Use of the liver tissue oxygenation index as a noninvasive parameter of intestinal ischemia in rabbits.

OBJECTIVE: The tissue oxygenation index (TOI), measured by spatially resolved spectroscopy (SRS), reflects the ratio between oxygenated and deoxygenated tissue hemoglobin. We investigated whether liver TOI is a noninvasive parameter for early detection of intestinal ischemia. METHODS: In seven adult New Zealand rabbits the superior mesenteric artery (SMA) and vein were exposed by laparotomy. The SRS probe was attached at the skin above the liver to calculate the TOI. The bowel (SbO(2)) and peripheral (SpO(2)) oxygen saturation were continuously measured. The SMA was occluded, creating small bowel ischemia for 90 minutes. Then reperfusion was started for 1 hour. The median TOI and interquartile range (IQR) of the TOI were calculated. A paired Wilcoxon test was used to evaluate changes in the liver TOI and SpO(2) during ischemia and reperfusion. RESULTS: The median TOI was 54.3% (IQR 8) at the start of ischemia, 54.9% (IQR 9) after 30 minutes, 51% (IQR 11) after 60 minutes, and 50.3% (IQR 10) after 90 minutes. The median TOI values were 46.3% (IQR 5) after 30 minutes of reperfusion and 41.2% (IQR 5) after 60 minutes. The decrease in TOI became significant (p < 0.05) after 90 minutes of ischemia. The SpO(2) was stable during the experiment. DISCUSSION: A significant decrease in liver TOI was seen after 90 minutes of occlusion of the SMA and is likely to be the consequence of bowel ischemia. The further decrease after reperfusion might reflect reperfusion injury. Liver TOI may be a new tool for noninvasive early detection of intestinal ischemia and reperfusion. Further study is needed to confirm these findings.

Cardiorespiratory events recorded on home monitors: the effect of prematurity on later serious events.

OBJECTIVE: To describe severe alarms on home-documented monitoring in infants born prematurely. METHODS: In infants born at a post-menstrual age (PMA) less than 35 weeks, a polysomnography was performed before discharge. A heart rate less than 50 beats per minute (bpm) for more than 3 seconds or an apnea lasting for more than 15 seconds with a heart rate less than 60 bpm were defined as abnormal. These babies were given cardiorespiratory home monitoring with memory. Serious alarms on the home monitor were defined as heart rate less than 50 bpm for more than 3 seconds. RESULTS: Of 1058 infants, 96 infants needed cardiorespiratory home monitoring. Sixty-one infants showed alarms at home. The mean post-conceptional age (PCA) when alarms stopped was 46 weeks. Seventeen patients had serious alarms above the PCA of 50 weeks. There was a significant negative correlation (r = -0.46 and p = 0.0002 by Spearman's rank correlation) between the PMA at birth and the PCA at which the last alarm was noted CONCLUSION: Prematurely born infants with an abnormal polysomnography at discharge are at high risk for developing acute events at home. A younger PMA at birth correlates with a higher risk of alarms at a later PCA.

Maturational changes in the in vivo activity of CYP3A4 in the first months of life.

OBJECTIVE: To document maturational changes of the in vivo activity of CYP3A4 in the first months of life. METHODS: The contribution of tramadol (M), O-demethyl tramadol (M1, CYP2D6-mediated) and N-demethyl tramadol (M2, CYP3A4-mediated) to the overall elimination of tramadol and the log M/M2 was assessed in 24-hour urine collections during continuous intravenous tramadol administration. Correlations with perinatal characteristics (postnatal age (PNA) and postmenstrual age (PMA)) were studied. RESULTS: Of the total amount of tramadol administered in a 24-hour interval to 25 neonates and young infants (PMA 25 - 53 weeks), 34.5% (SD 6.1) were retrieved in the urine as parent compound or metabolite in a 24-hour interval. This retrieved material consisted primarily of tramadol 79% (SD 18), M1 10% (SD 17) and M2 3% (SD 3.4). The contribution of M (r2 = -0.53), M1 (r2 = 0.46) and M2 (r2 = 0.16) to overall M elimination correlated with increasing PMA. The mean log M/M2 was 1.44 (SD 0.46) and there was an inverse correlation between the log M/M2 ratio and PMA (r2 = -0.43, 95% CI for r = -0.84 to -0.34, p = 0.0006) and PNA (r2 = -0.25, 95% CI for r = -0.78 to -0.16, p = 0.008). The maturational half-life of the log M/M2 ratio was 16 - 20 weeks. In a multiple regression model, PMA was the only significant variable accounting for the interindividual variability in log M/M2. CONCLUSIONS: PMA was found to be the most important maturational change determing the in vivo activity of CYP3A4. The activity of CYP3A4 is relatively delayed in the first months of life compared to the developmental changes in CYP2D6 activity described earlier, however, the overall weak correlations reflect that PMA explains only in part the interindividual variability observed.

