Ablation of Zfhx4 results in early postnatal lethality by disrupting the respiratory center in mice.

Breathing is an integrated motor behavior that is driven and controlled by a network of brainstem neurons. Zfhx4 is a zinc finger transcription factor and our results showed that it was specifically expressed in several regions of the mouse brainstem. Mice lacking Zfhx4 died shortly after birth from an apparent inability to initiate respiration. We also found that the electrical rhythm of brainstem‒spinal cord preparations was significantly depressed in Zfhx4-null mice compared to wild-type mice. Immunofluorescence staining revealed that Zfhx4 was coexpressed with Phox2b and Math1 in the brainstem and that Zfhx4 ablation greatly decreased the expression of these proteins, especially in the retrotrapezoid nucleus. Combined ChIP‒seq and mRNA expression microarray analysis identified Phox2b as the direct downstream target gene of Zfhx4, and this finding was validated by ChIP‒qPCR. Previous studies have reported that both Phox2b and Math1 play key roles in the development of the respiratory center, and Phox2b and Math1 knockout mice are neonatal lethal due to severe central apnea. On top of this, our study revealed that Zfhx4 is a critical regulator of Phox2b expression and essential for perinatal breathing.

The use of apnea test and brain death determination in patients on extracorporeal membrane oxygenation: A systematic review.

OBJECTIVE: To review practices of brain death (BD) determination in patients on extracorporeal membrane oxygenation (ECMO). METHODS: A systematic search was applied to PubMed and 6 electronic databases from inception to May 22, 2019. Studies reporting methods of BD assessment in adult patients (>18 years old) while on ECMO were included, after which data regarding BD assessment were extracted. RESULTS: Twenty-two studies (n = 177 patients) met the inclusion criteria. Eighty-eight patients (50%) in 19 studies underwent the apnea test (AT); most commonly through decreasing the ECMO sweep flow in 14 studies (n = 42, 48%), followed by providing CO2 through the ventilator in 2 studies (n = 6, 7%), and providing CO2 through the ECMO oxygenator in 1 study (n = 1, 1%). The details of the AT were not reported in 2 studies (n = 39, 44%). In 19 patients (22%), the AT was nonconfirmatory due to hemodynamic instability, hypoxia, insufficient CO2 rise, or unreliability of the AT. A total of 157 ancillary tests were performed, including electroencephalogram (62%), computed tomography angiography (22%), transcranial Doppler ultrasound (6%), cerebral blood flow nuclear study (5%), cerebral angiography (4%), and other (1%). Forty-seven patients (53% of patients with AT) with confirmatory AT still underwent additional ancillary for BD confirmation. Only 21 patients (12% of all patients) were declared brain-dead using confirmatory ATs alone without ancillary testing. CONCLUSIONS: Performing AT for patients with ECMO was associated with high failure rate and hemodynamic complications. Our study highlights the variability in practice in regard to the AT and supports the use of ancillary tests to determine BD in patients on ECMO.

Management of apnea in infants with trisomy 18.

This case series aimed to characterize the clinical features, management, and outcomes of apnea in infants with trisomy 18. Participants in this study were infants with trisomy 18 who were born alive and admitted to the neonatal intensive care unit in Kyushu University Hospital from 2000 to 2018. Retrospective analysis was performed on clinical data recorded in our department. Twenty-seven infants with trisomy 18 were admitted to our hospital during the study period, of which 25 (nine males, 16 females) were enrolled as eligible participants in this study. Among them, 14 started presenting with apnea from median 3.5 days of age (range 0-47d). In these infants with apnea, eight received respiratory support of positive pressure ventilation (PPV). The 1-year survival rate of infants in the PPV group was higher than that of non-PPV-supported infants (5 out of 8 vs 0 out of 6 infants). Five PPV-supported infants received a diagnosis of epilepsy, which was controlled by antiepileptic drugs. Postnatal respiratory intervention provides better prognosis in infants with trisomy 18. Improved survival leads to accurate diagnosis and treatment of apneic events in association with epilepsy. WHAT THIS PAPER ADDS: Respiratory support is effective against apnea in infants with trisomy 18. Intervention with ventilation provides a higher chance of prolonged survival. Improved survival leads to the accurate diagnosis and treatment of epilepsy-associated apnea.

