Risk-tailored prophylaxis for postoperative nausea and vomiting: still a messy issue
2018; Elsevier BV; Volume: 121; Issue: 1 Linguagem: Inglês
10.1016/j.bja.2018.04.004
ISSN1471-6771
AutoresRuth Landau, Piotr K. Janicki,
Tópico(s)Cardiac, Anesthesia and Surgical Outcomes
ResumoMuch has been written about risk stratification and effectiveness of postoperative nausea and vomiting (PONV) prophylaxis, and the challenges so far have consisted in identifying (i) who needs it most (optimal patient screening), (ii) what works best (treatment efficacy), and (iii) how to provide it consistently (process efficiency). We recently read with great interest about the implementation of a simplified non-automated algorithm, offering a pragmatic approach to better prevent a simple yet annoying side-effect of general inhalation anaesthesia, which seemed to result in the largest-ever reported decrease in PONV incidence (10%).1Dewinter G. Staelens W. Veef E. Teunkens A. Van de Velde M. Rex S. Simplified algorithm for the prevention of postoperative nausea and vomiting: a before-and-after study.Br J Anaesth. 2018; 120: 156-163Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Whilst the approach was promising, it raised more questions about the benefits of permissive algorithms, and highlighted the need for an 'increased administration of anti-emetics in very high-risk patients and a more restrictive administration in low-risk patients'.2Kappen T.H. Risk-tailored prophylaxis for postoperative nausea and vomiting: has the big little problem gotten any smaller?.Br J Anaesth. 2018; 120: 9-13Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar We, like others, agree that all efforts to reduce the likelihood of experiencing PONV are laudable, as this anaesthesia-related phenotype disrupts a patient's experience and immediate recovery in up to 40% of people undergoing general anaesthesia. Therefore, the article by Klenke and colleagues published in this issue of the British Journal of Anaesthesia3Klenke S. de Vries G.J. Schiefer L. et al.CHMR3 rs2165870 polymorphism is independently associated with postoperative nausea and vomiting, but combined prophylaxis is effective.Br J Anaesth. 2018; 121: 58-65Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, which proposes to use a validated clinical screening tool, the Apfel score,4Apfel C.C. Laara E. Koivuranta M. Greim C.A. Roewer N. A simplified risk score for predicting postoperative nausea and vomiting: conclusions from cross-validations between two centers.Anesthesiology. 1999; 91: 693-700Crossref PubMed Scopus (1383) Google Scholar alongside genetic testing, appeared as a savvy way to improve our ability to identify the subset of patients most at risk and most likely to benefit from PONV prophylaxis. In fact, the authors hypothesised that genetic factors independently increase the risk for PONV, which would explain why a proportion of patients, despite an a priori low risk for PONV but in the context of a particular genetic blueprint, may nonetheless experience PONV. To test the simple hypothesis that experiencing PONV despite lacking clinical risk factors is caused by the presence of genetic variants associated with that phenotype, a large observational study would suffice. With this concept in mind, screening patients with the Apfel score and establishing who was not at risk (approximately 50% of individuals typically fall into this category) but did experience PONV (up to 40% of patients but not necessarily those identified initially), and then assessing the genetic profile in these 'mismatched' individuals would provide valuable information about the genetic contribution to this common phenotype. The next step would then be to propose an effective regimen for this subset of patients only, without increasing side-effects and adverse events, not to mention costs, in the fortunate patients who should not experience PONV even without PONV prophylaxis. Klenke and colleagues decided not only