Asphyxial Episodes Research Articles

Negative pressure pulmonary edema in a patient with COVID-19.

Negative pressure pulmonary edema (NPPE) should be considered in the differential diagnosis from an episode of asphyxia, and even if NPPE is diagnosed, the possibility of COVID-19 should be kept in mind under coronavirus pandemic conditions.

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.

Neuron-specific enolase in cerebrospinal fluid as a biomarker of brain damage in infants with hypoxic-ischemic encephalopathy.

Adenoid cystic carcinoma of the larynx: A report of two cases.

Laryngeal adenoid cystic carcinoma (ACC) is extremely rare, worldwide. From January 1994 to January 2014, all cases of laryngeal ACC that were diagnosed in the four largest hospitals in Hainan province, were reviewed. Only two such cases were identified. The first patient had a tumor in the subglottic region and the second patient, in the glottic region. The patient with subglottic ACC, who had experienced ongoing symptoms for 3 years, had previously been diagnosed with asthma, at a local hospital. Both presented at an advanced stage. The patient with subglottic disease received a total laryngectomy with a positive surgical margin, was treated with adjuvant radiotherapy, and later succumbed to a pleural effusion as a result of pulmonary metastases. The patient with glottic disease received a partial laryngectomy and declined adjuvant radiotherapy. Subsequently, she developed recurrent disease and passed away following an episode of asphyxia at 14 months post-surgery. Each of these cases had a poor prognosis at presentation. For patients with locoregionally advanced laryngeal ACC, more effective management strategies are required.

Could Intra-alveolar Hemosiderin Deposition in Adults be Used as a Marker for Previous Asphyxial Episodes in Cases of Autoerotic Death?

Intra-alveolar hemorrhage and hemosiderin have been cited as possible markers of recent and remote asphyxial events. Little study has been undertaken of the potential significance of intra-alveolar hemosiderin in adults as a potential marker of previous sublethal asphyxial episodes. Ten cases of lethal sexual asphyxia (an entity known to be associated with repetitive sublethal asphyxial episodes) and 20 randomly selected, age- and sex-matched controls had sections of lung stained for hemosiderin. Subsequently, intra-alveolar, iron-containing macrophages were counted. All cases were men (ages 15-50 years; mean 31.8). No significant increase in hemosiderin was found in victims of sexual asphyxia, indicating that asphyxial episodes in sublethal sexual asphyxial activities may not be sufficiently intense or prolonged to cause intra-alveolar hemorrhage or that intra-alveolar hemorrhage in adults is a relatively nonspecific finding. These results do not support intra-alveolar hemosiderin deposition as a marker for previous sublethal asphyxial events in autoerotic asphyxia.

Fatal asphyxial episodes in the very young: classification and diagnostic issues.

Infants and young children are exposed to a relatively limited range of circumstances that may result in accidental or inflicted asphyxial deaths. These usually involve situations that interfere with oxygen uptake by the blood, or that decrease the amount of circulating oxygen. Typically infants and toddlers asphyxiate in sleeping accidents where they smother when their external airways are covered, hang when clothing is caught on projections inside cots, or wedge when they slip between mattresses and walls. Overlaying may cause asphyxiation due to a combination of airway occlusion and mechanical asphyxia, as may inflicted asphyxia with a pillow. The diagnosis of asphyxiation in infancy is difficult as there are usually no positive findings at autopsy and so differentiating asphyxiation from sudden infant death syndrome (SIDS) based purely on the pathological features will usually not be possible. Similarly, the autopsy findings in inflicted and accidental suffocation will often be identical. Classifications of asphyxia are sometimes confusing as particular types of asphyxiating events may involve several processes and so it may not be possible to precisely compartmentalize a specific incident. For this reason asphyxial events have been classified as being due to: insufficient oxygen availability in the surrounding environment, critical reduction of oxygen transfer from the atmosphere to the blood, impairment of oxygen transport in the circulating blood, or compromise of cellular oxygen uptake. The range of possible findings at the death scene and autopsy are reviewed, and the likelihood of finding markers/indicators of asphyxia is discussed. The conclusion that asphyxiation has occurred often has to be made by integrating aspects of the history, scene, and autopsy, while recognizing that none of these are necessarily pathognomonic, and also by excluding other possibilities. However, even after full investigation a diagnosis of asphyxia may not be possible and a number of issues concerning possible lethal terminal mechanisms may remain unresolved.

