- Email: [email protected]
Fatal morphine poisoning in a child due to accidental oral ingestion
Forensic Science International
ELSEVIER
76 (1995) 55-59
Forensic hhence international
Fatal morphine poisoning in a child due to accidental oral ingestion Alphonse
Poklis *a, Leslie E. Edinboro”, A. Shannon Wohler”, Faruk Presswallab, David Barronc
“Department of Pathology, Bo.x 0165 MCV Station, Medical College oJ’ Virginia, Virginia Commonwealril University, Richmond, VA 23298-0165, USA bMedical Examiners O&e ~ Tidewater Division NoTfolk, Virginia 23507, USA ‘Medical E.uaminers’ O&e -- Division of’ Forensic, Sciences, Not@lk, Virginia 23507, USA Received 16 May 1995; revision received 8 June 1995; accepted 13 June 1995
Abstract A case of fatal intoxication of an 8 year old child due to accidental oral ingestion of morphine is presented. Following a tonsillectomy and release from the hospital the decedent was prescribed meperidine syrup 50 mg per teaspoon (tsp) to be taken 2 tsps every 4 h. A pharmacist when filling her prescription mistakenly dispensed Roxanol” which contained 20 mg/ml morphine sulfate. She took 1 or 2 tsp of the prescription prior to bed and was found dead the next morning. Autopsy findings were unremarkable. Quantitation by gas chromatography/mass spectrometry (GC/MS) yielded the following morphine results: blood, 0.128 mg/l; bile, 135 mg/l and stomach contents, 16 mg/l (2.3 mg total). Based upon the clinical history, autopsy and toxicology finding the cause of death was determined to be poisoning by morphine and the manner of death accidental. Keywords: Morphine;
Poisoning; Children; Overdose
1. Introduction With ethanol and cocaine, morphine is among the three most commonly encountered drugs in postmortem toxicology [I]. The overwhelming majority of these cases are due to heroin abuse or administration of morphine for control of pain in cancer * Corresponding author, Tel.: (*804) 828 0272; Fax; (*804) 828 7722 0379-0738/95/$09.50 C 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0379-0738(95)01797-M
56
A. Poklis et al. ! Forensic Science International
76 (1995) 55-59
patients. With the exception of cancer patients, morphine is rarely prescribed on an out-patient basis, particularly for children. As a result, poisoning by oral morphine is extremely rare in children. We present a fatal intoxication of a child due to oral ingestion of morphine. A review of literature failed to disclose a comparable case. 2. History An 8 year old female had a tonsillectomy with an uneventful postoperative recovery. Upon release from the hospital she was prescribed meperidine syrup 50 mg per teaspoon (tsp) to be taken 2 tsp every 4 h. That evening she took 1 or 2 tsp of the prescription prior to bed. Early the next morning, her mother found her apparently sleeping soundly and did not disturb her. At 1030 h that morning her older sister attempted to awake her and found her unresponsive and without vital signs. A rescue squad was immediately called and carried her to an area hospital where she was pronounced dead on arrival. Autopsy findings were essentially unremarkable and a cause of death was not immediately apparent. There was some intravascular thrombosis in the main pulmonary arteries without a source for an embolus. The pelvic veins and veins of the inferior extremities were free of clotting. Histologically, the thrombus failed to demonstrate coarse fibrin polymerization; thus thrombus was an agonal event. Subsequent investigation revealed that a pharmacist when filling her prescription had mistakenly dispensed Roxanopm which contained 20 mg/ml morphine sulfate. Apparently, the pharmacist was under the impression that Roxanol@ was the equivalent of Demerola (meperidine). At autopsy, blood, bile and stomach contents had been collected. These were submitted for toxicological analysis. 3. Toxicological
analysis
