FETAL
AND
MEDICINE
NEONATAL Richardr. Behrman,Editor
Physiologic changes induced by theophylline in the treatment of apnea in preterm infants Ten preterm infants (birth weight 0.970 to 2.495 kg) with apnea due to periodic breathing (apneic interval = 5 to 10 seconds) or with "serious apnea'" (>_ 20 seconds) were studied before and after the administration of theophylline. We determined the incidence of apnea, respiratory minute volume, alveolar gases, arterial gases and pH, "specifc'" compliance, functional residual capacity, and work of breathing. Theophyl#ne decreased the incidenee of apnea (P < .05), increased respiratory minute volume (P < 0.001), deereitsed (PAco 2 (and Paco 2 P < 0.001), increased the slope of the CO~ response curve (P < 0.02) with a significant shift to the left (P < 0.02). These ftndings suggest that the decreased incidence of apnea after theophylline is associated with an increase in alveolar ventilation and increased sensitivity to CO~ with a pronounced shift of the CO~ response curve to the left. These data are consistent with the idea that apnea is a reflection of a depressed respiratory system.
Maria J. Davi, M.D., Koravangattu Sankaran, M.D., Keith J. Simons, Ph.D., F. Estelle R. Simons, M.D., Mary M. Seshia, M.B., Ch.B., and Henrique Rigatto, M.D.,* Winnipeg, Manitoba, Canada
IN 1 954, while studying preterm infants with periodic breathing, Cross 1 suggested that almost anything that stimulates respiration would tend to make breathing regular. Indeed, it does. Increased inspired 02, increased inspired CO2, and mechanical stimulation tend to stimulate breathing and reduce respiratory periodicity. Recent studies have shown that an old respiratory s t i m u l a n t theophylline-also reduces apnea in preterm infants? Because of the great promise attached to this discovery, we attempted to answer the question: What does theo-
From the Department of Paediatrics, University of Manitoba. Supported by a grant from the Medical Research Council of Canada (MA-4980) and by grants from The Children's Hospital of Winnipeg Research Foundation, Inc. Presented in part at the meeting of The Society for Pediatric Research, April, 1976, St. Louis, 34o. *Reprint address: Women's Centre, Health Sciences Centre, 700 William Ave., Winnipeg, Manitoba, R3E OZ3 Canada.
phylline do to respiration in order to reduce apnea in preterm infants?
SUBJECTS We studied ten preterm infants, 3 chiefly with periodic breathing (apneic interval = 5 to 10 seconds) and seven with "serious apnea" (apneic interval _> 20 seconds) before and 48 to 96 hours after the administration of Abbreviations used Po2: partial pressure of oxygen Pco2: partial pressure of carbon dioxide PAcoz: partial pressure of alveolar carbon dioxide Paco2: partial pressure of arterial carbon dioxide respiratory minute volume V~: FRC: functional residual capacity work of breathing theophylline. Mean gestational age (-+ SE) was 30 _+. 2 weeks; mean birth weight, 1,350 _+ 170 gin. Mean postnatal age was 16 + 3 days. There were five males and five females. Biochemical abnormalities, infection, and pulmonary disease were excluded before including the
The Journal o f P E D I A T R I CS Vol. 92, No. 1, pp. 91-95
91
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Davi et aL
The Journal of Pediatrics January 1978
Table I. Physiological changes induced by theophyltine in preterm infants with apnea
Infants 1 2 3 4 5 6 7 8 9 10 Mean _+SE P
Age (days)
Birth weight (gin)
17 25 39 15 17 6 6 16 16 2 16 _+3
1,180 1,260 l,lO0 980 1,210 2,495 2,240 970 1,120 960 1,350 _+173
No. of apnea/hr Before falter* 110 0 1 0 60 20 40 54 16 5 26 0 12 0 140 0 135 18 7 9 55 11 _+17 _+5 < 0.05
l~E (l/min/kg) Before
PACO~ (ram Hg)
After
0.243 0.368 0.343 0.364 0.270 0.308 0.278 0.356 0.242 0.323 0.219 0.334 0.204 0.344 0.244 0.361 0.220 0.321 0.202 0.230 0.246 0.331 _+0.013 _+0.013 < 0.001
Before I After 58 48 44 36 48 38 50 38 46 45 46 40 41 33 51 34 45 34 41 38 47 38 _+2 _+2 < 0,001
PAo2 (ram Hg) Before
After
174 176 88 104 152 157 154 164 222 228 93 98 96 103 88 112 158 172 169 167 139 148 _+15 _+13 < 0.01
Paco2 (ram Hg) Before
After
69 53 48 38 46 27 53 37 46 42 49 29 38 29 40 35 52 47 41 31 48 37 _+3 _+3 < 0.001
