Apparent hypoxic changes in pulmonary arterioles and small arteries in infancy.

The pulmonary arterioles and small arteries were studied and their musculature and its nuclei were quantified in 90 neonates, infants, and young children who had suffered from a variety of clinical and hypoxic conditions immediately before death. Among the 90 cases investigated in this study, 30 were of sudden infant death syndrome (SIDS). No evidence was found to support the view that cases of SIDS are subjected to chronic hypoxia before death as significantly more medial muscle tissue in the pulmonary arterioles and small arteries was found in the chronic hypoxic group compared to the SIDS, non-hypoxic, and acute hypoxic groups. Furthermore, there was no statistically significant difference in the amount of medial muscle tissue of the pulmonary vessels as between the SIDS, non-hypoxic, and acute hypoxic groups. With other signs of acute hypoxia found at the necropsy of SIDS, the results of this study could be considered to support the view that cases of SIDS succumb as a result of an acute episode of hypoxia, or possibly repeated short-duration episodes of acute hypoxia which do not produce pulmonary vascular changes.     

Postmortem vitreous humor chemistry in sudden infant death syndrome and in other causes of death in childhood.

Postmortem vitreous humor concentrations reflect antemortem serum chemical values. The authors measured the postmortem vitreous humor concentrations of Na+, K+, Cl-, Ca+2, Mg+2, urea nitrogen, creatinine, and total protein of 127 children who died from sudden infant death syndrome (SIDS) and other causes. Forty-seven children, 1 hour to 13 years old, had died of medical or surgical causes; 21 children, 7 weeks to 11 years old, had died following acute trauma; 59 children, 8 days to 1 year old, had died of SIDS. There was no significant difference between mean postmortem vitreous humor concentrations of those who died of medical and surgical causes and those who died after acute trauma (non-SIDS). in both groups, the mean postmortem vitreous humor concentrations of Mg+2 and Ca+2 were significantly higher in premature infants. There was direct correlation of postmortem vitreous humor concentration and postmortem interval for K+, but the variation, +/- 26 hours, was too large to be of practical importance in estimating time of death in individual cases. The three patient groups were compared and the mean postmortem vitreous humor concentrations of all eight constituents in the SIDS and non-SIDS groups were in the same ranges. In SIDS, the mean postmortem vitreous humor concentrations of Mg+2, Cl-, and urea nitrogen were significantly different from values of the non-SIDS cases, but not enough to indicate SIDS or to be informative about the etiology of SIDS. Measurement of the concentrations of postmortem vitreous humor constituents may not aid in the diagnosis of SIDS, but may aid in discovering unsuspected antemortem serum chemical abnormalities.     

Hypomagnesaemia and new data on vitreous humour magnesium concentration as a post-mortem marker in ruminants.

Magnesium deficit has been associated with many sub-clinical and clinical conditions in humans and animals. The incidence of hypomagnesaemia is high in lactating cows grazing spring pastures, occasionally resulting in the often fatal condition known as grass tetany. While plasma magnesium concentrations can be used to assess magnesium status in the live animal, post-mortem diagnosis of clinical grass tetany is difficult. Recent studies have investigated the potential of eye fluid magnesium concentration as a post-mortem marker of hypomagnesaemic tetany. In tetany induction studies carried out in adult ewes and lactating cows significant relationships were found to exist between the concentrations of magnesium in either cerebrospinal fluid or plasma and either aqueous or vitreous humour. In freshly dead animals aqueous humour magnesium concentrations of < 0.33 mmol/L in adult sheep and < 0.25 mmol/L in adult cattle were associated with severe hypomagnesaemia and tetany. However, aqueous humour was found to be unstable post-mortem. Vitreous humour was considerably more stable and a vitreous humour magnesium concentration in adult sheep of < 0.65 mmol/L for up to 24 hours post-mortem or < 0.55 mmol/L in adult cows for up to 48 hours was associated with severe hypomagnesaemia and tetany. Provided clear-fluid samples are taken from appropriate animals and processed correctly in the laboratory, the concentration of magnesium in vitreous humour is a useful and practical marker in the post-mortem diagnosis of hypomagnesaemic tetany in ruminants.     

Unacceptably high site variability in postmortem blood alcohol analysis.