Long‐term effects of a midgestational asphyxial episode in the ovine fetus

We and others have shown previously that fetuses at midgestation can survive 30 min of complete umbilical cord occlusion, although hydrops fetalis (or gross fetal edema) results. To investigate whether this hydrops resolves by late gestation and if there are any long-term consequences of the asphyxial insult on the heart and kidneys, eight fetuses were subjected to 30 min of complete umbilical cord occlusion at 0.6 gestation (90 days; term 150 days) and were compared to a sham group (n = 10). During the occlusion period, fetuses became severely hypoxemic, hypercapnemic, and acidotic, with both blood pressure and heart rate decreasing. Most variables had returned to normal by 2-hr recovery. At 129 +/- 1 days of gestation, approximately 40 days post occlusion, some fetuses were still slightly hydropic as skin fold measurements were increased (P < 0.01), although fetal body weight was not different from the sham group. The two groups had similar heart and kidney weights, ventricular cardiac myocyte nucleation, and glomerular number. By contrast, brain weight was reduced by 37% (P < 0.001) and the cerebral lateral ventricles were grossly dilated. Lungs were 50% smaller than in sham fetuses (P < 0.001). Thus, the hydrops that develops at midgestation as a result of a severe asphyxial episode can, but does not always, fully resolve by late gestation. Also, while fetuses at midgestation can survive this asphyxial episode with no long-term impact in renal or cardiac size, nephron number, or cardiomyocyte nucleation, the brain and lungs are severely affected.

Life-Threatening Asthma during Treatment with Salmeterol

To the Editor: Although the addition of a long-acting β2-agonist such as salmeterol to an inhaled corticosteroid has been demonstrated to provide greater control of asthma than does a substantially increased dose of the inhaled corticosteroid,1 this medication was associated with an increased risk of asthma-related death in a large population study.2 We have identified two adolescent boys with poorly controlled asthma and a history consistent with sudden asphyxial episodes during modest exertion while receiving inhaled corticosteroids and salmeterol. In addition to reporting an inadequate response to their rescue inhaler when symptomatic, they had no apparent bronchoprotective effect . . .

The Effect of Repeated Umbilical Cord Occlusions on Pulmonary Surfactant Protein mRNA Levels in the Ovine Fetus

In this study we sought to determine the effect of brief repeated umbilical cord occlusions (rUCO) on surfactant protein (SP) mRNA levels in the fetal sheep lung at two different gestational ages. Fourteen fetuses at 112 to 115 days' gestation (control n = 7, rUCO n = 7) and 15 fetuses at 130 to 133 days' gestation (control n = 7, rUCO n = 8) were studied over 4 successive days with rUCO of 90 seconds duration performed every 30 minutes for 3 to 5 hours each day in the rUCO animals. Blood samples were collected for corticotrophin (ACTH) and cortisol measurements. Animals were killed within 1 hour of the final cord occlusion. SP-A, -B, -C, and -D mRNA levels were determined in lung tissue using a ribonuclease protection assay. Cord occlusions resulted in temporary increases in circulating ACTH on day 1 with both gestational ages, but the elevations were blunted by day 4. Plasma cortisol levels increased transiently with the larger effect being observed on day 4, in particular with the near-term group. With advancing gestational age there was a significant (P < .05) increase in the level of SP-A (control 112-115 days: 0.01 +/- 0.01 vs control 130-133 days: 0.07 +/- 0.02 fmol/mg RNA), SP -B (control 112-115 days: 0.02 +/- 0.01 vs control 130-133 days: 0.07 +/- 0.01 fmol/mg RNA) and SP-C (control 112-115 days: 0.13 +/- 0.09 vs control 130-133 days: 0.51 +/- 0.10 fmol/mg RNA), but not SP-D mRNA levels (control 112-115 days: 0.002 +/- 0.002 vs control 130-133 days: 0.01 +/- 0.002 fmol/mg RNA). At 112 to 115 days, there was no significant change in any of the SP mRNA levels following rUCO compared to controls. However, the same regime of rUCO at 130 to 133 days resulted in an 85% reduction in SP-A and SP-B mRNA content and a 66% reduction in SP-C mRNA levels compared to controls. The surprising decrease in SP-A and SP-B mRNA levels, which contrasts with other studies, suggests intermittent asphyxial episodes impact differently on surfactant apoprotein mRNA expression than does prolonged hypoxia.