*Forty-eightto 96 hours after theophyllinehad been given every 6 hours, 3 rag/kg/dose. "}'Calculatedat "~E= 0.3 1/min/kg. infant in the study. F o u r infants had evidence of a patent ductus arteriosus. METHODS We have described the system to measure ventilation previously. ~r Briefly, we used a nosepiece and a flowmeter to measure respiratory minute volume and alveolar gases. We eliminated valves and reduced dead space by using a constant background flow (2.7 1/minute) that was electrically balanced to an artificial zero. The infant breathed through the nostril adapters and added to (expiration) or subtracted from (inspiration) the background flow. The flow signal was electrically integrated to give volume. We monitored breath-to-breath Po2 and Pc% using a catheter (PE 20) connected to a vacuum pump (Precision Scientific Co., Vac Tort 25). O2 and CO2 analyzers (Beckman OM-11 and LB2) were used in series as described elsewhere? A n air-filled intraesophageal balloon (2.5 • 1 cm, Youngs R u b b e r Co.) was connected to a Statham PM 5 pressure transducer to measure intraesophageal pressure. 9 Functional residual capacity was measured by Strang and McGrath's 7 adaptation of the N2 washout method described by Fowler and coworkers, s Blood samples were obtained from the temporal artery and analyzed for Pr Po~, and pH in a conventional blood gas machine (IL 113). Alveolar Pco~ during apnea was calculated according to the method previously described? The procedure was explained to the mother and her written consent obtained. The infants were studied on the
Ohio Neonatal Intensive Care Unit shortly after feeding. A b d o m i n a l skin temperature was kept at 36.5 ___ 0.003~ A 25-gauge scalp sample needle was inserted i n a temporal artery and a blood sample drawn while minute ventilation and alveolar Pco2 were recorded for a short interval (2 to 3 minutes). After removing the arterial line, the intraesophageal balloon was placed in the lower third of the esophagus. The infant was then allowed to breathe t h e control O2 mixture, usually 21% O2 or slightly above, then the same concentration plus 2 to 3% COs for 5 minutes. In infants, as opposed to adults, the increase in CO2 produces a substantial increase in ventilation. Considering that the CO2 response is linear in these infants, this challenge is adequate to assess the COs response curve? After discontinuing CO2 and when breathing returned to baseline levels, a N2 washout was obtained by having the infant breathing 100% 02. A representative tracing is shown in Fig. 1. After the study, theophylline was administered to the infant, 3 mg/kg, every 6 hours. The first dose was given intravenously and the others orally. Serum levels of the drug were monitored at 1, 2, 3, 6, and 48 hours and every 48 to 96 hours thereafter. Frequent measurements, determined by methods previously described, were part of a study which is trying to define the pharmacokinetics of this drug in preterm infants.during the neonatal period. 9 A second study of the physiologic variables was performed 48 to 96 hours later. We determined incidence of apnea (>__ 5 seconds), respiratory minute volume and frequency, alveolar Pco~
Volume 92 Number 1
Theophylline in preterm infants with apnea
93
C02 response Pao= (ram Hg) Before ] After 115 43 50 107 57 58 72 70 66 63 70 -+7
105 60 104 68 68 80 76 62 64 110 80 _+6 N.S.
pH
FB C (ml/kg)
Csp (em H~O-1)
Work of breathing (g em/mi)
Slope (1/min/ kg /mm Hg)
Position4( (mm Hg)
Before ] After
Before ] After
Before I After
Before I After
Before I After
Before After
7.21 7.39 7.33 7.38 7,35 7.38 7.28 7.37 7.34 7.36 7.35 7.40 7.34 7.36 7.40 7.40 7.26 7.33 7.36 7.40 7.32 7.38 _+0.02 +0.01 < 0.01
60 34 23 35 30 35 49 57 27 46 40 +4
47 23 21 29 25 57 56 31 32 52 37 -+4 N.S.
0.133 0.108 0.038 0.063 0.210 0.128 0.073 O.110 0.124 0.124 0.095 0.067 0.069 0.078 O.100 O.136 0.240 0.122 0.163 0:129 0.125 0.107 +0.020 _+0.009 N.S.
and Po2, heart rate, ventilatory response to CO2, functional residual capacity, "specific" compliance, and work of breathing. Measurements were made from 3 to 5 minutes while {he infant was breathing the various gas mixtures. The work of breathing was calculated by planimetry from pressure volume curves. To obtain volume for this calculation, we turned off the rectifier and recorded breath-to-breath changes in volume. The CO2 response curve was calculated from minute ventilation and PAco2 while the infant was breathing control O2 concentrations and when 2 to 3% COs was added. The incidence of apnea was determined from recordings of the infant's respirations for approximately 30 minutes during each study. We used the paired t test to assess the significance of the differences between values obtained before and after the administration of theophylline.