Cryotherapy versus laser photocoagulation for threshold retinopathy of prematurity: impact on early postoperative clinical recovery.

In a retrospective study in preterms treated with either cryotherapy (n= 16, 2000-2001) or laser photocoagulation (n= 19, 2002-2005) for threshold retinopathy, a significant decrease in duration of postoperative ventilation, in postoperative administration of analgesics and in time until regain of full enteral feeding was documented in infants who received laser photocoagulation. We therefore conclude that - compared to cryotherapy - laser treatment for threshold retinopathy is associated with a faster clinical postoperative recovery.

O-demethylation of tramadol in the first months of life.

OBJECTIVE: Assess in vivo O-demethylation activity in the first months of life. METHODS: Time-concentration profiles of tramadol (M) and O-demethyl tramadol (M1) in plasma and urine were simultaneously collected in the first 24 h of continuous intravenous tramadol administration in neonates and young infants. M and M1 were determined by high performance liquid chromatography. Correlations between perinatal characteristics [postnatal age (PNA), postmenstrual age (PMA)] and the contribution of metabolites (M, M1) to overall tramadol elimination and to the plasma and urine log M/M1 were calculated. RESULTS: Plasma samples were available in 20/29 and complete 24-h urine collections were available in 25/29 neonates (25-53 weeks PMA). Mean plasma log M/M1 value (>4 h, n=86) was 0.8 (SD 0.4). A significant correlation between plasma log M/M1 and PMA (r=-0.73, P<0.0001) and PNA (r=-0.58, P<0.005) was observed. In a multiple regression model, only PMA remained an independent variable. Mean urine log M/M1 was 0.94 (SD 0.7). Significant correlations of the urine log M/M1 ratio with PMA (r=-0.73, P<0.0001) and PNA (r=-0.56, P=0.0035) were observed. In a multiple regression model with the urine log M/M1 ratio as dependent variable, only PMA remained an independent variable. The maturational half-life of the log M/M1 ratio in early neonatal life in the age range evaluated is about 12-16 weeks without plateau. CONCLUSIONS: O-demethylation activity was already observed in early neonatal life. A significant correlation with PMA was documented, but PMA can only partially explain the observed variability in O-demethylation activity. Polymorphism therefore likely already contributes to the interindividual variability observed in neonates.

Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity.

BACKGROUND: Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and CYP2D6 activity in young infants are not available. METHODS: A population pharmacokinetic analysis of tramadol and M1 time-concentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 time-concentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity. RESULTS: Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h(-1) [70 kg](-1)) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric '1/4 power' models). The central volume of distribution decreased from 25 weeks PCA (256 litre [70 kg](-1)) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance. CONCLUSIONS: Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 microg litre(-1) is achieved after a bolus of tramadol hydrochloride 1 mg kg(-1) and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg(-1) h(-1) at 25 weeks PCA, 0.14 mg kg(-1) h(-1) at 30 weeks PCA, 0.17 mg kg(-1) h(-1) at 35 weeks PCA, 0.18 mg kg(-1) h(-1) at 40 weeks, 0.19 mg kg(-1) h(-1) at 50 weeks PCA to 1 yr, 0.18 mg kg(-1) h(-1) at 3 yr and 0.12 mg kg(-1) h(-1) in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established.

Tramadol concentrations in blood and in cerebrospinal fluid in a neonate.

Based on blood and cerebrospinal fluid samples collected in a full-term neonate, the penetration of tramadol in the central nervous system is described. Following intravenous administration of tramadol, a lag time of about 4 h was observed until full blood-brain equilibration was achieved. This pharmacokinetic observation is in line with a recent pharmacodynamic evaluation of the central opioid effects of tramadol in adults.

Clinical pharmacology of non opioid analgesics in neonates.