High versus standard dose caffeine for apnoea: a systematic review.

BACKGROUND: Placebo-controlled trials have shown that caffeine is highly effective in treating apnoea of prematurity and reduces the risk of bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI). OBJECTIVE: To identify, appraise and summarise studies investigating the modulating effect of different caffeine dosages. METHODS: A systematic review identified all randomised controlled trials (RCTs) comparing a high versus a standard caffeine treatment regimen in infants with a gestational age <32 weeks, by searching the main electronic databases and abstracts of the Pediatric Academic Societies. Studies comparing caffeine to placebo or theophylline only were excluded. Primary outcomes were BPD and mortality at 36 weeks postmenstrual age. Secondary key-outcome was neurodevelopmental outcome at 12 and 24 months corrected age. Meta-analysis was performed using RevMan 5.3. RESULTS: Six RCTs including 620 infants were identified. Meta-analysis showed a significant decrease in BPD, the combined outcome BPD or mortality, and failure to extubate in infants allocated to a higher caffeine dose. No differences were found in mortality alone and NDI. The quality of the outcome measures were deemed low to very low according to the Grading of Recommendations Assessment, Development and Evaluation guidelines. CONCLUSIONS: Although this review suggests that administering a higher dose of caffeine might enhance its beneficial effect on death or BPD, firm recommendations on the optimal caffeine dose cannot be given due to the low level of evidence. A large RCT is urgently needed to confirm or refute these findings and determine the optimal dose of caffeine.

Pediatric abusive head trauma in Taiwan: clinical characteristics and risk factors associated with mortality.

PURPOSE: To report the clinical characteristics of abusive head trauma (AHT) in Taiwan and identify the risk factors associated with mortality of these patients. METHODS: Children with clinically diagnosed AHT from January 1, 2000, to October 31, 2015 were reviewed. The demographic data, clinical features, and associated retinal and radiologic findings were analyzed. The multivariable logistic regression model analysis was performed to identify the risk factors associated with in-hospital mortality. RESULTS: A total of 75 children were included. The mean age was 7.31 ± 6.57 months (range, 1-36 months). Retinal hemorrhages were detected in 69 children with AHT (92%). The majority of retinal hemorrhages were characterized by hemorrhagic numbers higher than ten (74.7%), multi-layered (54.7%), and extension beyond the posterior pole to the peripheral retina (73.3%). Twenty children (26.7%) had macular retinoschisis. As a direct result of AHT, ten children died in the hospital (13.3%). Logistic regression showed that respiratory distress or apnea (adjusted odds ratio [OR] = 22.46; 95% confidence interval [CI], 2.24-225.33; P = .0082), vomiting (adjusted OR = 11.94; 95% CI, 1.31-108.403; P = .0276), retinal finding of macular retinoschisis (adjusted OR = 8.9; 95% CI, 1.01-78.65; P = .0493), and the presence of subarachnoid hemorrhage (SAH) (adjusted OR = 15.17; 95% CI, 1.40-64.84; P = .0255) were independently associated with mortality. CONCLUSIONS: Respiratory distress or apnea, vomiting, SAH, and macular retinoschisis are independently associated with mortality in abusive head trauma. A complete ophthalmologic examination with the immediate visualization of intraocular injury should be performed to clarify the likelihood of child abuse and predict a potential poor neurologic outcome.

Car Seat Tolerance Screening in the Neonatal Intensive Care Unit: Failure Rates, Risk Factors, and Adverse Outcomes.

