Journal of Analytical Toxicology, Vol. 14, July/August 1990
Case Report I
Cocaine-Associated Fetal Death In Utero Fred S.
Apple*
Clinical Laboratories, Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, Minnesota 55415
Susan
J. R o e * *
Hennepin County Medical Examiner's Office, 701 Park Avenue South, Minneapolis, Minnesota
55415
Methods
I Abstract I Cocaine and Its principle metabolite benzoylecgonine were quantltated in blood and liver in six cocaine-related deaths within the Hennepin County Medical Examiner's jurisdiction. Postmortem blood cocaine and benzoylecgonine concentrations ranged from O to 5.6 mg/L and 0.6 to 18.7 mg/L respectively. Postmortem liver concentrations ranged from 0 to 5.0 mg/kg and 0.4 to 24.1 mg/kg, respectively. All cases had benzoylecgonlne concentrations greater than cocaine concentrations. Most alarming were the findings regarding the cocaine and benzoylecgonine concentrations in the case of a dead pregnant woman. The amniotic fluid cocaine and benzoylecgonine concentrations of 3.3 mg/L and 1.6 mg/L displayed at parent drug to metabolite ratio greater than 1.0 compared to the blood (0.30) and liver (0.21) ratios. This was likely indicative of very recent exposure.
Introduction Cocaine is a nervous system stimulant that is widely used by drug abusers (1). Over the past decade there has been a dramatic increase in cocaine use at all socioeconomic levels. Even children in the care of adults who abuse free base cocaine have tested positive, presumably by passive inhalation (2). Its effects are well documented and numerous fatalities have been reported over the past several years (1-4). Studies of cocaine use during pregnancy have shown that the drug reduces birth weight, increases the stillbirth rate, and is associated with an increased malformation rate (4,5,6). Recently, several case reports have described cocaine deaths in infants (7,8). The present case report describes the findings of a fetal death in utero associated with the death of the mother who was exposed to large amounts of cocaine. Further, the distributions of cocaine and benzoylecgonine in postmortem blood and liver specimens in five additional cocaine-related deaths are reported.
9 Address correspondence to: FSA, Clinical Laboratories #812, Henneptn County Medical Center. 701 Park Avenue South, Minneapolis, MN 55415. "" Current address: Ramsay County Medical Examiner's Office, St. Paul, MN.
Postmortem blood and or liverspecimens were obtained from five cocaine-associated deaths from the Hennepin County Medical Examiner's Office. Liver, blood, and amniotic fluid were also obtained postmortem from the case described below (mother). No fetal tissues were obtained. Blood was collected in tubes containing about I-2~ NaF (w/v) to prevent enzymatic hydrolysis of cocaine (I3). All samples were refrigerated (4~ until analysis. Blood, liver,and amniotic fluid specimens were analyzed for cocaine and benzoylecgonine by gas chromatography/mass spectrometry (GC/MS) (9). Liver concentrations are expressed as micrograms per gram, wet weight of tissue.
Case History A 16-year-old female was found dead in a minimally furnished efficiency apartment. Several small empty ziplock bags were present at the scene. The autopsy revealed oral mucosal contusions and lacerations. The woman was discovered to have an intrauterine pregnancy and the gestational age of the fetus was approximately 16 weeks. Routine specimens were obtained for toxicologic examination and included blood and liver. Urine was not available but amniotic fluid was obtained. The cause of death was determined to be suffocation and the manner of death homicide. Recent cocaine use was listed on the death certificate as an associated significant condition. The results of the cocaine analyses are shown in Table I under Case A.
Results
The blood and liver cocaine and benzoylecgonine (major metabolite) concentrations in the six cocaine-associated deaths are shown in Table I. In all six cases, the benzoylecgonine concentration was greater than the cocaine concentration in both blood and liver. Analysis of the amniotic fluid from Case A showed that the cocaine concentration was greater than the benzoylecgonine concentration (ratio2.l), differing from the parent drug to major metabolite ratio trends found in both the blood (0.3) and liver (0.21).