Quantitation of morphine in blood, bile, and gastric samples was by gas chromatography/mass spectrometry (GC/MS). Bile, 1.O ml was hydrolyzed with 1.2 ml hydrochloric acid in an autoclave for 30 min as described by Lee and Lee [2]. To separate 16 ml disposable glass screw-cap tubes were added, 2.0 ml aliquots of sample (blood, hydrolyzed bile, homogenized stomach contents calibrators and controls) and 200 ~1 &morphine (0.4 pg/ml) internal standard. The samples were buffered to pH 9 with 2.0 ml potassium phosphate buffer (50%, pH 11) with a pinch of sodium bicarbonate/potassium carbonate (3:2 w/w) and 7.0 ml of chloroform/ ethanol (4:l v/v) extraction solvent was added. The samples were mixed on a rotorack for 10 min and centrifuged for 15 min at 2000 rev./min. The organic layer was transferred to a 15 ml conical screw-cap tube and evaporated to dryness in a 40°C water bath under a constant stream of air. The residues were then derivatized individually with 40 ~1 of N-methyl-bis-trifluoroacetamide (MBTFA, Regis) at 70” for 20 min [3]. Due to the instability of the derivatives, each sample was derivatized immediately before injection. Finally, 3-4 ~1 were injected into the GC system (Hewlett Packard 5890 GC coupled with a model 5971A mass spectrometer). A
A. Poklis
Table 1 Morphine
distribution
et al. i Forensic
Science
Internutionul
76 (1995)
55-59
51
(mg:l) Morphine
Blood (free) Bile (hydrolyzed) Stomach contents Total in aliquot submitted Prescription bottle
(mg,‘l)
0.128 135 16.0 2.3 mg 20 mg/ml Morphine
sulfate
12 m x 0.2 mm x 0.33 pm HP-l capillary column was used. Initial GC oven temp was 170°C for 1.O min, then programmed at 18”C/min to 280°C. Injection port was 195°C. Interface temperature was 280°C. The mass spectrometer was used in the SIM Mode monitoring the 364.1 and 477.1 ions of morphine and 367.1 and 480.1 ions of d,-morphine, both at a retention time of 5.3 s. 4. Results The results of the morphine analysis are presented in Table 1. The concentration of free morphine in blood is consistent with the development of respiratory depression in this child. Her father stated that she had ingested at least one and possibly two teaspoonfuls of the Roxanol prior to retiring to bed. Based upon the clinical history, autopsy and toxicology finding, the cause of death was determined to be poisoning by morphine and the manner of death accidental. 5. Discussion The decedent weighted only 37 kg (82 lbs); therefore, by history she would have ingested a dose of 2.7-5.4 mg/kg. Such a dose exceeds oral analgesic doses for children and are consistent with the development of respiratory distress. Doses of morphine in this range of 3-5 mg/kg are given during surgery under general anesthesia where respiration is mechanically supported. The huge concentration of morphine in the bile is consistent with rapid clearance by the liver following oral ingestion of a very large dose of morphine. In adults, intravenous, intramuscular or epidural administration of 0.10-o. 125 mg/kg (6-8 mg) typically results in blood concentrations of 0.01-0.02 mg/l 2-4 h after dosage [4]. Bioavailability of orally administered morphine varies widely, 15-64%, averaging about 38% [5]. Oral doses of morphine of 20-30 mg in adults are sufficient to maintain plasma concentrations of 0.020-0.025 mg/l, generally resulting in 4 h of analgesia. In children, neonates to 15 years old, the minimum morphine concentration in plasma necessary to suppress clinical signs of pain during surgery was found to be 0.065 mg/l, with 95% confidence limits of 0.046-0.083 mg/l [6]. However, the minimal analgesic concentration for post-operative pain control in cardiac surgical
58
A. Poklis
et al. 1 Forensic
Science
International
76 (1995)
55-59
