Scholarly article on topic 'Caffeine Administration to Prevent Apnea in Very Premature Infants'

Caffeine Administration to Prevent Apnea in Very Premature Infants Academic research paper on "Health sciences"

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{"apnea neonatorum" / caffeine / methylxanthine / "premature infant"}

Abstract of research paper on Health sciences, author of scientific article — Amir-Mohammad Armanian, Ramin Iranpour, Eiman Faghihian, Nima Salehimehr

Background Apnea intervals frequently occur in premature infants. Periods of apnea occur more often with decreases in gestational age. Periods of apnea can cause damage to the infant's developing brain and other organs. This study was designed to investigate the preventive effects of caffeine on apnea incidence in higher-risk neonates. Methods In this single-center randomized control trial study, premature infants with a birth weight of ≤1200 g were eligible for enrollment. Twenty-six infants were randomly assigned to receive 20 mg/kg caffeine, as the loading dose, which was followed by 5 mg/kg daily as the maintenance dose until the 10th day of life; these infants were compared with 26 infants in the control group. Primary outcomes were incidence of apnea, bradycardia, and cyanosis. Results Fifty-two infants were enrolled (26 in the caffeine group and 26 in the control group). The preventive effect of caffeine on apnea was significant in these infants. The relative risk for incidence of apnea in preterm neonates with a birth weight of <1200 g was 0.250 (95% confidence interval, 0.097–0.647). Only four infants (15.4%) in the caffeine group developed apnea, compared with 16 (61.5%) in the control group (p = 0.001). Conclusion It seems that preventative effects of caffeine on apnea become apparent by using the drug in very premature infants.

Academic research paper on topic "Caffeine Administration to Prevent Apnea in Very Premature Infants"

Accepted Manuscript

Caffeine Administration to Prevent Apnea in Very Premature Infants

Amir-Mohammad Armanian, MD, Assistant professor of neonatology, Ramin Iranpour, MD, Associate Professor, Eiman Faghihian, MD, Resident of pediatrics, Nima Salehimehr, MD, General physician

PII: S1875-9572(16)00004-8

DOI: 10.1016/j.pedneo.2015.10.007

Reference: PEDN 533

To appear in: Pediatrics & Neonatology

Received Date: 8 July 2015 Revised Date: 23 September 2015 Accepted Date: 8 October 2015

Please cite this article as: Armanian A-M, Iranpour R, Faghihian E, Salehimehr N, Caffeine Administration to Prevent Apnea in Very Premature Infants, Pediatrics and Neonatology (2016), doi: 10.1016/j.pedneo.2015.10.007.

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Original article

Caffeine Administration to Prevent Apnea in Very Premature Infants Running title: Prophylactic caffeine and apnea of prematurity

Amir-Mohammad Armanian1, Ramin Iranpour2, Eiman Faghihian3, Nima salehimehr4

1-Amir-Mohammad Armanian: MD, Assistant professor of neonatology, Division of Neonatology, Department of Pediatrics, Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

E-Mail: armanian@med.mui.ac.ir

2-Ramin Iranpour: MD, Associate Professor, Division of Neonatology, Department of Pediatrics, Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

Email: iranpour@med.mui.ac.ir

3-Eiman Faghihian: MD, Resident of pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran

Email: efaghihian@gmail.com

4-Nima Salehimehr: MD, General physician, almahdi University, Isfahan, Iran Email: dr.nsalehimehr@yahoo.com

Corresponding author: Amir-Mohammad Armanian

Mail address: Child Growth and Development Research Center, Research Institute for Primary Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Hezarjerib Ave, Isfahan, Iran

E-mail: armanian@med.mui.ac.ir

Tel: +989131294044 ,

Fax: +983112355059

Abstract

Background: Apnea intervals frequently occur in premature infants. Periods of apnea occur more often with decrease in gestational age. Periods of apnea can cause damage to the infant's developing brain and other organs. This study was designed to investigate the preventive effects of caffeine on apnea incidence in higher risk neonates. Methods: This single-center randomized control trial study, premature infants with birth weight < 1200 grams were eligible. Twenty-six infants were randomly assigned to receive 20 mg/kg caffeine, as loading dose, which was followed by 5 mg/kg daily as maintenance dose until the tenth day of life and compared with 26 infants in control group. Primary outcomes were incidence of apnea, bradycardia, and cyanosis.

