In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pum

Rex, S

Struys, Michel

Van de Velde, M

Vanneste, B

University of Groningen

   University of GroningenAcute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump.Vanneste, B; Van de Velde, M; Struys, Michel; Rex, SPublished in:Acta anaesthesiologica belgicaIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2017Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Vanneste, B., Van de Velde, M., Struys, M., & Rex, S. (2017). Acute and life-threatening remifentaniloverdose resulting from the misuse of a syringe pump. Acta anaesthesiologica belgica, 68(2), 87-89.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 13-11-2019© Acta Anæsthesiologica Belgica, 2017, 68, n° 2Abstract : In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.Key words : Remifentanil ; syringe pump ; critical incident ; difficult airway.IntroductIon In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.case report A 71-year-old, male patient (weight : 73 kg, height : 180 cm) was scheduled for the endovascular place-ment of an iliac branch prosthesis in order to correct an arterial aneurysm of the right common iliac artery and the right internal iliac artery. The past medical history included 30 pack-years of tobacco abuse (with smoking cessation in 2000), arterial hypertension (treated with nebivolol, amlodipine, olmesartan), hypercholesterolemia (treated with pravastatine) and an acute myocardial infarction in 2006, for which a drug-eluting stent had been placed in the left anterior descending artery (secondary prevention with low dose acetylsalicylic acid). For induction of total intravenous anesthesia, standard anesthesia monitors (non-invasive mea-surements of arterial blood pressure, 5-lead-electrocardiography, pulse-oximetry) were con-nected to the patient. A 16 G intravenous catheter (BD Insyte-W, Becton Dinckinson Infusion Therapy Systems Inc., Utah, USA) was placed in a dorsal vein of the left hand and connected to a triple lumen infusion device with three non-return valves (Octopus 3, Vycon, Ecouen, France). The first lumen was connected to a balanced crystalloid infusion (PLASMA-LYTE A, Baxter S.A., Lessines, Belgium). The second lumen was connected to a 50 ml prefilled propofol syringe (Diprivan 1%, AstraZeneca, Brussels, Belgium) through a 200-cm long, rigid extension tube (Original Perfusor Line, B. Braun, Melsungen, Germany). The third lumen was connected in the same way to a 50 mL syringe (Original Perfusor Syringe 50 mL, B. Braun, Escholzmatt, Switzerland) filled with remifentanil (Ultiva, GlaxoSmithKline Pharmaceuticals, Wavre, Belgium), 20 mL at a concentration of 100 µg/mL, equaling a total dose of 2 mg. Before connection to the patient, all tubing had been thoroughly flushed with the corresponding medications to evacuate all remaining air. Both syringes were placed horizontally into the syringe pumps (Alaris PK Syringe Pump, CareFusion, Rolle, Switzerland) that were fixed approximately 100 cm above the patient’s heart level. For the continuous monitoring of arterial blood pressure, the right arm of the patient was prepared for catheterization of the radial artery while awake. During puncturing, the right arm of the patient suddenly became spastic. The patient was unresponsive to both verbal and tactile stimulation. At this moment we noted that the remifentanil syringe was completely empty. We (Acta Anaesth. Belg., 2017, 68, 87-89)Bert Vanneste, Marc Van de Velde, M.M.R.F. Struys, Steffen Rex.(*) Department of Anesthesiology, University Hospitals of the KU Leuven, Leuven, Belgium.(**) Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.(***) Department of Anesthesiology, AZ Groeninge, Kortrijk, Belgium.(****) Department of Anesthesiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands and Department of Anesthesia, Ghent University, Gent, Belgium.Correspondence address : Bert Vanneste, President Kennedy-laan 4, 8500 Kortrijk, Belgium. Telephone: + 32 497 24 44 55.Email: bert.vanneste@azgroeninge.beInformed consent of the patient for publication of this case report was obtained.Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pumpB. Vanneste (*, ***), M. Van de Velde (*, **), M. M. R. F. struys (****) and S. rex (*, **)© Acta Anæsthesiologica Belgica, 2017, 68, n° 288 b. Vanneste et al. administration (2) and dose miscalculation (3). In our case, the syringe plunger had accidentally not been locked in the pusher lever of the syringe pump, allowing remifentanil to be evacuated as a bolus into the patient. Similar mishaps with syringe pumps have been described with morphine and midazo- lam (4), and with a patient-controlled analgesia pump (5). The physics underlying this accident have been previously described in detail by shenkman et al (4). Briefly, given the fact that the patient’s arm was positioned 100 cm lower than the syringe pump, the syringe plunger was displaced by the negative hydrostatic force resulting from this level difference between the intravenous catheter and the syringe (4). Additionally, the evacuation of the syringe might have been facilitated by the Venturi effect, elicited by the high-flow crystalloid infusion that was connected to the multilumen infusion device and hence indirectly also to the remifentanil syringe. We reproduced this incident using the same setting, however without patient and replacing remifentanil with a saline solution. After unlocking the pusher lever from the plunger, the syringe emptied spontaneously through the rigid extension tube into the fast-running infusion. Within less than 4 minutes, the total syringe volume of 20 mL had emptied. Our patient received 2 mg remifentanil over a time span of only a few minutes. A normal induction dose for this patient would be approximately 0.04 - 0.08 mg in one minute. This means that we inadvertently administered at least a 25-fold normal induction dose. We simulated the time course of the plasma concentration of remifentanil in this patient using a simulation program (RUGLOOP II, DEMED, Temse, Belgium), loaded with the compartmental pharmacokinetic model as published by mInto et al (6, 7). We found that this bolus administration resulted in a calculated plasma concentration of remifentanil of approximately 150 ng mL-1, a 30-fold normally targeted plasma concentration (8). Due to this massive overdose in our case, almost all side effects of remifentanil became instantaneously obvious : sedation, rigidity of skele-tal striated muscles, bradycardia (although not so marked in this case), respiratory depression and apnea (8). In this case, we were alerted by the spasticity and the tonic-clonic seizure of the patient. Normally, one would expect that desaturation would be the first sign of such a high dose of remifentanil. We believe that, due to the fast infusion of the medication and the rapid onset of remifentanil, the plasma also noticed that the plunger of the syringe was not locked in the pusher lever. These observations were suggestive for the diagnosis of an acute overdose of remifentanil due to an inadvertent bolus injection of 20 mL (2 mg) remifentanil. The left arm of the patient became also spastic at that time. Both legs showed a tonic-clonic seizure behavior, while the upper limbs developed flexion contracture, making accurate non-invasive measurement of arterial blood pressure impossible. The carotid pulse could still be palpated. The patient’s heart rate decreased from 80 beats min-1 to 65 beats min-1. Soon, the patient became apneic, and peripheral saturation decreased. An attempt was made to manually ventilate the patient through a face mask, which was however not successful, because of severe muscle rigidity of the chest. Due to an extreme spasm of both masseter muscles, the mouth of the patient could not be opened, for the placement of an endotracheal tube or a supraglottic device. The minimal measured saturation at that moment was 61 %. Therefore, we made the decision to immediately induce general anesthesia with an intravenous infusion of propofol (target controlled infusion, Marsh model, 4.0 µg mL -1) and rocuronium bromide 50 mg (Esmeron, Organon, Oss, Nederland). Thirty seconds later, the patient’s musculature started to relax and manual ventilation became possible. The trachea of the patient was intubated and the patient was mechanically ventilated. Next, the right radial artery was cannulated, revealing an arterial blood pressure of 94/46 mmHg. Total intravenous anesthesia was maintained using propofol (target-controlled infusion, Marsh model, 4.0 µg mL-1) and remifentanil (0.1 µg Kg-1 min-1). The surgical procedure was performed as scheduled, and was uneventful. After the end of surgery, the patient awoke 6 minutes after discontinuation of anesthesia. The patient was repeatedly evaluated: immediately after extubation, one hour after surgery in the recovery room, and thirty hours after surgery on the surgical ward. No adverse events could be documented. When answering the Brice questionnaire during the last post-anesthesia visit, the patient did not report any explicit awareness of the event. The last thing he could remember was that, before entering the operating room, one of the nurses placed a surgical cap on his head.dIscussIon The inadvertent administration of high doses of remifentanil have been described as a consequence of defective syringe pumps (1), accidental bolus © Acta Anæsthesiologica Belgica, 2017, 68, n° 2 acute and lIfe-threatenIng remIfentanIl oVerdose 89conclusIon Although frequently neglected by caregivers, the safe use of syringe pumps requires continuous attention and thorough understanding of the under-lying physics and possible sources of error.  We present a case in which an accidental overdose of remifentanil occurred because the syringe plunger had accidentally not been locked in the pusher lever, allowing the spontaneous evacuation of the syringe. A comparable incident outside the setting of a fully equipped anesthesia working place would have certainly been associated with major morbidity or even mortality of the affected patient. It is therefore important to note that any drug infusion should be connected to the patient only after the correct assembly of the syringe pump installation has been checked. Users must verify that the syringe plunger is properly secured to the pusher lever. Moreover, intravenous infusion lines containing vasoactive drugs or potent anesthetic drugs ideally need anti-reflux valves. A further preventive measure would be to place syringe pumps only below the patient’s heart level. At last the anesthesiologist should only turn the stopcock of the entry of the intravenous medication when he/she is sure that everything has been checked and safe administration of the medication can be guaranteed.Reference1.. Montserrat JM, Pérez-Hick PA, Remifentanil overdose in obstetric analgesia caused by a defective syringe in a patient-controlled analgesia system. reV esp anestesIol reanIm., 58(8), 530-531, 2011.2.  Bakan M, Cakmakkaya S, Onsel I, Kaya G. Inadvertent bolus administration of high-dose remifentanil during anesthesia in a 6-year-old girl. paedIatr anaesth., 16(11), 1202, 2006. 3.  Barak M, Greenberg Z, Danino J, Delayed awakening following inadvertent high-dose remifentanil infusion in a 13 year old patient. J clIn anesth., 23(4), 322-324, 2011.4.  Shenkman Z, Ornstein E, Adler D, Drug Overdose as a Consequence of Misuse of a Syringe Pump, anesth analg., 81(3), 652-653, 1995.5.  Steffen M, von Hintzenstern U, Obermayer A, Critical infusion incident caused by incorrect use of a patient-controlled analgesia pump, anaesthesIol reanIm., 27(4), 107-110, 2002.6.  Minto CF, Schnider TW, Egan TD, Youngs E et al., Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. anesthesIology., 86(1), 10-23, 1997.7.  Minto CF, Schnider TW, Shafer SL, Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. anesthesIology, 86(1), 24-33, 1997.8.  GlaxoSmithKline : Ultiva for injection. Available from : http://www.mhra.gov.uk/9.  Egan TD, Lemmens HJ, Fiset P, Hermann DJ et al., The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. anesthesIology., 79(5), 881-892, 1993.10.  B. Braun : Naloxone for injection. Available from: http://www.mhra.gov.uk/concentration for muscle rigidity and seizure was reached so quickly, that the patient did not had the time to desaturate. To the best of our knowledge, equally high doses of remifentanil in non-anesthetized and non-intubated patients have only been used and described in preclinical pharmacokinetic studies (9). Also in these studies, muscle rigidity was observed as a major side-effect and had to be treated with a continuous infusion of succinylcholine, to allow mask ventilation. The literature is silent about the appropriate management of such a remifentanil overdose. It could be argued that antagonizing remifentanil with naloxone might have been a suitable therapeutic approach. For opioid overdoses, the prescribing information of naloxone(10) recommends repetitive doses of 0.4 mg-2 mg until a total dose of 10 mg has been achieved. In our hospital, only ampullas of 0.4 mg of naloxone (Naloxone B. Braun 0.4 mg. mL-1, 1 mL, Melsungen, Germany) are available. Hence, the preparation of up to 10 mg naloxone would have been too time-consuming in order to prevent hypoxemia. Waiting for spontaneous metabolization of remifentanil would have also taken too long. The spontaneous recovery of ventilation can only be expected at a remifentanil plasma concentration of around 2 ng mL-1 (8), and a large interindividual variability exists. The applied pharmacokinetic modeling shows that this concentration would have been reached only 35 minutes after the termination of the accidental infusion. One could argument that immediately starting an intravenous infusion of propofol is, maybe, not necessary, insofar as a plasma concentration of remifentanil of 150 ng mL-1 is enough to guarantee unconsciousness and amnesia. However, propofol was added immediately for two reasons. First, at the moment of the acute event, we did not know what the plasma concentration of remifentanil was. We knew it would be high, but there was no time to calculate the exact plasma concentration. Since there were no signs of hemodynamic instability, propofol was added to guarantee unconsciousness and amnesia. Secondly, since propofol also gives a certain degree of muscle relaxation, it was added to optimize intubation conditions. In our case, with apnea, the impossibility of mask ventilation and instrumentation of the upper airway, a rapid induction of general anesthesia, muscle relaxation, subsequent endotracheal intuba-tion and mechanical ventilation seemed the only and best available option.

Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump.

In the perioperative setting, syringe pumps arefrequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pum

Proceedings - University of Groningen

   University of GroningenAcute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump.Vanneste, B; Van de Velde, M; Struys, Michel; Rex, SPublished in:Acta anaesthesiologica belgicaIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2017Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Vanneste, B., Van de Velde, M., Struys, M., & Rex, S. (2017). Acute and life-threatening remifentaniloverdose resulting from the misuse of a syringe pump. Acta anaesthesiologica belgica, 68(2), 87-89.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 05-06-2022© Acta Anæsthesiologica Belgica, 2017, 68, n° 2Abstract : In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.Key words : Remifentanil ; syringe pump ; critical incident ; difficult airway.IntroductIon In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.case report A 71-year-old, male patient (weight : 73 kg, height : 180 cm) was scheduled for the endovascular place-ment of an iliac branch prosthesis in order to correct an arterial aneurysm of the right common iliac artery and the right internal iliac artery. The past medical history included 30 pack-years of tobacco abuse (with smoking cessation in 2000), arterial hypertension (treated with nebivolol, amlodipine, olmesartan), hypercholesterolemia (treated with pravastatine) and an acute myocardial infarction in 2006, for which a drug-eluting stent had been placed in the left anterior descending artery (secondary prevention with low dose acetylsalicylic acid). For induction of total intravenous anesthesia, standard anesthesia monitors (non-invasive mea-surements of arterial blood pressure, 5-lead-electrocardiography, pulse-oximetry) were con-nected to the patient. A 16 G intravenous catheter (BD Insyte-W, Becton Dinckinson Infusion Therapy Systems Inc., Utah, USA) was placed in a dorsal vein of the left hand and connected to a triple lumen infusion device with three non-return valves (Octopus 3, Vycon, Ecouen, France). The first lumen was connected to a balanced crystalloid infusion (PLASMA-LYTE A, Baxter S.A., Lessines, Belgium). The second lumen was connected to a 50 ml prefilled propofol syringe (Diprivan 1%, AstraZeneca, Brussels, Belgium) through a 200-cm long, rigid extension tube (Original Perfusor Line, B. Braun, Melsungen, Germany). The third lumen was connected in the same way to a 50 mL syringe (Original Perfusor Syringe 50 mL, B. Braun, Escholzmatt, Switzerland) filled with remifentanil (Ultiva, GlaxoSmithKline Pharmaceuticals, Wavre, Belgium), 20 mL at a concentration of 100 µg/mL, equaling a total dose of 2 mg. Before connection to the patient, all tubing had been thoroughly flushed with the corresponding medications to evacuate all remaining air. Both syringes were placed horizontally into the syringe pumps (Alaris PK Syringe Pump, CareFusion, Rolle, Switzerland) that were fixed approximately 100 cm above the patient’s heart level. For the continuous monitoring of arterial blood pressure, the right arm of the patient was prepared for catheterization of the radial artery while awake. During puncturing, the right arm of the patient suddenly became spastic. The patient was unresponsive to both verbal and tactile stimulation. At this moment we noted that the remifentanil syringe was completely empty. We (Acta Anaesth. Belg., 2017, 68, 87-89)Bert Vanneste, Marc Van de Velde, M.M.R.F. Struys, Steffen Rex.(*) Department of Anesthesiology, University Hospitals of the KU Leuven, Leuven, Belgium.(**) Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.(***) Department of Anesthesiology, AZ Groeninge, Kortrijk, Belgium.(****) Department of Anesthesiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands and Department of Anesthesia, Ghent University, Gent, Belgium.Correspondence address : Bert Vanneste, President Kennedy-laan 4, 8500 Kortrijk, Belgium. Telephone: + 32 497 24 44 55.Email: bert.vanneste@azgroeninge.beInformed consent of the patient for publication of this case report was obtained.Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pumpB. Vanneste (*, ***), M. Van de Velde (*, **), M. M. R. F. struys (****) and S. rex (*, **)© Acta Anæsthesiologica Belgica, 2017, 68, n° 288 b. Vanneste et al. administration (2) and dose miscalculation (3). In our case, the syringe plunger had accidentally not been locked in the pusher lever of the syringe pump, allowing remifentanil to be evacuated as a bolus into the patient. Similar mishaps with syringe pumps have been described with morphine and midazo- lam (4), and with a patient-controlled analgesia pump (5). The physics underlying this accident have been previously described in detail by shenkman et al (4). Briefly, given the fact that the patient’s arm was positioned 100 cm lower than the syringe pump, the syringe plunger was displaced by the negative hydrostatic force resulting from this level difference between the intravenous catheter and the syringe (4). Additionally, the evacuation of the syringe might have been facilitated by the Venturi effect, elicited by the high-flow crystalloid infusion that was connected to the multilumen infusion device and hence indirectly also to the remifentanil syringe. We reproduced this incident using the same setting, however without patient and replacing remifentanil with a saline solution. After unlocking the pusher lever from the plunger, the syringe emptied spontaneously through the rigid extension tube into the fast-running infusion. Within less than 4 minutes, the total syringe volume of 20 mL had emptied. Our patient received 2 mg remifentanil over a time span of only a few minutes. A normal induction dose for this patient would be approximately 0.04 - 0.08 mg in one minute. This means that we inadvertently administered at least a 25-fold normal induction dose. We simulated the time course of the plasma concentration of remifentanil in this patient using a simulation program (RUGLOOP II, DEMED, Temse, Belgium), loaded with the compartmental pharmacokinetic model as published by mInto et al (6, 7). We found that this bolus administration resulted in a calculated plasma concentration of remifentanil of approximately 150 ng mL-1, a 30-fold normally targeted plasma concentration (8). Due to this massive overdose in our case, almost all side effects of remifentanil became instantaneously obvious : sedation, rigidity of skele-tal striated muscles, bradycardia (although not so marked in this case), respiratory depression and apnea (8). In this case, we were alerted by the spasticity and the tonic-clonic seizure of the patient. Normally, one would expect that desaturation would be the first sign of such a high dose of remifentanil. We believe that, due to the fast infusion of the medication and the rapid onset of remifentanil, the plasma also noticed that the plunger of the syringe was not locked in the pusher lever. These observations were suggestive for the diagnosis of an acute overdose of remifentanil due to an inadvertent bolus injection of 20 mL (2 mg) remifentanil. The left arm of the patient became also spastic at that time. Both legs showed a tonic-clonic seizure behavior, while the upper limbs developed flexion contracture, making accurate non-invasive measurement of arterial blood pressure impossible. The carotid pulse could still be palpated. The patient’s heart rate decreased from 80 beats min-1 to 65 beats min-1. Soon, the patient became apneic, and peripheral saturation decreased. An attempt was made to manually ventilate the patient through a face mask, which was however not successful, because of severe muscle rigidity of the chest. Due to an extreme spasm of both masseter muscles, the mouth of the patient could not be opened, for the placement of an endotracheal tube or a supraglottic device. The minimal measured saturation at that moment was 61 %. Therefore, we made the decision to immediately induce general anesthesia with an intravenous infusion of propofol (target controlled infusion, Marsh model, 4.0 µg mL -1) and rocuronium bromide 50 mg (Esmeron, Organon, Oss, Nederland). Thirty seconds later, the patient’s musculature started to relax and manual ventilation became possible. The trachea of the patient was intubated and the patient was mechanically ventilated. Next, the right radial artery was cannulated, revealing an arterial blood pressure of 94/46 mmHg. Total intravenous anesthesia was maintained using propofol (target-controlled infusion, Marsh model, 4.0 µg mL-1) and remifentanil (0.1 µg Kg-1 min-1). The surgical procedure was performed as scheduled, and was uneventful. After the end of surgery, the patient awoke 6 minutes after discontinuation of anesthesia. The patient was repeatedly evaluated: immediately after extubation, one hour after surgery in the recovery room, and thirty hours after surgery on the surgical ward. No adverse events could be documented. When answering the Brice questionnaire during the last post-anesthesia visit, the patient did not report any explicit awareness of the event. The last thing he could remember was that, before entering the operating room, one of the nurses placed a surgical cap on his head.dIscussIon The inadvertent administration of high doses of remifentanil have been described as a consequence of defective syringe pumps (1), accidental bolus © Acta Anæsthesiologica Belgica, 2017, 68, n° 2 acute and lIfe-threatenIng remIfentanIl oVerdose 89conclusIon Although frequently neglected by caregivers, the safe use of syringe pumps requires continuous attention and thorough understanding of the under-lying physics and possible sources of error.  We present a case in which an accidental overdose of remifentanil occurred because the syringe plunger had accidentally not been locked in the pusher lever, allowing the spontaneous evacuation of the syringe. A comparable incident outside the setting of a fully equipped anesthesia working place would have certainly been associated with major morbidity or even mortality of the affected patient. It is therefore important to note that any drug infusion should be connected to the patient only after the correct assembly of the syringe pump installation has been checked. Users must verify that the syringe plunger is properly secured to the pusher lever. Moreover, intravenous infusion lines containing vasoactive drugs or potent anesthetic drugs ideally need anti-reflux valves. A further preventive measure would be to place syringe pumps only below the patient’s heart level. At last the anesthesiologist should only turn the stopcock of the entry of the intravenous medication when he/she is sure that everything has been checked and safe administration of the medication can be guaranteed.Reference1.. Montserrat JM, Pérez-Hick PA, Remifentanil overdose in obstetric analgesia caused by a defective syringe in a patient-controlled analgesia system. reV esp anestesIol reanIm., 58(8), 530-531, 2011.2.  Bakan M, Cakmakkaya S, Onsel I, Kaya G. Inadvertent bolus administration of high-dose remifentanil during anesthesia in a 6-year-old girl. paedIatr anaesth., 16(11), 1202, 2006. 3.  Barak M, Greenberg Z, Danino J, Delayed awakening following inadvertent high-dose remifentanil infusion in a 13 year old patient. J clIn anesth., 23(4), 322-324, 2011.4.  Shenkman Z, Ornstein E, Adler D, Drug Overdose as a Consequence of Misuse of a Syringe Pump, anesth analg., 81(3), 652-653, 1995.5.  Steffen M, von Hintzenstern U, Obermayer A, Critical infusion incident caused by incorrect use of a patient-controlled analgesia pump, anaesthesIol reanIm., 27(4), 107-110, 2002.6.  Minto CF, Schnider TW, Egan TD, Youngs E et al., Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. anesthesIology., 86(1), 10-23, 1997.7.  Minto CF, Schnider TW, Shafer SL, Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. anesthesIology, 86(1), 24-33, 1997.8.  GlaxoSmithKline : Ultiva for injection. Available from : http://www.mhra.gov.uk/9.  Egan TD, Lemmens HJ, Fiset P, Hermann DJ et al., The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. anesthesIology., 79(5), 881-892, 1993.10.  B. Braun : Naloxone for injection. Available from: http://www.mhra.gov.uk/concentration for muscle rigidity and seizure was reached so quickly, that the patient did not had the time to desaturate. To the best of our knowledge, equally high doses of remifentanil in non-anesthetized and non-intubated patients have only been used and described in preclinical pharmacokinetic studies (9). Also in these studies, muscle rigidity was observed as a major side-effect and had to be treated with a continuous infusion of succinylcholine, to allow mask ventilation. The literature is silent about the appropriate management of such a remifentanil overdose. It could be argued that antagonizing remifentanil with naloxone might have been a suitable therapeutic approach. For opioid overdoses, the prescribing information of naloxone(10) recommends repetitive doses of 0.4 mg-2 mg until a total dose of 10 mg has been achieved. In our hospital, only ampullas of 0.4 mg of naloxone (Naloxone B. Braun 0.4 mg. mL-1, 1 mL, Melsungen, Germany) are available. Hence, the preparation of up to 10 mg naloxone would have been too time-consuming in order to prevent hypoxemia. Waiting for spontaneous metabolization of remifentanil would have also taken too long. The spontaneous recovery of ventilation can only be expected at a remifentanil plasma concentration of around 2 ng mL-1 (8), and a large interindividual variability exists. The applied pharmacokinetic modeling shows that this concentration would have been reached only 35 minutes after the termination of the accidental infusion. One could argument that immediately starting an intravenous infusion of propofol is, maybe, not necessary, insofar as a plasma concentration of remifentanil of 150 ng mL-1 is enough to guarantee unconsciousness and amnesia. However, propofol was added immediately for two reasons. First, at the moment of the acute event, we did not know what the plasma concentration of remifentanil was. We knew it would be high, but there was no time to calculate the exact plasma concentration. Since there were no signs of hemodynamic instability, propofol was added to guarantee unconsciousness and amnesia. Secondly, since propofol also gives a certain degree of muscle relaxation, it was added to optimize intubation conditions. In our case, with apnea, the impossibility of mask ventilation and instrumentation of the upper airway, a rapid induction of general anesthesia, muscle relaxation, subsequent endotracheal intuba-tion and mechanical ventilation seemed the only and best available option.

