Journal of Analytical Toxicology, Vol. 25, July/August 2001 [CaseReport Dermal Exposureto Strychnine

Richard Greene 1 and Robert MeatheralP,* 1Emergency Department, Grace General Hospital and 2Laboratory Medicine, St. Boniface General Hospital, Winnipeg, Manitoba, Canada Downloaded from https://academic.oup.com/jat/article/25/5/344/778260 by guest on 24 September 2021 t Abstract ] tents into the toilet. She accidently spilled about 1 cupful on the floor, which she wiped up with a cloth soaked in a diluted Javex A non-fatal case of strychnine poisoning through dermal exposure is solution (sodium hypochlorite). Her dermal exposure was limited described. About 24 b after cleaning up a strychnine spill, a 50-year- to her left palm; she washed her hands about 30 rain after old woman presented to the emergency department with classical cleaning up the spill. During the prodromal time period, she signs of strychnine poisoning, consisting of marked pain in the experienced no irritation or dermatitis to the left hand. Except for muscles of her lower limbs, dermal sensitivity, and stiffness in her a tingling sensation in her left hand, she was asymptomatic until jaw. Her treatment was intravenous fluid replacement and about 22:00 h when her arms and legs began to shake, pro- alkalinization in anticipation of potential renal failure due to gressing to spasms. Over the course of the night, the frequency rhabdomyolysis. Her plasma creatine kinase was elevated to 677 and duration of these muscle contractions increased. By U/L with no rise in the heart specific MB fraction. Serum myoglobin morning, the pain was more severe in the muscles of her lower level obtained retrospectively was 195 pg/L. Biological samples were taken approximately 28 h after her exposure. Strychnine was limbs, and she was having difficulty with weight bearing. She also measured in plasma (196 ng/mL) and urine (6850 ng/mL) by gas stated she was experiencing some stiffness in her jaw. There was chromatography-mass spectrometry. The small amount of no change in her level of consciousness, and she denied a pheniramine in the plasma (35 ng/mL) and urine (1255 ng/mL) is headache, fever, and shortness of breath. considered an inconsequential finding. That same morning (i.e., 24 h after the exposure), she arrived in the emergency department. On physical examination, she was alert and aware. She showed no signs of meningism. There were no bulbar signs. She was able to swallow and did not have any Introduction gross trismus, but was symptomatic for referred discomfort when she was opening her jaw. Neurologic examination showed no Strychnine competitively blocks the action of glycine, the neu- pronator drift. Power in the upper limbs was normal. The lower roinhibitory transmitter at the postsynaptic site. The resulting extremities were notable for marked pain with any movement in muscular hyperexcitability is characterized by spasms in the flexion of the knees and hips. The pain appeared to be localized to upper and lower limbs and jaw muscles (1). The usual cause of the calves. She was very tender on palpation of the calves bilater- death is respiratory failure due to chest muscle and diaphragm ally, to the point of crying. Also, her legs were extremely sensitive spasm (2). Strychnine fatalities are rare; non-fatal exposures are to light touch (i.e., dermal hypersensitivity). Her inability to walk uncommon. In 1999, there were 50 non-fatal and zero fatal poi- was secondary to the pain that occurred with any significant sonings reported by the American Association of Poison Control weight bearing. There were no gross signs of dorsal column or Centers (3). The statistical summary does not list analytical toxi- cerebellar dysfunction. cology findings and likely excludes fatalities outside the hospital Her past history included peripheral vascular disease; she had a reporting system. femoral popliteal bypass done some years previously. She had no The following is the first report in which strychnine is mea- cardiac or respiratory history. She had allergies to sulfa drugs and sured in plasma and urine following an accidental dermal expo- to carbamazepine. Tetanus and rabies were, by history, excluded sure. as she had not experienced any inadvertent lacerations outside the home over the previous two weeks nor suffered any inadver- tent animal bites. Case History Blood and urine were collected at 14:00 h, approximately 28 h following her strychnine exposure. Her plasma total creatine On the morning of her exposure, a 50-year-old woman was dis- kinase, CK, was 677 U/L (normal female = 28-110 U/L). The posing of an old bottle of strychnine solution by pouring the con- heart-specific CK-MB fraction was 17 U/L (normal < 21 U/L); the troponin I was < 0.10 IJg/L (normal < 0.1 lag/L), indicating no * Author to whom correspondenceshould be addressed. Robert Meatherall, PhD, Laboratory Medicine, St. BonifaceGeneral Hospital, 409 TachS.Ave, Winnipeg, Manitoba, Canada, R2H myocardial involvement. Arterial blood gases, CBC, and chest X- 2A6. E-mail: [email protected]. ray were all normal. Urine drug screen revealed strychnine,

