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[Cerebral death and bioethics].

INTRODUCTION: Brain death has been a topic of great interest for clinicians throughout the history of Neurosciences. There are so many different ideas about this topic that it has been necessary to constantly define further the criteria and medical decisions applicable in this field. Also about this matter there are a set of cultural, philosophical and religious aspects as well as autonomous principles in the people involved in such an event. Questions and dilemmas are still present in the individuality of every case and especially in terms of management of information and circumstances that define brain death. DEVELOPMENT: This essay tries to analyze the medical and historical issues around death and its relation to the context of brain death as such. There are also a series of reflections supported by the current bioethical thoughts that are identified with a cultural framework that is crucial to acknowledge the way in which the doctor, the family and society approach an event such as brain death. In spite of all the development of diagnostic technology and the extremes of the futility and extreme cruelty of treatments; there are still open questions that require to be looked into with objective criteria and scientific rigor. CONCLUSION: We should not put aside bioethical principles that are inherent to human quality and dignity that touch the sensitivity of those who give out the information and those who receive it within this process of interaction between the medical staff and the family.

Bioethics↗

Retardation of chemical hypoxia-induced necrotic cell death by Bcl-2 and ICE inhibitors: possible involvement of common mediators in apoptotic and necrotic signal transductions.

Inhibition of the respiratory chain reaction by cyanide, rotenone or antimycin A (chemical hypoxia) induces necrotic cell death characterized by apparently intact chromatin, remarkable mitochondrial swelling with loss of crista structure, and loss of plasma membrane integrity. The treatments induce no apoptotic cell death, as defined by fragmented nuclei with condensed chromatin, fragmented or condensed cytoplasm. The anti-apoptotic proteins Bcl-2 and Bcl-xL effectively retard the chemical hypoxia-induced necrotic cell death. The necrotic cell death is also retarded by inhibitors of ICE(-like) proteases, including interleukin-1beta converting enzyme (ICE), which are common mediators of apoptosis. These results indicate that Bcl-2/Bcl-xL and ICE(-like) proteases modulate apoptotic and at least some forms of necrotic cell death. Both cell death pathways appear to involve some common mediators; however necrotic or apoptotic cell death signals might be transduced through multiple pathways, because Bcl-2/ Bcl-xL or inhibitors of ICE(-like) proteases are relatively less potent in blocking necrotic cell death than in preventing apoptosis.

Amino Acid Sequence↗

[Brain death and organ procurement: a specific context].

Brain death is defined as an irreversible damage to the brain stem associated with lesions of the hemispheres. It determines the irremediable destruction of the whole body which occurs within a short delay. Brain death diagnosis is identified from a series of neurological criteria, i.e.: the loss of consciousness, the disappearance of brainstem reflexes, the lack of spontaneous breathing movements. Legal considerations in use in France imply that brain death must be confirmed by two isoelectric encephalographs or by the absence of cerebral perfusion on cerebral arteriography. The diagnosis must be established by two practitioners who are not involved in transplantation activity. Prexisting cardiac activity and organ perfusion allow indeed organs and tissue procurement for transplantation. Organ procurement is supported by intensive care of the brain dead patient aiming to correct hemodynamic, ventilatory and metabolic disorders related to brain death. Organ donation implies that one would know the patient's will which would have been clearly expressed during his lifetime. Organ harvesting is organized according to guidelines for local practice and regional and national allocation. In consideration of transplantation requirements there is a persisting organ shortage for several years. Efforts must be directed toward an improvement in brain dead patients identification and management.

Brain Death↗

Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.