RESULTS Results are summarized in Table 1. Theophylline produced a decrease in the n u m b e r of apneic episodes from 55 to 11 per hour (P < 0.05). This was associated with an increase in average VE from 0.246 to 0.331 1 / m i n u t e / k g (P < 0.00l). The increase in V~: was mostly due to an increase in tidal volume (P < 0.05). Alveolar and arterial Pco2 decreased (P < 0.001), and this was associated w i t h an increase in p H (P < 0.01). PAo~ increased (P < 0.01), but the increase in Pao~ was not significant. Theophylline also increased the slope of the COs response curve from 0.012 _+ 0.004 to 0.045 _+ 0.010
131 421 1,070 1,238 331 714 416 496 423 270 970 1,178 587 1,613 154 502 164 245 73 78 432 676 _+111 --+159 < 0.05
0.025 0.079 0 . 0 0 3 0.028 0.008 0.088 0 . 0 4 5 0.027 0 . 0 1 1 0.002 0.002 0.049 0.002 0.026 0 . 0 1 4 0.088 0.004 0.060 0 . 0 0 3 0.003 0 . 0 1 2 0.045 _+0.004 _+0.010 < 0.02
60 36 30 35 46 38 50 36 50 38 85 39 68 30 55 34 24 34 71 61 54 38 _+6 _+3 < 0.02
1 / m i n u t e / k g / m m PAco 2 (P < 0.02) (Fig. 2), and produced a pronounced shift to the left (P < 0.02). F R C and Csp did not change with theophylline, but Vq increased proportionately to the increase in "q~ (P < 0.05). Serum levels of theophylline ranged from 15 to 41.1 /xg/ml; toxic levels were, for practical purposes, absent. DISCUSSION We found that theophylline administered to preterm infants with periodic breathing or apnea (1) decreased the incidence of apnea; (2) this decrease was associated with an increase in alveolar ventilation, an increased sensitivity to CO2, and a pronounced shift of the COs response curve to the left; and (3) lung mechanics, as measured by specific compliance, were not affected by use of this drug. The data are consistent with the idea that apnea is a reflection of a depressed respiratory system. Our findings agree with previous observations that theophylline reduces or abolishes periodic breathing or apnea in small infants. 2' 10, 11K u z e m k o and Paala 2 showed that in preterm infants " . . . apnoeic attacks ceased or became infrequent after administration of aminophylfine . . . . " Shannon and associates TM showed that theophylline " . . . completely controlled apneic spells exceeding 20 sec in duration and markedly reduced 10-19-sec apneic episodes and any resultant bradycardia." U a u y and associates 11 also showed a " . . . significant reduction in the m e a n daily number and the severity of apneic episodes after treatment." Therefore, the experience is now
94
Davi et al.
The Journal of Pediatrics January 1978
Ap 0 H2O
~
cm
-4 VOLUMErnl2
6
-
/
~
0-3-
L/rain
10~ %C02
50%02
0
beats/min
I OJ
BEFORE
AFTER
Fig. 1. Representative tracing with infant breathing periodically before and regularly 48 hours after the administration of theophylline (Infant 1, 29 weeks, 1,150 gin). Small fluctuations in background flow are due to cardiac artifact.
.500 .400 AFTER
~/E .300 L/Kg/min
,/ BEFORE
,200
SLOPE P< 0,02 INTERCEPT p< 0.02
,100 0l
I 30
410
L 50
I 60
I 70
PA CO2 rnm Hg
Fig. 2, Steady-state CO~ response curves before and after administration of theophylline. The average slope of the curve increased significantly, and there was a pronounced shift to the left. convincing that theophylline is effective in reducing or abolishing apnea of prematurity. I n adult subjects aminophylline also tends to abolish Cheyne-Stokes respiration.~~' 1~ This is intriguing because in adults the disregulation of respiration during periodic breathing is thought to be associated with hyperventilation and high sensitivity of the respiratory control system (Sensitivity - A ~E/hPAco~) , whereas in preterm infants it is associated with hypoventilation and low sensitivity?. 14 Why should theophylline or other related drugs abolish periodicity in a highly sensitive system when ventilation is already increased? Th6 answer to this question is unknown. Our speculation is that 'the stimulus
induced by theophylline to drive ventilation is so strong that no matter whether the oscillation is associated with high or low sensitivity, breathing will become regular. Some analogy can be made between our physiologic measurements and those in adult subjects with CheyneStokes respiration. In them theophylline abolishes periodicity by inducing hyperventilation with decrease in arterial Pco~. 1~, 13, ~ The CO~ response curve is also shifted to the left, but there is no major change in slope. These patients, however, have normal or slightly decreased resting Pco~. Our infants had high resting Paco ~ and the increase in the slope of the CO~ response curve may have been a reflection of the flat response at this high resting Paco 2. What theophylline does in order to increase ventilation is unknown. The action is most likely central, as the response is similar to that of caffeine, a drug that lacks some of the peripheral effects of theophylline. The mechanism at cellular level is even more complex. Theophylline increases the intracellular concentration of 3'5 cyclic AMP. 17 Whether this increase at the central nervous system level leads to respiratory stimulation is a subject worth investigating. In general, theophylfine was well tolerated by our infants. Of its known toxic effects, tachycardia above 180 beats per minute was the most common complication, and vomiting occurred in two infants. This was relieved easily by either skipping a dose or reducing the dosage. Because the extension of the toxic effects of this drug are not well known in preterm infants, its use must be closely