to evaluate the influence of a genetic variant on PONV risk, but also to examine the effectiveness of a variety of interventions aiming to prevent PONV, which resulted in three treatment arms tested against placebo. The effect of dexamethasone 4 mg i.v. (or placebo) immediately after the induction of general anaesthesia in combination with acustimulation at the P6 point on the wrist (or sham) for 24 h was evaluated in the entire cohort, stratified by Apfel score and genetic risk. Therefore, to test their multiple hypotheses, rather than an observational study, the authors conducted a placebo-controlled randomised clinical study on a cohort of patients undergoing a variety of surgical procedures (gynaecological; ear, nose, and throat; and thyroid) receiving various anaesthetic induction and maintenance regimens. Opioids were given intra- and postoperatively for pain management, and granisetron (3 mg i.v.) was available for rescue of nausea or vomiting. With this ambitious goal, the authors chose to evaluate the influence of one single-nucleotide polymorphism (SNP) located in proximity of the promoter region (rs2165870) for the M3 muscarinic acetylcholine receptor gene (CHRM3) on PONV and the effect of various interventions. The choice of this specific SNP was based on findings from the first genome-wide association study (GWAS) evaluating PONV,5Janicki P.K. Vealey R. Liu J. Escajeda J. Postula M. Welker K. Genome-wide Association study using pooled DNA to identify candidate markers mediating susceptibility to postoperative nausea and vomiting.Anesthesiology. 2011; 115: 54-64Crossref PubMed Scopus (69) Google Scholar which found that patients carrying the minor allele of this SNP had a significantly increased risk for severe PONV compared with patients homozyogous for the wild-type allele. In that GWAS conducted in a North American cohort of 251 Caucasian patients undergoing surgery, PONV phenotype was defined by robust criteria of a repeated history of PONV on at least three occasions after general anaesthesia with inhalation agents; 122 participants in the exploratory GWAS met the criteria for PONV. In a validation cohort of 208 subjects, the risk of experiencing PONV was over two-fold amongst carriers of the minor allele of this SNP located upstream of CHRM3 (using a dominant inheritance model). Therefore, this European study serves as the much-needed independent validation study in a larger cohort of surgical patients. In this cohort, the overall proportion of patients experiencing PONV within 2–6 h after surgery was 37%; as hypothesised, the relative risk was increased to 1.5 with one minor allele (46% of the cohort), and to 1.6 with two minor alleles (12% of the cohort), compared with patients carrying two wild-type alleles (42% of the cohort) of whom 'only' 29% experienced PONV. Whilst this study confirms the previously observed association between this common SNP and PONV risk, the association was not as robust as that described in the GWAS.5Janicki P.K. Vealey R. Liu J. Escajeda J. Postula M. Welker K. Genome-wide Association study using pooled DNA to identify candidate markers mediating susceptibility to postoperative nausea and vomiting.Anesthesiology. 2011; 115: 54-64Crossref PubMed Scopus (69) Google Scholar This may be attributable to a variety of factors, including the fact that the PONV definition was different in the two studies, and the different populations. The authors concluded that the well-established Apfel score and CHRM3 rs2165870 SNP contribute in a similar and independent manner towards PONV susceptibility. However, it is essential to acknowledge that the proportion of 'mismatched' patients, in other words patients screened with a low Apfel score (n=259; 57% of the cohort) but having the genotype associated with highest PONV susceptibility defined here as homozygosity for the minor allele A/A (n=56; 12% of the cohort), was ultimately extremely low (n=31; 6.7%), and that the authors reported that