Digoxin-like immunoreactive substance in postmortem blood of infants and children

A digoxin-like immunoreactive substance (DLIS) has been reported in the serum of infants not receiving digoxin. This study was undertaken to determine if DLIS is present in the postmortem blood and tissues of infants or children and whether the endogenous substance could interfere with forensic toxicological analysis in suspected overdose. Ninety blood specimens taken from the heart at autopsy of children or infants were screened for DLIS using commercial radioimmunoassay kits. The average age at death in these cases was 8.6 months, the median age was 2 months. DLIS equivalent to 0.25 to 2.0 ng/mL digoxin was found in one third of the cases. The incidence of positive findings was 5/6 stillborns, 10/45 Sudden Infant Death Syndrome (SIDS), 10/15 deaths as a result of infection, 4/7 homicides, 1/8 deaths caused by congenital defects, and 0/9 accidental deaths. The body distribution of DLIS was investigated and highest levels were found in the liver. Findings of DLIS in blood were correlated with renal failure, (elevated vitreous urea nitrogen), electrolyte imbalance, and liver trauma. Apparent concentrations were in the equivalent therapeutic range of digoxin and would not be confused with accidental or intentional overdose with digoxin.     

Minimizing analytical interferences from digoxin-like immunoreactive substances (DLIS) in cases of digoxin toxicity

Recently, the value of therapeutic drug monitoring for digoxin has been called into question by the finding of endogenous digoxin-like immunoreactive substances (DLIS) in the serum of individuals, especially premature and full-term neonates, not being treated with digoxin. In some cases, values have been as high as 10 micrograms/L. Levels as high as 20 micrograms/L and 80 micrograms/g can be found in bile and meconium. Because of the magnitude of this interference, it is essential that methods be developed for measuring digoxin in the presence of DLIS. This is particularly important when such analyses are required in forensic science cases of suspected digoxin toxicity. This report outlines the high performance liquid chromatographic (HPLC) and radioimmunoassay (RIA) methods that we used in assessing the relative contribution made by digoxin, its metabolites, and DLIS to serum and tissue digoxin concentrations obtained by RIA in a forensic pediatric case of suspected digoxin toxicity.     

Digoxin, magnesium, and potassium levels in a forensic autopsy material of sudden death from ischemic heart disease

In 91 cases where the cause of death was heart disease, digoxin, Mg and K concentrations in serum and ventricular myocardium were measured post mortem. Forty per cent were positive for digoxin in both serum and myocardium. The mean serum level was 5.1 +/- 2.4 nmol/l and the mean myocardial level was 42.6 +/- 27.5 ng/g. Correlation could be established between serum and myocardial concentrations of digoxin. There were statistically significant differences in serum as well as in myocardial digoxin levels in persons on 0.13 mg and 0.25 mg per day, respectively. Myocardial levels of Mg and K were low as generally found in persons with ischemic heart disease. There was no correlation between these levels and myocardial digoxin concentrations. Caution must be exercised in the assessment of digoxin results from cadaver samples because of the postmortem rise of digoxin serum concentrations. Considering this fact, the results still indicate that the prevalence of toxic digoxin concentrations might be more common than previously thought.     

Postmortem redistribution of digoxin in rats

Adult male Wistar rats were treated with either 0.1 or 3 mg/kg body weight X day of digoxin for five days, then killed and stored at 4 degrees C for 12 h in an attempt to mimic the normal preautopsy procedures in our hospital. In rats treated with 0.1 mg/kg body weight X day, the antemortem serum digoxin concentrations (SDC) were 1.1 +/- 0.4 ng/mL while the 12-h postmortem concentration was markedly increased (16.3 +/- 5.9 ng/mL) (P less than 0.01). In rats treated with 3 mg/kg body weight X day, SDC was not changed significantly (11.2 +/- 4.8 ng/mL antemortem and 13.3 +/- 6 ng/mL postmortem). Postmortem redistribution of digoxin was assessed by injection of 125I-labelled digoxin with or without pretreatment with the unlabelled drug. The results indicate that after death passive redistribution of digoxin may take place. When the SDC are within the therapeutic or low toxic range, digoxin may reenter the blood. High antemortem serum concentrations of digoxin may prevent such passive redistribution. Therefore, antemortem digoxin intoxication cannot be reliably inferred on the basis of high postmortem levels of the drug. Digoxin intoxication can be ruled out when postmortem SDC remain within the therapeutic range. The above changes cast doubt on some of the forensic and cardiologic literature, which has in the past been based on incorrect assumptions concerning postmortem behavior of digoxin.     

