- Email: [email protected]
Prior Medical Therapy and Medical Intervention
3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION A variety of cases are submitted to the Medical Examiner’s Office where there is little to no medical history and/or medical interventions prior to death. An awareness of the history or interventions may prevent a misinterpretation of the toxicological findings. In addition to a history of drug abuse, the decedent’s medical history and/or scene investigation may indicate prescriptions for various therapeutic medications and/or the use of over-the-counter medications for the treatment of existing maladies. A patient with a history of attention deficit hyperactivity disorder would possibly explain the finding of amphetamine; a seizure disorder history may suggest use of various seizure medications and other psychotropic medications used in the adjunct treatment of seizures or chronic pain, along with various opioids. It is not uncommon for a chronic pain patient to be taking two different opioids, one for baseline pain control and the other for breakthrough pain, as well as a muscle relaxant, and an anxiolytic. Geriatric patients on average are taking eight different medications simultaneously [1]. Therefore the finding of these drugs in a decedent is not unexpected. When an illicit substance, such as marijuana or cocaine, is detected one may jump to the conclusion that it (1) should not be present and (2) may have played a role in the death of the individual. Thus, in some cases this may lead to the wrong conclusion and associate the death with a drug if the prior medicinal use is unknown. An example of such is in the finding of tetrahydrocannabinol (THC); Marinol (synthetic THC) is an FDA-approved medication for certain disorders related to cancer and HIV infection and since a number of states and countries have legalized the use of marijuana for either medicinal purposes or recreational use; the presence of THC may be explained by these reasonable reasons rather than marijuana abuse.
Postmortem Toxicology. DOI: https://doi.org/10.1016/B978-0-12-815163-1.00003-4 © 2019 Elsevier Inc. All rights reserved.
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Cocaine is a highly abused drug in today’s society. However, cocaine still has a minor niche in modern medicine, taking advantage of its local anesthetic properties and sympathomimetic (vasoconstrictive) properties; achieve a low blood field for certain types of surgical procedures [2,3]. ¨ ber Coca was published in 1884 by The monograph U Sigmund Freud [4,5] described the historical use of cocaine, botanical characteristics, and its pathophysiology and various therapeutic actions, including a “numbness of skin and mucous membranes” that had contact with solutions of cocaine. In 1884, Karl Ko¨ller described the use of cocaine as a local anesthetic in ophthalmological procedures [6,7]. In 1885, Halstead and Hall described the use of cocaine to serve as dental nerve blocks, thus allow for surgery of the maxilla without pain [8]. In addition to this historical use of cocaine, it is still limit use in some surgical procedures [3], such as nasal and lacrimal procedures. An alternative preparation for surgery is to mix cocaine with adrenaline (epinephrine) and sodium bicarbonate, also known as Moffett’s solution [9]; which is topically applied. Otolaryngologists have utilized the anesthetic and vasoconstrictive properties of cocaine in nasal surgery and/or intrusive examination of the nasal passages. Cocaine in these procedures is usually applied in one of two ways; insertion of cottonoids or pledgets in the nares for 10 minutes (total dose applied B160 mg) or an aerosol spray (total dose B20 60 mg) of 4% cocaine applied shortly before the procedure [10]. These authors designed a study to evaluate whether or not cocaine’s primary metabolite; benzoylecgonine would be detected in a urine drug screen following the medical application of the drug. They evaluated 12 patients who were to undergo elective nasal surgery where cocaine was applied via the cotton pledgets and 30 subjects who received the aerosolized cocaine for the presence of benzoylecgonine over a 24-hour period; not all subjects/volunteers participated in each collection period. In both study groups, the patient’s/subject’s urine were positive for benzoylecgonine 24 hours postdosing, with all samples negative after 72 hours (Tables 3.1 and 3.2). The authors established that a urine drug test may be positive due to medically used cocaine. Quiney [11] investigated whether or not medicinally used cocaine, for nasal surgery, could result in measurable serum cocaine levels when applied via two different techniques; “Moffett’s method” or topical applied cocaine paste using cotton pledgets; adrenaline was also applied prior to the procedure to assist with hemostasis. The author found an average serum
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Table 3.1 Surgical Patients Dosed With 4 mL 4% Cocaine on Cotton Pledgets Collection Time
Preprocedure Postprocedure 24 h 36 h 48 h 72 h
Positive Urine Drug Test Number of Positive Patients
Percent Positive for Benzoylecgonine (%)
0 of 12
0
12 of 12 3 of 6 0 of 12 0 of 6
100 50 0 0
Source: Adapted from Reichman OS, Otto RA. Effect of intranasal cocaine on the urine drug screen for benzoylecgonine. Otolaryngol Head Neck Surg 1992;106:223 5.
Table 3.2 Subjects Dosed With Cocaine Solution via an Atomizer Collection Time
Predosing Postdosing 12 h 24 h 36 h 48 h 72 h 96 h
Positive Urine Drug Test Number of Positive Subjects
Percent Positive for Benzoylecgonine (%)
0 of 30
0
20 of 20 30 of 30 16 of 20 18 of 30 1 of 10 0 of 10
100% 100 80 60 10 0
First 20 subjects were tested 12, 24, 36, and 48 h postdosing. Last 10 subjects were tested 24, 48, and 72 h postdosing. Source: Adapted from Reichman OS, Otto RA. Effect of intranasal cocaine on the urine drug screen for benzoylecgonine. Otolaryngol Head Neck Surg 1992;106:223 5.
cocaine concentration of 0.21 mg/L in all patients, between 10 and 60 minutes of application. A maximal concentration of 1.10 mg/L was observed in one patient. Quiney also observed that the absorption rate was slower in the cocaine paste
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Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
patients as compared to those where Moffett’s solution was used for cocaine introduction. This is mostly likely due to the bicarbonate in the Moffett’s solution; shifting more of the cocaine to the unionized form, thus more readily crossing the nasal membranes. In ophthalmology, cocaine is used as the local anesthetic in dacryocystorhinostomy or commonly referred to as lacrimal surgery. The physicians take advantage of the anesthetic and vasoconstrictive properties of cocaine as well in these surgeries. Bralliar et al. [12] reported positive urine drug tests for benzoylecgonine following ophthalmic application, two drops of a 10% cocaine solution was instilled in the cul-de-sac of each eye to 19 of their patients; estimated dose was B20 mg of cocaine. The patients were tested for the presence of cocaine metabolites utilizing immunoassay techniques (Syva EMIT) with a benzoylecgonine cut-off of 300 ng/mL. Four hours postapplication, all 19 patients tested positive for cocaine metabolite. At 24 hours postapplication, all patients still tested positive and by 36 hours 53% of the patients remained positive for cocaine metabolites as determined by immunoassay. Cruz et al. [14] performed a similar study with 12 of their patients undergoing lacrimal surgery. Their patients were dosed with cocaine by application a “single spray” of aerosolized 4% cocaine, followed by packing the nasal cavity with cotton strips lightly soaked with a 4% cocaine solution. The authors performed a quantitative study of benzoylecgonine in urine sample collected from their patients, utilizing gas chromatography/ mass spectrometry, over several days. They found that all 12 of their patients tested positive for benzoylecgonine [assay limit of detection (LOD) was 60 ng/mL] for 24 hours postoperatively, with 3 patients having detectable benzoylecgonine 72 hours after their surgical procedure (Table 3.3). These three patients were negative at 1 week postop for benzoylecgonine. Patrinely et al. [13] published in the same study and data in 1994; however, the reported LOD of the method was 50 ng/mL. Topical cocaine has also been used in the treatment of severe epistaxis (nosebleed) [15]. The literature is devoid of information as to whether or not enough cocaine is absorbed to produce a positive finding in urine. However, given the information known from the introduction of cocaine in otolaryngological procedures, one would expect that benzoylecgonine would be detected in these patients as well. TAC (mixture of tetracaine, adrenalin, and cocaine) has been used as topical anesthetic for the treatment of nonmucosal lacerations [16], especially in pediatric patients [17]. Several
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Table 3.3 Benzoylecgonine in Postlacrimal Surgery Patients Patient
Urinary Benzoylecgonine Concentration (ng/mL) 24 h Postop
1 2 3 4 5 6 7 8 9 10 11 12
a
661 568 259 375 133 2459 121 662 852 67 1226 1347
48 h Postop
72 h Postop
108 319 ND 70 93 387 NA 94 177 ND 218 220
60b ND ND ND ND 88b ND ND 72a,b ND 68b ND
NA, Not available—sample not collected; ND, not detected—below LOD of method. a Patrinely et al. [13]: Reported concentration was 660. b Negative at 1 week. Source: Adapted from Cruz OA, Patrinely JR, Reyna GS, King JW. Urine drug screening for cocaine after lacrimal surgery. Am J Ophthal 1991;111:703 5 [14].