BACKGROUND/AIMS: A double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) was conducted in 180 patients with primary biliary cirrhosis (PBC) to define the efficacy and safety of UDCA. Efficacy was assessed by time to treatment failure defined as death; liver transplantation; histological progression; development of varices, ascites, or encephalopathy; doubling of total serum bilirubin levels; progression of fatigue or pruritus; drug toxicity; or voluntary withdrawal. METHODS: Patients with well-defined PBC underwent complete history, physical examination, liver chemistries, ultrasonography, upper endoscopy, and liver biopsy at entry as well as at 2 years. Liver chemistries were determined every 3 months. RESULTS: In patients receiving UDCA, treatment failure was delayed compared with the placebo-treated group (P = 0.0003, log rank test). Seven patients receiving UDCA died or required transplantation compared with 12 in the placebo group (P = 0.18). No patients discontinued UDCA because of side effects of toxicity. CONCLUSIONS: UDCA was extraordinarily safe and well tolerated, and its use was associated with delayed progression of the disease as defined in this study. However, the lack of effects on symptoms, histology, and the need for liver transplantation or survival indicate that further evaluation is necessary to determine the ultimate role of UDCA in the treatment of PBC.

Adult↗

Macrophage-derived tumor necrosis factor alpha, an early developmental signal for motoneuron death.

Mechanisms inducing neuronal death at defined times during embryogenesis remain enigmatic. We show in explants that a developmental switch occurs between embryonic day 12 (E12) and E13 in rats that is 72-48 hr before programmed cell death. Half the motoneurons isolated from peripheral tissues at E12 escape programmed cell death, whereas 90% of motoneurons isolated at E13 enter a death program. The surrounding somite commits E12 motoneurons to death. This effect requires macrophage cells, is mimicked by tumor necrosis factor alpha (TNFalpha), and is inhibited by anti-TNFalpha antibodies. In vivo, TNFalpha is detected within somite macrophages, and TNF receptor 1 (TNFR1) is detected within motoneurons precisely between E12 and E13. Although motoneuron cell death occurs normally in TNFalpha-/- mice, this process is significantly reduced in explants from TNFalpha-/- and TNFR1-/- mice. Thus, embryonic motoneurons acquire the competence to die, before the onset of programmed cell death, from extrinsic signals such as macrophage-derived TNFalpha

Animals↗

Prolonged signal-averaged P wave duration as a prognostic marker for morbidity and mortality in patients with congestive heart failure.

OBJECTIVE: To evaluate the prognostic roles of prolonged signal-averaged P wave duration (SAPWD), raised levels of natriuretic peptides, and clinical characteristics in patients with stable congestive heart failure (CHF). DESIGN: The SAPWD was assessed from a signal-averaged electrocardiogram (SAECG), and the plasma levels of N-terminal pro-atrial natriuretic peptide (Nt-proANP) and N-terminal pro-brain natriuretic peptide (Nt-proBNP) were measured in 43 consecutive patients with stable CHF without prior supraventricular arrhythmia. Echocardiographic and clinical data were also recorded. Time to death, hospitalization due to deteriorated CHF, or ECG-documented atrial fibrillation (AF) was recorded over a 438-day median follow-up. RESULTS: During follow-up, 17 patients met an endpoint defined as death, AF, or hospitalization due to deteriorated CHF. Proportional hazard regression including the variables high age, prolonged SAPWD, raised levels of Nt-proANP and Nt-proBNP, and low ejection fraction (EF) showed that only prolonged SAPWD > or =149 ms was associated with an increased risk of meeting an early endpoint; the hazard ratio 3.94 with 95% confidence interval 1.50-10.42; p = 0.006. CONCLUSION: Prolonged SAPWD appears to predict early death, AF development, or hospitalization due to deterioration of CHF in patients with stable CHF.

Adrenergic beta-Antagonists↗

Mechanisms of apoptosis: integration of genetic, biochemical, and cellular indicators.

