Journal of Clinical Toxicology · novel metabolite ethylphenidate after methylphenidate overdose...
2
Volume 3 • Issue 1• 1000153 J Clinic Toxicol ISSN: 2161-0495 JCT, an open access journal Research Article Open Access Jansen et al., J Clinic Toxicol 2013, 3:1 DOI: 10.4172/2161-0495.1000153 Case Report Open Access Severe Methylphenidate Intoxication-Charcoal Hemoperfusion as an Aid in Treating the Patient Jansen T 1 *, Hoegberg LCG 1 , Gregersen JW 2 , Filipovski I 3 and Johansen SS 4 1 Department of Anaesthesiology and the Danish Poison Information Center, Bispebjerg University Hospital, Copenhagen, Denmark 2 Department of Nephrology, Aarhus University Hospital, Skejby , Denmark 3 Department of Anaesthesiology, Hospital Unit Horsens, Denmark 4 Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark *Corresponding author: Tejs Jansen, Department of Anaesthesiology and the Danish Poison Information Center, Bispebjerg University Hospital, Bispebjerg Bakke 242400 Copenhagen NV, Denmark, Tel: 0045 6133 3292; E-mail: [email protected] Received December 19, 2012; Accepted January 31, 2013; Published February 04, 2013 Citation: Jansen T, Hoegberg LCG, Gregersen JW, Filipovski I, Johansen SS (2013) Severe Methylphenidate Intoxication-Charcoal Hemoperfusion as an Aid in Treating the Patient. J Clinic Toxicol 3: 153. doi:10.4172/2161-0495.1000153 Copyright: © 2013 Jansen T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Case Report A 47-year-old woman was admitted to a local hospital 2 hours aſter the ingestion of 3000 mg methylphenidate, 360 mg duloxetine, 200 mg chlorprothixen, 400 mg quetiapin, 15 mg zopiclone, 60 mg mirtazapine and approximately 1 liter of strong alcohol (40% v/v). Her intention was suicidal. All the medication was her own prescription drugs except methylphenidate, which was prescribed to her 13-year-old son who was diagnosed with Attention Deficit and Hyperkinetic Disorder (ADHD). Due to Glascow Coma Score (GCS) 3 and the risk of aspiration she was incubated by the arriving Emergency Medical Service (EMS). Before intubation she presented slow reacting pupils. When arriving at the emergency room she presented dilated non-reacting pupils and increasing circulatory instability. e biochemistry of the patient (an arterial blood gas) revealed a metabolic acidosis pH 7.2, hypokalemia 3.2 mmol/L, blood glucose 3.0 mmol/L, standard base excess -8.7 mmol/L plasma lactate 3, 3 and hypocalcaemia 0.91 mmol/L. Due to severe circulatory instability and troubling CGC level the patient was transmitted to the ICU for further treatment. Biochemical date revealed increasingplasma lactate levels increasing from 3, 3 to 4, 7 mmol/l (normal range 0, 5-2, 5 mmol/l) and sustained hypokalemia2, 7-3, 3 (normal range 3, 5-4, 6). Gastrointestinal aspiration was performed and 50 grams of Activated Charcoal (AC) instilled. e patient developed circulatory shock (blood pressure 60/30 mmHg, pulse 90) and was in need of vasopressors (Epinephrine 20-25 microg/ kg/min and Dopamine 3-6 microg/kg/min). Intravenous lipid emulsion (Intralipid 20%, Fresenius Kabi, Uppsala, Sweden) was dosed as 100 ml followed by 50 ml aſter 5 minutes. However, her condition deteriorated and the severity of the condition demanded advanced ICU support. e patient was therefore transferred to the nearest large facility hospital where Charcoal Hemoperfusion (CHP) were available. Blood samples were drawn prior, during and aſter CHP in order to quantify the efficacy of the intervention. Charcoal hemoperfusion was commenced approximately 10 hours aſter the intended overdose. e patient was cannulated in the right jugular vein. Aſter 4 hours of treatment with CHP and simultaneous hemodialysis (filters: Adsorba 300C, Gambro and HPS F8, FreseniusKabi, Uppsala, Sweden) at a blood flow of 200-300 ml/ min, the patient recovered to GCS 15 and became hemodymanically and respiratory stable. She experienced severe mental depression and verbally expressed continuing suicidal thoughts. Biochemical values for electrolytes and arterial gasses were within normal range. Although the patient’s plasma lactate had been high, this is correlated to high morbidity and mortality [1]. e blood concentration of methylphenidate (racemate) was