studies have noted that the topical application of a TAC solution will result in the presence of cocaine and/or metabolites in urine and plasma. Altieri et al. [18] demonstrated the persistence of cocaine’s primary metabolite, benzoylecgonine in urine between 36 and 45 hours posttreatment in 15 of 18 of their patients. The benzoylecgonine concentrations were determined by gas chromatography/mass spectrometry, with an assay LOD of 75 ng/mL. Table 3.4 reflects benzoylecgonine urinary concentrations in patients treated with TAC. Fitzmaurice et al. [19] studied the systemic absorption of cocaine in 51 children when used as a topical anesthetic. Plasma samples were available from 46 children and were obtained 20 40 minutes after application of the topical anesthetic. The authors did not detect cocaine in any of the plasma samples; however, in 57% of the children cocaine metabolites were detected. Ecgonine methyl ester was found in 6 of the
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Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
Table 3.4 Benzoylecgonine in Post-TAC Treated Patients Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Urinary Benzoylecgonine Concentration (ng/mL) Day 1
Day 2
730 5 4300 690 840 1130 140 520 NA 270 1670 3630 1810 5 1260 930 250 2670
NA 5 240 5 5 160 5 110 150 5 140 330 320 5 5 5 5 570
5 , Negative result (less than LOD); NA, specimen not available. Source: Adapted from Altieri et al [18].
children with concentrations ranging from 59 to 985 ng/mL, whereas benzoylecgonine was detected 23 children with concentrations ranging from 40 to greater than 600 ng/mL. It should be noted that all the samples negative for benzoylecgonine were not preserved with sodium fluoride whereas the positive sample for benzoylecgonine did contain sodium fluoride as a preservative. According to Kundu and Achar [20], the use of TAC is no longer supported by the literature in general due to concerns about toxicity, expense, and the associated regulatory issues involving medications that contain cocaine. A newer formulation of a topical anesthetic has replaced cocaine with lidocaine and called LET (lidocaine, epinephrine, and tetracaine).
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
A proper medical history coupled with the understanding of the therapeutic uses of cocaine will prevent the misinterpretation of a positive cocaine and/or metabolite result in the decedent. There have also been several postmortem cases investigated by the authors office, where 24 48 hours post knee replacement surgery, anesthetics were detected in blood, tissue, and/or urine specimens collected at autopsy from deaths unrelated to the surgery; for example, propofol, etomidate, and bupivacaine. Sometimes appropriate prior medical therapy may lead to toxicity. The application of TAC to mucous membranes has caused status epilepticus in a patient and death in two pediatric patients [21]. Makaryus et al. [22] describe a case of a 68-yearold woman who underwent nasal surgery where cocaine was applied preoperatively. Shortly after the procedure, she developed an acute myocardial infarction. Rhidian and Greatorex [23] provide a case report in which a patient underwent elective septoplasty and was administered Moffett’s solution, after induction of general anesthesia. Upon awaking from the procedure the patient reported “Crushing” chest pain radiating to the left shoulder; troponin level was normal. After treatment with morphine, nitroglycerin, and oxygen, the pain resolved and was released the next day. A 5.5-year-old male underwent an exploratory nasopharyngoscopy procedure [24]. The nasal cavity was anesthetized by instilling 0.1 mL of 4% cocaine solution. Ninety minutes later, the young boy became agitated, diaphoretic, with dilated pupils. He was tachycardic and hypertensive; treatment with IV lorazepam over a 2-hour period to address the cardiac excitability and the neurological irritation and there was complete resolution of symptoms within 4 hours without sequelae.
Medical Intervention Medical intervention may lead to spurious findings and misinterpretation of result, especially in the absence of an adequate medical history. There are several factors that will aid in understudying and assigning the appropriate weight to an analytical finding, such as the time of the medical intervention relative to sampling of the biological fluid or tissue—hospital or autopsy samples. The types of intervention may in some cases, direct or focus the toxicological analyses; for example, Narcan may direct
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the analysis to opioids or flumazenil may direct the analysis to a variety of benzodiazepines. If the patient presents with a history of a recent oral ingestion of a large amount of medications, a gastric lavage may be performed. Thus, removing a significant portion of the drug from the stomach contents, so when quantitated the amount may be minimal and not necessarily support a suicide finding. Carbon monoxide poisoning is a frequent cause of death, with a carboxyhemoglobin (COHb) saturation of .50% considered lethal. However, oxygen therapy during the agonal stages of life can dramatically lower the measured saturation of carbon monoxide in blood taken at autopsy. The half-life of COHb in fresh air is about 5.5 hours, whereas with the administration of 100% oxygen, commonly used by first responders, the half-life of COHb is decreased to approximately 80 minutes and if the patient initially survives makes into a higher level of care and receives hyperbaric oxygen with 100% O2 at 3 atmospheres COHb half-life is reduced to 23 minutes [25]. Thus, medical intervention could reduce the measured COHb from an accepted lethal saturation, for example, B50% to a saturation consider to be mildly symptomatic with just an hour of hyperbaric treatment; thus, potentially calling into question of whether the toxic insult was due to carbon monoxide. Many medications are administered via an existing intravenous line. If blood at autopsy or at the scene is drawn through the existing line, in which a drug had recently been administered, for example, 2 mg of morphine was given for pain relief, there is a potential for an artificially elevation of the measured drug concentration in the collected sample. This artificially elevated blood drug concentration could lead to a misinterpretation of the toxicological result; leading one to believe that the cause of death was due to the narcotic overdose. Massive fluid resuscitation, via the placement of a central line, could lead to an opposite effect; that is, dilution of the drug concentration especially in the heart blood sample. Table 3.5 illustrates this occurrence in a couple of cases examined in the author’s laboratory. In both cases, a central line was placed for fluid resuscitation and the result was a significant decline in the heart blood alcohol result. Postmortem computed tomography (PMCT) has been increasingly used in the medicolegal investigation of death; for the visualization of vascular injuries from trauma or hemorrhages following rupture of small vessels. The injection of contrast media in these procedures could cause the dilution of postmortem blood samples or other fluids, such as vitreous or
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
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Table 3.5 Fluid Resuscitation and Alcohol Specimen
Case Number 1 (g%)
Case Number 2 (g%)
0.56
0.12
0.70
0.21
0.76
0.21
0.76
0.26
Heart Blood
Ethyl alcohol Femoral Blood
Ethyl alcohol Vitreous
Ethyl alcohol Urine
Ethyl alcohol
