Maturation of Paracetamol Elimination Routes in Preterm Neonates Born Below 32 Weeks of Gestation.

PURPOSE: Despite being off-label, intravenous paracetamol (PCM) is increasingly used to control mild-to-moderate pain in preterm neonates. Here we aim to quantify the maturation of paracetamol elimination pathways in preterm neonates born below 32 weeks of gestation. METHODS: Datasets after single dose (rich data) or multiple doses (sparse data) of intravenous PCM dose (median (range)) 9 (3-25) mg/kg were pooled, containing 534 plasma and 44 urine samples of PCM and metabolites (PCM-glucuronide, PCM-sulfate, PCM-cysteine, and PCM-mercapturate) from 143 preterm neonates (gestational age 27.7 (24.0-31.9) weeks, birthweight 985 (462-1,925) g, postnatal age (PNA) 5 (0-30) days, current weight 1,012 (462-1,959) g. Population pharmacokinetic analysis was performed using NONMEM® 7.4. RESULTS: For a typical preterm neonate (birthweight 985 g; PNA 5 days), PCM clearance was 0.137 L/h, with glucuronidation, sulfation, oxidation and unchanged renal clearance accounting for 5.3%, 73.7%, 16.3% and 4.6%, respectively. Maturational changes in total PCM clearance and its elimination pathways were best described by birthweight and PNA. Between 500-1,500 g birthweight, total PCM clearance increases by 169%, with glucuronidation, sulfation and oxidation clearance increasing by 347%, 164% and 164%. From 1-30 days PNA for 985 g birthweight neonate, total PCM clearance increases by 167%, with clearance via glucuronidation and oxidation increasing by 551%, and sulfation by 69%. CONCLUSION: Birthweight and PNA are the most important predictors for maturational changes in paracetamol clearance and its glucuronidation, sulfation and oxidation. As a result, dosing based on bodyweight alone will not lead to consistent paracetamol concentrations among preterm neonates.

Limited effects of intravenous paracetamol on patent ductus arteriosus in very low birth weight infants with contraindications for ibuprofen or after ibuprofen failure.

UNLABELLED: Finding the optimal pharmacological treatment of a patent ductus arteriosus (PDA) in preterm neonates remains challenging. There is a growing interest in paracetamol as a new drug for PDA closure. In this prospective observational cohort study, we evaluated the effectiveness of intravenous paracetamol in closing a PDA in very low birth weight infants with a hemodynamically significant PDA who either did not respond to ibuprofen or had a contraindication for ibuprofen. They received high-dose paracetamol therapy (15 mg/kg/6 h intravenous) for 3-7 days. Cardiac ultrasounds were performed before and 3 and 7 days after treatment. Thirty-three patients were included with a median gestational age of 25(1/7) weeks (IQR 1.66), a median birth weight of 750 g (IQR 327), and a median postnatal age of 14 days (IQR 12). Paracetamol was ineffective in 27/33 patients (82 %). Even more, after previous exposure to ibuprofen, this was even 100 %. CONCLUSION: In this study, paracetamol after ibuprofen treatment failure was not effective for PDA closure in VLBW infants. From the findings of this study, paracetamol treatment for PDA closure cannot be recommended for infants with a postnatal age >2 weeks. Earlier treatment with paracetamol for PDA might be more effective.

Randomized Controlled Trial Comparing Different Single Doses of Intravenous Paracetamol for Placement of Peripherally Inserted Central Catheters in Preterm Infants.

BACKGROUND: The availability of a safe and effective pharmacological therapy to reduce procedural pain in preterm infants is limited. The effective analgesic single dose of intravenous paracetamol in preterm infants is unknown. Comparative studies on efficacy of different paracetamol doses in preterm infants are lacking. OBJECTIVES: To determine the analgesic effects of different single intravenous paracetamol doses on pain from peripherally inserted central catheter (PICC) placement in preterm infants. METHODS: In a blinded randomized controlled trial, the analgesic effects of 10-, 15-, and 20-mg/kg single-dose intravenous paracetamol before PICC placement were compared in neonates with a gestational age <32 weeks. Secondly, a separate age-matched nonrandomized control group receiving oral sucrose was included. Pain was assessed with the Premature Infant Pain Profile (PIPP) and the COMFORTneo score. Peak plasma concentrations of paracetamol were determined. RESULTS: A total of 60 patients were included in the paracetamol dose groups (median gestational age = 27.8, IQR: 25.7-29.2 weeks). PIPP scores were comparable: median = 8 (IQR: 6-10.5), 7 (IQR: 6-9), and 8 (IQR: 6-10) for the 10-, 15-, and 20-mg/kg paracetamol groups, respectively (p = 0.94). COMFORTneo scores were not statistically different between the different paracetamol dose groups (p = 0.35). All randomized subjects, except for 3 who received 10 mg/kg of paracetamol, had peak paracetamol concentrations >9 mg/L. PIPP (p = 0.78) and COMFORTneo (p = 0.08) scores were also comparable between paracetamol- and sucrose-treated patients. CONCLUSIONS: We found no analgesic benefit from intravenous paracetamol studied in different single doses over sucrose for PICC placement in preterm infants. Paracetamol is not a suitable analgesic for this procedure in preterm infants.

Intravenous use of the calcium-channel blocker nicardipine as second-line treatment in severe, early-onset pre-eclamptic patients.

OBJECTIVE: To evaluate the efficacy of intravenous administration of nicardipine as a second-line temporizing treatment in severe, early-onset, pre-eclamptic patients. DESIGN: An open, prospective, evaluation study. SETTING: A high-care obstetric ward in a tertiary care centre. PATIENTS: Twenty-seven early-onset, pre-eclamptic patients with a median gestational age of 27 weeks 1 day (range, 21 weeks 2 days-32 weeks 4 days) with treatment failure on standard intravenous antihypertensive drugs (ketanserin, dihydralazin or labetalol). INTERVENTION: Nicardipine infusion was started for temporizing management of pre-eclampsia at a dosage of 3 mg/h and was subsequently titrated according to blood pressure. Nicardipine treatment was continued for as long as the maternal and foetal conditions allowed. MAIN OUTCOME MEASURES: The endpoints of the study were defined as the percentage of patients reaching the target diastolic intra-arterial blood pressure (< 100 mmHg or < 90 mmHg in Haemolysis, Elevated Liver Enzymes, Low Platelet Count syndrome patients) within 1 h after the start of treatment, and the number of days of prolongation of pregnancy under nicardipine treatment. Maternal and foetal side effects, foetal death and neonatal outcome were assessed. RESULTS: In all patients the target diastolic intra-arterial blood pressure was obtained within a median of 23 min (range, 5-60 min). Delivery was postponed for a median of 4.7 days (range, 1-26 days) using nicardipine treatment, in a maximum dosage ranging from 3 to 9 mg/h. Detailed haemodynamic parameters with corresponding nicardipine dosages were obtained in nine patients. In one-fifth of the patients, unwanted hypotensive periods were registered during treatment, manageable with dosage adaptation. Foetal well-being did not seem adversely affected. CONCLUSION: This evaluation shows that nicardipine is a potent antihypertensive drug and can be used for temporizing management in severe, early-onset pre-eclampsia when other antihypertensive drugs have failed.

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.

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 Children's 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.

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

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.

OBJECTIVES: Pain 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. METHODS: In 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. RESULTS: Interrater reliability was good: median linearly weighted Cohen kappa 0.79. Almost 3600 triple ratings were obtained for 286 neonates. Internal consistency was good (Cronbach alpha 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. DISCUSSION: The 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.