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   University of GroningenAcute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump.Vanneste, B; Van de Velde, M; Struys, Michel; Rex, SPublished in:Acta anaesthesiologica belgicaIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2017Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Vanneste, B., Van de Velde, M., Struys, M., & Rex, S. (2017). Acute and life-threatening remifentaniloverdose resulting from the misuse of a syringe pump. Acta anaesthesiologica belgica, 68(2), 87-89.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 31-10-2023© Acta Anæsthesiologica Belgica, 2017, 68, n° 2Abstract : In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.Key words : Remifentanil ; syringe pump ; critical incident ; difficult airway.IntroductIon In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.case report A 71-year-old, male patient (weight : 73 kg, height : 180 cm) was scheduled for the endovascular place-ment of an iliac branch prosthesis in order to correct an arterial aneurysm of the right common iliac artery and the right internal iliac artery. The past medical history included 30 pack-years of tobacco abuse (with smoking cessation in 2000), arterial hypertension (treated with nebivolol, amlodipine, olmesartan), hypercholesterolemia (treated with pravastatine) and an acute myocardial infarction in 2006, for which a drug-eluting stent had been placed in the left anterior descending artery (secondary prevention with low dose acetylsalicylic acid). For induction of total intravenous anesthesia, standard anesthesia monitors (non-invasive mea-surements of arterial blood pressure, 5-lead-electrocardiography, pulse-oximetry) were con-nected to the patient. A 16 G intravenous catheter (BD Insyte-W, Becton Dinckinson Infusion Therapy Systems Inc., Utah, USA) was placed in a dorsal vein of the left hand and connected to a triple lumen infusion device with three non-return valves (Octopus 3, Vycon, Ecouen, France). The first lumen was connected to a balanced crystalloid infusion (PLASMA-LYTE A, Baxter S.A., Lessines, Belgium). The second lumen was connected to a 50 ml prefilled propofol syringe (Diprivan 1%, AstraZeneca, Brussels, Belgium) through a 200-cm long, rigid extension tube (Original Perfusor Line, B. Braun, Melsungen, Germany). The third lumen was connected in the same way to a 50 mL syringe (Original Perfusor Syringe 50 mL, B. Braun, Escholzmatt, Switzerland) filled with remifentanil (Ultiva, GlaxoSmithKline Pharmaceuticals, Wavre, Belgium), 20 mL at a concentration of 100 µg/mL, equaling a total dose of 2 mg. Before connection to the patient, all tubing had been thoroughly flushed with the corresponding medications to evacuate all remaining air. Both syringes were placed horizontally into the syringe pumps (Alaris PK Syringe Pump, CareFusion, Rolle, Switzerland) that were fixed approximately 100 cm above the patient’s heart level. For the continuous monitoring of arterial blood pressure, the right arm of the patient was prepared for catheterization of the radial artery while awake. During puncturing, the right arm of the patient suddenly became spastic. The patient was unresponsive to both verbal and tactile stimulation. At this moment we noted that the remifentanil syringe was completely empty. We (Acta Anaesth. Belg., 2017, 68, 87-89)Bert Vanneste, Marc Van de Velde, M.M.R.F. Struys, Steffen Rex.(*) Department of Anesthesiology, University Hospitals of the KU Leuven, Leuven, Belgium.(**) Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.(***) Department of Anesthesiology, AZ Groeninge, Kortrijk, Belgium.(****) Department of Anesthesiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands and Department of Anesthesia, Ghent University, Gent, Belgium.Correspondence address : Bert Vanneste, President Kennedy-laan 4, 8500 Kortrijk, Belgium. Telephone: + 32 497 24 44 55.Email: bert.vanneste@azgroeninge.beInformed consent of the patient for publication of this case report was obtained.Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pumpB. Vanneste (*, ***), M. Van de Velde (*, **), M. M. R. F. struys (****) and S. rex (*, **)© Acta Anæsthesiologica Belgica, 2017, 68, n° 288 b. Vanneste et al. administration (2) and dose miscalculation (3). In our case, the syringe plunger had accidentally not been locked in the pusher lever of the syringe pump, allowing remifentanil to be evacuated as a bolus into the patient. Similar mishaps with syringe pumps have been described with morphine and midazo- lam (4), and with a patient-controlled analgesia pump (5). The physics underlying this accident have been previously described in detail by shenkman et al (4). Briefly, given the fact that the patient’s arm was positioned 100 cm lower than the syringe pump, the syringe plunger was displaced by the negative hydrostatic force resulting from this level difference between the intravenous catheter and the syringe (4). Additionally, the evacuation of the syringe might have been facilitated by the Venturi effect, elicited by the high-flow crystalloid infusion that was connected to the multilumen infusion device and hence indirectly also to the remifentanil syringe. We reproduced this incident using the same setting, however without patient and replacing remifentanil with a saline solution. After unlocking the pusher lever from the plunger, the syringe emptied spontaneously through the rigid extension tube into the fast-running infusion. Within less than 4 minutes, the total syringe volume of 20 mL had emptied. Our patient received 2 mg remifentanil over a time span of only a few minutes. A normal induction dose for this patient would be approximately 0.04 - 0.08 mg in one minute. This means that we inadvertently administered at least a 25-fold normal induction dose. We simulated the time course of the plasma concentration of remifentanil in this patient using a simulation program (RUGLOOP II, DEMED, Temse, Belgium), loaded with the compartmental pharmacokinetic model as published by mInto et al (6, 7). We found that this bolus administration resulted in a calculated plasma concentration of remifentanil of approximately 150 ng mL-1, a 30-fold normally targeted plasma concentration (8). Due to this massive overdose in our case, almost all side effects of remifentanil became instantaneously obvious : sedation, rigidity of skele-tal striated muscles, bradycardia (although not so marked in this case), respiratory depression and apnea (8). In this case, we were alerted by the spasticity and the tonic-clonic seizure of the patient. Normally, one would expect that desaturation would be the first sign of such a high dose of remifentanil. We believe that, due to the fast infusion of the medication and the rapid onset of remifentanil, the plasma also noticed that the plunger of the syringe was not locked in the pusher lever. These observations were suggestive for the diagnosis of an acute overdose of remifentanil due to an inadvertent bolus injection of 20 mL (2 mg) remifentanil. The left arm of the patient became also spastic at that time. Both legs showed a tonic-clonic seizure behavior, while the upper limbs developed flexion contracture, making accurate non-invasive measurement of arterial blood pressure impossible. The carotid pulse could still be palpated. The patient’s heart rate decreased from 80 beats min-1 to 65 beats min-1. Soon, the patient became apneic, and peripheral saturation decreased. An attempt was made to manually ventilate the patient through a face mask, which was however not successful, because of severe muscle rigidity of the chest. Due to an extreme spasm of both masseter muscles, the mouth of the patient could not be opened, for the placement of an endotracheal tube or a supraglottic device. The minimal measured saturation at that moment was 61 %. Therefore, we made the decision to immediately induce general anesthesia with an intravenous infusion of propofol (target controlled infusion, Marsh model, 4.0 µg mL -1) and rocuronium bromide 50 mg (Esmeron, Organon, Oss, Nederland). Thirty seconds later, the patient’s musculature started to relax and manual ventilation became possible. The trachea of the patient was intubated and the patient was mechanically ventilated. Next, the right radial artery was cannulated, revealing an arterial blood pressure of 94/46 mmHg. Total intravenous anesthesia was maintained using propofol (target-controlled infusion, Marsh model, 4.0 µg mL-1) and remifentanil (0.1 µg Kg-1 min-1). The surgical procedure was performed as scheduled, and was uneventful. After the end of surgery, the patient awoke 6 minutes after discontinuation of anesthesia. The patient was repeatedly evaluated: immediately after extubation, one hour after surgery in the recovery room, and thirty hours after surgery on the surgical ward. No adverse events could be documented. When answering the Brice questionnaire during the last post-anesthesia visit, the patient did not report any explicit awareness of the event. The last thing he could remember was that, before entering the operating room, one of the nurses placed a surgical cap on his head.dIscussIon The inadvertent administration of high doses of remifentanil have been described as a consequence of defective syringe pumps (1), accidental bolus © Acta Anæsthesiologica Belgica, 2017, 68, n° 2 acute and lIfe-threatenIng remIfentanIl oVerdose 89conclusIon Although frequently neglected by caregivers, the safe use of syringe pumps requires continuous attention and thorough understanding of the under-lying physics and possible sources of error.  We present a case in which an accidental overdose of remifentanil occurred because the syringe plunger had accidentally not been locked in the pusher lever, allowing the spontaneous evacuation of the syringe. A comparable incident outside the setting of a fully equipped anesthesia working place would have certainly been associated with major morbidity or even mortality of the affected patient. It is therefore important to note that any drug infusion should be connected to the patient only after the correct assembly of the syringe pump installation has been checked. Users must verify that the syringe plunger is properly secured to the pusher lever. Moreover, intravenous infusion lines containing vasoactive drugs or potent anesthetic drugs ideally need anti-reflux valves. A further preventive measure would be to place syringe pumps only below the patient’s heart level. At last the anesthesiologist should only turn the stopcock of the entry of the intravenous medication when he/she is sure that everything has been checked and safe administration of the medication can be guaranteed.Reference1.. Montserrat JM, Pérez-Hick PA, Remifentanil overdose in obstetric analgesia caused by a defective syringe in a patient-controlled analgesia system. reV esp anestesIol reanIm., 58(8), 530-531, 2011.2.  Bakan M, Cakmakkaya S, Onsel I, Kaya G. Inadvertent bolus administration of high-dose remifentanil during anesthesia in a 6-year-old girl. paedIatr anaesth., 16(11), 1202, 2006. 3.  Barak M, Greenberg Z, Danino J, Delayed awakening following inadvertent high-dose remifentanil infusion in a 13 year old patient. J clIn anesth., 23(4), 322-324, 2011.4.  Shenkman Z, Ornstein E, Adler D, Drug Overdose as a Consequence of Misuse of a Syringe Pump, anesth analg., 81(3), 652-653, 1995.5.  Steffen M, von Hintzenstern U, Obermayer A, Critical infusion incident caused by incorrect use of a patient-controlled analgesia pump, anaesthesIol reanIm., 27(4), 107-110, 2002.6.  Minto CF, Schnider TW, Egan TD, Youngs E et al., Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. anesthesIology., 86(1), 10-23, 1997.7.  Minto CF, Schnider TW, Shafer SL, Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. anesthesIology, 86(1), 24-33, 1997.8.  GlaxoSmithKline : Ultiva for injection. Available from : http://www.mhra.gov.uk/9.  Egan TD, Lemmens HJ, Fiset P, Hermann DJ et al., The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. anesthesIology., 79(5), 881-892, 1993.10.  B. Braun : Naloxone for injection. Available from: http://www.mhra.gov.uk/concentration for muscle rigidity and seizure was reached so quickly, that the patient did not had the time to desaturate. To the best of our knowledge, equally high doses of remifentanil in non-anesthetized and non-intubated patients have only been used and described in preclinical pharmacokinetic studies (9). Also in these studies, muscle rigidity was observed as a major side-effect and had to be treated with a continuous infusion of succinylcholine, to allow mask ventilation. The literature is silent about the appropriate management of such a remifentanil overdose. It could be argued that antagonizing remifentanil with naloxone might have been a suitable therapeutic approach. For opioid overdoses, the prescribing information of naloxone(10) recommends repetitive doses of 0.4 mg-2 mg until a total dose of 10 mg has been achieved. In our hospital, only ampullas of 0.4 mg of naloxone (Naloxone B. Braun 0.4 mg. mL-1, 1 mL, Melsungen, Germany) are available. Hence, the preparation of up to 10 mg naloxone would have been too time-consuming in order to prevent hypoxemia. Waiting for spontaneous metabolization of remifentanil would have also taken too long. The spontaneous recovery of ventilation can only be expected at a remifentanil plasma concentration of around 2 ng mL-1 (8), and a large interindividual variability exists. The applied pharmacokinetic modeling shows that this concentration would have been reached only 35 minutes after the termination of the accidental infusion. One could argument that immediately starting an intravenous infusion of propofol is, maybe, not necessary, insofar as a plasma concentration of remifentanil of 150 ng mL-1 is enough to guarantee unconsciousness and amnesia. However, propofol was added immediately for two reasons. First, at the moment of the acute event, we did not know what the plasma concentration of remifentanil was. We knew it would be high, but there was no time to calculate the exact plasma concentration. Since there were no signs of hemodynamic instability, propofol was added to guarantee unconsciousness and amnesia. Secondly, since propofol also gives a certain degree of muscle relaxation, it was added to optimize intubation conditions. In our case, with apnea, the impossibility of mask ventilation and instrumentation of the upper airway, a rapid induction of general anesthesia, muscle relaxation, subsequent endotracheal intuba-tion and mechanical ventilation seemed the only and best available option.