~176
Volume 92 Number 1
supervised. Safe serum levels h a v e not yet b e e n defined a n d changes in cerebral b l o o d flow s h o u l d be assessed in these infants, since adults h a v e s h o w n a 33% decrease in cerebral b l o o d flow with the a d m i n i s t r a t i o n of theophylline. U n t i l such answers are obtained, this drug must b e used with caution. TM
CONCLUSION W e studied ten p r e t e r m infants with periodic b r e a t h i n g or a p n e a before a n d 48 hours after the a d m i n i s t r a t i o n of theophylline. This drug was i n d e e d very effective in reducing or abolishing a p n e a in p r e t e r m infants. This was associated with a p r o n o u n c e d increase in alveolar ventilation a n d a n increase in the slope of the ventilatory response to COx with a shift to the left. T h e use o f theophylline was simple, a n d side effects, such as tachycardia a n d vomiting, were easily controlled. W e suggest, however, t h a t a n a t t e m p t should be m a d e to limit the a d m i n i s t r a t i o n of this drug until the p h a r m a c o k i n e t i c s a n d influence on cerebral blood flow h a v e b e e n elucidated. We acknowledge the invaluable help and advice of Dr. Victor Chernick, the skillful technical assistance of Don Cates and Marilyn MacCallum, and we thank Marilyn Szajcz for typing and helping in the preparation of the manuscript. REFERENCES
1. Cross KW: Respiratory patterns, in Wolfe H, editor: Mechanisms of congenital malformation, Proceedings of the Second Scientific Conference, New York, 1954, Association for the Aid of Crippled Children, pp 99-105. 2. Kuzemko JA, and Paala J: Apnoeic attacks in the newborn treated with aminophylline, Arch Dis Child 48:404, 1973. 3. Rigatto H, and Brady JP: Periodic breathing and apnea in preterm infants. I. Evidence for hypoventilation possibly d!le to central respiratory depression, Pediatrics 50:202, 1972.
.,
Theophylline in preterm infants with apnea
95
4. Rigatto H, and Brady JP: A new nosepiece for measuring ventilation in preterm infants, J Appl Physiol 32:423, 1972. 5. Rigatto H, de la Torre Verduzco R, and Cates DB: Effects of O~ on the ventilatory response to CO2 in preterm infants, J Appl Physiol 39:896, 1975. 6. Mead J, McIlroy MB, Selverstone N J, et al: Measurement of intraesophageal pressure, J Appl Physiol 7:491, 1955. 7. Strang LB, and McGrath MW: Alveolar ventilation in normal newborn infants studied by air wash-in after oxygen breathing, Clin Sci 23:129, 1962. 8. Fowler WS, Cornish ER, and Kety SS: Lung function studies. VIII. Analysis of alveolar ventilation by pulmonary N~ clearance curves. J Clin Invest 31:40, 1952. 9. Johnson GF, Dechtiaruk WA, and Solomon HM: Gaschromatographic determination of theophylline in human serum and saliva, Clin Chem 21"144, 1975. 10. Shannon DC, Gotay F, Stein IM, et al: Prevention of apnea and bradycardia in low-birthweight infants, Pediatrics 55"589, 1975. 11. Uauy R, Shapiro DL, Smith B, et al: Treatment of severe apnea in prematures with orally administered theophylline, Pediatrics 55"595, 1975. 12. Dowell AR, Heyman A, Sieker HO, et al: Effect of aminophylline on respiratory-center sensitivity in CheyneStokes respiration and in pulmonary emphysema, N Engl J Med 273:1447, 1965. 13. Marais OAS, and McMichael J: Theophylline-ethylenediamine in Cheyne-Stokes respiration, Lancet 2:437, 1937. 14. Plum F, and Brown WH: The effect on respiration of central nervous system disease, Ann NY Acad Sci 109:915, 1963. 15. Burnard ED, Brattan-Smith P, Pictorn-Warlow CG, et al: Pulmonary insufficiency in prematurity, Aust Paediatr J 1:12, 1965. 16. Moyer JH, Miller SI, Tashnek AB, et al: The effect of theophylline with ethylenediamine (aminophylline) on cerebral hemodynamics in the presence of cardiac failure with and without Cheyne-Stokes respiration, J Clin Invest 31:267, 1952. 17. Simons FER, Pierson WE, and Bierman CW: Current status of the use of theophylline in children, Pediatrics 55:735, 19751
AND
MEDICINE
NEONATAL Richardr. Behrman,Editor
Physiologic changes induced by theophylline in the treatment of apnea in preterm infants Ten preterm infants (birth weight 0.970 to 2.495 kg) with apnea due to periodic breathing (apneic interval = 5 to 10 seconds) or with "serious apnea'" (>_ 20 seconds) were studied before and after the administration of theophylline. We determined the incidence of apnea, respiratory minute volume, alveolar gases, arterial gases and pH, "specifc'" compliance, functional residual capacity, and work of breathing. Theophyl#ne decreased the incidenee of apnea (P < .05), increased respiratory minute volume (P < 0.001), deereitsed (PAco 2 (and Paco 2 P < 0.001), increased the slope of the CO~ response curve (P < 0.02) with a significant shift to the left (P < 0.02). These ftndings suggest that the decreased incidence of apnea after theophylline is associated with an increase in alveolar ventilation and increased sensitivity to CO~ with a pronounced shift of the CO~ response curve to the left. These data are consistent with the idea that apnea is a reflection of a depressed respiratory system.