urine and potentially have a negative impact on the toxicological results. Rutty et al. [26] investigated whether or not PMCT angiography would cause of significant effect, via dilution, on vitreous biochemistry, immunological (blood tryptase), or blood toxicological results. The authors did note slight variations in quantitative results; however, they opined that the procedure did not have a negative impact on the diagnostic utility of the test. Palmiere et al. [27] evaluated the impact of this procedure on urine samples screened for common drugs and illicit substances collected pre- and postPMCT angiography. Two compounds, hydroxyl-amitriptyline and venlafaxine were detected in the urine sample prior to angiography and not detected in the urine sample postangiography. Whereas, two compounds, zolpidem and carboxy-THC were detected in the postangiography sample but were not detected in the preangiography urine sample. The following three compounds, citalopram, cotinine, and oxazepam, were detected in both samples, however, in each case the postangiography cohort had one additional sample positive for the drug. The only significant quantitative difference observed was related to the analyses of THC and its metabolites (hydroxyl-THC and carboxy-THC). A frequently encountered toxicological finding in postmortem cases is the presence of lidocaine. Lidocaine is an administered drug used both as a local anesthetic, administered via infiltration or topically applied, and as an antiarrhythmic
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Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
medication. Also, a variety of endotracheal tubes are coated with xylocaine (2% lidocaine) jelly. In many cases, the source of detected lidocaine is from the endotracheal tube used in resuscitation or surgical procedure. Moriya and Hashimoto [28] describe the postmortem diffusion of tracheal lidocaine into heart blood in three patients. The lidocaine detected in heart blood samples ranged from 0.102 to 1.02 mg/L, with negative findings in brain or muscle tissue. In an animal experiment, the authors applied lidocaine to the trachea of rabbits. Lidocaine concentrations of 0.550 4.03 and 3.05 7.30 mg/L were found in heart blood on day 1 and day 3, respectively; lidocaine was not detected in brain tissue or muscle tissue. Wunder et al. [29] studied the plasma concentrations of lidocaine and its metabolite MEGX (monoethylglycinexylidide) in 35 surgical patient and compared to concentrations found in 18 postmortem cases following unsuccessful resuscitation. In the surgical patients, 1 hour postexposure lidocaine plasma concentrations were less than 0.2 mg/L and MEGX concentrations were less than 0.05 mg/L. Lidocaine and MEGX were also detected in urine samples from these patients. The lidocaine concentrations found in the decedents ranged from 0.02 to 1.07 mg/L (median 0.07), and MEGX ranged from ,0.001 to 0.044 mg/L (median 0.01); low concentration of lidocaine were reported in the urine. MEGX was only detected in the urine of two out of nine samples collected. Mainland et al. [30] evaluated blood concentrations of lidocaine resulting from its use as airway anesthesia for bronchoscopy in 96 patients. In patients receiving 0.3 mL of a 2% lidocaine solution, the highest concentration reported was 6.28 mg/L. Although some patients had significant lidocaine concentrations, there were no reported signs of toxicity. Lidocaine gel is widely used as a local anesthetic lubricant on various forms of transurethral instrumentation, for example, catheters [31,32]. This may lead to a positive finding of lidocaine in urine, and none detected in the blood. In trauma patients, multiple pharmacological treatments are utilized and if the patient dies shortly, thereafter it is common to detect these medications; for examples, opioids are commonly utilized in the treatment of acute pain, benzodiazepines are used for acute agitation, sedation, and intubation of patients, ketamine for analgesia [33] and/or sedation [34] especially in pediatric cases [35], and various anticonvulsants for seizure disorders. The assessment of the findings, as to whether they were therapeutic or a causative factor in the case, requires a careful review of the medical records to establish whether or
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
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Table 3.6 Hospice Patient Drug Findings Specimen
Morphine (mg/L)
Lorazepam
Blood (SC) Blood (FB) Urine
5.1 0.24 0.82 (total)
240 ng/mL NT NT
FB, Femoral blood; NT, Not tested; SC, Subclavian.
not they were given and at what time relative to the time blood samples were drawn, if antemortem specimens are examined. In some Medical Examiner jurisdictions, end-of-life care or hospice patients are referred to the office for examination. The patient will have several symptoms relating directly to the disease process and/or to the terminal stages of life. These may include pain, dyspnea, agitation/delirium, anxiety, and excess secretions, all of which may be managed in part through pharmacological interventions [36,37]. Hepatic and renal failure may impact the kinetics or clearance of a drug in the patient, as well as titrating upward to doses to treat symptomatically will lead to “apparently” high concentrations of drug measured at autopsy. Table 3.6 illustrates hospice case from the author’s laboratory where apparently high drug concentrations were found. The patient was an elderly female with bone cancer and multiple metastases. The medication consisted of sublingual morphine and lorazepam for the treatment of increasing pain, air hunger, and agitation, respectively. The dosing was increased in the last hour of life. The significant difference in the subclavian versus femoral blood concentrations of morphine is most likely due, for the most part, to incomplete distribution. Tissue donation and procurement provides a gift of life to other patients in need; 1 tissue donor can impact the lives of more than 75 people. Donated tissue such as skin, bone, and heart valves can be used in many surgical applications; benefiting patients in a number of serious or life-threatening medical situations, restoring sight, healing severe burns, repairing torn ligaments or tendons, and repairing musculoskeletal structures such as teeth, skin, and spinal components. However, the recovery process can artificially introduce drugs and chemicals to the postmortem specimen collected after the recovery procedure
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Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
and if undisclosed could potentially lead to misassignment of the cause of death. Papaverine is an alkaloid present in opium about a 1% concentration; clinically, it is used as a antispasmodic and vasodilator [38]. Therapeutic concentrations range from 0.1 to 0.4 mg/L. It also has been used in the recovery of saphenous veins harvested for cardiac bypass grafts. A bolus of papaverine solution is pushed through the vein to be harvested, prior to its removal. Its action as a calcium channel blocker helps preserves the integrity of the graft tissue. A case of papaverine artifact from a saphenous vein recovery has been reported [39]. A 52-year-old female was found dead after a protracted period of somnolence. An autopsy was performed and routine toxicological examination was conducted. A number of medications, that were prescribe or administered during resuscitation, were detected in aortic blood. However, there was one unexpected finding; papaverine at a concentration of 9.0 mg/L which was well above a “therapeutic” concentration. A distribution study of papaverine was conducted (Table 3.7). The author initially opined that the distribution of papaverine could be explained by a perimortem intravenous administration of the drug which could be followed by rapid death. Based upon this finding and other investigative information a homicide investigation was commenced. It was later
Table 3.7 Papaverine Distribution Papaverine Distribution Study Specimen
Concentration (mg/L or mg/kg)
Blood: aortic Urine Lung Muscle: pectoral Brain and kidney GI tract Liver Fat Injection site: Antecubital fossa Injection site: Tongue (suspected)
9.0 ND (LOD 0.02) 5.1 3.0 0.03 0.3 0.2 ND (LOD 0.08) ND (LOD 0.4) 1.4
Source: Adapted from Rieders MF. Papaverine as a postmortem artifact from saphenous vein harvesting procedure. ToXTalk 1996;20:6.
