ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–6 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.978757


Effect of caffeine on preterm infants’ cerebral cortical activity: an observational study Sahar M. A. Hassanein1, Ghada I. Gad1, Rania I. H. Ismail1, and Mohamed Diab2 J Matern Fetal Neonatal Med Downloaded from by Nyu Medical Center on 02/14/15 For personal use only.


Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt and 2Visitor NICU Resident, Ain Shams University, Cairo, Egypt



Objective: Our first aim was to investigate the effects of caffeine on preterm infants’ respiratory functions and brain cortical activity (conventional and amplitude-integrated electroencephalography (cEEG and aEEG)). Secondary aim was to study its long-term effects on respiratory system and electroencephalographic maturation by 36 weeks post-menstrual age. Methods: Prospective observational study on 33 consecutively admitted preterm infants less than 34-weeks-gestation. cEEG and aEEG, cardiopulmonary and sleep state were recorded in 20 preterm infants, before, during and 2-hours after intravenous (IV) caffeine (caffeine Group), and for 13 preterms (control group). Both groups were subjected to assessment of cerebral cortical maturation by cEEG and aEEG at 36-weeks post-menstrual age as an outcome measure. Results: IV caffeine administration significantly increased heart rate (p ¼ 0.000), mean arterial blood pressure (p ¼ 0.000), capillary oxygen saturation (p ¼ 0.003), arousability (p ¼ 0.000) and aEEG continuity (p ¼ 0.002) after half an hour. No clinical seizures were recorded and nonsignificant difference was found in electrographic seizures activity in cEEG. At 36-weeks postconceptional age, NICU stay was significantly longer in controls (p ¼ 0.022). aEEG score was significantly higher in caffeine group than the control group, (p ¼ 0.000). Conclusions: Caffeine increases preterm infants’ cerebral cortical activity during infusion and results in cerebral cortical maturation at 36weeks, without increase in seizure activity.

Amplitude-integrated electroencephalography, apnea of prematurity, cerebral cortical maturity, conventional electroencephalography, hospital stay

Introduction Preterm birth is a high-risk factor for perinatal morbidity, mortality, and later on neurodevelopmental disabilities and adverse respiratory outcome. Childhood cerebral palsy prevalence rates have been reported to be 19 per 1000 live births for infants born at 20–27 weeks gestation. Vision and hearing loss have been reported in less than 1% of survivors [1]. Studies on caffeine citrate, a methylxanthine treatment, proved to be effective as first-line pharmacotherapy in apnea of prematurity in reducing the frequency of apneic episodes and the need for mechanical ventilation [2,3]. Up-regulation of adenosinergic maturation in central cardio-respiratory areas in caffeine-treated neonatal rats could explain the pharmacological effects of caffeine observed in premature infants [4]. Amplitude-integrated electroencephalography (aEEG) or cerebral function monitoring (CFM), with limited number of electrodes, is easy to operate at bedside. It is feasible as a clinical and research tool for continuous brain monitoring in the NICU [5]. The aEEG of preterm infants appears to be a good tool for monitoring cerebral activity. Continuous activity

Address for correspondence: Sahar M. A. Hassanein, Department of Pediatrics, Faculty of Medicine, Ain Shams University, Abbassia Square 11381, Cairo, Egypt. Tel: +20123183943. Fax: +20224820237. E-mail: [email protected]

History Received 6 August 2014 Revised 12 October 2014 Accepted 16 October 2014 Published online 13 November 2014

seems to indicate maturation in the neonatal brain [6]. The evolution of the aEEG tracing depends on both gestational age (GA) and post menstrual age (PMA). At the same PMA, preterm infants of lower GA display an advanced maturation of the aEEG compared with others of higher GA [7]. Conventional EEG (cEEG) in neonates is considered the gold standard for evaluating EEG background and detecting electrographic seizures. However, cEEG is expensive and cumbersome for long-term monitoring [8]. The mechanisms underlying caffeine neuroprotection are incompletely understood. So, the primary aim of this study was to elucidate the acute clinical and aEEG effects of intravenous (IV) caffeine administration in preterm infant’s apnea prophylaxis. Secondary aim was to study electroencephalographic maturational changes by 36 weeks PMA among these neonates using both conventional and amplitude EEG.