patients aged 14 months to 17 years is 0.012 mg/l [7]. Olkkola et al. determined the minimal effective plasma concentration (MEC) of morphine for post-operative analgesia in three different age groups of children [8]. They found that with intravenous infusion of 8.05 mg/kg morphine, the mean MEC in children 2-6 years old was only 0.0038 mg/l, with a range of 0.0021-0.0075 mg/l, n = 13. However infants up to 6 months old required higher concentrations; mean MEC of 0.026 rig/ml, range 0.0075-0.064 mg/l, n = 7. These values are consistent with those reported by Westerling following rectal administration of morphine for analgesia in children undergoing eye surgery under general anesthesia [9]. Following morphine doses of 0.15 mg/kg and 0.5 mg/kg per OS, resultant plasma concentrations averaged 0.0065 mg/l (n = 6) and 0.025 mg/l (n = 1l), respectively. It should be noted that the children in these studies were hospitalized and under close medical supervision. A review of the literature failed to uncover a fatal morphine poisoning in a child similar to our case. Severe respiratory depression in children has been observed at plasma morphine concentrations of only 0.011 and 0.019 mg/l [7]. Gourlay and Boas reported the death of 7 month old infant due to morphine administration by rectal suppositories resulting in a plasma concentration of 0.094 mg/l [lo]. Kerey et al. have reported the development of grand ma1 seizures in two neonates with morphine serum concentrations of 0.009 mg/l and 0.061 mg/l [ll]. While the pharmacokinetics and toxicity of morphine has been investigated in infants [12], little data is available concerning toxic concentrations in older children. Gerber and Spseloff reported the death of a 15 year old black male during a sickle cell crisis after infusion of 298 mg of morphine over 3 days. [13]. Morphine plasma concentrations were not reported. Furthermore, it was summarized that the accumulation of morphine-6-glucuronide (M6G) played a significant role in the respiratory depression and sickle cell crisis in this child. However, accumulation of M6G is less significant in acute poisoning, such as our case. References [l] Drug Abuse Warning Network, Annual Medical Examiners Data 1993, Statistical Series I, Number 13-B. U.S. Department of Health and Human Services, Rockville Maryland, 1993, pp. 16. [2] H.M. Lee and C.W. Lee, Determination of morphine and codeine in blood and bile by gas chromatography with a derivatization procedure. J. Anal. To.~ico/., 15 (1991) 182- 187. [3] A. Solans, R. DeLaTorre and J. Sergura, Determination of morphine and codeine in urine by gas chromatography-mass spectrometry. .I. Pharma. Biomrd. Anal., 8 (1990) I23- 132. [4] R.C. Baselt and R.H. Cravey (eds.), Disposifion of’ Toxic Drugs and Cltrmiccds in Man, 4th edn., Chemical Institute of Toxicology, Foster City, CA, 1995, pp. 528531. [5] J. Sarve, B. Dahlstrom, L. Paalzow and A. Rane Morphine kinetics in cancer patients. Clin. Pharmacol. Therap., 30 (1981) 629- 635. [6] B. Dahlstrom, P. Bolme, H. Feychting, G. Noack and L. Paalzow, Morphine kinetics in children. Clin.
Pharmacol.
Therap.,
28 (1979)
354-365.
[7] A.E. Lynn, M.K.E. Opheim, and D.C. Tyler, Morphine infusion after pediatric cardiac surgery. Cd. Care Med., 12 (1984) 863-866. [8] K.T. Olkkola, B.L. Maunuksela, R. Korpela and P.H. Rosenberg, Kinetics and dynamics of post-operative intravenous morphine in children. Clin. Pharmacol. Therap., 44 (1988) I28- 136.
A. Poklis et al. i Forensic Science International
76 (199.5) 55-59
59
[9] D. Westerling, Rectally administered morphine: Plasma concentrations in children pre-medicated with morphine in hydrogel and in solution. Acta Anesthesiol. &and., 29 (1985) 653-656. [IO] G.K. Gourlay and R.A. Boas, Fatal outcome with use of rectal morphine for post-operative pain control in an infant. Br. Med. J., 304 (1992) 7666767. [I I] G. Karen, W. Butt, K. Pape and H. Cheryanga, Morphine- induced seizures in newborn infants. Vet. Hum. Toxicol., 27 (1983) 519-520. [I21 A.M. Lynn, J.T. Slattery, Morphine pharmacokinetics in early infancy. Anesthesiology, 66 (1987) 1366 139. [I31 N. Gerber and G. Apseloff, Death from a morphine infusion during a sickle cell crisis. J. Pediat., 123 (1993) 322-325.