Reproduction (photocopying) of editorial content of this journal is prohibited without publisher's permission,
259
Journal of Analytical Tox=cology, Vol. 14, July/August 1990
Discussion Cocaine-associated deaths have steadily increased over the past decade. Within the jurisdiction of the Hennepin County Medical Examiner's Office there have been 53 cocaine-associated deaths over the past two years. Most alarming were the findings regarding the postmortem cocaine and benzoylecgonine concentrations in the case of the deceased pregnant woman (Table 1, Case A). Though the mother's death was not determined to be directly caused by cocaine intoxication, the blood concentration of cocaine (5.6 mg/L) was high enough to cause an acute fatal cocaine intoxication. Fetal blood and tissue concentrations were not quantitated, but the concentrations of the amniotic fluid cocaine and benzoylecgonine were indicative of a very high cocaine exposure to the fetus. Cocaine is rapidly metabolized in the blood, principly by deesterification by plasma cholinesterases to biologically inactive ecgonine methyl ester and by nonenzymatic deesterification to benzoylecgonine (10). The half-life of cocaine ranges from 20 min to 5 h compared to the longer half-life of benzoylecgonine, which ranges from 7 to 17 h (11). The rapid degradation o f cocaine occurs both in vivo as well as in vitro. The addition of fluoride to blood samples collected postmortem has been shown to inhibit the cholinesterase hydrolysis of cocaine and should be added to all blood samples when cocaine analysis is probable (12,13). Therefore, it is extremely important to add sodium fluoride to blood tubes when collecting forensic specimens for cocaine analysis, as was done in all cases reported in this study. Little information regarding tissue distribution of cocaine is available in the scientific literature. The ranges of all postmortem blood and liver cocaine and benzoylecgonine concentrations (Table I) in the present study were similar to other reports of tissue concentrations in cocaine-associated deaths (1-4,7,8,14). Fewer reports are available regarding tissue distribution of cocaine in pregnant women and fetuses (7,8). Though fetal blood or tissue concentrations were not available in the present study, Table I. Postmortem Cocaine and Benzoylecgonine Concentrations in Liver and Blood from Six CocaineAssociated Deaths" Blood (moiL)
Liver (mglkg)
Amniotlc fluid (moiL)
Case Cocaine BE Cocaine BE Cocaine BE
9
A
5.6
18.7
5.0
24.1
8
0.2
3.6
ND
2.8
C
4.5
15.6
3.7
20.7
D
ND
4.1
ND
2.3
E
ND
0.6
ND
0.4
F
4,0
5.1
4.6
24.0
3.3
NO = None Detected; BE - benzoylecgonine,
260
Causeof death and assoclalsd significant conditions
1.6 Homicide, suffocation; recent cocaine use Homicide, opiate overdose; incidental cocaine finding Homicide, suffocation; recent cocaine use Accidental, narcotic overdose; incidental cocaine finding Homicide, stab wound; incidental cocaine finding Accidental cocaine overdose
the amniotic fluid concentrations in Case A for cocaine and benzoylecgonine were 3.3 m g / L and 1.6 m g / L respectively. The amniotic fluid cocaine-to-benzoylecgonine ratio of 2.1 was substantially greater than that found in the mother's blood (0.30) and liver (0.21). The higher ratio of cocaine to benzoylecgonine in amniotic fluid may have been caused by a very recent exposure with little transfer of metabolite into the amniotic sac a n d / o r low deesterification activity within the amniotic fluid. To our knowledge, this is the first case report to describe cocaine and benzoylecgonine concentrations in amniotic fluid. The limited information regarding fetal cocaine concentrations have shown that maternal blood cocaine concentrations are usually greater than fetal concentrations with a greater cocaine-to-benzoylecgonine ratio in blood than in liver (7,8). The lower fetal concentrations may result from cocaine-induced vasoconstriction and reduced uterine blood flow or lack of equilibration between maternal and fetal blood after a rapid, cocaine-associated maternal death (7).
Acknowledgments The authors acknowledge the helpful discussions and technical support of Drs. Bandt and Paterson and the Toxicology Laboratory staff.
