Daniella Roofthooft

Long-term effects of routine morphine infusion in mechanically ventilated neonates on children’s functioning: Five-year follow-up of a randomized controlled trial

&NA; Newborns on ventilatory support often receive morphine to induce analgesia. Animal experiments suggest that this may impair subsequent cognitive and behavioral development. There are sparse human data on long‐term effects of neonatal morphine. We aimed to investigate the effects of continuous morphine administered in the neonatal period on the child’s functioning. We conducted a follow‐up study among 5‐year‐olds who, as mechanically ventilated neonates, had participated in a placebo‐controlled trial on effects of morphine administration on pain and neurologic outcome. They were now tested on intelligence, visual motor integration, behavior, chronic pain, and health‐related quality of life. Univariate analyses showed significantly lower overall intelligence quotient (IQ) scores for children who earlier had received morphine, that is, mean 94 (SD 14.5) versus 100 (SD 12.9) for those who received placebo (P = 0.049). Other between‐group differences in outcomes were not found. The statistical difference disappeared after correction for treatment condition, open‐label morphine consumption over the first 28 days, and a propensity score for clinically relevant co‐variables in multiple regression analyses. However, scores on one IQ subtest, “visual analysis,” were significantly negatively related to having received morphine and to open‐label morphine consumption the first 28 days. The finding of a significant effect of morphine on the “visual analysis” IQ subtest calls for follow‐up at a later age focusing on the higher‐order neurocognitive functions. Morphine received in the neonatal period has negative effects on the child’s cognitive functioning at the age of 5 years which warrants follow‐up at a later age.

Taking up the challenge of measuring prolonged pain in (premature) neonates the COMFORTneo scale seems promising

ObjectivesPain assessment is essential to tailor intensive care of neonates. The present focus is on acute procedural pain; assessment of pain of longer duration remains a challenge. We therefore tested a modified version of the COMFORT-behavior scale—named COMFORTneo—for its psychometric qualities in the Neonatal Intensive Care Unit setting. MethodsIn a clinical observational study, nurses assessed patients with COMFORTneo and Numeric Rating Scales (NRS) for pain and distress, respectively. Interrater reliability, concurrent validity, and sensitivity to change were calculated as well as sensitivity and specificity for different cut-off scores for subsets of patients. ResultsInterrater reliability was good: median linearly weighted Cohen κ 0.79. Almost 3600 triple ratings were obtained for 286 neonates. Internal consistency was good (Cronbach α 0.84 and 0.88). Concurrent validity was demonstrated by adequate and good correlations, respectively, with NRS-pain and NRS-distress: r=0.52 (95% confidence interval 0.44-0.59) and r=0.70 (95% confidence interval 0.64-0.75). COMFORTneo cut-off scores of 14 or higher (score range is 6 to 30) had good sensitivity and specificity (0.81 and 0.90, respectively) using NRS-pain or NRS-distress scores of 4 or higher as criterion. DiscussionThe COMFORTneo showed preliminary reliability. No major differences were found in cut-off values for low birth weight, small for gestational age, neurologic impairment risk levels, or sex. Multicenter studies should focus on establishing concurrent validity with other instruments in a patient group with a high probability of ongoing pain.

Eight Years Later, Are We Still Hurting Newborn Infants?

