Near-fatal Events Research Articles

Pharmacologic approaches to life-threatening asthma

Following a peak in asthma mortality in the late 1980s and early 1990s, we have been fortunate to see a substantial decrease in asthma deaths in recent years. Although most asthma deaths occur outside the hospital, near-fatal events are commonplace, with anywhere from 2-20% of patients with acute asthma admitted to intensive care, and 2-4% intubated for respiratory failure. Standard therapies for acute severe and near-fatal asthma include administration of systemic corticosteroids, and frequent or continuous inhaled beta agonists. Controversy remains regarding the optimal therapy of those who fail to respond to these initial treatments, those who remain at risk of acute respiratory failure, and patients requiring mechanical ventilation. There remain significant gaps in our knowledge regarding relative benefits of intravenous versus oral corticosteroids, intermittent versus continuous beta agonists, and the role of various adjunctive treatments including intravenous magnesium, systemic beta agonists, aminophylline, and helium-oxygen mixtures. Using models and radiolabeled aerosols, there is a greater understanding regarding effective administration of inhaled beta-agonists in ventilated patients. There is limited available evidence for treatment of near-fatal asthma, a fact reflected by the significant variability in asthma critical care practice. Much of the data guiding treatment in this setting has been generalized from studies of acute asthma in the ED and from general populations of hospitalized patients with acute asthma. This review will focus on pharmacologic approaches to life-threatening asthma by reviewing current guideline recommendations, reviewing the scientific basis of the guidelines, and highlighting gaps in our knowledge in treatment of refractory acute or near-fatal asthma.

Risk Factors for Recurrent Syncope and Subsequent Fatal or Near-Fatal Events in Children and Adolescents With Long QT Syndrome

We aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS). Data regarding risk assessment in LQTS after the occurrence of the first syncope episode are limited. The Prentice-Williams-Peterson conditional gap time model was used to identify risk factors for recurrent syncope from birth through age 20 years among 1,648 patients from the International Long QT Syndrome Registry. Multivariate analysis demonstrated that corrected QT interval (QTc) duration (≥500 ms) was a significant predictor of a first syncope episode (hazard ratio: 2.16), whereas QTc effect was attenuated when the end points of the second, third, and fourth syncope episodes were evaluated (hazard ratios: 1.29, 0.99, 0.90, respectively; p < 0.001 for the null hypothesis that all 4 hazard ratios are identical). A genotype-specific subanalysis showed that during childhood (0 to 12 years), males with LQTS type 1 had the highest rate of a first syncope episode (p = 0.001) but exhibited similar rates of subsequent events as other genotype-sex subsets (p = 0.63). In contrast, in the age range of 13 to 20 years, long QT syndrome type 2 females experienced the highest rate of both first and subsequent syncope events (p < 0.001 and p = 0.01, respectively). Patients who experienced ≥1 episodes of syncope had a 6- to 12-fold (p < 0.001 for all) increase in the risk of subsequent fatal/near-fatal events independently of QTc duration. Beta-blocker therapy was associated with a significant reduction in the risk of recurrent syncope and subsequent fatal/near-fatal events. Children and adolescents who present after an episode of syncope should be considered to be at a high risk of the development of subsequent syncope episodes and fatal/near-fatal events regardless of QTc duration.

Attenuated recovery of heart rate turbulence early after myocardial infarction identifies patients at high risk for fatal or near-fatal arrhythmic events