   University of GroningenAcute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump.Vanneste, B; Van de Velde, M; Struys, Michel; Rex, SPublished in:Acta anaesthesiologica belgicaIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2017Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Vanneste, B., Van de Velde, M., Struys, M., & Rex, S. (2017). Acute and life-threatening remifentaniloverdose resulting from the misuse of a syringe pump. Acta anaesthesiologica belgica, 68(2), 87-89.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 10-09-2023© Acta Anæsthesiologica Belgica, 2017, 68, n° 2Abstract : In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.Key words : Remifentanil ; syringe pump ; critical incident ; difficult airway.IntroductIon In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.case report A 71-year-old, male patient (weight : 73 kg, height : 180 cm) was scheduled for the endovascular place-ment of an iliac branch prosthesis in order to correct an arterial aneurysm of the right common iliac artery and the right internal iliac artery. The past medical history included 30 pack-years of tobacco abuse (with smoking cessation in 2000), arterial hypertension (treated with nebivolol, amlodipine, olmesartan), hypercholesterolemia (treated with pravastatine) and an acute myocardial infarction in 2006, for which a drug-eluting stent had been placed in the left anterior descending artery (secondary prevention with low dose acetylsalicylic acid). For induction of total intravenous anesthesia, standard anesthesia monitors (non-invasive mea-surements of arterial blood pressure, 5-lead-electrocardiography, pulse-oximetry) were con-nected to the patient. A 16 G intravenous catheter (BD Insyte-W, Becton Dinckinson Infusion Therapy Systems Inc., Utah, USA) was placed in a dorsal vein of the left hand and connected to a triple lumen infusion device with three non-return valves (Octopus 3, Vycon, Ecouen, France). The first lumen was connected to a balanced crystalloid infusion (PLASMA-LYTE A, Baxter S.A., Lessines, Belgium). The second lumen was connected to a 50 ml prefilled propofol syringe (Diprivan 1%, AstraZeneca, Brussels, Belgium) through a 200-cm long, rigid extension tube (Original Perfusor Line, B. Braun, Melsungen, Germany). The third lumen was connected in the same way to a 50 mL syringe (Original Perfusor Syringe 50 mL, B. Braun, Escholzmatt, Switzerland) filled with remifentanil (Ultiva, GlaxoSmithKline Pharmaceuticals, Wavre, Belgium), 20 mL at a concentration of 100 µg/mL, equaling a total dose of 2 mg. Before connection to the patient, all tubing had been thoroughly flushed with the corresponding medications to evacuate all remaining air. Both syringes were placed horizontally into the syringe pumps (Alaris PK Syringe Pump, CareFusion, Rolle, Switzerland) that were fixed approximately 100 cm above the patient’s heart level. For the continuous monitoring of arterial blood pressure, the right arm of the patient was prepared for catheterization of the radial artery while awake. During puncturing, the right arm of the patient suddenly became spastic. The patient was unresponsive to both verbal and tactile stimulation. At this moment we noted that the remifentanil syringe was completely empty. We (Acta Anaesth. Belg., 2017, 68, 87-89)Bert Vanneste, Marc Van de Velde, M.M.R.F. Struys, Steffen Rex.(*) Department of Anesthesiology, University Hospitals of the KU Leuven, Leuven, Belgium.(**) Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.(***) Department of Anesthesiology, AZ Groeninge, Kortrijk, Belgium.(****) Department of Anesthesiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands and Department of Anesthesia, Ghent University, Gent, Belgium.Correspondence address : Bert Vanneste, President Kennedy-laan 4, 8500 Kortrijk, Belgium. Telephone: + 32 497 24 44 55.Email: bert.vanneste@azgroeninge.beInformed consent of the patient for publication of this case report was obtained.Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pumpB. Vanneste (*, ***), M. Van de Velde (*, **), M. M. R. F. struys (****) and S. rex (*, **)© Acta Anæsthesiologica Belgica, 2017, 68, n° 288 b. Vanneste et al. administration (2) and dose miscalculation (3). In our case, the syringe plunger had accidentally not been locked in the pusher lever of the syringe pump, allowing remifentanil to be evacuated as a bolus into the patient. Similar mishaps with syringe pumps have been described with morphine and midazo- lam (4), and with a patient-controlled analgesia pump (5). The physics underlying this accident have been previously described in detail by shenkman et al (4). Briefly, given the fact that the patient’s arm was positioned 100 cm lower than the syringe pump, the syringe plunger was displaced by the negative hydrostatic force resulting from this level difference between the intravenous catheter and the syringe (4). Additionally, the evacuation of the syringe might have been facilitated by the Venturi effect, elicited by the high-flow crystalloid infusion that was connected to the multilumen infusion device and hence indirectly also to the remifentanil syringe. We reproduced this incident using the same setting, however without patient and replacing remifentanil with a saline solution. After unlocking the pusher lever from the plunger, the syringe emptied spontaneously through the rigid extension tube into the fast-running infusion. Within less than 4 minutes, the total syringe volume of 20 mL had emptied. Our patient received 2 mg remifentanil over a time span of only a few minutes. A normal induction dose for this patient would be approximately 0.04 - 0.08 mg in one minute. This means that we inadvertently administered at least a 25-fold normal induction dose. We simulated the time course of the plasma concentration of remifentanil in this patient using a simulation program (RUGLOOP II, DEMED, Temse, Belgium), loaded with the compartmental pharmacokinetic model as published by mInto et al (6, 7). We found that this bolus administration resulted in a calculated plasma concentration of remifentanil of approximately 150 ng mL-1, a 30-fold normally targeted plasma concentration (8). Due to this massive overdose in our case, almost all side effects of remifentanil became instantaneously obvious : sedation, rigidity of skele-tal striated muscles, bradycardia (although not so marked in this case), respiratory depression and apnea (8). In this case, we were alerted by the spasticity and the tonic-clonic seizure of the patient. Normally, one would expect that desaturation would be the first sign of such a high dose of remifentanil. We believe that, due to the fast infusion of the medication and the rapid onset of remifentanil, the plasma also noticed that the plunger of the syringe was not locked in the pusher lever. These observations were suggestive for the diagnosis of an acute overdose of remifentanil due to an inadvertent bolus injection of 20 mL (2 mg) remifentanil. The left arm of the patient became also spastic at that time. Both legs showed a tonic-clonic seizure behavior, while the upper limbs developed flexion contracture, making accurate non-invasive measurement of arterial blood pressure impossible. The carotid pulse could still be palpated. The patient’s heart rate decreased from 80 beats min-1 to 65 beats min-1. Soon, the patient became apneic, and peripheral saturation decreased. An attempt was made to manually ventilate the patient through a face mask, which was however not successful, because of severe muscle rigidity of the chest. Due to an extreme spasm of both masseter muscles, the mouth of the patient could not be opened, for the placement of an endotracheal tube or a supraglottic device. The minimal measured saturation at that moment was 61 %. Therefore, we made the decision to immediately induce general anesthesia with an intravenous infusion of propofol (target controlled infusion, Marsh model, 4.0 µg mL -1) and rocuronium bromide 50 mg (Esmeron, Organon, Oss, Nederland). Thirty seconds later, the patient’s musculature started to relax and manual ventilation became possible. The trachea of the patient was intubated and the patient was mechanically ventilated. Next, the right radial artery was cannulated, revealing an arterial blood pressure of 94/46 mmHg. Total intravenous anesthesia was maintained using propofol (target-controlled infusion, Marsh model, 4.0 µg mL-1) and remifentanil (0.1 µg Kg-1 min-1). The surgical procedure was performed as scheduled, and was uneventful. After the end of surgery, the patient awoke 6 minutes after discontinuation of anesthesia. The patient was repeatedly evaluated: immediately after extubation, one hour after surgery in the recovery room, and thirty hours after surgery on the surgical ward. No adverse events could be documented. When answering the Brice questionnaire during the last post-anesthesia visit, the patient did not report any explicit awareness of the event. The last thing he could remember was that, before entering the operating room, one of the nurses placed a surgical cap on his head.dIscussIon The inadvertent administration of high doses of remifentanil have been described as a consequence of defective syringe pumps (1), accidental bolus © Acta Anæsthesiologica Belgica, 2017, 68, n° 2 acute and lIfe-threatenIng remIfentanIl oVerdose 89conclusIon Although frequently neglected by caregivers, the safe use of syringe pumps requires continuous attention and thorough understanding of the under-lying physics and possible sources of error.  We present a case in which an accidental overdose of remifentanil occurred because the syringe plunger had accidentally not been locked in the pusher lever, allowing the spontaneous evacuation of the syringe. A comparable incident outside the setting of a fully equipped anesthesia working place would have certainly been associated with major morbidity or even mortality of the affected patient. It is therefore important to note that any drug infusion should be connected to the patient only after the correct assembly of the syringe pump installation has been checked. Users must verify that the syringe plunger is properly secured to the pusher lever. Moreover, intravenous infusion lines containing vasoactive drugs or potent anesthetic drugs ideally need anti-reflux valves. A further preventive measure would be to place syringe pumps only below the patient’s heart level. At last the anesthesiologist should only turn the stopcock of the entry of the intravenous medication when he/she is sure that everything has been checked and safe administration of the medication can be guaranteed.Reference1.. Montserrat JM, Pérez-Hick PA, Remifentanil overdose in obstetric analgesia caused by a defective syringe in a patient-controlled analgesia system. reV esp anestesIol reanIm., 58(8), 530-531, 2011.2.  Bakan M, Cakmakkaya S, Onsel I, Kaya G. Inadvertent bolus administration of high-dose remifentanil during anesthesia in a 6-year-old girl. paedIatr anaesth., 16(11), 1202, 2006. 3.  Barak M, Greenberg Z, Danino J, Delayed awakening following inadvertent high-dose remifentanil infusion in a 13 year old patient. J clIn anesth., 23(4), 322-324, 2011.4.  Shenkman Z, Ornstein E, Adler D, Drug Overdose as a Consequence of Misuse of a Syringe Pump, anesth analg., 81(3), 652-653, 1995.5.  Steffen M, von Hintzenstern U, Obermayer A, Critical infusion incident caused by incorrect use of a patient-controlled analgesia pump, anaesthesIol reanIm., 27(4), 107-110, 2002.6.  Minto CF, Schnider TW, Egan TD, Youngs E et al., Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. anesthesIology., 86(1), 10-23, 1997.7.  Minto CF, Schnider TW, Shafer SL, Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. anesthesIology, 86(1), 24-33, 1997.8.  GlaxoSmithKline : Ultiva for injection. Available from : http://www.mhra.gov.uk/9.  Egan TD, Lemmens HJ, Fiset P, Hermann DJ et al., The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. anesthesIology., 79(5), 881-892, 1993.10.  B. Braun : Naloxone for injection. Available from: http://www.mhra.gov.uk/concentration for muscle rigidity and seizure was reached so quickly, that the patient did not had the time to desaturate. To the best of our knowledge, equally high doses of remifentanil in non-anesthetized and non-intubated patients have only been used and described in preclinical pharmacokinetic studies (9). Also in these studies, muscle rigidity was observed as a major side-effect and had to be treated with a continuous infusion of succinylcholine, to allow mask ventilation. The literature is silent about the appropriate management of such a remifentanil overdose. It could be argued that antagonizing remifentanil with naloxone might have been a suitable therapeutic approach. For opioid overdoses, the prescribing information of naloxone(10) recommends repetitive doses of 0.4 mg-2 mg until a total dose of 10 mg has been achieved. In our hospital, only ampullas of 0.4 mg of naloxone (Naloxone B. Braun 0.4 mg. mL-1, 1 mL, Melsungen, Germany) are available. Hence, the preparation of up to 10 mg naloxone would have been too time-consuming in order to prevent hypoxemia. Waiting for spontaneous metabolization of remifentanil would have also taken too long. The spontaneous recovery of ventilation can only be expected at a remifentanil plasma concentration of around 2 ng mL-1 (8), and a large interindividual variability exists. The applied pharmacokinetic modeling shows that this concentration would have been reached only 35 minutes after the termination of the accidental infusion. One could argument that immediately starting an intravenous infusion of propofol is, maybe, not necessary, insofar as a plasma concentration of remifentanil of 150 ng mL-1 is enough to guarantee unconsciousness and amnesia. However, propofol was added immediately for two reasons. First, at the moment of the acute event, we did not know what the plasma concentration of remifentanil was. We knew it would be high, but there was no time to calculate the exact plasma concentration. Since there were no signs of hemodynamic instability, propofol was added to guarantee unconsciousness and amnesia. Secondly, since propofol also gives a certain degree of muscle relaxation, it was added to optimize intubation conditions. In our case, with apnea, the impossibility of mask ventilation and instrumentation of the upper airway, a rapid induction of general anesthesia, muscle relaxation, subsequent endotracheal intuba-tion and mechanical ventilation seemed the only and best available option.