Maria J. Davi, M.D., Koravangattu Sankaran, M.D., Keith J. Simons, Ph.D., F. Estelle R. Simons, M.D., Mary M. Seshia, M.B., Ch.B., and Henrique Rigatto, M.D.,* Winnipeg, Manitoba, Canada
IN 1 954, while studying preterm infants with periodic breathing, Cross 1 suggested that almost anything that stimulates respiration would tend to make breathing regular. Indeed, it does. Increased inspired 02, increased inspired CO2, and mechanical stimulation tend to stimulate breathing and reduce respiratory periodicity. Recent studies have shown that an old respiratory s t i m u l a n t theophylline-also reduces apnea in preterm infants? Because of the great promise attached to this discovery, we attempted to answer the question: What does theo-
From the Department of Paediatrics, University of Manitoba. Supported by a grant from the Medical Research Council of Canada (MA-4980) and by grants from The Children's Hospital of Winnipeg Research Foundation, Inc. Presented in part at the meeting of The Society for Pediatric Research, April, 1976, St. Louis, 34o. *Reprint address: Women's Centre, Health Sciences Centre, 700 William Ave., Winnipeg, Manitoba, R3E OZ3 Canada.
phylline do to respiration in order to reduce apnea in preterm infants?
SUBJECTS We studied ten preterm infants, 3 chiefly with periodic breathing (apneic interval = 5 to 10 seconds) and seven with "serious apnea" (apneic interval _> 20 seconds) before and 48 to 96 hours after the administration of Abbreviations used Po2: partial pressure of oxygen Pco2: partial pressure of carbon dioxide PAcoz: partial pressure of alveolar carbon dioxide Paco2: partial pressure of arterial carbon dioxide respiratory minute volume V~: FRC: functional residual capacity work of breathing theophylline. Mean gestational age (-+ SE) was 30 _+. 2 weeks; mean birth weight, 1,350 _+ 170 gin. Mean postnatal age was 16 + 3 days. There were five males and five females. Biochemical abnormalities, infection, and pulmonary disease were excluded before including the
The Journal o f P E D I A T R I CS Vol. 92, No. 1, pp. 91-95
91
92
Davi et aL
The Journal of Pediatrics January 1978
Table I. Physiological changes induced by theophyltine in preterm infants with apnea
Infants 1 2 3 4 5 6 7 8 9 10 Mean _+SE P
Age (days)
Birth weight (gin)
17 25 39 15 17 6 6 16 16 2 16 _+3
1,180 1,260 l,lO0 980 1,210 2,495 2,240 970 1,120 960 1,350 _+173
No. of apnea/hr Before falter* 110 0 1 0 60 20 40 54 16 5 26 0 12 0 140 0 135 18 7 9 55 11 _+17 _+5 < 0.05
l~E (l/min/kg) Before
PACO~ (ram Hg)
After
0.243 0.368 0.343 0.364 0.270 0.308 0.278 0.356 0.242 0.323 0.219 0.334 0.204 0.344 0.244 0.361 0.220 0.321 0.202 0.230 0.246 0.331 _+0.013 _+0.013 < 0.001
Before I After 58 48 44 36 48 38 50 38 46 45 46 40 41 33 51 34 45 34 41 38 47 38 _+2 _+2 < 0,001
PAo2 (ram Hg) Before
After
174 176 88 104 152 157 154 164 222 228 93 98 96 103 88 112 158 172 169 167 139 148 _+15 _+13 < 0.01
Paco2 (ram Hg) Before
After
69 53 48 38 46 27 53 37 46 42 49 29 38 29 40 35 52 47 41 31 48 37 _+3 _+3 < 0.001
*Forty-eightto 96 hours after theophyllinehad been given every 6 hours, 3 rag/kg/dose. "}'Calculatedat "~E= 0.3 1/min/kg. infant in the study. F o u r infants had evidence of a patent ductus arteriosus. METHODS We have described the system to measure ventilation previously. ~r Briefly, we used a nosepiece and a flowmeter to measure respiratory minute volume and alveolar gases. We eliminated valves and reduced dead space by using a constant background flow (2.7 1/minute) that was electrically balanced to an artificial zero. The infant breathed through the nostril adapters and added to (expiration) or subtracted from (inspiration) the background flow. The flow signal was electrically integrated to give volume. We monitored breath-to-breath Po2 and Pc% using a catheter (PE 20) connected to a vacuum pump (Precision Scientific Co., Vac Tort 25). O2 and CO2 analyzers (Beckman OM-11 and LB2) were used in series as described elsewhere? A n air-filled intraesophageal balloon (2.5 • 1 cm, Youngs R u b b e r Co.) was connected to a Statham PM 5 pressure transducer to measure intraesophageal pressure. 