Results: Fifty-two infants were enrolled (26 in the caffeine and 26 in the control group). Caffeine's preventive power of apnea was significant in these infants. The relative risk (RR) for incidence of apnea in preterm neonates with a weight below 1200 gr. was 0.250 (95% CI, 0.097-0.647). Only four infants (15.4%) in the caffeine group developed apnea, compared to 16 (61.5%) infants in the control group (P=0.001).

Conclusion: It seems that preventative effects of caffeine on apnea become apparent by using the drug among very premature infants.

Keywords: premature infant; apnea neonatorum; methylxanthine; caffeine

INTRODUCTION

Apnea intervals frequently occur in preterm infants . ' The American Academy of Pediatrics (AAP) describes apnea as a non-inspiratory period lasting for at least 20 seconds or below 20

seconds, together with bradycardia and/or cyanosis. ' Periods of apnea occur more often with decrease in gestational age.4 Despite the fact that apnea can occur solely because of the prematurity of the infant, there are certain situations, like hypoxic periods, metabolic disorders, intracranial pathologies and infections, which can also trigger it. 1

Long periods of apnea can result in infant cyanosis or bradycardia and the further need to resuscitate the neonate as cardiopulmonary arrest occurs.1Periods of apnea can cause damage to the infant's developing brain and also disrupt the function of the intestine and other organs .4 Recurrent and long intervals of apnea can result in respiratory failure and therefore need for intubation and mandatory ventilation. 1 Apnea and hypoxemia cause EEG abnormalities and also leuckomalacia leading to behavioral and neurological difficulties.5 After the 1980s pulse oximetry and heart monitoring for premature infants were routinely used.5 Premature infants usually experience sudden decrease in blood oxygen saturation, which is sometimes accompanied with apnea period, and requires immediate medical support. Methylxanthines help breathing efforts and, therefore, they have long been used as a treatment for apnea of prematurity.1,6,7 They also decrease the need for mechanical ventilation and can be useful before extubation ; while the mechanism of action is not yet clearly known, optimizing the response of chemoreceptors to pCo2 rise, improving the function of respiratory muscles and CNS stimulation have been noted -1 Two commonly available forms of methylxanthines are theophylline and caffeine.5 Compared to the former, caffeine has more certain intestinal absorption, a wider therapeutic index ,and a longer half-life, which makes it possible to be administered daily.6 Preventing apnea and hypoxic intervals avoids the side effects of using

oxygen, intubation, and related complications. - In consequence, there have been several

trials to discover a treatment for neonatal apnea.6,7,11-13 However, few have aimed aim to find preventing agents for apnea of premature neonates.5,9 The hypothesis of the present study was that the use of prophylactic caffeine would reduce the incidence of apnea in preterm neonates who weighed less than 1200 gr. The objectives were to compare the frequency of the incidence of apnea, bradycardia, cyanosis, duration of continuous positive airway pressure (CPAP), or need of mechanical ventilation, duration of hospitalization and death (if occurring) in a double-blind randomized trial.

MATERIALS AND METHODS

This study was a double-blinded, placebo-controlled, randomized clinical trial which was approved by the Institutional Review Board at the Isfahan University of Medical Sciences. The study sample was composed of infants that were admitted to the NICU at Alzahra and Shahid Beheshti hospitals in Isfahan-Iran, between September 2013 and January 2014, who were born prematurely with a birth weight (BW) of <1200 gr and had spontaneous breathing at 24 hours of life. Infants who had major congenital anomalies, asphyxia, congenital cyanotic heart disease, intra-uterine growth retardation (IUGR), need for mandatory ventilation in the first day of life and sepsis in the first week of life were excluded. The preventive impact of caffeine on the incidence of apnea was studied in two groups of caffeine (group C) and placebo (group P). Randomization was performed 1:1 using a computergenerated randomization list prepared by an independent statistician who was not involved in the rest of the investigation. In intervention group, caffeine 20 mg/kg (IV) was administered as beginning dose in the first day of life and then 5 mg/kg (IV) daily was used as maintenance dose for the first 10 days of life. The placebo group received an equivalent volume of normal saline daily during first ten days of life. Caffeine and normal saline were prepared in similar syringes by a trained nurse who was blind to the group assignment. A trained nurse numbered the syringes, and the investigator, who was blind to the numbering, allocated numbers to infants in sequence of entry into the study.