cleared from severely toxic levels to below therapeutic concentration (Figure 1). Postmortem methylphenidate concentration has been reported at levels from 0.310 mg/L (racemate) [2]. e therapeutic concentration interval is not uniformly described, but mean peak plasma concentrations of 0.0106 mg/L (D-methylphenidate) aſter a 54 mg dose (racemate) has been reported [3]. Methylphenidate elimination half life was 13.5 hrs during CHP (no 1) and 161 hrs between the two CHP treatments. Due to the sustained release formulation of the methylphenidate a second CHP was performed all though the patient was fully awake and circulatory stabile (Figure 1). e patient was then discharged to a general ward for further psychiatric observation the following day. e use of methylphenidate for various psychiatric conditions is rapidly increasing. In Denmark a more than six-fold increase in sold daily doses was observed from 2005 to 2010 (Figure 2) [4]. e Danish Medicines Agency presents data, which shows that the drug is mainly prescribed to youngsters, aged 10-14 with a second prescription top in adulthood in the range 30-39 years of age. Primary diagnosis for the users of methylphenidate is the ADHD patients [5]. Records at the Danish Poisons Information Center reveal a 0.000 0.050 0.100 0.150 0.200 0.250 0.300 0.350 0.400 05/02/11 19:12 05/02/11 21:36 06/02/11 00:00 06/02/11 02:24 06/02/11 04:48 06/02/11 07:12 06/02/11 09:36 06/02/11 12:00 06/02/11 14:24 06/02/11 16:48 06/02/11 19:12 Methylphenidate concentration, periferal blood (mg/L) Date and time CHP (1) start 23:30 CHP (1) end 03:30 CHP (2) start 12:10 CHP (2) end 16:10 Figure 1: Methylphenidate concentrations measured in serum. J o u r n a l o f C li n i c a l T o x i c o l o g y ISSN: 2161-0495 Journal of Clinical Toxicology
Transcript of Journal of Clinical Toxicology · novel metabolite ethylphenidate after methylphenidate overdose...
Volume 3 • Issue 1• 1000153J Clinic ToxicolISSN: 2161-0495 JCT, an open access journal
Research Article Open Access
Jansen et al., J Clinic Toxicol 2013, 3:1
DOI: 10.4172/2161-0495.1000153
Case Report Open Access
Severe Methylphenidate Intoxication-Charcoal Hemoperfusion as an Aid in Treating the PatientJansen T1*, Hoegberg LCG1, Gregersen JW2, Filipovski I3 and Johansen SS4
1Department of Anaesthesiology and the Danish Poison Information Center, Bispebjerg University Hospital, Copenhagen, Denmark2Department of Nephrology, Aarhus University Hospital, Skejby, Denmark3Department of Anaesthesiology, Hospital Unit Horsens, Denmark4Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
*Corresponding author: Tejs Jansen, Department of Anaesthesiology and the Danish Poison Information Center, Bispebjerg University Hospital, Bispebjerg Bakke 242400 Copenhagen NV, Denmark, Tel: 0045 6133 3292; E-mail: [email protected]
Received December 19, 2012; Accepted January 31, 2013; Published February 04, 2013
Citation: Jansen T, Hoegberg LCG, Gregersen JW, Filipovski I, Johansen SS (2013) Severe Methylphenidate Intoxication-Charcoal Hemoperfusion as an Aid in Treating the Patient. J Clinic Toxicol 3: 153. doi:10.4172/2161-0495.1000153
Copyright: © 2013 Jansen T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Case ReportA 47-year-old woman was admitted to a local hospital 2 hours after
the ingestion of 3000 mg methylphenidate, 360 mg duloxetine, 200 mg chlorprothixen, 400 mg quetiapin, 15 mg zopiclone, 60 mg mirtazapine and approximately 1 liter of strong alcohol (40% v/v). Her intention was suicidal. All the medication was her own prescription drugs except methylphenidate, which was prescribed to her 13-year-old son who was diagnosed with Attention Deficit and Hyperkinetic Disorder (ADHD). Due to Glascow Coma Score (GCS) 3 and the risk of aspiration she was incubated by the arriving Emergency Medical Service (EMS). Before intubation she presented slow reacting pupils. When arriving at the emergency room she presented dilated non-reacting pupils and increasing circulatory instability. The biochemistry of the patient (an arterial blood gas) revealed a metabolic acidosis pH 7.2, hypokalemia 3.2 mmol/L, blood glucose 3.0 mmol/L, standard base excess -8.7 mmol/L plasma lactate 3, 3 and hypocalcaemia 0.91 mmol/L.
