Article
Reference
Severe and persistent morphine-induced respiratory depression associated with ATP-Binding Cassette Subfamily B Member 1 and
catechol-O-methyltransferase genetic defects: A case report
AEBISCHER, Gaspard, et al .
AEBISCHER, Gaspard, et al . Severe and persistent morphine-induced respiratory depression associated with ATP-Binding Cassette Subfamily B Member 1 and catechol-O-methyltransferase genetic defects: A case report. European Journal of Anaesthesiology , 2018, vol. 35, no. 7, p.
540-542
DOI : 10.1097/EJA.0000000000000801 PMID : 29870475
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Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
groups, nor by analysis of covariates; thus, we rejected this hypothesis.
Our data are in line with studies using single direct assessment of intravascular volume1 – 3 or functional assessments.4 Single measurements preclude detection of individual changes. We have assessed such changes and demonstrate that no clinically relevant losses in total blood volume occur. We excluded patients with condi- tions predisposing to hypovolaemia. They include a broad range of conditions from obvious to the very subtle than occur especially in the elderly.
Our findings lay the physiological basis for current goal- directed strategies of peri-operative fluid administration that explicitly preclude initial fluid loading and signifi- cantly reduce adverse outcomes. Vice versa, our data show that preventive administration of large volumes of intravenous fluids during induction of general anaes- thesia to compensate for erroneously presumed fluid losses lack scientific reason.
Acknowledgements relating to this article
Assistance with the letter: none.
Financial support and sponsorship: a calibrated scale (Tanita SL 450 Body Composition Analyzer Tanita Inc. Tanita Europe B.V.
Amsterdam, The Netherlands) was used with the kind permission of the Department of Clinical Chemistry and Clinical Pharmacolo- gy of the University of Bonn.
Conflicts of interest: none.
References
1 Rehm M, Orth V, Kreimeier U,et al.Changes in intravascular volume during acute normovolemic hemodilution and intraoperative retransfusion in patients with radical hysterectomy.Anesthesiology2000;92:657–664.
2 Rehm M, Haller M, Orth V,et al.Changes in blood volume and hematocrit during acute preoperative volume loading with 5% albumin or 6% hetastarch solutions in patients before radical hysterectomy.Anesthesiology2001;
95:849–856.
3 Jacob M, Chappell D, Conzen P,et al.Blood volume is normal after preoperative overnight fasting.Acta Anaesthesiol Scand2008;52:
522–529.
4 Muller L, Brie`re M, Bastide S,et al.Preoperative fasting does not affect haemodynamic status: a prospective, noninferiority, echocardiography study.Br J Anaesth2014;112:835–841.
5 Thacker JK, Mountford WK, Ernst FR,et al.Perioperative fluid utilization variability and association with outcomes: considerations for enhanced recovery efforts in sample US surgical populations.Ann Surg2016;
263:502 –510.
6 Robarts WM, Parkin JV, Hobsley M. A simple clinical approach to quantifying losses from the extracellular and plasma compartments.Ann R Coll Surg Engl1979;61:142–145.
7 Nadler SB, Hidalgo JH, Bloch T. Prediction of blood volume in normal human adults.Surgery1962;51:224–232.
DOI:10.1097/EJA.0000000000000811
Severe and persistent morphine-induced respiratory depression associated with ATP-Binding Cassette Subfamily B
Member 1 and catechol-O-methyltransferase genetic defects
A case report
Gaspard Aebischer, Kuntheavy Ing Lorenzini, Simon Tomala, Jules Desmeules, Youssef Daali and Caroline F. Samer
From the Division of General Internal Medicine (GA), Division of Clinical Pharmacology and Toxicology (RIK, JD, YD, CS) and Division of Anaesthesiology, Geneva University Hospitals, Geneva, Switzerland (ST)
Correspondence to Dr Caroline F. Samer, Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, Switzerland
Tel: +41 22 3729947; e-mail: [email protected]
Editor,
Although uncommon in the peri-operative setting, opi- oid-induced respiratory depression represents an impor- tant medical issue in surgical patients taken as a whole.
Cases are most often the consequences of inappropriate administration of opioids, but certain situations are not so easily explained. When opiate plasma concentrations are within normal range, pharmacogenetic analyses may provide an additional explanation for opioid toxicity.
Morphine is well absorbed after oral administration, but extensive hepatic first-pass metabolism results in a 20 to 30% bio-availability. The primary metabolic pathway is conjugation with glucuronic acid into morphine-3-glucu- ronide (M3G) and into morphine-6-glucuronide (M6G).