9 Functional residual capacity was measured by Strang and McGrath's 7 adaptation of the N2 washout method described by Fowler and coworkers, s Blood samples were obtained from the temporal artery and analyzed for Pr Po~, and pH in a conventional blood gas machine (IL 113). Alveolar Pco~ during apnea was calculated according to the method previously described? The procedure was explained to the mother and her written consent obtained. The infants were studied on the
Ohio Neonatal Intensive Care Unit shortly after feeding. A b d o m i n a l skin temperature was kept at 36.5 ___ 0.003~ A 25-gauge scalp sample needle was inserted i n a temporal artery and a blood sample drawn while minute ventilation and alveolar Pco2 were recorded for a short interval (2 to 3 minutes). After removing the arterial line, the intraesophageal balloon was placed in the lower third of the esophagus. The infant was then allowed to breathe t h e control O2 mixture, usually 21% O2 or slightly above, then the same concentration plus 2 to 3% COs for 5 minutes. In infants, as opposed to adults, the increase in CO2 produces a substantial increase in ventilation. Considering that the CO2 response is linear in these infants, this challenge is adequate to assess the COs response curve? After discontinuing CO2 and when breathing returned to baseline levels, a N2 washout was obtained by having the infant breathing 100% 02. A representative tracing is shown in Fig. 1. After the study, theophylline was administered to the infant, 3 mg/kg, every 6 hours. The first dose was given intravenously and the others orally. Serum levels of the drug were monitored at 1, 2, 3, 6, and 48 hours and every 48 to 96 hours thereafter. Frequent measurements, determined by methods previously described, were part of a study which is trying to define the pharmacokinetics of this drug in preterm infants.during the neonatal period. 9 A second study of the physiologic variables was performed 48 to 96 hours later. We determined incidence of apnea (>__ 5 seconds), respiratory minute volume and frequency, alveolar Pco~
Volume 92 Number 1
Theophylline in preterm infants with apnea
93
C02 response Pao= (ram Hg) Before ] After 115 43 50 107 57 58 72 70 66 63 70 -+7
105 60 104 68 68 80 76 62 64 110 80 _+6 N.S.
pH
FB C (ml/kg)
Csp (em H~O-1)
Work of breathing (g em/mi)
Slope (1/min/ kg /mm Hg)
Position4( (mm Hg)
Before ] After
Before ] After
Before I After
Before I After
Before I After
Before After
7.21 7.39 7.33 7.38 7,35 7.38 7.28 7.37 7.34 7.36 7.35 7.40 7.34 7.36 7.40 7.40 7.26 7.33 7.36 7.40 7.32 7.38 _+0.02 +0.01 < 0.01
60 34 23 35 30 35 49 57 27 46 40 +4
47 23 21 29 25 57 56 31 32 52 37 -+4 N.S.
0.133 0.108 0.038 0.063 0.210 0.128 0.073 O.110 0.124 0.124 0.095 0.067 0.069 0.078 O.100 O.136 0.240 0.122 0.163 0:129 0.125 0.107 +0.020 _+0.009 N.S.
and Po2, heart rate, ventilatory response to CO2, functional residual capacity, "specific" compliance, and work of breathing. Measurements were made from 3 to 5 minutes while {he infant was breathing the various gas mixtures. The work of breathing was calculated by planimetry from pressure volume curves. To obtain volume for this calculation, we turned off the rectifier and recorded breath-to-breath changes in volume. The CO2 response curve was calculated from minute ventilation and PAco2 while the infant was breathing control O2 concentrations and when 2 to 3% COs was added. The incidence of apnea was determined from recordings of the infant's respirations for approximately 30 minutes during each study. We used the paired t test to assess the significance of the differences between values obtained before and after the administration of theophylline.