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
learned that the saphenous vein was harvested and the procurement procedure involved the use of papaverine. This information provided an alternative more probable reason for the presence of papaverine. This was further substantiated by testing of a postmortem blood sample that was drawn prior to the vein recovery. In corneal procurement, the field surrounding the eye of the decedent may be washed with isopropanol to cleanse the area. Contamination of the vitreous sample which is subsequently collected may result from puncture of the skin or scleral surface prior to complete evaporation of the isopropanol and/or passive diffusion into the vitreous from the surrounding tissue. Vitreous isopropanol concentrations may be exceed 0.100 g% in some cases, where the companion blood sample will be negative for isopropanol. The previously described cases in this chapter illustrate the need for complete information prior to forming an opinion and the consideration of alternative explanations for toxicological results.
References [1] Salzman C. Medications compliance in the elderly. J Clin Psychiatry 1995;56 Suppl. 1:18 22. [2] Verlander Jr JM, Johns ME. The clinical use of cocaine. Otolaryngol Clin North Am 1981;14:521 31. [3] Dwyer C, Sowerby L, Rotenberg BW. Is cocaine a safe topical agent for use during endoscopic sinus surgery? Laryngoscope 2016;126:1721 3. [4] Freud S. Uber Coca. Wein Centralblatt Therapie fu¨r die management 1884;2:289 314. ¨ ber Coca: Sigmund Freud, Carl Koller, and cocaine. JAMA [5] Markel H. U 2011;305:1360 1. [6] Grzybowski A. Cocaine and the eye: a historical overview. Ophthalmologica 2008;222:296 301. [7] Reis Jr. A. Sigmund Freud (1856-1939) and Karl Ko¨ller (1857-1944) and the discovery of local anesthesia. Rev Bras Anestesiol 2009;2:244 57. [8] Lopez-Valverde A, DeVicente J, Cutando A. The surgeons Halsted and Hall, cocaine and the discovery of dental anaesthesia by nerve blocking. Br Dent J 2011;211:485 7. [9] Benjamin E, Wong DK, Choa D. Moffett’s solution: a review of the evidence and scientific basis for the topical preparation of the nose. Clin Otolaryngol Allied Sci 2004;29:582 7. [10] Reichman OS, Otto RA. Effect of intranasal cocaine on the urine drug screen for benzoylecgonine. Otolaryngol Head Neck Surg 1992;106:223 5. [11] Quiney RE. Intranasal topical cocaine: Moffett’s method or topical cocaine paste? J Laryngol Otol 1986;100:279 83. [12] Bralliar BB, Skarf B, Owens JB. Opthalmic use of cocaine and the urine test for benzoylecgonine. NEJM 1989;320:1757 8.
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[13] Patrinely JR, Cruz OA, Reyna GS, King JW. The use of cocaine as an anesthetic in lacrimal surgery. J Anal Tox 1994;18:54 6. [14] Cruz OA, Patrinely JR, Reyna GS, King JW. Urine drug screening for cocaine after lacrimal surgery. Am J Ophthal 1991;111:703 5. [15] Richards JR, Laurin EG, Tabish N, Lange RA. Acute toxicity from topical cocaine for epistaxis: treatment with labetalol. J Emerg Med 2017;52:311 13. [16] Pryor GJ, Kilparick WR, Opp DR. Local anesthesia in minor lacerations: topical TAC vs lidocaine infiltration. Ann Emerg Med 1980;9:568 71. [17] Tipton GA, DeWitt GW, Eisenstein SJ. Topical TAC (tetracaine, adrenaline, cocaine) solution for local anesthesia in children: prescribing inconsistency and acute toxicity. South Med J 1989;82:1344 6. [18] Altieri M, Bogema S, Schwartz RH. TAC topical anesthesia produces positive urine tests for cocaine. Ann Emerg Med 1990;19:577 9. [19] Fitzmaurice LS, Wasserman GS, Knapp JF, Roberts DK, Waeckerie JF, Fox M. TAC use and absorption of cocaine in a pediatric emergency department. Ann Emerg Med 1990;19:515 18. [20] Kundu S, Achar S. Principles of office anesthesia: Part II. Topical anesthesia. Am Fam Physician 2002;66:99 102. [21] Grant SA, Hoffman RS. Use of tetracaine, epinephrine, and cocaine as a topical anesthetic in the emergency department. Ann Emerg Med 1992;21:987 97. [22] Makaryus JN, Makaryus AN, Johnson M. Acute myocardial infarction following the use of intranasal anesthetic cocaine. South Med J 2006;99:759 61. [23] Rhidian R, Greatorex B. Chest pain in the recovery room, following topical intranasal cocaine solution use. BMJ Case Rep 2015. Available from: https://doi.org/10.1136/bcr-2015-209698. [24] Rezvani M, Hartfield D. Cocaine toxicity after laryngoscopy in an infant. Can J Clin Pharmacol 2006;13:e232 5. [25] Peterson JE, Stewart RD. Absorption and elimination of carbon monoxide by inactive young men. Arch Environ Health 1970;21:165 71. [26] Rutty GN, Smith P, Visser T, Barber J, Amorosa J, Morgan B. The effect on toxicology, biochemistry and immunology investigations by the use of targeted post-mortem computed tomography angiography. Forensic Sci Int 2013;225:42 7. [27] Palmiere C, Grabherr S, Augsburger M. Postmortem computed tomography, contrast medium administration and toxicological analyses in urine. Leg Med 2015;17:157 62. [28] Moriya F, Hashimoto Y. Postmortem diffusion of tracheal lidocaine into heart blood following intubation for cardiopulmonary resuscitation. J Forensic Sci 1997;42:296 9. [29] Wunder C, Meier J, Reyher C, Ko¨nitz V, Paulke A, Zacharowski K, et al. Use of lidocaine in endotracheal intubation. Blood and urine concentrations in patients and deceased after unsuccessful resuscitation. Forensic Sci Int 2014;244:259 62. [30] Mainland PA, Kong AS, Chung DC, Chan CH, Lai CK. Absorption of lidocaine during aspiration anesthesia of the airway. J Clin Anesth 2001;13:440 6. [31] Tzortzis V, Gravas S, Melekos MM, de la Rosette JJ. Intraurethral lubricants: a critical literature review and recommendations. J Endourol 2009;23:821 6.
