Original Article

Respiratory Arrest in near-Fatal Asthma

Nestor A. Molfino, M.D., Luis J. Nannini, M.D., Alberto N. Martelli, M.D., and Arthur S. Slutsky, M.D.

N Engl J Med 1991; 324:285-288January 31, 1991

Abstract

Abstract

Background and Methods.

The majority of asthma-related deaths occur outside the hospital, and therefore the exact factors leading to the terminal event are difficult to ascertain. To examine the mechanisms by which patients might die during acute exacerbations of asthma, we studied 10 such patients who arrived at the hospital in respiratory arrest or in whom it developed soon (within 20 minutes) after admission.

Full Text of Background and Methods....

Results.

The characteristics of the group were similar to those associated in the literature with a high risk of death from asthma, including a long history of the disease in young to middle-aged patients, previous life-threatening attacks or hospitalizations, delay in obtaining medical aid, and sudden onset of a rapidly progressive crisis. Extreme hypercapnia (mean [±SD] partial pressure of arterial carbon dioxide, 97.1 ±31.1 mm Hg) and acidosis (mean [±SD] pH, 7.01±0.11) were found before mechanical ventilation was begun, and four patients had hypokalemia on admission. Despite the severe respiratory acidosis, no patient had a serious cardiac arrhythmia during the resuscitation maneuvers or during hospitalization. We observed systemic hypertension and sinus tachycardia in eight patients, atrial fibrillation in one, and sinus bradycardia in another. In both patients with arrhythmia the heart reverted to sinus rhythm immediately after manual ventilation with 100 percent oxygen was begun. The median duration of mechanical ventilation was 12 hours, and all patients had normocapnla on discharge from the hospital.

Full Text of Results....

Conclusions.

We conclude that at least in this group of patients, the near-fatal nature of the exacerbations was the result of severe asphyxia rather than cardiac arrhythmias. These results suggest that undertreatment rather than overtreatment may contribute to an increase in mortality from asthma. (N Engl J Med 1991; 324:285–8.)

Full Text of Conclusions....

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Media in This Article

Table 1General Characteristics of All Patients and Their Outcomes.*

Table 2Findings at the Time of Respiratory Arrest.*

Article Activity

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Article

A LARGE number of previous studies, many epidemiologic in nature,1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 have investigated the growing problem of death from asthma. Although these studies have identified such deaths as a major health policy issue, in general they have not elucidated the pathophysiologic processes and mechanisms causing death. The principal reason for this lack of data is that the majority of asthma-related deaths are preceded by rapid and severe deterioration,23 and many occur outside the hospital.1 Thus, such an important and fundamental issue as the relative roles of cardiac arrhythmias and asphyxia in causing these deaths remains controversial.

In this study we examined the question of how and why patients die during acute exacerbations of asthma outside the hospital. The ideal approach would be to obtain biochemical and physiologic data immediately before death, but this is extremely difficult in a population of ambulatory patients. To address this problem, we studied patients who presented to the emergency room with respiratory arrest due to acute asthmatic attacks. On the basis of the clinical presentation and laboratory data, these patients probably would have died within a very short time if they had not been treated aggressively. Our objectives were to determine probable mechanisms for near-fatal asthma, evaluate the circumstances leading to the near-fatal attack, and identify coexisting morbid conditions, particularly cardiac arrhythmias, during severe respiratory compromise.

Methods

Between October 1986 and October 1987 10 patients were admitted on 11 occasions (Patient 8 was admitted twice) to the respiratory intensive care unit of Hospital Nacional Maria Ferrer, Buenos Aires, Argentina. All patients had asthma according to the criteria of the American Thoracic Society21 and had never smoked. They arrived at the hospital in respiratory arrest or had overt respiratory failure within the first 20 minutes after admission, despite vigorous conventional therapy. Respiratory arrest was defined on clinical grounds as cessation of breathing associated with unconsciousness. None of the patients had aspirin-induced asthma or had received beta-blockers, central depressants, or sedatives. Patients who required intubation and mechanical ventilation after 20 minutes of in-hospital treatment were excluded from the study.

During resuscitation maneuvers, all patients received manual ventilation with hyperoxic gas mixtures, while electrocardiographic monitoring was recorded and arterial blood samples were obtained for gas analysis and the determination of pH, acid–base status (Radiometer ABL 1, Copenhagen), and serum potassium level. Immediately thereafter, we performed orotracheal intubation; none of the patients received sedatives or central depressants before this procedure since they were already unconscious. The patients were then given artificial ventilation (Kontron ABT 4100 or OHIO CCV 2000) with small tidal volumes of 8 to 10 ml per kilogram of body weight,22 respiratory rates of 8 to 14 cycles a minute, ratios of inspiration to expiration of 1:3, and an inspired oxygen fraction adjusted according to the partial pressure of arterial oxygen. Diazepam and curare were prescribed for the first few hours. Airway pressures were recorded immediately after admission with the patient totally relaxed.

