Caffeine Discontinuation Research Articles

Caffeine and kidney function at two years in former extremely low gestational age neonates.

Extremely low gestational age neonates (ELGANs) are at risk for chronic kidney disease. The long-term kidney effects of neonatal caffeine are unknown. We hypothesize that prolonged caffeine exposure will improve kidney function at 22-26 months. Secondary analysis of the Preterm Erythropoietin Neuroprotection Trial of neonates <28 weeks' gestation. Participants included if any kidney outcomes were collected at 22-26 months corrected age. Exposure was post-menstrual age of caffeine discontinuation. 'reduced eGFR' <90 ml/min/1.73 m2, 'albuminuria' (>30 mg albumin/g creatinine), or 'elevated blood pressure' (BP) >95th %tile. A general estimating equation logistic regression model stratified by bronchopulmonary dysplasia (BPD) status was used. 598 participants had at least one kidney metricat follow up. Within the whole cohort, postmenstrual age of caffeine discontinuation was not associated with any abnormal measures of kidney function at 2 years. In the stratified analysis, for each additional week of caffeine, the no BPD group had a 21% decreased adjusted odds of eGFR <90ml/min/1.73m2 (aOR 0.78; CI 0.62-0.99) and the BPD group had a 15% increased adjusted odds of elevated BP (aOR 1.15; CI: 1.05-1.25). Longer caffeine exposure during the neonatal period is associated with differential kidney outcomes at 22-26 months dependent on BPD status. In participants born <28 weeks' gestation, discontinuation of caffeine at a later post menstrual age was not associated with abnormal kidney outcomes at 22-26 months corrected age. When assessed at 2 years of age, later discontinuation of caffeine in children born <28 weeks' gestation was associated with a greater risk of reduced eGFR in those without a history of BPD and an increased odds of hypertension in those with a history of BPD. More work is necessary to understand the long-term impact of caffeine on the developing kidney.

National survey on caffeine use in neonatal units across the United Kingdom.

To understand the variations in practice for caffeine use among neonatal units in the United Kingdom. An online survey was sent to every neonatal unit in the United Kingdom. We received a response from 92 neonatal units (47%) with the proportion of response from special care, Local neonatal units, neonatal intensive care units and neonatal surgical units were 23%, 34%, 23% and 21% respectively. All the units reported the use of caffeine, and 40 units (46%) initiated caffeine within 24h of birth. Fifty-nine units (64%) reported routine use of caffeine for pre-term infants <32 weeks. Seventy-one units (77%) reported that they continue caffeine for infants needing mechanical ventilation. Thirty-one units (34%) discontinued caffeine at 34 weeks post-menstrual age, irrespective of the respiratory support. Ten units (11%) reported discontinuation of caffeine only after weaning off all respiratory support, and 40% of units had a variable practice of discontinuing caffeine depending on the individual baby. Seventy-nine units (86%) reported they would regularly optimise caffeine dose based on weight checks. Our survey showed some variation in practice with regards to the timing of caffeine initiation, gestational age cut-off for routine caffeine prescription and discontinuation.

Efficacy and Safety of Caffeine for Preterm Infants with Apnea According to Birth Weight

Apnea of prematurity is one of the most common problems in preterm and low birth weight infants, and it is reported to be more likely to occur in infants of lower gestational age and lower birth weight. The present study investigated the efficacy and safety of caffeine according to weight, based on birth weight. We defined preterm infants with birth weights of < 1,000 g, 1,000 g to < 1,500 g, and 1,500 g to < 2,500 g as the extremely low birth weight (ELBW), very low birth weight (VLBW), and low birth weight (LBW) groups, respectively. There was a significant difference among the three groups in the rate of improvement of apnea attacks from days 1 to 10 of administration. The percentage of cases that showed “improvement” on each day tended to be higher in the LBW group. The incidence of adverse events was 100％ in the ELBW group, 90.9％ in the VLBW group, and 64.7％ in the LBW group (P < 0.001). However, regarding adverse events that were suspected to have been caused by caffeine or events that required dose reduction or discontinuation of caffeine due to adverse events, there were no significant differences among the three groups in any of the items that were investigated. These results suggest that the greater the birth weight, the more likely effects of treatment will occur, and that although careful administration is required, the administration of caffeine to infants of lower birth weight may be feasible.