Apoptosis, or programmed cell death, is defined by morphologic change resulting in nonpathologic cell loss and is relevant to a wide spectrum of biology. The process is best characterized in the nematode Caenorhabditis elegans where ced genes mediate the death of specific cells during development. Some corresponding genes have been identified in mammalian cells. Expression of the mammalian bcl-2 gene (homologous to ced-9) suppresses apoptosis in many systems. The ced-3 gene is homologous to a mammalian protease. Increased levels of the tumor suppressor p53 due to DNA damage may result in either blockage of the cell cycle at G1 or apoptosis. Mutation of p53 is associated with decreased cell death from radiation and cytotoxic drugs. Initiation of the apoptotic pathway may occur as a consequence of conflicting growth signals. Hierarchical relationships variously between bcl-2, p53, myc, and other genes indicate a complex pattern of regulation. Stimuli resulting in apoptosis may cause production of free radicals and increased intracellular calcium concentration. The relationship of these changes to the hallmark of apoptosis, internucleosomal fragmentation of DNA, is unclear, and "laddering" of DNA is not always evident. Apoptotic DNA degradation probably occurs sequentially, initially involving breakage into 50 kilobases or larger fragments. The nuclease(s) responsible have not been identified, but deoxyribonuclease I is implicated. The association between nuclease activation and chromatin condensation is complex, and programmed cell death may be subject to cytoplasmic regulation. Available data suggest that clearer understanding of apoptosis will result in better cancer therapy.

Animals↗

Control of mitochondrial integrity by Bcl-2 family members and caspase-independent cell death.

Programmed cell death (PCD) is essential for normal development and maintenance of tissue homeostasis in multicellular organisms. While it is now evident that PCD can take many different forms, apoptosis is probably the most well-defined cell death programme. The characteristic morphological and biochemical features associated with this highly regulated form of cell death have until recently been exclusively attributed to the caspase family of cysteine proteases. As a result, many investigators affiliate apoptosis with its pivotal execution system, i.e. caspase activation. However, it is becoming increasingly clear that PCD or apoptosis can also proceed in a caspase-independent manner and maintain key characteristics of apoptosis. Mitochondrial integrity is central to both caspase-dependent and-independent cell death. The release of pro-apoptotic factors from the mitochondrial intermembrane space is a key event in a cell's commitment to die and is under the tight regulation of the Bcl-2 family. However, the underlying mechanisms governing the efflux of these pro-death molecules are largely unknown. This review will focus on the regulation of mitochondrial integrity by Bcl-2 family members with particular attention to the controlled release of factors involved in caspase-independent cell death.

Animals↗

PERINATAL MORTALITY AND SURVIVAL. A COMPARISON OF EXPERIENCE IN CALIFORNIA IN 1949 AND 1959. I--STATISTICAL TRENDS.

The California State Department of Public Health has made an analysis of descriptive items from 369,304 birth and death certificates for 1959 and 252,400 certificates for 1949 in order to identify demographic characteristics associated with perinatal mortality and survival. If the time span of risk of perinatal death is defined as 20 weeks gestation through 27 days after birth, 97 of 100 infants born in California during 1949 and 1959 were born alive and survived the first month of life. Fetal and neonatal death rates decreased over the decade to new lows. Since most of the improvement was among infants that weighed 2,501 grams or more at birth, a greater proportion of all perinatal deaths occurred among premature infants in 1959 than 1949. Survival chances for premature infants remained 75 out of 100 total births. Trends shown by a comparison of the years 1949 and 1959 include a 47 per cent increase in number of births, proportionately more births to mothers under 20 and to women with four or more previous live births, more Negro births and fewer births outside a hospital. An important gain in perinatal survival was found among babies of multiparous mothers. All types of hospitals had lower fetal and neonatal mortality, but county hospitals showed the greatest improvement. Less populated areas lowered their perinatal death rates more than major metropolitan areas when average rates for 1945-1949 and 1955-1959 were compared.

Black People↗

Inhaled nitric oxide in premature infants--a meta-analysis.