Cardiac glycosides and metabolites--problems of recovery in tissue extracts. Separation of visible substance spots in the nanogram range (author's transl)]

The recovery measurements in rat tissues performed via i.p. injected radioactive digoxin derivates (3H-digoxin, 125J-digoxin derivative) showed that approximately 50% of the total glycoside content will be extracted. Thus, an addition of digoxin standards to drug-free tissues may lead to false negative determinations. By comparison of the radioactivity before and after extraction the following results were obtained: Recovery from tissues 3H-digoxin 50% 125J-digoxin 40% from serum 3H-digoxin 60% added to drug free tissue homogenates 3H-digoxin 85% After i.p. application of 15 mg/kg of beta-methyldigoxin to BD9 (Berlin)-rats the resulting tissue concentrations were extracted by Amberlite XAD-2. beta-Methyldigoxin and its metabolites digoxin and digoxinbisdigitoxide could be separated and distinguished from artifacts by fluorescence detection on HPTLC-plates with a detection limit of 60 ng/spot. Concentration determined by radioimmunoassay are in satisfactory agreement with HPTLC results.     

Hemosiderin findings in the liver, spleen and lung in newborn infants and infants

The content and distribution of hemosiderin in the liver, spleen and lungs of stillborn children, newborns and infants were determined histologically by Perl's method (Prussian blue reaction). We describe a study of 59 deaths up to the age of 2 years. The hemosiderin content depends on age and decreases with increasing age. No relevant differences were found in cases of sudden infant death syndrome (SIDS). In the liver hemosiderin is localized preponderantly in the periphery of the lobules. The spleen shows a diffuse siderosis of the red pulp. Minimal intrapleural, septal and perivasal depositions of hemosiderin can be found in the lung tissue. The significance of these findings is discussed.     

Interpretation of postmortem digoxin levels: evaluating a "corrective factor" for postmortem blood digoxin concentration

Interpretation of postmortem serum digoxin levels is made difficult above all by a possible prefinal or postmortem rise in digoxin concentrations in the blood. To compensate for this postmortem increase, Eriksson et al. (1984) divided the level of postmortem digoxin in femoral venous blood by a factor of 1.5; in the opinion of these authors, postmortem digoxin levels still exceeding "therapeutic levels" after division by 1.5 are an index of digoxin overdose. The diagnostic value of this "correction factor" was investigated. In 56 cases with documented digoxin medication, samples of postmortem femoral venous blood were taken and the level of digoxin determined. In none of the cases had there been a clinical diagnosis of digoxin intoxication. Fifty percent of the measured values were above "therapeutic levels" (0.7 ng/ml to 2.2 ng/ml). Following division by 1.5, 20% of the cases still showed levels exceeding 2.2 ng/ml; the highest "corrected" value was 4.44 ng/ml. Taking into account the length of time between final dosage and death, individual differences in sensitivity to digitalis glycoside, and the complexity of ante- and postmortem dispersion processes, we concluded for the cases we studied that an (undetected) digoxin overdose was not even likely in those cases whose postmortem values after division by 1.5 lie above "therapeutic levels". The "correction factor" proposed by Eriksson et al. (1984) is only of limited diagnostic value; at best the "corrected" values can give an approximate indication of the corresponding antemortem serum digoxin concentrations. In particular, "corrected" values only a little above "therapeutic levels" could not confirm suspicion of an overdose with sufficient certainty.     