Achievement of maturational milestones among very low birth weight infants.

Very low birth weight (VLBW) infants must achieve several maturational milestones to be discharged home from the NICU. Describe the timing of maturational milestones in VLBW infants and the impact of clinical variables and milestone achievement on postmenstrual age (PMA) at discharge. For VLBW infants without severe lung disease discharged home from a level IV NICU, we assessed PMA at the achievement of thermoregulation, cardiorespiratory stability, feeding, and discharge. In 400 infants (median GA 28.4 weeks), lower birth weight, white race, and having multiple comorbidities of prematurity predicted later discharge PMA. The most common milestone sequence was CPAP discontinuation, caffeine discontinuation, thermoregulation, apnea resolution, and full oral feeds. PMA at apnea resolution and full oral feeds correlated highly with discharge PMA. In a single-center VLBW cohort, comorbidities of prematurity impacted the timing of NICU discharge through delay in oral feeding and cardiorespiratory stability.

Caffeine-Induced Effects on Human Skeletal Muscle Contraction Time and Maximal Displacement Measured by Tensiomyography.

Studies on muscle activation time in sport after caffeine supplementation confirmed the effectiveness of caffeine. The novel approach was to determine whether a dose of 9 mg/kg/ body mass (b.m.) of caffeine affects the changes of contraction time and the displacement of electrically stimulated muscle (gastrocnemius medialis) in professional athletes who regularly consume products rich in caffeine and do not comply with the caffeine discontinuation period requirements. The study included 40 professional male handball players (age = 23.13 ± 3.51, b.m. = 93.51 ± 15.70 kg, height 191 ± 7.72, BMI = 25.89 ± 3.10). The analysis showed that in the experimental group the values of examined parameters were significantly reduced (p ≤ 0.001) (contraction time: before = 20.60 ± 2.58 ms/ after = 18.43 ± 3.05 ms; maximal displacement: before = 2.32 ± 0.80 mm/after = 1.69 ± 0.51 mm). No significant changes were found in the placebo group. The main achievement of this research was to demonstrate that caffeine at a dose of 9 mg/kg in professional athletes who regularly consume products rich in caffeine has a direct positive effect on the mechanical activity of skeletal muscle stimulated by an electric pulse.

Stopping caffeine in premature neonates: how long does it take for the level of caffeine to fall below the therapeutic range?

Background Caffeine is routinely used in preterm infants for apnea of prematurity. Preterm infants are usually monitored for 5 days after discontinuation of caffeine to assess for possible recurrence of apnea. Our objective was to determine if the serum concentration of caffeine decreases to a subtherapeutic level 5 days after its discontinuation. Methods This is a retrospective analysis of caffeine levels after the drug was discontinued in preterm neonates (birth weight ≤1500 g) born between January 2010 and June 2017. The primary outcome was the proportion of infants with therapeutic levels of caffeine 5 days after the drug was stopped. Results Caffeine levels were measured in 353 samples from 280 infants (birth weight 1246 ± 390 g and gestational age 29.2 ± 2.4 weeks) after discontinuation of the drug. Five and more days after discontinuation of caffeine, 29.3% (82/280) of the infants had caffeine levels ≥5 mg/L. Approximately 41% (75/181) of the caffeine levels measured between 5 and 7 days and 18% (17/95) between 8 and 10 days were ≥5 mg/L. A caffeine dose of >5 mg/kg/day when discontinued was associated with the caffeine level of ≥5 mg/L (OR 2.3, 95% CI 1.28–4.13, p = .005). Conclusions Preterm infants treated with caffeine frequently had therapeutic levels of caffeine 5–10 days after discontinuation of the drug. The infants receiving higher doses were more likely to have a therapeutic level of caffeine 5 days after stopping the medication. Preterm infants should be monitored for recurrence of apnea for more than 5 days after stopping caffeine or levels should be monitored prior to discharge.

