Small Cerebellar Hemorrhage in Preterm Infants: Perinatal and Postnatal Factors and Outcome High versus low-dose caffeine for apnea of prematurity: a randomized controlled trial A pilot randomized trial of high-dose caffeine therapy in preterm infants Extremely low birthweight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes. Obstructive, mixed, and central apnea in the neonate: physiologic correlates. Population pharmacokinetics of intravenous caffeine in neonates with apnea of prematurity High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial Developmental sequelae in preterm infants having a diagnosis of bronchopulmonary dysplasia: analysis using a severity-based classification system. Caffeine or theophylline for neonatal apnoea? Long-term effects of caffeine therapy for apnea of prematurity. Population-based study of bronchopulmonary dysplasia in very low birth weight infants in Switzerland Caffeine citrate for very preterm infants: Effects on development, temperament and behaviour. Caffeine Citrate Treatment for Extremely Premature Infants With Apnea: Population Pharmacokinetics, Absolute Bioavailability, and Implications for Therapeutic Drug Monitoring Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups. Periextubation caffeine in preterm neonates: a randomized dose response trial. Association of early versus late caffeine administration on neonatal outcomes in very preterm neonates
The objective of the study is to determine perinatal and postnatal factors that may affect the occurrence of  small cerebellar hemorrhage ( CBH )  and to evaluate the effect of small CBH on neurodevelopmental outcome in very preterm infants . This prospect i ve study in an unselected cohort of very preterm infants was approved by the medical ethics committee , and informed parental consent was obtained . Presence of small CBH ( < 4 mm ) was assessed with magnetic resonance imaging around term equivalent age in 108 preterm infants ( < 32 weeks gestation ) . We compared infants with and without small CBH for perinatal and postnatal factors , supratentorial brain injury , and for neurodevelopmental outcome at 2 years corrected age . Follow-up consisted of a neurological examination , mental and developmental assessment ( Bayley Scales of Infant Development ) , and behavior checklist . Univariate and multivariate logistic regression analyses were performed to examine the relationships between variables .  Small CBH  was diagnosed in 16/108 very preterm infants . Univariate analyses identified gestational age , high-frequency oscillation ( HFO ) ventilation , and grade 3–4 intraventricular hemorrhage ( IVH ) as factors associated with small CBH . HFO ventilation and severe IVH were independent predictors of small CBH . We found no association between small CBH and neurodevelopmental outcome at 2 years of age . Small CBH is a frequent finding in preterm infants . These hemorrhages are independently associated with HFO ventilation and severe supratentorial hemorrhage and seem to have a favorable short-term prognosis Abstract The optimum caffeine dose in preterm infants has not been well investigated . We aim ed to compare the efficacy and safety of high versus low-dose caffeine citrate on  apnea of prematurity ( AOP )  and successful extubation of preterm infants from mechanical ventilation . We compared high-dose ( loading 40 mg/kg/day and maintenance of 20 mg/kg/day ) versus low-dose ( loading 20 mg/kg/day and maintenance of 10 mg/kg/day ) caffeine citrate in preterm infants < 32 weeks gestation , presented with AOP within the first 10 days of life . A total of 120 neonates ( 60 in each group ) were enrolled . High-dose caffeine was associated with a significant reduction in extubation failure in mechanically ventilated preterm infants ( p < 0.05 ) , the frequency of apnea ( p < 0.001 ) , and days of documented apnea ( p < 0.001 ) . High-dose caffeine was associated with significant increase in episodes of tachycardia ( p < 0.05 ) without a significant impact on physician decision to withhold caffeine . Conclusion : The use of higher , than current st and ard , dose of caffeine may decrease the chance of extubation failure in mechanically ventilated preterm infants and frequency of AOP without significant side effects . What is Known:• Caffeine therapy for treatment of apnea of prematurity has been well established over the past few years . The optimal loading and maintenance dose of caffeine in preterm infants is not well-studied . What is New:• This double blind r and omized controlled trial demonstrated that using a higher , than current st and ard , loading and maintenance doses of caffeine for treatment of apnea in preterm infants is well tolerated and significantly decrease the frequency of apnea Background : St and ard-dose caffeine improves white matter microstructural development assessed