The effects of asphyxia on renal function in fetal sheep at midgestation.

To determine whether damage to the fetal kidneys plays a role in the formation of hydrops fetalis following a severe asphyxial episode, six chronically catheterised fetal sheep, at 0.6 gestation (90 days; term 150 days), were subjected to 30 min of complete umbilical cord occlusion. During the occlusion period, mean arterial pressure, heart rate and renal blood flow decreased (P < 0.001). There were falls in arterial pH and PO2 and a rise in PCO2 (P < 0.001). Urine flow rate decreased (P < 0.005), as did the excretion rates of sodium and osmoles (P < 0.05). However, by 60 min after release of occlusion, urine flow rate was similar to control values. By the end of day 1, most renal variables returned to normal. At post-mortem, 72 h after occlusion, all asphyxiated fetuses showed gross signs of hydrops. Body weight was higher (P < 0.05) due to fluid accumulation in the peritoneal (P < 0.001) and pleural cavities (P < 0.05) as well as subcutaneously (P < 0.05). Amniotic/allantoic fluid volume was increased (P < 0.05). Kidney histology was normal except for clusters of apoptotic cells in some proximal tubules. In conclusion, this severe asphyxial episode caused surprisingly little damage to the kidney and the changes in renal function were very transient. Thus renal damage was not important in the development of hydrops. Possibly, the midgestation fetal kidney has a limited capacity to increase urinary salt and water excretion in response to increased fluid delivery across the placenta.

Recovery of metabolic acidosis in term infants with postasphyxial hypoxic‐ischemic encephalopathy*

To describe the base deficit (BD) values and the rate of postnatal recovery of the BD of infants with hypoxic ischemic encephalopathy due to intrapartum asphyxia; and to explore the relationships between the rate of recovery of BD, severe adverse outcome and different time patterns (acute total vs prolonged partial) of asphyxia. Clinical and laboratory data were collected from the neonatal period (n = 244) and outcome data to a minimal age of 1 y (n = 218). Rates of recovery of BD were described in four 60 min blocks of time. The values of rate of recovery were compared between the outcome groups, ignoring correlation structure within subjects and with adjustment by the generalized estimating equations method. The BD normalized within 4 h of birth in all but 9 of 244 infants. The rates of recovery of BD in infants with good and severe adverse outcome respectively were 0.11 [95% confidence interval (95% CI) 0.07, 0.14] and 0.09 (95% CI 0.07, 0.12) mmol l(-1) min(-1) over the first 4 h after birth. The rates of recovery were similar with or without buffer therapy, and after acute near-total and prolonged partial asphyxia. The BD in the great majority of infants with severe intrapartum asphyxia normalizes within 4 h of birth. The BD recovery rate of infants with adverse outcomes was similar to those with relatively good outcome. The different time patterns of asphyxial episode were not associated with differential recovery profiles.

A confidential enquiry into cases of neonatal encephalopathy

Objectives: To assess the quality of care and timing of possible asphyxial events for infants with neonatal encephalopathy; to compare the quality of care findings with those relating to the...

Association between Timing of Asphyxial Episode and Distribution of Central Nervous System (CNS) Injury in Human Infants

Association between Timing of Asphyxial Episode and Distribution of Central Nervous System (CNS) Injury in Human Infants