Objective: To study whether new pharmacological and nonpharmacological guidelines lowered numbers of painful procedures in neonates and changed the amount and frequency of analgesic therapy as compared to the results of our previous study in 2001. Design: A prospective observational study. Setting: Level III NICU of the Erasmus MC-Sophia Childrens Hospital, Rotterdam. Participants: Neonates admitted at postnatal ages less than 3 days with length of stay at least 72 h. Main Outcome Measures: Number of all potentially painful procedures and analgesic therapy recorded at the bedside during the first 14 days of NICU stay. Results: A total number of 21,076 procedures were performed in the 175 neonates studied during 1,730 patient-days (mean 12.2). The mean number of painful procedures per neonate per day was 11.4 (SD 5.7), significantly lower than the number of 14.3 (SD 4.0) in 2001 (p < 0.001). The use of analgesics was 36.6% compared to 60.3% in 2001. Sixty-three percent of all peripheral arterial line insertions failed versus 37.5% in 2001 and 9.1% venipunctures failed versus 21% in 2001. Conclusions: The mean number of painful procedures per NICU patient per day declined. Nonpharmacological pain- or stress-reducing strategies like NIDCAP and sucrose were fully embedded in our pain management. As further reduction of the number of painful procedures is unlikely, we should apply more nonpharmacological interventions and explore newer pharmacological agents.

Randomised controlled trial evaluating effects of morphine on plasma adrenaline/noradrenaline concentrations in newborns

Objectives: To determine the effects of continuous morphine infusion in ventilated newborns on plasma concentrations of adrenaline (epinephrine) and noradrenaline (norepinephrine) and their relation to clinical outcome. Design: Blinded, randomised, placebo controlled trial. Setting: Level III neonatal intensive care units in two centres. Patients: A total of 126 ventilated neonates (inclusion criteria: postnatal age <3 days, duration of ventilation <8 hours, indwelling arterial catheter for clinical purposes; exclusion criteria: severe asphyxia, severe intraventricular haemorrhage, major congenital anomalies, neuromuscular blockers). Interventions: Plasma adrenaline and noradrenaline concentrations were determined in patients during blinded morphine (n  =  60) and placebo (n  =  66) infusion (100 μg/kg plus 10 μg/kg/h). Results: Plasma concentrations at baseline (nmol/l with interquartile range in parentheses) were comparable in infants treated with morphine (adrenaline, 0.22 (0.31); noradrenaline, 2.52 (2.99)) or placebo (adrenaline, 0.29 (0.46); noradrenaline, 2.44 (3.14)). During infusion, median adrenaline concentrations were 0.12 (0.28) and 0.18 (0.35) and median noradrenaline concentrations were 2.8 (3.7) and 3.8 (4.0) for the morphine and placebo treated infants respectively. Multivariate analyses showed that noradrenaline (p  =  0.029), but not adrenaline (p  =  0.18), concentrations were significantly lower in the morphine group than the placebo group. Furthermore, noradrenaline concentrations were related to the length of stay in the neonatal intensive care unit. Conclusions: Continuous morphine infusion significantly decreased plasma noradrenaline concentrations in ventilated newborns compared with placebo treatment. The results of this study support the idea that routine morphine administration decreases stress responses in ventilated neonates.

Morphine in ventilated neonates: Its effects on arterial blood pressure

Objective: To study the effects of continuous morphine infusion on arterial blood pressure in ventilated neonates. Design: Blinded randomised placebo controlled trial. Setting: Level III neonatal intensive care unit in two centres. Patients: A total of 144 ventilated neonates. Inclusion criteria were postnatal age <3 days, ventilation <8 hours, and indwelling arterial line. Exclusion criteria were severe asphyxia, severe intraventricular haemorrhage, major congenital anomalies, neuromuscular blockers. Intervention: Arterial blood pressure was measured before the start and during the first 48 hours of masked infusion of drug (morphine/placebo; 100 μg/kg + 10 μg/kg/h). Outcome measures: Arterial blood pressure and blood pressure variability. Results: There were no significant differences in overall mean arterial blood pressure between the morphine group (median (interquartile range) 36 mm Hg (6) and the placebo group (38 mm Hg (6)) (p  =  0.11). Although significantly more morphine treated patients (70%) showed hypotension than the placebo group (47%) (p  =  0.004), the use of volume expanders and vasopressor drugs was not significantly different (morphine group, 44%; placebo group, 48%; p  =  0.87), indicating the limited clinical significance of this side effect. Blood pressure variability was not influenced by routine morphine analgesia (p  =  0.81) or additional morphine (p  =  0.80). Patients with and without intraventricular haemorrhage showed no differences in blood pressure (Mann-Whitney U test 1953; p  =  0.14) or incidence of hypotension (χ2 test 1.16; df 1; p  =  0.28). Conclusions: Overall arterial blood pressure, use of inotropes, and blood pressure variability were not influenced by morphine infusion. Therefore the clinical impact of hypotension as a side effect of low dose morphine treatment in neonates is negligible.

