Eur J Anaesthesiol 2014; 31:708–721

CORRESPONDENCE Failure of sugammadex to reverse rocuronium-induced neuromuscular blockade A case report Jose´ R. Ortiz-Go´mez, Francisco J. Palacio-Abizanda and Inocencia Fornet-Ruiz From the Department of Anesthesiology, Complejo Hospitalario de Navarra B, Hospital Virgen del Camino, Pamplona (JRQ-G), Department of Anesthesiology, Hospital Gregorio Maran˜o´n (FJP-A), and Department of Anesthesiology, Hospital Puerta de Hierro Majadahonda, Madrid, Spain (IF-R) Correspondence to Dr Jose´ R. Ortiz-Go´mez, Department of Anesthesiology, Complejo Hospitalario de Navarra B, Hospital Virgen del Camino, Irunlarrea 8 St., 31008 Pamplona, Navarra, Spain Tel: +34 848 422222; fax: +34 848 429924; e-mail: [email protected] Published online 8 April 2014

Editor, Sugammadex provides fast dose-dependent reversal of neuromuscular blockade (NMB) by rocuronium. However, delayed recovery has been reported.1 We would like to report a case of failure of sugammadex to reverse rocuronium NMB. A 60-year-old man, weight 115 kg, height 175 cm, American Society of Anesthesiologists’ (ASA) physical status 2 (arterial hypertension) was anaesthetised for laparoscopic resection of the sigmoid colon. He received midazolam and target-controlled infusions of propofol and remifentanil. NMB monitoring was performed using train-of-four (TOF) nerve stimulation with acceleromyography (TOF-Watch SX, Bluestar Enterprises, Omaha, Nebraska, USA) at the adductor pollicis muscle following internationally accepted rules2 and calibrated before the administration of succinylcholine 100 mg (risk of difficult intubation or ventilation). The trachea was intubated within 2 min (single twitch height ¼ 0%). Seven minutes after administration of suxamethonium, recovery was observed (movements and acceleromyographic evidence) and a 2T ED95 bolus dose of rocuronium (70 mg) was administered. Central body temperature was measured and maintained using standard techniques of heat conservation. A continuous infusion of rocuronium 1 to 4 mg kgS1 minS1 (total 83 mg) was used to maintain a posttetanic count of zero to one responses. The patient also received cefotaxime, metronidazole, dexamethasone, ondansetron, pantoprazole and morphine. At the end of the 6 h operation (and 27 min after the rocuronium infusion was stopped) with one TOF response (T1 height amplitude 4%), he was given

intravenous sugammadex 4 mg kgS1 (460 mg), but 5.5 min later, NMB was unchanged. Further doses of sugammadex were administered: 4 mg kgS1 at 5.5 min; and 200 mg at 11.5 min, both without clinical and acceleromyographic effect, with a total dose of 1120 mg (9.74 mg kgS1). To exclude malfunction of the TOFWatch, a different peripheral nerve stimulator was used at the facial nerve, with the same visual result as in the adductor pollicis: one weak response to TOF stimulation. Neostigmine 1 mg was then injected 26.5 min after the first dose of sugammadex, and 1.5 mg 3 min later. The patient started breathing spontaneously, but was still curarised (four responses to TOF with T1 of 8 to 9% in the adductor pollicis muscle, four weak responses to TOF stimulation at the facial nerve, low inspiratory volumes, carbon dioxide retention, sweating and so on), so he was transferred intubated to the postanaesthesia care unit and extubated there without incident 3 h later. There are several possible explanations for our observation, relating to the drug, the monitoring or the patient. There was evidence of recovery from succinylcholine, so an abnormal effect of the drug or impaired plasma cholinesterase activity was rejected. An administration error was excluded after checking medication vials used and faulty medications were also dismissed because drugs are kept in accordance with the manufacturer’s recommendations and subsequent doses of the same batch of sugammadex and rocuronium were used without problems. An NMB monitor malfunction was rejected because the TOF-Watch SX performed normally before and after this case, the patient remained in the same position with his hand properly secured during surgery and its data were consistent with the second NMB monitor and the clinical signs. Hypothermia was excluded and there were no ionic or pH alterations or diseases that could explain these findings; renal function was normal, and the patient was neither a smoker nor drinker and had no hepatic or neuromuscular diseases. Drug interactions were also considered. Sugammadex has been specifically designed to form high-affinity complexes with rocuronium, but might also form complexes with other molecules. Interactions could be due to capture or displacement reactions.3 In a capturing reaction, when the affinity of sugammadex for a certain molecule is sufficiently high, sugammadex may

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encapsulate it and reduce the effect of the remaining drug. In a displacement reaction, after successful NMB reversal, administration of another molecule with highaffinity for sugammadex may displace a fraction of the encapsulated rocuronium from its complex with sugammadex, potentially resulting in recurrence of NMB. The drugs identified with potential interactions with sugammadex include toremifene, flucloxacillin, fusidic acid and the oral contraceptive pill. There is no previous evidence of an interaction between sugammadex and the anaesthetic drugs used in this case, nor with the patient’s regular medication (valsartan and hydrochlorothiazide). Other possibilities such as an endogenous molecule in the patient, or even immunological resistance to cyclodextrins, might be considered; of note, cyclodextrins are normal molecules in our daily diet (4 g per day). Overall, this hypothesis seems unlikely unless a very potent displacement reaction occurs, because with the high doses of sugammadex used, at least a minimal recovery response should have been seen. The reversal of rocuronium by sugammadex is very selective and both molecules bind in a 1 : 1 molar ratio, so one molecule of sugammadex (molecular weight of 2.178 kDa) antagonises one molecule of rocuronium (610 kDa); thus, theoretically, 3.57 mg of sugammadex is required to bind 1 mg of rocuronium.4 This patient received 1160 mg of sugammadex and 153 mg of rocuronium (2 : 1 molar ratio), which should have been a sufficient dose to cause a substantial reversal despite drug interactions unless a displacement reaction was potent enough to cause almost immediate recurarisation.