References 1. R.E. MJttleman and C.V. Wetli. Death caused by recreational cocaine use. J. Am. Mad. Assoc. 252:1889-93 (1984). 2. D.A. Bateman and M.C. Heagarty. Passive freebase cocaine (crack) inhalation by infants and toddlers. AJDC 143:25-27 (1989). 3. K. Tardiff, E. Gross, J. Wu, et al. Analysis of cocaine-positive fatalities. J. Forens. Sci. 34:53-63 (1989). 4. A. Poklis, M.A. Mackell, and M. Graham. Disposition of cocaine in fetal poisoning in man. J. Anal ToxicoL 9:227-29 (1985). 5. I.J. Chasnoff, W.J. Burns, S.H. Schnoll, and K.A. Burns. Cocaine use in pregnancy. N. EngL J. Med. 313:666-69 (1985). 6. N. Bingol, M. Fuchs, V. Diaz, et al. Tetratogenicity of cocaine in humans. J. Pediatr, 110:93-96 (1987). 7. R.E. Mittleman, J.C. Cofino, and W.L. Hearn. Tissue distribution of cocaine in a pregnant woman. J. Forens. Sci. 34:481-86 (1989). 8. R.H. Cravey. Cocaine deaths in infants. J. Anal. Toxicol. 12: 354-55 (1988). 9. S.R Jindal and R Vestergaard. Quantitation of cocaine and its principle metabolite benzoylecgonine by GC-mass spectrometry using stable isotope labelled analogs as internal standard. J. Pharmacol. Sci. 67:811-14 (1978). 10. D.J. Stewart. Cocaine metabolism: cocaine and norcocalne hydrolysis by liver and serum esterase. C/in. Pharmacol. That. 25:464-68 (1979). 11. J.J. Ambre. The urinary excretion of cocaine and metabolites in humans: A kinetic analysis of published data. J. Anat. Toxico/. 9:241-45 (1985). 12. B. Barnett, R. Hawks, and R. Resnick. Cocaine pharmacokinetics in humans. J. Ethnopharmacol. 3:353-66 (1981). 13. D.S. Isenschmid, B.S. Levine, and Y.H. Caplan. A comprehensive study of the stability of cocaine and its metabolites. J. Anal ToxicoL 13:250-56 (1989). 14. D.N. Bailey and R.F. Shaw. Cocaine- and methamphetaminerelated deaths in San Diego county (1987): homocides and accidental overdoses. J. Forens. Sci. 34: 407-22. Manuscript received October 23, 1989; revision received January 24, 1990.
Case Report I
Cocaine-Associated Fetal Death In Utero Fred S.
Apple*
Clinical Laboratories, Hennepin County Medical Center, 701 Park Avenue South, Minneapolis, Minnesota 55415
Susan
J. R o e * *
Hennepin County Medical Examiner's Office, 701 Park Avenue South, Minneapolis, Minnesota
55415
Methods
I Abstract I Cocaine and Its principle metabolite benzoylecgonine were quantltated in blood and liver in six cocaine-related deaths within the Hennepin County Medical Examiner's jurisdiction. Postmortem blood cocaine and benzoylecgonine concentrations ranged from O to 5.6 mg/L and 0.6 to 18.7 mg/L respectively. Postmortem liver concentrations ranged from 0 to 5.0 mg/kg and 0.4 to 24.1 mg/kg, respectively. All cases had benzoylecgonlne concentrations greater than cocaine concentrations. Most alarming were the findings regarding the cocaine and benzoylecgonine concentrations in the case of a dead pregnant woman. The amniotic fluid cocaine and benzoylecgonine concentrations of 3.3 mg/L and 1.6 mg/L displayed at parent drug to metabolite ratio greater than 1.0 compared to the blood (0.30) and liver (0.21) ratios. This was likely indicative of very recent exposure.
Introduction Cocaine is a nervous system stimulant that is widely used by drug abusers (1). Over the past decade there has been a dramatic increase in cocaine use at all socioeconomic levels. Even children in the care of adults who abuse free base cocaine have tested positive, presumably by passive inhalation (2). Its effects are well documented and numerous fatalities have been reported over the past several years (1-4). Studies of cocaine use during pregnancy have shown that the drug reduces birth weight, increases the stillbirth rate, and is associated with an increased malformation rate (4,5,6). Recently, several case reports have described cocaine deaths in infants (7,8). The present case report describes the findings of a fetal death in utero associated with the death of the mother who was exposed to large amounts of cocaine. Further, the distributions of cocaine and benzoylecgonine in postmortem blood and liver specimens in five additional cocaine-related deaths are reported.