Due to severe circulatory instability and troubling CGC level the patient was transmitted to the ICU for further treatment. Biochemical date revealed increasingplasma lactate levels increasing from 3, 3 to 4, 7 mmol/l (normal range 0, 5-2, 5 mmol/l) and sustained hypokalemia2, 7-3, 3 (normal range 3, 5-4, 6). Gastrointestinal aspiration wasperformed and 50 grams of Activated Charcoal (AC) instilled. Thepatient developed circulatory shock (blood pressure 60/30 mmHg,pulse 90) and was in need of vasopressors (Epinephrine 20-25 microg/kg/min and Dopamine 3-6 microg/kg/min). Intravenous lipid emulsion(Intralipid 20%, Fresenius Kabi, Uppsala, Sweden) was dosed as 100 mlfollowed by 50 ml after 5 minutes. However, her condition deterioratedand the severity of the condition demanded advanced ICU support. Thepatient was therefore transferred to the nearest large facility hospitalwhere Charcoal Hemoperfusion (CHP) were available. Blood samples
were drawn prior, during and after CHP in order to quantify the efficacy of the intervention.
Charcoal hemoperfusion was commenced approximately 10 hours after the intended overdose. The patient was cannulated in the right jugular vein. After 4 hours of treatment with CHP and simultaneous hemodialysis (filters: Adsorba 300C, Gambro and HPS F8, FreseniusKabi, Uppsala, Sweden) at a blood flow of 200-300 ml/min, the patient recovered to GCS 15 and became hemodymanically and respiratory stable. She experienced severe mental depression and verbally expressed continuing suicidal thoughts. Biochemical values for electrolytes and arterial gasses were within normal range. Although the patient’s plasma lactate had been high, this is correlated to high morbidity and mortality [1]. The blood concentration of methylphenidate (racemate) was cleared from severely toxic levels to below therapeutic concentration (Figure 1).
Postmortem methylphenidate concentration has been reported at levels from 0.310 mg/L (racemate) [2]. The therapeutic concentration interval is not uniformly described, but mean peak plasma concentrations of 0.0106 mg/L (D-methylphenidate) after a 54 mg dose (racemate) has been reported [3]. Methylphenidate elimination half life was 13.5 hrs during CHP (no 1) and 161 hrs between the two CHP treatments. Due to the sustained release formulation of the methylphenidate a second CHP was performed all though the patient was fully awake and circulatory stabile (Figure 1).
The patient was then discharged to a general ward for further psychiatric observation the following day.
The use of methylphenidate for various psychiatric conditions is rapidly increasing. In Denmark a more than six-fold increase in sold daily doses was observed from 2005 to 2010 (Figure 2) [4]. The Danish Medicines Agency presents data, which shows that the drug is mainly prescribed to youngsters, aged 10-14 with a second prescription top in adulthood in the range 30-39 years of age. Primary diagnosis for the users of methylphenidate is the ADHD patients [5].
Records at the Danish Poisons Information Center reveal a
0.000
0.050
0.100
0.150
0.200
0.250
0.300
0.350
0.400
05/0
2/11
19:
12
05/0
2/11
21:
36
06/0
2/11
00:
00
06/0
2/11
02:
24
06/0
2/11
04:
48
06/0
2/11
07:
12
06/0
2/11
09:
36
06/0
2/11
12:
00
06/0
2/11
14:
24
06/0
2/11
16:
48
06/0
2/11
19:
12
Met
hylp
heni
date
con
cent
ratio
n, p
erife
ral b
lood
(mg/
L)
Date and time
CHP
(1) s
tart
23:
30
CHP
(1) e
nd 0
3:30
CHP
(2) s
tart
12:
10
CHP
(2) e
nd 1
6:10
Figure 1: Methylphenidate concentrations measured in serum.