344 Reproduction(photocopying) of editorial contentof this journal is prohibitedwithout publisher'spermission. Journal of Analytical Toxicology, Vol. 25, July/August 2001 pheniramine, and acetaminophen by gas chromatography-mass pation of the calf muscles and was able to ambulate normally with spectrometry (GC-MS). Urine cannabinoidsscreened positive (54 only minimal discomfort to her calveswith weight bearing. Her ng/mL), just above the 50-ng/mL cutoff used with the Emit II renal and respiratory functions remained normal. She was dis- Plus Cannabinoids method. Urine benzodiazepineswere positive charged from hospital two days after admission. On phone follow- (1018 ng/mL) by CEDIAusing a 100-ng/mL cutoff. Quantitations up one month later she was essentiallyasymptomatic. were later performed on the urine and plasma samples. The patient was started on fluid rehydration and alkalinization as prophylaxis against renal failure secondaryto rhabdomyolysis. Methods Myoglobin, measured retrospectively on the admission plasma, was 195 pg/L. Local experience has shown that renal failure is Urine was screened by GC-MS for basic drugs using a modified associated with myoglobin concentrations exceeding 800 pg/L method of Foerster et al. (4) and for acid drugs using the method Over the ensuing 48 h, her CK dropped to 331 U/L. Her dermal of Meatherall (5). Drugs of abuse were screened on a Hitachi 717 hypersensitivityand symptomatic tightness around her jaw com- analyzer (Roche Diagnostics, Laval, QC, Canada) using EMIT II pletely resolved. She had only residual tenderness to deeper pal- Plus (Syva,Palo Alto, CA), except for benzodiazepines,which were Downloaded from https://academic.oup.com/jat/article/25/5/344/778260 by guest on 24 September 2021 screened using CEDIA (Microgenics,Fremont, CA). The positive benzodiazepinescreening result was confirmed by GC-MS (6). The positive cannabis screening result was confirmed by GC-MS using a modification of the method described by Wimbish and Johnson (7). I'07 Acetaminophenwas quantitated in plasma and urine by high-performance liquid chromatography (HPLC) (8).

.... , Strychnine, brucine free bases, and pheniramine "' I , -, [,,,+I , + I 1 maleate were purchased from Sigma-Aldrich (Oakville,

itrychnlne ON, Canada). Individual stock standards were prepared 334 "55-~ ~1~ ~ ..... m/z- "" 6850 ng/mL in methanol at 1000 pg/mL. Working strychnine and pheniramine plasma- and urine-based standards were prepared from the stocks at 0, 50, 100, 200, 400, 600, 11 T Intemll - standard 800, and 1000 ng/mL. Brucine working internal stan- nt/z dard was prepared by diluting the stock standard into I I l I 9 l 0.01N HCI to give 10 pg/mL. phenlramlne Drug screening and subsequent strychnine and pheni- 169 1255nglnL .~..+IIp9. .i. Z4,1 ,, ramine quantitations were performed by GC-MS on an I I TI I 9 rl 3+, ' ~ 'oJ. ,,.. m'.B ITS40 ion trap and running on Magnum software. Retention time (s) Separation was performedwith a DB-1 (15 m x 0.25 mm, 0.25-pm film thickness) methyl silicone capillary Figure1. Total ion and extracted ion chromatograms from the patient's urine. column. A 1-m x 0.52-mm retention gap deactivatedwith 5% phenyl methyl silicone connected the analytical column to the temperature-programmable injector. Helium carrier gas flowedat 45 cm/s. The oven was ini- tially held a 80~ for I min, then programmed at 10~ to a final temperature of 290~ where it was held for 5 min. 701 The temperature-programmable injector was ramped from 85 to 290~ at 13~ Electron impact mass spectra were collectedin full scan from 44 to 650 amu at I scan/s. I I I I

stnJchnlne l 334 196 ng/mL

1 I 9 , . , , ,i Analysis of Strychnine and Pheniramine

394 Internal standard Samples were prepared by a modified method first described by Foerster et al. (4) for drug screening. One l i milliliter of sample was combined with 50 pL of brucine phonlramlne l internal standard (10 pg/mL), 500 pL of 1 mol/L sodium 169 35 ng/nL bicarbonate (pH 9), 4 mL of methyl tert-butyl ether, and 2 mL of chloroform in a 20-mL 150-ram x 16-ram glass Retention time (s) extraction tube. The tube was capped and rotated for 15 rain. After a brief centrifugation, the upper organic layer Figure2. Total ion and extracted ion chromatograms from the patient's plasma. was transferred to a clean extraction tube to which 2 mL