by diffusion magnetic resonance imaging ( MRI ) . We hypothesized that early high-dose caffeine would result in further improvement in white matter microstructural development . Methods : Seventy-four preterm infants ( ≤30 wk gestational age ) were r and omly assigned to either a high ( 80 mg/kg i.v . ) or st and ard ( 20 mg/kg i.v . ) loading dose of caffeine citrate in the first 24 h of life . MRI and neurobehavioral testing were undertaken at term equivalent age . Infants returned at 2 y of age for developmental testing . Results : Clinical characteristics were similar between groups , with the exception of higher maternal age in the high-dose caffeine group . There was an increased incidence of cerebellar hemorrhage in infants r and omized to high-dose caffeine ( 36 vs. 10 % , P = 0.03 ) . Infants in the high-dose caffeine group also demonstrated more hypertonicity ( P = 0.02 ) and more deviant neurologic signs ( P = 0.04 ) at term equivalent age . Diffusion measures at term equivalent age and developmental outcomes at 2 y of age did not differ between groups . Conclusion : Preterm infants r and omized to early high-dose caffeine had a higher incidence of cerebellar injury with subsequent alterations in early motor performance . The results of this pilot trial discourage a larger r and omized controlled trial OBJECTIVE To compare duration of ventilation to mortality and adverse neurodevelopmental outcomes among extremely low birth weight ( ELBW ; 501 - 1000 g ) infants . STUDY DESIGN Retrospective analysis of prospect ively collected data from 5364 infants with a birthweight of 501 to 1000 g born at National Institute of Child Health and Human Development ( NICHD ) Neonatal Research Network centers from 1995 to 1998 . The main outcome measures were : survival , duration of mechanical ventilation , and neurodevelopmental outcome . RESULTS Overall survival was 71 % . The median duration of ventilation for survivors was 23 days ; 75 % were free of mechanical ventilation by 39 days , and 7 % were ventilated for > or = 60 days . Of those ventilated for > or = 60 days , 24 % survived without impairment . Of those ventilated for > or = 90 days , only 7 % survived without impairment . Of those ventilated > or = 120 days , all survivors were impaired . CONCLUSIONS The prognosis for ELBW with protracted ventilation remains grim . The cohort who remain intubated have diminished survival and high rates of impairment . Parents of these infants should be informed of changes in prognosis as the time of ventilation increases In an attempt to determine physiologic responses to neonatal apnea , we evaluated changes in heart rate and oxygen saturation as measured by pulse oximetry during 2082 episodes of apnea lasting 15 seconds or more in 47 infants less than 34 weeks of gestational age with idiopathic apnea of prematurity . Of these episodes , 832 ( 39.9 % ) were central , 1032 ( 49.6 % ) were mixed , and 218 ( 10.5 % ) were obstructive . Oxygen saturation decreased with increasing duration of apnea regardless of type or treatment , and the decrease in saturation was correlated with preapnea saturation . The baseline heart rate was similar for all apnea types . Infants receiving doxapram had a lower baseline heart rate ( 137.8 + /- 10.5 beats/min ) than did infants receiving no therapy ( 142.8 + /- 16.6 beats/min ) and infants receiving theophylline ( 149.7 + /- 15.0 beats/min ) ( p = < 0.001 ) . A heart rate fall to less than 100 beats/min was seen more frequently with central apnea than with mixed or obstructive events , and in infants who were not receiving therapy . Falls in heart rate were significantly less in infants receiving doxapram ( 27.8 % + /- 18.0 % ) than in infants receiving theophylline ( 44.5 % + /- 19.0 % ) or no therapy ( 48.4 % + /- 18.3 % ) ( p = < 0.001 ) . The most common heart rate pattern overall was a gradual decrease interrupted by accelerations , whereas an initial heart rate acceleration was the most common pattern in obstructive apnea . We conclude that heart rate response to  neonatal apnea is a complex and is dependent on therapy and on type and duration of apnea To study the population pharmacokinetics of caffeine after intravenous administration to premature infants with apnea Objective : To compare two dosing regimens for caffeine citrate in the periextubation period for neonates born at less than 30 weeks gestation in terms of successful extubation and adverse effects . Design : A multicentre , r and omised , double blind , clinical trial . Setting : Four tertiary neonatal units within Australia . Patients : Infants born less than 30 weeks gestation ventilated for more than 48 hours . Interventions : Two dosing regimens of caffeine citrate ( 20 v 5 mg/kg/day ) for periextubation management . Treatment started 24 hours before a planned extubation or within six hours of an