OBJECTIVE: To characterize the epidemiology of Car Seat Tolerance Screening (CSTS) failure and the association between test failure and all-cause 30-day postdischarge mortality or hospital readmission in a large, multicenter cohort of preterm infants receiving neonatal intensive care. STUDY DESIGN: This retrospective cohort study used the prospectively collected Optum Neonatal Database. Study infants were born at <37 weeks of gestation between 2010 and 2016. We identified independent predictors of CSTS failure and calculated the risk-adjusted odds of all-cause 30-day mortality or hospital readmission associated with test failure. RESULTS: Of 7899 infants cared for in 788 hospitals, 334 (4.2%) failed initial CSTS. Greater postmenstrual age at testing and African American race were independently associated with decreased failure risk. Any treatment with an antacid medication, concurrent use of caffeine or supplemental oxygen, and a history of failing a trial off respiratory support were associated with increased failure risk. The mean adjusted post-CSTS duration of hospitalization was 3.1 days longer (95% CI, 2.7-3.6) among the infants who failed the initial screening. Rates of 30-day all-cause mortality or readmission were higher among infants who failed the CSTS (2.4% vs 1.0%; P = .03); however, the difference was not significant after confounder adjustment (OR, 0.38; 95% CI, 0.11-1.31). CONCLUSION: CSTS failure was associated with longer post-test hospitalization but no difference in the risk-adjusted odds for 30-day mortality or hospital readmission. Whether CSTS failure unnecessarily prolongs hospitalization or results in appropriate care that prevents adverse postdischarge outcomes is unknown. Further research is needed to address this knowledge gap.

Apparent Life-Threatening Events (ALTE): Italian guidelines.

Five years after the first edition, we have revised and updated the guidelines, re-examining the queries and relative recommendations, expanding the issues addressed with the introduction of a new entity, recently proposed by the American Academy of Pediatrics: BRUE, an acronym for Brief Resolved Unexplained Events. In this manuscript we will use the term BRUE only to refer to mild, idiopathic cases rather than simply replace the acronym ALTE per se.In our guidelines the acronym ALTE is used for severe cases that are unexplainable after the first and second level examinations.Although the term ALTE can be used to describe the common symptoms at the onset, whenever the aetiology is ascertained, the final diagnosis may be better specified as seizures, gastroesophageal reflux, infection, arrhythmia, etc. Lastly, we have addressed the emerging problem of the so-called Sudden Unexpected Postnatal Collapse (SUPC), that might be considered as a severe ALTE occurring in the first week of life.

Impact brain apnoea - A forgotten cause of cardiovascular collapse in trauma.

OBJECTIVE: Early death following cranial trauma is often considered unsurvivable traumatic brain injury (TBI). However, Impact Brain Apnoea (IBA), the phenomenon of apnoea following TBI, may be a significant and preventable contributor to death attributed to primary injury. This paper reviews the history of IBA, cites case examples and reports a survey of emergency responder experience. METHODS: Literature and narrative review and focused survey of pre-hospital physicians. RESULTS: IBA was first reported in the medical literature in 1705 but has been demonstrated in multiple animal studies and is frequently anecdotally witnessed in the pre-hospital arena following human TBI. It is characterised by the cessation of spontaneous breathing following a TBI and is commonly accompanied by a catecholamine surge witnessed as hypertension followed by cardiovascular collapse. This contradicts the belief that isolated traumatic brain injury cannot be the cause of shock, raising the possibility that brain injury may be misinterpreted and therefore mismanaged in patients with isolated brain injury. Current trauma management techniques (e.g. rolling patients supine, compression only cardiopulmonary resuscitation) could theoretically compound hypoxia and worsen the effects of IBA. Anecdotal examples from clinicians attending head injured patients within a few minutes of injury are described. Proposals for the study and intervention for IBA using advances in remote technology are discussed. CONCLUSION: IBA is a potential cause of early death in some head injured patients. The precise mechanisms in humans are poorly understood but it is likely that early, simple interventions to prevent apnoea could improve clinical outcomes.