During each day of mechanical ventilation, all patients received the following: 24 mg of dexamethasone intravenously, 0.6 mg of theophylline per kilogram per hour by continuous infusion, intravenous ranitidine, and nebulized adrenergic bronchodilators (5 mg of albuterol per dose or 2.5 rag of fenoterol per dose) every four hours. Three patients (Patients 9 and 10 and Patient 8 during his first admission) received conventional in-hospital therapy consisting of continuous nebulization with oxygen and high doses of inhaled beta-agonists (10 to 15 mg of albuterol or 5 mg of fenoterol), intravenous theophylline, and steroids in the doses just described in the 10 to 15 minutes preceding the respiratory arrest. A Vitalograph dry spirometer (Buckingham, United Kingdom) was used to measure forced expiratory volume in one second (FEV₁) from the weaning period until discharge.

All data are expressed as means ±SD except for the duration of symptoms and the duration of mechanical ventilation, which are expressed as medians and interquartile ranges.

Results

The general characteristics of all patients and their outcomes are shown in Table 1Table 1General Characteristics of All Patients and Their Outcomes.*. All the patients were transported to the hospital from their homes by relatives or friends. Six patients came between 8 p.m. and 8 a.m. None had asked for medical help before the attack except Patient 2, who had been discharged from our emergency room six hours earlier with an FEV₁ 70 percent of the predicted value. None of the patients received supplemental oxygen before reaching the hospital. In Patients 1 and 6 symptoms were present for more than 96 hours. Nevertheless, in all patients there was a sudden deterioration in the final phase, leading to respiratory arrest. Patients 2 and 5 had a history of respiratory arrest, and seven patients had been hospitalized within the previous year. Thus, before this study, the pattern of asthma in all the patients except one (Patient 6) was similar to the pattern that has previously been defined as severe.5 In spite of this, only Patient 9 and Patient 8 during his second admission were receiving tapered doses of oral prednisone (10 mg a day). In nine patients (including Patient 8 during his first admission), treatment consisted of 600 mg of oral theophylline daily and inhaled beta₂-agonists (albuterol or fenoterol); one patient was being treated with an inhaled bronchodilator alone. All treatments were given on a regular basis. All patients increased their use of inhaled beta-agonists before reaching the hospital; however, we could not obtain accurate data concerning the doses of these drugs.

Four patients (Patients 1, 2, 3, and 4) were in respiratory arrest on arrival at the hospital. In Patients 5, 6, 7, and 8 (during his first admission), respiratory arrest occurred in the emergency room before any treatment was administered. In the remaining three patients (Patients 9, 10, and 8 [during his second admission]) it developed suddenly in the respiratory intensive care unit within the first 20 minutes after admission to the hospital. Seven of the 11 arrests were witnessed by two physicians. Immediately before the onset of the arrest these patients experienced severe dyspnea, had no audible breath sounds on auscultation, and were using their accessory muscles of respiration. All orotracheal intubations were performed in the respiratory intensive care unit. Maximal insufflation airway pressure exceeded 45 cm of water in six patients when controlled mechanical hypoventilation was begun.

The biochemical and clinical data obtained during resuscitation maneuvers in all patients are shown in Table 2Table 2Findings at the Time of Respiratory Arrest.*. Electrocardiograms obtained at that time revealed atrial fibrillation in Patient 2, relative sinus bradycardia in Patient 7, and sinus tachycardia in the remaining eight patients (during both admissions in Patient 8). Both arrhythmias reverted to sinus rhythm after the initiation of manual ventilation with hyperoxic gas mixtures.

The partial pressure of arterial carbon dioxide exceeded 60 mm Hg in all cases and was as high as 155 mm Hg in one patient. Despite the fact that ventilation was performed with 100 percent oxygen, two patients had a partial pressure of arterial oxygen of less than 100 mm Hg (73 and 99 mm Hg). We found hypokalemia (serum potassium level of less than 3.5 mmol per liter) in four of the eight patients in whom potassium was measured.

Seven patients were hospitalized for less than a week24; Patient 5 left the hospital against medical advice. The average FEV₁ before discharge was 77 percent of the predicted value.23 We found no correlation between the duration of symptoms before admission and the duration of mechanical ventilation (r = 0.008, P>0.5) or the hospital stay (r = 0.14, P>0.5).

During a subsequent admission, Patient 1 arrived in cardiac and respiratory arrest. According to her relatives, the patient lost consciousness several minutes before reaching the hospital. She recovered sinus rhythm during resuscitation maneuvers; unfortunately, she had a "flat" electroencephalogram and died in the respiratory intensive care unit. Patient 4 died suddenly at home five months after discharge. The rest of the patients survived without obvious sequelae.