   University of GroningenAcute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump.Vanneste, B; Van de Velde, M; Struys, Michel; Rex, SPublished in:Acta anaesthesiologica belgicaIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2017Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Vanneste, B., Van de Velde, M., Struys, M., & Rex, S. (2017). Acute and life-threatening remifentaniloverdose resulting from the misuse of a syringe pump. Acta anaesthesiologica belgica, 68(2), 87-89.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 21-06-2022© Acta Anæsthesiologica Belgica, 2017, 68, n° 2Abstract : In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.Key words : Remifentanil ; syringe pump ; critical incident ; difficult airway.IntroductIon In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.case report A 71-year-old, male patient (weight : 73 kg, height : 180 cm) was scheduled for the endovascular place-ment of an iliac branch prosthesis in order to correct an arterial aneurysm of the right common iliac artery and the right internal iliac artery. The past medical history included 30 pack-years of tobacco abuse (with smoking cessation in 2000), arterial hypertension (treated with nebivolol, amlodipine, olmesartan), hypercholesterolemia (treated with pravastatine) and an acute myocardial infarction in 2006, for which a drug-eluting stent had been placed in the left anterior descending artery (secondary prevention with low dose acetylsalicylic acid). For induction of total intravenous anesthesia, standard anesthesia monitors (non-invasive mea-surements of arterial blood pressure, 5-lead-electrocardiography, pulse-oximetry) were con-nected to the patient. A 16 G intravenous catheter (BD Insyte-W, Becton Dinckinson Infusion Therapy Systems Inc., Utah, USA) was placed in a dorsal vein of the left hand and connected to a triple lumen infusion device with three non-return valves (Octopus 3, Vycon, Ecouen, France). The first lumen was connected to a balanced crystalloid infusion (PLASMA-LYTE A, Baxter S.A., Lessines, Belgium). The second lumen was connected to a 50 ml prefilled propofol syringe (Diprivan 1%, AstraZeneca, Brussels, Belgium) through a 200-cm long, rigid extension tube (Original Perfusor Line, B. Braun, Melsungen, Germany). The third lumen was connected in the same way to a 50 mL syringe (Original Perfusor Syringe 50 mL, B. Braun, Escholzmatt, Switzerland) filled with remifentanil (Ultiva, GlaxoSmithKline Pharmaceuticals, Wavre, Belgium), 20 mL at a concentration of 100 µg/mL, equaling a total dose of 2 mg. Before connection to the patient, all tubing had been thoroughly flushed with the corresponding medications to evacuate all remaining air. Both syringes were placed horizontally into the syringe pumps (Alaris PK Syringe Pump, CareFusion, Rolle, Switzerland) that were fixed approximately 100 cm above the patient’s heart level. For the continuous monitoring of arterial blood pressure, the right arm of the patient was prepared for catheterization of the radial artery while awake. During puncturing, the right arm of the patient suddenly became spastic. The patient was unresponsive to both verbal and tactile stimulation. At this moment we noted that the remifentanil syringe was completely empty. We (Acta Anaesth. Belg., 2017, 68, 87-89)Bert Vanneste, Marc Van de Velde, M.M.R.F. Struys, Steffen Rex.(*) Department of Anesthesiology, University Hospitals of the KU Leuven, Leuven, Belgium.(**) Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.(***) Department of Anesthesiology, AZ Groeninge, Kortrijk, Belgium.(****) Department of Anesthesiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands and Department of Anesthesia, Ghent University, Gent, Belgium.Correspondence address : Bert Vanneste, President Kennedy-laan 4, 8500 Kortrijk, Belgium. Telephone: + 32 497 24 44 55.Email: bert.vanneste@azgroeninge.beInformed consent of the patient for publication of this case report was obtained.Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pumpB. Vanneste (*, ***), M. Van de Velde (*, **), M. M. R. F. struys (****) and S. rex (*, **)© Acta Anæsthesiologica Belgica, 2017, 68, n° 288 b. Vanneste et al. administration (2) and dose miscalculation (3). In our case, the syringe plunger had accidentally not been locked in the pusher lever of the syringe pump, allowing remifentanil to be evacuated as a bolus into the patient. Similar mishaps with syringe pumps have been described with morphine and midazo- lam (4), and with a patient-controlled analgesia pump (5). The physics underlying this accident have been previously described in detail by shenkman et al (4). Briefly, given the fact that the patient’s arm was positioned 100 cm lower than the syringe pump, the syringe plunger was displaced by the negative hydrostatic force resulting from this level difference between the intravenous catheter and the syringe (4). Additionally, the evacuation of the syringe might have been facilitated by the Venturi effect, elicited by the high-flow crystalloid infusion that was connected to the multilumen infusion device and hence indirectly also to the remifentanil syringe. We reproduced this incident using the same setting, however without patient and replacing remifentanil with a saline solution. After unlocking the pusher lever from the plunger, the syringe emptied spontaneously through the rigid extension tube into the fast-running infusion. Within less than 4 minutes, the total syringe volume of 20 mL had emptied. Our patient received 2 mg remifentanil over a time span of only a few minutes. A normal induction dose for this patient would be approximately 0.04 - 0.08 mg in one minute. This means that we inadvertently administered at least a 25-fold normal induction dose. We simulated the time course of the plasma concentration of remifentanil in this patient using a simulation program (RUGLOOP II, DEMED, Temse, Belgium), loaded with the compartmental pharmacokinetic model as published by mInto et al (6, 7). We found that this bolus administration resulted in a calculated plasma concentration of remifentanil of approximately 150 ng mL-1, a 30-fold normally targeted plasma concentration (8). Due to this massive overdose in our case, almost all side effects of remifentanil became instantaneously obvious : sedation, rigidity of skele-tal striated muscles, bradycardia (although not so marked in this case), respiratory depression and apnea (8). In this case, we were alerted by the spasticity and the tonic-clonic seizure of the patient. Normally, one would expect that desaturation would be the first sign of such a high dose of remifentanil. We believe that, due to the fast infusion of the medication and the rapid onset of remifentanil, the plasma also noticed that the plunger of the syringe was not locked in the pusher lever. These observations were suggestive for the diagnosis of an acute overdose of remifentanil due to an inadvertent bolus injection of 20 mL (2 mg) remifentanil. The left arm of the patient became also spastic at that time. Both legs showed a tonic-clonic seizure behavior, while the upper limbs developed flexion contracture, making accurate non-invasive measurement of arterial blood pressure impossible. The carotid pulse could still be palpated. The patient’s heart rate decreased from 80 beats min-1 to 65 beats min-1. Soon, the patient became apneic, and peripheral saturation decreased. An attempt was made to manually ventilate the patient through a face mask, which was however not successful, because of severe muscle rigidity of the chest. Due to an extreme spasm of both masseter muscles, the mouth of the patient could not be opened, for the placement of an endotracheal tube or a supraglottic device. The minimal measured saturation at that moment was 61 %. Therefore, we made the decision to immediately induce general anesthesia with an intravenous infusion of propofol (target controlled infusion, Marsh model, 4.0 µg mL -1) and rocuronium bromide 50 mg (Esmeron, Organon, Oss, Nederland). Thirty seconds later, the patient’s musculature started to relax and manual ventilation became possible. The trachea of the patient was intubated and the patient was mechanically ventilated. Next, the right radial artery was cannulated, revealing an arterial blood pressure of 94/46 mmHg. Total intravenous anesthesia was maintained using propofol (target-controlled infusion, Marsh model, 4.0 µg mL-1) and remifentanil (0.1 µg Kg-1 min-1). The surgical procedure was performed as scheduled, and was uneventful. After the end of surgery, the patient awoke 6 minutes after discontinuation of anesthesia. The patient was repeatedly evaluated: immediately after extubation, one hour after surgery in the recovery room, and thirty hours after surgery on the surgical ward. No adverse events could be documented. When answering the Brice questionnaire during the last post-anesthesia visit, the patient did not report any explicit awareness of the event. The last thing he could remember was that, before entering the operating room, one of the nurses placed a surgical cap on his head.dIscussIon The inadvertent administration of high doses of remifentanil have been described as a consequence of defective syringe pumps (1), accidental bolus © Acta Anæsthesiologica Belgica, 2017, 68, n° 2 acute and lIfe-threatenIng remIfentanIl oVerdose 89conclusIon Although frequently neglected by caregivers, the safe use of syringe pumps requires continuous attention and thorough understanding of the under-lying physics and possible sources of error.  We present a case in which an accidental overdose of remifentanil occurred because the syringe plunger had accidentally not been locked in the pusher lever, allowing the spontaneous evacuation of the syringe. A comparable incident outside the setting of a fully equipped anesthesia working place would have certainly been associated with major morbidity or even mortality of the affected patient. It is therefore important to note that any drug infusion should be connected to the patient only after the correct assembly of the syringe pump installation has been checked. Users must verify that the syringe plunger is properly secured to the pusher lever. Moreover, intravenous infusion lines containing vasoactive drugs or potent anesthetic drugs ideally need anti-reflux valves. A further preventive measure would be to place syringe pumps only below the patient’s heart level. At last the anesthesiologist should only turn the stopcock of the entry of the intravenous medication when he/she is sure that everything has been checked and safe administration of the medication can be guaranteed.Reference1.. Montserrat JM, Pérez-Hick PA, Remifentanil overdose in obstetric analgesia caused by a defective syringe in a patient-controlled analgesia system. reV esp anestesIol reanIm., 58(8), 530-531, 2011.2.  Bakan M, Cakmakkaya S, Onsel I, Kaya G. Inadvertent bolus administration of high-dose remifentanil during anesthesia in a 6-year-old girl. paedIatr anaesth., 16(11), 1202, 2006. 3.  Barak M, Greenberg Z, Danino J, Delayed awakening following inadvertent high-dose remifentanil infusion in a 13 year old patient. J clIn anesth., 23(4), 322-324, 2011.4.  Shenkman Z, Ornstein E, Adler D, Drug Overdose as a Consequence of Misuse of a Syringe Pump, anesth analg., 81(3), 652-653, 1995.5.  Steffen M, von Hintzenstern U, Obermayer A, Critical infusion incident caused by incorrect use of a patient-controlled analgesia pump, anaesthesIol reanIm., 27(4), 107-110, 2002.6.  Minto CF, Schnider TW, Egan TD, Youngs E et al., Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. anesthesIology., 86(1), 10-23, 1997.7.  Minto CF, Schnider TW, Shafer SL, Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. anesthesIology, 86(1), 24-33, 1997.8.  GlaxoSmithKline : Ultiva for injection. Available from : http://www.mhra.gov.uk/9.  Egan TD, Lemmens HJ, Fiset P, Hermann DJ et al., The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. anesthesIology., 79(5), 881-892, 1993.10.  B. Braun : Naloxone for injection. Available from: http://www.mhra.gov.uk/concentration for muscle rigidity and seizure was reached so quickly, that the patient did not had the time to desaturate. To the best of our knowledge, equally high doses of remifentanil in non-anesthetized and non-intubated patients have only been used and described in preclinical pharmacokinetic studies (9). Also in these studies, muscle rigidity was observed as a major side-effect and had to be treated with a continuous infusion of succinylcholine, to allow mask ventilation. The literature is silent about the appropriate management of such a remifentanil overdose. It could be argued that antagonizing remifentanil with naloxone might have been a suitable therapeutic approach. For opioid overdoses, the prescribing information of naloxone(10) recommends repetitive doses of 0.4 mg-2 mg until a total dose of 10 mg has been achieved. In our hospital, only ampullas of 0.4 mg of naloxone (Naloxone B. Braun 0.4 mg. mL-1, 1 mL, Melsungen, Germany) are available. Hence, the preparation of up to 10 mg naloxone would have been too time-consuming in order to prevent hypoxemia. Waiting for spontaneous metabolization of remifentanil would have also taken too long. The spontaneous recovery of ventilation can only be expected at a remifentanil plasma concentration of around 2 ng mL-1 (8), and a large interindividual variability exists. The applied pharmacokinetic modeling shows that this concentration would have been reached only 35 minutes after the termination of the accidental infusion. One could argument that immediately starting an intravenous infusion of propofol is, maybe, not necessary, insofar as a plasma concentration of remifentanil of 150 ng mL-1 is enough to guarantee unconsciousness and amnesia. However, propofol was added immediately for two reasons. First, at the moment of the acute event, we did not know what the plasma concentration of remifentanil was. We knew it would be high, but there was no time to calculate the exact plasma concentration. Since there were no signs of hemodynamic instability, propofol was added to guarantee unconsciousness and amnesia. Secondly, since propofol also gives a certain degree of muscle relaxation, it was added to optimize intubation conditions. In our case, with apnea, the impossibility of mask ventilation and instrumentation of the upper airway, a rapid induction of general anesthesia, muscle relaxation, subsequent endotracheal intuba-tion and mechanical ventilation seemed the only and best available option.