Distribution of digoxin, digitoxin and their cardioactive metabolites in human heart and kidney tissue. A postmortem study

A method was developed for the specific determination of digoxin and digitoxin, as well as their semisynthetic derivatives and dependent cardioactive metabolites, in autopsy samples of heart and kidney. A collective of six patients on long-term treatment with therapeutic doses of beta-acetyldigoxin had a mean myocardial digoxin content of 46.1 +/- 25.0 ng/g (SD); kidney: 50.3 +/- 30.3 ng/g. Digoxigenin bisdigitoxoside represented the second most important metabolite in heart and kidney; digoxigenin monodigitoxoside and digoxigenin follow, respectively. In a collective of seven patients on maintenance treatment with digitoxin, the mean tissue levels were higher but the metabolic pattern was similar (myocardial digitoxin content: 78.9 +/- 38.4 ng/g, renal content: 104.1 +/- 44.1 ng/g). The amount of digoxin formed by hydroxylation under long-term treatment with digitoxin in heart and kidney were approximately 10 ng/g. A case of digoxin intoxication differed both in the tissue content and in the metabolic distribution.     

Fatal choking in infants and children

Food asphyxiation in infants/children follows a different pattern from the adult "cafe coronary." In the absence of ethanol intoxication, infants/children are prone to mishandling nonfriable, firm, slippery foods/objects with a rounded contour. The Dade County Medical Examiner's files were searched from 1956 to mid-1983 for accidental pediatric choking deaths. Seventeen food and six foreign body asphyxiations were found. The male/female ratio was 1.4/1 and 1/1, respectively. The white/black ratio was 0.9/1 for food asphyxiation whereas no black victims were encountered choking upon foreign objects. Seventy-eight percent of all victims were between 2 months and 4 years of age. Infants/children asphyxiated on items such as a hot dog, hard candy, peanut, toy rattle, tissue paper, balloon, marble, etc. The choking event was recognized by nearby adults in most instances. Risk factors include the availability of riskful foods/objects, natural diseases with difficulty feeding, poor eating habits, and uneducated or ignorant parents/others at the scene. Although public education, package labeling, and changes in food/object design may be appropriate, the ubiquituous risk foods and small foreign objects will, on occasion, escape the eye of even the most watchful parent.     

我国刑事责任年龄之检视

刑事责任年龄在中外刑事立法中均有明文规定,由于各国的刑事政策和少年儿童的生长发育情况不同,故刑事责任的起始年龄也有较大差异。我国刑法规定该年龄的起点为14周岁,为了适应犯罪低龄化及未成年人身心发育成熟提前等客观形势,有必要将该年龄适当下调至13周岁。     

Findings in newborns of cocaine-abusing mothers

Cocaine has recently been shown to affect the outcome of pregnancy when taken by pregnant women. The authors measured fetal concentrations of cocaine and benzoylecgonine and reviewed autopsy and historical data for 62 successive infants who died at less than two days of age and were seen at the Los Angeles County Office of the Chief Medical Examiner-Coroner. Of 43 infants without an obvious cause of death at autopsy, cocaine or benzoylecgonine or both were present in 40%. None of the parameters studied predicted which infants would show cocaine or benzoylecgonine. We conclude that cocaine and benzoylecgonine concentrations should be measured on all infants who die at less than two days of age when the cause of death is not evident at gross autopsy.     

