Molina, D. Kimberley MD; Neerman, Michael F. PhD; Wilk, Sarah A. BS
The medications used during resuscitation are often in and of themselves toxic. Lidocaine, atropine, and procainamide, to name a few, are all potentially lethal medications used to save lives. Several reports have been published regarding toxicities of these drugs, both when used therapeutically and when misused.1–7 For drugs such as these, those used mainly in hospital and medical settings, how does a forensic pathologist or toxicologist differentiate a possible intoxication from therapeutic or resuscitation use? Often, therapeutic concentrations found in living patients are used as guides for postmortem concentrations. Unfortunately, although the pharmacokinetics of most medications used during resuscitation have been previously studied, the concentrations of those drugs, when used in the setting of resuscitation, have not. Thus, a study was designed to address this deficiency in our knowledge base. Concentrations of a well-known resuscitation medication, atropine, were assessed in cases where it was administered before death during resuscitative efforts.
Atropine, a racemic mixture of L- and D-hyoscyamine, is a naturally occurring alkaloid found in several plant species including Datura stramonium (jimsonweed), Atropa belladonna (deadly nightshade), and Mandragora offinarum (mandrake). Atropine exhibits its actions by competitively antagonizing the muscarinic acetylcholine receptors located mainly along the parasympathetic nerve terminals of muscles and glands. In humans, it has a half-life of approximately 4 hours and a volume of distribution ranging from 1.7 to 4 L/kg.8,9 It is used as a cardiac resuscitation drug, in the treatment of organophosphate poisoning and as an ophthalmic agent; it is also a well-known potentially lethal intoxicant. Symptoms of intoxication include blurry vision, decreased sweating, nausea, dry mouth, confusion, hallucinations, and cardiac dysrhythmias. Medical students are often taught the classic phrase “hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter” to describe atropine intoxication symptoms. Atropine toxicity can be treated with supportive care and physostigmine; although if untreated, it can also be fatal.
MATERIALS AND METHODS
A review of the deaths occurring in 2009, which fell under the jurisdiction of the Bexar County Medical Examiner, was undertaken to identify cases where drugs known to be used during resuscitation were present on toxicological analysis. Postmortem toxicology results were further reviewed for the presence or absence of atropine and, when present, the concentration. Autopsy reports and medical records were examined to determine how much atropine was administered, the timing and route of the administration, the time the sample was drawn (antemortem and postmortem), the source of the sample, and the ultimate cause of death. For each case, the time between the last administered dose of atropine and the time that sample was drawn, as well as the postmortem interval (PMI; for postmortem samples), was calculated.
Atropine was isolated using a liquid-liquid alkaline drug extraction method currently used at the toxicology laboratory of Bexar County Medical Examiner’s Office. Postmortem and antemortem testing were performed on whole blood. Drug quantitation was achieved using an Agilent 6890 (Agilent Technologies Inc, Wilmington, Del) gas chromatograph with a flame-ionization detector and full-scan electron impact mass spectral identification was attained using an Agilent 6890 coupled with 5975 mass selective detector.
Analysis of means was performed using either the Student t test (parametric data) or the Mann-Whitney U test (nonparametric data). Proportion data were analyzed by the Fisher exact test. Significance was defined as P < 0.05.
One hundred cases that met criteria for inclusion in the study were identified. In 3 cases, the atropine concentrations could not be calculated because of technical difficulties. Eleven cases were identified in which atropine was administered before death, yet it was not detected in the postmortem blood. Eighty-six cases were, therefore, available for analysis. The 11 cases where atropine was not detected will be discussed separately.
Overall, mean age was 41 years, ranging from 2 weeks to 92 years. There were 65 males and 35 females. The overall median dose of atropine given was 3 mg, ranging from 0.12 to 5.2 mg. The overall median difference between the time of last administration of the atropine to the time of death (or draw for antemortem samples) was 15 minutes, ranging from 1 to 262 minutes. In 75% of cases, death or draw occurred within 20 minutes of administration. The median PMI was 15 hours (range, 3–35 hours) with 75% of the postmortem examinations occurring within 20 hours of death.
The overall median atropine concentration was 0.1 mg/L, ranging from none detected to 1.17 mg/L, with 75% of the results being less than 0.15 mg/L.
Overall data are summarized in Table 1.
Effect of Route of Administration
Of the 86 cases, 50 had the atropine administered purely by an intravenous (IV) route, 26 were solely intraosseous (IO), and 10 were administered both IV and IO atropine. The median atropine concentrations were 0.09, 0.1, and 0.12 mg/L for the IV, IO, and IV + IO groups, respectively. Analysis failed to reveal a significant difference (P > 0.3) in the atropine concentrations between any of the groups.
Effect of Sample Site—Peripheral Versus Central Blood
In 84 of the 86 cases available for analysis, the sample site of the blood specimen was available. In 57 cases, the sample site was peripheral (femoral blood); in 19 cases, the source was central (subclavian, cardiac, or aortic blood); in 3 cases, the source of the sample was chest blood; and in 5 cases, an antemortem sample was analyzed, all of which were whole blood samples. The median atropine concentrations found were as follows: peripheral, 0.09 mg/L; central, 0.13 mg/L; antemortem, 0.06 mg/L; and chest blood, 0.15 mg/L.
Comparisons between the peripheral and central sites showed a statistically significant difference (P = 0.004) with the atropine concentrations from a central site being higher than those from the peripheral site. Analysis of the antemortem and chest samples was limited because of the small sample sizes in these groups.
Effect of Cause of Death—Traumatic Versus Natural
Most deaths studied were natural, accounting for 56% of the 86 cases analyzed. Traumatic deaths accounted for 28% of cases followed by drug intoxications (10%) and other causes including drowning, choking, and unknown (6%). The mean concentrations of atropine found ranged from 0.09 mg/L in natural deaths to 0.13 mg/L in traumatic deaths. Analysis failed to reveal a statistical difference in the atropine concentrations found between any of the groups (P > 0.07).
