Clinical and laboratory observations

Respiratory instability in neonates with in utero exposure to cocaine

Cindy Chen, MD, Shahnaz Duara, MD, Gald ino Silva Neto, MD, Sidhartha Tan, MD, Emmalee S, Bandstra, MD, Tilo Gerhardt, MD, and Eduardo Bancalari, MD

From the Department of Pediatrics, Division of Neonatology, University of Miami School of Medicine, Miami, Florida

Ventilatory abnormalities have been reported in infants ex- posed in utero to heroin and methadone, 1 and a similar as-

sociation has been suggested with in utero cocaine exposure, z Facial airstream stimulation elicits reflex apnea in healthy newborn infants, presumably through trigeminal afferents, 3 and causes a greater number of respiratory pauses in preterm infants than in term infants. 4, 5 We hy- pothesized that apparently healthy cocaine-exposed neo- nates would have subclinical respiratory abnormalities that would be elicitable by trigeminal airstream stimulation and

hypercapnia.

M E T H O D S

Twenty-one term neonates born at the University of Mi- ami-Jackson Memorial Medical Center were enrolled in the study with informed parental consent. Infants of moth-

ers with a history of tobacco, alcohol (> 1 drink a week), or illicit drug use other than cocaine were prospectively excluded from both the study and control groups; all infants were apparently healthy and free of withdrawal symptoms. Enrollment was based on maternal drug history and results of a urine toxicology screen of the infants. Eleven cocaine-

exposed neonates were identified by positive results of a urine screen (fluorescence polarization immunoassay [TDx, Abbott Laboratories Diagnostic Division, Abbott Park, Ilk]

Presented in part at the Society for Pediatric Research, Washing- ton, D.C., May 1989. Supported by Children's Medical Service of Florida, University of Miami Project: New Born. Submitted for publication July 30, 1990; accepted Feb. 4, 1991. Reprint requests: Shahnaz Duara, MD, University of Miami School of Medicine, Department of Pediatrics (R-131), PO Box 016960, Miami, FL 33101. 9/24/28473

for the cocaine metabolite benzoylecgonine) at a mean (_+ SD) gestational age of 39.2 ___ 1.0 weeks, as determined by examination; birth weight of 3650 + 385 gin; and post- natal age at study of 4.6 _+ 1.6 days. The infants were con- sidered only cocaine exposed because the drug's short half- life ensured its elimination from the infants by day 4 of life and because its main metabolite, benzoylecgonine, has no cardiovascular or ventilatory effects. The control group of 10 neonates had a negative maternal history for drug use

and a negative result on a urine toxicology screen for cocaine, marijuana, and opiates (gestational age 39.1 _+ 0.9 weeks by examination; birth weight 3650 _ 405 gm; post- natal age at study 4.1 _+ 2.2 days).

Unsedated infants were studied supine during quiet sleep, 6 with a constant ambient temperature. Any trials in-

terrupted by startles or arousal were judged unacceptable and were repeated after the appropriate state returned. Tidal volume was measured by inductance plethysmogra- phy (Respigraph monitor, Non-Invasive Monitoring Sys- tems, Miami Beach, Fla.), oxygen saturation by a pulse oximeter (Nellcor Inc., Hayward, Calif.), heart rate by a

cardiotachometer (Gould, Inc., Cleveland, Ohio), and end-

tidal carbon dioxide by a four-gas mass spectrometer (Chemtron Supply Corp., St. Louis, Mo.). All signals were recorded on a stripchart recorder (Gould model 2800) and calculated by two independent investigators, one of whom was unaware of the study grouping.

Airstream trials used a flow of 5 L/min at 25 ~ C directed toward both nostrils from a distance of 1 to 2 cm, for a du- ration of 10 seconds. Five or six trials were performed in each infant. Between trials, respiration was allowed to re- turn to a baseline rate and depth. A respiratory pause was defined as absence of breathing for >__2 seconds within the 10 seconds of each airstream application. The number of infants with respiratory pauses and the average duration of

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1 1 2 Clinical and laboratory observations The Journal of Pediatrics July 1991

respiratory pauses (measured in seconds) per child were derived. Tidal volume was measured in arbitrary units; our interest was in relative change, so the inductance signal was not calibrated. The summed tidal volume of all breaths in the 10-second period preceding stimulus and the summed tidal volume of all breaths during the 10 seconds of stimu- lus were used to derive minute ventilation.