Association of early caffeine administration and neonatal outcomes in very preterm neonates.

IMPORTANCE: Advantages of caffeine for apnea of prematurity have prompted clinicians to use it prophylactically even before apnea. OBJECTIVE: To determine the effect of early initiation of caffeine therapy on neonatal outcomes in very preterm infants born in Canada. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted. Patients included preterm neonates born at less than 31 weeks' gestation admitted to 29 participating Canadian Neonatal Network neonatal intensive care units between January 1, 2010, and December 31, 2012. EXPOSURES: Neonates who received caffeine were divided into 2 groups based on the following timing of caffeine initiation: within the first 2 days after birth (early) and on or after the third day following birth (late). MAIN OUTCOME AND MEASURE: A composite of death or bronchopulmonary dysplasia. RESULTS: Of 5517 eligible neonates, 5101 (92.5%) received caffeine (early: 3806 [74.6%]; late: 1295 [25.4%]). There was no difference in weight or gestational age at birth between the groups. Neonates in the early group had decreased odds of a composite outcome of death or bronchopulmonary dysplasia (adjusted odds ratio [AOR], 0.81; 95% CI, 0.67-0.98) and patent ductus arteriosus (AOR, 0.74; 95% CI, 0.62-0.89). There was no difference between the groups in mortality (AOR, 0.98; 95% CI, 0.70-1.37), necrotizing enterocolitis (AOR, 0.88; 95% CI, 0.65-1.20), severe neurological injury (AOR, 0.80; 95% CI, 0.63-1.01), or severe retinopathy of prematurity (AOR, 0.78; 95% CI, 0.56-1.10). CONCLUSIONS AND RELEVANCE: In very preterm neonates, early (prophylactic) caffeine use was associated with a reduction in the rates of death or bronchopulmonary dysplasia and patent ductus arteriosus. No adverse impact on any other outcomes was observed.

Can home monitoring reduce mortality in infants at increased risk of sudden infant death syndrome? A systematic review.

AIM: To conduct a systematic review to evaluate the effectiveness of home monitoring devices in the prevention of sudden infant death syndrome (SIDS). METHODS: Systematic literature review to June 30, 2010. RESULTS: Eleven unique studies were identified. Only one of these studies involved a comparison of home monitoring with a control intervention and so could be deemed level I evidence. The remaining studies constituted level III evidence. CONCLUSIONS: There is no high-level evidence that home monitoring may be of use in preventing SIDS; further research is needed.

Factors influencing the survival of newborn babies weighing <1.5 kg in Sagamu, Nigeria.

BACKGROUND: Identification of the causes of death among low birth weight babies may facilitate interventions required to improve their survival. OBJECTIVE: To determine the epidemiological factors associated with the survival of very low- and extremely low birth weight babies. METHODS: Consecutive low birth weight babies aged <168 h in a Nigerian tertiary hospital were studied between January and December 2008 using bivariate and multivariate methods. RESULTS: Out of 160 babies weighing <2.5 kg admitted, 78 (48.8%) weighed 0.65-1.49 kg. Survival rates were 6.7% for <1 kg, 57.4% for 1-1.49 kg and 84.9% for 1.5-2.49 kg. Overall, survival rate was 84.9% for babies weighing ≥ 1.5 kg (84.9%) compared to 46.4% among babies weighing <1.5 kg (P < 0.0001). Survival among babies who weighed <1.5 kg was associated with EGA ≥ 32 weeks and caesarean delivery while death was associated with the occurrence of asphyxia, apnea and respiratory distress. EGA ≥ 32 weeks (OR = 1.7), absence of respiratory distress (OR = 2.1) and absence of apnea (OR = 5.3) were independent determinants of survival. CONCLUSION: Survival rate of babies weighing <1.5 kg remains high in this population. The poor state of diagnostic and therapeutic facilities in the centre may be contributory.

Ventilator autocycling and delayed recognition of brain death.