(though very rare) in whom fast reversal with sugammadex may not be achievable.

Finally, and this is the explanation that the authors believe to be probable, this patient may be what is described in statistical terms as ‘an extreme outlier’. Usually, when we use a drug in the clinical scenario, the drug has been studied previously in a large number of patients, and the doses recommended are the most common for almost everybody.5 A small number of patients, however, have either a left-shift of the dose–response curve (more sensitivity to the drug) or a right-shift (relative resistance to the drug). We suggest that this case report represents an extreme outlier with a marked rightward shift of the dose– response curve.

Tim Warrener, Mark Tindall and David Stanley

Sugammadex has been described as the ideal reversal drug.1 Nevertheless, delayed recovery has been described previously;6,7 in these cases, the time to recovery of TOF ratio to 0.9 after treatment with sugammadex 4 mg kgS1 took 24.6 and 22.3 min respectively, compared with a mean of 173 s in other patients. The present case report shows not just delay but failure to reverse rocuronium 45 min after the first dose of sugammadex was administered. These data suggest that excessive NMB depth should not be considered a well tolerated practice in all circumstances, because there are some patients

Acknowledgements relating to this article Assistance with the letter: we would like to thank the patient for his kindness in giving written informed consent for publication. Conflict of interests: none. Financial support and sponsorship: none.

References 1 2

3 4 5

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Brull SJ. Patient safety revisited: reliability is paramount. Anesth Analg 2009; 108:702–703. Fuchs-Buder T, Claudius C, Skovgaard LT, et al. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand 2007; 51:789–808. Mirakhur RK. Sugammadex in clinical practice. Anaesthesia 2009; 64 (Suppl 1):45–54. Donati F. Sugammadex: an opportunity for more thinking or more cookbook medicine? Can J Anesth 2007; 54:689–695. Puhringer FK, Rex C, Sielenkamper AW, et al. Reversal of profound, highdose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter, randomized, dosefinding, safety assessor-blinded, phase II trial. Anesthesiology 2008; 109:188–197. Sparr HJ, Vermeyen KM, Beaufort AM, et al. Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics. Anesthesiology 2007; 106:935–943. White PF, Tufanogullari B, Sacan O, et al. The effect of residual neuromuscular blockade on the speed of reversal with sugammadex. Anesth Analg 2009; 108:846–851. DOI:10.1097/EJA.0000000000000082

The return of halothane anaesthesia? From the Department of Anaesthetics and Critical Care, Russells Hall Hospital, The Dudley Group NHS Foundation Trust, Dudley, UK Correspondence to Dr Tim Warrener, MBChB, MRCP, Russells Hall Hospital, Dudley DY1 2HQ, UK E-mail: [email protected] Published online 6 May 2014

Editor, During a routine list, we were a little surprised for two reasons, when we noticed an end-tidal concentration of 0.9% halothane (>1 minimum alveolar concentration) appear on the monitor. First, the Datex-Ohmeda Avance (GE Medical Systems Ltd, Hatfield, UK) machines had only recently been installed and had never had halothane delivered through them. Second, the procedure was performed under spinal anaesthesia with a target controlled infusion of propofol for sedation. The gas sampling line had been inserted into the patient’s facemask using a cannula. The monitor registered an end-tidal concentration of halothane for several minutes until it returned to zero. Even after finishing the case (see picture), the monitor still read ‘Et Hal %’, though at a concentration of zero.

Eur J Anaesthesiol 2014; 31:708–721 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

710 Correspondence

this does not correlate with the clinical scenario. Clinical judgement and questioning of unusual observations remains paramount in this technological age.

Acknowledgements relating to this article Assistance with the letter: none. Financial support and sponsorship: none. Conflicts of interest: none.

References 1 2

On consulting with colleagues there was awareness that combinations of volatile agents, such as isoflurane and sevoflurane, can cause similar errors. This prompted a literature search, which revealed the following. Finn et al.1 in fact attributed a very similar incident to the detection of methane in exhaled gases.2 According to Cloarec et al.,3 exhaled methane is actually present in 30 to 50% of healthy adults and it has been suggested that the infrared monitors used in most modern anaesthetic machines to measure the concentration of inhaled volatile anaesthetic agents can confuse methane with halothane. The infrared absorption spectrum of methane has been measured from 2470 to 3200 cm
1.4 The gas analysers incorporated into our machines are nondispersive infrared, side-stream analysers that measure the gas sample at seven different wavelengths, selected using optical narrow band filters. The infrared detectors are thermopiles (many thermocouples connected in parallel). Identification of the anaesthetic agents and calculation of their concentration occurs by measurement of absorbance at five wavelengths in the 8-9 micron band, which does not overlap the infrared absorption spectrum of methane quoted above.5 However, halothane does absorb infrared light at 3.3 microns6 and this overlap between the absorption spectra of halothane and methane has been highlighted by Mortier et al.7 as a potential source of erroneous anaesthetic agent readings. In retrospect, the factitious reading of halothane described above was possibly due to the detection of methane and not a mixture of isolfurane and sevoflurane, based on the fact that no volatile agent was being used in this case. However, we cannot be certain of the exact cause of this anomaly. Hawkes8 described a similar case in which the detection of halothane in a patient who was known to be malignant hyperthermia susceptible and who was anaesthetised with total intravenous anaesthesia. We believe our case is another example of the need for vigilance when using monitoring, especially when