To measure the ventilatory response to hypercapnia, we administered 4% carbon dioxide to each infant through a plastic hood at a flow rate of 5 L/min, for a duration of 3 to 5 minutes. Minute ventilation was calculated from the 20 seconds preceding hypercapnia and during the last minute of hypercapnia. Heart rate was averaged from values obtained at 2-second intervals from the cardiotachometer for the same duration used to calculate minute ventilation befor e and during the stimuli. Oxygen saturation measure- ments were obtained with the same periodicity as for heart rate calculations.

Statistical analyses were performed by one-way analysis of variance for the duration of respiratory pauses and changes in heart rate and oxygen saturation with the stim- uli, by Fisher Exact Test for comparison of the incidence of respiratory pause produced by airstream stimuli between control and cocaine-exposed infants, and by Mann-Whitney 13 test for changes in minute ventilation.

R E S U L T S

Data analysis was performed on 59 separate trials in the cocaine-exposed group of infants and 56 trials in the con- trol group of infants. Each infant received an average of five trials.

In the cocaine-exposed infants, 54.8 -+ 33% of all the stimuli resulted in respiratory pauses; in the control infants only 16.6 + 27% of all the stimuli resulted in respiratory pauses (p <0.02). Nine of the eleven cocaine-exposed infants had at least one respiratory pause in response to the five airstream trials, in contrast to such changes in only 4 of 10 control babies (p <0.05). The mean duration of a respiratory pause was 4,9 _+ 1.9 seconds in the cocaine- exposed group and 3.1 _+ 0.7 seconds in t h e control group.

In the cocaine-exposed infants, stimuli caused a signifi- cantly greater decrease in minute ventilation ( -22 _+ 20%) than in the control group (1 _+ 11%) (p <0.0!). Even stim- uli that failed to induce respiratory pauses of __2 seconds produced a decrease in minute ventilation, which was sig- nificantly more pronounced in the cocaine-exposed infants ( -24 _+ 33%, decreased from baseline) than in the control group ( - 10.9 + 11%, decreased from baseline) (p <0.01).

Neither oxygen saturation nor heart rate in the two groups was different during baseline measurements or with stimulus.

End-tidal carbon dioxide was in the same range during baseline conditions in both groups (control 37.6 _+ 3.6 mm Hg; cocaine-exposed 38.8 + 4.2 mm Hg). With hypercap- nia, end-tidal carbon dioxide increased by 20% in both groups, with ventilation increasing 94.3 _ 41% above base- line in the cocaine-exposed infants and 92.0 _+ 37% above baseline in the control infants (difference not significant).

D I S C U S S I O N

Relatively few objective differences have been described between the respiratory pattern of cocaine-exposed infants and that of control infants, 7 in contrast to what is known in regard to opiatesfl s Our study shows that respiratory pauses ca n be readily elicited in apparently healthy cocaine- exposed infants with a relatively innocuous stimulus (facial airstream). This finding supports earlier observations that in utero cocaine exposure produces respiratory disturbance in otherwise healthy offspring. 2

The subtle respiratory abnormalities in term cocaine-ex- posed infants are similar to those previously reported in otherwise healthy preterm infants. 4'5 Whether these ab- normalities represent relative immaturity of respiratory control mechanisms in term cocaine-exposed infants or neurologic damage from toxic drug effects 9 remains un- known.

No significant change in heart rate accompanied the res- piratory pauses in this study, which differs from the findings of Allen et al. 3 Differences in methods may be responsible; Allen et al. used a higher flow rate for 2 seconds, whereas we used a lower flow rate for 10 seconds. The brief respira- tory pauses did not induce hypoxia, so bradycardia should not be expected.

A decreased ventilatory response to hypercapnia has been reported in methadone-exposed infants. 1 We found no sig- nificant difference between the ventilatory response to hy- percapnia of control infants and that of cocaine-exposed in- fants; the results are similar to the findings of McCann and Lewis. 1~ Wasiewski and Hansen 11 demonstrated that co- caine-exposed rabbit pups hyperventitated in comparison with control animals for comparable levels of arterial car- bon dioxide tension, and explained this finding as possibly related to increased carbon dioxide productio n in the cocaine-exposed group. In our study, carbon dioxide pro- duction was not measured.

We conclude that otherwise healthy infants who are pre- natally exposed to cocaine have subtle respiratory abnor- malities, manifested by a higher frequency of respiratory pauses and a decrease in minute ventilation in response to facial airstream stimulation. These results indicate that prenatal exposure to cocaine causes a residual respiratory instability that can be made apparent by stimulation of fa- cial receptors.