Sex-based differences in apnoea of prematurity: A retrospective cohort study.

What is the central question of the study? Is there a sex-based difference in the incidence of apnoea of prematurity and the success or failure of caffeine therapy in preterm infants? What is the main finding and its importance? Our data show that females received fewer days of caffeine treatment than males. This was most noticeable in infants born between 260/7 and 276/7 weeks of gestational age. These results highlight the importance of considering sex in clinical and basic research investigating the pathophysiology of apnoea of prematurity. This retrospective cohort study assessed whether sex influences the occurrence of apnoea of prematurity (AOP) in preterm infants. The analysis included a cohort of 24,387 preterm infants born between the gestational ages (GA) of 240/7 and 336/7 weeks that were admitted to tertiary neonatal care units participating in the Canadian Neonatal Network from January 2011 to December 2015. Of those, 13,983 (57%) were diagnosed with AOP. More females were diagnosed with AOP than males, but the difference in the male/female ratio was marginal (P=0.058). The majority (89%) of infants diagnosed with AOP received caffeine (89% of males; 89% of females). By using the discontinuation of caffeine therapy as a proxy for the resolution of significant AOP, data analysis showed that females born before 336/7 weeks of GA stopped caffeine treatment earlier than males whether the caffeine was discontinued before 34 or 37 weeks of GA. Consequently, females had fewer days of caffeine therapy than males, especially infants born between 260/7 and 276/7 weeks (P<0.004), 280/7 and 296/7 weeks (P<0.03), and 320/7 and 336/7 weeks of GA (P<0.04). Similar trends were observed when the corrected GA at discontinuation of caffeine was used. Given that AOP is indicative of an immature respiratory system, our data suggest that the maturation of the respiratory system might occur more rapidly in females than males. We conclude that sex needs to be considered in future studies on AOP.

Stopping caffeine in premature neonates: How long does it take for level of caffeine to fall below the therapeutic range?

Background: Caffeine is routinely used in preterm infants for apnea of prematurity. The use of caffeine in preterm infants also improves respiratory and neurodevelopmental outcomes. In the past, the standard dosage of caffeine was 5mg/kg/day. More recently, a higher dose of caffeine is used in preterm infants as it has a wide therapeutic window. Because of the long half-life of caffeine, preterm infants are usually monitored for 5 days after discontinuation of caffeine to assess for possible recurrence of apnea. However, with the use of a higher …

Impact of Caffeine Boluses and Caffeine Discontinuation on Apnea and Hypoxemia in Preterm Infants.

Background: Apnea of prematurity often occurs during and following caffeine therapy. We hypothesized that number of apnea events would be impacted by adjustments in caffeine therapy. Materials and Methods: An automated algorithm was used in all infants ≤32 weeks gestation admitted to a level IV Neonatal Intensive Care Unit from 2009 to 2014 to analyze chest impedance, electrocardiogram, and oxygen saturation data around the time of serum caffeine levels, caffeine boluses while on maintenance therapy, and caffeine discontinuation. Episodes of central apnea/bradycardia/desaturation (ABDs), and percent time with SpO2 <88% and <75% were measured. Results: ABDs were analyzed in 302 preterm infants (mean gestational age 27.6 weeks) around the time of 485 serum caffeine levels, 90 caffeine boluses, and 273 episodes of caffeine discontinuation. Higher serum caffeine levels were not associated with fewer ABDs or higher heart rate. For caffeine boluses given due to clinically recognized spells, hypoxemia and algorithm-detected ABDs decreased day 1-2 after the bolus compared to the day before and day of the bolus (mean 4.4 events/day after vs. 6.6 before, p = 0.004). After caffeine discontinuation, there was no change in hypoxemia and a small increase in ABDs (2 events/day 3-5 days after discontinuation vs. 1 event/day before and >5 days after, p < 0.01). This increase in ABDs occurred irrespective of gestational age, respiratory support, or postmenstrual age at the time caffeine was stopped. Conclusions: In this retrospective analysis, caffeine boluses and caffeine discontinuation were associated with a small change in the number of ABD events in preterm infants.