BACKGROUND: Improvements in technology play an important role in caring for critically ill patients. One example is the advance in ventilator design to facilitate triggering of mechanical breaths. Minimal changes in circuit flow unrelated to respiratory effort can trigger a ventilator breath and may mislead caregivers in recognizing brain death. METHODS: We observed patients with devastating brain injuries in a mixed medical/surgical intensive care unit (ICU) with a high clinical suspicion for brain death including the absence of cranial nerve function with apparent spontaneous breathing during patient-triggered modes of mechanical ventilation. Further clinical observation for spontaneous respirations was assessed upon removal of ventilatory support. RESULTS: Nine patients with brain injury due to multiple etiologies were identified and demonstrated no spontaneous respirations when formally assessed for apnea. Length of time between brain death and its recognition could not be determined. CONCLUSION: When brain-dead patients who are suitable organ donors are mistakenly identified as having cerebral activity, the diagnosis of brain death is delayed. This delay impacts resource utilization, impedes recovery and function of organs for donation, and adversely affects donor families, potential recipients of organs, and patient donors who may have testing and treatment that cannot be beneficial. Patients with catastrophic brain injury and absent cranial nerve function should undergo immediate formal apnea testing.

Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development.

Central serotonin (5-HT) neurons modulate many vital brain functions, including respiratory control. Whether breathing depends critically on 5-HT neurons, or whether their influence is excitatory or inhibitory, remains controversial. Here we show that neonatal Lmx1b(flox/flox;ePet-Cre/+) mice (also called Lmx1b(f/f/p) mice), which selectively lack serotonin neurons, display frequent and severe apnea lasting as long as 55 s. This was associated with a marked decrease in ventilation to less than one-half of normal. These respiratory abnormalities were most severe during the postnatal period, markedly improving by the time the pups were 2-4 weeks old. Despite the severe breathing dysfunction, many of these mice survived, but there was a high perinatal mortality, and those that survived had a decrease in growth rate until the age at which the respiratory defects resolved. Consistent with these in vivo observations, respiratory output was markedly reduced in isolated brainstem-spinal cord preparations from neonatal Lmx1b(f/f/p) mice and completely blocked in perfused brain preparations from neonatal rats treated with selective antagonists of 5-HT(2A) and neurokinin 1 (NK-1) receptors. The ventilatory deficits in neonatal Lmx1b(f/f/p) mice were reversed in vitro and in vivo with agonists of 5-HT(2A) and/or NK-1 receptors. These results demonstrate that ventilatory output in the neonatal period is critically dependent on serotonin neurons, which provide excitatory drive to the respiratory network via 5-HT(2A) and NK-1 receptor activation. These findings provide insight into the mechanisms of sudden infant death syndrome, which has been associated with abnormalities of 5-HT neurons and of cardiorespiratory control.

Intermittent hypoxia degrades HIF-2alpha via calpains resulting in oxidative stress: implications for recurrent apnea-induced morbidities.

Intermittent hypoxia (IH) occurs in many pathological conditions including recurrent apneas. Hypoxia-inducible factors (HIFs) 1 and 2 mediate transcriptional responses to low O(2). A previous study showed that HIF-1 mediates some of the IH-evoked physiological responses. Because HIF-2alpha is an orthologue of HIF-1alpha, we examined the effects of IH on HIF-2alpha, the O(2)-regulated subunit expression, in pheochromocytoma 12 cell cultures. In contrast to the up-regulation of HIF-1alpha, HIF-2alpha was down-regulated by IH. Similar down-regulation of HIF-2alpha was also seen in carotid bodies and adrenal medullae from IH-exposed rats. Inhibitors of calpain proteases (ALLM, ALLN) prevented IH-evoked degradation of HIF-2alpha whereas inhibitors of prolyl hydroxylases or proteosome were ineffective. IH activated calpain proteases and down-regulated the endogenous calpain inhibitor calpastatin. IH-evoked HIF-2alpha degradation led to inhibition of SOD2 transcription, resulting in oxidative stress. Over-expression of transcriptionally active HIF-2alpha prevented IH-evoked oxidative stress and restored SOD2 activity. Systemic treatment of IH-exposed rats with ALLM rescued HIF-2alpha degradation and restored SOD2 activity, thereby preventing oxidative stress and hypertension. These observations demonstrate that, unlike continuous hypoxia, IH leads to down-regulation of HIF-2alpha via a calpain-dependent signaling pathway and results in oxidative stress as well as autonomic morbidities.