Autonomic dysfunction tends to improve over time after acute myocardial infarction (MI), but the clinical significance of autonomic remodeling is not well known. The purpose of this study was to test the hypothesis that the amount of recovery of autonomic function early after MI is associated with a risk for serious arrhythmias. The prognostic significance of autonomic remodeling after MI was assessed in one post-MI cohort [Cardiac Arrhythmia and Risk Stratification after Myocardial Infarction (CARISMA)] and validated in a second cohort [Risk Estimation After Infarction, Noninvasive Evaluation (REFINE)]. Changes in heart rate variability (DeltaHRV) and heart rate turbulence (DeltaHRT) were measured from 24-hour ECG recordings performed early (5-21 days) and later (6 weeks) after MI in CARISMA (n = 312). DeltaHRV and DeltaHRT were similarly measured from early (2-4 weeks) and later (10-14 weeks) post-MI recordings in REFINE (n = 322). HRV and HRT increased over time in both cohorts. Attenuated recovery of autonomic function, defined as DeltaHRT slope <2.0 ms/RR, was associated with a 9.4-fold (95% confidence interval 1.2-71.6; P = .03) higher risk of ECG-documented sustained ventricular tachycardia or ventricular fibrillation in CARISMA and a 7.0-fold (95% confidence interval 1.6-29.6; P = .009) higher risk of fatal or near-fatal events in REFINE. Changes in HRV and HRT were not predictive of nonarrhythmic death in either cohort. Attenuated recovery of autonomic function early after MI consistently predicts a higher risk of fatal or near-fatal arrhythmic events. A lack of improvement in HRT early after MI appears to be a specific marker for serious arrhythmic events.

Increased vagal airway tone in fatal asthma

Slow-onset asthma deaths are characterized by eosinophilic airway infiltrates and thickening of the basal membrane, while rapid-onset asthma deaths are associated with fewer airway inflammatory changes, suggesting that bronchospasm may be responsible for the latter events. Airway tone is primarily controlled by the autonomous nervous system and can be pharmacologically modified. Therapies that stimulate the sympathetic beta(2) adrenoreceptor or inhibit the muscarinic receptor signal transduction induce bronchodilation. Parasympathetic (vagal) airway tone is enhanced in some asthmatics due to a number of stimuli, while in others it is constitutively heightened. Mainstream asthma therapy, however, only consists of corticosteroids and beta(2) agonists, not addressing this aspect. In this publication, I propose that increased vagal airway tone resulting in overwhelming bronchoconstriction and mucus plugging could be responsible for the near-fatal or fatal events observed in a number of asthmatics, in spite of their adequate treatment with standard therapies. On the basis of this hypothesis, I recommend that vagal airway tone be assessed in all patients with asthma, particularly in those with a history of near-fatal events. If the airway tone is increased, individuals should be treated with a triple combination of long-acting beta(2) agonists, inhaled steroids, and inhaled anticholinergics to prevent vagally mediated fatal events.

Clinical Implications for Patients With Long QT Syndrome Who Experience a Cardiac Event During Infancy

This study was designed to evaluate the clinical and prognostic aspects of long QT syndrome (LQTS)-related cardiac events that occur in the first year of life (infancy). The clinical implications for patients with long QT syndrome who experience cardiac events in infancy have not been studied previously. The study population of 3,323 patients with QT interval corrected for heart rate (QTc) > or =450 ms enrolled in the International LQTS Registry involved 20 patients with sudden cardiac death (SCD), 16 patients with aborted cardiac arrest (ACA), 34 patients with syncope, and 3,253 patients who were asymptomatic during the first year of life. The risk factors for a cardiac event among 212 patients who had an electrocardiogram recorded in the first year of life included QTc > or =500 ms, heart rate < or =100 beats/min, and female sex. An ACA before age 1 year was associated with a hazard ratio of 23.4 (p < 0.01) for ACA or SCD during ages 1 to 10 years. During the 10-year follow-up after infancy, beta-blocker therapy was associated with a significant reduction in ACA/SCD only in those with a syncopal episode within 2 years before ACA/SCD but not for those who survived ACA in infancy. Patients with LQTS who experience ACA during the first year of life are at very high risk for subsequent ACA or death during their next 10 years of life, and beta-blockers might not be effective in preventing fatal or near-fatal cardiac events in this small but high-risk subset.

