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Caffeine Impairs Cerebral and Intestinal Blood Flow Velocity in Preterm Infants

From the Department of Paediatrics, Division of Neonatology, University of Heidelberg, Heidelberg, Germany

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	ABSTRACT

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Objective. In adults, a single dose of 250 mg of caffeine may decrease cerebral blood flow by 30%. In preterm infants, caffeine is commonly used for the treatment and prophylaxis of apnea. The purpose of this investigation was to assess effects of caffeine on circulatory parameters in preterm infants.

Methods. We studied 16 preterm neonates with a mean gestational age (mean ± standard deviation) of 31 ± 1.2 weeks (range: 29–33 weeks), birth weight of 1400 ± 380 g (range: 625-2060 g), and postnatal age of 24 to 72 hours before and 1 and 2 hours after an oral loading dose of 25 mg/kg pure caffeine. We investigated left ventricular output (LVO), cerebral blood flow velocity (BFV) of the internal carotid artery (ICA) and the anterior cerebral artery, and intestinal BFV of the celiac artery and superior mesenteric artery by Doppler sonography.

Results. Mean BFV in the ICA decreased significantly 1 (17%) and 2 hours (22%) after caffeine administration. Mean BFV in the anterior cerebral artery showed a reduction of 14% after 2 hours. The mean BFV in the superior mesenteric artery decreased significantly 1 and 2 hours after caffeine administration (30%). Mean BFV in the celiac artery showed a significant reduction of 14% 1 hour after caffeine. No changes were observed in LVO, blood pressure, and heart rate.

Conclusion. Oral administration of a high loading dose of caffeine results in marked reduction of cerebral and intestinal BFV, without changing LVO, blood pressure, and heart rate.

Key Words: circulation • caffeine • Doppler-sonography • blood flow velocity • preterm infant • apnea

Abbreviations: BFV, blood flow velocity • SMA, superior mesenteric artery • CA, celiac artery • BP, blood pressure • LVO, left ventricular output • HR, heart rate • ICA, internal carotid artery • ACA, anterior cerebral artery

	INTRODUCTION

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The methylxanthines aminophylline and caffeine are commonly used for treatment and prophylaxis of apnea in preterm infants.^1,2 Caffeine has several advantages over theophylline, such as a higher therapeutic ratio, more reliable enteral absorption, and longer half-life.³ However, there is concern that these methylxanthines may reduce blood flow to the brain and the gastrointestinal tract, although the published results are conflicting. A loading dose of theophylline of 5 to 7.5 mg/kg markedly diminished cerebral blood flow or flow velocity at 60 to 120 minutes after intravenous bolus administration.^4–8

A loading dose of 10 mg/kg of caffeine did not alter cerebral hemodynamics in preterm infants at 30 to 120 minutes⁹ and at 24 hours.¹⁰ Lundstrom et al¹¹ observed a marked reduction of cerebral blood flow 2 hours after intravenous administration of 5 mg/kg aminophylline when compared with 10 mg/kg caffeine. In adults, oral ingestion of 250 mg of caffeine was found to be associated with a significant reduction in cerebral perfusion at 30 and 90 minutes.^12,13

A loading dose of 25 mg/kg caffeine has been shown to improve apneas in 72% of treated preterm infants, whereas a loading dose of 12.5 mg/kg was effective in only 25%.¹⁴ Lane et al¹⁵ observed that the blood flow velocity (BFV) in intestinal arteries (superior mesenteric artery [SMA] and celiac artery [CA]) rapidly falls during a 30-minute intravenous infusion of 25 mg/kg caffeine with the minimum values at approximately 120 minutes. Although oral loading doses of caffeine have been shown to be effective,¹⁴ no studies of oral loading doses on hemodynamic parameters in preterm infants have been reported in the literature.

The present investigation was designed to study effects of an oral loading dose of 25 mg/kg caffeine on cardiac output and BFV in cerebral and intestinal arteries.

	METHODS

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After local ethical committee approval and informed parental consent had been obtained, 16 preterm neonates with a mean (standard deviation) gestational age of 31 (1.2) weeks (range: 29–33 weeks) and a mean birth weight of 1400 (380) g (range: 625–2060 g) were studied. Postnatal age at the start of caffeine medication was 24 to 72 hours.

Caffeine medication was started for treatment of idiopathic apnea-bradycardia syndrome or weaning from mechanical ventilation. We started with a loading dose of 25 mg/kg pure caffeine (given as caffeine citrate) via a nasogastric tube over 15 to 20 minutes. The maintenance dose was 5 mg/kg daily. Infants who were not stable enough for the Doppler investigations were excluded from the study, as were infants with suspected or proven infection, malformations, patent ductus arteriosus, perinatal asphyxia, diabetic mothers, and hyperbilirubinemia requiring phototherapy. Two patients had to be excluded because of vomiting after the caffeine medication. We registered no other adverse effects of the caffeine therapy.