Subjects and methods A prospective observational study was carried out at Neonatal Intensive Care Unit (NICU), Ain Shams University, in the period from June 2012 to May 2013. An informed consent was taken from parents of neonates before enrollment in the study. The study was approved by ethical committee of the Pediatric Department, Faculty of Medicine, Ain Shams University.


S. M. A. Hassanein et al.

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Participants Preterm infants less than 34 weeks gestational age consecutively admitted to the NICU were included in the study. Gestational age was calculated from the date of last menstrual cycle and confirmed by antenatal trans-abdominal ultrasonography and modified Ballard scoring system [9]. Preterm neonates with severe CNS infection, congenital anomalies, suspected chromosomal aberrations or hypoxic ischemic insult were excluded from the study. Preterm neonates recruited were subdivided into (caffeine group): 20 preterm infants scheduled to receive a first dose of caffeine for apnoea prophylaxis or treatment according to our NICU’s protocol [apnea prophylaxis for preterms 32 weeks gestation and apnea treatment for those 33 or 34 weeks gestation], and (control group): 13preterm infants for whom caffeine was not given, either it was not indicated, not available or parents refused its use. Apnea was treated when frequent (more than 3 times per hour) or life threatening (requiring frequent bag and mask ventilation). Study design Before caffeine infusion IV line was inserted, the infant was calm and warm. Peripheral venous blood samples were collected and divided into two specimens; first, on EDTA tube for Complete blood count assay by the Symex sf-3000 auto analyzer and second, on plain tube for immediate assessment of C-reactive protein using latex agglutination test to exclude neonatal sepsis. Loading dose of caffeine of (20 mg/kg body weight (IV)) was administrated [10]. Caffeine preparation used in the form of caffeine citrate (caffeinospireÕ ) 60 mg/3ml vial, supplied by Memphis for Pharmaceuticals & Chemical Industries, Egypt; for: Inspire Pharmaceutical Co. (IPC Pharma), USA. For the caffeine group: continuous cardiovascular monitoring (heart rate, capillary perfusion time, mean arterial pressure); respiratory monitoring (Apnea, capillary oxygen saturation); neurological monitoring, and change in sleep state or arousability were recorded. Sleep state differentiated into six stages according to: 1-Quiet sleep; 2-Active sleep; 3-Drowsy; 4-Quiet alert; 5-Active alert; 6-crying [11]. Continuity of amplitude-integrated electroencephalogram aEEG/CFM (cerebral function monitor) and electrographic seizure activity was assessed in conventional video-EEG (cEEG) recordings for 1 hour before, during and 2 hours after the administration of caffeine (the recording time was 210–250 minutes). aEEG and cEEGwere recorded for 60 minutes at 36 weeks PMA to assess brain maturational changes for all preterm infants in the caffeine and the control group. aEEG/cEEG recording Apparatus aEEG/cEEG was recorded using NIHON KOHDEN Ls-120, Irvine, CA. Conventional EEG electrodes were applied to the scalp at Fp1, Fp2, C3, C4, T3, T4, O1, O2, and CZ (according to the international 10–20 system of electrode placement, as modified for neonates). Single-biparietal-channel aEEG was