Clinical Summaries

Clinical Summaries

Incidence and Risk Factors of Arrhythmic Events in Catecholaminergic Polymorphic Ventricular Tachycardia

The pathophysiological background of catecholaminergic polymorphic ventricular tachycardia is well understood, but the clinical features of this stress-induced arrhythmic disorder, especially the incidence and risk factors of arrhythmic events, have not been fully ascertained. The outcome in 101 catecholaminergic polymorphic ventricular tachycardia patients, including 50 probands, was analyzed. During a mean follow-up of 7.9 years, cardiac events defined as syncope, aborted cardiac arrest, including appropriate discharges from implantable defibrillators, or sudden cardiac death occurred in 27 patients, including 2 mutation carriers with normal exercise tests. The estimated 8-year event rate was 32% in the total population and 27% and 58% in the patients with and without beta-blockers, respectively. Absence of beta-blockers (hazard ratio [HR], 5.48; 95% CI, 1.80 to 16.68) and younger age at diagnosis (HR, 0.54 per decade; 95% CI, 0.33 to 0.89) were independent predictors. Fatal or near-fatal events defined as aborted cardiac arrest or sudden cardiac death occurred in 13 patients, resulting in an estimated 8-year event rate of 13%. Absence of beta-blockers (HR, 5.54; 95% CI, 1.17 to 26.15) and history of aborted cardiac arrest (HR, 13.01; 95% CI, 2.48 to 68.21) were independent predictors. No difference was observed in cardiac and fatal or near-fatal event rates between probands and family members. Cardiac and fatal or near-fatal events were not rare in both catecholaminergic polymorphic ventricular tachycardia probands and affected family members during the long-term follow-up, even while taking beta-blockers, which was associated with a lower event rate. Further studies evaluating concomitant therapies are necessary to improve outcome in these patients.

Abstract 2145: Recovery of Cardiac Autonomic Dysfunction after Acute Myocardial Infarction as a Predictor of Fatal of Near-Fatal Arrhythmic Events

Background. Changes in cardiac autonomic function have been documented after myocardial infraction (MI), but their significance is unknown. We assessed the amount of recovery of autonomic dysfunction after MI and its significance among the patients with depressed left ventricular ejection fraction (LVEF ≤ 0.40 - CARISMA and ≤ 0.50 - REFINE). Methods and Results. Changes in heart rate variability (dHRV) and turbulence (dHRT) were measured from 24-hour ECG recordings performed 5–21 days and again at six weeks post-MI in 312 patients included in the Cardiac Arrhythmias and Risk Stratification after Myocardial Infarction (CARISMA) study. The primary endpoint was sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) recorded by an implantable device. Non-arrhythmic death was a secondary endpoint. HRV and HRT measures increased significantly from baseline to six weeks post-AMI (p&lt;0.001 for dHRV and p=0.017 for dHRT slope). The patients with attenuated recovery of autonomic function had a higher incidence of VT/VF events (n=25), e.g. those with a dHRT slope &lt; 2.0 ms/RRi (optimized cut-off) had a hazard ratio of 10.2 (95% CI from 1.35 to 77.9, p=0.03) of experiencing the VT or VF. The change of very-low (dVLF) and low-frequency (dLF) spectral components also predicted the VT/VF events (p=0.03 for dVLF and p=0.02 for dLF). Only one patient with a dHRT slope ≥2.0 mm/RRi (n=79) experienced VT/VF event (negative accuracy 99%). Validation was performed in the Risk Estimation Following Infarction Non-invasive Evaluation (REFINE) post-MI population (n=322). Of the 24 fatal or non-fatal cardiac arrests that occurred in REFINE, all but two were identified by a lack of improvement in HRT slope as defined in CARISMA (negative accuracy 98%). The risk of fatal or non-fatal cardiac arrest was 7.0-fold (95% CI from 1.6 to 29.6; p = 0.009) higher in patients without improvement in HRT. Lack of improvement in HRT was not predictive of non-arrhythmic death in either post-MI population. Conclusions. Autonomic function undergoes a substantial improvement early after MI, which is associated with vulnerability to VT or VF. A marked recovery of autonomic dysfunction protects from the occurrence of fatal or near-fatal arrhythmic events after MI despite depressed LVEF

Prediction of fatal or near-fatal cardiac arrhythmia events in patients with depressed left ventricular function after an acute myocardial infarction