University of Groningen Research Database

  
 University of Groningen
Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump.
Vanneste, B; Van de Velde, M; Struys, Michel; Rex, S
Published in:
Acta anaesthesiologica belgica
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2017
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Vanneste, B., Van de Velde, M., Struys, M., & Rex, S. (2017). Acute and life-threatening remifentanil
overdose resulting from the misuse of a syringe pump. Acta anaesthesiologica belgica, 68, 87-89.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
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Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 11-04-2018
© Acta Anæsthesiologica Belgica, 2017, 68, n° 2
Abstract : In the perioperative setting, syringe pumps are 
frequently used. They guarantee constant plasma levels 
of hypnotics, opioids, cardiovascular medication, insulin 
or other drugs. We present a case in which an inadvertent 
rapid intravenous injection of 2 mg remifentanil occurred 
due to the misuse of a syringe pump.
Key words : Remifentanil ; syringe pump ; critical 
incident ; difficult airway.
IntroductIon
 In the perioperative setting, syringe pumps 
are frequently used. They guarantee constant 
plasma levels of hypnotics, opioids, cardiovascular 
medication, insulin or other drugs. We present a case 
in which an inadvertent rapid intravenous injection 
of 2 mg remifentanil occurred due to the misuse of 
a syringe pump.
case report
 A 71-year-old, male patient (weight : 73 kg, 
height : 180 cm) was scheduled for the endovascular 
place-ment of an iliac branch prosthesis in order to 
correct an arterial aneurysm of the right common 
iliac artery and the right internal iliac artery. The past 
medical history included 30 pack-years of tobacco 
abuse (with smoking cessation in 2000), arterial 
hypertension (treated with nebivolol, amlodipine, 
olmesartan), hypercholesterolemia (treated with 
pravastatine) and an acute myocardial infarction in 
2006, for which a drug-eluting stent had been placed 
in the left anterior descending artery (secondary 
prevention with low dose acetylsalicylic acid).
 For induction of total intravenous anesthesia, 
standard anesthesia monitors (non-invasive mea-
surements of arterial blood pressure, 5-lead-
electrocardiography, pulse-oximetry) were con-
nected to the patient. A 16 G intravenous catheter 
(BD Insyte-W, Becton Dinckinson Infusion 
Therapy Systems Inc., Utah, USA) was placed in 
a dorsal vein of the left hand and connected to a 
triple lumen infusion device with three non-return 
valves (Octopus 3, Vycon, Ecouen, France). The 
first lumen was connected to a balanced crystalloid 
infusion (PLASMA-LYTE A, Baxter S.A., Lessines, 
Belgium). The second lumen was connected to a 
50 ml prefilled propofol syringe (Diprivan 1%, 
AstraZeneca, Brussels, Belgium) through a 200-cm 
long, rigid extension tube (Original Perfusor Line, 
B. Braun, Melsungen, Germany). The third lumen 
was connected in the same way to a 50 mL syringe 
(Original Perfusor Syringe 50 mL, B. Braun, 
Escholzmatt, Switzerland) filled with remifentanil 
(Ultiva, GlaxoSmithKline Pharmaceuticals, Wavre, 
Belgium), 20 mL at a concentration of 100 µg/mL, 
equaling a total dose of 2 mg. Before connection 
to the patient, all tubing had been thoroughly 
flushed with the corresponding medications to 
evacuate all remaining air. Both syringes were 
placed horizontally into the syringe pumps (Alaris 
PK Syringe Pump, CareFusion, Rolle, Switzerland) 
that were fixed approximately 100 cm above the 
patient’s heart level.
 For the continuous monitoring of arterial 
blood pressure, the right arm of the patient was 
prepared for catheterization of the radial artery 
while awake. During puncturing, the right arm of 
the patient suddenly became spastic. The patient 
was unresponsive to both verbal and tactile 
stimulation. At this moment we noted that the 
remifentanil syringe was completely empty. We 
(Acta Anaesth. Belg., 2017, 68, 87-89)
Bert Vanneste, Marc Van de Velde, M.M.R.F. Struys, Steffen 
Rex.
(*) Department of Anesthesiology, University Hospitals of the 
KU Leuven, Leuven, Belgium.
(**) Department of Cardiovascular Sciences, KU Leuven, 
Leuven, Belgium.
(***) Department of Anesthesiology, AZ Groeninge, Kortrijk, 
Belgium.
(****) Department of Anesthesiology, University of Groningen 
and University Medical Center Groningen, Groningen, 
The Netherlands and Department of Anesthesia, Ghent 
University, Gent, Belgium.
Correspondence address : Bert Vanneste, President Kennedy-
laan 4, 8500 Kortrijk, Belgium. Telephone: + 32 497 24 44 
55.
Email: bert.vanneste@azgroeninge.be
Informed consent of the patient for publication of this case 
report was obtained.
Acute and life-threatening remifentanil overdose resulting from the 
misuse of a syringe pump
B. Vanneste (*, ***), M. Van de Velde (*, **), M. M. R. F. struys (****) and S. rex (*, **)
© Acta Anæsthesiologica Belgica, 2017, 68, n° 2
88 b. Vanneste et al. 
administration (2) and dose miscalculation (3). In 
our case, the syringe plunger had accidentally not 
been locked in the pusher lever of the syringe pump, 
allowing remifentanil to be evacuated as a bolus into 
the patient. Similar mishaps with syringe pumps 
have been described with morphine and midazo- 
lam (4), and with a patient-controlled analgesia 
pump (5).
 The physics underlying this accident have 
been previously described in detail by shenkman 
et al (4). Briefly, given the fact that the patient’s 
arm was positioned 100 cm lower than the syringe 
pump, the syringe plunger was displaced by the 
negative hydrostatic force resulting from this level 
difference between the intravenous catheter and 
the syringe (4). Additionally, the evacuation of the 
syringe might have been facilitated by the Venturi 
effect, elicited by the high-flow crystalloid infusion 
that was connected to the multilumen infusion 
device and hence indirectly also to the remifentanil 
syringe.
 We reproduced this incident using the same 
setting, however without patient and replacing 
remifentanil with a saline solution. After unlocking 
the pusher lever from the plunger, the syringe emptied 
spontaneously through the rigid extension tube into 
the fast-running infusion. Within less than 4 minutes, 
the total syringe volume of 20 mL had emptied. Our 
patient received 2 mg remifentanil over a time span 
of only a few minutes. A normal induction dose for 
this patient would be approximately 0.04 - 0.08 mg 
in one minute. This means that we inadvertently 
administered at least a 25-fold normal induction 
dose. We simulated the time course of the plasma 
concentration of remifentanil in this patient using 
a simulation program (RUGLOOP II, DEMED, 
Temse, Belgium), loaded with the compartmental 
pharmacokinetic model as published by mInto et 
al (6, 7). We found that this bolus administration 
resulted in a calculated plasma concentration of 
remifentanil of approximately 150 ng mL-1, a 30-
fold normally targeted plasma concentration (8).
 Due to this massive overdose in our case, 
almost all side effects of remifentanil became 
instantaneously obvious : sedation, rigidity of skele-
tal striated muscles, bradycardia (although not so 
marked in this case), respiratory depression and 
apnea (8).
 In this case, we were alerted by the spasticity 
and the tonic-clonic seizure of the patient. Normally, 
one would expect that desaturation would be the first 
sign of such a high dose of remifentanil. We believe 
that, due to the fast infusion of the medication 
and the rapid onset of remifentanil, the plasma 
also noticed that the plunger of the syringe was not 
locked in the pusher lever. These observations were 
suggestive for the diagnosis of an acute overdose of 
remifentanil due to an inadvertent bolus injection 
of 20 mL (2 mg) remifentanil. The left arm of the 
patient became also spastic at that time. Both legs 