345 Journal of Analytical Toxicology,Vol. 25, July/August2001

of 0.1 mol/L HCI was added. Drugs were back extracted into the poisonings (]2,13). Clinical symptoms in the latter two patients hydrochloric acid by vortex mixing the tube for 30 s. The organic were more severe than with this patient; they included seizures layer was aspirated to waste, and 150 tJL of concentrated ammo- and lactic acidosis in addition to rhabdomyolysis. nium hydroxide and I mL of chloroform added. The tube was Fatalities resulting from the ingestion of strychnine have been again vortex mixed for 30 s and briefly centrifuged. The upper reported with postmortem blood and urine concentrations of aqueous layer was aspirated to waste and the organic transferred to 500-6100 and 1000-33,000 ng/mL, respectively (14). a 5-mL conical glass tube. After the addition of 200 IJL of ethyl The exposure dose may be calculated from the expression: Dose acetate, the organic extract was reduced to 30 IJL, which was trans- --- Vd x wt x CE = 13 x 64 x 0.000786 = 0.6 g, where Vd is the ferred to an autosampler vial. One microliter was injected onto the volume of distribution, 13 L/kg, as estimated by Heiser (15); wt is GC-MS. Ions used for quantitation were 334 for strychnine, 394 the patient weight, 64 kg; and CE is the estimated strychnine con- for brucine, and 169 for pheniramine. Linear regression of the cal- centration 4 h after initial exposure, 786 ng/mL. ibration standards was handled by the Magnum software. The brand name and strychnine concentration of the solution Quantitation of the patient's urine was done on a 10-fold dilution are unknown. There was no label on the bottle, and the bottle was