AimsTo determine whether risk stratification tests can predict serious arrhythmic events after acute myocardial infarction (AMI) in patients with reduced left ventricular ejection fraction (LVEF ≤ 0.40).Methods and resultsA total of 5869 consecutive patients were screened in 10 European centres, and 312 patients (age 65 ± 11 years) with a mean LVEF of 31 ± 6% were included in the study. Heart rate variability/turbulence, ambient arrhythmias, signal-averaged electrocardiogram (SAECG), T-wave alternans, and programmed electrical stimulation (PES) were performed 6 weeks after AMI. The primary endpoint was ECG-documented ventricular fibrillation or symptomatic sustained ventricular tachycardia (VT). To document these arrhythmic events, the patients received an implantable ECG loop-recorder. There were 25 primary endpoints (8.0%) during the follow-up of 2 years. The strongest predictors of primary endpoint were measures of heart rate variability, e.g. hazard ratio (HR) for reduced very-low frequency component (<5.7 ln ms2) adjusted for clinical variables was 7.0 (95% CI: 2.4–20.3, P < 0.001). Induction of sustained monomorphic VT during PES (adjusted HR = 4.8, 95% CI, 1.7–13.4, P = 0.003) also predicted the primary endpoint.ConclusionFatal or near-fatal arrhythmias can be predicted by many risk stratification methods, especially by heart rate variability, in patients with reduced LVEF after AMI.

Risk Factors for Aborted Cardiac Arrest and Sudden Cardiac Death in Children With the Congenital Long-QT Syndrome

The congenital long-QT syndrome (LQTS) is an important cause of sudden cardiac death in children without structural heart disease. However, specific risk factors for life-threatening cardiac events in children with this genetic disorder have not been identified. Cox proportional-hazards regression modeling was used to identify risk factors for aborted cardiac arrest or sudden cardiac death in 3015 LQTS children from the International LQTS Registry who were followed up from 1 through 12 years of age. The cumulative probability of the combined end point was significantly higher in boys (5%) than in girls (1%; P<0.001). Risk factors for cardiac arrest or sudden cardiac death during childhood included corrected QT interval [QTc] duration > 500 ms (hazard ratio [HR]; 2.72; 95% confidence interval [CI], 1.50 to 4.92; P=0.001) and prior syncope (recent syncope [< 2 years]: HR, 6.16; 95% CI 3.41 to 11.15; P<0.001; remote syncope [> or = 2 years]: HR, 2.67; 95% CI, 1.22 to 5.85; P=0.01) in boys, whereas prior syncope was the only significant risk factor among girls (recent syncope: HR, 27.82; 95% CI, 9.72 to 79.60; P<0.001; remote syncope: HR, 12.04; 95% CI, 3.79 to 38.26; P<0.001). Beta-blocker therapy was associated with a significant 53% reduction in the risk of cardiac arrest or sudden cardiac death (P=0.01). LQTS boys experience a significantly higher rate of fatal or near-fatal cardiac events than girls during childhood. A QTc duration > 500 ms and a history of prior syncope identify risk in boys, whereas prior syncope is the only significant risk factor among girls. Beta-blocker therapy is associated with a significant reduction in the risk of life-threatening cardiac events during childhood.

Near-fatal asthma: recognition and management

Near-fatal asthma continues to be a significant problem despite the decline in overall asthma mortality. The purpose of this review is to discuss recent advances in our understanding of the pathophysiology, diagnosis and treatment of near-fatal asthma. Two distinctive phenotypes of near-fatal asthma have been identified: one with eosinophilic inflammation associated with a gradual onset and a slow response to therapy and a second phenotype with neutrophilic inflammation that has a rapid onset and rapid response to therapy. Patients who develop sudden-onset near-fatal asthma seem to have massive allergen exposure and emotional distress. In stable condition, near-fatal asthma frequently cannot be distinguished from mild asthma. Diminished perception of dyspnea plays a relevant role in treatment delay, near-fatal events, and death in patients with severe asthma. Reduced compliance with anti-inflammatory therapy and ingestion of medications or drugs (heroin, cocaine) have been associated with fatal or near-fatal asthma. Near-fatal asthma is a subtype of asthma with unique risk factors and variable presentation that requires early recognition and aggressive intervention.