PONV occurred in 'only' 42% of these patients (n=13) (see Fig 1). Looking at the response to the various interventions, and stratifying these 31 'mismatched' patients by treatment allocation (three interventions vs placebo), the PONV rate in the placebo/sham acustimulation group was 71%; however, based on the numbers presented by the authors in Table 1 of their paper, one has to assume that there were <10 patients in that subgroup. In contrast, the combined prophylaxis by dexamethasone with acustimulation resulted in a significant risk reduction with only 10% of patients experiencing PONV (again, this subgroup must have included 5% in the population) on any phenotype, the actual impact observed here is rather limited (∼50% increase in PONV risk) in contrast to the impact of rare genetic variants, where the effect often exceeds three-fold.6Bomba L. Walter K. Soranzo N. The impact of rare and low-frequency genetic variants in common disease.Genome Biol. 2017; 18: 77Crossref PubMed Scopus (195) Google Scholar Therefore, the presence of one (or two) minor allele(s) of the SNP under consideration here explains only a minute fraction of the genetic susceptibility to PONV, and other genetic variants need to be evaluated to fully elucidate the genetic predisposition to PONV and the response to various anti-emetic approaches. The possible role of genetics on the occurrence of PONV emerged more than a decade ago with several pharmacogenetic studies evaluating the analgesic and side-effect profile of opioids. These studies ahowed that pain itself, the analgesic response to opioids, and an array of opioid-induced side-effects are all, to some degree, influenced by genetic factors. Genetic-association studies exploring the response to opioids after surgery reported not only on analgesic effects, but also on opioid-induced nausea and vomiting (OINV),7Sia A.T. Lim Y. Lim E.C. et al.A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia.Anesthesiology. 2008; 109: 520-526Crossref PubMed Scopus (249) Google Scholar and on the response to 5-HT3 serotonin receptor antagonist anti-emetic drugs in the context of general inhalation anaesthesia.8Choi E.M. Lee M.G. Lee S.H. Choi K.W. Choi S.H. Association of ABCB1 polymorphisms with the efficacy of ondansetron for postoperative nausea and vomiting.Anaesthesia. 2010; 65: 996-1000Crossref PubMed Scopus (45) Google Scholar, 9Janicki P.K. Schuler H.G. Jarzembowski T.M. Rossi 2nd, M. Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP2D6 genotype.Anesth Analg. 2006; 102: 1127-1133Crossref PubMed Scopus (41) Google Scholar, 10Ho K.Y. Gan T.J. Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting.Curr Opin Anaesthesiol. 2006; 19: 606-611Crossref PubMed Scopus (89) Google Scholar, 11Janicki P.K. Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting.Med Sci Monit. 2005; 11 (RA322-328)PubMed Google Scholar, 12Candiotti K.A. Birnbach D.J. Lubarsky D.A. et al.The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis?.Anesthesiology. 2005; 102: 543-549Crossref PubMed Scopus (162) Google Scholar, 13Song J.W. Shim J.K. Choi S.H. Soh S. Jang J. Kwak Y.L. Comparison of ramosetron and palonosetron for preventing nausea and vomiting after spinal surgery: association with ABCB1 polymorphisms.J Neurosurg Anesthesiol. 2017; 29: 406-414Crossref PubMed Scopus (11) Google Scholar, 14Babaoglu M.O. Bayar B. Aynacioglu A.S. et al.Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists.Clin Pharmacol Ther. 2005; 78: 619-626Crossref PubMed Scopus (68) Google Scholar In particular, the OPRM1 gene that encodes several mu-opioid receptor isoforms has been extensively studied in the context of OINV and PONV,7Sia A.T. Lim Y. Lim E.C. et al.A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia.Anesthesiology. 