3

4 5 6 7

8

Finn D, Jefferson P, Ball DR. Spurious detection of halothane. Anaesthesia 2011; 66: Correspondence. Cassidy CJ, Smith A, Arnot-Smith J. Critical incident reports concerning anaesthetic equipment: analysis of the UK National Reporting and Learning System (NRLS) data from 2006–2008. Anaesthesia 2011; 66:879–888. Cloarec D, Bornet F, Gouilloud S. Breath hydrogen response to lactulose in healthy subjects: relationship to methane producing status. Gut 1990; 31:300–304. Journal of Research of the National Bureau of Standards, Section A. Physics and Chemistry 1960; 64A:201. Datex-Ohmeda E-Modules. Document no. M1027822. Pinnock CA, Lin ES, Smith T. Fundamentals of anaesthesia. 2nd ed. Greenwich Medical Media Ltd., 2003, Section 4: Chapter 2. Mortier E, Struys M, Versichelen L, et al. Influence of methane on infrared gas analysis of volatile anaesthetics. Acta Anaesthesiol Belg 1999; 50:119– 123. Hawkes CA. Factitious halothane detection during trigger-free anaesthesia in a malignant hyperthermia susceptible patient. Can J Anesth 1999; 46:567–570.

DOI:10.1097/EJA.0000000000000069

Delayed recurarisation after sugammadex reversal Ana Bellod Jr, Xavier March, Carmen Hernandez and Antonio Villalonga From the Hospital Universitari de Girona Doctor Josep Trueta, Avenida Franc¸a, s/n, Girona, Spain Correspondence to Ana Bellod Jr, Hospital Universitari de Girona Doctor Josep Trueta, Avenida Franc¸a, s/n, 17007 Girona, Spain Tel: +34 676331878; fax: +34 972940270; e-mail: [email protected] Published online 6 August 2014

Editor, Residual paralysis is a postoperative complication that occurs in between 4 and 50% of patients.1,2 We read with great interest the first case report of recurarisation 20 min after reversal of rocuronium-induced neuromuscular block with sugammadex by Le Corre et al.3 We report here two clinical cases suggestive of delayed recurarisation in patients reversed with sugammadex. The first case was a 58-year-old man who was scheduled for aortofemoral bypass for infrarenal aortic aneurysm. The patient’s medical conditions included hypertension, chronic renal failure [creatinine 132.6 mmol l
1

Eur J Anaesthesiol 2014; 31:708–721 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

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(1.5 mg dl
1)], sleep apnoea syndrome and being overweight (weight 89 kg, height 1.64 m). Pulse oximetry, electrocardiogram and invasive arterial blood pressure monitoring were applied. Anaesthesia was induced with midazolam 2 mg intravenously (i.v.), fentanyl 300 mg i.v., propofol 160 mg i.v. and rocuronium 80 mg i.v., and maintained with remifentanil 0.1 mg kg
1 min
1 i.v., sevoflurane (MAC 1) and rocuronium 0.45 mg kg
1 h
1 i.v. (total dose 260 mg i.v.). Surgery lasted 5 h. Analgesia was started at the end of the procedure with 5 mg of morphine via epidural catheter (L1-L2). Sugammadex 200 mg i.v. (2.25 mg kg
1) was administered when the patient began to breathe spontaneously. Four minutes later, end-tidal CO2 was 5.2 kPa (39 mmHg) and the patient responded to verbal commands, and so the endotracheal tube was removed. The patient was transferred to the postanaesthesia care unit (PACU). On arrival in the PACU, the patient was conscious and oriented, blood pressure was 140/70 mmHg, heart rate 70 bpm, respiratory rate 12 bpm, SpO2 100% and axillary temperature 35.68C. Arterial blood gas showed a mixed acidosis. Epidural infusion was started with bupivacaine 0.125% and fentanyl 1 mg ml
1 at 6 ml h
1. Two hours later, the patient experienced uncoordinated muscle movements and dyspnoea with subsequent apnoea, hypertension and tachyarrhythmia. Postoperative recurarisation was suspected and so assisted ventilation was started and sugammadex 200 mg i.v. was given. The patient recovered completely within 30 s. The second case was a 77-year-old man (weight 69 kg, height 1.62 m) who was scheduled for laparoscopic total gastrectomy. The patient’s medical conditions included hypertension and dyslipidaemia. Pulse oximetry, electrocardiogram and noninvasive arterial blood pressure monitoring were applied on arrival in the operating room. Anaesthesia was induced with atropine 0.6 mg i.v., midazolam 2 mg i.v., fentanyl 100 mg i.v., propofol 120 mg i.v. and rocuronium 70 mg i.v., and maintained with remifentanil 0.2 mg kg
1 min
1 i.v., desflurane (MAC 1) and rocuronium 0.5 mg kg
1 h
1 i.v. (total dose 235 mg i.v.). Surgery lasted 5 h. Analgesia was started at the end of the procedure with fentanyl 75 mg and bupivacaine 0.125% 10 ml via epidural catheter (T9-T10). Sugammadex 200 mg i.v. (3.3 mg kg
1) was administered when the patient began to breathe spontaneously. Five minutes later, end-tidal CO2 was 4.7 kPa (35 mmHg) and the patient responded to verbal command, and so the endotracheal tube was removed. The patient was transferred to the PACU. On arrival in the PACU, the patient was conscious and oriented, blood pressure was 210/80 mmHg, heart rate 100 bpm, respiratory rate 13 bpm, SpO2 100% and axillary temperature 36.68C. Urapidil 30 mg i.v. was

