Alterations in state in apneic pre-term infants receiving theophylline The present study is a report on 9 premature infants treated with aminophylline for relief of apnea. With serum theophylline levels of 2 to 10 p.g/ml, all infants experienced significant decrease of apneic episodes in association with increased wakefulness and increased amounts of active (REM) sleep. These effects may occur independently, but it is possible that the alteration of sleep states may be partially responsible for the decrease in apneic episodes in these infants.
Jeanne Dietrich, B.A., Alfred N. Krauss, M.D., Marcus Reidenberg, M.D., Dennis E. Drayer, Ph.D., and Peter A. M. Auld, M.D. New York, N. Y. The Perinatology Center and the Departments of Pediatrics, Pharmacology, and Medicine, The New York Hospital-Cornell Medical Center
Apnea of prematurity is an important problem in the pre-term infant. It is often associated with serious systemic illness, such as infection, hypoglycemia, or central nervous system hemorrhage. 12 In many instances, no specific cause of apnea is found and nonspecific therapy must be initiated. Respiratory stimulants have been used to treat apnea of prematurity. 3, 14, 19, 20 In particular, theophylline has been shown to increase minute volume, to increase sensitivity to elevated levels of carbon dioxide, and to reduce the frequency and severity of apneic spells in pre-term infants. The purpose of our report is to compare the sleep-wake characteristics of infants before and during the administration of aminophylline (theophylline ethylenediamine) for the relief of the apnea of prematurity.
Received for publication June 17, 1978. Accepted for publication July II, 1978. Reprint requests to: Dr. Alfred N. Krauss, Perinatology Center, Department of Pediatrics, New York Hospital, 525 E. 68th St., New York, NY 10021.
474
Methods and materials
Our subjects were 9 infants, ranging from 26 to 32 wk gestational age at birth and weighing 840 to 1,200 gm at birth. Infants were considered for theophylline therapy when clinicians and nurses caring for the infants noted an apparently high incidence of apnea and bradycardia unresponsive to simple stimulation and often associated with cyanosis. All infants were patients in the Neonatal Intensive Care Unit at the New York Hospital. Infants were monitored within 6 hr before the initiation of theophylline therapy and again 24 to 36 hr after therapy had been initiated. Clinical monitoring included measurement of heart rate, derived from R-R intervals obtained from standard electrocardiographic leads, and impedance monitoring of respiration from two transthoracic electrodes. State was determined by direct behavioral observation of the infant concurrently with two bipolar electroencephalograph channels with the use of motor-parietal and anterioposterior lead placements. Electro-
0009-9236/78/100474+05$00.50/0 © 1978 The C. V. Mosby Co.
Volume 24 Number 4
encephalographic and impedance monitoring of respiration were performed simultaneously. The record and observations were divided into 20-sec epochs. With standard electroencephalographic and behavioral criteria,l. 16 each epoch was classified into 1 of 4 states. Waking was identified by open eyes and a characteristic electroencephalogram. Quiet non-REM sleep was identified by quiet activity, lack of gross body movements except for occasional startle movements, and a characteristic electroencephalographic pattern. REM sleep was identified by closed eyes and visible eye movements beneath closed lids, frequent facial movements, and the characteristic electroencephalographic pattern associated with this state. Transitional sleep characterized epochs which did not completely meet the criteria of either REM or nonREM sleep. Bradycardia was defined as a heart rate under 100 beats/min. Apnea was defined as the absence of respiratory movements on the impedance tracing for at least 10 sec. The apnea attack rate was calculated as follows: Number of apneic spells of 10 or more sec . _.urnber 0 f mm . In . a specl'fic state = spells per mm.
Each infant was monitored for at least 1 hr both before and during the administration of theophylline. Theophylline was administered by intravenous injection. An initial dose of S mg/kg of body weight of theophylline (S.8 mg/kg of aminophylline) was given to institute therapy. Doses of 1.2 mg/kg of theophylline 0.4 mg/kg of aminophylline) were given intravenously every 8 hr to maintain therapy. Plasma levels of theophylline and caffeine were measured by high-pressure liquid chromatography with blood being drawn at the end of a dosing interval to determine the trough level. 10 All infants were investigated for the presence of septicemia, meningitis, central nervous system hemorrhage, hypoglycemia, and electrolyte imbalance. None of the infants in this report demonstrated any of these abnormalities. Results
Clinical data on the patients included in this study are given in Table I. A statistical com-
Theophylline in apneic pre-term infants
1.0 0.8 ;!!