Definitive establishment of airway control is critical for optimal outcome in lower cervical spinal cord injury.

BACKGROUND: Respiratory complications can undermine outcome from low cervical spinal cord injury (SCI) (C5-T1). Most devastating of these is catastrophic loss of airway control. This study sought to determine the incidence and effect of catastrophic airway loss (CLA) and to define the need for elective intubation with subsequent tracheostomy to prevent potentially fatal outcomes. METHODS: A database of 54,838 consecutive patients treated in a level I trauma center between January 1988 and December 2004 was queried to identify patients with low cervical SCI, without traumatic brain injury. Patients were then stratified into complete or incomplete SCI groups, based on clinical assessment of their SCI. Mortality, age, injury severity, need for intubation, and tracheostomy were analyzed for each group using Fisher's exact test or Student's t test, as appropriate, accepting p < 0.05 as significant. RESULTS: One hundred eighty-six patients met inclusion criteria. The majority of low cervical spinal cord injuries were complete (58%). Overall, 127 (68%) patients required intubation, 88 (69%) required tracheostomy, and 27 died (15% of study population). Between each group there were significant differences in age and Injury Severity Score, however, within each group there were no significant differences in either. Eleven CSCI patients were not intubated; four of whom were at family request. Six of the remaining seven patients encountered fatal catastrophic airway loss. One patient was discharged to rehabilitation. Patients with incomplete SCI required intubation less frequently (38%); however, 50% of those required tracheostomy for intractable pulmonary failure. CONCLUSIONS: These data indicate that regardless of severity of low cervical SCI, immediate, thorough evaluation for respiratory failure is necessary. Early intubation is mandatory for CSCI patients. For incomplete patients evidence of respiratory failure should prompt immediate airway intervention, half of whom will require tracheostomy.

Apparent life-threatening events and sudden infant death syndrome: comparison of risk factors.

OBJECTIVE: To compare the risk factors of 153 cases of apparent life-threatening event (ALTE) enrolled in the multicenter Collaborative Home Infant Monitoring Evaluation (CHIME) from 1994 to 1998 with the published risk factors for sudden infant death syndrome (SIDS). STUDY DESIGN: Trained CHIME interviewers gathered histories of infants with ALTE who met the criteria. The following risk factors were analyzed: male predominance, gestational age, low birth weight, very low birth weight, incidence of small for gestational age (SGA), age at the event, multiparity, maternal age, and smoking. Population-based SIDS studies with >100 deaths, focusing on 1 or more pertinent risk factors and carried out during the decade in which CHIME data were collected, were chosen for comparison. RESULTS: One of the 153 infants with ALTE in this study died during follow-up (0.6%). CHIME ALTE differed significantly from SIDS in 4 respects: fewer infants with low birth weight and SGA at birth, fewer teenage pregnancies, and a younger infant age at ALTE. CONCLUSIONS: Although a number of risk factors for ALTE are similar to those for SIDS, the differences warrant a separate focus on ALTE beyond that on SIDS.

Long-term effects of caffeine therapy for apnea of prematurity.