The role of inhaled nitric oxide (iNO) in the treatment of severe hypoxemic respiratory failure of term neonates has been firmly established in several randomized trials. In contrast, the use of iNO in premature newborns has remained controversial. As of 1999, there are data of three randomized controlled trials involving a total of 210 infants below 33 weeks of gestation. None of the trials was able to demonstrate a benefit of iNO with respect to mortality or chronic lung disease. We performed a meta-analysis of the three published trials. Of 111 infants receiving iNO, 44 deaths were observed, compared to 40 of 99 control infants (p = 0.91). The odds ratio in favor of iNO was 0.97 (95% confidence interval 0.54-1.75). There was also no significant difference for treatment failure, defined as death or chronic lung disease (iNO: 32 of 111 infants versus control: 34 of 99, p = 0.39, odds ratio 0.77, 95% confidence interval 0.41-1.45). The rates of intracranial hemorrhage were similar in both groups (35 of 111 infants receiving iNO vs 25 of 99 controls, p = 0.33, odds ratio 1.37, 95% confidence interval 0.69-2.74). We conclude that the use of inhaled nitric oxide may improve oxygenation but not survival in preterm infants with severe hypoxemic respiratory failure.

Administration, Inhalation↗

Time trends and demographics of deaths from congenital hydrocephalus in children in the United States: National Center for Health Statistics data, 1979 to 1998.

OBJECT: Congenital hydrocephalus has an estimated population incidence of 0.2 to 0.8/1000 live births. With improvements in techniques for cerebrospinal fluid shunting, treatment of hydrocephalus has become safe and routine, yet data describing mortality from congenital hydrocephalus or demonstrating improvements in mortality with the advent of modern treatment are scarce. The authors' analysis sought to rectify this situation. METHODS: The authors performed an electronic search of National Center for Health Statistics death certificate databases to identify deaths from 1979 to 1998 attributed to congenital hydrocephalus, spina bifida with hydrocephalus, and acquired hydrocephalus (both obstructive and communicating) in all children in the US aged 1 day to 20 years. Mortality rates were defined as deaths per 100,000 person-years and were analyzed for differences on the basis of age, race, sex, and year. The authors identified 10,406 deaths attributed to childhood hydrocephalus within the 20-year study period. The overall mortality rate was 0.71 per 100,00 person-years. Mortality rates were highest in infants, with 3979 deaths; they were similar between girls and boys. Compared with white infants, black infants had higher relative risk (RR) for death caused by congenital hydrocephalus (RR 1.46, p value < 0.0001) and acquired hydrocephalus (RR 2.58, p value < 0.0001) but not for that caused by hydrocephalus with spina bifida (RR 0.65, p value < 0.0001). From 1979 to 1998, the mortality rate due to congenital hydrocephalus declined 66.3%, from spina bifida with hydrocephalus it declined by 30.4%, and from acquired hydrocephalus it declined by 67.5%. CONCLUSIONS: Mortality rates from childhood hydrocephalus have declined in US children over the previous 20 years. Black race is associated with higher mortality rates in infants for both congenital and acquired hydrocephalus, whereas sex has no effect.

Adolescent↗

Selection for necropsy: evaluation of 321 autopsied cases from 3041 consecutive deaths among residents of a defined geographical area.

By undertaking to act as 'medico necroscopo' (the medical doctors in charge of authorizing every burial) in the Unità Socio-Sanitaria Locale (USSL) 70, a region containing 92,500 inhabitants, we were able to collect over a four-year period (1985-88) information on 3371 deaths among residents of the area. Of these, 68.1% died at home, 12.6% in hospital with no autopsy, 9.5% in hospital with an autopsy and 9.8% outside of the USSL region. For the analysis, age, sex and leading cause of death were considered as explanatory variables and place of death and proportion of autopsied cases as the response variables. The factors found to be associated with deaths occurring in hospital were non-neoplastic (particularly cardiovascular and digestive) pathological conditions in patients under the age of 60. People with malignant neoplasms usually died at home, especially when they had a gastric or breast cancer. Factors associated with autopsy were: death at a young age, short length of hospitalization and death from a cardiovascular disease. Sex did not appear to play a direct role in selection for necropsy. Our results indicate that, in our and similar regions, the cases selected for autopsy form a subset that is so specific that any extrapolation to the total deceased population is misleading.