ELSEVIER
76 (1995) 55-59
Forensic hhence international
Fatal morphine poisoning in a child due to accidental oral ingestion Alphonse
Poklis *a, Leslie E. Edinboro”, A. Shannon Wohler”, Faruk Presswallab, David Barronc
“Department of Pathology, Bo.x 0165 MCV Station, Medical College oJ’ Virginia, Virginia Commonwealril University, Richmond, VA 23298-0165, USA bMedical Examiners O&e ~ Tidewater Division NoTfolk, Virginia 23507, USA ‘Medical E.uaminers’ O&e -- Division of’ Forensic, Sciences, Not@lk, Virginia 23507, USA Received 16 May 1995; revision received 8 June 1995; accepted 13 June 1995
Abstract A case of fatal intoxication of an 8 year old child due to accidental oral ingestion of morphine is presented. Following a tonsillectomy and release from the hospital the decedent was prescribed meperidine syrup 50 mg per teaspoon (tsp) to be taken 2 tsps every 4 h. A pharmacist when filling her prescription mistakenly dispensed Roxanol” which contained 20 mg/ml morphine sulfate. She took 1 or 2 tsp of the prescription prior to bed and was found dead the next morning. Autopsy findings were unremarkable. Quantitation by gas chromatography/mass spectrometry (GC/MS) yielded the following morphine results: blood, 0.128 mg/l; bile, 135 mg/l and stomach contents, 16 mg/l (2.3 mg total). Based upon the clinical history, autopsy and toxicology finding the cause of death was determined to be poisoning by morphine and the manner of death accidental. Keywords: Morphine;
Poisoning; Children; Overdose
1. Introduction With ethanol and cocaine, morphine is among the three most commonly encountered drugs in postmortem toxicology [I]. The overwhelming majority of these cases are due to heroin abuse or administration of morphine for control of pain in cancer * Corresponding author, Tel.: (*804) 828 0272; Fax; (*804) 828 7722 0379-0738/95/$09.50 C 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0379-0738(95)01797-M
56
A. Poklis et al. ! Forensic Science International
76 (1995) 55-59
patients. With the exception of cancer patients, morphine is rarely prescribed on an out-patient basis, particularly for children. As a result, poisoning by oral morphine is extremely rare in children. We present a fatal intoxication of a child due to oral ingestion of morphine. A review of literature failed to disclose a comparable case. 2. History An 8 year old female had a tonsillectomy with an uneventful postoperative recovery. Upon release from the hospital she was prescribed meperidine syrup 50 mg per teaspoon (tsp) to be taken 2 tsp every 4 h. That evening she took 1 or 2 tsp of the prescription prior to bed. Early the next morning, her mother found her apparently sleeping soundly and did not disturb her. At 1030 h that morning her older sister attempted to awake her and found her unresponsive and without vital signs. A rescue squad was immediately called and carried her to an area hospital where she was pronounced dead on arrival. Autopsy findings were essentially unremarkable and a cause of death was not immediately apparent. There was some intravascular thrombosis in the main pulmonary arteries without a source for an embolus. The pelvic veins and veins of the inferior extremities were free of clotting. Histologically, the thrombus failed to demonstrate coarse fibrin polymerization; thus thrombus was an agonal event. Subsequent investigation revealed that a pharmacist when filling her prescription had mistakenly dispensed Roxanopm which contained 20 mg/ml morphine sulfate. Apparently, the pharmacist was under the impression that Roxanol@ was the equivalent of Demerola (meperidine). At autopsy, blood, bile and stomach contents had been collected. These were submitted for toxicological analysis. 3. Toxicological
analysis