The same respiratory management protocol was used for treatment of patients studied. If clinical evidence of respiratory distress and/or reduction of arterial oxygen saturation by pulse-oximetry (SpO2) existed, nasal continuous positive airway pressure (NCPAP) was initiated at a continuous pressure of 5-6 cmH2O with a flow of 8-10 L/min. Short bi-nasal prongs delivered CPAP to the infants. Settings in both groups were adjusted according to

arterial blood gases (ABG), and clinical parameters and SpO2 was maintained between 88% and 92%. Surfactant (Survanta or Curosurf) was administered if studied neonates needed a fraction of inspired oxygen (FIO2) of >30% to keep the SpO2 of >88% and 92%. Intubation-surfactant-extubation (INSURE) approach was used in both groups, only as rescue therapy. We gave a second or third dose of surfactant if the neonates required a FIO2 of >40% to maintain the desired saturation.

The impact of caffeine to prevent apnea, bradycardia, and cyanosis in first ten days of life was the primary outcome in the two groups. Apnea was counted if a breathing pause for at least 20 seconds or below 20 seconds with bradycardia and/or cyanosis occurred. Bradycardia was considered present if the heart rate slowed down at least 20% from the baseline for 20 seconds. Cyanosis was considered present if the neonate had a SpO2 <85%. All data were based on daily NICU reports and monitor downloads. The secondary outcomes were measurements of the duration of CPAP, need to use mandatory ventilation, and incidence of intraventricular hemorrhage (IVH), patent ductus arteriosus (PDA), necrotizing enterocolitis, (NEC), and drug side effects (such as tachycardia; e.g. increase in the sinus rate above 160 to 180 beats per minute 14) which was monitored daily. The expected scale for intubation and use of mandatory ventilation was more than 3 repeated of apnea per hour and bradycardia or a one-time incidence of apnea that needed ventilating with bag and mask. The times of hospitalization and death (if occurring) were noted. Duration of dependency on oxygen and the incidence of chronic lung disease (CLD; oxygen dependency at 28 days of life) 15, 16 were noted by long-term follow-up. Because of ethical issues and safety, if apnea occurred caffeine, was also administered to the control group infants. Primary and secondary outcomes were recorded by certified personnel who were blinded to the infant randomization.

Statistical analysis

The sample size of 52 infants was based on the sample size design for the primary outcome of a previous study (the effect of prophylactic methylxanthines on prevention of apnea in preterm infants). 9 The sample size was adjusted according to the opinion of a statistical

consultant and based on the formula: N=(Z1 + Z2)2(2P(1 -P)] in which Z1 is confidence interval of

95% or 1.96; Z2 is the power of the test that was 0/80 or 0/84; P is an estimate of the frequency of incidence of each the factors in both groups, in which 0.5 was considered regarding the variations in each group; and "d" is the minimum difference of incidence of each variable between the two groups in which statistically significant difference of 0.8P was considered. Data are expressed as means with standard deviations (continuous variables) or as numbers with percentages (categorical variables). The characteristics of the study subjects were analyzed using Chi-square test, Fisher's exact test, Mann-Whitney test, independent t-test, or analysis of variance (ANOVA), as appropriate. All data were analyzed by SPSS software, version 20.0 (SPSS, Chicago, IL, USA). All testing for statistical significance was two-tailed, with an a-error of 0.05. The adjusted relative risks (RRs) (with 95% CIs) for the incidence of apnea, bradycardia, cyanosis, need for mechanical ventilation, IVH, PDA, NEC, drug side effects (tachycardia), CLD and death were calculated by logistic regression analysis.

Ethics statement

Prior to the enrollment, parents of all study participants were provided with written informed consent forms. This paper is derived from a residency thesis No. 292152 in Isfahan University of Medical Sciences. This trial was registered at IRCT.ir with a reference number as IRCT2013110610026N3. RESULTS

Throughout the trial, a total of 114 preterm infants with a BW < 1200 grams were assessed for eligibility. Fifty-six infants were excluded because of not meeting the inclusion criteria, their parents' refusal to participate, major congenital anomalies, and occurrence of apnea in the first day of life. Fifty-eight neonates were randomized and finally 52 infants completed the study (Figure 1). Demographic characteristics were similar between the two groups (Table 1). In the caffeine group, there were 15 (57.7%) males and 11 (42.3%) females. The placebo group consisted of 13 (50.0%) males and 13 (50.0%) females. No statistically significant difference between the two groups was noted by the chi-square test (P=0.57) (Table 1).