Volume 119 Clinical and laboratory observations 1 1 3 Number 1, Part 1

REFERENCES

1. Olsen GD, Lees MH. Ventilatory response to CO2 of infants following chronic prenatal methadone exposure. J PED1ATR 1980;96:983-9.

2. Chasnoff I J, Hunt CE, Kletter R, Kaplan D. Prenatal cocaine exposure is associated with respiratory pattern abnormalities. Am J Dis Child 1989;143:583-7.

3. Allen LG, Howard G, Baldwin Smith J, McCubbin JA, Weaver RL. Infant heart rate response to trigeminal airstream stimulation: determination of normal and deviant value. Pedi- atr Res 1979;13:184-7.

4. Chen C, Hurtwitz BE, Duara S, et al. Maturation of the car- diorespiratory response to trigeminal stimulation in neonates [Abstract]. Pediatr Res 1988;23:253A.

5. Ramet J, Proud JP, Dehan M, Gaultier C. Cardiac and ven- tilatory response to trigeminal airflow stimulation in sleeping infants [Abstract]. Am Rev Resp Dis 1989;139:A177.

6. Prechtl, HFR. The behavioural states of newborn infant (a re- view). Brain Res 1974;76:185-212.

7. Riley JG, Porat R. Abnormal pneumograms in infants with in utero cocaine exposure [Abstract]. Pcdiatr Res 1987;21:262A.

8. Ward SLD, Schuetz S, Krishna V, et al. Abnormal sleeping ventilatory patterns in infants of substance-abusing mothers. Am J Dis Child 1986;140:1015-20.

9. Mathews S, Tyrala EE, Rao GS. Effect of intra-uterine expo- sure of cocaine on acetylcholine esterase (ACE) in primary cultures of embryonic mouse brain cells [Abstract]. Pediatr Res 1988;23:418A.

10. McCann E, Lewis K. Control of breathing in babies of substance-abusing mothers [Abstract]. Pediatr Res 1989; 25:369A.

11. Wasiewski WW, Hansen TW. Intrauterine cocaine exposure alters respiratory control in newborn rabbit pups [Abstract]. Pediatr Res 1989;25:74A.

Colony-stimulating factor levels in the human newborn infant

Philip Roth, MD, PhD

From the Division of Neonatology, Department of Pediatrics, Albert Einstein College of Med- icine, Bronx, New York

The increased susceptibility of the newborn infant to infec-

tion originates from relative deficiencies in multiple com-

partments of the immune system, including the mononu-

clear phagocyte.l Although the mediators of the alterations

in number, function, and location of this cell lineage in the developing human neonate have not been delineated, a po-

tential candidate is colony-stimulating factor 1. This 45 to

90 kd homodimeric molecule is produced by fibroblasts,

monocytes, and endothelial cells and by uterine epithelial

cells during pregnancy. 2 In addition to regulating the sur-

vival, proliferation, and differentiation of mononuclear

phagocytes, CSF-1 also is chemotactic for monocytic cells, 3

making it possible that local growth factor production plays

a role in the influx of macrophages into particular tissues,

Supported in part by a grant from the New York Lung Associa- tion. Presented in part at the Eastern Society for Pediatric Research Meeting, New York, Oct. 19-20, 1990.

Submitted for publication Nov. 2, 1990; accepted Feb. 4, 1991. Reprint requests: Philip Roth, MD, PhD, Division of Neonatology, Rm. 725, Einstein Hospital, 1825 Eastchester Rd., Bronx, NY 10461. 9/24/28475

such as the lung. Because little is known about the role of

CSF-1 in ontogeny and the regulation of its expression and

function in the fetus and newborn infant, 4 we undertook this

study of the levels of CSF-1 in neonatal serum to evaluate

the potential importance of this growth factor in mononu- clear phagocyte development.

M E T H O D S

Cord and peripheral blood. Newborn infants were in-

cluded in the study only if they were (1) >--37 weeks of ges-

CSF-1 Colony-stimulating factor 1 [ PEG Polyethylene glycol

tational age, (2) appropriate in weight for gestational age,

(3) without signs and symptoms of infection, (4) without congenital malformations, and (5) without signs of as-

phyxia. Cord blood was obtained at birth; a single neonatal sample was collected between days 2 and 5 of life to coin- cide with collection of blood for routine New York State metabolic screening. Each blood sample was collected in

two separate tubes, one without additives and one with EDTA, for measurement of CSF-1 and leukocyte counts,

respectively. Peripheral blood samples were also obtained from healthy adults and analyzed only for their CSF-1 con-