RESPIRATORY PROBLEMS

Bradycardia Preceding Apneic Attacks in Low-Birthweight Infants The

Ira W.

Relationship of Recognition and Management

DuBrow, M.D., Jackson W. Chen, M.D., Paul W. K. Wong, M.D.

Two premature infants had frequent episodes of prolonged apnea. The apneic spells were not due to the more commonly known causes of apnea in infancy, but were consistently preceded by severe bradycardia. Atropine or ephedrine produced favorable therapeutic results. Since severe bradycardia may be a cause of sudden death in infants, its recognition and treatment is important in the management of apneic infants.

apparently normal infants, on the other hand, apneic spells following severe bradycardia are much less common. However, an attack of severe bradycardia may be a cause syndrome.&dquo;

of sudden death. This paper reports two infants with sudden recurrent attacks of severe bradycardia followed by apnea.

Case

ACI~.StJN

AND WINDLE showed that bradycardia regularly followed asphyxia in experimental animals’ and that the heart rate promptly recovered after reoxygenation.

Bradycardia also frequently accompanies apneic attacks in sick newborn and premature infants. For example, during 51 apneic episodes (lasting more than 30 seconds) in eight infants, Girdling2 observed that in 41 per cent the heart rate fell by ten or more beats a minute. Steinsehneider~ reported that two of five infants, who had repeated episodes of apnea, subsequently died of &dquo;sudden death

Department of Pediatrics, Sections of Cardiology and Neonatology, Abraham Lincoln School of Medicine, University of Illinois 840 South Wood Street, Chicago, Ill. 60612.

Correspondence to Ira W. DuBrow, M.D., Section of Pediatric Cardiology, University of Illinois Hospital, 840 South Wood Street, Chicago, Ill. 60612.

In

Reports

.

Case 1 This 2,290 g white male was delivered at 34 weeks of gestation. His Apgar score was 8 at 1 minute and 9 at 5 minutes. He had mild respiratory distress and was treated with 30 to 40 per cent oxygen in an isolette and 10 per cent dextose intravenously. The respiratory distress resolved within 36 hours. During this period, his blood levels of glucose, calcium, electrolytes, arterial pH, and blood gases were within normal limits. From one to 25 days of age, numerous attacks of bradycardia preceding apnea were observed during simultaneous heart rate and respiration monitoring. These attacks responded readily to tactile stimulation. Between the attacks the infant was active. Repeated examinations showed no cardiac or neurologic abnormalities. Electrocardiograms, chest and skull x-rays, and several determinations of blood glucose, calcium, electrolytes, pH, arterial blood gases, and white cell counts were normal. Blood cultures were sterile. An electroencephalogram, performed after an attack, showed a few medium voltage, slow spike

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discharges from the left mid-temporal and parietal regions and a few low voltage spindles. A seizure disorder was suspected. At age 25 days, phenobarbital (6 mg/kg/day) was begun, with no effect on the bradycardiac attacks. From the age of 28 days, 5 mg/kg/day of dilantin was added, also without benefit. A second electroencephalogram was normal. As the frequency of the bradycardiac attacks did not change, the anticonvulsants were discontinued. Simultaneous electrocardiographic and respiratory monitoring was carried out to document the sequence of the spells further. In each spell, bradycardia (heart rate 40-80 per minute) (Fig.

lA) was observed attacks, heart rate

apnea. Between the 150 to 170 per minute and blood chemistries were normal. Such attacks varied from zero to eight times a day and occurred suddenly, apparently without provocation. At the age of 34 days, atropine (0.03 mg/kg q8h orally) was begun. No further attacks were observed after 24 hours of treatment. The dose was then decreased to 0.01 mg/kg q8h. The infant remained free from bradycardiac spells for one week and the atropine was discontinued at the age of 41 days, without further recurrence of bradycardia or apnea. He was discharged at 47 days of age weighing 3,610 g. At the latest follow-up at four months of age, he showed normal development and no further spells were observed. Cardiovascular examination, chest x-ray, and electrocardiogram were normal. to

precede

was

Case 2 This 800 g white female was delivered at 29 weeks of gestation. The Apgar score was 3 at 1 minute and 8 at 5 minutes. She had mild respiratory distress and required 30 to 60 per cent oxygen in an isolette. At the age of 24 hours, continuous nasojejunal feeding was started. She did well until nine days of age when she began to have episodes of

apnea which responded to tactile stimulation. Blood glucose, calcium, electrolytes, pH, p0z and pC02 were normal. Lumbar puncture, skull, and chest x-rays were also normal. Ampicillin and kanamycin were given for seven days. Blood, urine, and throat cultures were negative. The frequency of apneic spells gradually diminished, but at age 25 days became frequent once more. Again, no cause was found after thorough investigation. At age 43 days, these attacks were less responsive to tactile stimulation. Cardiac and neurologic status in the infant were reassessed but no abnormality was detected. Blood gases, glucose, calcium, electrolytes, white cell counts, and blood cultures were also normal. Simultaneous electrocardiographic and respiratory monitoring showed that bradycardia (Fig. 1B) consistently preceded apnea. During these sudden attacks, there was marked sinus bradycardia with occasional junctional escapes (heart rate 40-80 per

minute).