Effect of Time Since Administration
Most cases (51%) analyzed either had the sample drawn (antemortem cases) or died within 15 minutes of being last administered atropine. Twenty-three percent of cases died/had the sample drawn within 16 to 30 minutes of administration, 17% between 31 and 60 minutes, and 8% more than 1 hour after administration of the drug. The median atropine concentrations for the IV groups were 0.11, 0.09, 0.08, and 0.09 mg/L, respectively. Analysis failed to reveal a statistical difference within the atropine concentrations between any of the groups (P > 0.2).
Effect of Postmortem Interval
In 81 of the 86 cases available for analysis, the PMI was calculated to ascertain if the PMI affected the atropine concentrations seen. The 5 cases not analyzed for PMI were the 5 cases in which antemortem blood was used in the analysis.
Most cases (86%) were examined within 24 hours of death, with 36% being examined within 12 hours of death. The remaining cases were examined between 25 and 32 hours of death, with no examination being performed more than 32 hours after death.
Analysis showed no significant difference between the atropine concentrations seen in cases with a PMI of 0 to 12 hours and those with a PMI of 13 to 24 hours (P = 0.44); median atropine concentrations were 0.1 and 0.09 mg/L, respectively. However, comparison of both the 0- to 12-hour group and the 13- to 24-hour group, as well as these 2 groups combined, to the 25- to 32-hour group did show a significant difference (P < 0.03), with the 25- to 32-hour group having higher atropine concentrations (median atropine concentration, 0.17 mg/L) than either of the other groups or the groups combined.
Summary of None Detected Cases
Eleven cases were identified where atropine was given during resuscitation but was not detected in the postmortem blood. The mean age in these cases was 43 years, ranging from 18 to 59 years, and all were men. The median time between the administration of atropine and either the blood draw or death was 18 minutes, ranging from 3 to 33 minutes, and the median PMI was 13 hours, ranging from 6 to 35 hours. The median total dose of atropine given was 2 mg with a range of 1 to 4 mg.
Most cases had peripheral blood samples drawn (54%), with 27% being central and 9% (one case each) being antemortem or unknown. Most deaths were traumatic (5 cases) or natural (4 cases), with 3 deaths being due to drug intoxications. Ninety-one percent of the cases had the atropine administered intravascularly, with only 1 case in which the drug was administered IO.
There was not a statistically significant difference between any of the demographic factors or measured variables between the none-detected and the detected groups (P = 0.19–0.88), with the exception of sex where there was a statistically significant difference (P = 0.006).
In many forensic toxicology laboratories, when drugs that are commonly used during resuscitation are found in postmortem blood samples, they are often not quantified but simply noted that they are present. Although uncommon, it has been reported that the same drugs used in resuscitation can also be the cause death. Several cases of atropine intoxications have been reported in the literature with plasma and serum concentrations ranging from 0.001 to 0.2 mg/L8,10–14 (Table 2). These results show considerable overlap with the previous studies addressing the pharmacokinetics of atropine in humans during therapeutic use in which concentrations ranging from 0.001 to 0.3 mg/L were obtained9,15–17 (Table 3). The results of the present study are consistent with this overlap as well, showing concentrations between none detected and 1.17 mg/L, with a median of 0.1 mg/L when atropine is used during resuscitation.
Unfortunately, studies addressing the concentrations found of the medications used in resuscitation are uncommonly performed. Prete et al18 studied atropine concentrations given IV, IO, and endotracheally in macaques in an attempt to address this question. They found that atropine concentrations increase the fastest after IV administration, followed by IO, but that after the initial minute, IO concentrations remain higher than either other routes of administration18—results that are not consistent with the results of the current study. In addition, the actual concentrations found in the study of Prete et al cannot be directly converted to those found in humans. At the 2010 Annual Meeting of the American Academy of Forensic Sciences, Brad Hall (Travis County, TX) presented a small data set addressing this issue as it pertains to lidocaine.19 He found that there was some overlap between lidocaine cases where the drug was given therapeutically (0.4–4.2 mg/L) and in intoxication cases (3.6–39 mg/L), although he was able to use monoethylglycinexylidide (an active lidocaine metabolite) concentrations to further assist in the differentiation.19 Unfortunately, with many drugs administered therapeutically, the metabolites may not be routinely measured or even reported.
The present study illustrates that atropine concentrations do not vary considerably by cause of death, route of administration, or time since administration within the first 1 to 2 hours (the period consistently covered by this study). The study does demonstrate that atropine concentrations did vary by site of sample (peripheral vs central blood) and the PMI, indicating that atropine likely undergoes some degree of postmortem redistribution.
Although not directly measured in this study, it could be theorized that circulation and the adequacy of cardiopulmonary resuscitation may also play a role in resuscitative atropine concentrations. Eleven cases were identified where atropine was administered before death but could not be detected in postmortem blood. These cases did not differ significantly from the cases where atropine was identified. Thus, it could be hypothesized that, if the cardiopulmonary resuscitative efforts were insufficient to produce adequate circulation and that the atropine was unable to properly distribute, which may account for the negative results.
This study, as well as that of Hall, reveals that the issue of differentiating concentrations of drugs used during resuscitation versus intoxication can be difficult. The variability of the concentrations seen is great and there is considerable overlap between therapeutic and lethal/toxic concentrations. More research needs to be done in this area especially addressing the newer drugs that are commonly used therapeutically but are entering the arena of abuse, for example, propofol. In the best-case scenario, the medical examiner can differentiate these cases by circumstances, although this may not always be possible.
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