unplanned extubation . Main outcome measure : Failure to extubate within 48 hours of caffeine loading or reintubation and ventilation or  doxapram  within seven days of caffeine loading . Results : A total of 234 neonates were enrolled . A significant reduction in failure to extubate was shown for the 20 mg/kg/day dosing group ( 15.0 % v 29.8 % ; relative risk 0.51 ; 95 % confidence interval ( CI ) 0.31 to 0.85 ; number needed to treat 7 ( 95 % CI 4 to 24 ) ) . A significant difference in duration of mechanical ventilation was shown for infants of less than 28 weeks gestation receiving the high dose of caffeine ( mean ( SD ) days 14.4 ( 11.1 ) v 22.1 ( 17.1 ) ; p = 0.01 ) . No difference in adverse effects was detected in terms of mortality , major neonatal morbidity , death , or severe disability or general quotient at 12 months . Conclusions : This trial shows short term benefits for a 20 mg/kg/day dosing regimen of caffeine citrate for neonates born at less than 30 weeks gestation in the periextubation period , without evidence of harm in the first year of life OBJECTIVE To investigate the relationship between the severity-based definition of bronchopulmonary dysplasia ( BPD ) , choice of treatment , and neurocognitive outcomes at age 3 and 8 years . DESIGN This is a secondary analysis of data collected from a prospect i ve , longitudinal sample of 99 children with a history of BPD . SETTING Children born with BPD admitted to 3 hospitals from February 1 , 1989 , to November 31 , 1991 . PARTICIPANTS Ninety-nine children with BPD were longitudinally assessed at age 3 and 8 years . Three severity groups ( mild , moderate , and severe ) were formed based on gestational age and need for supplemental oxygen therapy . MAIN EXPOSURES Supplemental oxygen therapy for 28 days or longer , birth weight less than 1500 g , and radiographic evidence of lung disease . MAIN OUTCOME MEASURES Neurologic and medical outcomes ; type of medical management ; and language , achievement , and cognitive functioning were compared among the 3 severity groups . RESULTS Severity classification of BPD was associated with poorer outcomes . Compared with children with mild or moderate BPD , children with severe BPD performed more poorly on IQ tests ( Mental Development Index , 90 vs 76.4 ; and Psychomotor Development Index , 92.5 vs 73.9 ) and language measures ( total , 95 vs 82 ) at age 3 years and performance IQ ( 86 vs 75 ) and perceptual organization ( 86 vs 76 ) at age 8 years . Severity of BPD was not associated with choice of medical management but was related to educational interventions . Children with severe BPD received more special education services ( 69 % vs 44 % ) than did children with mild BPD . CONCLUSIONS The severity-based classification clarifies the relationship between BPD and developmental sequelae . Children with severe BPD required more interventions at age 8 years than did children with mild or moderate BPD Caffeine , in the dose usually recommended ( 12.5 mg/kg loading dose and 3 mg/kg daily maintenance ) , and a higher dose regimen ( 25 mg/kg loading and 6 mg/kg daily maintenance ) , was compared with theophylline ( 7.5 mg/kg loading and 3 mg/kg thrice daily maintenance ) . The study was a r and omised controlled trial in the treatment of a group of 44 infants of less than 31 weeks ' gestation ( mean gestational age 28.3 weeks ) who were suffering from frequent apnoeic attacks .  All three regimens produced a significant reduction in apnoeic attacks within 24 hours , but only the higher dose caffeine and theophylline groups showed a significant improvement in apnoea within eight hours . The use of caffeine for the treatment of neonatal apnoea is recommended , because a once daily dose is more easily administered , and because it was found that plasma concentrations were more predictable than those of theophylline . If used in very preterm infants , however , its is suggested that a higher dose regimen than that previously recommended be used to achieve a faster response BACKGROUND Methylxanthine therapy is commonly used for apnea of prematurity but in the absence of adequate data on its efficacy and safety . It is uncertain whether methylxanthines have long-term effects on neurodevelopment and growth . METHODS We r and omly assigned 2006 infants with birth weights of 500 to 1250 g to receive either caffeine or placebo until therapy for apnea of prematurity was no longer needed . The primary outcome was a composite of death , cerebral palsy , cognitive delay ( defined as a Mental Development Index score of < 85 on the Bayley Scales of Infant Development ) , deafness , or blindness at a corrected age of 18 to 21 months . RESULTS Of the 937 infants assigned to caffeine for whom adequate data on the primary outcome were available , 377 ( 40.2 % ) died or survived with a neurodevelopmental disability , as compared with 431 of the 932 infants ( 46.2 % ) assigned to placebo for whom adequate data on the primary outcome were available ( odds ratio adjusted for center , 0.77 ; 95 % confidence interval [ CI ] , 0.64 to 0.93 ; P=0.008 ) . Treatment with caffeine as compared with placebo reduced the incidence of cerebral palsy ( 4.4 % vs. 7.3 % ; adjusted odds ratio , 0.58 ; 95 % CI , 0.39 to 0.87 ; P=0.009 ) and of cognitive delay ( 33.8 % vs. 38.3 % ; adjusted odds ratio , 0.81 ; 95 % CI , 0.66 to 0.99 ; P=0.04 ) . The rates of death , deafness , and blindness and the mean percentiles for height , weight , and head circumference at follow-up did not differ significantly between the two groups . CONCLUSIONS Caffeine therapy for apnea of prematurity improves the rate of survival without neurodevelopmental disability at 18 to 21 months in infants with very low birth weight . ( Clinical Trials.gov number , NCT00182312 [ Clinical Trials.gov ] . ) In Switzerl and , data are collected prospect ively by collaborators from all nine neonatal intensive care units and their affiliated paediatric units caring for neonates , to determine survival and ( pulmonary ) outcome of infants with birth weights ranging from 501 to 1500 g. To assess the pulmonary outcome of very low birth weight ( VLBW ) infants in Switzerl and in 1996 and 2000 , factors associated with bronchopulmonary dysplasia ( BPD ) were identified and compared with pulmonary outcomes from the Vermont Oxford Network data . BPD was defined as a requirement for supplemental oxygen at 36 weeks postmenstrual age . Complete data were available for 600 and 636 VLBW infants in 1996 and in 2000 , respectively .  Mortality rates in Switzerl and were significantly higher ( 1996 : 19.2 % , 2000 : 20.8 % ) than in the Vermont Oxford Network ( 1996 : 14 % , 2000 : 14 % ) . Expressed as percentage of infants still hospitalised at 36 weeks postmenstrual age , 16.7 % and 13.2 % of Swiss VLBW infants were diagnosed with BPD in 1996 and 2000 , respectively . These rates were significantly lower than in the Vermont Oxford Network ( 1996 : 28 % , 2000 : 35 % ) . Infants exposed to factors previously shown to be associated with BPD were investigated : in Switzerl and , infants with a history of surfactant replacement therapy and /or mechanical ventilation had a significantly higher rate of BPD in both cohorts . Infants with postnatal transport , sepsis proven by positive blood culture and patent ductus arteriosus had a higher BPD rate only in the 1996 cohort . Between 1996 and 2000 , mortality rates and incidence of BPD in VLBW infants remained unchanged in Switzerl and . BPD rates in Switzerl and are lower than those found in the Vermont Oxford Network whereas a mortality rate comparison displays an inverted picture . We suspect that these effects are interrelated and may be due in part to a selective approach of Swiss neonatologists to resuscitation of infants in the smallest birth weight stratum . Conclusion : The factors listed above have apparently become less important in the context of bronchopulmonary dysplasia and other influences , including prenatal conditions , will need to be investigated AIM To compare two dosing regimens for caffeine citrate for neonates born less than 30 weeks gestation in terms of development , temperament and behaviour . METHODS A multi-centre , r and omised , controlled trial design was undertaken . A total of 287 infants with apnoea of prematurity or in the peri-extubation period were r and omised to receive one of two dosage regimens ( 20 vs. 5 mg/kg/day ) . The main outcome measure was cognitive development at 1 year of age on the Griffiths Mental Development Scales . Secondary outcome measures included neonatal morbidity , death and disability , temperament at 1 year and behaviour at 2 years of age . RESULTS Data on the primary outcome were available for 190 survivors at 12 months corrected for prematurity . A significantly greater mean general quotient was found in the high-dose group ( mean ( st and ard deviation ) , 98.0 ( 13.8 ) vs. 93.6 ( 16.5 ) , P = 0.048 ) . On omission of two infants for whom cognitive assessment was not possible because of disability while the mean general quotient remained higher for infants in the high-dose group , this was no longer statistically significant ( P= 0.075 ) . There was a non-significant trend for benefit in the high-dose caffeine group for death or major disability , 15.4 % versus 24.2 % ; relative risk 0.75 ( 95 % confidence interval 0.49 - 1.14 ) . No differences in the mean values between the two groups were shown for temperament and behaviour . CONCLUSIONS Caffeine citrate with a dosage regimen of 20 mg/kg/day did not result in adverse outcomes for development , temperament and behaviour . The borderline benefit in cognition with high-dose caffeine needs further investigation The