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[32] Chan MF, Tan HY, Lian X, Ng LY, Ang LL, Lim LH, et al. A randomized controlled study to compare the 2% lignocaine and aqueous lubricating gels for female urethral catheterization. Pain Pract 2014;14:140 5. [33] Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol 2013;77:357 67. [34] Parashchanka A, Schelfout S, Coppens M. Role of novel drugs in sedation outside the operating room: dexmedetomidine, ketamine and remifentanil. Curr Opin Anaesthesiol 2014;27:442 7. [35] Oh S, Kingsley K. Efficacy of ketamine in pediatric sedation dentistry: a systematic review. Compend Contin Educ Dent 2018;39:e1 4. [36] Prommer E, Ficek B. Management of pain in the elderly at the end of life. Drugs Aging 2012;29:285 305. [37] Masman AD, van Dijk M, Tibboel D, Baar FPM, Mathoˆt RAA. Medication use during end-of-life care in a palliative care center. Int J Clin Pharm 2015;37:767 75. [38] Panigrahy N, Kumar PP, Chirla DK, Vennapusa SR. Papaverine for ischemia following peripheral arterial catheterization in neonates. Indian Pediatr 2016;53:169. [39] Rieders MF. Papaverine as a post-mortem artifact from saphenous vein harvesting procedure. ToXTalk 1996;20:6.
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Postmortem Toxicology. DOI: https://doi.org/10.1016/B978-0-12-815163-1.00003-4 © 2019 Elsevier Inc. All rights reserved.
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Cocaine is a highly abused drug in today’s society. However, cocaine still has a minor niche in modern medicine, taking advantage of its local anesthetic properties and sympathomimetic (vasoconstrictive) properties; achieve a low blood field for certain types of surgical procedures [2,3]. ¨ ber Coca was published in 1884 by The monograph U Sigmund Freud [4,5] described the historical use of cocaine, botanical characteristics, and its pathophysiology and various therapeutic actions, including a “numbness of skin and mucous membranes” that had contact with solutions of cocaine. In 1884, Karl Ko¨ller described the use of cocaine as a local anesthetic in ophthalmological procedures [6,7]. In 1885, Halstead and Hall described the use of cocaine to serve as dental nerve blocks, thus allow for surgery of the maxilla without pain [8]. In addition to this historical use of cocaine, it is still limit use in some surgical procedures [3], such as nasal and lacrimal procedures. An alternative preparation for surgery is to mix cocaine with adrenaline (epinephrine) and sodium bicarbonate, also known as Moffett’s solution [9]; which is topically applied. Otolaryngologists have utilized the anesthetic and vasoconstrictive properties of cocaine in nasal surgery and/or intrusive examination of the nasal passages. Cocaine in these procedures is usually applied in one of two ways; insertion of cottonoids or pledgets in the nares for 10 minutes (total dose applied B160 mg) or an aerosol spray (total dose B20 60 mg) of 4% cocaine applied shortly before the procedure [10]. These authors designed a study to evaluate whether or not cocaine’s primary metabolite; benzoylecgonine would be detected in a urine drug screen following the medical application of the drug. They evaluated 12 patients who were to undergo elective nasal surgery where cocaine was applied via the cotton pledgets and 30 subjects who received the aerosolized cocaine for the presence of benzoylecgonine over a 24-hour period; not all subjects/volunteers participated in each collection period. In both study groups, the patient’s/subject’s urine were positive for benzoylecgonine 24 hours postdosing, with all samples negative after 72 hours (Tables 3.1 and 3.2). The authors established that a urine drug test may be positive due to medically used cocaine. Quiney [11] investigated whether or not medicinally used cocaine, for nasal surgery, could result in measurable serum cocaine levels when applied via two different techniques; “Moffett’s method” or topical applied cocaine paste using cotton pledgets; adrenaline was also applied prior to the procedure to assist with hemostasis. The author found an average serum
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
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Table 3.1 Surgical Patients Dosed With 4 mL 4% Cocaine on Cotton Pledgets Collection Time
Preprocedure Postprocedure 24 h 36 h 48 h 72 h
Positive Urine Drug Test Number of Positive Patients
Percent Positive for Benzoylecgonine (%)
0 of 12
0
12 of 12 3 of 6 0 of 12 0 of 6
100 50 0 0
Source: Adapted from Reichman OS, Otto RA. Effect of intranasal cocaine on the urine drug screen for benzoylecgonine. Otolaryngol Head Neck Surg 1992;106:223 5.
Table 3.2 Subjects Dosed With Cocaine Solution via an Atomizer Collection Time
Predosing Postdosing 12 h 24 h 36 h 48 h 72 h 96 h
Positive Urine Drug Test Number of Positive Subjects
Percent Positive for Benzoylecgonine (%)
0 of 30
0
20 of 20 30 of 30 16 of 20 18 of 30 1 of 10 0 of 10
100% 100 80 60 10 0
First 20 subjects were tested 12, 24, 36, and 48 h postdosing. Last 10 subjects were tested 24, 48, and 72 h postdosing. Source: Adapted from Reichman OS, Otto RA. Effect of intranasal cocaine on the urine drug screen for benzoylecgonine. Otolaryngol Head Neck Surg 1992;106:223 5.
cocaine concentration of 0.21 mg/L in all patients, between 10 and 60 minutes of application. A maximal concentration of 1.10 mg/L was observed in one patient. Quiney also observed that the absorption rate was slower in the cocaine paste
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Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
patients as compared to those where Moffett’s solution was used for cocaine introduction. This is mostly likely due to the bicarbonate in the Moffett’s solution; shifting more of the cocaine to the unionized form, thus more readily crossing the nasal membranes. In ophthalmology, cocaine is used as the local anesthetic in dacryocystorhinostomy or commonly referred to as lacrimal surgery. The physicians take advantage of the anesthetic and vasoconstrictive properties of cocaine as well in these surgeries. Bralliar et al. [12] reported positive urine drug tests for benzoylecgonine following ophthalmic application, two drops of a 10% cocaine solution was instilled in the cul-de-sac of each eye to 19 of their patients; estimated dose was B20 mg of cocaine. The patients were tested for the presence of cocaine metabolites utilizing immunoassay techniques (Syva EMIT) with a benzoylecgonine cut-off of 300 ng/mL. Four hours postapplication, all 19 patients tested positive for cocaine metabolite. At 24 hours postapplication, all patients still tested positive and by 36 hours 53% of the patients remained positive for cocaine metabolites as determined by immunoassay. Cruz et al. [14] performed a similar study with 12 of their patients undergoing lacrimal surgery. Their patients were dosed with cocaine by application a “single spray” of aerosolized 4% cocaine, followed by packing the nasal cavity with cotton strips lightly soaked with a 4% cocaine solution. The authors performed a quantitative study of benzoylecgonine in urine sample collected from their patients, utilizing gas chromatography/ mass spectrometry, over several days. They found that all 12 of their patients tested positive for benzoylecgonine [assay limit of detection (LOD) was 60 ng/mL] for 24 hours postoperatively, with 3 patients having detectable benzoylecgonine 72 hours after their surgical procedure (Table 3.3). These three patients were negative at 1 week postop for benzoylecgonine. Patrinely et al. [13] published in the same study and data in 1994; however, the reported LOD of the method was 50 ng/mL. Topical cocaine has also been used in the treatment of severe epistaxis (nosebleed) [15]. The literature is devoid of information as to whether or not enough cocaine is absorbed to produce a positive finding in urine. However, given the information known from the introduction of cocaine in otolaryngological procedures, one would expect that benzoylecgonine would be detected in these patients as well. TAC (mixture of tetracaine, adrenalin, and cocaine) has been used as topical anesthetic for the treatment of nonmucosal lacerations [16], especially in pediatric patients [17]. Several
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
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Table 3.3 Benzoylecgonine in Postlacrimal Surgery Patients Patient
Urinary Benzoylecgonine Concentration (ng/mL) 24 h Postop
1 2 3 4 5 6 7 8 9 10 11 12
a
661 568 259 375 133 2459 121 662 852 67 1226 1347
48 h Postop
72 h Postop
108 319 ND 70 93 387 NA 94 177 ND 218 220
60b ND ND ND ND 88b ND ND 72a,b ND 68b ND
NA, Not available—sample not collected; ND, not detected—below LOD of method. a Patrinely et al. [13]: Reported concentration was 660. b Negative at 1 week. Source: Adapted from Cruz OA, Patrinely JR, Reyna GS, King JW. Urine drug screening for cocaine after lacrimal surgery. Am J Ophthal 1991;111:703 5 [14].