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administered and epidural infusion was started with bupivacaine 0.125% and fentanyl 1 mg ml
1 at 5 ml h
1. An hour and a half later, the patient experienced weakness and dyspnoea, and his SpO2 had decreased to 67%. Postoperative recurarisation was suspected and so assisted ventilation was started and sugammadex 200 mg i.v. was given. The patient recovered completely within 2 min. Both patients were discharged from the PACU the day after entry without further complications. Both patients gave written informed consent for the publication of their cases. The clinical characteristics of respiratory failure and muscle weakness, in both cases, and uncoordinated muscle movements in the first patient, together with clinical reversal after sugammadex are highly suggestive of recurarisation.1,3 Unlike Le Corre et al.,3 recurarisation after sugammadex reversal in our patients was delayed. Factors that may have influenced the recurarisation in both cases are overdose of rocuronium, not monitoring the neuromuscular block, underdosage of sugammadex and, in the first case, moderate hypothermia, obesity, acidosis and renal failure.1,3 It is highly recommended to monitor the level of muscle relaxation, although Naguib et al.4 report that 19.3% of European and 9.4% of American anaesthesiologists never use neuromuscular monitoring. There is great variability in the metabolism and elimination of rocuronium, and therefore sugammadex should be dosed according to the depth of the neuromuscular blockade.1,3,5 A recent incidence of 2% of postoperative residual paralysis in PACU after sugammadex reversal has been described,2 and although sugammadex provides rapid reversal of neuromuscular block, unexpectedly long recovery times have been reported.6 Thus, the effectiveness of sugammadex-induced reversal should also be monitored.

Acknowledgements relating to this article Assistance with the letter: none. Financial support and sponsorship: none. Conflict of interest: none.

References 1 2

3 4

Plaud B, Debaene B, Donati F, Marty J. Residual paralysis after emergence from anesthesia. Anesthesiology 2010; 112:1013–1022. Cammu G, Smet V, De Jongh K, Vandeput D. A prospective, observational study comparing postoperative residual curarisation and early adverse respiratory events in patients reversed with neostigmine or sugammadex or after apparent spontaneous recovery. Anaesth Intensive Care 2012; 40:999–1006. Le Corre F, Nejmeddine S, Fatahine C, et al. Recurarization after sugammadex reversal in an obese patient. Can J Anesth 2011; 58:944–947. Naguib M, Kopman AF, Lien CA, et al. A survey of current management of neuromuscular block in the United States and Europe. Anesth Analg 2010; 111:110–119.

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Rex C, Bergner UA, Pu¨hringer FK. Sugammadex: a selective relaxantbinding agent providing rapid reversal. Curr Opin Anaesthesiol 2010; 23:461–465. Van Gestel L, Cammu G. Is the effect of sugammadex always rapid in onset? Acta Anaesth Belg 2013; 63:41–47.

DOI:10.1097/EJA.0000000000000132

Ondansetron-induced oculogyric crisis Joselo D. Macachor, Margareth Kurniawan and Suresh B. Loganathan From the Department of Anaesthesia, Khoo Teck Puat Hospital, Yishun, Singapore Correspondence to Joselo D. Macachor, Department of Anaesthesia, Khoo Teck Puat Hospital, 90 Yishun Central, Yishun, Singapore 768828 Tel: +65 90609627; e-mail: [email protected] Published online 10 October 2014

Editor, A 41-year-old woman with an unremarkable medical history and normal laboratory results underwent a volar ganglion cyst excision on the left wrist under general anaesthesia. She denied any history of allergy and previous reaction to medications. Her preoperative blood pressure and heart rate were 118/81 and 75 beats per minute, respectively. Surgery was performed under general anaesthesia using a combination of fentanyl, propofol and sevoflurane and 50% O2 in air via a laryngeal mask airway. About 10 min before emergence from anaesthesia, she was given 4 mg of ondansetron intravenously to prevent postoperative nausea and vomiting. The laryngeal mask airway was removed at the postanaesthesia care unit. She opened her eyes on command, but manifested upward and outward deviation of the eyeballs. On neurological examination, she was oriented but distressed because of her inability to see. The patient had intermittent, conjugate, spasmodic eye movements in lateral and vertical directions to each side, consistent with an oculogyric crisis and presented with limb dystonia with plantar flexion. She had purposeful movement of all four extremities, deep tendon reflexes were diffusely and symmetrically brisk, plantar responses were extensor and there was sustained clonus bilaterally. High flow O2 was given, vital signs were stable, blood pressure (BP) was 120/70 mmHg and heart rate (HR) was 62 beats per minute. An internet search for medications that could trigger oculogyric crisis was made and ondansetron was the only temporally related drug. Other causes of central nervous disturbances such as hypoxia, epilepsy, hypoglycaemia and cardiovascular disturbances were excluded, before the diagnosis of oculogyric crisis was made based on our examination and literature

search. The patient did not have any psychiatric conditions. As the patient was anxious, midazolam 2 mg was given. Benztropine 1 mg intravenously was injected and repeated 20 min later. A 2 mg dose was repeated 2 h later as her symptoms did not settle. Complete resolution took place in the third hour. As she was keen to go home, oral benztropine 1 mg twice daily was prescribed for two more days and she was advised to seek help for recurrent eye signs. An outpatient neurology consult was arranged 2 days later. She was informed to warn the anaesthetists of this drug reaction in case she undergoes surgery in the future. She gave her consent for this case report to be published. Perioperative dystonic reactions are rare, but can be painful and frightening when they occur. Symptoms may include involuntary movements, changes in tone and posture, dysarthria, oculogyric crisis, opisthotonus and laryngospasm.1 Extrapyramidal side effects (EPSEs) are known to occur with antiemetic therapy. Recently2 described droperidolinduced sustained upward eyes deviation, inner tension, anxiety and motor restlessness were diagnosed as akathisia. But unlike other antiemetic agents, ondansetron is believed to be free of EPSE, as it does not affect dopamine, histamine, adrenergic or cholinergic receptor activity.3 However, there are several case reports of EPSEs1,2,4–6 since its approval by the Food and Drug Administration. Ondansetron has the potential to inhibit or reduce elevated dopamine activity and to antagonise increased locomotor activity caused by dopamine excess.7 Blockade of 5-HT3 receptors at central sites, blockade of cell firing and dopamine release in the nucleus acumens are possible mechanisms of central nervous system-related effects of ondansetron.4 Although ondansetron is believed not to have an affinity for dopamine receptors, it may produce dopamine receptor-mediated side effects in certain patients by an unknown mechanism. The treatment of an acute dystonic reaction to either phenothiazines or metoclopramide consists of intravenous diphenhydramine, but because ondansetron acts mainly at serotonergic receptor sites, neurological sequelae may not be reversed by anticholinergic medications1; thus, benzodiazepines may be the recommended treatment. Our patient was given both a benzodiazepine and an anticholinergic, and resolution did not take place until 3 h later. The neurochemical basis of extrapyramidal or other acute neurological symptoms following intravenous administration is still not completely understood.1 The differential diagnosis of an acute dystonic reaction may include local anaesthetic reaction, emergence delirium, hysterical reaction, postanaesthesia shivering response and seizure.1

