bupivacaine overdose following genital injection - … · bupivacaine overdose following genital...

Bupivacaine Overdose Following Genital Injection

Sarah Kerrigan, Ph.D.Bureau Chief

New Mexico Dept. HealthScientific Laboratory Division

History of Local AnestheticsFirst clinical operation under anesthesia performed in 1884 using cocaineCocaine widely utilized until toxic effects and death widely reportedCocaine was chemically synthesized in 1891, allowing structural amino ester analogs to be produced (tetracaine, benzocaine)Between 1898-1972 novel amide local anetheticsproduced (procaine, lidocaine, mepivacaine, bupivacaine)

NH

O

N NH

O

N

NH

O

N NH

O

N

RopivacaineBupivacaine

Lidocaine

Mepivacaine

Bupivacaine UsesSpecial interest due to long duration of action (up to 7 hours)Most widely used long-acting local anesthetic for surgery and obstetricsBupivacaine HCl doses 12-225 mgDoses of 150 mg for peridural anesthesia gave peak plasma concentrations of 1.1 mg/L after 20 minsBlood/Plasma ratios 1.2-1.3Metabolism likely involves N-dealkylation and hydroxylation; not widely studied in humans

Case HistoryDecedent LSA at 8:30 am when spouse left for churchWife returned at 1:00 pmHusband found dead in upstairs den with pants removed, pornography playing on VCRSexual paraphernalia in the vicinity including magazines, collars, tubing, rope, plastic bags, rubber rings and metal clipsSyringes, lidocaine cream, xylocaine jelly and three empty vials of Marcaine (5 mg/mL) present

Case HistoryDecedent led a “high stress job” as a car salesmanHistory of moderate alcohol useNo history of serious medical or mental health problemsPostmortem performed 24 hours after the discovery of the body

Postmortem Findings – External ExamLaceration and contusion of the lower lipSuperficial abrasion to left kneeSmall contusion to deep scalpMultiple needle punctures on scrotum with contusionsMild scrotal edemaThree small contusions on thorax and abdomen

Postmortem Findings – Internal ExamCongestion and edema of the lungsDiffuse fibrous adhesions within the scrotumFibrosis and hemorrhage of penis and and testiclesMild atherosclerotic stenosis of the coronary arteries, nephrosclerotic changes of the kidneys, mild steatosis of the liverRemainder of the postmortem was unremarkable

ToxicologySpecimens

Femoral BloodHeart BloodVitreous HumorUrine

TestsBlood AlcoholDrug ScreenComprehensive Tox(Basic, acidic, neutral drugs)

Toxicology MethodsAlcohol

Dual column GC-FIDHP 6890 GCRestek BAC1/BAC2 capillary columnsN-Propanol, t-Butanolinternal standards

Drugs of Abuse ScreenELISAOraSure TechnologiesWhole bloodOpiates, Methamphetamine, Benzodiazepines, Cocaine metabolite, Cannabinoids, Propoxyphene, Methadone, Barbiturates

Toxicology MethodsBasic, Acidic, Neutral Drugs by SPE and GC/MSPolyChrom Clin II SPEInternal standards (mepivacaine, hexobarbital)DB5 capillary column, 30m (0.25mm id x 25µm)160°C (2m); 30°C/min to 230°C (2m); 30°C/min to 290°C (12 m)Total run time 20 minsFlow rate (He) 1.3 mL/min

2 mL blood + 2 mL Phosphate buffer (pH 6, 0.1M)↓

Sonicate (15m), Centrifuge (4500rpm, 15m)↓

Add to SPE↓

Wash with 1mL DIW, 1mL acetic acid (1M)↓

Dry (full vac, 5m)↓

Wash 1 mL hexane↓

Elute acidic/neutral drugs, 1mL ethyl acetate↓

Wash 1 mL methanol

↓Elute basic drugs, 1 mL ethyl acetate with 2% NH4OH

ResultsNo ethanol, methanol, acetone, isopropanolDrugs of abuse screen negativeTrace of salicylate in femoral bloodBupivacaine only drug of toxicological significance

Bupivacaine QuantitationBovine blood fortified with bupivacaineMepivacaine internal standardFull scan acquisitionQuantitation ions (in bold)m/z 140, 84 (bupivacaine)m/z 98, 70 (mepivacaine)Calibration range (0-4mg/L)R2 = 0.999S/N ratio using lowest calibrator (0.08 mg/L) was 341:1