Uridine diphospho-glucuronosyltransferase (UGT) 1A3 catalyses the formation of M3G, whereas UGT2B7 forms M6G. Morphine is also a substrate of the efflux transporter P-glycoprotein (P-gp). Existing reports suggest that the pharmacokinetics of opioids are influenced by numerous gene polymorphisms such as ATP-Binding Cassette Sub- family B Member 1 (ABCB1), and UGT2B7, and their
540 Correspondence
Table 1 Changes of haematocrit and derived parameters before and after 12 h of fasting
All patients No heart failure Heart failure Pvalue
Hctbaseline(%) 40.42.9 40.82.8 40.03.0 0.36M
Hctfasted(%) 40.93.5 41.33.7 40.63.4 0.04/0.17/0.13MM
TBVbaseline(ml) 48731034 51551305 4592570 0.46M
DTBV (ml) 57218 60247 54190 0.08/0.16/0.27MM
DWeight (g) 1100534 1190478 1010583 <0.001/<0.001/<0.001MM Data presented as meanSD. Hct, haematocrit; TBV, total blood volume.MNo heart failure vs. heart failure.MMBaseline vs. fasted for all patients/no heart failure/heart failure, respectively.
Eur J Anaesthesiol 2018; 35:539–552
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
pharmacodynamics by mu opioid receptor 1 (OPRM1) and catechol-O-methyltransferase (COMT), for example, and these polymorphisms might affect the efficacy or toxicity of opioids. However, the clinical significance of these genetic variants is still unclear.1–5
We report the case of a 72-year-old woman with a kidney transplant who had an elective right hemicolectomy for a stage 2 adenocarcinoma and developed severe morphine- induced intoxication in the postoperative period. This was unrelated to the dose of opioid administered and lasted long after the suspected cause was stopped. The patient has provided written informed consent for this publication, and confidentiality of the data has been ensured.
In the immediate postoperative period, the patient re- ceived a total dose of 7 mg intravenous morphine. On the following day, oral morphine was started at 15 mg six times a day, taking into account her weight of 84 kg and her kidney function (creatinine clearance estimated at 70 ml min1using the Cockroft–Gault equation). On the first day, all doses were administered with only one supplementary 10 mg dose in the morning, at the initia- tion of oral treatment. She received, in total, 100 mg of morphine during the first 24 h. The next morning, she experienced respiratory depression and a concomitant altered state of consciousness. Suspecting morphine-in- duced intoxication, naloxone was administered. The first two boluses of naloxone (0.1 mg each) improved the level of consciousness, but she relapsed quickly and a contin- uous intravenous infusion had to be started (0.1 mg h1) and was continued until the following morning. After the intravenous naloxone infusion was stopped, she relapsed again and two other boluses of naloxone were needed to finally reverse the morphine-induced intoxication which had lasted more than 24 h after the last morphine was administered.
Laboratory investigations were performed to explore a possible cause of the adverse effects of the therapeutic doses of morphine. These investigations included
morphine and metabolites (M3G and M6G) plasma con- centrations as well as pharmacogenetic testing (genotyp- ing) for ABCB1, UGT2B7, OPRM1 and COMT.
Morphine and M3G/M6G plasma concentrations are shown in Fig. 1. M6G and M3G concentrations measured 3 h after the last dose of morphine were, respectively, 403 and 2730 ng ml1. The M6G : morphine and M3G : mor- phine Area Under the Curve (AUC) ratios were, respec- tively, 10.5 and 86.4. The patient was found to be a homozygous carrier of both ABCB1 variant alleles tested (c.2677TT and c.3435TT) as well as a homozygous carrier of the COMT variant allele tested (c.322AA).
The genotypes for UGT2B7 (c.372AA) and OPRM1 (c.118AA) were normal.
In spite of decades of research, there is still an incomplete understanding of the desired therapeutic levels for the analgesic efficacy of morphine without morphine-related side effects.6In the present case, morphine concentra- tions measured 3 h after the last dose were similar to those reported in studies of cancer and postoperative pain in patients receiving a comparable oral morphine dose.7 – 9 M6G and M3G concentrations measured 3 h after the last dose were also in the expected range,7 – 9 as were the M6G : morphine and M3G : morphine AUC ratios (10.5 and 86.4).10 We postulate that the persistent morphine- induced respiratory depression, despite plasma concen- trations of its morphine and its metabolites in the normal range, was probably a consequence of the genotypic alterations on theABCB1andCOMTgenes. A correlation between various ABCB1 variant alleles (rs2032582, c.2677G>T; rs1045642, c.3435C>T) and an increased opioid sensitivity has been described.2 As our patient was homozygous for both ABCB1 variant alleles tested, these genotypic alterations probably contributed to the morphine-induced intoxication experienced.