Eur J Anaesthesiol 2014; 31:708–721 Copyright © European Society of Anaesthesiology. Unauthorized reproduction of this article is prohibited.

Correspondence

In conclusion, we describe a dramatic presentation of oculogyric crisis following ondansetron administration to raise awareness of this side effect in the anaesthesia community.

Acknowledgements relating to this article Assistance with the letter: none. Financial support and sponsorship: none.

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(TBW), ideal body weight (IBW) and lean body weight (LBW).2 – 5 As etomidate has some pharmacological properties similar to propofol, it may be suitable for dosing based on corrected body weight (CBW). The aim of our study was to compare the observed doses of etomidate required to achieve anaesthesia using bispectral index (BIS) monitoring with those predicted using TBW, IBW, LBW and CBW for the recommended dose of 0.3 mg kg
1.

Conflicts of interest: none.

References 1

2

3

4 5

6 7

Spiegel JE, Kang V, Kunze L, Hess P. Ondansetron-induced extrapyramidal symptoms during cesarean section. Int J Obstet Anesth 2005; 14:368– 369. Berna F, Timbolschi ID, Diemunsch P, Vidailhet P. Acute dystonia and akathisia following droperidol administration misdiagnosed as psychiatric disorders. J Anesth 2013; 27:803–804. Sprung J, Choudhry FM, Hall BA. Extrapyramidal reactions to ondansetron: cross-reactivity between ondansetron and prochlorperazine? Anesth Analg 2003; 96:1374–1376. Ritter MJ, Goodman BP, Sprung J, Wijdicks EF. Ondansetron-induced multifocal encephalopathy. Mayo Clin Proc 2003; 78:1150–1152. Tolan MM, Fuhrman TM, Tsueda K, Lippmann SB. Perioperative extrapyramidal reactions associated with ondansetron. Anesthesiology 1999; 90:340–341. Stonell C. An extrapyramidal reaction to ondansetron. Br J Anaesth 1998; 81:658. Wilde MI, Markham A. Ondansetron. A review of its pharmacology and preliminary clinical findings in novel applications. Drugs 1996; 52:773–794.

DOI:10.1097/EJA.0000000000000169

Etomidate can be dosed according to ideal body weight in morbidly obese patients Tomasz M. Gaszynski, Jakub Jakubiak and Tomasz Szewczyk From the Department of Emergency and Disaster Medicine (TG), Department of Anaesthesiology and Intensive Therapy, Medical University of Lodz (JJ), and Department of Gastroenterological, Oncological and General Surgery, Barlicki University Hospital, Lodz, Poland (TS) Correspondence to Tomasz M. Gaszynski, PhD, Department of Anaesthesiology and Intensive Therapy, Barlicki University Hospital, ul. Kopcinskiego 22, 90-153 Lodz, Poland E-mail: [email protected] Published online 6 August 2014

Editor, According to the WHO, obesity reached epidemic proportions worldwide in May 2012. Every year, at least 2.8 million people die due to being overweight or obese and BMI positively correlates with the number of admissions to hospital and duration of hospital stay.1 Rapid sequence induction (RSI) is often required for morbidly obese patients.2 Etomidate, a carboxy-imidazole intravenous anaesthetic, may be preferred for RSI because it is associated with relative cardiovascular stability.2 It acts by modulating g-aminobutyric acid receptor functions in the central nervous system. There are various recommendations on the dosing of etomidate in the morbidly obese based on total body weight

After obtaining approval of the ethical committee (protocol number RNN/767/11/KB date 18 November 2011, Chairman: Prof. Przedzislaw Polakowski) of Medical University of Lodz, morbidly obese patients (n ¼ 50), scheduled for elective bariatric surgery, were enrolled after written informed consent in this open-label study. Inclusion criteria were BMI more than 40 kg m
2 and age 18 to 65 years. Exclusion criteria were allergy to etomidate and suggestion of difficult tracheal intubation. A control group (n ¼ 20) consisted of nonobese patients (BMI 0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 >0.9 ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF 2.0 4.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 2.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 0.13 0.10 0.30 0.20 0.30 0.20 0.60 0.20 0.40 0.30 0.42

ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio 3 ratio 1 1 1 1 1 1 1 3 TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF PTC TOF PTC PTC PTC PTC PTC PTC PTC PTC 72.5 10 25 95 27.5 47.5 115 14 100 65 14 60 22 24 25.5 24.2 24 22.2 50 74 100 TIVA TIVA TIVA TIVA Volatile Volatile TIVA Volatile Volatile Volatile Volatile TIVA TIVA TIVA TIVA TIVA TIVA TIVA TIVA TIVA TIVA 0 0 0 0 0 0 0 0 0 0 0

ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio ratio 2 ratio 1 1 1 1 1 0 0 1 TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF TOF PTC TOF PTC PTC PTC PTC PTC PTC PTC PTC 0.25 0.10 0.10 0.50 0.15 0.30 0.30 0.10 0.30 0.60 0.20 0.15 0.15 0.15 0.15 0.15 0.15 0.15 1.0 1.0 1.0

Maximum level of NMB Initial dose (mg kgS1) NMBA Pre-NMBA TOF ratio Preop Chol-inhib No.