J Matern Fetal Neonatal Med, Early Online: 1–6

recorded and displayed at 6 cm/h, and high impedance records were excluded from the analysis. Scoring and interpretation aEEG continuity: aEEG tracings were evaluated visually for continuity before and after caffeine administration by dividing each trace into 10-minute epochs. A line is drawn through the upper and lower margins of the band of aEEG activity and the voltage measured from the scale[12], and classifying each epoch as either continuous (minimum amplitude 45 mV, maximum amplitude 10–50 mV) or discontinuous (minimum amplitude variable but 5 5 mV, maximum amplitude 410 mV) [13]. aEEG brain maturation at 36 PMA: Parameters included are: (1) level by bandwidth span in mV and amplitude of lower border; (2) amplitude of lower border in mV; (3) continuity and (4) cycling. Total score ¼ sum points for all 4 scored parameters. Minimum score is zero; maximum score is 12; the higher the score, the more mature the neonate’s brain. The maximum scores occurred at 35–36 weeks postconception (last menstrual period minus 2 weeks) [14]. Electrographic seizures in cEEG were classified according to duration of EEG recorded seizures activity in relation to total EEG recording time as follows: no seizures – no EEG seizures activity at all; mild electrical seizures – EEG seizures activity is less than 5% of total recording time; moderate electrical seizures – EEG seizures activity is 5–10% of total recording time; and marked electrical seizures – EEG seizures activity is more than 10% of total recording time. cEEG brain maturation at 36 PMA: Background cerebral activity was classified as normal or mildly, moderately, or markedly abnormal [15]. Grade 1 ¼ mildly abnormal: Normal background with one mild EEG abnormality, or asymmetry, asynchrony, or mild voltage depression; Grade 2 ¼ moderately abnormal: Normal background with two or more EEG abnormalities, asymmetry, asynchrony mild voltage depression with additional abnormality; and Grade 3 ¼ markedly abnormal: burst-suppression, or markedly depression/isoelectric background activity. Sample size determination: A sample size of at least 16 cases achieves 80% power to detect a mean of paired differences of 15.0 with an estimated standard deviation of differences of 20.0 and with a significance level (alpha) of 0.05 using a two-sided paired t-test. Statistical analysis of the data Quantitative data are presented as mean and standard deviation. Independent t-test was used to compare means of two independent groups (e.g. cases and controls) while paired t-test was used to compare means of the paired observations (e.g. before and after). Categorical data are presented as number and appropriate proportion/percent. Chi-square test was used to test the distribution of categorical variables in two independent groups while McNemar’s test was used to compare paired observations. A p value of 0.05 or less is considered statistically significant, i.e. the difference observed cannot be attributed to sampling variation but due to a real difference. SPSS

Caffeine & preemies

DOI: 10.3109/14767058.2014.978757

(statistical package for social science) version 22.0 (Chicago, IL) was used in data entry and analysis.

J Matern Fetal Neonatal Med Downloaded from by Nyu Medical Center on 02/14/15 For personal use only.

Results Thirty-three preterm infants were enrolled in the study, 20 preterm neonates received caffeine (12 were 32 weeks and 8 were 33 weeks gestation); and 13 neonates did not receive caffeine (7 were 32 weeks and 6 were 33 weeks gestation). Postnatal age among cases at start of caffeine therapy ranged from 1st to 7th day of life, mean 2.85 ± 2.005, median to interquartile 1–4.25. They were comparable in demographic and laboratory data (Table 1). Intravenous caffeine administration significantly increased heart rate (p ¼ 0.000), mean arterial blood pressure (p ¼ 0.000), capillary oxygen saturation (p ¼ 0.003) and arousability (p ¼ 0.000) after half an hour; whereas no-significant effect was noticed in capillary refill time (CRT) and apnea. Statistically significant increase in aEEG continuity was detected starting after half an hour of caffeine administration compared to before (p ¼ 0.002), with non-significant difference in electrographic seizures activity in cEEG (Table 2). No clinical seizures were recorded. At 36 weeks PMA only 10 neonates from the caffeine group continued at follow up, compared to 13 preterm

neonates who did not receive caffeine (control group). Mean duration of caffeine therapy was 5.05 ± 3.28 days, and mean maintenance caffeine dose was 8.75 ± 2.24 mg/kg/day. There were no significant differences in the need for neither respiratory support (p ¼ 0.795), nor clinical outcome (p ¼ 0.771). Length of NICU stay was significantly longer among controls (p ¼ 0.022). aEEG score was significantly higher among caffeine group (10.11 ± 1.616) compared to the control group, (p ¼ 0.000) (Table 3; Figure 1), whereas conventional EEG background cerebral activity grade and electrographic seizure activity showed non-significant difference between both the studied groups (p ¼ 0.091) (Table 3).

Discussion Our study showed non-significant changes in electrographic seizure activity in preterm cases during IV caffeine administration (p ¼ 0.414). This comes in agreement with previous animal study of a single dose of caffeine (40 mg/kg intraperitoneal) given after the onset of seizures in a mouse model; they noted significant increase in survival time from 24 to 55 minutes and explained this by the protective effect of acute caffeine that antagonizing a seizure-induced surge of adenosine, which had experimentally been exacerbated by pharmacological disruption of adenosine clearance [16]. However, an

Table 1. Comparison for demographic and laboratory characteristics between Caffeine and control groups.