Caffeine discontinuation improves acute migraine treatment: a prospective clinic-based study.

BackgroundCaffeine has both excitatory and vasoconstrictive effects on central nervous system. Caffeine use might be associated with development and chronification of migraine. We aimed to evaluate the effect of caffeine cessation on the acute treatment of migraine.MethodsWe prospectively recruited migraine patients who consumed caffeine drinks daily and instructed them to discontinue their caffeine intake. Triptans were prescribed for acute treatment. Patients were followed up after at least two weeks after screening and evaluated the efficacy of acute treatment with the migraine assessment of current therapy (Migraine-ACT) questionnaire. Excellent efficacy was defined as Migraine-ACT score of 4. Chronic migraine, body mass index, allodynia, depression, anxiety, antiemetic use, and use of prophylactic medication were included in the multivariate analysis if the univariate p < 0.2.FindingsAmong 108 patients included, 36 completely discontinued their caffeine intake (abstinence group). The efficacy of acute treatment was assessed at median 34.5 days (interquartile range, 28–89) after the screening. Twenty-six patients (72.2 %) in the abstinence group and 29 (40.3 %) in the non-abstinence group reported an excellent efficacy (p = 0.002). The abstinence group also showed a trend toward greater reduction of headache impact test-6 (HIT-6) scores (p = 0.085). Caffeine abstinence was independently associated with an excellent efficacy of acute treatment (multivariate odds ratio, 3.2; 95 % confidence interval, 1.2–8.4; p = 0.018) after controlling for covariates.ConclusionsCaffeine abstinence is associated with better efficacy of acute migraine treatment. Our uncontrolled study results encourage a further confirmatory study on this issue.

Clinical associations with immature breathing in preterm infants: part 2—periodic breathing

BackgroundPeriodic breathing (PB) is a normal immature breathing pattern in neonates that, if extreme, may be associated with pathologic conditions.MethodsWe used our automated PB detection system to analyze all bedside monitor chest impedance data on all infants <35 weeks’ gestation in the University of Virginia Neonatal Intensive Care Unit from 2009-2014 (n=1211). Percent time spent in PB was calculated hourly (>50 infant-years’ data). Extreme PB was identified as a 12h period with PB >6 standard deviations above the mean for gestational age (GA) and post-menstrual age (PMA) and >10% time in PB.ResultsPB increased with GA, with the highest amount in infants 30-33 weeks’ GA at about 2 weeks’ chronologic age. Extreme PB was identified in 76 infants and in 45% was temporally associated with clinical events including infection or necrotizing enterocolitis (NEC), immunizations, or caffeine discontinuation. In 8/28 cases of septicemia and 10/21 cases of NEC there was a >2-fold increase in %PB over baseline in the day prior to diagnosis.ConclusionInfants <35 weeks GA spend, on average, <6% of the time in PB. An acute increase in PB may reflect illness or physiological stressors or may occur without any apparent clinical event.

Apnea of prematurity and caffeine pharmacokinetics: potential impact on hospital discharge.

To determine the half-life of serum caffeine concentrations and its relation to apnea of prematurity (AOP) after caffeine is discontinued in preparation for hospital discharge. Prospective cohort study involving preterm infants with gestational ages ⩽33 weeks at birth. After caffeine was discontinued, serum caffeine concentrations and electronic detection of pathologic apnea, defined a priori, were obtained at 24 and 168 h, respectively. Caffeine levels decreased from 13.3±3.8 to 4.3±2 mg l(-1) (n=50, mean±s.d.) at 24 and 168 h, respectively (P<0.01). The mean caffeine half-life was 87±25 h at 35±1 weeks postmenstrual age. Seven days after discontinuation of caffeine, 64% of the infants had pathologic apnea. Hospital discharge planning for preterm infants with a history of AOP should be carefully considered after discontinuing caffeine. This study showed that caffeine may not reach subtherapeutic levels until around 11-12 days.