Paracetamol for Ductus Arteriosus Closure: Not Always a Success Story

median birth weight: 700 g (min. 365, max. 950)] all received 60 mg/kg/day paracetamol for 3–8 days (i.v.: n = 9; oral: n = 1). Eight patients received ibuprofen [6 days (n = 6), 4 days (n = 1), 3 days (n = 1)] prior to paracetamol, and 2 patients received no ibuprofen. Paracetamol was started after a median postnatal age of 22 days (IQR: 13; min. 13, max. 30). One patient (10%) died after 7 days of paracetamol because of preexisting gastrointestinal problems before the ductus was reevaluated. In 2 patients (20%), no additional ductus treatment was needed (ductus closed in 1 patient, small insignificant ductus in 1 patient). These were the 2 patients that did not receive ibuprofen prior to paracetamol. In 7 patients (70%), paracetamol treatment failed and they needed surgical ligation. No elevations in ASAT and ALAT were found in our patients. Although the high paracetamol doses in the small groups of VLBW infants seem safe from a short-term perspective, further exploration is necessary [5] . The efficacy of paracetamol for PDA closure in our patients was dramatically lower compared to previously reported studies. A relatively old postnatal age in most of our patients might be important in explaining these differences in results. The role of paracetamol in PDA treatment during the first postnatal days needs further evaluation. Until eviDear Sir, We would like to respond to the article of Oncel et al. [1] entitled ‘Intravenous paracetamol treatment in the management of patent ductus arteriosus in extremely low birth weight infants’. They showed that high doses of intravenous paracetamol are effective for ductus arteriosus closure in preterm infants. In 2011, Hammerman et al. [2] first suggested that oral paracetamol would be a drug with high potential for neonatal ductus closure. Currently, there are 4 observational studies [1–4] that have included oral or intravenous paracetamol for patent ductus arteriosus (PDA). A total number of 29 neonates [median gestational age: 28+4 weeks (interquartile range [IQR]: 3); median weight: 925 g (IQR: 493); median postnatal age: 7 days (IQR: 6; min. 2, max. 27)] were included in those reports and showed an overall closure rate of 93% (27/29 patients) [5] . Guided by these promising reports, we implemented the use of paracetamol for PDA in very low birth weight (VLBW) neonates if ibuprofen therapy was contraindicated or if ibuprofen therapy had failed. Since December 2012, we have included 10 VLBW neonates with a hemodynamically significant PDA who received paracetamol because of a contraindication for ibuprofen (n = 4) or after ibuprofen failure (n = 6). The included patients [median gestational age: 25+1 weeks (min. 23+6, max. 26+6); Received: May 30, 2013 Accepted: June 4, 2013 Published online: July 31, 2013

Congenital hypomyelinating neuropathy, a long term follow-up study in an affected family

Congenital hypomyelinating neuropathy is a rare condition characterized by prenatal, neonatal or early infantile onset of hypotonia, paresis and areflexia. Most of the few patients described in literature die within the first years of life. Histopathologically there are no or thin myelin sheaths. Mutations have been described in the following genes, MPZ, EGR2, PMP22, and MTMR2. Here we describe a family with a heterozygous mutation in MPZ, confirmed in two generations.

Insufficient Sedation and Severe Side Effects after Fast Administration of Remifentanil during INSURE in Preterm Newborns.