showed a tonic-clonic seizure behavior, while the 
upper limbs developed flexion contracture, making 
accurate non-invasive measurement of arterial blood 
pressure impossible. The carotid pulse could still be 
palpated. The patient’s heart rate decreased from 
80 beats min-1 to 65 beats min-1. Soon, the patient 
became apneic, and peripheral saturation decreased. 
An attempt was made to manually ventilate the 
patient through a face mask, which was however 
not successful, because of severe muscle rigidity of 
the chest. Due to an extreme spasm of both masseter 
muscles, the mouth of the patient could not be 
opened, for the placement of an endotracheal tube 
or a supraglottic device. The minimal measured 
saturation at that moment was 61 %. Therefore, we 
made the decision to immediately induce general 
anesthesia with an intravenous infusion of propofol 
(target controlled infusion, Marsh model, 4.0 µg 
mL -1) and rocuronium bromide 50 mg (Esmeron, 
Organon, Oss, Nederland). Thirty seconds later, 
the patient’s musculature started to relax and 
manual ventilation became possible. The trachea 
of the patient was intubated and the patient was 
mechanically ventilated. Next, the right radial artery 
was cannulated, revealing an arterial blood pressure 
of 94/46 mmHg. Total intravenous anesthesia 
was maintained using propofol (target-controlled 
infusion, Marsh model, 4.0 µg mL-1) and remifentanil 
(0.1 µg Kg-1 min-1). The surgical procedure was 
performed as scheduled, and was uneventful. After 
the end of surgery, the patient awoke 6 minutes 
after discontinuation of anesthesia. The patient was 
repeatedly evaluated: immediately after extubation, 
one hour after surgery in the recovery room, and 
thirty hours after surgery on the surgical ward. 
No adverse events could be documented. When 
answering the Brice questionnaire during the last 
post-anesthesia visit, the patient did not report 
any explicit awareness of the event. The last thing 
he could remember was that, before entering the 
operating room, one of the nurses placed a surgical 
cap on his head.
dIscussIon
 The inadvertent administration of high doses of 
remifentanil have been described as a consequence 
of defective syringe pumps (1), accidental bolus 
© Acta Anæsthesiologica Belgica, 2017, 68, n° 2
 acute and lIfe-threatenIng remIfentanIl oVerdose 89
conclusIon
 Although frequently neglected by caregivers, 
the safe use of syringe pumps requires continuous 
attention and thorough understanding of the under-
lying physics and possible sources of error. 
 We present a case in which an accidental 
overdose of remifentanil occurred because the 
syringe plunger had accidentally not been locked 
in the pusher lever, allowing the spontaneous 
evacuation of the syringe. A comparable incident 
outside the setting of a fully equipped anesthesia 
working place would have certainly been associated 
with major morbidity or even mortality of the 
affected patient. It is therefore important to note that 
any drug infusion should be connected to the patient 
only after the correct assembly of the syringe pump 
installation has been checked. Users must verify 
that the syringe plunger is properly secured to the 
pusher lever. Moreover, intravenous infusion lines 
containing vasoactive drugs or potent anesthetic 
drugs ideally need anti-reflux valves. A further 
preventive measure would be to place syringe 
pumps only below the patient’s heart level. At last 
the anesthesiologist should only turn the stopcock of 
the entry of the intravenous medication when he/she 
is sure that everything has been checked and safe 
administration of the medication can be guaranteed.
Reference
1.. Montserrat JM, Pérez-Hick PA, Remifentanil overdose 
in obstetric analgesia caused by a defective syringe in a 
patient-controlled analgesia system. reV esp anestesIol 
reanIm., 58(8), 530-531, 2011.
2.  Bakan M, Cakmakkaya S, Onsel I, Kaya G. Inadvertent 
bolus administration of high-dose remifentanil during 
anesthesia in a 6-year-old girl. paedIatr anaesth., 16(11), 
1202, 2006. 
3.  Barak M, Greenberg Z, Danino J, Delayed awakening 
following inadvertent high-dose remifentanil infusion in a 
13 year old patient. J clIn anesth., 23(4), 322-324, 2011.
4.  Shenkman Z, Ornstein E, Adler D, Drug Overdose as a 
Consequence of Misuse of a Syringe Pump, anesth analg., 
81(3), 652-653, 1995.
5.  Steffen M, von Hintzenstern U, Obermayer A, Critical 
infusion incident caused by incorrect use of a patient-
controlled analgesia pump, anaesthesIol reanIm., 27(4), 
107-110, 2002.
6.  Minto CF, Schnider TW, Egan TD, Youngs E et al., 
Influence of age and gender on the pharmacokinetics and 
pharmacodynamics of remifentanil. I. Model development. 
anesthesIology., 86(1), 10-23, 1997.
7.  Minto CF, Schnider TW, Shafer SL, Pharmacokinetics and 
pharmacodynamics of remifentanil. II. Model application. 
anesthesIology, 86(1), 24-33, 1997.
8.  GlaxoSmithKline : Ultiva for injection. Available from : 
http://www.mhra.gov.uk/
9.  Egan TD, Lemmens HJ, Fiset P, Hermann DJ et al., 
The pharmacokinetics of the new short-acting opioid 
remifentanil (GI87084B) in healthy adult male volunteers. 
anesthesIology., 79(5), 881-892, 1993.
10.  B. Braun : Naloxone for injection. Available from: http://
www.mhra.gov.uk/
concentration for muscle rigidity and seizure was 
reached so quickly, that the patient did not had the 
time to desaturate.
 To the best of our knowledge, equally high 
doses of remifentanil in non-anesthetized and 
non-intubated patients have only been used and 
described in preclinical pharmacokinetic studies (9). 
Also in these studies, muscle rigidity was observed 
as a major side-effect and had to be treated with a 
continuous infusion of succinylcholine, to allow 
mask ventilation.
 The literature is silent about the appropriate 
management of such a remifentanil overdose. It 
could be argued that antagonizing remifentanil with 
naloxone might have been a suitable therapeutic 
approach. For opioid overdoses, the prescribing 
information of naloxone(10) recommends repetitive 
doses of 0.4 mg-2 mg until a total dose of 10 mg has 
been achieved. In our hospital, only ampullas of 0.4 
mg of naloxone (Naloxone B. Braun 0.4 mg. mL-1, 
1 mL, Melsungen, Germany) are available. Hence, 
the preparation of up to 10 mg naloxone would 
have been too time-consuming in order to prevent 
hypoxemia.
 Waiting for spontaneous metabolization of 
remifentanil would have also taken too long. The 
spontaneous recovery of ventilation can only be 
expected at a remifentanil plasma concentration of 
around 2 ng mL-1 (8), and a large interindividual 
variability exists. The applied pharmacokinetic 
modeling shows that this concentration would have 
been reached only 35 minutes after the termination 
of the accidental infusion.
 One could argument that immediately starting 
an intravenous infusion of propofol is, maybe, not 
necessary, insofar as a plasma concentration of 
remifentanil of 150 ng mL-1 is enough to guarantee 
unconsciousness and amnesia. However, propofol 
was added immediately for two reasons. First, at 
the moment of the acute event, we did not know 
what the plasma concentration of remifentanil was. 
We knew it would be high, but there was no time 
to calculate the exact plasma concentration. Since 
there were no signs of hemodynamic instability, 
propofol was added to guarantee unconsciousness 
and amnesia. Secondly, since propofol also gives a 
certain degree of muscle relaxation, it was added to 
optimize intubation conditions.
 In our case, with apnea, the impossibility of 
mask ventilation and instrumentation of the upper 
airway, a rapid induction of general anesthesia, 
muscle relaxation, subsequent endotracheal intuba-
tion and mechanical ventilation seemed the only 
and best available option.


In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump

Vanneste, B.

Van de Velde, M.

Rex, S.