Multiples studies have shown a possible correlation between a specific COMT polymorphism (rs4680, Val158Met) and increased sensitivity to opioids.4Due to
Correspondence 541
Fig. 1
1 10 100 1000 10000
0 10 20 30 40 50 60
Concentration (ngml–1 )
Time after last dose (hours)
Morphine concentration (ng·ml–1)
M6G concentration (ng·ml–1) M3G concentration (ng·ml–1)
Morphine, morphine-6-glucuronide and morphine-3-glucuronide plasma concentrations.
Eur J Anaesthesiol 2018; 35:539–552
Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.
a higher expression of COMT, patients with the homozy- gous mutation (Met/Met) might need lower doses of opioids, and this genotypic alteration most probably con- tributed to the abnormal response to opioids seen in our patient. Among other contributive factors, we should con- sider concurrent medication. Specifically, a possible phar- macokinetic interaction between morphine and tacrolimus is suspected; this immunosuppressant being an inhibitor of UGT2B7 in vitro. However, this explanation becomes less plausible when considering that M6G and M3G plasma concentrations and M6G : morphine and M3G : morphine ratios were in the normal range. Finally, other factors such as age and kidney transplantation have to be taken into consideration.
Pharmacogenetic testing from a single blood DNA sam- ple is now offered routinely in major university hospitals, and may be ordered by physicians from different special- ties. The results are rapidly available, and the cost of testing is in decline worldwide.
In conclusion, despite preserved kidney function our patient developed severe and persistent morphine-in- duced intoxication, requiring a prolonged intravenous infusion of naloxone. Laboratory investigations showed morphine and glucuronide metabolite concentrations in the expected range. The pharmacogenetic analysis revealed that the patient was a homozygous carrier of both ABCB1 variant alleles tested. This would result in reduced efflux transport P-gp activity with accumulation of mor- phine and its metabolites at the target, thus explaining the morphine intoxication. Furthermore, she exhibited a con- current COMT variant allele, also linked to an increased opioid sensitivity, that probably helped exacerbate the severity of the event. Pharmacogenetic tests are therefore useful in identifying those at risk of opioid-induced intox- ication and represent a valuable tool in addition to plasma drug concentration measurements.
Acknowledgements relating to this article
Assistance with the letter: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
References
1 Hodges LM, Markova SM, Chinn LW,et al.Very important pharmacogene summary: ABCB1 (MDR1,P-glycoprotein).Pharmacogenet Genomics 2011;21:152–161.
2 Rhodin A, Gronbladh A, Ginya H,et al.Combined analysis of circulating beta-endorphin with gene polymorphisms in OPRM1, CACNAD2 and ABCB1 reveals correlation with pain, opioid sensitivity and opioid-related side effects.Mol Brain2013;6:8.
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DOI:10.1097/EJA.0000000000000801
Anaesthesia and orphan diseases:
difficult tracheal intubation in a child with Frank–ter Haar syndromeConcezione Tommasino and Maura Albicini
From the Anaesthesia and Intensive Care, Department of Biomedical, Surgical and Odontoiatric Sciences, University of Milano (CT), and Anaesthesia and Intensive Care, ASST Santi Paolo e Carlo University Hospital, Milano, Italy (CT, MA)
Correspondence to Concezione Tommasino, MD, Anaesthesia and Intensive Care, ASST Santi Paolo e Carlo University Hospital, Via di Rudinı` 8, 20142 Milano, Italy
Tel: +39 02 50319039/þ39 347 8348888;
e-mail: [email protected]
Editor,
Frank–ter Haar syndrome (FTHS) is a very rare genetic disease following an autosomal recessive pattern of in- heritance.1 – 3 It is characterised by multiple skeletal abnormalities, developmental delay, cardiac defects and characteristic facial features.
We present a case of a child affected by FTHS with a difficult airway whom we intubated with a fibreoptic bronchoscope (FOB) through the AirQ intubating laryngeal airway (ILA) device (Cookgas LLC, Mercury Medical, Clearwater, Florida, USA)4after two unsuccess- ful videolaryngoscopy attempts using Glidescope (Verathon Medical Europe, Ijsselstein, Netherlands) and McGrath (Aircraft Medical Ltd, Edinburgh, UK) devices.
Written consent was obtained from the parents for the publication of this case report.
A 5-year-old boy (16.9 kg, 107 cm) was referred to our University Hospital for dental restoration under general anaesthesia. FTHS was diagnosed after birth (one living brother with FTHS) and genetic screening (SH3PXD2B
542 Correspondence