Caffeine induces alveolar apoptosis in the hyperoxia-exposed developing mouse lung

BackgroundCaffeine is a nonspecific adenosine receptor antagonist used in premature neonates to treat apnea of prematurity. While its use may reduce the incidence of bronchopulmonary dysplasia (BPD), the precise mechanisms remain unknown. Evidence of increased adenosine levels are noted in chronic lung diseases including tracheal aspirates of infants with BPD. Utilizing a well characterized newborn mouse model of alveolar hypoplasia, we hypothesized that hyperoxia-induced alveolar inflammation and hypoplasia is associated with alterations in the adenosine signaling pathway.MethodsNewborn murine pups were exposed to a 14-day period of hyperoxia and daily caffeine administration followed by a 14-day recovery period in room air. Lungs were collected at both time points for bronchoalveolar fluid (BAL) analysis as well as histopathology and mRNA and protein expression.ResultsCaffeine treatment increased inflammation and worsened alveolar hypoplasia in hyperoxia exposed newborn mice. These changes were associated with decreased alveolar type II cell numbers, increased cell apoptosis, and decreased expression of A2A receptors. Following discontinuation of caffeine and hyperoxia, lung histology returned to baseline levels comparable to hyperoxia exposure alone.ConclusionResults of this study suggest a potentially adverse role of caffeine on alveolar development in a murine model of hyperoxia-induced alveolar hypoplasia.

Chronic caffeine consumption prevents cognitive decline from young to middle age in rats, and is associated with increased length, branching, and spine density of basal dendrites in CA1 hippocampal neurons

Chronic caffeine consumption has been inversely associated with the risk of developing dementia and Alzheimer's disease. Here we assessed whether chronic caffeine treatment prevents the behavioral and cognitive decline that male Wistar rats experience from young (≈3 months) to middle age (≈10 months). When animals were young they were evaluated at weekly intervals in three tests: motor activity habituation in the open field (30-min sessions at the same time on consecutive days), continuous spontaneous alternation in the Y-maze (8 min), and elevated plus-maze (5 min). Afterward, rats from the same litter were randomly assigned either to a caffeine-treated group (n=13) or a control group (n=11), which received only tap water. Caffeine treatment (5 mg/kg/day) began when animals were ≈4 months old, and lasted for 6 months. Behavioral tests were repeated from day 14 to day 28 after caffeine withdrawal, a time period that is far in excess for the full excretion of a caffeine dose in this species. Thirty days after caffeine discontinuation brains were processed for Golgi-Cox staining. Compared with controls, we found that middle-aged rats that had chronically consumed low doses of caffeine (1) maintained their locomotor habituation during the second consecutive day exposure to the open field (an index of non-associative learning), (2) maintained their exploratory drive to complete the conventional minimum of nine arm visits required to calculate the alternation performance in the Y-maze in a greater proportion, (3) maintained their alternation percentage above chance level (an index of working memory), and (4) did not increase the anxiety indexes assessed by measuring the time spent in the open arms of the elevated plus maze. In addition, morphometric analysis of hippocampal neurons revealed that dendritic branching (90–140 μm from the soma), length of 4th and 5th order branches, total dendritic length, and spine density in distal dendritic branches were greater in the basal but not the apical dendrites of CA1 pyramidal neurons from rats chronically treated with caffeine, in comparison with their age- and littermate-matched controls. Altogether, the present findings strengthen the epidemiological observations suggesting that prolonged caffeine intake prevents the cognitive decline associated with aging, and open the possibility that this process could be mediated by promoting the growth of dendrites and spines in neurons of the adult mammalian brain.