Blood alcohol concentration is a frequently requested test in forensic pathology. The variability of this value was studied by measuring the blood alcohol concentration from six sites in nine subjects at necropsy in whom alcohol was the implicated cause of death. There were small consistent differences in the blood alcohol concentrations between the sites in the nine subjects (p < 0.04). Calculation of the mean blood:vitreous humour alcohol concentration ratio (B:V ratio) showed that vitreous humour alcohol concentration most closely reflected the concentration at the femoral vein (B:V ratio = 0.94, r = 0.98), which is considered the optimal site for blood alcohol measurement. The correlation of left heart blood with femoral blood was lower compared with the other sites. There is a potential for an unacceptably large variation in the postmortem measurement of blood alcohol within each subject.     

The cardiac conduction system in sudden infant death syndrome: a report on three cases.

The cardiac conduction systems in three cases of sudden infant death syndrome (SIDS) were compared with those in children dying from known causes. Foci of inflammatory cells and areas of necrosis were found in SIDS. Lymphocytes and eosinophils were counted in the adjacent myocardium and significantly larger numbers were present in SIDS. These parhological changes in the conduction systems may be capable of producing cardiac arrhythmia and sudden death.     

Intrauterine hypoxia and sudden infant death syndrome

Sudden infant death syndrome (SIDS) or crib or cot death are synonyms for the sudden, unexpected and unexplained death of an infant. The incidence of SIDS has been estimated to be from 1-2% to 3%. Protracted intrauterine hypoxia or recurrent hypoxic insults during fetal life undoubtedly influence the development of the central nervous structures as a tissue most susceptible to hypoxia, although well developed mechanisms of defense against hypoxia exist during the fetal life. The mechanisms underlying SIDS include neurologically compromised infants who are deprived of compensatory mechanisms during sleep, sustaining a hypoxic insult with alterations in neurotransmitter receptors within the regions involved in chemoreception and cardiovascular control. Changes in the brain result from perinatal prolonged hypoxia (persistent reticular pathways in the pons and medulla, astroglia in the brainstem, gliosis of brain nerve nuclei, defects in neurotransmitter receptors, neuronal apoptosis, microthrombosis, and hypoxic ischemic lesion). Hypoxic perinatal risk factors for SIDS included passive and active exposure to cigarette smoking in pregnancy, abuse of drugs, alcohol, coffee and medication in pregnancy, intrauterine growth retardation, perinatal hypoxia with or without resuscitation, preeclampsia, anemia in pregnancy, prematurity, multiparity, multiple pregnancy, pregnant women aged < 20 years and > 35 years, cardiocirculatory, pulmonary and endocrine diseases in pregnancy, and short time interval between two pregnancies. As cigarette smoking has been demonstrated to lead to fetoplacental insufficiency, which result in fetal hypoxia, it is concluded that hypoxia is a precondition for the occurrence of SIDS. Prenatal exposure to cigarette smoke decreases maternal red blood cell count, and concentrations of tyrosine and selenium, reduces fetal and neonatal cerebral blood flow, and increases maternal MCV, leukocytosis, especially neutrophils, monocytes and lymphocytes, maternal and fetal heart rate, systolic and diastolic blood pressure, resistance index in umbilical artery, fetal hemoglobin, cytokine, serotonine, dopamine, catecholamine, hypoxanthine, endorphin and interleukin-6. Pregnancy at a risk of hypoxia, especially in heavy smokers, is a major risk factor for SIDS, and such pregnancy requires close and intensive antenatal monitoring.     

Biochemical assessment of acute myocardial ischaemia.

AIMS--To evaluate the efficacy of biochemical parameters in different fluids in the diagnosis of myocardial infarction of different causes, analysed after death. METHODS--The myoglobin concentration and total creatine kinase (CK) and creatine kinase MB isoenzyme (CK-MB) activities were measured in serum, pericardial fluid, and vitreous humour from seven diagnostic groups of cadavers classified according to the severity of myocardial ischaemia and cause of death. Lactate dehydrogenase (LDH) and myosin were measured only in serum and pericardial fluid, and cathepsin D only in pericardial fluid. Routine haematoxylin and eosin and acridine orange staining were used for microscopy studies of heart tissue. RESULTS--In pericardial fluid there were substantial differences between the different groups with respect to CK, CK-MB, and LDH activities and myosin concentrations. The highest values were found in cases with morphological evidence of myocardial ischaemia. CONCLUSIONS--Biochemical parameters, which reach the pericardial fluid via passive diffusion and ultrafiltration due to a pressure gradient, were thus detectable in this fluid earlier than in serum in cases with myocardial ischaemia. These biochemical parameters may be of use for ruling out myocardial ischaemia in those controversial cases in which reliable morphological findings are lacking.     