INCIDENCE AND OUTCOMES OF CARDIOPULMONARY RESUSCITATION IN PATIENTS WITH END-STAGE DUCHENNE MUSCULAR DYSTROPHY

PURPOSE: Although technological cardiopulmonary therapies, such as noninvasive ventilation (NIV), have increased life span for patients (pts) with Duchenne muscular dystrophy (DMD), the disease remains fatal. Pts with end-stage DMD who forgo “do not resuscitate” directives may be partially resuscitated after near-fatal events, exposing them to the risk of brain damage. PURPOSE: To assess the frequency of attempted resuscitation among pts with DMD in our clinic who experienced cardiopulmonary arrest, and to describe their outcomes.

Severe asthma: An overview

Severe asthma represents less than 10% of all asthma, but these patients are responsible for a disproportionate share of the health care costs and morbidity associated with the disease. A significant challenge in the diagnosis and management of severe asthma is the ability to identify accurately the patients most at risk for adverse outcomes, such as medication side effects, emergency department visits, hospitalization, near-fatal events, or disability from persistent symptoms or chronic lung function abnormalities. To improve the treatment of these patients, we must improve our understanding of the mechanisms responsible for severe disease. To achieve this goal, it is imperative to develop a common definition of severe asthma to allow adequate characterization of the disease clinically and provide the opportunity to compare results from many studies. Several severe asthma phenotypes have been described in the literature on the basis of the age of patients, age of disease onset, corticosteroid resistance, chronic airflow obstruction, and evidence for eosinophilic airway inflammation on biopsy. These phenotypes have led to an emerging interest in the use of noninvasive methods to monitor airway inflammation in severe asthma. Treatment algorithms based on markers of airway inflammation may decrease measures of health care utilization in severe asthma.

Cost‐Effectiveness of Implanted Defibrillators in Young People with Inherited Cardiac Arrhythmias

The implanted cardioverter-defibrillator (ICD) has been shown to improve survival in adult patients with high risk acquired cardiac disease, with a cost-effectiveness ratio in the range of $30,000 to $185,000 per quality-adjusted-life-year saved. However, data on the benefit and cost-effectiveness of device therapy in high-risk patients with inherited cardiac disorders are limited. We developed two separate computer-based analytical models to compare non-ICD with ICD therapy in patients (age range: 10-75 years) with long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM). In each disease entity patients were stratified into low-risk (no known risk factors); high-risk (known risk factors [primary prevention]); and very high-risk (prior near-fatal events [secondary prevention]). Net costs were defined as the difference between costs resulting from treatment of the disease and savings due to gained productivity attributable to prevention of sudden cardiac death. Outcome was defined as costs per quality-adjusted life-years saved. In LQTS, defibrillator therapy was shown to be cost effective in high-risk male patients (incremental cost-effectiveness ratio [ICER]=$3328 per quality-adjusted-life-year saved), and cost saving in high-risk females (ICER=$7102 gained per quality-adjusted-life-year saved) and very high-risk males and females (ICER=$15,483 and 19,393 gained per quality-adjusted-life-year saved, respectively). In HCM, defibrillator therapy was cost saving in both male and female high-risk (ICER=$17,892 and $17,526 gained per quality-adjusted-life-year saved, respectively) and very high-risk (ICER $22,944 and $22,329 gained per quality-adjusted-life-year saved, respectively) patients. Defibrillator therapy was not shown to be cost effective in low-risk patients with either LQTS or HCM (ICER in the range of $400,000 to $600,000 lost per quality-adjusted-life-year saved). Sensitivity analyses were consistent with the results in each risk group. In appropriately selected patients with inherited cardiac disorders, early intervention with ICD therapy is cost-effective to cost saving due to added years of gained productivity when the lifespan of an individual at risk is considered.