'"c
E
o
Before theropy
~
During therapy
475
Mean±SE.
0.6
"-
-'"
"
0.4
Cl.
fJ)
0.2 0
REM
Non-REM
TransItional
All stages
p< .1
p
Jeanne Dietrich, B.A., Alfred N. Krauss, M.D., Marcus Reidenberg, M.D., Dennis E. Drayer, Ph.D., and Peter A. M. Auld, M.D. New York, N. Y. The Perinatology Center and the Departments of Pediatrics, Pharmacology, and Medicine, The New York Hospital-Cornell Medical Center
Apnea of prematurity is an important problem in the pre-term infant. It is often associated with serious systemic illness, such as infection, hypoglycemia, or central nervous system hemorrhage. 12 In many instances, no specific cause of apnea is found and nonspecific therapy must be initiated. Respiratory stimulants have been used to treat apnea of prematurity. 3, 14, 19, 20 In particular, theophylline has been shown to increase minute volume, to increase sensitivity to elevated levels of carbon dioxide, and to reduce the frequency and severity of apneic spells in pre-term infants. The purpose of our report is to compare the sleep-wake characteristics of infants before and during the administration of aminophylline (theophylline ethylenediamine) for the relief of the apnea of prematurity.
Received for publication June 17, 1978. Accepted for publication July II, 1978. Reprint requests to: Dr. Alfred N. Krauss, Perinatology Center, Department of Pediatrics, New York Hospital, 525 E. 68th St., New York, NY 10021.
474
Methods and materials
Our subjects were 9 infants, ranging from 26 to 32 wk gestational age at birth and weighing 840 to 1,200 gm at birth. Infants were considered for theophylline therapy when clinicians and nurses caring for the infants noted an apparently high incidence of apnea and bradycardia unresponsive to simple stimulation and often associated with cyanosis. All infants were patients in the Neonatal Intensive Care Unit at the New York Hospital. Infants were monitored within 6 hr before the initiation of theophylline therapy and again 24 to 36 hr after therapy had been initiated. Clinical monitoring included measurement of heart rate, derived from R-R intervals obtained from standard electrocardiographic leads, and impedance monitoring of respiration from two transthoracic electrodes. State was determined by direct behavioral observation of the infant concurrently with two bipolar electroencephalograph channels with the use of motor-parietal and anterioposterior lead placements. Electro-
0009-9236/78/100474+05$00.50/0 © 1978 The C. V. Mosby Co.
Volume 24 Number 4
encephalographic and impedance monitoring of respiration were performed simultaneously. The record and observations were divided into 20-sec epochs. With standard electroencephalographic and behavioral criteria,l. 16 each epoch was classified into 1 of 4 states. Waking was identified by open eyes and a characteristic electroencephalogram. Quiet non-REM sleep was identified by quiet activity, lack of gross body movements except for occasional startle movements, and a characteristic electroencephalographic pattern. REM sleep was identified by closed eyes and visible eye movements beneath closed lids, frequent facial movements, and the characteristic electroencephalographic pattern associated with this state. Transitional sleep characterized epochs which did not completely meet the criteria of either REM or nonREM sleep. Bradycardia was defined as a heart rate under 100 beats/min. Apnea was defined as the absence of respiratory movements on the impedance tracing for at least 10 sec. The apnea attack rate was calculated as follows: Number of apneic spells of 10 or more sec . _.urnber 0 f mm . In . a specl'fic state = spells per mm.
Each infant was monitored for at least 1 hr both before and during the administration of theophylline. Theophylline was administered by intravenous injection. An initial dose of S mg/kg of body weight of theophylline (S.8 mg/kg of aminophylline) was given to institute therapy. Doses of 1.2 mg/kg of theophylline 0.4 mg/kg of aminophylline) were given intravenously every 8 hr to maintain therapy. Plasma levels of theophylline and caffeine were measured by high-pressure liquid chromatography with blood being drawn at the end of a dosing interval to determine the trough level. 10 All infants were investigated for the presence of septicemia, meningitis, central nervous system hemorrhage, hypoglycemia, and electrolyte imbalance. None of the infants in this report demonstrated any of these abnormalities. Results
Clinical data on the patients included in this study are given in Table I. A statistical com-
Theophylline in apneic pre-term infants
1.0 0.8 ;!!
'"c
E
o
Before theropy
~
During therapy
475
Mean±SE.
0.6
"-
-'"
"
0.4
Cl.
fJ)
0.2 0
REM
Non-REM
TransItional
All stages
p< .1
p