Atropine (0.01 mg/kg q8h orally) was started at age 45 days and the spells decreased in frequency and severity. When atropine was increased to 0.011 mg/kg q4h at the age of 48 days, no further attack was observed. At 51 days of age, the infant became ill with aspiration pneumonia. The atropine was replaced by ephedrine sulfate (0.75 mg/kg q6h orally), to avoid the &dquo;drying effect&dquo; of the former. No further bradycardiac attack wa~s observed. Ephedrine sulfate was therefore reduced to 0.5 mg/kg q6h and then to 0.25 mg/kg q6h. It was discontinued at age 64 days. Three days later, bradycardia preceding apneic spells recurred as documented again by simultaneous electrocardiographic and respiratory monitoring. These spells were controlled by 0.5 mg/kg q6h of ephedrine sulfate. The dose of ephedrine given was gradually reduced and discontinued at age 99 days. At age 113 days, she had another attack of bradycardia preceding apnea. Ephedrine sulfate (0.5 mg/kg q6h orally) was reinstituted until age 122 days. She had no further attacks and was discharged at age 132 days, when her body weight was 3,390 g. The infant remained well and was neurologically normal on follow-up one month after discharge. Discussion

FIG. 1. Figures A and B are representive EKGs of Case I and Case 2, respectively, during bradycardia preceding apnea spells. Note the absence of P waves and the narrow QRS complexes that indicate junctional (nodal) bradycardia.

The frequency of apneic attacks preceded by severe bradycardia in premature infants is unknown. It seems probable that some infants may die of apnea without the preceding bradycardia being suspected or detected. In 1964, Lipton et al. 4 reported that bradycardia was frequently associated with increased vagal activity during hiccups, yawning, defecation and nasogastric intubation in

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newborn infants. No such association was observed in our two patients. Church et al.5 observed sinus arrhythmia in 30 lowbirthweight infants. Ninety per cent of these had marked bradycardia, frequently accompanied by nodal escape. Morgan et al.~6 reported marked sinus bradycardia (a 50% decrease in heart rate within 10 seconds) in 8 of 20 premature infants, and bradycardia associated with nodal escape in 5. Girling2 observed that only 4 of 51 apneic attacks in 8 infants were preceded by a fall of heart rate. The pathogenesis of severe bradycardia in premature infants is not well defined. Church 5 et awl. suggested that autonomic nervous system &dquo;immaturity&dquo; might be a factor in the production of arrhythmia in the premature infants and a cause of sudden death. Rigatto and Brady7>8 suggested that the major defect of hypoventilation in premature infants was neither in the lung nor in the peripheral chemoreceptors, but in the respiratory center (central receptors). Thus hypoxia might be a primary event leading to periodic breathing and apnea. More recent reports indicated that one could identify apneic episodes due to central respiratory chemoreceptor or peripheral respiratory pump failure.9,10 Although our patients had mild transient respiratory distress, their blood gases and blood pH were normal and their respiratory distress resolved with minimal intervention. This led us to conclude that their respiratory apparatus was intact. In addition, our patients had sinus bradycardia with junctional (A-V nodal) escape rhythm preceding apnea, indicating that bradycardia was a primary phenomenon. It seems probable, although it cannot be proven, that hypoxia secondary to severe bradycardia was the sequence of events leading to apneic spells in our two patients. The cause of the bradycardia remains

speculative. In

1973, Baehmanll observed that stimulat-

ing the intact vagal nerve in unanesthetized monkeys resulted in apnea, bradycardia, and cardiac arrhythmia. Bachman and Steinschneider suggested that atropine might be able to overcome vagal overactivity. 12 On the other hand, Ingman, et al. 13 observed that

infants treated with

atropine continued to have prolonged apneic episodes even though the concommitant bradycardia was delayed. Phillips, et all. demonstrated increased parasympathetic response to cardioinhibitory StiMUli.14 Because of these observations, we attempted to counteract the negative chrono-

tropic response which was probably vagal in origin. Although we cannot exclude central nervous

patients,

system abnormalities in our two the favorable effect of atropine and

probable, although it cannot be hypoxia secondary to severe bradycardia was the sequence of events leading to apneic spells in our two patients. The cause of the bradycardia remains speculative. It

seems

proven, that

ephedrine on these infants suggests vagal overactivity. Atropine competes with acetylcholine, the parasympathetic, postganglionic neurotransmitter, at the receptor site. Hence, atropine prevents or reduces the vagal effect and allows increased sympathetic tone. In the heart, this would block the inhibition of pacemaking and thereby prevent bradycardia. 15 With both of our patients, atropine was effective. With the second patient, atropine was discontinued during the treatment for aspiration pneumonia because it would decrease the secretion of the mucous glands by inhibiting vagal stimulation. Ephedrine sulfate, a sympathomimetic, was given in its place because of its beta stimulating properties, to increase pacemaker automaticity and con-