Quantitation of morphine in blood, bile, and gastric samples was by gas chromatography/mass spectrometry (GC/MS). Bile, 1.O ml was hydrolyzed with 1.2 ml hydrochloric acid in an autoclave for 30 min as described by Lee and Lee [2]. To separate 16 ml disposable glass screw-cap tubes were added, 2.0 ml aliquots of sample (blood, hydrolyzed bile, homogenized stomach contents calibrators and controls) and 200 ~1 &morphine (0.4 pg/ml) internal standard. The samples were buffered to pH 9 with 2.0 ml potassium phosphate buffer (50%, pH 11) with a pinch of sodium bicarbonate/potassium carbonate (3:2 w/w) and 7.0 ml of chloroform/ ethanol (4:l v/v) extraction solvent was added. The samples were mixed on a rotorack for 10 min and centrifuged for 15 min at 2000 rev./min. The organic layer was transferred to a 15 ml conical screw-cap tube and evaporated to dryness in a 40°C water bath under a constant stream of air. The residues were then derivatized individually with 40 ~1 of N-methyl-bis-trifluoroacetamide (MBTFA, Regis) at 70” for 20 min [3]. Due to the instability of the derivatives, each sample was derivatized immediately before injection. Finally, 3-4 ~1 were injected into the GC system (Hewlett Packard 5890 GC coupled with a model 5971A mass spectrometer). A
A. Poklis
Table 1 Morphine
distribution
et al. i Forensic
Science
Internutionul
76 (1995)
55-59
51
(mg:l) Morphine
Blood (free) Bile (hydrolyzed) Stomach contents Total in aliquot submitted Prescription bottle
(mg,‘l)
0.128 135 16.0 2.3 mg 20 mg/ml Morphine
sulfate
12 m x 0.2 mm x 0.33 pm HP-l capillary column was used. Initial GC oven temp was 170°C for 1.O min, then programmed at 18”C/min to 280°C. Injection port was 195°C. Interface temperature was 280°C. The mass spectrometer was used in the SIM Mode monitoring the 364.1 and 477.1 ions of morphine and 367.1 and 480.1 ions of d,-morphine, both at a retention time of 5.3 s. 4. Results The results of the morphine analysis are presented in Table 1. The concentration of free morphine in blood is consistent with the development of respiratory depression in this child. Her father stated that she had ingested at least one and possibly two teaspoonfuls of the Roxanol prior to retiring to bed. Based upon the clinical history, autopsy and toxicology finding, the cause of death was determined to be poisoning by morphine and the manner of death accidental. 5. Discussion The decedent weighted only 37 kg (82 lbs); therefore, by history she would have ingested a dose of 2.7-5.4 mg/kg. Such a dose exceeds oral analgesic doses for children and are consistent with the development of respiratory distress. Doses of morphine in this range of 3-5 mg/kg are given during surgery under general anesthesia where respiration is mechanically supported. The huge concentration of morphine in the bile is consistent with rapid clearance by the liver following oral ingestion of a very large dose of morphine. In adults, intravenous, intramuscular or epidural administration of 0.10-o. 125 mg/kg (6-8 mg) typically results in blood concentrations of 0.01-0.02 mg/l 2-4 h after dosage [4]. Bioavailability of orally administered morphine varies widely, 15-64%, averaging about 38% [5]. Oral doses of morphine of 20-30 mg in adults are sufficient to maintain plasma concentrations of 0.020-0.025 mg/l, generally resulting in 4 h of analgesia. In children, neonates to 15 years old, the minimum morphine concentration in plasma necessary to suppress clinical signs of pain during surgery was found to be 0.065 mg/l, with 95% confidence limits of 0.046-0.083 mg/l [6]. However, the minimal analgesic concentration for post-operative pain control in cardiac surgical
58
A. Poklis
et al. 1 Forensic
Science
International
76 (1995)
55-59