Discussion

There is a paucity of information concerning the development of respiratory arrest in fatal or near-fatal asthma. This lack of data can be attributed at least partially to the fact that the majority of deaths from asthma occur outside the hospital and that death is frequently sudden and unexpected.1 , 6 , 7

It is important to note the limitations inherent in our study. The underlying assumption that we used in interpreting the data was that the pathophysiologic processes in patients who actually die of asthma are similar to those in our patients who had near-fatal events. Clearly, this is not necessarily correct, and it is possible that we were observing a so-called survivor effect. However, in the light of the clinical and biochemical data obtained on admission, our patients clearly had potentially fatal asthmatic attacks, and they probably survived because they were fortunate enough to reach the hospital and receive mechanical ventilation. Thus, at the very least, they are probably representative of a subgroup of patients who die of their asthma.5

Although we did not find life-threatening cardiac arrhythmias in our patients, it could be argued that electrocardiographic monitoring did not begin promptly enough, so that the arrhythmias, if present, disappeared immediately after hyperoxic mixtures of gas were administered. For ethical reasons, we did not perform electrocardiography before oxygen was given. However, we do not think that this slight delay had a major bearing on our results, since such arrhythmias, if they were present, did not alter the heart rate or blood pressure. Except in two patients, both heart rate and blood pressure remained relatively unchanged during resuscitation. Furthermore, if there were arrhythmias that reverted to normal sinus rhythm after a few minutes of ventilation and oxygenation, then the underlying pathophysiologic process was likely to be asphyxia and not a primary cardiac-rhythm disturbance.

Two hypotheses have been proposed to explain deaths from acute asthma: cardiac arrhythmias related to adverse effects of antiasthmatic drugs,25 26 27 and asphyxia due to severe airway obstruction.28 In support of the former hypothesis, many authors11 , 25 , 29 have suggested that in patients with hypoxemia and severe acidosis, the association of oral theophylline and inhaled beta₂-agonists could increase myocardial irritability, predisposing them to circulatory arrest.27 , 29 30 31 However, a number of investigators have reported no increase in cardiac side effects with combined therapy.32 33 34 Nevertheless, this information is anecdotal,11 scarce or incomplete,32 and controversial.27 , 32 33 34 35 Nine patients in our series were receiving combined therapy with oral theophylline and inhaled bronchodilators (albuterol or fenoterol), similar to the regimens followed by the subjects described in two of those studies.25 , 27 Despite this, we found only one patient with atrial fibrillation and one with sinus bradycardia; both reverted to sinus rhythm soon after manual hyperoxic ventilation was begun.

Perhaps the strongest indirect evidence suggesting the importance of cardiac arrhythmias is that unexpected deaths from asthma are often relatively sudden.2 , 3 Three of our patients had symptoms that persisted for less than eight hours. Patient 2 had been discharged from our emergency room with an FEV₁ that was 70 percent of the predicted value only six hours before he was readmitted with severe respiratory failure (partial pressure of arterial carbon dioxide, 100 mm Hg). Had this patient died immediately before admission to the hospital, his death might have been classified as due primarily to a cardiac cause.25 This suggests that asthma-related deaths classified as "sudden" may not necessarily indicate a primary cardiac event.

The second possible explanation for sudden death, asphyxia, was first proposed in 200 B.C.36 and was carefully analyzed first in autopsy studies37 and later by Rebuck and Read,38 who concluded that this was the chief mechanism of death from acute asthma. The administration of oxygen must have contributed at least in part to the marked hypercapnia in some of the patients with extremely high values for partial pressure of arterial carbon dioxide. However, its role in the development of the arrest is unclear, since only three of the patients in 11 episodes received oxygen before the onset of respiratory arrest.

Finally, hypokalemia, caused in part by the action of beta₂-agonists,39 , 40 has been proposed as another indicator of the severity of an asthmatic crisis10 and as a potential factor leading to death, either by facilitating arrhythmias28 or by inducing muscle weakness.41 This latter factor may have played a part in the events in our patients, since they had relatively low potassium levels despite severe respiratory acidosis.

These data allow us to comment on recent speculation about the increase in the number of deaths from asthma. It has been proposed that this increase may be iatrogenic, due to the drugs used to treat asthma,11 , 25 , 27 leading to the suggestion that physicians should be more conservative in the use of antiasthmatic agents. In accord with the results of a number of other investigations,28 , 35 , 42 our data suggest that undertreatment, as evidenced by severe asphyxia, rather than overtreatment, which might have been evidenced by cardiotoxicity, is one of the major factors underlying the increase in the number of deaths from asthma.

Dr. Molfino is the recipient of a Will Rogers Fellowship.

We are indebted to Dr. E. Schiavi for his encouragement during the study and to Dr. N. Zamel for reviewing the manuscript.

Source Information

From Hospital Nacional Maria Ferrer, Buenos Aires, Argentina (N.A.M., L.J.N., A.N.M.), and the Department of Medicine, Respiratory Division, Mount Sinai Hospital, University of Toronto, Toronto (N.A.M., A.S.S.). Address reprint requests to Dr. Molfino at Respiratory Special Procedures and Research Laboratory, Toronto General Hospital, 101 College St. CW 2–202, Toronto, ON M5G 2C4, Canada.

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