2.4 (1.9 to 2.9)]; nonsmoking status Cohort A, 1.8 (1.3 to 2.5), Cohort B 1.9 (1.6 to 2.5); SS genotype of the promoter polymorphism of 5-HTTLPR Cohort A, 1.5 (1.1 to 2.1), Cohort B, 1.8 (1.4 to 2.3). In contrast, increasing age was protective. Patients undergoing laparoscopic surgery were at a higher risk of PONV in Cohort B, but in Cohort A, the number of patients undergoing laparoscopic surgery was too low to reveal significant differences (Table 3). The possible confounder PONV prophylaxis was only significant in Cohort B, with prophylaxis being more frequent in the Intermediate and Severe PONV groups compared with the No PONV group. In addition, longer duration of surgery and increasing morphine doses were associated with PONV in Cohort B (Table 3).
After stepwise variable selection, the sex-specific analysis revealed 5-HTTLPR as the only genetic variable included in the model for women: Cohort A, 1.8 (1.1 to 3.1), P = 0.025; Cohort B, 1.6 (1.2 to 2.4), P = 0.004. For men, results for 5-HTTLPR were in line with this: Cohort A, 1.5 (0.98 to 2.2), P = 0.06; Cohort B, 2.0 (1.4 to 3.0), P = 0.0003. VNTR STin2 of 5HTT in men was only significantly associated with PONV in a combined analysis of Cohorts A and B, 1.3 [(1.03 to 1.6), P = 0.029].
This prospective association study performed in two independent and different cohorts in routine clinical settings focused on genetic variants of neurotransmitters involved in the multifactorial adverse event, PONV. In both cohorts, the SS genotype of 5-HTTLPR was independently associated with PONV.
This study design is special in that the cohorts were chosen by consecutive inclusion of patients from routine peri-operative medicine in two different university hospitals. Thus, cohorts differ in sex, surgery, anaesthesia, analgesia and prophylaxis of PONV, representing real clinical life rather than artificial study settings.
Genetic variants and postoperative nausea and vomiting
Genetic susceptibility is one focus of the current Precision Medicine Initiative, which evaluates the complex mechanisms underlying patient health and disease in order to improve prediction and enable personalised and cost-effective therapy.27 No widespread translation of genetic findings into clinical anaesthesia practise has taken place up to now. There are multiple reasons for this. Among them are the complexity of the field, the lack of cost--benefit analyses and insufficient knowledge. Identifying patients at risk of PONV via biomarkers may contribute to future precision medicine.
A comparison of the present results with previous reports has limitations, as patient characteristics, clinical settings and phenotype definition vary considerably.9,11–14,25,26,28 In this study, some previous positive associations with PONV could not be replicated (e.g. the association of DRD2, HTR3B and OPMR1), nor could we replicate the results of the only genome-wide association study (CHRM3) investigating PONV published to date.8,10,12–14,25,26,28 In the past, the number of patients enrolled in these studies was rather small, resulting in low statistical power. The lack of reproducibility of some positive biomarker findings underlines the need for ‘real life’ cohort studies to test for usability of those markers in daily practice.
The monoamine neurotransmitter serotonin regulates several biological functions and has been linked to some psychiatric disorders and their pharmacological response as well as to migraines and fibromyalgia.29,30 In addition, serotonin is a key transmitter within the PONV pathway,31 which makes serotonin receptors and transporters promising candidate genes for association studies. The bi-allelic polymorphism of HTT [5-HTTLPR (5-HTT-linked polymorphic region)], a 44-bp insertion/deletion resulting in the L or S allele, is crucial for the regulation of serotonin concentrations.30 The S allele is associated with decreased transcriptional rates and lower expression of HTT-mRNA and HTT transporters in membranes, finally reducing 5-HT reuptake from the synaptic cleft into presynaptic neurons.22,30 In earlier research on breast cancer patients, the analysis was extended to an A/G base exchange (rs25531), resulting in a tri-allelic 5-HTTLPR polymorphism (alleles La, Lg and S).12 An association between La/La carriers and postdischarge PONV was detected, a finding we could not replicate. In the present study, both the LL genotype and the La/La genotype were associated with no PONV, whereas the SS genotypes resulting in low 5-HTT expression showed increased PONV rates. Pronounced remifentanil effects measured by a decrease in pain intensity have been reported from an experimental setting in individuals carrying the SS genotype,31 which might support varying opioid sensitivity considering analgesia and side effects.