studies have noted that the topical application of a TAC solution will result in the presence of cocaine and/or metabolites in urine and plasma. Altieri et al. [18] demonstrated the persistence of cocaine’s primary metabolite, benzoylecgonine in urine between 36 and 45 hours posttreatment in 15 of 18 of their patients. The benzoylecgonine concentrations were determined by gas chromatography/mass spectrometry, with an assay LOD of 75 ng/mL. Table 3.4 reflects benzoylecgonine urinary concentrations in patients treated with TAC. Fitzmaurice et al. [19] studied the systemic absorption of cocaine in 51 children when used as a topical anesthetic. Plasma samples were available from 46 children and were obtained 20 40 minutes after application of the topical anesthetic. The authors did not detect cocaine in any of the plasma samples; however, in 57% of the children cocaine metabolites were detected. Ecgonine methyl ester was found in 6 of the
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Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
Table 3.4 Benzoylecgonine in Post-TAC Treated Patients Patient
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Urinary Benzoylecgonine Concentration (ng/mL) Day 1
Day 2
730 5 4300 690 840 1130 140 520 NA 270 1670 3630 1810 5 1260 930 250 2670
NA 5 240 5 5 160 5 110 150 5 140 330 320 5 5 5 5 570
5 , Negative result (less than LOD); NA, specimen not available. Source: Adapted from Altieri et al [18].
children with concentrations ranging from 59 to 985 ng/mL, whereas benzoylecgonine was detected 23 children with concentrations ranging from 40 to greater than 600 ng/mL. It should be noted that all the samples negative for benzoylecgonine were not preserved with sodium fluoride whereas the positive sample for benzoylecgonine did contain sodium fluoride as a preservative. According to Kundu and Achar [20], the use of TAC is no longer supported by the literature in general due to concerns about toxicity, expense, and the associated regulatory issues involving medications that contain cocaine. A newer formulation of a topical anesthetic has replaced cocaine with lidocaine and called LET (lidocaine, epinephrine, and tetracaine).
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
A proper medical history coupled with the understanding of the therapeutic uses of cocaine will prevent the misinterpretation of a positive cocaine and/or metabolite result in the decedent. There have also been several postmortem cases investigated by the authors office, where 24 48 hours post knee replacement surgery, anesthetics were detected in blood, tissue, and/or urine specimens collected at autopsy from deaths unrelated to the surgery; for example, propofol, etomidate, and bupivacaine. Sometimes appropriate prior medical therapy may lead to toxicity. The application of TAC to mucous membranes has caused status epilepticus in a patient and death in two pediatric patients [21]. Makaryus et al. [22] describe a case of a 68-yearold woman who underwent nasal surgery where cocaine was applied preoperatively. Shortly after the procedure, she developed an acute myocardial infarction. Rhidian and Greatorex [23] provide a case report in which a patient underwent elective septoplasty and was administered Moffett’s solution, after induction of general anesthesia. Upon awaking from the procedure the patient reported “Crushing” chest pain radiating to the left shoulder; troponin level was normal. After treatment with morphine, nitroglycerin, and oxygen, the pain resolved and was released the next day. A 5.5-year-old male underwent an exploratory nasopharyngoscopy procedure [24]. The nasal cavity was anesthetized by instilling 0.1 mL of 4% cocaine solution. Ninety minutes later, the young boy became agitated, diaphoretic, with dilated pupils. He was tachycardic and hypertensive; treatment with IV lorazepam over a 2-hour period to address the cardiac excitability and the neurological irritation and there was complete resolution of symptoms within 4 hours without sequelae.
Medical Intervention Medical intervention may lead to spurious findings and misinterpretation of result, especially in the absence of an adequate medical history. There are several factors that will aid in understudying and assigning the appropriate weight to an analytical finding, such as the time of the medical intervention relative to sampling of the biological fluid or tissue—hospital or autopsy samples. The types of intervention may in some cases, direct or focus the toxicological analyses; for example, Narcan may direct
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the analysis to opioids or flumazenil may direct the analysis to a variety of benzodiazepines. If the patient presents with a history of a recent oral ingestion of a large amount of medications, a gastric lavage may be performed. Thus, removing a significant portion of the drug from the stomach contents, so when quantitated the amount may be minimal and not necessarily support a suicide finding. Carbon monoxide poisoning is a frequent cause of death, with a carboxyhemoglobin (COHb) saturation of .50% considered lethal. However, oxygen therapy during the agonal stages of life can dramatically lower the measured saturation of carbon monoxide in blood taken at autopsy. The half-life of COHb in fresh air is about 5.5 hours, whereas with the administration of 100% oxygen, commonly used by first responders, the half-life of COHb is decreased to approximately 80 minutes and if the patient initially survives makes into a higher level of care and receives hyperbaric oxygen with 100% O2 at 3 atmospheres COHb half-life is reduced to 23 minutes [25]. Thus, medical intervention could reduce the measured COHb from an accepted lethal saturation, for example, B50% to a saturation consider to be mildly symptomatic with just an hour of hyperbaric treatment; thus, potentially calling into question of whether the toxic insult was due to carbon monoxide. Many medications are administered via an existing intravenous line. If blood at autopsy or at the scene is drawn through the existing line, in which a drug had recently been administered, for example, 2 mg of morphine was given for pain relief, there is a potential for an artificially elevation of the measured drug concentration in the collected sample. This artificially elevated blood drug concentration could lead to a misinterpretation of the toxicological result; leading one to believe that the cause of death was due to the narcotic overdose. Massive fluid resuscitation, via the placement of a central line, could lead to an opposite effect; that is, dilution of the drug concentration especially in the heart blood sample. Table 3.5 illustrates this occurrence in a couple of cases examined in the author’s laboratory. In both cases, a central line was placed for fluid resuscitation and the result was a significant decline in the heart blood alcohol result. Postmortem computed tomography (PMCT) has been increasingly used in the medicolegal investigation of death; for the visualization of vascular injuries from trauma or hemorrhages following rupture of small vessels. The injection of contrast media in these procedures could cause the dilution of postmortem blood samples or other fluids, such as vitreous or
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
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Table 3.5 Fluid Resuscitation and Alcohol Specimen
Case Number 1 (g%)
Case Number 2 (g%)
0.56
0.12
0.70
0.21
0.76
0.21
0.76
0.26
Heart Blood
Ethyl alcohol Femoral Blood
Ethyl alcohol Vitreous
Ethyl alcohol Urine
Ethyl alcohol