9 Address correspondence to: FSA, Clinical Laboratories #812, Henneptn County Medical Center. 701 Park Avenue South, Minneapolis, MN 55415. "" Current address: Ramsay County Medical Examiner's Office, St. Paul, MN.
Postmortem blood and or liverspecimens were obtained from five cocaine-associated deaths from the Hennepin County Medical Examiner's Office. Liver, blood, and amniotic fluid were also obtained postmortem from the case described below (mother). No fetal tissues were obtained. Blood was collected in tubes containing about I-2~ NaF (w/v) to prevent enzymatic hydrolysis of cocaine (I3). All samples were refrigerated (4~ until analysis. Blood, liver,and amniotic fluid specimens were analyzed for cocaine and benzoylecgonine by gas chromatography/mass spectrometry (GC/MS) (9). Liver concentrations are expressed as micrograms per gram, wet weight of tissue.
Case History A 16-year-old female was found dead in a minimally furnished efficiency apartment. Several small empty ziplock bags were present at the scene. The autopsy revealed oral mucosal contusions and lacerations. The woman was discovered to have an intrauterine pregnancy and the gestational age of the fetus was approximately 16 weeks. Routine specimens were obtained for toxicologic examination and included blood and liver. Urine was not available but amniotic fluid was obtained. The cause of death was determined to be suffocation and the manner of death homicide. Recent cocaine use was listed on the death certificate as an associated significant condition. The results of the cocaine analyses are shown in Table I under Case A.
Results
The blood and liver cocaine and benzoylecgonine (major metabolite) concentrations in the six cocaine-associated deaths are shown in Table I. In all six cases, the benzoylecgonine concentration was greater than the cocaine concentration in both blood and liver. Analysis of the amniotic fluid from Case A showed that the cocaine concentration was greater than the benzoylecgonine concentration (ratio2.l), differing from the parent drug to major metabolite ratio trends found in both the blood (0.3) and liver (0.21).
Reproduction (photocopying) of editorial content of this journal is prohibited without publisher's permission,
259
Journal of Analytical Tox=cology, Vol. 14, July/August 1990
Discussion Cocaine-associated deaths have steadily increased over the past decade. Within the jurisdiction of the Hennepin County Medical Examiner's Office there have been 53 cocaine-associated deaths over the past two years. Most alarming were the findings regarding the postmortem cocaine and benzoylecgonine concentrations in the case of the deceased pregnant woman (Table 1, Case A). Though the mother's death was not determined to be directly caused by cocaine intoxication, the blood concentration of cocaine (5.6 mg/L) was high enough to cause an acute fatal cocaine intoxication. Fetal blood and tissue concentrations were not quantitated, but the concentrations of the amniotic fluid cocaine and benzoylecgonine were indicative of a very high cocaine exposure to the fetus. Cocaine is rapidly metabolized in the blood, principly by deesterification by plasma cholinesterases to biologically inactive ecgonine methyl ester and by nonenzymatic deesterification to benzoylecgonine (10). The half-life of cocaine ranges from 20 min to 5 h compared to the longer half-life of benzoylecgonine, which ranges from 7 to 17 h (11). The rapid degradation o f cocaine occurs both in vivo as well as in vitro. The addition of fluoride to blood samples collected postmortem has been shown to inhibit the cholinesterase hydrolysis of cocaine and should be added to all blood samples when cocaine analysis is probable (12,13). Therefore, it is extremely important to add sodium fluoride to blood tubes when collecting forensic specimens for cocaine analysis, as was done in all cases reported in this study. Little information regarding tissue distribution of cocaine is available in the scientific literature. The ranges of all postmortem blood and liver cocaine and benzoylecgonine concentrations (Table I) in the present study were similar to other reports of tissue concentrations in cocaine-associated deaths (1-4,7,8,14). Fewer reports are available regarding tissue distribution of cocaine in pregnant women and fetuses (7,8). Though fetal blood or tissue concentrations were not available in the present study, Table I. Postmortem Cocaine and Benzoylecgonine Concentrations in Liver and Blood from Six CocaineAssociated Deaths" Blood (moiL)