Long-lasting resistance to haloperidol-induced catalepsy in male rats chronically treated with caffeine

Chronic caffeine consumption has been inversely associated with the risk of developing Parkinson's disease. Here we assessed whether chronic caffeine treatment increases the resistance of male Wistar rats to haloperidol (1 mg/kg, s.c.)-induced catalepsy, measured in the bar test at 15 min intervals during 3 h. Caffeine (5 mg/kg/day) was delivered for 6 months via drinking water. Control rats received only tap water. Treatments began when animals were 3–4 months old. In order to unveil long-lasting catalepsy refractoriness not attributable to the presence of caffeine in the brains of rats, they were evaluated from day 18 to day 27 after caffeine withdrawal, a time that is far in excess for the full excretion of a caffeine dose in this species. The average cataleptic immobility measured in caffeine-treated rats ( n = 23) was 1148 ± 140 s, a value 34 ± 8% lower than that recorded in control animals ( n = 20), whose mean immobility was 1736 ± 137 s ( P = 0.0026, t-test). The percentage of catalepsy reduction measured in caffeine-treated rats evaluated on days 18–20 after caffeine discontinuation (−32 ± 13%, n = 12, P < 0.05) was comparable to the catalepsy decrease recorded in those animals tested on days 21–27 (−36 ± 10%, n = 11, P < 0.02), a finding compatible with the notion that the effect was indeed mediated by enduring changes of brain functioning and not by the physical presence of caffeine or its metabolites. Caffeine-treated rats also had higher catalepsy latency scores compared with control rats ( P < 0.01, U-test). The present findings show that chronic consumption of caffeine produces perdurable resistance to catalepsy induced by dopamine receptor blockade, possibly through enhancement of dopamine transmission, giving further support to the epidemiological results indicating that prolonged caffeine consumption affords neuroprotection against Parkinson's disease.

Caffeine: Sleep and daytime sleepiness

Caffeine is one of the most widely consumed psychoactive substances and it has profound effects on sleep and wake function. Laboratory studies have documented its sleep-disruptive effects. It clearly enhances alertness and performance in studies with explicit sleep deprivation, restriction, or circadian sleep schedule reversals. But, under conditions of habitual sleep the evidence indicates that caffeine, rather then enhancing performance, is merely restoring performance degraded by sleepiness. The sleepiness and degraded function may be due to basal sleep insufficiency, circadian sleep schedule reversals, rebound sleepiness, and/or a withdrawal syndrome after the acute, over-night, caffeine discontinuation typical of most studies. Studies have shown that caffeine dependence develops at relatively low daily doses and after short periods of regular daily use. Large sample and population-based studies indicate that regular daily dietary caffeine intake is associated with disturbed sleep and associated daytime sleepiness. Further, children and adolescents, while reporting lower daily, weight-corrected caffeine intake, similarly experience sleep disturbance and daytime sleepiness associated with their caffeine use. The risks to sleep and alertness of regular caffeine use are greatly underestimated by both the general population and physicians.

Human brain metabolic response to caffeine and the effects of tolerance.

Since there is limited information concerning caffeine's metabolic effects on the human brain, the authors applied a rapid proton echo-planar spectroscopic imaging technique to dynamically measure regional brain metabolic responses to caffeine ingestion. They specifically measured changes in brain lactate due to the combined effects of caffeine's stimulation of glycolysis and reduction of cerebral blood flow. Nine heavy caffeine users and nine caffeine-intolerant individuals, who had previously discontinued or substantially curtailed use of caffeinated products because of associated anxiety and discomforting physiological arousal, were studied at baseline and then during 1 hour following ingestion of caffeine citrate (10 mg/kg). To assess state-trait contributions and the effects of caffeine tolerance, five of the caffeine users were restudied after a 1- to 2-month caffeine holiday. The caffeine-intolerant individuals, but not the regular caffeine users, experienced substantial psychological and physiological distress in response to caffeine ingestion. Significant increases in global and regionally specific brain lactate were observed only among the caffeine-intolerant subjects. Reexposure of the regular caffeine users to caffeine after a caffeine holiday resulted in little or no adverse clinical reaction but significant rises in brain lactate which were of a magnitude similar to that observed for the caffeine-intolerant group. These results provide direct evidence for the loss of caffeine tolerance in the human brain subsequent to caffeine discontinuation and suggest mechanisms for the phenomenon of caffeine intolerance other than its metabolic effects on elevating brain lactate.