objective of this study was to develop a population model of the pharmacokinetics ( PK ) of caffeine after orogastric or intravenous administration to extremely premature neonates with apnea of prematurity who were to undergo extubation from ventilation . Infants of gestational age < 30 weeks were r and omly allocated to receive maintenance caffeine citrate dosing of either 5 or 20 mg/kg/d . Four blood sample s were drawn at prer and omized times from each infant during caffeine treatment . Serum caffeine was assayed by enzyme-multiplied immunoassay technique . Concentration data ( 431 sample s , median : 4 per subject ) were obtained from 110 ( 52 male ) infants of mean birth weight of 1009 g , current mean weight ( WT ) of 992 g , mean gestational age of 27.6 weeks , and mean postnatal age ( PNA ) of 12 days . Of 1022 doses given , 145 were orogastric , permitting estimation of absolute bioavailability . A 1-compartment model with first-order absorption was fitted to the data in NONMEM . Patient characteristics were screened ( P < 0.01 ) in nested models for pharmacokinetic influence . Model stability was assessed by nonparametric bootstrapping . Clearance ( CL ) increased nonlinearly with increasing PNA , whereas volume of distribution ( Vd ) increased linearly with WT , according to the following allometric models : CL ( L/h ) = 0.167 (WT/70)0.75 (PNA/12)0.358 ; Vd ( L ) = 58.7 (WT/70)0.75 . The mean elimination half-life was 101 . Interindividual variability ( IIV ) of CL and Vd was 18.8 % and 22.3 % , respectively . Interoccasion variability ( IOV ) of CL and Vd was 35.1 % and 11.1 % , respectively . This study established that the elimination of caffeine was severely depressed in extremely premature infants but increased nonlinearly after birth up to age 6 weeks . Caffeine was completely absorbed , which has favorable implication s for switching between intravenous and orogastric routes . The interoccasion variability about CL was twice the interindividual variability , which , among other factors , indicates that routine serum concentration monitoring of caffeine in these patients is not warranted OBJECTIVE To determine whether the benefits of caffeine vary in three subgroups of 2006 participants in the Caffeine for Apnea of Prematurity ( CAP ) trial . STUDY DESIGN Post-hoc subgroup analyses were performed on the basis of : ( 1 ) indication for commencement of study drug : treat apnea , prevent apnea , or facilitate extubation ; ( 2 ) positive pressure ventilation ( PPV ) at r and omization : endotracheal tube ( ETT ) , noninvasive ventilation , or none ; and ( 3 ) timing of commencement of study drug : early or late ( < or =3 versus > 3 days ) . Outcomes assessed were those showing treatment effects in the original analyses . We investigated the consistency of caffeine effects by using regression models that incorporated treatment/subgroup factor interactions . RESULTS There was little evidence of a differential treatment effect of caffeine in subgroups defined by the clinical indication for starting study drug . The size and direction of the caffeine effect on death or disability differed depending on PPV at r and omization ( P = .03 ) . Odds ratios ( 95 % CI ) were : no support , 1.32 ( 0.81 - 2.14 ) ; noninvasive support , 0.73 ( 0.52 - 1.03 ) ; and ETT , 0.73 ( 0.57 - 0.94 ) . Adjustment for baseline factors strengthened this effect ( P = .02 ) . Starting caffeine early result ed in larger reductions in days of respiratory support . Postmenstrual age at time of discontinuing PPV was shorter with earlier treatment ( P = .01 ) . Mean differences ( 95 % CI ) were : early , 1.35 weeks ( 0.90 - 1.81 ) ; and late 0.55 weeks ( -0.11 - 0.99 ) . Adjustment for baseline factors weakened this effect ( P = .03 ) . CONCLUSIONS There is evidence of variable beneficial effects of caffeine .  Infants receiving respiratory support appeared to derive more neurodevelopmental benefits from caffeine than infants not receiving support . Earlier initiation of caffeine may be associated with a greater reduction in time on ventilation OBJECTIVE To compare the effectiveness of three dosing regimens of caffeine for preterm infants in the periextubation period . METHODS A r and omized double-blind clinical trial of three dosing regimens of caffeine citrate ( 3 , 15 and 30 mg/kg ) for periextubation management of ventilated preterm infants was undertaken . Infants born < 32 weeks gestation who were ventilated for>48 h were eligible for the study .  