Biochemical and histological assessment of hepatic lipid in sudden infant death syndrome

A biochemical and histological study of hepatic lipid in children dying from the sudden infant death syndrome (SIDS) and children of a similar age dying explicably are reported. Contrary to a previous report based on histological assessment of hepatic lipid, no significant increase of total lipid content in livers of children dying from SIDS was found. Analysis of hepatic phospholipid fatty acid esters, however, revealed a significant difference between SIDS and children of similar age dying acutely and explicably. The phospholipid abnormality found in SIDS was similar to that found in children dying subacutely with hypoxia and would be consistent with increased cell membrane fluidity. The implications of these findings in the pathogenesis of SIDS are discussed.     

A review of the status of magnesium and related minerals in the sudden infant death syndrome (SIDS).

Sudden infant death syndrome (SIDS) is the sudden death of an infant under 1 year of age that remains unexplained after a thorough case investigation, including performance of a complete autopsy. Despite recent reductions in the SIDS rate attributed to placing the baby to sleep on his back, SIDS remains the most common cause of infant mortality between 1 month and 1 year of age in developed countries. This review concerns the current state of a hypothesis (1972) that magnesium deficiency, which causes sudden death in young mammals, is the major cause of SIDS. Numerous investigators have compared the concentration of magnesium, and other minerals from soft tissues and bone in SIDS with non-SIDS controls (normal infants who died suddenly of known cause such as trauma). Because of rapid shifts of minerals during early development, SIDS and control infants must be matched for gestational and postnatal age. About 95 per cent of SIDS occurs between 1-6 months of life, with peak incidence at 2-4 months, when vitreous magnesium is high. There is little change in magnesium in the relatively inert vitreous despite extremes in dietary magnesium. All values fall within a small range, with scatter. Magnesium rapidly increases in foetal cartilage with ossification of the bone. Early in magnesium deficiency, liver magnesium may be increased or unchanged, but it does not increase during magnesium excess. Lead accumulation is increased in magnesium deficiency. Among infants with high environmental exposure to lead, those who die of SIDS rather than non-SIDS infants have the greater lead burden. Soft water with low magnesium and calcium and with high concentration of sodium have been linked to higher SIDS rates, which have been attributed to low magnesium. It is concluded that the SIDS hypothesis has neither been proved nor disproved.     

Cerebrospinal fluid concentrations of hypoxanthine, xanthine, uridine and inosine: high concentrations of the ATP metabolite, hypoxanthine, after hypoxia

CSF obtained for clinical purposes from newborn, children and adults has been analysed by high pressure liquid chromatography for hypoxanthine, xanthine, inosine, uridine and urate. Large rises in hypoxanthine and to a lesser extent xanthine occur for about 24 h after hypoxia. High concentrations were associated with later evidence of brain damage or subsequent death. Changes in CSF could be independent of those in plasma. Small or negligible rises were associated with localised and generalised infections including bacterial meningitis, fits, or both. Marked and rapid rises were found after death. These estimations may "predict" the extent of brain damage or brain death.     

Sudden infant death syndrome Part 2: the response of the reticuloendothelial system to hypoxemia and infection.