Ischemia and Reperfusion Injury: The Ultimate Pathophysiologic Paradox

It seems clear that the abundance of potential treatment options reflects the dearth of proved, effective options. Thus, although we appear to be on the brink of many potentially major breakthroughs in treatment, there currently remains a multitude of unanswered questions and the need for further study. At this point clinical recommendations must be limited to supportive care with moderation: oxygenation without hyperoxia; ventilation without hypocarbia; avoiding extremes of blood pressure, hematocrit, blood glucose, and body temperature. Unfortunately, data from human trials are extremely limited and often poorly controlled. Furthermore, even those few existing human studies have rarely--if ever--dealt with newborns infants (Table 2). In addition, many of the existing studies do not relate to generalized asphyxia but rather to single-organ reperfusion insults. Finally, there is the critical issue of timing. Unfortunately, much of the existing experimental data relate to prophylaxis rather than treatment, severely limiting their potential for clinical applicability. Interventions may have quite different effects when administered at different phases of this most intricate process. Hyperglycemia, for example, may be neuroprotective before an insult but detrimental if induced after an asphyxial episode. Conversely, the NMDA blocker MK-801 can adversely affect outcome when given before a global asphyxial insult but can reduce seizure-related damage when given during the hyperexcitability phase. Insulin-like growth factor is also neuroprotective only when given after an insult, but it is not helpful if given before. An intimate understanding of the pathophysiologic processes involved is essential before any attempts at applying the diverse data derived from numerous animal studies to the human situation in an intelligent manner. Future studies may focus on cocktails of different mixtures of the compounds discussed or on single multipotential drugs, which would make possible a multipronged approach. However, it is essential to investigate fully the potential for toxic drug interactions, as some combinations may be produce serious consequences. For example, Gluckman and Williams evaluated the potential of combining calcium channel blockers with NMDA receptor antagonists in hypoxic-ischemic rats and found that this combination led to rapid cardiovascular collapse. Other enticing approaches for future investigations will probably include some genetic-engineering-related studies in attempt to enhance endogenous antioxidant defenses with regulon stimulation or the administration of neurotrophic growth factors. Unavoidably, the trip from the laboratory to the bedside must of necessity be an arduous and rigorous one.

Effect of allopurinol on NMDA receptor modification following recurrent asphyxia in newborn piglets

The present study tests the hypothesis that repeated episodes of asphyxia will lead to alterations in the characteristics of the N-methyl- d-aspartate (NMDA) receptor in the brain cell membrane of newborn piglets and that pre-treatment with allopurinol, a xanthine oxidase inhibitor, will prevent these modifications. Eighteen newborn piglets were studied. Six untreated and six allopurinol treated animals were subjected to eight asphyxial episodes and compared to six normoxic, normocapneic controls. Brain cell membrane Na +,K +-ATPase activity was determined to assess membrane function. Na +,K +-ATPase activity was decreased from control following asphyxia in both the untreated and treated animals (47.7±3.2 vs. 43.0±2.2 and 41.0±5.3 μmol Pi/mg protein/h, p<0.05, respectively). 3H-MK-801 binding studies were performed to measure NMDA receptor binding characteristics. The receptor density ( B max) in the untreated asphyxia group was decreased compared to control animals (0.80±0.11 vs. 1.13±0.33, p<0.05); furthermore, the dissociation constant ( K d) was also decreased (3.8±0.7 vs. 9.2±2.2, p<0.05), indicating an increase in receptor affinity. In contrast, B max in the allopurinol treated asphyxia group was similar to control (1.06±0.37); and K d was higher (lower affinity) than in the untreated group (6.5±1.4, p<0.05). The data indicate that recurrent asphyxial episodes lead to alterations in NMDA receptor characteristics; and that despite cell membrane dysfunction as seen by a decrease in Na +,K +-ATPase activity, allopurinol prevents modification of NMDA receptor–ion channel binding characteristics induced by repeated episodes of asphyxia.

Magnetic resonance spectroscopy and near-infrared spectroscopy in the assessment of the asphyxiated term infant

Magnetic resonance spectroscopy (MRS) and near-infrared spectroscopy (NIRS) are capable of providing detailed information on cerebral oxidative metabolism in infants who have been resuscitated following an acute asphyxial episode. In severely affected infants studied by phosphorus and proton MRS, a consistent observation has been the development of deranged cerebral energy metabolism 12–48 hours after resuscitation, despite the maintenance of cardiovascular and respiratory homeostasis. Follow-up studies have indicated that the development of delayed energy failure is closely associated with the development of microcephaly and an adverse neurodevelopmental outcome. This pathophysiologic sequence has been modelled in newborn animals, allowing the mechanisms of delayed energy failure to be elucidated and cerebroprotective treatments to be tested. New developments in MRS and magnetic resonance imaging will enable quantitative and highly localised information on cerebral metabolism to be obtained in asphyxiated infants, increasing the accuracy of early clinical assessment. Significant cerebral vasodilatation and vasoparalysis of the cerebral circulation have been observed by NIRS in asphyxiated infants following resuscitation, but the prognostic value of this observation remains uncertain. Technical advances in NIRS are likely to improve the reproducibility and accuracy of the technique, allowing the assessment of regional cerebral haemodynamics and metabolism at the bedside. MRDD Research Reviews 3:42–48, 1997. © 1997 Wiley-Liss, Inc.