An integrated approach of neonatal analgesia starts with the systematic evaluation of pain and should be followed by effective interventions, mainly based on the appropriate (i.e. safe and effective) administration of analgesics. In contrast to the more potent opioids, data on the pharmacokinetics and -dynamics of non-opioid analgesics in this specific population are still rare or even lacking. We therefore evaluated various aspects of developmental pharmacology of non-opioid analgesics (paracetamol, ibuprofen, acetylsalicyl acid) in neonates. We first performed a single dose propacetamol study in preterm and term neonates. Based on these preliminary findings, a repeated dose administration scheme was developed and tested and maturational aspects from preterm till teenage were documented. Although non-selective COX-inhibitors might be effective in the treatment of postoperative or inflammatory pain syndromes in neonates, potential efficacy should be balanced against the drugs' safety profile. Neonatal renal clearance strongly depends on glomerular filtration rate (GFR) and GFR itself strongly depends on the vaso-dilatative of prostaglandins on the afferent arterioli. We therefore evaluated the impact of the administration of ibuprofen or acetylsalicylic acid on renal clearance in preterm infants and hereby used amikacin clearance as a surrogate marker. We hereby documented the negative effect of ibuprofen on glomerular filtration rate in preterm infants up to 34 weeks and we were able to show that ibuprofen and acetylsalicylic acid had an equal impact on the glomerular filtration rate.

Ibuprofen and cerebral oxygenation and circulation.

The effect of prophylactic administration of ibuprofen on the cerebral circulation in preterm babies was measured with near infrared spectroscopy. No significant difference in the change in cerebral blood volume, change in cerebral blood flow, or tissue oxygenation index was found between administration of ibuprofen or placebo.

Continuous measurement of cerebral blood volume and oxygenation during rewarming of neonates.

AIM: To investigate the effect of rewarming in preterm infants presenting with hypothermia at admission. METHODS: The tissue oxygenation index (TOI), changes in cerebral blood volume (DeltaCBV) and changes in intravascular oxygenation (DeltaHbD) were measured in eight preterm infants, presenting with a temperature less than 35 degrees C at admission. RESULTS: A significant increase in HbD and TOI was seen in four patients (group A), while a significant increase in CBV and a decrease in HbD was seen in four other patients (group B). Retrospective analysis showed that group A had important signs of peripartal asphyxia. CONCLUSION: While infants with peripartal asphyxia showed an important increase in oxygenation during rewarming, no significant changes were seen in the non-asphyxiated infants.

Effects of co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin in preterm infants during the first days of life.

The aim of this study was to assess the effects of intravenous co-administration of ibuprofen-lysine on the pharmacokinetics of amikacin during the first days of life in preterm infants. The pharmacokinetics of amikacin were retrospectively calculated in a cohort of 73 neonates (gestational age <31 weeks) who received either ibuprofen-lysine or placebo following inclusion in the multicentre ibuprofen prophylaxis study. Assuming a one-compartment model with instantaneous input and first-order output, there was no significant difference in the median distribution volume (0.63 vs. 0.59 liters/kg), but the median serum half-life (16.4 vs. 12.4 h) of amikacin was significantly longer (p <0.02), and the clearance (0.36 vs. 0.6 ml/kg/min; p <0.005) of amikacin was significantly lower in infants who received ibuprofen-lysine. We conclude that the time interval between consecutive amikacin administrations should be prolonged, if ibuprofen-lysine is co-administered.

Video reveals self-stimulation in infancy.

UNLABELLED: The medical literature on early childhood masturbation is sparse. Only 12 patients who presented with infantile self-stimulation under the age of 1 y are described. During the last 2 y, five girls under 1 y of age presented at our department with self-stimulating behaviour. The diagnosis of this behaviour was difficult, but could be made by watching a video of the attacks. Infantile self-stimulation is often misdiagnosed and unnecessary investigations and useless treatments are often prescribed. Video recording can be of great help to put forward the correct diagnosis. Masturbation is not so uncommon and treatment consists mostly in reassuring the parents. It can, however, be associated with behavioural problems. Few data are available on the clinical outcome of childhood masturbation, but most children seem to develop normally. CONCLUSION: Infantile self-stimulation should always be considered in the differential diagnosis of "strange episodes or attacks".

Characteristics of respiratory syncytial virus-related apnoea in three infants.