Blood pressure (BP) determinations were performed using a noninvasive oscillometric method (Dinamap 847; Critikon, Ascot, United Kingdom). Levels of PCO₂ were measured transcutaneously in 10 infants before, during, and after the caffeine medication.

Eight preterm infant were breathing spontaneously at the time of investigation. Five had nasal continuous positive airway pressure, and 3 were mechanically ventilated. Two infants were small for gestational age (below 10th percentile), and 14 were appropriate for gestational age (10th–90th percentile).

All Doppler ultrasound studies were performed by the same investigator (C.H.) immediately before and 1 and 2 hours after the end of caffeine administration with an Interspect XL pulsed Doppler ultrasound system (Interspect, Inc, Conshohocken, PA). Details of the measurements of the diameter of the aortic valve annulus and of BFV in the aortic valve annulus and cerebral and intestinal arteries have been described previously.¹⁶ The aortic valve annulus was visualized by M-mode echocardiography using the parasternal long axis, and the diameter was measured using the leading edge method from the anterior aortic wall to the anterior boundary of the posterior aortic wall in late diastole over 5 consecutive cycles. From an apical 4-chamber view, the pulsed Doppler sample volume was placed at the level of the aortic valve annulus. Aortic velocity integrals were recorded with a mechanical 5.0-MHz transducer using the duplex mode in an attempt to obtain the fastest spectral envelopes. Doppler wave forms were analyzed by the software of the ultrasound system for peak velocity, mean velocity, and average time velocity integral.

Stroke volume was calculated as the product of the average time velocity integral and cross-sectional area of the aorta. Left ventricular output (LVO) was calculated as the product of stroke volume and heart rate (HR). At a constant HR (ie, sinus rhythm), the average of 5 consecutive, homogeneous flow waves were taken in all measurements after 60 constant flow waves were recorded. When beat-to-beat coefficient of variation was <5%, Doppler recordings were taken as stable.

Cerebral BFV in the internal carotid artery (ICA) and anterior cerebral artery (ACA) were measured using a 5.0-MHz pulsed Doppler transducer from a coronal scan via the anterior fontanel. The arteries were identified by duplex scan mode. The system software was used to calculate maximal systolic, maximal end diastolic, and mean average flow velocity from 5 consecutive, homogeneous flow waves. Flow velocities in the SMA and CA were measured from a longitudinal abdominal approach using a 5.0- or 7.5-MHz transducer. Angle corrections of velocities were made in all cases.

Intestinal blood flow increases 15, 45, and 90 minutes after feeding, with a peak at 45 minutes,¹⁷ whereas cerebral blood flow decreases during the first 5 to 11 minutes after feeding and reach prefeeding values after 20 minutes.¹⁸ For minimizing the effect of feeding, caffeine was given 2 hours after the last meal and the subsequent meal was left out. One of the children had an intravenous infusion into a scalp vein close to the anterior fontanel. The cerebral measurements therefore could not be taken in this infant. In 3 patients BFV measurements in the SMA were not possible because of air-filled bowels in front of the artery.

Results are presented as mean ± standard deviation. A paired t test was used to test for changes in the measured parameters before and 1 and 2 hours after the caffeine medications.

	RESULTS

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Cerebral BFV (systolic, end diastolic, and mean) of the ICA decreased by approximately 15% at 1 hour and by approximately 20% at 2 hours (Table 1) after an oral caffeine loading dose of 25 mg/kg. Two hours after caffeine, mean BFV in the ICA decreased in 11 of the 15 infants. In the ACA, the decreases were smaller than in the ICA.

The transcutaneously PCO₂ values measured in 10 infants averaged 44 ± 5 mm Hg before and 42 ± 5 mm Hg 2 hours after caffeine administration.

	DISCUSSION

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From the present data, we come to the conclusion that a relatively high oral caffeine loading dose of 25 mg/kg reduces BFV in cerebral and intestinal arteries at 1 and 2 hours after the administration of the drug (Table 1), whereas cardiac output does not change.