2008; 109: 520-526Crossref PubMed Scopus (249) Google Scholar, 15Sugino S. Hayase T. Higuchi M. et al.Association of mu-opioid receptor gene (OPRM1) haplotypes with postoperative nausea and vomiting.Exp Brain Res. 2014; 232: 2627-2635Crossref PubMed Scopus (20) Google Scholar, 16Chen L.K. Chen S.S. Huang C.H. et al.Polymorphism of mu-Opioid Receptor Gene (OPRM1:c.118A>G) Might Not Protect against or Enhance Morphine-Induced Nausea or Vomiting.Pain Res Treat. 2013; 2013259306PubMed Google Scholar, 17Pang G.S. Ithnin F. Wong Y.Y. et al.A non-synonymous single nucleotide polymorphism in an OPRM1 splice variant is associated with fentanyl-induced emesis in women undergoing minor gynaecological surgery.PLoS One. 2012; 7: e48416Crossref PubMed Scopus (6) Google Scholar, 18Zhang W. Yuan J.J. Kan Q.C. Zhang L.R. Chang Y.Z. Wang Z.Y. Study of the OPRM1 A118G genetic polymorphism associated with postoperative nausea and vomiting induced by fentanyl intravenous analgesia.Minerva Anestesiol. 2011; 77: 33-39PubMed Google Scholar along with numerous SNPs of the 5-HT3A and 5-HT3B serotonin receptor genes (HTR3A and HTR3B),19Joy Lin Y.M. Hsu C.D. Hsieh H.Y. Tseng C.C. Sun H.S. Sequence variants of the HTR3A gene contribute to the genetic prediction of postoperative nausea in Taiwan.J Hum Genet. 2014; 59: 655-660Crossref PubMed Google Scholar, 20Ma X.X. Chen Q.X. Wu S.J. Hu Y. Fang X.M. Polymorphisms of the HTR3B gene are associated with post-surgery emesis in a Chinese Han population.J Clin Pharm Ther. 2013; 38: 150-155Crossref PubMed Scopus (18) Google Scholar, 21Rueffert H. Thieme V. Wallenborn J. et al.Do variations in the 5-HT3A and 5-HT3B serotonin receptor genes (HTR3A and HTR3B) influence the occurrence of postoperative vomiting?.Anesth Analg. 2009; 109: 1442-1447Crossref PubMed Scopus (51) Google Scholar the serotonin transport gene (SLC6A4),22Wesmiller S.W. Bender C.M. Sereika S.M. et al.Association between serotonin transport polymorphisms and postdischarge nausea and vomiting in women following breast cancer surgery.Oncol Nurs Forum. 2014; 41: 195-202Crossref PubMed Scopus (12) Google Scholar the organic cation transporter-1 gene (OCT1),23Balyan R. Zhang X. Chidambaran V. et al.OCT1 genetic variants are associated with postoperative morphine-related adverse effects in children.Pharmacogenomics. 2017; 18: 621-629Crossref PubMed Scopus (35) Google Scholar the dopamine D2 receptor gene (DRD2),24Frey U.H. Schnee C. Achilles M. Silvanus M.T. Esser J. Peters J. Postoperative nausea and vomiting: The role of the dopamine D2 receptor TaqIA polymorphism.Eur J Anaesthesiol. 2016; 33: 84-89Crossref PubMed Scopus (14) Google Scholar the catechol-o-methyl-transferase gene (COMT),25Wesmiller S.W. Sereika S.M. Bender C.M. et al.Exploring the multifactorial nature of postoperative nausea and vomiting in women following surgery for breast cancer.Auton Neurosci. 2017; 202: 102-107Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 26Kolesnikov Y. Gabovits B. Levin A. Voiko E. Veske A. Combined catechol-O-methyltransferase and mu-opioid receptor gene polymorphisms affect morphine postoperative analgesia and central side effects.Anesth Analg. 2011; 112: 448-453Crossref PubMed Scopus (102) Google Scholar the adenosine triphosphate-binding cassette subfamily B member 1 gene (ABCB1),27Ren Z.Y. Xu X.Q. Bao Y.P. et al.The impact of genetic variation on sensitivity to opioid analgesics in patients with postoperative pain: a systematic review and meta-analysis.Pain Physician. 2015; 18: 131-152PubMed Google Scholar the TACR1 gene that encodes NK1 receptors,28Hayase T. Sugino S. Moriya H. Yamakage M. TACR1 gene polymorphism and sex differences in postoperative nausea and vomiting.Anaesthesia. 2015; 70: 1148-1159Crossref PubMed Scopus (14) Google Scholar and the CYP2D6 isoform of the cytochrome P450 superfamily.29Wesmiller S.W. Henker R.A. Sereika S.M. et al.The association of CYP2D6 genotype and postoperative nausea and vomiting in orthopedic trauma patients.Biol Res Nurs. 2013; 15: 382-389Crossref PubMed Scopus (26) Google Scholar This list might not even be exhaustive, and in addition, the response to 5-HT3 serotonin receptor antagonist anti-emetic drugs (e.g. ondansetron and tropisetron) has been evaluated in several pharmacogenetic studies evaluating the impact of CYP2D6 genotypes9Janicki P.K. Schuler H.G. Jarzembowski T.M. Rossi 2nd, M. Prevention of postoperative nausea and vomiting with granisetron and dolasetron in relation to CYP2D6 genotype.Anesth Analg. 