The primary outcomes were clearly different between the two groups. Only 4 infants (15.4%) in the caffeine group developed apnea, compared to 16 (61.5%) infants in the placebo group (P=0.001). In the caffeine group, 2 (7.7%) and 5 (19.2%) of the neonates developed bradycardia and cyanosis, respectively, compared to 16 infants (61.5%) who did not receive caffeine (P<0.05). The RR and 95% CI values of developing apnea, bradycardia, and cyanosis were 0.250 (0.097-0.647), 0.125 (0.032-0.490) and 0.313 (0.134-0.727) respectively (Table 2). Three infants in the caffeine group developed severe apnea and needed mechanical ventilation (P=0.118). The incidence of IVH, PDA, and NEC were similar in the two groups: (P=0.233), (P=0.760), and (P=0.245); respectively. No medication side effect (tachycardia) was reported in the neonates (P=1) (Table 2). The incidence of CLD showed a statistically significant difference between the two groups. Only 4 infants (15.4%) in the caffeine group developed CLD, compared to 11 infants (44.0%) in the placebo group (P=0.025). The RR and 95% CI values of developing CLD were 0.350 (0.128-0.954). Only one baby died in the caffeine group while no death was reported in the placebo group (P=0.510) (Table 2).

DISCUSSION

In our randomized double-blind placebo-controlled trial, the occurrence of apnea in the

caffeine group was clearly less than the control group. A few trials have tested drugs for

preventing apnea of premature neonates. Bucher et al. 5 and Levitt et al. 9studied preterm

infants, to whom; caffeine citrate was administered with a starting dose of 20 mg/kg. The

maintenance doses used in Levitt's study and Bucher's study were 5 mg/kg/day and 10

mg/kg/day; respectively. 5,9,10 Levitt et al. continued the trial until the postmenstrual age of 32

weeks, while Bucher et al. discontinued the trial after 96 hours. Bucher reported bradycardia

and hypoxia intervals as primary outcomes but apnea was not directly measured.5 Levitt

reported apnea as the initial result and described it as a non-inspiratory period lasting for at

least 20 seconds with cyanosis or bradycardia. In these trials, no changes in the primary

outcomes between the caffeine group and placebo group were noted. The occurrence of side

effects and need of mandatory ventilation were also similar. 5,9,10 The prophylactic effect of

caffeine in the present trial is probably because apnea occurrence was investigated instead of

bradycardia and hypoxemia, as was the case in the Bucher's trial. It may be claimed that these

incidents are scaled up in the case group because caffeine probably increases awareness,

motion and metabolic rate. Secondly, the present clinical trial was conducted on very high-

risk infants (premature infants with a birth weight under 1200 gr). Davis et al. studied outcomes of premature infants treated with either caffeine or placebo until 18 to 21 months of their modified ages. The occurrence rate of apnea was not noted in this trial but the need for

PDA closure and the duration of mandatory ventilation were lower in the group that received

12 1 prophylactic caffeine. Henderson-Smart DJ et al., after reviewing these researches,

reported that methylxanthines did not have a preventive effect for premature neonate apnea

but concluded with the recommendation that oncoming trials should measure

methylxanthines' apnea-preventing effects in very high-risk premature neonates. 1 This study

was designed for higher risk neonates and also for the investigation of the preventive effects of caffeine on neonatal apnea. Incidentally, it appears that when infants at higher risk are studied the preventive effects of caffeine become apparent.

The small number of subjects in this study was a limitation, although the results were significant. The results revealed that the more immature the infant, the greater the benefit of prophylactic caffeine on the incidence and severity of apnea. Fifty-two premature neonates were included in the present study; therefore, our study can be considered as a pilot study, and further studies are warranted to confirm this association.

Conclusion: Our study was designed the investigation preventive effects of caffeine on neonatal apnea in higher risk neonates. It seems that preventative effects of caffeine on apnea become apparent by using the drug on very premature infants. However, further studies with larger sample sizes are recommended to investigate the issue.

Conflict of Interest: All authors had no conflicts of interest to disclose.

References:

1. Henderson-Smart DJ, De Paoli AG. Prophylactic methylxanthine for prevention of apnoea in preterm infants. Cochrane Database Syst Rev. 2010:CD000432. DOI: 10.1002/14651858.CD000432

2. Finer NN, Higgins R, Kattwinkel J, Martin RJ. Summary proceedings from the apnea-of-prematurity group. Pediatrics. 2006;117(Supplement 1):S47-S51.