Neuromuscular and recovery characteristics Table 2

The TOF ratios immediately before NMBA administration were more than 0.9 in all but one case, in which it was 0.45. Rocuronium was used in 13 patients and vecuronium in eight patients. The intubating dose of rocuronium and vecuronium ranged from 0.1 to 1.0 and 0.1 to 0.2 mg kg
1, respectively. In 18 patients, the initial intubating dose of NMBA was followed by a repeat dose of the same drug; in the remaining three cases, the patient received a single intubating dose of rocuronium. The maximal level of neuromuscular blockade was moderate in one patient (rocuronium), deep in seven patients (rocuronium) and intense (or profound) in 13 patients (rocuronium n ¼ 11, vecuronium n ¼ 2). All surgical procedures were uneventful. Upon completion of surgery, sugammadex 2 or 4 mg kg
1 was administered to reverse residual moderate (12 patients; rocuronium n ¼ 10, vecuronium n ¼ 2) or deep neuromuscular blockade (nine patients, rocuronium), respectively. The mean reversal time, which was defined as the time from administration of sugammadex to recovery of a TOF ratio of more than 0.9, was 79.7 s (range 30 to 268 s) for moderate neuromuscular

Maintenance TIVA/volatile

Myasthenia patients were assessed as Osserman class II (n ¼ 13) or III (n ¼ 8). Most patients were female (13 vs. eight men). The average age was 56 years (range 26 to 80 years) and the average weight was 77.6 kg (range 54 to 123 kg). The average daily dose of pyridostigmine was 275 mg (range 0 to 480 mg). The neuromuscular management data, including NMBAs used, the maximum level of neuromuscular blockade, type of anaesthesia, sugammadex dose and the neuromuscular recovery characteristics, are summarised in Table 2.

Rocuronium Rocuronium Rocuronium Rocuronium Rocuronium Rocuronium Rocuronium Vecuronium Rocuronium Rocuronium Vecuronium Rocuronium Rocuronium Rocuronium Rocuronium Rocuronium Rocuronium Rocuronium Rocuronium Rocuronium Rocuronium

Total NMBA dose (mg)

Level of NMB at end of surgery

Sugammadex dose (mg kgS1)

Neuromuscular monitoring was performed as defined in the guidelines for Good Clinical Practice in neuromuscular monitoring, by acceleromyography using a TOF-watch SX (N.V. Organon, Oss, Netherlands) in all patients. In each case, the ulnar nerve was supramaximally stimulated near the wrist with square wave pulses of 0.2 ms, delivered as a train-of-four (TOF) or posttetanic count (PTC). The contractions of the adductor pollicis muscle were measured quantitatively using acceleromyography. Recovery of neuromuscular function was defined as a TOF ratio of more than 0.9 or 90% of the baseline TOF ratio prior to NMBA administration.11,12 The level of neuromuscular blockade was defined as follows: intense (or profound) neuromuscular blockade, no responses to either TOF or PTC; deep neuromuscular blockade, response to PTC, but not to TOF stimulation; and moderate neuromuscular blockade, the reappearance of the response to TOF stimulation.12

0.96 0.45 0.9 0.9 1.0 0.9 1.0 0.92 0.9 1.0 0.98 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0

Maximum TOF ratio following reversal

Time to full reversal (s)

remifentanil (0.1 to 0.4 mg kg
1 min
1), or with a bolus dose of propofol (1 to 2 mg kg
1) and sevoflurane (endtidal concentration 1.0 to 2.0%) for maintenance of anaesthesia.

717

60 60 268 84 60 30 65 72 30 35 42 123 150 135 150 165 135 105 240 195 240

Correspondence

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718 Correspondence

blockade and 165 s (range 105 to 240 s) for deep neuromuscular blockade. For moderate neuromuscular block induced by either rocuronium or vecuronium, there was no significant difference in reversal times. A summary of neuromuscular characteristics is shown in Table 2. After the TOF ratio had remained stable (>0.9) for a few minutes, the trachea was extubated and the patient was transferred to the postanaesthesia care unit (PACU). In both hospitals, the possibility of postoperative recurrence of neuromuscular blockade (recurarisation) was assessed by monitoring oxygen saturation, breathing pattern and respiratory rate in the PACU for at least 120 min after the administration of sugammadex. In the Martini General Hospital, the possibility of postoperative recurrence of neuromuscular blockade was also assessed by monitoring neuromuscular function in the PACU (TOF stimulation every 5 min for at least 30 min). Recurrence of neuromuscular blockade was defined as deterioration in clinical signs or as a relapse to a lower TOF ratio attributed to neuromuscular blockade. No signs of recurarisation were reported in the PACU and no patient required admission to the ICU following surgery; all were discharged directly from the PACU to a surgical ward. Oral pyridostigmine was administered when patients were able to tolerate swallowing safely, which usually coincided with the scheduled timing of the drug. The literature search on sugammadex and myasthenia gravis found 21 articles, of which 15 met the inclusion criteria. In one publication, the purpose was not to evaluate recovery after sugammadex but the difference in recovery of two different muscle groups. In the remaining 14 publications, which are presented in Table 3, 24 cases of patients with myasthenia gravis were described.13–25 In 23 cases, rocuronium was used to induce neuromuscular block; vecuronium was used in