Caffeine Withdrawal in Normal School-Age Children

Caffeine is widely consumed by children around the world. The purpose of this study was to determine whether children manifest withdrawal effects after cessation of caffeine intake. Thirty normal children completed the single-blind, within-subjects, repeated-measures study with weekly sessions. Subjects were tested four times: (1) baseline (on regular caffeine diet); (2) on caffeine (approximately 120 to 145 mg/day); (3) during withdrawal (24 hours after discontinuation of caffeine taken for 13 consecutive days); and (4) at return to baseline. Subjects were evaluated with self-report measures of symptoms and objective measures of attention, motor performance, processing speed, and memory. During caffeine withdrawal, there was a significant deterioration on response time of a visual continuous performance test of attention. This finding is consistent with caffeine withdrawal. The deterioration in response time appeared to persist for 1 week. Twenty-four hours after children discontinued caffeine, there was a decrease in performance on reaction time of a task requiring sustained attention. Further work is indicated to determine whether children manifest caffeine withdrawal effects after cessation of caffeine intake.

Impact of Critical Pathway Implementation on NICU Length of Stay † 1033

Critical pathways (CP) are multidisciplinary care guidelines developed to improve efficiency of care. Their effectiveness in an NICU setting is not well documented. Aim: To examine whether implementation of CP's decreased length of stay, reflected by postconceptional age (PCA) at time of discharge home, for preterm infants. Methods: CP's using PCA dependent care guidelines focusing on the growing preterm neonate were developed and implemented in March, 1997, in our referral perinatal unit. CP's were initiated for infants admitted to the NICU once they were stable and had been transferred to the step-down nursery. Data were collected for infants transferred at ≤ 35 weeks PCA and subsequently discharged home. Two cohorts were compared: Aug - Nov 1996 (pre CP, n=48) and July - Nov 1997 (post CP, n=50). Results: Factors associated with length of stay were similar in the 2 groups. Although post-CP infants had been cared for using CP's for 32±17(sd) days, their PCA at discharge was significantly greater and introduction of nipple feeds and discontinuation of caffeine and cardiorespiratory monitoring did not occur earlier. Identical results were obtained for the subgroup ≤ 30 weeks gestation. Cost data did not show significant reduction in average cost / case for a post-CP cohort. Conclusion: Implementation of CP's did not appear to promote earlier discharge nor improve efficiency of care. This emphasizes the importance of evaluating innovations in care. Table

Anticonvulsant Activity of Phenobarbital and Valproate Against Maximal Electroshock in Mice During Chronic Treatment with Caffeine and Caffeine Discontinuation

We evaluated the protective activity (expressed as ED50 values in mg/kg of phenobarbital (PB, 120 min before testing) and valproate (30 min) alone or combined with caffeine in male mice with seizures induced by maximal electroshock (MES). Both antiepileptic drugs (AEDs) were administered by intraperitoneal (i.p.) injection in a single dose to mice receiving intraperitoneal caffeine either in a single dose 30 min before the test or as pretreatment every 12 h for 3 and 14 days. In addition, we determined the ED50 values of the AEDs 24 and 72 h after 14-day treatment with caffeine. Finally, we studied the influence of a challenge dose of caffeine, injected in mice 24 and 72 h after 14 days of treatment with caffeine, on the protective activity of PB or VPA. Caffeine in a single dose of 23.1 mg/kg reduced the anticonvulsant effect of PB. Its protective activity was further impaired after 3 and 14 days of caffeine treatment. The ED50 for VPA was significantly increased both by the single dose of caffeine and by chronic treatment. The anticonvulsant activity of PB and VPA measured 24 and 72 h after 14-day treatment with caffeine did not differ from control values, but a challenge dose of caffeine injected 24 or 72 h after daily injections for 14 days resulted in a significant reduction in the protective activity of both AEDs. Measurement of the total plasma levels of caffeine, VPA, and PB did not suggest pharmacokinetic interactions as an explanation for our results. Our results indicate that chronic caffeine exposure may progressively reduce the antiepileptic potency of VPA and PB.