urine and potentially have a negative impact on the toxicological results. Rutty et al. [26] investigated whether or not PMCT angiography would cause of significant effect, via dilution, on vitreous biochemistry, immunological (blood tryptase), or blood toxicological results. The authors did note slight variations in quantitative results; however, they opined that the procedure did not have a negative impact on the diagnostic utility of the test. Palmiere et al. [27] evaluated the impact of this procedure on urine samples screened for common drugs and illicit substances collected pre- and postPMCT angiography. Two compounds, hydroxyl-amitriptyline and venlafaxine were detected in the urine sample prior to angiography and not detected in the urine sample postangiography. Whereas, two compounds, zolpidem and carboxy-THC were detected in the postangiography sample but were not detected in the preangiography urine sample. The following three compounds, citalopram, cotinine, and oxazepam, were detected in both samples, however, in each case the postangiography cohort had one additional sample positive for the drug. The only significant quantitative difference observed was related to the analyses of THC and its metabolites (hydroxyl-THC and carboxy-THC). A frequently encountered toxicological finding in postmortem cases is the presence of lidocaine. Lidocaine is an administered drug used both as a local anesthetic, administered via infiltration or topically applied, and as an antiarrhythmic
34
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
medication. Also, a variety of endotracheal tubes are coated with xylocaine (2% lidocaine) jelly. In many cases, the source of detected lidocaine is from the endotracheal tube used in resuscitation or surgical procedure. Moriya and Hashimoto [28] describe the postmortem diffusion of tracheal lidocaine into heart blood in three patients. The lidocaine detected in heart blood samples ranged from 0.102 to 1.02 mg/L, with negative findings in brain or muscle tissue. In an animal experiment, the authors applied lidocaine to the trachea of rabbits. Lidocaine concentrations of 0.550 4.03 and 3.05 7.30 mg/L were found in heart blood on day 1 and day 3, respectively; lidocaine was not detected in brain tissue or muscle tissue. Wunder et al. [29] studied the plasma concentrations of lidocaine and its metabolite MEGX (monoethylglycinexylidide) in 35 surgical patient and compared to concentrations found in 18 postmortem cases following unsuccessful resuscitation. In the surgical patients, 1 hour postexposure lidocaine plasma concentrations were less than 0.2 mg/L and MEGX concentrations were less than 0.05 mg/L. Lidocaine and MEGX were also detected in urine samples from these patients. The lidocaine concentrations found in the decedents ranged from 0.02 to 1.07 mg/L (median 0.07), and MEGX ranged from ,0.001 to 0.044 mg/L (median 0.01); low concentration of lidocaine were reported in the urine. MEGX was only detected in the urine of two out of nine samples collected. Mainland et al. [30] evaluated blood concentrations of lidocaine resulting from its use as airway anesthesia for bronchoscopy in 96 patients. In patients receiving 0.3 mL of a 2% lidocaine solution, the highest concentration reported was 6.28 mg/L. Although some patients had significant lidocaine concentrations, there were no reported signs of toxicity. Lidocaine gel is widely used as a local anesthetic lubricant on various forms of transurethral instrumentation, for example, catheters [31,32]. This may lead to a positive finding of lidocaine in urine, and none detected in the blood. In trauma patients, multiple pharmacological treatments are utilized and if the patient dies shortly, thereafter it is common to detect these medications; for examples, opioids are commonly utilized in the treatment of acute pain, benzodiazepines are used for acute agitation, sedation, and intubation of patients, ketamine for analgesia [33] and/or sedation [34] especially in pediatric cases [35], and various anticonvulsants for seizure disorders. The assessment of the findings, as to whether they were therapeutic or a causative factor in the case, requires a careful review of the medical records to establish whether or
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
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Table 3.6 Hospice Patient Drug Findings Specimen
Morphine (mg/L)
Lorazepam
Blood (SC) Blood (FB) Urine
5.1 0.24 0.82 (total)
240 ng/mL NT NT
FB, Femoral blood; NT, Not tested; SC, Subclavian.
not they were given and at what time relative to the time blood samples were drawn, if antemortem specimens are examined. In some Medical Examiner jurisdictions, end-of-life care or hospice patients are referred to the office for examination. The patient will have several symptoms relating directly to the disease process and/or to the terminal stages of life. These may include pain, dyspnea, agitation/delirium, anxiety, and excess secretions, all of which may be managed in part through pharmacological interventions [36,37]. Hepatic and renal failure may impact the kinetics or clearance of a drug in the patient, as well as titrating upward to doses to treat symptomatically will lead to “apparently” high concentrations of drug measured at autopsy. Table 3.6 illustrates hospice case from the author’s laboratory where apparently high drug concentrations were found. The patient was an elderly female with bone cancer and multiple metastases. The medication consisted of sublingual morphine and lorazepam for the treatment of increasing pain, air hunger, and agitation, respectively. The dosing was increased in the last hour of life. The significant difference in the subclavian versus femoral blood concentrations of morphine is most likely due, for the most part, to incomplete distribution. Tissue donation and procurement provides a gift of life to other patients in need; 1 tissue donor can impact the lives of more than 75 people. Donated tissue such as skin, bone, and heart valves can be used in many surgical applications; benefiting patients in a number of serious or life-threatening medical situations, restoring sight, healing severe burns, repairing torn ligaments or tendons, and repairing musculoskeletal structures such as teeth, skin, and spinal components. However, the recovery process can artificially introduce drugs and chemicals to the postmortem specimen collected after the recovery procedure
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Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
and if undisclosed could potentially lead to misassignment of the cause of death. Papaverine is an alkaloid present in opium about a 1% concentration; clinically, it is used as a antispasmodic and vasodilator [38]. Therapeutic concentrations range from 0.1 to 0.4 mg/L. It also has been used in the recovery of saphenous veins harvested for cardiac bypass grafts. A bolus of papaverine solution is pushed through the vein to be harvested, prior to its removal. Its action as a calcium channel blocker helps preserves the integrity of the graft tissue. A case of papaverine artifact from a saphenous vein recovery has been reported [39]. A 52-year-old female was found dead after a protracted period of somnolence. An autopsy was performed and routine toxicological examination was conducted. A number of medications, that were prescribe or administered during resuscitation, were detected in aortic blood. However, there was one unexpected finding; papaverine at a concentration of 9.0 mg/L which was well above a “therapeutic” concentration. A distribution study of papaverine was conducted (Table 3.7). The author initially opined that the distribution of papaverine could be explained by a perimortem intravenous administration of the drug which could be followed by rapid death. Based upon this finding and other investigative information a homicide investigation was commenced. It was later
Table 3.7 Papaverine Distribution Papaverine Distribution Study Specimen
Concentration (mg/L or mg/kg)
Blood: aortic Urine Lung Muscle: pectoral Brain and kidney GI tract Liver Fat Injection site: Antecubital fossa Injection site: Tongue (suspected)
9.0 ND (LOD 0.02) 5.1 3.0 0.03 0.3 0.2 ND (LOD 0.08) ND (LOD 0.4) 1.4
Source: Adapted from Rieders MF. Papaverine as a postmortem artifact from saphenous vein harvesting procedure. ToXTalk 1996;20:6.