tractility. ~& Management Atropine toxicity is due to sympathetic blockade resulting in tachycardia, abdominal distension, constipation, and urinary retention. Ephedrine toxicity is due to sympathetic discharge resulting in tachycardia and irritability. As experience with these agents is limited in small infants, doses should be kept at a

minimum for the desired effect. Furthera salutory response is observed,

more, once

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the drug doses should be decreased to prevent

toxicity. In infants with prolonged apnea, it would appear advisable to search carefully for sudden bradycardia when other causes of apnea (such as pulmonary pathology, hypoglycemia, along with hypocalcemia and CNS abnormalities) can be excluded. Atropine or ephedrine, cardiac and respiratory monitoring, may be required for the infant in order to prevent sudden death. As most intensive care nurseries are not equipped with direct writeout-ECG-monitors with a memory loop, the instances here reported may serve as an impetus for others to look for bradycardia preceding apnea by simultaneous recording of respiration and electrocardiogram in premature infants. An unequivocal documentation of severe bradycardia as the antecedent of apnea is essential before treatment zuith atropine or other vagal blockers should be considered. Recent observations9,10 on the importance of peripheral vagal influence to respiratory drive in small premature infants make the use of atropine potentially lethal when the apnea is due to mechanisms other than severe bradycardia.

References 1.

Jacobson,

H. N., and

5.

6.

7.

8.

9.

10.

11.

12. 13.

14.

15.

Windle, W. F.: Responses of

fetal and newborn monkeys to asphyxia. J. Physiology 153: 447, 1960. 2. Girling, D.J.: Changes in heart rate, blood pressure, and pulse pressure during apneic attacks in newborn babies. Arch. Dis. Child. 47: 405, 1972. 3. Steinschneider, A.: Prolonged apnea and the sudden infant death syndrome: clinical and laboratory observations. Pediatrics 50: 646, 1972. 4. Lipton, E. L., Steinschneider, A., and Richmond, J.

16.

B.: Autonomic function in the neonate. VIII. Cardiopulmonary observations. Pediatrics 33: 212, 1964. Church, S. C., Morgan, B. C., Oliver, T. K., Jr., and Guntheroth, W. G.: Cardiac arrhythmias in premature infants: an indication of autonomic immatur: 542, 1967. ity ? J. Ped. 71 Morgan, B. C., Bloom, R. S., and Guntheroth, W. G.: Cardiac arrhythmia in premature infants. Pediatrics 35: 658, 1965. Rigatto, H., and Brady, J. P.: Periodic breathing and apnea in preterm infants. I. Evidence for hypoventilation possibly due to central respiratory depression. Pediatrics 50: 202, 1972. —, and Brady, J. P.: Periodic breathing and apnea in preterm infants. II. Hypoxia as a primary event. Pediatrics 50: 219, 1972. Frantz, I. D. III, Taeusch, W. Jr., Wyszogrodski, I., Whitclaw W., Milic-Emile, J., and Avery, M. E.: Respiratory center output in infants as indicated by inspiratory pressure during airway occlusion. Ped. Res. 8: 193, (Abst), 1974. Cosgrove, J., Cooper, D., Bryan, A. C., Neuburger, N., and Levison, H.: A new method of evaluating the chemosensitivity of the respiratory center in children. Ped. Res. 8: 192, (Abst), 1974. Bachman, D. S.: A technique for vagal stimulation in chronic experiments. J. Appl. Physiol. 33: 402, 1972. Bachman, D. S.: Prolonged apnea, vagal overactivity and sudden death. Pediatrics 51: 755, 1973. Ingman, M. J., Ackerman, B. D., Kearns, M. S., and Sattler, F. P.: Bradycardia—an early indicator of apnea in premature infants. JAMA 211: 1622, 1970. Phillips, S. J., Agate, F. J., Silverman, W. A., and Steiner, P.: Autonomic cardiac reactivity in premature infants. Biol. Neonat. 6: 225, 1964. Innes, I. R., and Nicherson, M.: Drugs inhibiting the action of acetylcholine on structures innervated by postganglionic parasympathetic nerves. In Pharmacologic Basis of Therapeutics, Goodman, L. S., and Gilman, A., Eds. New York, Macmillan Company, 1968.

Drugs acting on postganglionic adrenergic nerve ending and structures innervated by them. In Pharmacologic Basis of Therapeutics, Goodman, L. S., and Gilman, A., Eds. New York, Macmillan

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Bradycardia preceding apneic attacks in low-birthweight infants. The relationship and management.

Two premature infants had frequent episodes of prolonged apnea. The apneic spells were not due to the more commonly known causes of apnea in infancy, ...
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