2006; 102: 1127-1133Crossref PubMed Scopus (41) Google Scholar, 10Ho K.Y. Gan T.J. Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting.Curr Opin Anaesthesiol. 2006; 19: 606-611Crossref PubMed Scopus (89) Google Scholar, 11Janicki P.K. Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting.Med Sci Monit. 2005; 11 (RA322-328)PubMed Google Scholar, 12Candiotti K.A. Birnbach D.J. Lubarsky D.A. et al.The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis?.Anesthesiology. 2005; 102: 543-549Crossref PubMed Scopus (162) Google Scholar and that of ABCB1.8Choi E.M. Lee M.G. Lee S.H. Choi K.W. Choi S.H. Association of ABCB1 polymorphisms with the efficacy of ondansetron for postoperative nausea and vomiting.Anaesthesia. 2010; 65: 996-1000Crossref PubMed Scopus (45) Google Scholar, 13Song J.W. Shim J.K. Choi S.H. Soh S. Jang J. Kwak Y.L. Comparison of ramosetron and palonosetron for preventing nausea and vomiting after spinal surgery: association with ABCB1 polymorphisms.J Neurosurg Anesthesiol. 2017; 29: 406-414Crossref PubMed Scopus (11) Google Scholar, 14Babaoglu M.O. Bayar B. Aynacioglu A.S. et al.Association of the ABCB1 3435C>T polymorphism with antiemetic efficacy of 5-hydroxytryptamine type 3 antagonists.Clin Pharmacol Ther. 2005; 78: 619-626Crossref PubMed Scopus (68) Google Scholar In this study, granisetron, which undergoes CYP2D6-independent metabolism, was used for the treatment of PONV. In summary, Klenke and colleagues report the results of a four-group placebo-controlled randomised controlled trial, in which patients were stratified according to clinical risk score (Apfel score) and genetic profile (one SNP). Whilst the polymorphism of interest did seem to independently increase the risk for PONV, the effect is at most moderate, confirming the well-known premise that relatively common genetic variants usually exert small clinical effects. A strategy that might prove useful in the not-so-distant future would be to conduct whole exome sequencing on a cohort of patients suffering severe intractable PONV or OINV. This would allow the identification of (i) novel genes and underlying pathways that might result in the development of targeted pharmacological treatments, and (ii) the patients most at risk for PONV or OINV, who are most likely to benefit from opioid-free anaesthesia and omission of PONV-inducing drugs (e.g. inhalation agents). In the meantime and until further notice, we will continue to screen patients and identify their risk for PONV, apply approaches to reduce PONV risks, provide PONV prophylaxis with pharmacological and non-pharmacological approaches, and treat PONV when it occurs.30Gan T.J. Diemunsch P. Habib A.S. et al.Consensus guidelines for the management of postoperative nausea and vomiting.Anesth Analg. 2014; 118: 85-113Crossref PubMed Scopus (928) Google Scholar The authors declare that they have no conflicts of interest. CHRM3 rs2165870 polymorphism is independently associated with postoperative nausea and vomiting, but combined prophylaxis is effectiveBritish Journal of AnaesthesiaVol. 121Issue 1PreviewClinical risk factors for postoperative nausea and vomiting (PONV) are evaluated with the Apfel score, however patients with low Apfel scores still experience PONV suggesting a genetic predisposition. PONV risk associates with specific M3 muscarinic acetylcholine receptor (CHRM3) rs 2165870 polymorphism. We investigated whether the Apfel score and this genetic variation independently contribute to PONV risk and whether prophylaxis reduces PONV in patients with low Apfel score but at high genetic risk. Full-Text PDF Open Archive
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