to bring the analytes within the range of the calibration curve. discarded soon after the spill, making it impossible to analyze the Downloaded from https://academic.oup.com/jat/article/25/5/344/778260 by guest on 24 September 2021 strength of the solution. However, typical commercial prepara- tions are reported as 0.3-3% (14) and 0.3-5% (16). If one assumes a 2% solution, then the contents from approximately 30 mL Results strychnine solution must have been absorbed. The pheniramine is of no consequence. The plasma and urine The GC-MS urine drug screen indicated strychnine and pheni- concentrations were 35 and 1255 ng/mL, respectively. Following ramine. Because no brucine was detected, it was selected as the the oral administration of therapeutic doses, peak serum concen- internal standard for the subsequent strychnine quantitation. trations are typically less than 270 ng/mL (17). Postmortem blood Chromatograms of urine and plasma extracts are presented in and urine concentrations associated with fatalities were reported Figures 1 and 2. Extracted ions used in the quantitations are dis- as 1900-30,000 and 149,000-362,000 ng/mL, respectively (17). played below the total ion chromatograms. Strychnine concen- trations in the plasma and urine were 196 ng/mL and 6850 ng/mL, respectively. Pheniramine concentrations in the plasma and urine were 35 ng/mL and 1255 ng/mL, respectively. Urine References acetaminophen was 24 IJg/mL; none was detected in the plasma. Nordiazepam (388 ng/mL) and oxazepam (124 ng/mL) were con- 1. M.J. Ellenhorn and D.G. Barceloux. Medical Toxicology: Diagnosis firmed present in the urine. There was insufficient sample for and Treatment of Human Poisoning, 1st ed. Elsevier, New York, NY, quantitative analysis in the plasma, but the concentrations would 1988, pp 1086-1087. likely be subtherapeutic based on the low urine values. The urine 2. B.A. Smith. Strychnine poisoning. J. Emerg. Med. 8:321-325 (1990). b9-carboxy-tetrahydrocannabinol concentration was 10 ng/mL. 3. Ti. Litonitz, W. Klein-Schwartz, S. White, D.J. Cobaugh, J. Youniss, A. Drab, and B.E. 8enson. 1999 annual report of the American Association of Poison Control Centers toxic exposure surveillance system. Am. J. Emerg. Med. 18:517-574 (2000). 4. E.H. Foerster, D. Hatchett, and J.C. Garriott. A rapid comprehensive Discussion screening procedure for basic drugs in blood or tissues by gas chro- matography. J. Anal. Toxicol. 2:50-55 (1978). This is the first report of accidental strychnine poisoning via 5. R. Meatherall. GC/MS confirmation of barbiturates in blood and urine. ]. Forensic Sci. 42:1160-1170 (1997). dermal exposure. Plasma and urine strychnine concentrations 6. R. Meatherall. GC-MS confirmation of urinary benzodiazepine were 196 and 6850 ng/mL, respectively, approximately 28 h after metabolites. J. Anal. Toxicol. 18" 369-381 (1994). exposure. Bleach was used to mop up the spill. Being strongly 7. G.H. Wimbish and K.G. Johnson. Full spectral GC/MS identification alkaline, it converted strychnine salt to a free base that was more of Ag-carboxy-tetrahydrocannabino] in urine with the Finnigan efficiently absorbed through the skin. As stated in the case history, ITS40. J. Anal. ToxicoL 14:292-295 (1990). 8. R. Meatherall and D. Ford. Isocratic liquid chromatographic deter- she had no cuts on her hands. Strychnine is known to be rapidly mination of theophylline, acetaminophen, chloramphenicol, caf- absorbed through the gastrointestional tract (9) and mucous feine, anticonvulsants and barbiturates in serum. Ther. Drug Monit. membranes (10). The plasma half-life, following oral ingestion, 10:101-115 (1988). was previously shown to be 10-16 h and followed first-order elim- 9. G.P. Sgargli and P.F.Mannaioni. Pharmacokinetics observations on a ination pharmacokinetics (11). Assuming a half-life of 12 h and case of massive strychnine poisoning. Clin. Toxicol. 6:533-540 (1973). assuming the systemic distribution is complete within the first 4 10. W.G. O'Callaghan, N. Joyce, H.E. Counihan, M. Ward, P. Lavelle, h of dermal exposure, the anticipated peak plasma concentration and E. O'Brien. Unusual strychnine poisoning and its treatment: would have been 786 ng/mL. 1 Peak serum strychnine concentra- report of eight cases. Br. Med. J. (Clin. Res. Ed.) 285:478 (1982). tions of 1600 and 2200 ng/mL have been reported in two non-fatal 11. W. Palatnick, R. Meatherall, D. Sitar, and M. Tenenbein. Toxicokinetics of acute strychnine poisoning. Clin. Toxicol. 35: 617-620 (1997). I According to first order kinetics, CE =CBE x e ~/* = 196 x e 1.39= 786 ng/mL where C[ = the 12. A.F. Hernandez, J. Pomares, S. Schiaffino, A. Pla, and E. Villanueva. plasma concentration 4 h after the initial exposure; CBE = the plasma concentration 28 h after ini- tial exposure, 196 ng/mL; t = the time interval between blood sampling and complete absorption, Acute chemical pancreatitis associated with nonfatal strychnine poi- 24 h; and * = tln/ln 2 = 12/0.694 = 17.3 h. soning. J. Toxicol. Clin. Toxicol. 36:67-71 (1998).

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13. M. Edmunds, T.M.T. Sheehan, and W.V. Hoff. Strychnine poisoning: 16. M.L. Drost. Strychnine overdose in man. Can. Soc. Forensic Sci. clinical and toxicological observations on a non-fatal case.J. Toxicol. J. 12:125-131 (1979). Clin. ToxicoL 24" 245-255 (1986). 17. R.C. Baselt. Disposition of Toxic Drugs and Chemicals in Man, 5th 14. R.C. Baselt. Disposition of Toxic Drugs and Chemicals in Man, 5th ed. Chemical Toxicology Institute, Foster City, CA, 2000, pp ed. Chemical Toxicology Institute, Foster City, CA, 2000, pp 686-687. 790-792. 15. J.M. Heiser, M.R. Daya, A.R. Magnussen, R.L. Norton, D.A. Spyker, D.W. Allen, and W. Krasselt. Massive strychnine intoxication: serial Manuscript received November 27, 2000; blood levels in a fatal case. Clin. ToxicoL 30:269-283 (1992). revision received February 15, 2001. Downloaded from https://academic.oup.com/jat/article/25/5/344/778260 by guest on 24 September 2021

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