Adult↗

Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis).

The term cell necrobiology is introduced to comprise the life processes associated with morphological, biochemical, and molecular changes which predispose, precede, and accompany cell death, as well as the consequences and tissue response to cell death. Two alternative modes of cell death can be distinguished, apoptosis and accidental cell death, generally defined as necrosis. The wide interest in necrobiology in many disciplines stems from the realization that apoptosis, whether it occurs physiologically or as a manifestation of a pathological state, is an active mode of cell death and a subject of complex regulatory processes. A possibility exists, therefore, to interact with the regulatory machinery and thereby modulate the cell's propensity to die in response to intrinsic or exogenous signals. Flow cytometry appears to be the methodology of choice to study various aspects of necrobiology. It offers all the advantages of rapid, multiparameter analysis of large populations of individual cells to investigate the biological processes associated with cell death. Numerous methods have been developed to identify apoptotic and necrotic cells and are widely used in various disciplines, in particular in oncology and immunology. The methods based on changes in cell morphology, plasma membrane structure and transport function, function of cell organelles, DNA stability to denaturation, and endonucleolytic DNA degradation are reviewed and their applicability in the research laboratory and in the clinical setting is discussed. Improper use of flow cytometry in analysis of cell death and in data interpretation also is discussed. The most severe errors are due to i) misclassification of nuclear fragments and individual apoptotic bodies as single apoptotic cells, ii) assumption that the apoptotic index represents the rate of cell death, and iii) failure to confirm by microscopy that the cells classified by flow cytometry as apoptotic or necrotic do indeed show morphology consistent with this classification. It is expected that flow cytometry will be the dominant methodology for necrobiology.

Apoptosis↗

Influence of projected complication rates on estimated appropriate use rates for carotid endarterectomy. Appropriateness Project Investigators. Academic Medical Center Consortium.

OBJECTIVE: To examine specifically the influence of estimated perioperative mortality and stroke rate on the assessment of appropriateness of carotid endarterectomy. DATA SOURCES/STUDY SETTING: An expert panel convened to rate the appropriateness of a variety of potential indications for carotid endarterectomy based on various rates of perioperative complications. We then applied these ratings to the charts of 1,160 randomly selected patients who had carotid endarterectomy in one of the 12 participating academic medical centers. STUDY DESIGN: An expert panel evaluated indications for carotid endarterectomy using the modified Delphi approach. Charts of patients who received surgery were abstracted, and clinical indications for the procedure as well as perioperative complications were recorded. To examine the impact of surgical risk assessment on the rates of appropriateness, three different definitions of risk strata for combined perioperative death or stroke were used: Definition A, low risk < 3 percent; Definition B, low risk < 5 percent; and Definition C, low risk < 7 percent. PRINCIPAL FINDINGS: Overall hospital-specific mortality ranged from 0 percent to 4.0 percent and major complications, defined as death, stroke, intracranial hemorrhage, or myocardial infarction, varied from 2.0 percent to 11.1 percent. Most patients (72 percent) had surgery for transient ischemic attack or stroke; 24 percent of patients were asymptomatic. Most patients (82 percent) had surgery on the side of a high-grade stenosis (70-99 percent). When the thresholds for operative risk were placed at the values defined by the expert panel (Definition A), only 33.5 percent of 1,160 procedures were classified as "appropriate." When the definition of low risk was shifted upward, the proportion of cases categorized as appropriate increased to 58 percent and 81.5 percent for Definitions B and C, respectively. CONCLUSIONS: Despite the high proportion of procedures performed for symptomatic patients with a high degree of ipsilateral extracranial carotid artery stenosis and generally low rates of surgical complications at the participating institutions, the overall rate of "appropriateness" using a perioperative complication rate of < 3 percent was low. However, the rate of "appropriateness" was extremely sensitive to judgments about a single clinical feature, surgical risk. These data show that before applying such "appropriateness" ratings, it is crucial to perform sensitivity analyses in order to assess the stability of the results. Results that are robust to moderate in variation in surgical risk provide a much sounder basis for policy making than those that are not.