Gestational age (weeks) Birth weight (kg) Maternal age (years) Weight (kg) Weight centile (%) OFC (cm) OFC centile (%) Length (cm) Length centile (%) Gender Male Female Mode of delivery Vaginal CS Apgar1 4 5 6 7 Apgar5 7 8 9 Gravidity Primigravida Multigravida Prematurity cause PROM Maternalb Othersc TLC Hb PLT a

Caffeine group Mean ± SD

Control group Mean ± SD

31.70 ± 1.16 1.35 ± 0.28 28.70 ± 6.48 1.87 ± .33 15.40 ± 10.88 31.40 ± 1.20 27.30 ± 22.07 43.30 ± 1.64 16.60 ± 9.24

31.85 ± 1.34 1.27 ± 0.37 28.31 ± 6.28 1.86 ± 0.40 15.23 ± 14.22 30.88 ± 1.18 18.08 ± 19.49 44.46 ± 1.78 23.00 ± 19.90

5(50.0) 5(50.0)


p value

0.59 0.15 0.10 0.03 1.03 1.06 1.60 0.94

0.559 0.885 0.921 0.975 0.313 0.300 0.124 0.359

6(46.2) 7(53.8)



2(20.0) 8(80.0)

4(30.8) 9(69.2)



0(0.0) 0(0.0) 4(40.0) 6(60.0)

1(7.7) 3(23.1) 2(15.4) 7(53.8)



0(0.0) 1(10.0) 9(90.0)

2(15.4) 4(30.8) 7(53.8)



5(50.0) 5(50.0)

4(30.8) 9(69.2)



4(40.0) 6(60.0) 0(0.0) 9.36 ± 1.67 14.04 ± 3.81 205.60 ± 87.30

4(30.8) 6(46.2) 3(23.0) 11.28 ± 4.65 12.70 ± 2.47 256.23 ± 99.07



1.24 1.02 1.28

0.230 0.318 0.215

Number of cases (%)/Chi square TEST. Maternal causes includes: diabetic mother, preclamptic, cardiac, etc. c Other causes for prematurity, e.g. twin pregnancy, unexplained. b



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Table 2. Effect of IV caffeine administration on clinical and EEG parameters in caffeine group (n ¼ 20).

CRT(second) HR(beat/min.) Mean Arterial blood Pressure (mmHg) Capillary Oxygen Saturation (%) Apnea Apnea No Apnea Arousability Quiet sleep Active sleep Drowsiness Quite alert Active alert Crying aEEG Continuity (%) Electrographic Seizures Activity No seizure activity Mild seizures Moderate seizures Marked seizures

Before IV caffeine Mean ± SD

After IV caffeine Mean ± SD

Paired-t test

p value

3.35 ± 0.687 139.75 ± 13.32 37.05 ± 6.36 93.30 ± 3.05

3.30 ± 0.470 142.85 ± 12.58 39.25 ± 6.54 94.10 ± 2.57

1.00 4.233 6.114 3.387

0.330 0.000 0.000 0.003

12(60.0) 8(40.0) 3(15.0) 10(50.0) 7(35.0) 0(0.0) 0(0.0) 0(0.0) 33.33 ± 30.05 15(78.9) 2(10.5) 2(10.5) 0(0.0)


10(50.0) 10(50.0) 0(0.0) 4(20.0) 2(10.0) 8(40.0) 3(15.0) 3(15.0) 51.96 ± 34.30



0.002 0.414a

12(66.7) 4(22.2) 2(11.1) 0(0.0)


Number of cases(%)/Chi square TEST, CRT ¼ capillary refill time, HR ¼ Heart rate.

Table 3. Comparison for outcome and EEG characteristics between caffeine and control groups at 36 weeks PCA. Caffeine group at 36 weeks PCA (n ¼ 10) Mean ± SD Mode of ventilation Off O2 4(40.0) Incubator O2 3(30.0) C-PAP 3(30.0) SIMV 0(0.0) Length of Stay (days) 38.20 ± 11.23 Outcome Discharged 9(90.0) Morbidityb 1(10.0) Died 0(0.0) Electrographic Seizure Activity No seizures 8(80.0) Mild seizures 2(20.0) Moderate seizures 0(0.0) Marked seizures 0(0.0) Conventional EEG background cerebral activity grade Normal 6(60.0) 1 4(40.0) 2 0(0.0) 3 0(0.0) aEEG Score 10.11 ± 1.616