Ghent University Academic Bibliography

Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump

   University of GroningenAcute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump.Vanneste, B; Van de Velde, M; Struys, Michel; Rex, SPublished in:Acta anaesthesiologica belgicaIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2017Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Vanneste, B., Van de Velde, M., Struys, M., & Rex, S. (2017). Acute and life-threatening remifentaniloverdose resulting from the misuse of a syringe pump. Acta anaesthesiologica belgica, 68(2), 87-89.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 09-09-2023© Acta Anæsthesiologica Belgica, 2017, 68, n° 2Abstract : In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.Key words : Remifentanil ; syringe pump ; critical incident ; difficult airway.IntroductIon In the perioperative setting, syringe pumps are frequently used. They guarantee constant plasma levels of hypnotics, opioids, cardiovascular medication, insulin or other drugs. We present a case in which an inadvertent rapid intravenous injection of 2 mg remifentanil occurred due to the misuse of a syringe pump.case report A 71-year-old, male patient (weight : 73 kg, height : 180 cm) was scheduled for the endovascular place-ment of an iliac branch prosthesis in order to correct an arterial aneurysm of the right common iliac artery and the right internal iliac artery. The past medical history included 30 pack-years of tobacco abuse (with smoking cessation in 2000), arterial hypertension (treated with nebivolol, amlodipine, olmesartan), hypercholesterolemia (treated with pravastatine) and an acute myocardial infarction in 2006, for which a drug-eluting stent had been placed in the left anterior descending artery (secondary prevention with low dose acetylsalicylic acid). For induction of total intravenous anesthesia, standard anesthesia monitors (non-invasive mea-surements of arterial blood pressure, 5-lead-electrocardiography, pulse-oximetry) were con-nected to the patient. A 16 G intravenous catheter (BD Insyte-W, Becton Dinckinson Infusion Therapy Systems Inc., Utah, USA) was placed in a dorsal vein of the left hand and connected to a triple lumen infusion device with three non-return valves (Octopus 3, Vycon, Ecouen, France). The first lumen was connected to a balanced crystalloid infusion (PLASMA-LYTE A, Baxter S.A., Lessines, Belgium). The second lumen was connected to a 50 ml prefilled propofol syringe (Diprivan 1%, AstraZeneca, Brussels, Belgium) through a 200-cm long, rigid extension tube (Original Perfusor Line, B. Braun, Melsungen, Germany). The third lumen was connected in the same way to a 50 mL syringe (Original Perfusor Syringe 50 mL, B. Braun, Escholzmatt, Switzerland) filled with remifentanil (Ultiva, GlaxoSmithKline Pharmaceuticals, Wavre, Belgium), 20 mL at a concentration of 100 µg/mL, equaling a total dose of 2 mg. Before connection to the patient, all tubing had been thoroughly flushed with the corresponding medications to evacuate all remaining air. Both syringes were placed horizontally into the syringe pumps (Alaris PK Syringe Pump, CareFusion, Rolle, Switzerland) that were fixed approximately 100 cm above the patient’s heart level. For the continuous monitoring of arterial blood pressure, the right arm of the patient was prepared for catheterization of the radial artery while awake. During puncturing, the right arm of the patient suddenly became spastic. The patient was unresponsive to both verbal and tactile stimulation. At this moment we noted that the remifentanil syringe was completely empty. We (Acta Anaesth. Belg., 2017, 68, 87-89)Bert Vanneste, Marc Van de Velde, M.M.R.F. Struys, Steffen Rex.(*) Department of Anesthesiology, University Hospitals of the KU Leuven, Leuven, Belgium.(**) Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium.(***) Department of Anesthesiology, AZ Groeninge, Kortrijk, Belgium.(****) Department of Anesthesiology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands and Department of Anesthesia, Ghent University, Gent, Belgium.Correspondence address : Bert Vanneste, President Kennedy-laan 4, 8500 Kortrijk, Belgium. Telephone: + 32 497 24 44 55.Email: bert.vanneste@azgroeninge.beInformed consent of the patient for publication of this case report was obtained.Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pumpB. Vanneste (*, ***), M. Van de Velde (*, **), M. M. R. F. struys (****) and S. rex (*, **)© Acta Anæsthesiologica Belgica, 2017, 68, n° 288 b. Vanneste et al. administration (2) and dose miscalculation (3). In our case, the syringe plunger had accidentally not been locked in the pusher lever of the syringe pump, allowing remifentanil to be evacuated as a bolus into the patient. Similar mishaps with syringe pumps have been described with morphine and midazo- lam (4), and with a patient-controlled analgesia pump (5). The physics underlying this accident have been previously described in detail by shenkman et al (4). Briefly, given the fact that the patient’s arm was positioned 100 cm lower than the syringe pump, the syringe plunger was displaced by the negative hydrostatic force resulting from this level difference between the intravenous catheter and the syringe (4). Additionally, the evacuation of the syringe might have been facilitated by the Venturi effect, elicited by the high-flow crystalloid infusion that was connected to the multilumen infusion device and hence indirectly also to the remifentanil syringe. We reproduced this incident using the same setting, however without patient and replacing remifentanil with a saline solution. After unlocking the pusher lever from the plunger, the syringe emptied spontaneously through the rigid extension tube into the fast-running infusion. Within less than 4 minutes, the total syringe volume of 20 mL had emptied. Our patient received 2 mg remifentanil over a time span of only a few minutes. A normal induction dose for this patient would be approximately 0.04 - 0.08 mg in one minute. This means that we inadvertently administered at least a 25-fold normal induction dose. We simulated the time course of the plasma concentration of remifentanil in this patient using a simulation program (RUGLOOP II, DEMED, Temse, Belgium), loaded with the compartmental pharmacokinetic model as published by mInto et al (6, 7). We found that this bolus administration resulted in a calculated plasma concentration of remifentanil of approximately 150 ng mL-1, a 30-fold normally targeted plasma concentration (8). Due to this massive overdose in our case, almost all side effects of remifentanil became instantaneously obvious : sedation, rigidity of skele-tal striated muscles, bradycardia (although not so marked in this case), respiratory depression and apnea (8). In this case, we were alerted by the spasticity and the tonic-clonic seizure of the patient. Normally, one would expect that desaturation would be the first sign of such a high dose of remifentanil. We believe that, due to the fast infusion of the medication and the rapid onset of remifentanil, the plasma also noticed that the plunger of the syringe was not locked in the pusher lever. These observations were suggestive for the diagnosis of an acute overdose of remifentanil due to an inadvertent bolus injection of 20 mL (2 mg) remifentanil. The left arm of the patient became also spastic at that time. Both legs showed a tonic-clonic seizure behavior, while the upper limbs developed flexion contracture, making accurate non-invasive measurement of arterial blood pressure impossible. The carotid pulse could still be palpated. The patient’s heart rate decreased from 80 beats min-1 to 65 beats min-1. Soon, the patient became apneic, and peripheral saturation decreased. An attempt was made to manually ventilate the patient through a face mask, which was however not successful, because of severe muscle rigidity of the chest. Due to an extreme spasm of both masseter muscles, the mouth of the patient could not be opened, for the placement of an endotracheal tube or a supraglottic device. The minimal measured saturation at that moment was 61 %. Therefore, we made the decision to immediately induce general anesthesia with an intravenous infusion of propofol (target controlled infusion, Marsh model, 4.0 µg mL -1) and rocuronium bromide 50 mg (Esmeron, Organon, Oss, Nederland). Thirty seconds later, the patient’s musculature started to relax and manual ventilation became possible. The trachea of the patient was intubated and the patient was mechanically ventilated. Next, the right radial artery was cannulated, revealing an arterial blood pressure of 94/46 mmHg. Total intravenous anesthesia was maintained using propofol (target-controlled infusion, Marsh model, 4.0 µg mL-1) and remifentanil (0.1 µg Kg-1 min-1). The surgical procedure was performed as scheduled, and was uneventful. After the end of surgery, the patient awoke 6 minutes after discontinuation of anesthesia. The patient was repeatedly evaluated: immediately after extubation, one hour after surgery in the recovery room, and thirty hours after surgery on the surgical ward. No adverse events could be documented. When answering the Brice questionnaire during the last post-anesthesia visit, the patient did not report any explicit awareness of the event. The last thing he could remember was that, before entering the operating room, one of the nurses placed a surgical cap on his head.dIscussIon The inadvertent administration of high doses of remifentanil have been described as a consequence of defective syringe pumps (1), accidental bolus © Acta Anæsthesiologica Belgica, 2017, 68, n° 2 acute and lIfe-threatenIng remIfentanIl oVerdose 89conclusIon Although frequently neglected by caregivers, the safe use of syringe pumps requires continuous attention and thorough understanding of the under-lying physics and possible sources of error.  We present a case in which an accidental overdose of remifentanil occurred because the syringe plunger had accidentally not been locked in the pusher lever, allowing the spontaneous evacuation of the syringe. A comparable incident outside the setting of a fully equipped anesthesia working place would have certainly been associated with major morbidity or even mortality of the affected patient. It is therefore important to note that any drug infusion should be connected to the patient only after the correct assembly of the syringe pump installation has been checked. Users must verify that the syringe plunger is properly secured to the pusher lever. Moreover, intravenous infusion lines containing vasoactive drugs or potent anesthetic drugs ideally need anti-reflux valves. A further preventive measure would be to place syringe pumps only below the patient’s heart level. At last the anesthesiologist should only turn the stopcock of the entry of the intravenous medication when he/she is sure that everything has been checked and safe administration of the medication can be guaranteed.Reference1.. Montserrat JM, Pérez-Hick PA, Remifentanil overdose in obstetric analgesia caused by a defective syringe in a patient-controlled analgesia system. reV esp anestesIol reanIm., 58(8), 530-531, 2011.2.  Bakan M, Cakmakkaya S, Onsel I, Kaya G. Inadvertent bolus administration of high-dose remifentanil during anesthesia in a 6-year-old girl. paedIatr anaesth., 16(11), 1202, 2006. 3.  Barak M, Greenberg Z, Danino J, Delayed awakening following inadvertent high-dose remifentanil infusion in a 13 year old patient. J clIn anesth., 23(4), 322-324, 2011.4.  Shenkman Z, Ornstein E, Adler D, Drug Overdose as a Consequence of Misuse of a Syringe Pump, anesth analg., 81(3), 652-653, 1995.5.  Steffen M, von Hintzenstern U, Obermayer A, Critical infusion incident caused by incorrect use of a patient-controlled analgesia pump, anaesthesIol reanIm., 27(4), 107-110, 2002.6.  Minto CF, Schnider TW, Egan TD, Youngs E et al., Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. anesthesIology., 86(1), 10-23, 1997.7.  Minto CF, Schnider TW, Shafer SL, Pharmacokinetics and pharmacodynamics of remifentanil. II. Model application. anesthesIology, 86(1), 24-33, 1997.8.  GlaxoSmithKline : Ultiva for injection. Available from : http://www.mhra.gov.uk/9.  Egan TD, Lemmens HJ, Fiset P, Hermann DJ et al., The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. anesthesIology., 79(5), 881-892, 1993.10.  B. Braun : Naloxone for injection. Available from: http://www.mhra.gov.uk/concentration for muscle rigidity and seizure was reached so quickly, that the patient did not had the time to desaturate. To the best of our knowledge, equally high doses of remifentanil in non-anesthetized and non-intubated patients have only been used and described in preclinical pharmacokinetic studies (9). Also in these studies, muscle rigidity was observed as a major side-effect and had to be treated with a continuous infusion of succinylcholine, to allow mask ventilation. The literature is silent about the appropriate management of such a remifentanil overdose. It could be argued that antagonizing remifentanil with naloxone might have been a suitable therapeutic approach. For opioid overdoses, the prescribing information of naloxone(10) recommends repetitive doses of 0.4 mg-2 mg until a total dose of 10 mg has been achieved. In our hospital, only ampullas of 0.4 mg of naloxone (Naloxone B. Braun 0.4 mg. mL-1, 1 mL, Melsungen, Germany) are available. Hence, the preparation of up to 10 mg naloxone would have been too time-consuming in order to prevent hypoxemia. Waiting for spontaneous metabolization of remifentanil would have also taken too long. The spontaneous recovery of ventilation can only be expected at a remifentanil plasma concentration of around 2 ng mL-1 (8), and a large interindividual variability exists. The applied pharmacokinetic modeling shows that this concentration would have been reached only 35 minutes after the termination of the accidental infusion. One could argument that immediately starting an intravenous infusion of propofol is, maybe, not necessary, insofar as a plasma concentration of remifentanil of 150 ng mL-1 is enough to guarantee unconsciousness and amnesia. However, propofol was added immediately for two reasons. First, at the moment of the acute event, we did not know what the plasma concentration of remifentanil was. We knew it would be high, but there was no time to calculate the exact plasma concentration. Since there were no signs of hemodynamic instability, propofol was added to guarantee unconsciousness and amnesia. Secondly, since propofol also gives a certain degree of muscle relaxation, it was added to optimize intubation conditions. In our case, with apnea, the impossibility of mask ventilation and instrumentation of the upper airway, a rapid induction of general anesthesia, muscle relaxation, subsequent endotracheal intuba-tion and mechanical ventilation seemed the only and best available option.

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Acute and life-threatening remifentanil overdose resulting from the misuse of a syringe pump.

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