Classification of digoxin concentrations in blood and tissues in cases under suspicion of poisoning

The clarification of a suspicion of poisoning at all times poses a problem to the forensic toxicologist, when a narrow margin of therapeutic safety and a low dosage coincide as in cases of digoxin poisoning. Statistical methods may serve as an aid. The post mortem digoxin concentration in the tissues of heart, kidney, liver and in blood of 45 patients who had received therapeutic daily doses and of 13 cases of fatal poisoning are compared. After logarithmic transformation of the individual concentration values a two modal distribution is obtained. There is one concentration calculated with equal probability of being classified to "therapeutic or toxic", as well as the probability of observing the "critical" concentrations of 400 ng digoxin/g cardiac tissue, 500 ng/g kidney and 250 ng/g liver after therapeutic dosing. Using the discriminant analysis each of the cases clearly falls into one of the two collectives "therapeutic" and "toxic", when taken as a separate observation. Concentration data of fatal poisonings taken from the literature are as successfully classified as the analytical results of some exhumed bodies under suspicion but not poisoned. As expected the power of discrimination increases with the number of parameters. Because of the relatively slow body distribution of digoxin the blood taken from peripheral vessels is of most important evidence.     

Maternal Separations During the Reentry Years for 100 Infants Raised in a Prison Nursery

Prison nurseries prevent maternal separations related to incarceration for the small subset of children whose pregnant mothers are incarcerated in states with such programs. For a cohort of 100 children accepted by corrections into one prison nursery, subsequent separation patterns are analyzed. The largest numbers are caused by corrections' removal of infants from the nursery and infants reaching a one-year age limit. Criminal recidivism and substance abuse relapse threaten continued mothering during reentry. Focused and coordinated services are needed during prison stay and reentry years to sustain mothering for women and children accepted into prison nursery programs.     

Lactic acid concentrations in vitreous humor: their use in asphyxial deaths in children

Lactic acid concentrations in brain tissue of humans have been shown to increase with an extended agonal period. Infants and children dying from various causes are undergoing different stress conditions terminally and the postulate of this study is that natural death cases and traumatic asphyxia cases are characterized by varying agonal periods, the former being somewhat prolonged with the latter being rather brief. One-hundred-and-two cases of infants and children were examined for vitreous humor lactic acid concentrations. They were divided into two major categories, Sudden Infant Death Syndrome (SIDS) and non-SIDS cases. SIDS was further divided into SIDS without additional findings and SIDS with secondary findings which contributed to death. The non-SIDS category included traumatic asphyxia cases as well as those dying from blunt trauma, known respiratory diseases, and other causes. Categorical mean values and standard deviations were calculated. The vitreous humor lactic acid mean value for traumatic asphyxia was significantly lower than the mean value for SIDS. Also the mean value for known respiratory diseases was statistically lower than the mean value for SIDS with secondary findings. These findings are probably suggestive of agonal time differences and may be a reflection of the various mechanisms of death.     

An autopsy case of combined drug intoxication involving verapamil,metoprolol and digoxin

We present here a fatal poisoning case involving verapamil, metoprolol and digoxin. A 39-year-old male was found dead in his room, and a lot of empty packets of prescribed drugs were found near the corpse. The blood concentrations of verapamil, metoprolol and digoxin were 9.2 microg/ml, 3.6 microg/ml and 3.2 ng/ml, respectively. The cause of death was given as cardiac failure, hypotension and bradycardia due to a mixed drug overdose of verapamil, metoprolol and digoxin, based on the results of the autopsy and toxicological examination. We speculate that the toxicity of verapamil is potentiated by drug interaction with metoprolol and digoxin.     

Immunofluorescence demonstration of digoxin in human myocardial tissue and isolated rat cardiac myocytes with monoclonal antibodies

The aim of the present investigation was to identify the morphological correlates of digoxin binding sites in human heart muscle tissue and isolated viable rat heart myocytes. Cardiac glycoside linked to myocardial cells was demonstrated by monoclonal digoxin specific antibody and by FITC-conjugated anti-mouse immunoglobin serum. This versatile immunofluorescence method can be used in diagnostic and experimental studies of cardiac glycoside binding.     