Academic Medical Centers↗

Long-term prognosis and causes of death in systemic lupus erythematosus.

PURPOSE: We studied survival rate, prognostic factors, and causes of death in patients with systemic lupus erythematosus (SLE), particularly focusing on the influence of disease severity. PATIENTS AND METHODS: A cohort of 207 consecutive Italian patients with SLE were prospectively studied. All prominent clinical and serologic parameters were evaluated and considered as prognostic risk factors. Causes of death were defined on the basis of clinical data and, when available, postmortem examination. Survival was calculated from the time of diagnosis by Kaplan-Meier method. RESULTS: A total of 17 of 207 patients died; causes of death were active disease manifestations in 35.3% of cases and complication of the disease or its treatment in 64.7% of cases. The survival rates at 5, 10, and 15 years after the diagnosis were 96%, 93% and 76%, respectively. By multivariate analysis of the risk factors, a predictive model consisting of male gender, positive lupus anticoagulant, and "severe" SLE was identified. The survival curve of the patients with severe disease was similar to that of patients with mild disease until 10 to 15 years from the diagnosis. Thereafter the two curves tended to diverge, showing a clear survival decline in patients with severe disease. CONCLUSIONS: Our study confirms the increase of short- and medium-term survival in patients with SLE, but long-term prognosis remains poor in patients with severe SLE manifestations.

Adolescent↗

D-galactosamine based canine acute liver failure model.

BACKGROUND: Appropriate preclinical evaluation of a bioartificial liver assist device (BAL) demands a large animal model, as presented here, that demonstrates many of the clinical features of acute liver failure and that is suitable for clinical qualitative and quantitative evaluation of the BAL. A lethal canine liver failure model of acute hepatic failure that removes many of the artifacts evidenced in prior canine models is presented. METHODS: Six male hounds, 24-30 kg, under isoflurane anesthesia, were administered 1.5 g/kg D-galactosamine intravenously. Canine supportive care followed a well-defined management protocol that was guided by electrolyte and invasive monitoring consisting of arterial pressure, central venous pressure, extradural intracranial pressure (ICP), pulmonary artery pressure, and end-tidal CO2. The animals were treated until death-equivalent, defined as inability to sustain systolic blood pressure >80 mmHg for 20 minutes despite maximal fluids and 20 microg/kg/min dopamine infusion. RESULTS: The mean survival time was 43.7+/-4.6 hours (mean+/-SE). All animals showed evidence of progressive liver failure characterized by increasing liver enzymes (aspartate transaminase from 26 to 5977 IU/L; alanine transaminase from 32 to 9740 IU/L), bilirubin (0.25 to 1.30 mg/dl), ammonia (19.8 to 85.3 micromol/L), and coagulopathy (prothrombin time from 8.7 to 46 s). Increased lability and elevations in intracranial pressures were observed. All animals were refractory to maintenance of cerebral perfusion pressure even with only moderately elevated intracranial pressure. Severe neurologic obtundation, seen in 2 of 6 animals, was associated with elevations of ICP above 50 mmHg. Post-mortem liver histology showed evidence of massive hepatic necrosis. Postmortem blood and ascites microbial growth was consistent with possible translocation of intestinal microbes. CONCLUSIONS: The improved lethal canine liver failure model presented here reproduces many of the clinical features of acute liver failure. The model may prove useful for qualitative and quantitative evaluation of BALs.

Animals↗

Relationship of protein catabolic rate or Kt/V with morbidity.