BACKGROUND: Methylxanthine therapy is commonly used for apnea of prematurity but in the absence of adequate data on its efficacy and safety. It is uncertain whether methylxanthines have long-term effects on neurodevelopment and growth. METHODS: We randomly assigned 2006 infants with birth weights of 500 to 1250 g to receive either caffeine or placebo until therapy for apnea of prematurity was no longer needed. The primary outcome was a composite of death, cerebral palsy, cognitive delay (defined as a Mental Development Index score of <85 on the Bayley Scales of Infant Development), deafness, or blindness at a corrected age of 18 to 21 months. RESULTS: Of the 937 infants assigned to caffeine for whom adequate data on the primary outcome were available, 377 (40.2%) died or survived with a neurodevelopmental disability, as compared with 431 of the 932 infants (46.2%) assigned to placebo for whom adequate data on the primary outcome were available (odds ratio adjusted for center, 0.77; 95% confidence interval [CI], 0.64 to 0.93; P=0.008). Treatment with caffeine as compared with placebo reduced the incidence of cerebral palsy (4.4% vs. 7.3%; adjusted odds ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009) and of cognitive delay (33.8% vs. 38.3%; adjusted odds ratio, 0.81; 95% CI, 0.66 to 0.99; P=0.04). The rates of death, deafness, and blindness and the mean percentiles for height, weight, and head circumference at follow-up did not differ significantly between the two groups. CONCLUSIONS: Caffeine therapy for apnea of prematurity improves the rate of survival without neurodevelopmental disability at 18 to 21 months in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312 [ClinicalTrials.gov].).

Management of pulseless and apneic trauma patients: are aggressive measures justified?

This study prospectively examined the care of trauma patients in extremis on presentation to a tertiary medical center between January 2000 and August 31, 2002. There were 144 patients who presented without a pulse or spontaneous respiration and required cardiopulmonary resuscitation (mean age, 41.5+/-2.3 years; male-to-female ratio, 105:39). Successfully resuscitated patients, who were either admitted to the surgical intensive care unit (SICU) or who were taken to the operating room for surgical exploration, had significantly shorter duration of cardiopulmonary resuscitation (14.55+/-1.64 minutes vs. 33.32+/-1.23 minutes; P < 0.001) and received less amounts of epinephrine than those who died in the emergency room (P < 0.05). One hundred sixteen patients died in the emergency room. Nineteen admitted patients died within 24 hours of presentation. Nine patients survived beyond 24 hours and all of them were admitted directly to the SICU for the management of brain injury. Six patients were taken to the operating room for surgical exploration to control the bleeding; all of them died in the operating room or shortly thereafter in the SICU. No patient in this study survived to be discharged. The financial cost of successfully resuscitated patients was significantly higher than that of patients who died in the emergency room (P < 0.001). Instead of insisting on aggressive measures to resuscitate trauma patients in extremis on presentation, the authors suggest we should redirect that fervor toward efforts made to promote trauma awareness and injury prevention programs.

Methylxanthine therapy for apnea of prematurity: evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial.

Methylxanthine therapy reduces the frequency of apnea and the need for mechanical ventilation. Recent research has raised concerns about the safety of methylxanthines in very preterm infants. Possible adverse effects include poor growth, worsening of hypoxic-ischemic brain damage and abnormal childhood behavior. Over 2,000 infants with birth weights 500-1,250 g have been randomized in the international placebo-controlled Caffeine for Apnea of Prematurity (CAP) trial to examine the long-term efficacy and safety of methylxanthine therapy for the management of apnea of prematurity. Additional therapies such as continuous positive airway pressure were used as necessary to control apneic attacks. At 18 months we measure the combined rate of death or survival with one or more of the following impairments: cerebral palsy, cognitive deficit, blindness and deafness. This outcome was chosen because of the need to evaluate the impact of common neonatal therapies beyond discharge from the intensive care unit. However, several potential long-term consequences of methylxanthine therapy may not become apparent until the study cohort reaches pre-school age. We will therefore extend the follow-up to age 5 years. The main outcome at 5 years will be a composite of death or survival with severe disability in at least one of six domains: cognition, neuromotor function, vision, hearing, behavior, and general health. Once this project is completed, caffeine will be one of the most rigorously evaluated neonatal therapies.