Facial soft tissue thickness in skeletal type I Japanese children

Facial reconstruction techniques used in forensic anthropology require knowledge of the facial soft tissue thickness of each race if facial features are to be reconstructed correctly. If this is inaccurate, so also will be the reconstructed face. Knowledge of differences by age and sex are also required. Therefore, when unknown human skeletal remains are found, the forensic anthropologist investigates for race, sex, and age, and for other variables of relevance. Cephalometric X-ray images of living persons can help to provide this information. They give an approximately 10% enlargement from true size and can demonstrate the relationship between soft and hard tissue. In the present study, facial soft tissue thickness in Japanese children was measured at 12 anthropological points using X-ray cephalometry in order to establish a database for facial soft tissue thickness. This study of both boys and girls, aged from 6 to 18 years, follows a previous study of Japanese female children only, and focuses on facial soft tissue thickness in only one skeletal type. Sex differences in thickness of tissue were found from 12 years of age upwards. The study provides more detailed and accurate measurements than past reports of facial soft tissue thickness, and reveals the uniqueness of the Japanese child's facial profile.     

Toxic environmental factors in sudden infant death (SIDS)

The increasing number of discussions on the influence of toxic environmental factors, including SIDS, prompted systematic postmortem chemical-toxicological investigations to be carried out on 54 SIDS cases and 2 control cases of the same age group. Tissue levels of arsenic, lead, cadmium, mercury, and pentachlorphenol, as well as other organic noxious agents, were measured in several organs. In addition, the COHb concentrations were determined. In spite of the widely scattered values, the extreme levels measured and the arithmetic means and median averages of As, Pb, Cd, Hg, PCP, and COHb had no more range in concentrations than can be expected for toxic effects - according to present knowledge anyway. It was observed that infants from an urban environment showed no greater concentration of noxious agents than did infants from rural regions. There were also no differences between SIDS cases and the controls, nor was there a correlation between infections of the respiratory system that are often morphologically detected - including laryngitis - and higher concentrations of these agents in the organs of SIDS cases.     

Frequency of pulmonary hemosiderosis in Eastern North Carolina

Pulmonary hemosiderosis has been attributed to airborne fungi in water-damaged homes in studies of a cluster of cases in infants and children in Cleveland, Ohio, in 1997. We have searched for such emerging infectious agents in the Coastal Plain of North Carolina, which is subject to intermittent flooding. Pulmonary tissue from 206 infants and young children whose deaths had been investigated from October 1978 to September 1996 was retained at East Carolina University School of Medicine. Ages ranged from premature newborns to 49-months. One hundred and ten deaths were attributed to sudden infant death syndrome (SIDS). New sections were cut and analyzed using hematoxylin and eosin, Prussian blue for iron, and Gomori methenamine silver for fungal organisms. Twenty-three infants and children had iron-containing macrophages. Sixteen of these had underlying illnesses, but 4 were originally diagnosed as SIDS. Only one of these had sufficient hemosiderosis to be considered as having pulmonary hemosiderosis and no fungi were present. One case without iron had fungi and was not originally diagnosed as SIDS. The single case of pulmonary hemosiderosis found in this rural area is not similar to the cluster in Cleveland. The study identifies no fungal organisms as emerging infectious diseases in this area.     

USING THE EMPIRICAL LITERATURE TO GUIDE THE DEVELOPMENT OF PARENTING PLANS FOR YOUNG CHILDREN

Most infants form attachments to both of their parents at roughly the same age. These relationships are consolidated by continued interactions, ideally in a broad array of contexts, whether or not the parents live together. The mechanisms underlying the formation and consolidation of relationships with both parents appear to be similar, although most infants establish preferential relationship with the persons who take major responsibility for their care. When parents separate, children often experience distress, and their adjustment is adversely affected when the relationship with one of their parents is severed. This can be avoided by developing parenting plans that continue to ensure that children have regular interaction with both parents in a broad array of contexts. Overnight periods provide opportunities for many important interactions.