Control group at 36 weeks PCA (n ¼ 13) Mean ± SD 6(46.2) 3(23.1) 3(23.1) 1(7.7) 47.54 ± 11.84


p value





9(69.2) 3(23.1) 1(7.7)




9(69.2) 1(7.7) 2(15.4) 1(7.7)



5(38.5) 2(15.4) 5(38.5) 1(7.7) 6.85 ± 1.77






Number of cases(%)/Chi-square test. Morbidity includes discharged with Ryle tube feeding.


earlier study reported that high doses (100 mg/kg or above) of caffeine provoke electrical modifications in the hippocampus similar to those recorded during generalized seizures [17]. Furthermore, it was reported that caffeine-induced release of Ca2+ from ryanodine-sensitive calcium stores in the neuronal endoplasmic reticulum and pathological mechanisms that potentiate this response may render neurons more vulnerable to excitotoxicity and to expression of seizures [18]. In our study, statistically significant increase in arousability and aEEG continuity in preterm infants was demonstrated after IV caffeine, (p ¼ 0.002), indicating that caffeine

increases pretem infants’ cerebral cortical activity. This could be explained by the pharmacological action of caffeine through stimulation of all levels of the CNS. The ability of caffeine to enhance activity-dependent brain-derived neurotrophic factor BDNF expression may contribute to the neurological benefit observed in infants receiving caffeine treatment [19]. These findings are supported by another study which reported that, after caffeine administration aEEG became increasingly continuous, and aEEG amplitudes increased, this increase persisted throughout the 2-hour period after caffeine administration [20]. In addition, caffeine

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DOI: 10.3109/14767058.2014.978757


or increase in electrographic seizures activity. Caffeine therapy markedly improved aEEG score at 36 weeks postmenstrual age, whereas conventional EEG background cerebral activity grade and electrographic seizure activity were not affected.

Acknowledgements Thanks to all of the team caring for the sick neonates in the Neonatal Intensive Care, Faculty of Medicine, Ain Shams University. They helped us throughout the study by giving the best care for the preemies.

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Declaration of interest The authors have no conflicts of interests to be declared. The authors report no funding relevant to the manuscript. Figure 1. aEEG score in caffeine treated preterm neonates and controls at 36 weeks PMA.

can be used to increase arousal in children [21]. In contrary to our results, non-significant differences in sleep organization between 33-and-34-week PMA infants receiving maintenance-dose caffeine citrate (5 mg/kg/day) and matched control infants were reported [22]. In our study mean heart rate increased significantly after caffeine administration, associated with significant increase in mean blood pressure and capillary oxygen saturation. This is in agreement with previous studies describing acute hemodynamic effects of intravenous caffeine in premature infants and reporting increased left ventricular cardiac output; stroke volume and heart rate [23], in addition mean arterial pressure increased significantly [20,23]. Caffeine administration increased respiratory muscle function and was associated with lung function improvement in prematurely born infants being weaned from mechanical ventilation [24]. In our study both caffeine and control groups were gender, gestational age, birth weight, and delivery mode matched. Laboratory data including total lymphocytic count, Hb level, platelets count and CRP showed non-significant difference between cases at 36 weeks PMA and controls. Also, nonsignificant difference in outcome (p ¼ 0.771); mode of ventilation (p ¼ 0.795) and recorded electrographic seizures activity was detected between caffeine group at 36 weeks and the control group. In our study there was no statistically significant difference in conventional EEG grade between cases at 36 weeks and controls (p ¼ 0.091) with significantly higher aEEG score in cases compared to controls, indicating higher cerebral cortical maturation in caffeine-treated infants. In a large-scale randomized, placebo-controlled Caffeine for Apnea of Prematurity trial, demonstrated that Caffeine therapy for apnea of prematurity reduces the rates of cerebral palsy and cognitive delay at 18 months of age. Also, it reduces the rate of developmental coordination disorder at 5 years of age [25].

Conclusion aEEG continuity significantly increased among preterms after intravenous caffeine administration with no adverse effect

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Effect of caffeine on preterm infants' cerebral cortical activity: an observational study.

Our first aim was to investigate the effects of caffeine on preterm infants' respiratory functions and brain cortical activity (conventional and ampli...
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