Caffeine citrate was given as a once daily dose for a period of 6 days commencing 24 h prior to a planned extubation , or within 6 h of an unplanned extubation . The primary outcome measure was extubation failure , defined as neonates who were unable to be extubated within 48 h of caffeine loading or who required reventilation or doxapram dose within 7 days of caffeine loading . Continuous recordings of oxygen saturation and heart rate were undertaken in a subgroup of enrolled infants . RESULTS A total of 127 babies were enrolled into the study ( 42 , 40 , 45 , in the 3 , 15 , and 30 mg/kg groups , respectively ) . No statistically significant difference was demonstrated in the incidence of extubation failure between dosing groups ( 19 , 10 , and 11 infants in the 3 , 15 , and 30 mg/kg groups , respectively ) , however , infants in the two higher dose groups had statistically significantly less documented apnoea than the lowest dose group . Of the 37 neonates with continuous pulse oximetry recordings , those on higher doses of caffeine recorded a statistically significantly higher mean heart rate , oxygen saturations and less time with oxygen saturations < 85 % . CONCLUSIONS This trial indicated there were short-term benefits of decreased apnoea in the immediate periextubation period for ventilated infants born < 32 weeks gestation receiving higher doses of caffeine . Further studies with larger numbers of infants assessing longer-term outcomes are necessary to determine the optimal dosing regimen of caffeine in preterm infants Caffeine is commonly used for preterm infants with apnoea of prematurity . The caffeine for apnoea of prematurity trial ( CAP ) was launched to determine whether survival without neurodevelopmental disability at a corrected age of 18 months is improved if apnoea of prematurity is managed without methylxanthines in infants at a high risk of apnoeic attacks ( 1 ) . Infants had to be within 10 days of birth . Forty per cent of the patients assigned to caffeine  died or survived with a neurodevelopmental disability compared with 46 % assigned to placebo ( OR 0.77 , 95 % CI 0.64–0.93 ; p = 0.008 ) . Physicians were not asked to alter their own prescribing indications for caffeine . However , only 22.5 % of the neonatologists in the trial started caffeine to prevent apnoea ( 2 ) . Thus , the risk – benefit ratio of caffeine administered exclusively for prophylaxis and therefore likely earlier remains unclear . This was emphasised by Schmidt in a recent editorial ( 3 ) commenting upon a large observational cohort study that showed that early administration decreased the incidence of BPD  in their US group of NICUs ( 4 ) . This is in line with another retrospective data analysis by Taha et al. ( 5 ) . In addition , a subgroup analysis of the CAP trial demonstrated that early caffeine treatment correlated with a larger reduction in days of respiratory support compared to late caffeine ( 6 ) . In this third large-scale observational study of the Canadian Neonatal Network , Lodha et al. retrospectively investigated the effect of early versus late initiation of caffeine therapy on  neonatal short-term outcomes  of very preterm infants . The nationwide participation result ed in an impressive number of included infants . Nevertheless , there are a few comments to make . First , the diagnosis of a PDA was based on clinical signs , with or without echocardiography . However , several studies have demonstrated that echocardiograms are required for the diagnosis of a PDA in preterm infants , as clinical signs are not reliable in the first few days of life ( 7,8 ) . Second , there are imbalances between the infants of the early and those of the late treatment groups . We also suggest that some baseline characteristics should rather be declared as outcomes and /or co- interventions ( table 3 ) due to their timely relation to the intervention . The late treatment group , for example , showed a more frequent use of postnatal steroids and an increased occurrence of air leak syndromes . The differences in baseline characteristics may have result ed in an early administration of caffeine in those babies without and a late administration in those with major risk factors for adverse outcomes , such as BPD for example . Despite adjustments for known imbalances between groups , observational studies do not have the ability to completely eliminate selection bias and observational studies investigating the effect of drug treatments are prone to confounding by indication . Thirdly , information concerning the indication to start caffeine is lacking , and no information on dosages is provided . In conclusion , this is an important study , but more data from r and omised controlled trials on the optimal timing of caffeine administration are needed before introducing early prophylactic caffeine into routine clinical practice ( 9 )
Background Placebo-controlled trials have shown that caffeine is highly effective in treating  apnoea of prematurity  and reduces the  risk  of  bronchopulmonary dysplasia ( BPD ) and neurodevelopmental impairment ( NDI ) .
Objective To identify , appraise and summarise studies investigating the modulating effect of different caffeine dosages .