The incidence of ascites in chicks raised in a high-altitude chamber doubled from 6500 feet to 8000 feet. A similar condition developed in calves transported to pasture at high altitude. Chicks raised in a high-altitude chamber (compared to controls) produced more plasma cells in the germinal centres of the spleen about four days after an antigen challenge. Children usually suffering from a mild respiratory infection at sea level often developed pulmonary edema (HAPE) on transfer to high altitude. Sudden infant death syndrome (SIDS) victims produced more plasma cells in the germinal centers of the spleen. In one survey of SIDS, about half of the infants suffered an upper respiratory tract infection in the two weeks prior to death and the lungs were filled with fluid at autopsy. Elevated levels of hypoxanthine indicated hypoxemia before death, and a presumed response to hypoxemia in SIDS was the presence of extramedullary hematopoiesis in the liver.The effect of prolonged hypoxemia and infection are additive in increasing vascular permeability and the accumulation of edema fluid. The preferential uptake of zinc by edema fluid proteins at the expense of inflammatory cells increases the motility and metabolism of zinc-deprived activated macrophages. Activated macrophages release cytokines which in turn stimulate the release of pro-inflammatory peptides which increase vascular permeability and mortality. These inflammatory peptides are under proteolytic control. The neutral endopeptidase (NEP) is a cell-surface zinc metalloproteinase which modulates toxic shock.Zinc also modulates the inflammatory response of the activated macrophage. Interleukin-12 (IL-12), predominantly a product of macrophages, is involved in regulating both hematopoiesis and the adaptive immune response. IL-12 promotes interferon gamma (IFNgamma) production by T cells. IFNgamma acts on macrophages to release large amounts of nitric oxide (NO). An elevated immune response leads to NO overload, dilation of the cardiovascular system and toxic shock. A mechanism resulting in cardiovascular failure and a shock-like sequence is described in some cases of SIDS.Bradycardia, recorded on cardiorespiratory monitors in six SIDS infants, was considered a late event. Cytokines regulate all aspects of the immune response.Extramedullary hematopoiesis in the liver was one anatomical marker of hypoxemia in SIDS. This survey traces the function of the activated macrophage with the cytokines regulating extramedullary hematopoiesis and the precocious immune response in SIDS.     

Hypoxia recruits a respiratory-related excitatory pathway to brainstem premotor cardiac vagal neurons in animals exposed to prenatal nicotine

The most ubiquitous form of arrhythmia is respiratory sinus arrhythmia in which the heart beat slows during expiration and heart rate increases during inspiration. Whereas respiratory sinus arrhythmia benefits pulmonary gas exchange respiratory dysfunction presents a major challenge to the cardiorespiratory system. Hypoxia evokes a pronounced bradycardia mediated by increases in parasympathetic cardiac activity. It has been hypothesized that the fatal events in sudden infant death syndrome (SIDS) are exaggerated cardiorespiratory responses to hypoxia. This study tests whether premotor cardiac vagal neurons receive rhythmic respiratory-related excitatory synaptic inputs during normoxia and hypoxia, and if animals exposed to nicotine in the prenatal period have exaggerated responses to hypoxia. Premotor cardiac vagal neurons in the nucleus ambiguus were identified in rats by the presence of a fluorescent tracer in medullary slices that generate rhythmic inspiratory-related motor discharge. Respiratory activity was recorded from the hypoglossal nerve and excitatory synaptic events in cardiac vagal neurons were isolated using patch clamp techniques. Adult female rats were implanted with osmotic minipumps that delivered nicotine at a level approximately equivalent to those that occur in moderate to heavy smokers. During normal eupneic respiration, as well as during hypoxia, premotor cardiac vagal neurons from control animals did not receive any rhythmic respiratory-related excitatory inputs. However in animals exposed to nicotine throughout the prenatal period respiratory bursts during hypoxia dramatically increased the frequency of excitatory synaptic events in cardiac vagal neurons. In summary, in animals exposed to nicotine throughout the prenatal period, but not in unexposed animals, respiratory bursts that occur during hypoxia dramatically increase the frequency of excitatory synaptic events in cardiac vagal neurons. This study establishes a likely neurochemical mechanism for the heart rate responses to hypoxia and a link between prenatal nicotine exposure and exaggerated bradycardia responses during hypoxia that may contribute to sudden infant death syndrome.     

Importance of postmortem changes in measurements of thyroid function in studies of sudden infant death syndrome.

Various measurements of thyroid function were made from serum sampled at necropsy by cardiac puncture in adults and compared with the equivalent values before death. There were significant increases in serum total T3 (0.66 before death, 1.14 nmol/l after death), free T3 (0.82 to 1.52 pmol/l), and reverse T3 (1.12 to 1.75 nmol/l); and significant decreases in total T4 (73.7 to 56.6 nmol/l), free thyroxine index (FTI) (83.2 to 56.6), and free T4 (14.2 to 11.9 pmol/l). The increase in serum T3, presumably from T4 deiodination after death, observed in this study may explain the increased T3 concentration reported in serum sampled from cases of sudden infant death syndrome (SIDS).     