RESULTS Results are summarized in Table 1. Theophylline produced a decrease in the n u m b e r of apneic episodes from 55 to 11 per hour (P < 0.05). This was associated with an increase in average VE from 0.246 to 0.331 1 / m i n u t e / k g (P < 0.00l). The increase in V~: was mostly due to an increase in tidal volume (P < 0.05). Alveolar and arterial Pco2 decreased (P < 0.001), and this was associated w i t h an increase in p H (P < 0.01). PAo~ increased (P < 0.01), but the increase in Pao~ was not significant. Theophylline also increased the slope of the COs response curve from 0.012 _+ 0.004 to 0.045 _+ 0.010
131 421 1,070 1,238 331 714 416 496 423 270 970 1,178 587 1,613 154 502 164 245 73 78 432 676 _+111 --+159 < 0.05
0.025 0.079 0 . 0 0 3 0.028 0.008 0.088 0 . 0 4 5 0.027 0 . 0 1 1 0.002 0.002 0.049 0.002 0.026 0 . 0 1 4 0.088 0.004 0.060 0 . 0 0 3 0.003 0 . 0 1 2 0.045 _+0.004 _+0.010 < 0.02
60 36 30 35 46 38 50 36 50 38 85 39 68 30 55 34 24 34 71 61 54 38 _+6 _+3 < 0.02
1 / m i n u t e / k g / m m PAco 2 (P < 0.02) (Fig. 2), and produced a pronounced shift to the left (P < 0.02). F R C and Csp did not change with theophylline, but Vq increased proportionately to the increase in "q~ (P < 0.05). Serum levels of theophylline ranged from 15 to 41.1 /xg/ml; toxic levels were, for practical purposes, absent. DISCUSSION We found that theophylline administered to preterm infants with periodic breathing or apnea (1) decreased the incidence of apnea; (2) this decrease was associated with an increase in alveolar ventilation, an increased sensitivity to CO2, and a pronounced shift of the COs response curve to the left; and (3) lung mechanics, as measured by specific compliance, were not affected by use of this drug. The data are consistent with the idea that apnea is a reflection of a depressed respiratory system. Our findings agree with previous observations that theophylline reduces or abolishes periodic breathing or apnea in small infants. 2' 10, 11K u z e m k o and Paala 2 showed that in preterm infants " . . . apnoeic attacks ceased or became infrequent after administration of aminophylfine . . . . " Shannon and associates TM showed that theophylline " . . . completely controlled apneic spells exceeding 20 sec in duration and markedly reduced 10-19-sec apneic episodes and any resultant bradycardia." U a u y and associates 11 also showed a " . . . significant reduction in the m e a n daily number and the severity of apneic episodes after treatment." Therefore, the experience is now
94
Davi et al.
The Journal of Pediatrics January 1978
Ap 0 H2O
~
cm
-4 VOLUMErnl2
6
-
/
~
0-3-
L/rain
10~ %C02
50%02
0
beats/min
I OJ
BEFORE
AFTER
Fig. 1. Representative tracing with infant breathing periodically before and regularly 48 hours after the administration of theophylline (Infant 1, 29 weeks, 1,150 gin). Small fluctuations in background flow are due to cardiac artifact.
.500 .400 AFTER
~/E .300 L/Kg/min
,/ BEFORE
,200
SLOPE P< 0,02 INTERCEPT p< 0.02
,100 0l
I 30
410
L 50
I 60
I 70
PA CO2 rnm Hg
Fig. 2, Steady-state CO~ response curves before and after administration of theophylline. The average slope of the curve increased significantly, and there was a pronounced shift to the left. convincing that theophylline is effective in reducing or abolishing apnea of prematurity. I n adult subjects aminophylline also tends to abolish Cheyne-Stokes respiration.~~' 1~ This is intriguing because in adults the disregulation of respiration during periodic breathing is thought to be associated with hyperventilation and high sensitivity of the respiratory control system (Sensitivity - A ~E/hPAco~) , whereas in preterm infants it is associated with hypoventilation and low sensitivity?. 14 Why should theophylline or other related drugs abolish periodicity in a highly sensitive system when ventilation is already increased? Th6 answer to this question is unknown. Our speculation is that 'the stimulus
induced by theophylline to drive ventilation is so strong that no matter whether the oscillation is associated with high or low sensitivity, breathing will become regular. Some analogy can be made between our physiologic measurements and those in adult subjects with CheyneStokes respiration. In them theophylline abolishes periodicity by inducing hyperventilation with decrease in arterial Pco~. 1~, 13, ~ The CO~ response curve is also shifted to the left, but there is no major change in slope. These patients, however, have normal or slightly decreased resting Pco~. Our infants had high resting Paco ~ and the increase in the slope of the CO~ response curve may have been a reflection of the flat response at this high resting Paco 2. What theophylline does in order to increase ventilation is unknown. The action is most likely central, as the response is similar to that of caffeine, a drug that lacks some of the peripheral effects of theophylline. The mechanism at cellular level is even more complex. Theophylline increases the intracellular concentration of 3'5 cyclic AMP. 17 Whether this increase at the central nervous system level leads to respiratory stimulation is a subject worth investigating. In general, theophylfine was well tolerated by our infants. Of its known toxic effects, tachycardia above 180 beats per minute was the most common complication, and vomiting occurred in two infants. This was relieved easily by either skipping a dose or reducing the dosage. Because the extension of the toxic effects of this drug are not well known in preterm infants, its use must be closely