Jour
nal o
f Clinical Toxicology
ISSN: 2161-0495
Journal of Clinical Toxicology
Page 2 of 2
Volume 3 • Issue 1 • 1000153J Clinic ToxicolISSN: 2161-0495 JCT, an open access journal
Citation: Jansen T, Hoegberg LCG, Gregersen JW, Filipovski I, Johansen SS (2013) Severe Methylphenidate Intoxication-Charcoal Hemoperfusion as an Aid in Treating the Patient. J Clinic Toxicol 3: 153. doi:10.4172/2161-0495.1000153
steep increase in inquiries regarding accidental and non-accidental consumption of large doses of methylphenidate, an increase that reflects the increase in sold daily doses [6]. The most common symptoms following methylphenidate overdose are agitation, tachycardia and lethargy. Severe toxicity from high dose intake includes cardiotoxicity, hyperthermia, mydriasis and neurologic effect ranging from agitation and confusion to CNS depression, seizures and coma [7].
The rationale of using CHP in preference of standard hemodialysis is further enhancement in the elimination of the absorbed toxic agents [8,9]. This in coherence with physiochemical properties of methylphenidate with a low protein binding 10-33% and a volume of distribution ranging from 1,8 to 2,65 l/kg depending on the isomer in question supports the use of CHP as the choice for extracorporeal removal technique used to increase the clearance of this xenobiotic [7].
Standard treatment with oral AC might be insufficient when large quantities of tablets are ingested. The laboratory test shows a small incline in methylphenidate concentration after CHP is commenced which can be explained by formation of a gastrointestinal pharmacobezoar leaking the active pharmaceutical agent to the blood. To our knowledge there are no previous cases or studies of full recovery from acute deep toxic coma to normal mental status after 4 hours of CHP, and no case reports on CHP use in methylphenidate intoxication.
The lack of effect from the intravenous lipid emulsion might
have been caused by a combination of an insufficient dose for clinical effect and the only slightly lipophilic physicochemical properties of methylphenidate. The predicted log P value for methylphenidate is 1.47 but vary depending of methods of determination [10]. Though there are no standard methods available in the literature for intravenous lipid emulsion therapy, a higher dose than the patient received in the present case for cardiac resuscitation is suggested [11].
When treating methylphenidate overdose, practitioners should remain alert when the standard AC treatment is insufficient and think of the possibility of CHP assistance.
References
1. Kruse O, Grunnet N, Barfod C (2011) Blood lactate as a predictor for in-hospital mortality in patients admitted acutely to hospital: a systematic review. Scand J Trauma Resusc Emerg Med 19: 74.
2. Markowitz JS, Logan BK, Diamond F, Patrick KS (1999) Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion. J Clin Psychopharmacol 19: 362-366.
3. Modi NB, Wang B, Noveck RJ, Gupta SK (2000) Dose-proportional and stereospecific pharmacokinetics of methylphenidate delivered using an osmotic, controlled-release oral delivery system. J Clin Pharmacol 40: 1141-1149.
4. Folkenberg M, Callréus T, Svanström H, Valentiner-Branth P, Hviid A (2011) Spontaneous reporting of adverse events following immunisation against pandemic influenza in Denmark November 2009-March 2010. Vaccine 29: 1180-1184.
5. Ritalin (methylphenidate) (2011). Summary of product characteristics. The Danish Medicines Agency.
6. Bøgevig S, Høgberg LC, Dalhoff KP, Mortensen OS (2011) Status and trends in poisonings in Denmark 2007-2009. Dan Med Bull 58: A4268.
7. POISINDEX® System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc Updated periodically/May 2011.
8. Shalkham AS, Kirrane BM, Hoffman RS, Goldfarb DS, Nelson LS (2006) The availability and use of charcoal hemoperfusion in the treatment of poisoned patients. Am J Kidney Dis 48: 239-241.
9. Fertel BS, Nelson LS, Goldfarb DS (2010) Extracorporeal removal techniques for the poisoned patient: a review for the intensivist. J Intensive Care Med 25: 139-148.
10. DrugBank Open Data Drug & Drug Target Database.
11. LipidRescue™ Resuscitation for cardiac toxicity.
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
9,000
2004 2005 2006 2007 2008 2009 2010 2011
Met
hylp
heni
dat d
oses
sol
d (1
.000
dai
ly d
oses
)
Year
Male
Female
Figure 2: Methylphenidate, sold daily doses 2005-2010.