VNTR in STin2, a variable number of tandem repeats in the second intron of 5HTT (SLC6A4), results in the main alleles with 10 and 12 repeats. The 12 repeats variant shows increased transcriptional activity,32 with varying results in studies considering personality traits, abuse, psychiatric disorders and efficacy of antidepressants.33 No studies on PONV are available so far. Interestingly, a meta-analysis reported an increased risk of migraine in 12/12 genotypes.34 As migraine can be accompanied by emesis, it appears that the present results with more PONV in 12/12 carriers might be in line with these previous findings.
For the rare allele rs1176713 of HTR3A, a 2.9-fold increased risk of postoperative vomiting has been described,11 with conflicting results from a Chinese study.9 The present results show a trend in line with the latter (n.s.); however, significance of rs176713 for PONV was confirmed only in the bivariate statistics of Cohort B. In the largest study on nausea and vomiting, 1597 cancer patients under opioid medication were enrolled8: of the 96 SNPs analysed in 16 genes, carriers of the T allele of rs1672717 in HTR3B had less nausea and vomiting.8 A similar trend was observed in the present trial.
Considering the predictive value of genetics compared with clinical variables, the analysis of both cohorts showed consistent results. Female sex was the leading factor for PONV, which is in line with published data and everyday clinical experience. The 5-HTTLPR genotype showed a stronger association in terms of ORs than patient's age, or amount of opioids for postoperative analgesia, or laparoscopic surgery.
Clinical aspects and postoperative nausea and vomiting
In both cohorts, PONV prophylaxis was inconsistently performed, a fact underlining findings from other authors also demonstrating inadequate implementation of the recommended risk-adapted approach.35 There is currently no validated tool to categorise the outcome of PONV for distinct phenotypes to be used in genetic association studies. In the past, each research group employed its own definition, thus rendering comparison of trials difficult.
Some PONV episodes are mild, transient and inconsequential, and the use of cut-offs to define clinically significant PONV from the patient's viewpoint is emphasised.18 Thus, apart from documentation by study nurses, the patient questionnaire asking for subjective nausea intensities by NRS scores and episodes of vomiting/retching to clearly define the extreme phenotypes No PONV versus Severe PONV was a key measure in the present trial. This does not mean that intermediate PONV is ‘unimportant’ and can be neglected. Emesis should be managed rigorously in any individual complaining of this side effect. Of the study cohort, 10.2% (Cohort A) and 16.9% (Cohort B) of the patients were allocated to the Severe PONV group, a proportion somewhat comparable to previously reported frequencies ranging from 14 to 19%.18,19,36
Study limitations and strengths
Pharmacogenetics, with possible variance in the metabolism of antiemetics (e.g. ondansetron), which might influence efficacy of antiemetic treatment,26,37 was not considered in this analysis. To avoid confounding of population stratification by ethnicity,7 we included only patients of European ancestry. The extent to which the results are transferable to other ethnicities has to be subject of further studies.
Our study design is special in that cohorts were chosen by consecutive inclusion of patients from routine peri-operative medicine in two different university hospitals, representing a real-life clinical scenario rather than an artificial study setting. It has to be clearly stated that the second cohort was not intended to be a replication cohort with exactly the same structure of the patients enrolled and the same surgical procedures, but, in contrast, rather an independent validation cohort enrolled in a different hospital displaying different types of surgeries, a different mix of patients in terms of sex and age, and different preferences for anaesthesia and analgesia. This fact may be judged as a limitation of the trial; however, it rather strengthens the validity of the results, as in two different settings, similar associations were detected. Thus, the results appear to be more robust, as they support the relevance of genetic predisposition to PONV in two independent cohorts that reflect everyday clinical practise in the two respective institutions.
In two cohorts undergoing different surgical procedures in two different hospitals, in addition to the well described nongenetic clinical factors, the SS genotype of 5-HTTLPR was independently associated with PONV. Whether this genetic variant might serve as a potential biomarker for better risk prediction of PONV and whether it can be used in everyday clinical practice for personalised prophylaxis and treatment awaits further clinical studies.
Acknowledgements relating to this article
Assistance with the study: We acknowledge the excellent technical assistance of Makbule Kobilay (Department of Anaesthesiology and Intensive Care Medicine, University of Bonn, Germany), Marcel Schiff and Sibylle Rohrbach (Department of Anaesthesiology and Pain Medicine, University of Bern). Furthermore, we thank the study nurses Béatrice Kobel and Fabienne Tornare as well as Jeannie Wurz for careful editing of the manuscript.
Financial support and sponsoring: This work was supported by a grant from the foundation Research in Anaesthesia and Intensive Care Medicine of Bern University Hospital.
Conflict of interests: US received honoraria and reimbursement for travel costs from Syntetica and Grünenthal.
Presentation: Data of this study were presented in part at the Swiss National Anaesthesia Congress (SGAR), 9 to 11 November 2017, Interlaken, Switzerland.
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