3 Metabolic acidosis and fetal reserve

Dr Bailey, Director of the National Institute of Neurological Diseases and Blindness, Bethesda, Maryland, introduced the 1956 symposium on 'Neurological and psychological deficits of asphyxia neonatorum' by saying. 'Medical research in regard to cerebral palsy and other neurological disabilities has been relatively neglected. For a truly comprehensive attack on this problem we must focus a sharper scientific search for greater knowledge of those adverse biological factors which operate in the perinatal period. The proper point of departure in such a search is through controlled animal observations, for which purpose monkeys are best suited' (Windle, 1958). Our understanding of the significance of asphyxia is built on the foundation of the laboratory research that has followed upon this initiative. Laboratory studies in fetal monkeys and fetal lambs have clearly demonstrated that the fetus can initially compensate for an asphyxial insult and protect the vital organs. However, if the hypoxaemia progresses to a severe metabolic acidosis and cardiovascular decompensation with hypotension, brain damage will occur. There is a growing body of clinical evidence that supports the contention that the human fetus responds in a similar manner. The varied nature of hypoxic and ischaemic insults has been well demonstrated in animal studies. Total anoxia and isolated cerebral ischaemia are uncommon events in the human fetus. The common insult, particularly during labour, is a degree of hypoxia present over a variable period of time. This is fortunate in that such insults are associated with a period of fetal compensation that may last several hours, during which time a diagnosis of a developing metabolic acidosis can be made. This is the clinician's window of opportunity, when a definitive diagnosis of an asphyxial insult can be made and if necessary intervention made before the threshold of decompensation has been reached. A consensus on the threshold of decompensation has yet to be achieved. However, there is a growing body of evidence that the threshold is in the range of an umbilical artery base deficit of 12-16 mmol/l. Since the aim of the obstetrician during labour is the prevention of asphyxial morbidity and mortality, the determination of this threshold is important to provide criteria for clinical action. A blood gas and acid-base assessment with the determination of a metabolic acidosis is the best measure of an asphyxial insult that may be of clinical significance. The definition of the threshold of metabolic acidosis requiring intervention will continue to be clarified with future clinical research. However, there are many factors that will influence the fetal response to an asphyxial insult, which may require that a range of threshold be acknowledged. The effect upon the fetus will be influenced by whether the asphyxial event is the first or the last of a series of asphyxial episodes, and the duration of the asphyxial episode. The characteristics of the fetus, i.e. maturity (pre-term versus term), and fetal growth small for gestational age (SGA) or appropriate for gestational age (AGA) may influence the fetal response to an asphyxial insult. Improved understanding of these issues will provide a better rationale for clinical management.

Long-term effect of perinatal and postnatal asphyxia on developing human auditory brainstem responses: peripheral hearing loss

Peripheral hearing was assessed by examining brainstem auditory evoked responses (BAER) in children who suffered perinatal or postnatal asphyxia, particularly in those with residual neurodevelopmental deficits, to investigate the long-term effect of asphyxia on the developing auditory sensitivity. The BAER data were collected at least 6 months after the episode of asphyxia. Of the children who suffered perinatal asphyxia, hearing loss was found more frequently in those who exhibited residual neurodevelopmental deficits (17.1%) than in those who did not (6.3%), but this difference did not reach statistical significance. This implied that the long-term effect of perinatal asphyxia on the peripheral auditory system and its effect on the central nervous system may be relatively discrete or not closely correlated. The occurrence of hearing loss did not appear to be closely related to the degree of perinatal asphyxia, although hearing loss occurred more frequently in the children after severe asphyxia compared to those after mild asphyxia. There was no evidence for permanent hearing loss in the children who survived severe, prolonged postnatal asphyxia and exhibited residual neurodevelopmental deficits. These findings suggest that a critical period of particular sensitivity to the effect of hypoxia may exist during the development of the human peripheral auditory system. This period may range from some time prenatally to some time shortly after birth, probably the third postnatal month. After that, hypoxia is unlikely to lead to permanent hearing loss.