Liver (mglkg)
Amniotlc fluid (moiL)
Case Cocaine BE Cocaine BE Cocaine BE
9
A
5.6
18.7
5.0
24.1
8
0.2
3.6
ND
2.8
C
4.5
15.6
3.7
20.7
D
ND
4.1
ND
2.3
E
ND
0.6
ND
0.4
F
4,0
5.1
4.6
24.0
3.3
NO = None Detected; BE - benzoylecgonine,
260
Causeof death and assoclalsd significant conditions
1.6 Homicide, suffocation; recent cocaine use Homicide, opiate overdose; incidental cocaine finding Homicide, suffocation; recent cocaine use Accidental, narcotic overdose; incidental cocaine finding Homicide, stab wound; incidental cocaine finding Accidental cocaine overdose
the amniotic fluid concentrations in Case A for cocaine and benzoylecgonine were 3.3 m g / L and 1.6 m g / L respectively. The amniotic fluid cocaine-to-benzoylecgonine ratio of 2.1 was substantially greater than that found in the mother's blood (0.30) and liver (0.21). The higher ratio of cocaine to benzoylecgonine in amniotic fluid may have been caused by a very recent exposure with little transfer of metabolite into the amniotic sac a n d / o r low deesterification activity within the amniotic fluid. To our knowledge, this is the first case report to describe cocaine and benzoylecgonine concentrations in amniotic fluid. The limited information regarding fetal cocaine concentrations have shown that maternal blood cocaine concentrations are usually greater than fetal concentrations with a greater cocaine-to-benzoylecgonine ratio in blood than in liver (7,8). The lower fetal concentrations may result from cocaine-induced vasoconstriction and reduced uterine blood flow or lack of equilibration between maternal and fetal blood after a rapid, cocaine-associated maternal death (7).
Acknowledgments The authors acknowledge the helpful discussions and technical support of Drs. Bandt and Paterson and the Toxicology Laboratory staff.
References 1. R.E. MJttleman and C.V. Wetli. Death caused by recreational cocaine use. J. Am. Mad. Assoc. 252:1889-93 (1984). 2. D.A. Bateman and M.C. Heagarty. Passive freebase cocaine (crack) inhalation by infants and toddlers. AJDC 143:25-27 (1989). 3. K. Tardiff, E. Gross, J. Wu, et al. Analysis of cocaine-positive fatalities. J. Forens. Sci. 34:53-63 (1989). 4. A. Poklis, M.A. Mackell, and M. Graham. Disposition of cocaine in fetal poisoning in man. J. Anal ToxicoL 9:227-29 (1985). 5. I.J. Chasnoff, W.J. Burns, S.H. Schnoll, and K.A. Burns. Cocaine use in pregnancy. N. EngL J. Med. 313:666-69 (1985). 6. N. Bingol, M. Fuchs, V. Diaz, et al. Tetratogenicity of cocaine in humans. J. Pediatr, 110:93-96 (1987). 7. R.E. Mittleman, J.C. Cofino, and W.L. Hearn. Tissue distribution of cocaine in a pregnant woman. J. Forens. Sci. 34:481-86 (1989). 8. R.H. Cravey. Cocaine deaths in infants. J. Anal. Toxicol. 12: 354-55 (1988). 9. S.R Jindal and R Vestergaard. Quantitation of cocaine and its principle metabolite benzoylecgonine by GC-mass spectrometry using stable isotope labelled analogs as internal standard. J. Pharmacol. Sci. 67:811-14 (1978). 10. D.J. Stewart. Cocaine metabolism: cocaine and norcocalne hydrolysis by liver and serum esterase. C/in. Pharmacol. That. 25:464-68 (1979). 11. J.J. Ambre. The urinary excretion of cocaine and metabolites in humans: A kinetic analysis of published data. J. Anat. Toxico/. 9:241-45 (1985). 12. B. Barnett, R. Hawks, and R. Resnick. Cocaine pharmacokinetics in humans. J. Ethnopharmacol. 3:353-66 (1981). 13. D.S. Isenschmid, B.S. Levine, and Y.H. Caplan. A comprehensive study of the stability of cocaine and its metabolites. J. Anal ToxicoL 13:250-56 (1989). 14. D.N. Bailey and R.F. Shaw. Cocaine- and methamphetaminerelated deaths in San Diego county (1987): homocides and accidental overdoses. J. Forens. Sci. 34: 407-22. Manuscript received October 23, 1989; revision received January 24, 1990.
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