only one patient. The results of the literature search are discussed in the following section. In all patients, the reversal of rocuronium or vecuroniuminduced neuromuscular blockade by sugammadex was fast and complete. All 21 patients recovered after reversal with sugammadex to the initial preoperative level of neuromuscular function. The recovery times from deep neuromuscular blockade were slightly longer than the reversal times from moderate neuromuscular blockade. There was no significant difference in the recovery time of reversal from either rocuronium or vecuroniuminduced neuromuscular blockade. Neuromuscular blockade was reversed in all patients within 4 min and no signs of residual curarisation or recurarisation occurred irrespective of the NMBA used. Myasthenia gravis patients are challenging to the anaesthesiologist because even the smallest dose of NMBA can lead to profound (or intense) neuromuscular blockade with prolonged spontaneous recovery or inadequate reversal by neostigmine.5 However, neuromuscular blockade is needed to create optimal intubation conditions and avoid vocal cord sequelae such as postoperative hoarseness, oedema or haematoma of the vocal cords, or even lacerations of the vocal cords. Therefore, anaesthesiologists often administer small doses of NMBA, but these patients often need postoperative mechanical ventilation and are admitted to the ICU. There is wide variability in the response to NMBAs and it is impossible to predict the appropriate initial dose of NMBA in such patients.11 Myasthenia gravis patients have been shown to be resistant to the depolarising NMBA succinylcholine with an ED95 that is 2.6 times higher than that in the healthy patient population.26 Therefore, succinylcholine is not recommended in myasthenia patients because the usual doses of 1.5 to 2.0 mg kg
1 may not only induce an inadequate neuromuscular blockade but also well known undesirable side effects such as bradycardia.26,27

Summary of cases from literature review in which rocuronium or vecuronium and sugammadex had been used in patients with myasthenia gravis

Table 3

Reference 13

Nakamori et al. Sugawara et al.14 Kiss et al.15 Sungur Ulke et al.16 Takeda et al.17 Garcia et al.18 Rudzka-Nowak and Piechota4,b Jakubiak et al.19 Komasawa et al.20 Argiriadou et al.21 de Boer et al.22 Petrun et al.23 de Boer et al.24 Unterbuchner et al.25 a

n

Level of NMB

1 1 1 10 1 1 1 1 1 1 2 1 1 1

Moderate Moderate Moderate Moderate Moderate Deep Unknown Moderate Moderate Moderate Deep Moderate Deep Moderate

Sugammadex dose (mg kgS1)

Recovery timea (s)

2.0 0.5 and 1.5 12.0 2 2.0 4.0 3.0 1.25 2 2 4 2 4 2

102 n/a n/a 111 (35 to 240) 120 240 Unknown 168 30 0.9. b Neuromuscular blockade induced by vecuronium. n/a, not available; NMB, neuromuscular blockade.

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Correspondence

Short-acting NMBAs such as mivacurium (1 to 2 x ED95) are used in small doses and can result in acceptable neuromuscular blockade with safe recovery, as reported in several publications. However, the ED95 of these drugs in myasthenia gravis patients is unknown. The use of intermediate NMBAs such as rocuronium, vecuronium and cis-atracurium has been reported to be adequate, but often in reduced doses that ranged between 0.1 and 0.5 times the standard doses.5,23,28–33 The ED95 for vecuronium in myasthenia gravis patients is 56% of normal, but for rocuronium, the ED95 in these patients is unknown.2,24 However, rocuronium should be given in doses smaller than the standard dose for patients without the disease. In our patients, the intubating dose of rocuronium and vecuronium ranged from 0.1 to 1.0 mg kg
1 and from 0.1 to 0.2 mg kg
1, respectively. Repeat administration of rocuronium or vecuronium was indicated in 18 patients in order to achieve satisfactory neuromuscular blockade throughout the surgical procedure. Three patients in the rocuronium group did not receive follow-up doses. One patient who had an initial TOF ratio of 0.45 received a single intubating dose of 0.15 mg kg
1, which resulted in deep neuromuscular blockade, sufficient for the surgical procedure. In the other two patients, a rapid sequence induction procedure was performed with rocuronium 1.0 mg kg
1, which was also sufficient for the whole surgical procedure. As spontaneous recovery of neuromuscular blockade in myasthenia gravis is much slower than in patients without the disease, it is mandatory to apply objective quantitative neuromuscular monitoring and important to reverse neuromuscular blockade pharmacologically.24 Reversal of neuromuscular blockade leads to restoration of neuromuscular function to the preoperative level and prevents postoperative residual curarisation with the risk of increased morbidity and mortality. Reversal of neuromuscular blockade in myasthenia gravis patients who are already receiving cholinesterase inhibitor medication is complicated by a variable response and unreliable effect.1,2,5 Moreover, patients using acetylcholinesterase inhibitors chronically may already have optimal inhibition of the enzyme, and reversal of nondepolarising neuromuscular blockade with these compounds is therefore not possible. Additional doses of cholinesterase inhibitors may even lead to a cholinergic crisis, characterised by muscle weakness, bradycardia and increased secretions and gut motility. 2,5,34,35 Rocuronium-induced neuromuscular blockade can be reversed by cholinesterase inhibitors such as neostigmine, edrophonium or pyridostigmine in some patients with myasthenia gravis. However, cholinesterase inhibitors have a number of undesirable side effects (bradycardia, bronchoconstriction, hypersalivation, abdominal cramps and nausea and vomiting), which can be counteracted by coadministration of muscarinic antagonists (atropine or

