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Original Investigation |

Effects of Caffeine on Intermittent Hypoxia in Infants Born Prematurely:  A Randomized Clinical Trial

Lawrence M. Rhein, MD1; Nicole R. Dobson, MD2; Robert A. Darnall, MD3; Michael J. Corwin, MD4,5; Tim C. Heeren, PhD6; Christian F. Poets, MD7; Betty L. McEntire, PhD8; Carl E. Hunt, MD2; and The Caffeine Pilot Study Group
[+] Author Affiliations
1Newborn Medicine and Respiratory Diseases, Boston Children’s Hospital, Boston, Massachusetts
2Department of Pediatrics, Uniformed Services University of Health Sciences, Bethesda, Maryland
3Department of Pediatrics, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
4Department of Pediatrics, Boston University School of Medicine, Boston, Massachusetts
5Slone Epidemiology Center at Boston University, Boston, Massachusetts
6Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
7Department of Neonatology, University of Tübingen, Tübingen, Germany
8American SIDS Institute, Naples, Florida
JAMA Pediatr. 2014;168(3):250-257. doi:10.1001/jamapediatrics.2013.4371.
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Importance  Preterm infants have immature respiratory control and resulting intermittent hypoxia (IH). The extent of IH after stopping routine caffeine treatment and the potential for reducing IH with extended caffeine treatment are unknown.

Objectives  To determine (1) the frequency of IH in premature infants after discontinuation of routine caffeine treatment and (2) whether extending caffeine treatment to 40 weeks’ postmenstrual age (PMA) reduces IH.

Design, Setting, and Participants  A prospective randomized clinical study was conducted at 16 neonatal intensive care units in the United States, with an 18-month enrollment period. Preterm infants (<32 weeks’ gestation) previously treated with caffeine were randomized to extended caffeine treatment or usual care (controls) at a PMA of at least 34 weeks but less than 37 weeks. Continuous pulse oximeter recordings were obtained through 40 weeks’ PMA. Oximeter data were analyzed by persons masked to patient group.

Intervention  Continued treatment with caffeine.

Main Outcomes and Measures  Number of IH events and seconds with less than 90% hemoglobin oxygen saturation (Sao2) per hour of recording.

Results  Our analysis included 95 preterm infants. In control infants, the mean (SD) time at less than 90% Sao2 at 35 and 36 weeks’ PMA was 106.3 (89.0) and 100.1 (114.6) s/h, respectively. The number of IH events decreased significantly from 35 to 39 weeks’ PMA (P = .01). Extended caffeine treatment reduced the mean time at less than 90% Sao2 by 47% (95% CI, −65% to −20%) to 50.9 (48.1) s/h at 35 weeks and by 45% (95% CI, −74% to −17%) to 49.5 (52.1) s/h at 36 weeks.

Conclusions and Relevance  Substantial IH persists after discontinuation of routine caffeine treatment and progressively decreases with increasing PMA. Extended caffeine treatment decreases IH in premature infants.

Trial Registration  clinicaltrials.gov Identifier: NCT01875159

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Figure 1.
Flow Diagram of Study

Flow diagram from initial screening to enrollment, randomization, and completion of study.

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Figure 2.
Time Below 3 Different Hemoglobin Oxygen Saturation (Sao2) Thresholds at 35 and 36 Weeks’ Postmenstrual Age (PMA) at 3 Different Saturation Thresholds

Time (in seconds per hour) of Sao2 at thresholds of less than 90%, less than 85%, and less than 80% are shown for the total cohort (n = 95) at 35 and 36 weeks’ PMA. Although the total time was greater with a threshold of less than 90% or less than 85%, the magnitude of the decrease with caffeine is comparable for a threshold of less than 80% at both 35 and 36 weeks. *P < .01; P < .05. With extended caffeine treatment, intermittent hypoxia at the less-than-80% threshold was decreased by 64% at 35 weeks’ PMA (P = .002), but the 45% decrease at 36 weeks’ PMA was only borderline significant (P = .051).

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