Fibromuscular hyperplasia of the pulmonary artery in sudden infant and perinatal unexpected death

IntroductionThe purpose of this study was to describe cases presenting with fibromuscular hyperplasia of the pulmonary arteries that could belong to the group of sudden infant death syndrome (SIDS) and sudden unexpected perinatal death “gray zone” or borderline cases.MethodsIn a total of 12 cases, eight females and four males, ranging in age from 39 gestational weeks to 93 postnatal days, dying suddenly and unexpectedly, a fibromuscular hyperplasia of the pulmonary artery was detected. Postmortem examinations were requested with a clinical SIDS or sudden unexpected perinatal death. A complete autopsy was performed, including close examination of the brainstem and cardiac conduction system.ResultsHistological examination showed the presence of various degrees of fibromuscular hyperplasia with fibrosis of the right (six cases), left (five cases) or both (one case) pulmonary arteries.ConclusionsIn our cases, fibromuscular hyperplasia of the pulmonary artery alone might or might not have accounted for the sudden deaths, if it had not been for the concomitant presence of hypoplasia of the arcuate nucleus in the brainstem and/or cardiac conduction system abnormalities. Therefore, they were classified as SIDS/sudden unexpected perinatal death gray zone or borderline cases. Necropsy studies of sudden infant and perinatal death should always include an accurate gross and histological examination of the pulmonary arteries, as well as of the brainstem and cardiac conduction system.     

A hypothesis: Sudden Infant Death Syndrome is a disorder of entrainment

A hypothesis is presented that explains Sudden Infant Death Syndrome (SIDS) as a disorder of entrainment. This hypothesis fits the known characteristics of SIDS i.e., age at death, sleep-related, natural death and absence of a lethal lesion. The spectrum from reversible hypoxia (near-miss SIDS) to irreversible hypoxia (SIDS) can be explained by the presence or absence of brainstem lesions in infants with a disorder of entrainment.     

Sudden infant death syndrome associated with rotavirus infection

Rotavirus was detected in the stools of five children stricken with sudden infant death syndrome (SIDS) over a three-week period. While none of the children had acute gastroenteritis, four of the five had acute upper respiratory infections. Rotavirus was also identified in tracheal aspirates from two of the infants. Extensive investigations failed to reveal the presence of any other viruses or toxins in specimens obtained from the five children with SIDS. Rotavirus was not found in the stool specimens obtained from a control group of 36 infants including six who died of causes other than SIDS. Future attempts at the prevention of rotavirus infections should be directed at populations susceptible to sudden infant death syndrome.     

The dorsal motor nucleus of the vagus (DMNV) in sudden infant death syndrome (SIDS): Pathways leading to apoptosis

Sudden infant death syndrome (SIDS) remains the commonest cause of death in the post-neonatal period in the developed world. A leading hypothesis is that an abnormality in the brainstem of infants who succumb to SIDS, either causes or predisposes to failure to respond appropriately to an exogenous stressor. Neuronal apoptosis can lead to loss of cardiorespiratory reflexes, compromise of the infant's ability to respond to stressors such as hypoxia, and ultimately a sleep-related death. The dorsal motor nucleus of the vagus (DMNV) is a medullary autonomic nucleus where abnormalities have regularly been identified in SIDS research. This review collates neurochemical findings documented over the last 30 years, including data from our laboratory focusing on neuronal apoptosis and the DMNV, and provides potential therapeutic interventions targeting neurotransmitters, growth factors and/or genes.     

Xanthine and hypoxanthine in amniotic fluid during pregnancy

Xanthine and hypoxanthine are indicators of cellular hypoxia. The purpose of our study was to establish a reference range for the concentrations of xanthine and hypoxanthine in amniotic fluid. Of a total of 38 included in the investigation, 27 pregnant women were found to have low values for xanthine (less than 1.2 mumol/l) and hypoxanthine (less than 0.4 mumol/l). To our knowledge, this is the first attempt to define a reference range for xanthine and hypoxanthine concentration in amniotic fluid during pregnancy.     

Role of disorders of metabolism in rat myocardium and endotoxemia in the pathogenesis of post-resuscitation cardiodepression

The model of 4-min clinical death due to acute blood loss was used to study cardiac contractility, myocardial metabolism and causes of endotoxemia in early postresuscitation period. The investigations were made on the whole body, isolated, isovolemically contracting heart and isolated papillary muscle. A marked reduction in functional myocardial reserves, maximal within the first 24 hours of postresuscitation, with dominant defects in relaxation was seen. Pathogenetic factors responsible for cardiodepression are the following: hypoxia, impairment of bioenergetics, hyperactivation of lipid peroxidation, acidosis, membrane destruction, endotoxemia.