The authors investigated the influence of Kt/V and protein catabolic rate (PCR) on dialysis failure for 689 hemodialysis (HD) outpatients treated at the seven dialysis facilities in Aichi Prefecture, Japan. Dialysis failure was defined as death or hospitalization for reasons other than blood access, accident, wound, or mental disease. Patients were followed for 2 years. The rate of patients who developed dialysis failure during the observation period relative to the total patient population was defined as the dialysis failure rate. A total of 123 patients developed dialysis failure, which was fatal in 33 cases. In patients with Kt/V values of 1.6 or higher, the mean dialysis failure rate was significantly lower at 12.0% than that (19.2%) of patients with Kt/V values between 0.8 and 1.6 (p < 0.04). In patients that had PCR values under 0.8 g/kg/day, the dialysis failure rate was significantly higher at 32.5% than that (15.8%) of patients with PCR values between 0.8 and 1.4 g/kg/day (p < 0.0001).

Adult↗

Predictors of mortality from fires in young children.

BACKGROUND: In the United States in 1994, fires claimed 3.75 lives per 100 000 child years and accounted for 17.3% of all injury deaths in children <5 years of age. OBJECTIVES: To conduct a historical cohort study that uses maternal demographic characteristics to identify young children at high risk of fire-related deaths, thus defining appropriate targets for prevention programs. METHODS: The cohort consisted of children born to mothers who resided in the state of Tennessee between 1980 and 1995. Information was obtained by linking birth certificates, 1990 census data, and death certificates. Children were eligible for the study if they were <5 years of age at any time within the study period and if key study variables were present (99.2% of births). Birth certificates provided information on maternal characteristics including age, race, education, previous live births, use of prenatal care, and residence (in standard metropolitan statistical area). Child characteristics included gender, gestational age, and birth type (singleton/multiple gestation). Neighborhood income was estimated by linking the mother's address at the time of birth to the 1990 census (block group mean per capita income). The study outcome was a fire resulting in at least one fatality (fatal fire event) during the study period, identified from death certificates (coded E880 through E889 in the International Classification of Diseases, 9th rev). We calculated the fatal fire event rate corresponding to each stratum of maternal/child characteristics. We assessed the independent association between each characteristic and the risk of a fatal fire event from a Poisson regression multivariate analysis. RESULTS: During the study period, 1 428 694 children contributed 5 415 213 child years to the cohort: there were 270 deaths from fire (4.99 deaths per 100 000 child years) and 231 fatal fire events. In the multivariate analysis, factors associated with greater than a threefold increase in fatal fire events included maternal education, age, and number of other children. Compared with children whose mothers had a college education, children whose mothers had less than a high school education had 19.4 times (95% confidence interval [CI], 2.6-142.4) an increased risk of a fatal fire event. Children whose mothers had more than two other children had 6.1 times (95% CI, 3.8-9.8) an increased risk of a fatal fire event compared with children whose mothers had no other children. Children of mothers <20 years of age had 3.9 times (95% CI, 2.2-7.1) increased risk of a fatal fire event compared with children whose mothers were >/=30 years old. Although both maternal neighborhood income and race were associated strongly with increased rates of fatal fire events in the univariate analysis, this association did not persist in the multivariate analysis. Other factors that were associated with increased risk of fatal fire events in the multivariate analysis were male gender and having a mother who was unmarried or who had delayed prenatal care. The three factors associated most strongly with fire mortality were combined to create a risk score based on maternal education (>/=16 years, 0 points; 13 to 15 years, 1 point; 12 years, 2 points; <12 years, 3 points); age (>/=30 years, 0 points; 25 to 29 years, 1 point; 20 to 24 years, 2 points; <20 years, 3 points); and number of other children (none, 0 points; one, 1 point; two, 2 points; three or more, 3 points). The lowest-risk group (score <3) included 19% of the population and had 0.19 fatal fire events per 100 000 child years. In contrast, highest-risk children (score >7) comprised 1.5% of the population and had 28.6 fatal fire events per 100 000 child years, 150 times higher than low-risk children. Children with risk scores >5 contributed 26% of child years but experienced 68% of all fatal fire events. If the fatal fire event rate for all children had been equal to that of the low-risk group (risk score <3), then 95% of deaths from

Burns↗