Chapter 3 PRIOR MEDICAL THERAPY AND MEDICAL INTERVENTION
learned that the saphenous vein was harvested and the procurement procedure involved the use of papaverine. This information provided an alternative more probable reason for the presence of papaverine. This was further substantiated by testing of a postmortem blood sample that was drawn prior to the vein recovery. In corneal procurement, the field surrounding the eye of the decedent may be washed with isopropanol to cleanse the area. Contamination of the vitreous sample which is subsequently collected may result from puncture of the skin or scleral surface prior to complete evaporation of the isopropanol and/or passive diffusion into the vitreous from the surrounding tissue. Vitreous isopropanol concentrations may be exceed 0.100 g% in some cases, where the companion blood sample will be negative for isopropanol. The previously described cases in this chapter illustrate the need for complete information prior to forming an opinion and the consideration of alternative explanations for toxicological results.
References [1] Salzman C. Medications compliance in the elderly. J Clin Psychiatry 1995;56 Suppl. 1:18 22. [2] Verlander Jr JM, Johns ME. The clinical use of cocaine. Otolaryngol Clin North Am 1981;14:521 31. [3] Dwyer C, Sowerby L, Rotenberg BW. Is cocaine a safe topical agent for use during endoscopic sinus surgery? Laryngoscope 2016;126:1721 3. [4] Freud S. Uber Coca. Wein Centralblatt Therapie fu¨r die management 1884;2:289 314. ¨ ber Coca: Sigmund Freud, Carl Koller, and cocaine. JAMA [5] Markel H. U 2011;305:1360 1. [6] Grzybowski A. Cocaine and the eye: a historical overview. Ophthalmologica 2008;222:296 301. [7] Reis Jr. A. Sigmund Freud (1856-1939) and Karl Ko¨ller (1857-1944) and the discovery of local anesthesia. Rev Bras Anestesiol 2009;2:244 57. [8] Lopez-Valverde A, DeVicente J, Cutando A. The surgeons Halsted and Hall, cocaine and the discovery of dental anaesthesia by nerve blocking. Br Dent J 2011;211:485 7. [9] Benjamin E, Wong DK, Choa D. Moffett’s solution: a review of the evidence and scientific basis for the topical preparation of the nose. Clin Otolaryngol Allied Sci 2004;29:582 7. [10] Reichman OS, Otto RA. Effect of intranasal cocaine on the urine drug screen for benzoylecgonine. Otolaryngol Head Neck Surg 1992;106:223 5. [11] Quiney RE. Intranasal topical cocaine: Moffett’s method or topical cocaine paste? J Laryngol Otol 1986;100:279 83. [12] Bralliar BB, Skarf B, Owens JB. Opthalmic use of cocaine and the urine test for benzoylecgonine. NEJM 1989;320:1757 8.
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[13] Patrinely JR, Cruz OA, Reyna GS, King JW. The use of cocaine as an anesthetic in lacrimal surgery. J Anal Tox 1994;18:54 6. [14] Cruz OA, Patrinely JR, Reyna GS, King JW. Urine drug screening for cocaine after lacrimal surgery. Am J Ophthal 1991;111:703 5. [15] Richards JR, Laurin EG, Tabish N, Lange RA. Acute toxicity from topical cocaine for epistaxis: treatment with labetalol. J Emerg Med 2017;52:311 13. [16] Pryor GJ, Kilparick WR, Opp DR. Local anesthesia in minor lacerations: topical TAC vs lidocaine infiltration. Ann Emerg Med 1980;9:568 71. [17] Tipton GA, DeWitt GW, Eisenstein SJ. Topical TAC (tetracaine, adrenaline, cocaine) solution for local anesthesia in children: prescribing inconsistency and acute toxicity. South Med J 1989;82:1344 6. [18] Altieri M, Bogema S, Schwartz RH. TAC topical anesthesia produces positive urine tests for cocaine. Ann Emerg Med 1990;19:577 9. [19] Fitzmaurice LS, Wasserman GS, Knapp JF, Roberts DK, Waeckerie JF, Fox M. TAC use and absorption of cocaine in a pediatric emergency department. Ann Emerg Med 1990;19:515 18. [20] Kundu S, Achar S. Principles of office anesthesia: Part II. Topical anesthesia. Am Fam Physician 2002;66:99 102. [21] Grant SA, Hoffman RS. Use of tetracaine, epinephrine, and cocaine as a topical anesthetic in the emergency department. Ann Emerg Med 1992;21:987 97. [22] Makaryus JN, Makaryus AN, Johnson M. Acute myocardial infarction following the use of intranasal anesthetic cocaine. South Med J 2006;99:759 61. [23] Rhidian R, Greatorex B. Chest pain in the recovery room, following topical intranasal cocaine solution use. BMJ Case Rep 2015. Available from: https://doi.org/10.1136/bcr-2015-209698. [24] Rezvani M, Hartfield D. Cocaine toxicity after laryngoscopy in an infant. Can J Clin Pharmacol 2006;13:e232 5. [25] Peterson JE, Stewart RD. Absorption and elimination of carbon monoxide by inactive young men. Arch Environ Health 1970;21:165 71. [26] Rutty GN, Smith P, Visser T, Barber J, Amorosa J, Morgan B. The effect on toxicology, biochemistry and immunology investigations by the use of targeted post-mortem computed tomography angiography. Forensic Sci Int 2013;225:42 7. [27] Palmiere C, Grabherr S, Augsburger M. Postmortem computed tomography, contrast medium administration and toxicological analyses in urine. Leg Med 2015;17:157 62. [28] Moriya F, Hashimoto Y. Postmortem diffusion of tracheal lidocaine into heart blood following intubation for cardiopulmonary resuscitation. J Forensic Sci 1997;42:296 9. [29] Wunder C, Meier J, Reyher C, Ko¨nitz V, Paulke A, Zacharowski K, et al. Use of lidocaine in endotracheal intubation. Blood and urine concentrations in patients and deceased after unsuccessful resuscitation. Forensic Sci Int 2014;244:259 62. [30] Mainland PA, Kong AS, Chung DC, Chan CH, Lai CK. Absorption of lidocaine during aspiration anesthesia of the airway. J Clin Anesth 2001;13:440 6. [31] Tzortzis V, Gravas S, Melekos MM, de la Rosette JJ. Intraurethral lubricants: a critical literature review and recommendations. J Endourol 2009;23:821 6.
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[32] Chan MF, Tan HY, Lian X, Ng LY, Ang LL, Lim LH, et al. A randomized controlled study to compare the 2% lignocaine and aqueous lubricating gels for female urethral catheterization. Pain Pract 2014;14:140 5. [33] Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol 2013;77:357 67. [34] Parashchanka A, Schelfout S, Coppens M. Role of novel drugs in sedation outside the operating room: dexmedetomidine, ketamine and remifentanil. Curr Opin Anaesthesiol 2014;27:442 7. [35] Oh S, Kingsley K. Efficacy of ketamine in pediatric sedation dentistry: a systematic review. Compend Contin Educ Dent 2018;39:e1 4. [36] Prommer E, Ficek B. Management of pain in the elderly at the end of life. Drugs Aging 2012;29:285 305. [37] Masman AD, van Dijk M, Tibboel D, Baar FPM, Mathoˆt RAA. Medication use during end-of-life care in a palliative care center. Int J Clin Pharm 2015;37:767 75. [38] Panigrahy N, Kumar PP, Chirla DK, Vennapusa SR. Papaverine for ischemia following peripheral arterial catheterization in neonates. Indian Pediatr 2016;53:169. [39] Rieders MF. Papaverine as a post-mortem artifact from saphenous vein harvesting procedure. ToXTalk 1996;20:6.
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