719

glycopyrrolate). Importantly, such muscarinic antagonists also have side effects (blurred vision, dry mouth and tachycardia). Furthermore, cholinesterase inhibitors are unable to reverse deep neuromuscular blockade due to their mechanism of action.35,36 In our patients, the pre-NMBA TOF ratio ranged from 0.45 to 1.0 and administration of the NMBA resulted in a maximal depth of neuromuscular blockade ranging from a TOF ratio of 0 to 0.19, or a PTC of 0 to 1. After reversal of neuromuscular blockade with sugammadex, all patients recovered from neuromuscular blockade to their preoperative TOF ratio, indicating that sugammadex reversal was complete and led to a rapid reappearance of normal muscle activity in our patients with myasthenia gravis. The results of our case series are in line with the results found in the literature. We reviewed publications describing the use of sugammadex for reversal of rocuronium- or vecuronium-induced neuromuscular blockade. When used in the recommended dosage, the recovery was fast and complete. However, in two cases, moderate neuromuscular blockade was reversed with a lower dose of sugammadex than recommended (0.5 mg kg
1and additional doses of 1.5 and 1.25 mg kg
1).14,19 The recovery time (168 s) was available in only one of these reports.19 In another case, a very high dose of 12.0 mg kg
1 of sugammadex was administered.15 In this case, a patient with an Osserman-Jenkins score of IIIa and initial TOF ratio of 0.97 was given rocuronium 30 mg. At the end of surgery, monitoring showed a TOF ratio of 0.36 and several bolus doses of sugammadex (to a total of 12.0 mg kg
1) were administered before the patient’s trachea was extubated at a TOF ratio of 0.71. The authors did not indicate clearly the cause or any consequences of the delay in recovery. In one case in which vecuronium was used to induce neuromuscular blockade, sugammadex 3.0 mg kg
1 was administered, but no information about the level of neuromuscular blockade or the exact recovery time was provided.4 In most of the cases in which the depth of neuromuscular blockade was based on quantitative neuromuscular monitoring, sugammadex was administered in a dose of either 2.0 or 4.0 mg kg
1 for moderate or deep neuromuscular block, respectively. These recovery times were in line with the recovery times found in our patients and also, as seen in our patients, without signs of postoperative residual curarisation or recurarisation.13,16–25 This means that recommended doses of sugammadex 2.0 or 4.0 mg kg
1 have produced similar recovery times in all published myasthenia gravis patients for whom detailed information is available. These findings are also in line with the recovery times in patients without neuromuscular disease.

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720 Correspondence

Patients with myasthenia gravis may present for any type of surgery and need to be evaluated preoperatively. This evaluation should include assessment of respiratory and bulbar function. A reduced forced vital capacity and poor bulbar function are strong indicators of risk that postoperative mechanical ventilation will become necessary.3 None of our patients needed postoperative mechanical ventilation and none was transferred to the ICU. Myasthenia gravis patients may also suffer from cardiac arrhythmias, such as atrial fibrillation and bradycardia.2 This may evoke complications when neuromuscular blockade is reversed with cholinesterase inhibitors and muscarinic antagonists such as atropine. Preoperative optimisation of neuromuscular function is important and therefore cholinesterase inhibitors should be continued perioperatively.5,24 The TOF ratio in myasthenia gravis patients immediately prior to NMBA administration has frequently been reported to be less than 0.9 as a result of the disease itself, but also due to the effects of discontinuation of pyridostigmine.11 Discontinuation of cholinesterase inhibitors in combination with general anaesthesia, including neuromuscular blockade, may lead to weakness of pharyngeal muscles, disco-ordinated swallowing and airway obstruction, and a reduction of the ventilatory response to hypercapnia may result following anaesthesia.3,37,38 This may partly be explained by the lingering effects of hypnotic agents and the use of NMBAs. The quality and speed of reversal of muscle paralysis seen following sugammadex and the administration of pyridostigmine immediately following surgery should reduce this risk in patients with myasthenia gravis. Reversal of neuromuscular blockade with sugammadex does not interfere with cholinergic transmission, and therefore, continuation of cholinesterase inhibitors does not affect the efficacy of reversal of neuromuscular blockade by sugammadex as seen in our patients, but also in the patients presented in the review of the literature. This strategy, including continuation of cholinesterase inhibitors and reversal with sugammadex, will preserve optimal neuromuscular function. Reversal of neuromuscular blockade in myasthenia gravis by sugammadex both in our own patients and in the patients reported in the literature demonstrated rapid and complete recovery of neuromuscular function without signs of postoperative residual neuromuscular blockade. Importantly, postoperative residual neuromuscular blockade or recurarisation should not only be assessed in normal patients when indicated but also in the more vulnerable myasthenia gravis patients. This assessment should consist of quantitative neuromuscular monitoring in the PACU because evaluation of clinical signs of residual neuromuscular blockade or recurarisation is not reliable and lacks the accuracy to exclude the presence of residual neuromuscular blockade.39 Reversal of

neuromuscular blockade by sugammadex may eliminate the risk of residual neuromuscular blockade in this vulnerable patient population, as reported in patients without myasthenia gravis.40 These findings are supported by results found in the literature. Our cases series suggests that the combination of either rocuronium or vecuronium and sugammadex is beneficial in myasthenia gravis by eliminating the risk of residual paralysis. We suggest that the perioperative management strategy for patients with myasthenia gravis should include assessment of respiratory and bulbar function, continuation of cholinesterase inhibitors, quantitative neuromuscular monitoring, administration of aminosteroidal NMBAs (rocuronium or vecuronium) and reversal of neuromuscular blockade with sugammadex. This strategy represents a departure from traditional teaching. It is simple and easy to follow and is effective in all patients irrespective of the severity of their symptoms or the inter-patient variability seen in response to NMBAs. Finally, it adds many aspects of safety, particularly a greatly reduced need for postoperative mechanical ventilation in the ICU, and may prevent dangerous postoperative curarisation in this vulnerable patient population.

Acknowledgements relating to this article Assistance with the letter: none. Financial support and sponsorship: none. Conflict of interest: all three authors have provided lectures about sugammadex sponsored by the pharmaceutical company Merck Sharp & Dohme.

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DOI:10.1097/EJA.0000000000000153

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