Severe Asthma in Adults

Severe asthma remains poorly understood and frustrating to care for, partly because it is a heterogeneous disease. Patients with severe asthma disproportionately consume health care resources related to asthma. Severe asthma may develop over time, or shortly after onset of the disease. The genetic and environmental elements that may be most important in the development of severe disease are poorly understood, but likely include both allergic and nonallergic elements. Physiologically, these patients often have air trapping, airway collapsibility, and a high degree of methacholine hyperresponsiveness. Specific phenotypes of severe asthma are only beginning to be defined. However, describing severe asthma by age at onset (early- vs. late-onset) appears to describe two phenotypes that differ at immunologic, physiologic, epidemiologic, and pathologic levels. In particular, early-onset severe asthma is a more allergic-associated disease than late-onset severe asthma. In addition, patients with severe asthma can be defined on the basis of presence and type of inflammation. Severe asthma with persistent eosinophilia (of either early or late onset) is more symptomatic and has more near-fatal events. However, at least 50% of patients with severe asthma have very little identifiable inflammation. Thus, "steroid resistance" may occur at numerous levels, not all of which are caused by a lack of effect of steroids on inflammation. Treatment remains problematic, with corticosteroids remaining the most effective therapy. However, 5-lipoxygenase inhibitors, anti-IgE, and immunomodulatory drugs are also likely to have a place in treatment. Improving therapy in this disease will require a better understanding of the phenotypes involved.

Acute severe asthma in adults

Despite major improvements in the recognition of patients with asthma and their treatment, both chronically and for acute episodes, acute severe asthma remains a life-threatening condition. Most patients who die from asthma have a history of chronic, often severe disease, but fatal or near-fatal events can occur in patients who have previously exhibited only mild or moderate symptoms. A background of poor behavioural and psychosocial features is well recognized in these patients (Figure 1). Medical factors in at-risk patients include: • prior severe episodes • admission to or attendance at an A&E department with asthma during the last year • ‘heavy’ use of β 2-agonists • those taking three or more classes of asthma medication. • those with 'brittle' asthma. Peaks of asthma deaths occur in the summer in younger patients and the winter in older patients, possibly reflecting triggers of the event. Most asthma deaths occur in the community, and in most patients symptoms develop over hours or days rather than minutes. The importance of patient education about asthma in general, how to recognize the severity of symptoms and the institution of preventive therapy cannot be over-emphasized.

ANESTHESIA FOR PATIENTS WITH A MEDIASTINAL MASS

Anesthesia for patients with mediastinal masses carries a significant risk for fatal or near-fatal cardiorespiratory events. Careful history taking and thorough preoperative investigation, including CT, identify most susceptible patients. Preoperative fiberoptic bronchoscopy performed by or involving the anesthesiologist is invaluable for determining the plan for intubation and ventilation. A coordinated approach involving anesthesiologists and surgeons is essential.

A community-based study of near-fatal asthma.

The purpose of this study was to describe the community-based impact of near-fatal asthma within the District of Columbia (Washington, DC). The design was a prospective cohort study. Subjects included all persons in 1993 who presented to Washington, DC hospitals alive, requiring intubation for respiratory failure (including subjects who subsequently died in the hospital). Washington, DC hospitals were contacted on a biweekly basis to identify subjects. Patients were contacted by mail, followed by an interview with the subject or proxy. Of the 35 case subjects identified, 31 (88.6%) were interviewed. Sixty-one percent of the subjects were female; 84% were African-American; and 45.2% were less than 18 years old. Forty-five percent had asthma for 10 or more years. Twenty-three percent reported the emergency department as their usual source of health care, and 32% saw a provider on a weekly basis. Fifty-two percent were taking four or more prescription medications, and 29% were taking no anti-inflammatory medications. In the 24 hours before the event, 77% reported difficulty breathing, but only 64% reported contacting a health care provider. Community-based investigation of near-fatal asthma may lead to a better characterization of risk factors associated with this event. Findings from this study suggest that some of the factors associated with near-fatal events may be different from those associated with fatal asthma and that up to one third of the events may have been preventable.