Repeated asphyxia causes loss of striatal projection neurons in the fetal sheep brain.

Repeated episodes of cerebral hypoxia-ischemia can cause primarily striatal neuronal loss in the developing brain. We investigated the effect of repeated episodes of asphyxia on specific neuronal sub-populations of the basal ganglia in late-gestation fetal sheep. Asphyxia was induced in 10 fetal sheep (118-126 days gestation) by occluding the umbilical cord for 5 min. This procedure was repeated four times at 30 min intervals and the brains were fixed 3 days later for histopathology. Immunohistochemical markers were used to identify various populations of neurons in the striatum. Antibodies to calbindin were used to stain the GABAergic medium-sized striatal projection neurons and antibodies to somatostatin and parvalbumin to identify striatal interneurons. Striatal projection neurons to the globus pallidus were recognized by enkephalin immunoreactivity, while the striatonigral terminals were identified in the substantia nigra pars reticulata by substance P immunohistochemical labelling. The results showed a marked loss of calbindin staining in the striatum, evident by both reduced cell numbers and a decrease in neuropil staining. The number of parvalbumin immunoreactive cells was also reduced in the striatum, while somatostatin interneurons were selectively preserved. In addition, immunostaining for enkephalin in the globus pallidus and for substance P in the substantia nigra was markedly reduced. These results show that the stiatal GABAergic medium-sized projection neurons are severely affected by recurrent episodes of asphyxia. These findings are confirmed and extended by the results demonstrating that both the enkephalin/GABA striatopallidal and the substance P/GABA stiatonigral pathways are affected. The results of this study therefore suggest that the efferent striatal projections to the globus pallidus and to the substantia nigra may be involved in asphyxial episodes resulting in cerebral palsy.

Pathophysiology of Perinatal Asphyxia

Following a severe asphyxial episode many cells can recover metabolically, and a cascade of processes are triggered in which intervention, even some hours later, can allow rescue of some cells that would otherwise die. A number of principles, however, needs to be carefully considered before extrapolating from animal to human trials. In particular, the effects on long-term outcome and on those who are compromised by intrauterine growth retardation need to be determined. It is critical to be able to identify rapidly those infants in terms of nature and severity of injury who are most likely to benefit from treatment. The dimension of time and phase of injury or recovery are key factors to effective intervention. Novel continuous cerebral function monitoring techniques such as those based on real-time spectral analysis of the EEG activity, cortical impedance monitoring, and near-infrared spectroscopy have considerable potential for determining the severity and pathophysiologic phase of injury on line.

Fatal and Near-Fatal Autoerotic Asphyxial Episodes in Women

As asphyxial episodes during autoerotic activity are rarely reported in women, a review of eight fatal cases and one near-fatal case was conducted to delineate more clearly the characteristics of this syndrome in women. Six cases involved characteristic fatal autoerotic asphyxial activity. The remaining two fatal cases were atypical in that the apparatus that was used for sexual purposes was not intended to cause asphyxia in one case and did not directly cause asphyxial death in the second case. The final case was not fatal. Significantly, the majority of women did not use unusual clothing, props, or devices to augment their activity, for example, five were completely naked and only one was found with elaborate clothing and extra ligatures. Six of the fatal cases had objective evidence of sexual activity, three had used neck padding to prevent chafing, and eight had failed self-rescue mechanisms. Of note, the initial impression in four cases (44%) was homicide (two), attempted suicide (one), and accidental death during sexual activity with a partner (one). These results support the assertion that the manifestations of female autoerotic asphyxial activity reported to date may be initially misleading to investigators. Our purpose in presenting these findings, therefore, is to increase awareness of the more subtle features of this syndrome in women in an attempt to reduce the potential for underdiagnosis or confusion with nonaccidental death in future cases.