Background: Neonatal intubation is stressful and should be performed with premedication. In the case of an INSURE (intubation/surfactant/extubation) procedure a short duration of action of the premedication used is needed to facilitate fast extubation. Given its pharmacological profile, remifentanil seems a suitable candidate. Objectives: The aim here was to evaluate the effect and side effects of remifentanil as a premedication for preterm neonates undergoing INSURE. Methods: A prospective, single-center study in a level III neonatal intensive care unit was conducted. The quality of sedation was assessed in preterm infants receiving remifentanil prior to intubation for the INSURE procedure. Intravenous remifentanil was administered quickly and followed by a saline flush in approximately 30 s. The quality of sedation was defined by a combination of adequate sedation score, good intubation conditions and absence of side effects. Results: The study was terminated after the inclusion of 14 patients because of the high rate of side effects and the poor intubation conditions. Adequate sedation was achieved in only 2 patients (14%). Six patients (43%) needed additional propofol to obtain adequate sedation. Chest wall rigidity occurred in 6 patients (43%). Conclusions: The rapid administration of remifentanil provides insufficient sedation and is associated with a high risk of chest wall rigidity in preterm neonates.

Exposure to acetaminophen and all its metabolites upon 10, 15, and 20 mg/kg intravenous acetaminophen in very-preterm infants.

BackgroundExposure to acetaminophen and its metabolites in very-preterm infants is partly unknown. We investigated the exposure to acetaminophen and its metabolites upon 10, 15, or 20 mg/kg intravenous acetaminophen in preterm infants.MethodsIn a randomized trial, 59 preterm infants (24–32 weeks’ gestational age, postnatal age <1 week) received 10, 15, or 20 mg/kg acetaminophen intravenously. Plasma concentrations of acetaminophen and its metabolites (glucuronide, sulfate, cysteine, mercapturate, and glutathione) were determined in 293 blood samples. Area under the plasma concentration–time curves (AUC0–500 min) was related to dose and gestational age.ResultsBetween 10 and 20 mg/kg dose, median AUCs of acetaminophen, glucuronide, sulfate, and cysteine increased significantly resulting in unchanged ratios of AUC of metabolite to acetaminophen. The AUC ratio of glucuronide to acetaminophen increased with gestational age, that of sulfate decreased, and the ratio of cysteine and mercapturate remained unchanged.ConclusionWe found a gestational-age-dependent increase in glucuronidation but no evidence for saturation of a specific pathway as there was a proportional increase in exposure of acetaminophen and all metabolites. Compared with adults, very low exposure to glucuronide but higher exposure to sulfate, cysteine, and mercapturate metabolites was found, of which the relevance is not yet known.

Pain Management in Neonatal Intensive Care: Evaluation of the Compliance with Guidelines

Background:A pain management protocol was implemented in our neonatal intensive care unit in 2005, including individual pain assessments and pain treatment guidelines with a decision tree. Objectives:To prospectively evaluate the degree of compliance of medical and nursing staff with the pain protocol. Methods:Prospectively recorded pain scores (COMFORTneo score) and all prescribed analgesics and sedatives for the calendar year 2011 were retrieved. The primary outcome was the degree of compliance to the protocol with respect to pain assessments and treatment; the secondary outcome consisted of reasons for noncompliance. Results:Of the 732 included patients, 660 (90%) received fewer than the stipulated 3 assessments per day. Eighty-six per cent of all assessments yielded a score between 9 and 14, suggesting a comfortable patient. In cases of high pain scores (≥14), reassessment within 60 minutes took place in 31% of cases and in 40% treatment was started or adjusted. In cases of low pain scores (⩽8) during treatment, 13% of the 457 assessments were reassessed within 120 minutes and in 17% a dose reduction was performed. Conclusions:Although the majority of pain assessments suggested comfortable patients, there is room for improvement with respect to reassessments after adjustment of analgesic/sedative treatment. Some protocol violations such as oversedation in palliative patients are acceptable but should be well documented.