patients aged 14 months to 17 years is 0.012 mg/l [7]. Olkkola et al. determined the minimal effective plasma concentration (MEC) of morphine for post-operative analgesia in three different age groups of children [8]. They found that with intravenous infusion of 8.05 mg/kg morphine, the mean MEC in children 2-6 years old was only 0.0038 mg/l, with a range of 0.0021-0.0075 mg/l, n = 13. However infants up to 6 months old required higher concentrations; mean MEC of 0.026 rig/ml, range 0.0075-0.064 mg/l, n = 7. These values are consistent with those reported by Westerling following rectal administration of morphine for analgesia in children undergoing eye surgery under general anesthesia [9]. Following morphine doses of 0.15 mg/kg and 0.5 mg/kg per OS, resultant plasma concentrations averaged 0.0065 mg/l (n = 6) and 0.025 mg/l (n = 1l), respectively. It should be noted that the children in these studies were hospitalized and under close medical supervision. A review of the literature failed to uncover a fatal morphine poisoning in a child similar to our case. Severe respiratory depression in children has been observed at plasma morphine concentrations of only 0.011 and 0.019 mg/l [7]. Gourlay and Boas reported the death of 7 month old infant due to morphine administration by rectal suppositories resulting in a plasma concentration of 0.094 mg/l [lo]. Kerey et al. have reported the development of grand ma1 seizures in two neonates with morphine serum concentrations of 0.009 mg/l and 0.061 mg/l [ll]. While the pharmacokinetics and toxicity of morphine has been investigated in infants [12], little data is available concerning toxic concentrations in older children. Gerber and Spseloff reported the death of a 15 year old black male during a sickle cell crisis after infusion of 298 mg of morphine over 3 days. [13]. Morphine plasma concentrations were not reported. Furthermore, it was summarized that the accumulation of morphine-6-glucuronide (M6G) played a significant role in the respiratory depression and sickle cell crisis in this child. However, accumulation of M6G is less significant in acute poisoning, such as our case. References [l] Drug Abuse Warning Network, Annual Medical Examiners Data 1993, Statistical Series I, Number 13-B. U.S. Department of Health and Human Services, Rockville Maryland, 1993, pp. 16. [2] H.M. Lee and C.W. Lee, Determination of morphine and codeine in blood and bile by gas chromatography with a derivatization procedure. J. Anal. To.~ico/., 15 (1991) 182- 187. [3] A. Solans, R. DeLaTorre and J. Sergura, Determination of morphine and codeine in urine by gas chromatography-mass spectrometry. .I. Pharma. Biomrd. Anal., 8 (1990) I23- 132. [4] R.C. Baselt and R.H. Cravey (eds.), Disposifion of’ Toxic Drugs and Cltrmiccds in Man, 4th edn., Chemical Institute of Toxicology, Foster City, CA, 1995, pp. 528531. [5] J. Sarve, B. Dahlstrom, L. Paalzow and A. Rane Morphine kinetics in cancer patients. Clin. Pharmacol. Therap., 30 (1981) 629- 635. [6] B. Dahlstrom, P. Bolme, H. Feychting, G. Noack and L. Paalzow, Morphine kinetics in children. Clin.
Pharmacol.
Therap.,
28 (1979)
354-365.
[7] A.E. Lynn, M.K.E. Opheim, and D.C. Tyler, Morphine infusion after pediatric cardiac surgery. Cd. Care Med., 12 (1984) 863-866. [8] K.T. Olkkola, B.L. Maunuksela, R. Korpela and P.H. Rosenberg, Kinetics and dynamics of post-operative intravenous morphine in children. Clin. Pharmacol. Therap., 44 (1988) I28- 136.
A. Poklis et al. i Forensic Science International
76 (199.5) 55-59
59
[9] D. Westerling, Rectally administered morphine: Plasma concentrations in children pre-medicated with morphine in hydrogel and in solution. Acta Anesthesiol. &and., 29 (1985) 653-656. [IO] G.K. Gourlay and R.A. Boas, Fatal outcome with use of rectal morphine for post-operative pain control in an infant. Br. Med. J., 304 (1992) 7666767. [I I] G. Karen, W. Butt, K. Pape and H. Cheryanga, Morphine- induced seizures in newborn infants. Vet. Hum. Toxicol., 27 (1983) 519-520. [I21 A.M. Lynn, J.T. Slattery, Morphine pharmacokinetics in early infancy. Anesthesiology, 66 (1987) 1366 139. [I31 N. Gerber and G. Apseloff, Death from a morphine infusion during a sickle cell crisis. J. Pediat., 123 (1993) 322-325.