6.70 6.75 6.80 6.85 6.90 6.95 7.00 7.050200000

600000

1000000

1400000

Abundance6.85

6.70 6.75 6.80 6.85 6.90 6.95 7.00 7.05200000

600000

1000000

1400000

Time-->

AbundanceIon 70.00 (69.70 to 70.70): 1901020.D

6.89

40 100 160 200 240 280 320 360 400

200000

400000

600000

800000

1000000

1200000

1400000

m/z-->

Abundance 98

7042 120 148 176 246215197 280

6.70 6.75 6.80 6.85 6.90 6.95 7.00 7.05200000

600000

1000000

1400000


6.85

6.70 6.75 6.80 6.85 6.90 6.95 7.00 7.05200000

600000

1000000

1400000

Time-->


6.85

40 100 160 200 240 280 320 360 40040 100 160 200 240 280 320 360 400

200000

400000

600000

800000

1000000

1200000

1400000

m/z-->

Abundance 98

7042 120 148 176 246215197 280

NH

O

N

Mepivacaine

7.90 7.95 8.00 8.05 8.10 8.15 8.20 8.2501000000

3000000

5000000

Abundance Ion 140.00 (139.70 to 140.70): 1901020.D

7.91

8.05

8.20 8.24

7.90 7.95 8.00 8.05 8.10 8.15 8.20 8.2501000000

3000000

5000000

Time-->


7.91 8.05 8.21 8.25

50 100 150 200 250 300 350 400 4500

1000000

2000000

3000000

4000000

5000000

m/z-->

AbundanceScan 939 (8.046 min): 1901020.D (-935) (-)140

8456 120 245160 287215183 369343 475447

7.90 7.95 8.00 8.05 8.10 8.15 8.20 8.25

1000000

3000000

5000000


7.91

8.05

8.20 8.24

7.90 7.95 8.00 8.05 8.10 8.15 8.20 8.25

1000000

3000000

5000000

Time-->


7.91 8.05 8.21 8.25

50 100 150 200 250 300 350 400 4500

1000000

2000000

3000000

4000000

5000000

m/z-->


8456 120 245160 287215183 369343 475447

7.90 7.95 8.00 8.05 8.10 8.15 8.20 8.25

1000000

3000000

5000000


7.91

8.05

8.20 8.24

7.90 7.95 8.00 8.05 8.10 8.15 8.20 8.25

1000000

3000000

5000000

Time-->


7.91 8.05 8.21 8.25

50 100 150 200 250 300 350 400 4500

1000000

2000000

3000000

4000000

5000000

m/z-->


8456 120 245160 287215183 369343 475447

NH

O

N

Bupivacaine

Bupivacaine Quantitation

Heart Blood 2.8 mg/LFemoral Blood 3.8 mg/LVitreous Humor 1.3 mg/LUrine 11.4 mg/L

Genital InjectionsPractice of injecting foreign substances into external genitalia well described in medical literatureScrotal inflation with saline most common; oils, gels have also been usedThis practice can lead to local tissue damage or death (if substance enters the vascular system Internet sites describe materials needed, injection sites, what to expect and how to avoid infection

Bupivacaine ToxicitySince introduction in 1965, CNS and cardiovascular toxicity have been reportedA stereoselective isomer (levobupivacaine) and ropivacaine (replacement of butyl with propyl) are reported to be less cardiotoxic/increased margins of safetyToxicity includes CV collapse, respiratory depression/arrest, arrhythmia, deathMost frequently associated with seizuresMore cardiotoxic than many structurally related analogs; eliminated from myocardium slower than lidocaine

Bupivacaine ToxicityOverlap of adverse/therapeutic concentrations:Hypertension, bradycardia, cyanosis, loss of consciousness, convulsions, respiratory arrest reported between 0.7-1.8 mg/L (Holmboe et al 1982; Rosenburg et al 1983; Hasselstrom et al 1984)Clinical study using high dose bupivacaine (400 mg) in ten patients produced peak plasma levels averaging 2.5 mg/L (Moore et al 1976)

Case ConclusionsDecedent injecting bupivacaine into genitalia to enhance/prolong sexual endeavorsContusions and internal scarring consistent with long-term activityHistology consistent with injection of foreign materialMinor abrasion on knee and contusion to scalp consistent with terminal collapseLaceration to lip consistent with biting (possible seizure activity prior to death)Cause of death: Bupivacaine intoxicationManner of death: Accidental

Acknowledgements

Janice Yazzie, B.S.Scientific Laboratory Division

Sean Kelly, M.D.Office of the Medical Investigator

Ross E. Zumwalt, M.D.Office of the Medical Investigator

bupivacaine overdose following genital injection - … · bupivacaine overdose following genital...

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