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supervised. Safe serum levels h a v e not yet b e e n defined a n d changes in cerebral b l o o d flow s h o u l d be assessed in these infants, since adults h a v e s h o w n a 33% decrease in cerebral b l o o d flow with the a d m i n i s t r a t i o n of theophylline. U n t i l such answers are obtained, this drug must b e used with caution. TM
CONCLUSION W e studied ten p r e t e r m infants with periodic b r e a t h i n g or a p n e a before a n d 48 hours after the a d m i n i s t r a t i o n of theophylline. This drug was i n d e e d very effective in reducing or abolishing a p n e a in p r e t e r m infants. This was associated with a p r o n o u n c e d increase in alveolar ventilation a n d a n increase in the slope of the ventilatory response to COx with a shift to the left. T h e use o f theophylline was simple, a n d side effects, such as tachycardia a n d vomiting, were easily controlled. W e suggest, however, t h a t a n a t t e m p t should be m a d e to limit the a d m i n i s t r a t i o n of this drug until the p h a r m a c o k i n e t i c s a n d influence on cerebral blood flow h a v e b e e n elucidated. We acknowledge the invaluable help and advice of Dr. Victor Chernick, the skillful technical assistance of Don Cates and Marilyn MacCallum, and we thank Marilyn Szajcz for typing and helping in the preparation of the manuscript. REFERENCES
1. Cross KW: Respiratory patterns, in Wolfe H, editor: Mechanisms of congenital malformation, Proceedings of the Second Scientific Conference, New York, 1954, Association for the Aid of Crippled Children, pp 99-105. 2. Kuzemko JA, and Paala J: Apnoeic attacks in the newborn treated with aminophylline, Arch Dis Child 48:404, 1973. 3. Rigatto H, and Brady JP: Periodic breathing and apnea in preterm infants. I. Evidence for hypoventilation possibly d!le to central respiratory depression, Pediatrics 50:202, 1972.
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Theophylline in preterm infants with apnea
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4. Rigatto H, and Brady JP: A new nosepiece for measuring ventilation in preterm infants, J Appl Physiol 32:423, 1972. 5. Rigatto H, de la Torre Verduzco R, and Cates DB: Effects of O~ on the ventilatory response to CO2 in preterm infants, J Appl Physiol 39:896, 1975. 6. Mead J, McIlroy MB, Selverstone N J, et al: Measurement of intraesophageal pressure, J Appl Physiol 7:491, 1955. 7. Strang LB, and McGrath MW: Alveolar ventilation in normal newborn infants studied by air wash-in after oxygen breathing, Clin Sci 23:129, 1962. 8. Fowler WS, Cornish ER, and Kety SS: Lung function studies. VIII. Analysis of alveolar ventilation by pulmonary N~ clearance curves. J Clin Invest 31:40, 1952. 9. Johnson GF, Dechtiaruk WA, and Solomon HM: Gaschromatographic determination of theophylline in human serum and saliva, Clin Chem 21"144, 1975. 10. Shannon DC, Gotay F, Stein IM, et al: Prevention of apnea and bradycardia in low-birthweight infants, Pediatrics 55"589, 1975. 11. Uauy R, Shapiro DL, Smith B, et al: Treatment of severe apnea in prematures with orally administered theophylline, Pediatrics 55"595, 1975. 12. Dowell AR, Heyman A, Sieker HO, et al: Effect of aminophylline on respiratory-center sensitivity in CheyneStokes respiration and in pulmonary emphysema, N Engl J Med 273:1447, 1965. 13. Marais OAS, and McMichael J: Theophylline-ethylenediamine in Cheyne-Stokes respiration, Lancet 2:437, 1937. 14. Plum F, and Brown WH: The effect on respiration of central nervous system disease, Ann NY Acad Sci 109:915, 1963. 15. Burnard ED, Brattan-Smith P, Pictorn-Warlow CG, et al: Pulmonary insufficiency in prematurity, Aust Paediatr J 1:12, 1965. 16. Moyer JH, Miller SI, Tashnek AB, et al: The effect of theophylline with ethylenediamine (aminophylline) on cerebral hemodynamics in the presence of cardiac failure with and without Cheyne-Stokes respiration, J Clin Invest 31:267, 1952. 17. Simons FER, Pierson WE, and Bierman CW: Current status of the use of theophylline in children, Pediatrics 55:735, 19751