Orally administered caffeine is rapidly absorbed and reaches a peak plasma level within 30 to 120 minutes.¹⁹ We did not measure plasma caffeine levels to avoid additional blood sampling for the study. It has not been recommended to study caffeine concentration in the first hours after the administration.¹⁴ However, it seems likely that at 2 hours after caffeine application, when the maximum reductions in BFV occurred, plasma caffeine levels were high. Caffeine was given orally and not intravenously because in our neonatal intensive care unit, oral feeding of preterm infants is usually started within 12 hours of birth. Other authors found similar plasma caffeine concentrations after oral and intravenous administration of caffeine.^14,19

Previous studies using caffeine loading doses of 10 mg/kg given intravenously or subcutaneously showed no effect on BFV in cerebral vessels using the Doppler method.^9,10 Cerebral blood flow measured by a xenon-clearance technique was significantly lower after aminophylline than after caffeine.¹¹ In adults, a caffeine dose of 250 mg produced a 30% decrease in whole-brain cerebral blood flow without regional differences measured by positron emission tomography.¹³ Mathew and Wilson¹² found with a xenon inhalation technique a significant reduction in cerebral perfusion 30 and 90 minutes after 250 mg of caffeine.

Lane et al¹⁵ studied peak systolic BFV in the CA and the SMA and observed maximum reductions of approximately 30% at 146 and 103 minutes, respectively, after the end of a caffeine loading dose of 25 mg/kg infused over 30 minutes. These flow velocity reductions agree with our results (Table 1). LVO did not change meaningfully during 2 hours after caffeine treatment (Table 1). Short-term effects of caffeine on cardiac output in preterm infants have not been found in the literature.

Walther et al²⁰ determined LVO every 24 hours after an intravenous caffeine loading dose of 10 mg/kg and a maintenance dose of 2.5 mg/kg/d. They found an increase in LVO by 20% after the first 24 hours and a maximum increase of 30% after 3 days. BP increased by approximately 10%, indicating that most of the increase in LVO could be explained by a reduction in the peripheral vascular resistance. Oxygen consumption increased by a similar amount after 48 hours of caffeine treatment²¹ as cardiac output.²⁰ Thus, mixed venous oxygen concentration probably remains unchanged. It is unclear whether oxygen consumption increases already during the first hours of caffeine treatment. A rise in oxygen consumption could seriously jeopardize oxygen supply to vital tissues, particularly to those with reduced blood flow.

The decrease in BFV in cerebral arteries after a high caffeine loading dose is probably attributable to vasoconstriction. In theophylline-treated infants, cerebral vasoconstriction has been explained by a concomitant decrease in PCO₂.⁴ Conversely, a marked reduction in cerebral perfusion after theophylline has also been observed without decrease in PCO₂.^5,6 We found no change in transcutaneous PCO₂ in 10 preterm infants during the first 2 hours after caffeine treatment. At high concentrations, theophylline and caffeine are potent inhibitors of adenosine, which is a vasodilating agent. Inhibition of this vasodilator may result in vasoconstriction of cerebral vessels.²² Reduced BFV in intestinal arteries after a caffeine loading dose of 25 mg/kg may be explained by endothelium-dependent and -independent vasoconstriction.²³

Whether our observations of reduced BFV in cerebral and intestinal arteries after a high oral caffeine loading dose of 25 mg/kg are of clinical importance is unclear. Reduction of cerebral blood flow may increase the risk of preterm infants to periventricular leukomalacia and hemorrhage, and a decrease in intestinal blood flow may increase the risk of necrotizing enterocolitis. Apneas increase the risk for cerebral lesions²⁴ as a result of hypoxemia and, if combined with bradycardias, to hypoperfusion of the brain. It is unclear whether xanthines further increase the risk of cerebral lesions in preterm infants with apneas and bradycardias. Xanthines seem to increase slightly the risk for necrotizing enterocolitis in preterm infants,²⁵ but, again, apneas and bradycardias may predispose the infants to necrotizing enterocolitis as a result of hypoxia and hypoperfusion independent of xanthine treatment.

Although the clinical relevance of our data are unclear, it seems to be safer to recommend smaller loading doses of caffeine than the high dose of 25 mg/kg used in the present study. Because a smaller loading dose of 12.5 mg/kg may fail to decrease the number of apneas sufficiently in 2 of 3 infants,¹⁴ a second dose of 12.5 mg/kg may be given several hours after the first loading dose if the frequency of apneas remains high. The influence of 2 repeated smaller caffeine loading doses on circulatory parameters in preterm infants has to be evaluated.

	FOOTNOTES

 
Received for publication May 8, 2001; Accepted Nov 8, 2001.

Reprint requests to (C.H.) Division of Neonatology, Department of Paediatrics, University of Heidelberg, Im Neuenheimer Feld 150, 69120 Heidelberg, Germany. E-mail: christina_hoecker{at}med.uni-heidelberg.de

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