UNLABELLED: Apnoea is a common sign in respiratory syncytial virus (RSV) infections in young infants and can be the first presentation of an acquired RSV infection. We describe polysomnographic recordings of three infants revealing prolonged RSV-related apnoea before RSV infection was diagnosed. The apnoeas were of central origin. The caregivers had not noted any apparent life-threatening events (ALTE) prior to the polysomnography. Cardiorespiratory monitoring after the acute infection did not reveal any further apnoeas. CONCLUSION: Central, prolonged apnoea can be the first sign of an acquired RSV infection in young infants in the absence of other respiratory symptoms and without any previous observation of apnoea by the caregivers.

Continuous infusion of medications in very low birth weight infants.

OBJECTIVE: To develop a safe and accurate method for the administration in the neonatal intensive care unit of several potent medications as a continuous infusion without overloading the infant, especially the very low birth weight (VLBW) infant by diluents. METHOD: The method designed is based on a weight-adapted solution limiting the diluent administration and allowing for a versatile modulation of dose administration. As this method was initially designed for VLBW infants, the point of departure of this method is a standard maximal fluid load of 0.3 ml/h for each medication, delivered in a low compliant circuit with a high-precision syringe driver. Solutions are made for 24 h, which is a compromise between drug stability and repeated pressure drops in the circuit when changing the syringe and administration set. To translate a prescription into a solution a conversion factor is calculated. In addition to the calculation principle, this conversion factor is given for a number of commonly used drugs in neonatal care. CONCLUSIONS: In our experience, the method described adds to the safety and accuracy of continuous drug administration in neonatal care.

The use of methohexital during chest tube removal in neonates.

BACKGROUND: The aim of the study was the evaluation of the effect of methohexital during chest tube removal (CTR) in neonates. METHODS: Evaluation was based on the degree of sedation (grades 1-4) and relaxation (grades 1-4) and trends in vital signs heart rate, mean arterial blood pressure (MAP), oxygen saturation at time points (-10, -5, -3, -1, 0, 1, 3, 5, and 10 min) before and after administration of methohexital. A multidimensional pain scale [Leuven Neonatal Pain Scale (LNPS)] was used to evaluate pain expression. Effective sedation and relaxation (grade >2) would enable the physician to perform CTR without difficulties. Paired Wilcoxon was used to compare vital signs and pain expression before and after the procedure. RESULTS: Twenty-two procedures in 22 infants were recorded. Eleven infants were ventilated and 21 infants were having intravenous analgesics during CTR. Birth weight was 2645 g (range 1235-4500 g). Postnatal age was 6 days (range 1-80 days). Methohexital had no effect on ventilatory weaning, MAP or oxygen saturation. Heart rate increased from 144 (49) to 162 (43) (P = 0.012) b.min(-1). Sedation and relaxation were effective (>grade 2) and lasted for <5 min. No major side effects were documented. Adequate analgesia by LNPS was more difficult to evaluate as clinical pain evaluation was not feasible during full muscular relaxation. CONCLUSIONS: Administration of methohexital for CTR resulted in adequate sedation and relaxation without major side effects in neonates. This approach should be compared with other strategies.

Pharmacokinetics of single dose intravenous propacetamol in neonates: effect of gestational age.

AIM: To investigate the pharmacokinetics and pharmacodynamics of single dose propacetamol in preterm and term infants on the first day of life. METHODS: Neonates were stratified by gestational age. Preterm (< 37 weeks) and term (37-41 weeks) infants received a single dose of propacetamol in the first 24 hours of life when they had minor, painful procedures or as additional treatment in infants receiving opioids. Blood samples were taken from an arterial line, and pain was evaluated by a multidimensional pain scale. Results were reported as mean (SD). Student's t and Wilcoxon tests were used to compare the groups. RESULTS: Thirty neonates were included, 10 of which were term infants. Serum half life was 277 (143) minutes in the preterm infants and 172 (59) minutes in the term infants (p < 0.05). Clearance was 0.116 (0.08) litre/kg/h in the preterm infants and 0.170 (0.06) litre/kg/h in the term infants (p < 0.05). Gestational age correlated with serum half life (r = -0.46). No effect of sex or administration of prenatal steroids was found on the pharmacokinetics of paracetamol. In neonates who only received propacetamol (n = 15), the level of analgesia seemed to be associated with the therapeutic (> 5 mg/l) level. CONCLUSIONS: A correlation was found between gestational age and the serum half life of propacetamol. The maturational trend of clearance and half life in preterm and term neonates is in line with data on the pharmacokinetics of propacetamol beyond the newborn period.