Fatal and near-fatal asthma questionnaire: Prelude to a national registry

Background: Asthma mortality rates continue to be unacceptably high in the United States. As a follow-up to the initiatives proposed by the Asthma Mortality Task Force in 1987, the Committee on Asthma Mortality of the American Academy of Allergy, Asthma, and Immunology developed a questionnaire on fatal and near-fatal asthma. Objective: This study assessed completeness of answers from participating physicians and described characteristics of patients with fatal and near-fatal asthma. Methods: There were 111 survey items intended to characterize patients with fatal or near-fatal exacerbations of asthma. The questionnaire was sent to the members of the American Academy of Allergy, Asthma, and Immunology (approximately 3900), and a total of 143 usable questionnaires were received. Results: Responding physicians had information on most items in the questionnaire; the mean number of responses was 120 of 143 possible, with a median of 128 and a range of 40 to 143. Patient demographics, description of the event, identification of overall risk for the event, use of medications, and characteristics of asthma management had the most complete responses (median response rates were 126-143). Presence of factors contributing to the event had fewer responses (range, 44-125). The physicians frequently had information on some psychologic characteristics (eg, 108 responses for depression and/or hopelessness and 127 responses for social support) but less information on several others (eg, 62 responses for family dysfunction). Statistical analysis of the completed surveys indicated that only 2 characteristics distinguished fatal from near-fatal asthma: progression in minutes (adjusted odds ratio, 4.89; 95% confidence interval, 2.05-12.90) and absence of a past history of intubation (adjusted odds ratio, 3.55; 95% confidence interval, 1.55-8.97). Conclusions: There is a need to gather further data on patients with fatal and near-fatal events to design appropriate prospective studies on asthma morbidity and mortality rates. Physicians can contribute important information about these patients. Gathering such data would be enhanced by establishing a national registry on fatal and near-fatal asthma. (J Allergy Clin Immunol 1999;104:763-8.)

Early Mortality and the Retinoic Acid Syndrome in Acute Promyelocytic Leukemia: Impact of Leukocytosis, Low-Dose Chemotherapy, PMN/RAR-α Isoform, and CD13 Expression in Patients Treated With All-Trans Retinoic Acid

All-trans retinoic acid (RA) has proven a major advance in the treatment of acute promyelocytic leukemia (APL). However, the proper management of patients who present with or develop leukocytosis during remission induction with all-trans RA is not established, nor is there a clear relation between leukocytosis and the development of the retinoic acid syndrome. We reviewed the course of our patients who underwent induction with all-trans RA to identify potential factors that might predict for the development of this syndrome and to identify which patients, if any, might specifically benefit from additional treatment with cytotoxic chemotherapy. Seventy-eight courses of all-trans RA therapy were administered to patients with a molecular diagnosis of APL. Initial and peak leukocyte counts, their rate of rise, leukocyte count criteria developed in Europe, and cell surface marker expression were all analyzed relative to subsequent development of both the RA syndrome as well as all causes of early mortality. The outcome of patients who received specific treatment for retinoid-induced leukocytosis was also examined. No factor was found to consistently predict for the development of the RA syndrome. Although the occurrence of the syndrome was positively associated with the peak value of the peripheral blood leukocyte count (P = .001), neither the initial leukocyte count nor the rate of rise in leukocyte counts on days preceding onset of the syndrome were sufficiently well-correlated to be clinically useful (P = .21). The leukocyte count criteria developed in Europe had a sensitivity of 62%, a specificity of 69%, and a positive predictive value that ranged from only 44% to 72%. However, we unexpectedly found that basal expression of CD13 (aminopeptidase N), a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia, was highly associated with both development of the syndrome (P < .05) as well as an elevated leukocyte count (P = .006). Neither low-dose chemotherapy nor leukapheresis prevented development of the syndrome nor ameliorated its effects. In fact, 9 of 11 patients who received these interventions sustained fatal or near-fatal events, most of which were due to hemorrhage. However, early treatment with a short-course of high-dose corticosteroids halted progression of the syndrome in most cases. Finally, we found that expression of the type "A" isoform of PML/RAR-alpha (also known as bcr3 or "short") was associated with a significantly shorter duration of relapse-free and overall survival (P = .005).(ABSTRACT TRUNCATED AT 400 WORDS)