3. Pediatrics AAo. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics. 2003;111(4):914-7.

4. Santin R, Porat R. Apnea of prematurity. eMedicine; 2005. http://www.emedicine.com/ ped/topic1157.htm

5. Bucher H, Duc G. Does caffeine prevent hypoxemic episodes in premature infants? European journal of pediatrics. 1988; 147(3):288-91.

6. Henderson-Smart DJ, Steer PA. Caffeine versus theophylline for apnea in preterm infants. The Cochrane Library. 2010.

7. Henderson-Smart D, De Paoli A. Methylxanthine treatment for apnea in preterm infants. Evid Based Med. 2011; 16(4):120-1.

8. Henderson-Smart DJ, Davis PG. Prophylactic methylxanthines for extubation in preterm infants. Cochrane Database Syst Rev. 2003:CD000139.

9. Levitt G, Harvey D. The use of prophylactic caffeine in the prevention of neonatal apnoeic attacks. Unpublished manuscript. 1988:235-43.

10. Levitt G, Mushin A, Bellman S, Harvey D. Outcome of preterm infants who suffered neonatal apnoeic attacks. Early human development. 1988;16(2):235-43.

11. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Caffeine therapy for apnea of prematurity. New England Journal of Medicine. 2006;354(20):2112-21.

12. Davis PG, Schmidt B, Roberts RS, Doyle LW, Asztalos E, Haslam R, et al. Caffeine for apnea of prematurity trial: benefits may vary in subgroups. The Journal of pediatrics. 2010;156(3):382-7. e3..

13. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, et al. Long-term effects of caffeine therapy for apnea of prematurity. New England Journal of Medicine. 2007;357(19):1893-902.

14. Martin RJ, Fanaroff AA, Walsh MC. Fanaroff and Martin's neonatal-perinatal medicine: diseases of the fetus and infant: Elsevier Health Sciences; 2014.

15. Goldsmith JP, Karotkin E. Assisted ventilation of the neonate: Elsevier Health Sciences; 2010.

16. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. American journal of respiratory and critical care medicine. 2001;163(7):1723-9.

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Analysis

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Figure 1 CONSORT flow diagram.

Table 1 Characteristics of the study population and the continuous variables measured.

Variables Caffeine group (n=26) placebo group (n=26) P value

Male (%) 15 (57.7%) 13 (50.0%) 0.578

Female (%) 11 (42.3%) 13 (50.0%) 0.536

Gestational age (weeks) Mean ± SD 28.73 ± 1.95 28.57 ± 2.06 0.783

Birth weight (grams) Mean ± SD 966.9 ± 194.14 1007.7 ± 134.02 0.382

Need of CPAP (days) Mean ± SD 3.96 ± 3.98 5.96 ± 3.20 0.052

Oxygen dependency time (days) Mean ± SD 14.42 ± 19.08 22.69 ± 23.14 0.166

Time of hospitalization (days) Mean ± SD 47.19 ± 26.17 41.80 ± 18.25 0.394

Table 2 The study outcomes.

Variables Caffeine group (n=26) placebo group (n=26) P value RR 95% CI

Apnea No. (%) 4 (15.4%) 16 (61.5%) 0.001 0.250 0.097-0.647

Bradycardia No. (%) 2 (7.7%) 16 (61.5%) <0.001 0.125 0.032-0.490

Cyanosis No. (%) 5 (19.2%) 16 (61.5%) 0.002 0.313 0.134-0.727

Mechanical ventilation No. (%) 3 (11.5%) 0 (0.0%) 0.118 Not calculated Not calculated

IVH No. (%) 6 (23.1%) 3 (11.5%) 0.233 2.000 0.559-7.156

PDA No. (%) 7 (26.9%) 8 (30.8%) 0.760 0.875 0.372-2.060

NEC No. (%) 0 (0.0%) 2 (7.7%) 0.245 Not calculated Not calculated

Tachycardia No. (%) 0 (0.0%) 0 (0.0%) > 0.999

CLD No. (%) 4 (15.4%) 11 (44.0%) 0.025 0.350 0.128-0.954

Death No. (%) 1 (3.8%) 0 (0.0%) 0.510 Not calculated Not calculated

p values and adjusted relative risks (RRs), with 95% confidence intervals (CIs), for the incidence of apnea, bradycardia, cyanosis, need for mechanical ventilation, IVH, PDA, NEC, drug side effect (tachycardia), CLD and death in the two groups.