Morphine more fine? Its effects in critically ill newborns

The pharmacist Sertürner first isolated morphine from opium in 1803 and named it after Morpheus, the god of dreams in Greco-Roman mythology. Ever since, it has been one of the most frequently used drugs to relieve pain, for a variety of age groups. In our days, however, there is still debate whether morphine and analgesic therapy should serve as standard of care for hospitalized newborns. Until the last decade of the 20th century, premature neonates were generally believed to have little pain sensation and thus not in need of analgesic therapy. The studies of Anand et al., which showed decreased morbidity and mortality in neonatal patients receiving adequate analgesic therapy after surgery, were instrumental in altering this notion. At present it is widely recognized that even the most premature neonates can feel pain. While neonatal pain experiences have been suggested to bring about short and long-term negative consequences, analgesic therapy in the vulnerable newborns can also carry risks, such as increased incidence of seizures. This leaves us with the question whether the benefits of treatment will outweigh the side effects and potential hazards of analgesic treatment. Or, in other words, is morphine more fine? The studies described in this thesis generally aim to improve neonatal pain treatment, by investigating the beneficial and adverse effects of neonatal morphine use. They also aim at improving our knowledge of how newborns respond to pain and how to measure pain objectively: pain assessment

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

Evaluation of an Intubation Readiness Score to Assess Neonatal Sedation before Intubation

Background: Premedication for neonatal intubation facilitates the procedure and reduces stress and physiological disturbances. However, no validated scoring system to assess the effect of premedication prior to intubation is available. Objective: To evaluate the usefulness of an Intubation Readiness Score (IRS) to assess the effect of premedication prior to intubation in newborn infants. Methods: Two-center prospective study in neonates who needed endotracheal intubation. Intubation was performed using a standardized procedure with propofol 1-2 mg/kg as premedication. The level of sedation was assessed with the IRS by evaluating the motor response to a firm stimulus (1 = spontaneous movement; 2 = movement on slight touch; 3 = movement on firm stimulus; 4 = no movement). Intubation was proceeded if an adequate effect, defined as an IRS of 3 or 4, was reached. IRS was compared to the quality of intubation measured with the Viby-Mogensen intubation score. Results: A total of 115 patients, with a median gestational age of 27.7 weeks (interquartile range 5.3) and a median birth weight of 1,005 g (interquartile range 940), were included. An adequate IRS was achieved in 105 patients, 89 (85%) of whom also had a good Viby-Mogensen intubation score and 16 (15%) had an inadequate Viby-Mogensen intubation score. The positive predictive value of the IRS was 85%. Conclusions: Preintubation sedation assessment using the IRS can adequately predict optimal conditions during intubation in the majority of neonates. We suggest using the IRS in routine clinical care. Further research combining the IRS with other parameters could further improve the predictability of adequate sedation during intubation

Sedation of newborn infants for the INSURE procedure, are we sure?

Background. Neonatal intubation is a stressful procedure that requires premedication to improve intubation conditions and reduce stress and adverse physiological responses. Premedication used during the INSURE (INtubation, SURfactant therapy, Extubation) procedure should have a very short duration of action with restoration of spontaneous breathing within a few minutes. Aims. To determine the best sedative for intubation during the INSURE procedure by systematic review of the literature. Methods. We reviewed all relevant studies reporting on premedication, distress, and time to restoration of spontaneous breathing during the INSURE procedure. Results. This review included 12 studies: two relatively small studies explicitly evaluated the effect of premedication (propofol and remifentanil) during the INSURE procedure, both showing good intubation conditions and an average extubation time of about 20 minutes. Ten studies reporting on fentanyl or morphine provided insufficient information about these items. Conclusions. Too little is known in the literature to draw a solid conclusion on which premedication could be best used during the INSURE procedure. Both remifentanil and propofol are suitable candidates but dose-finding studies to detect effective nontoxic doses in newborns with different gestational ages are necessary

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

Acute Pain Assessment in Prematurely Born Infants Below 29 Weeks A Long Way to Go

Objectives: Neonates born extremely prematurely are at high risk of acute and prolonged pain. Effective treatment requires reliable pain assessment, which is currently missing. Our study explored whether existing pain assessment tools and physiological indicators measure pain and comfort accurately in this population. Materials and Methods: We prospectively collected data in 16 neonates born at less than 29 weeks’ gestational age during 3 conditions: skin-to-skin care, rest, and heelstick procedure for capillary blood sampling in the incubator. The neonates were video recorded in these situations, and recordings were coded using 5 observational pain assessment tools and numeric rating scales for pain and distress. We simultaneously collected heart rate, respiratory rate, arterial oxygen saturation, regional cerebral oxygenation, and the number of skin conductance peaks. All measures across the 3 conditions were compared using general linear modeling. Results: The median gestational age was 27.1 weeks (range: 24.1 to 28.7). Forty measurement periods across the 3 conditions were analyzed. Heart rate was significantly higher during heelstick procedures compared with during rest, with a mean difference of 10.7 beats/min (95% confidence interval [CI]: 2.7-18.6). Oxygen saturation was significantly higher during skin-to-skin care compared with during heelstick procedures with a mean difference of 5.5% (95% CI: 0.2-10.8). The Premature Infant Pain Profile-revised (PIPP-R) score was significantly higher during heelstick procedures compared with skin-to-skin care with a mean difference of 3.2 points (95% CI: 1.6-5.0). Discussion: Pain measurement in clinical practice in prematurely born infants below 29 weeks remains challenging. The included behavioral and physiological indicators did not adequately distinguish between a painful situation, rest, and skin-to-skin care in premature neonates

Morphine Pharmacodynamics in Mechanically Ventilated Preterm Neonates Undergoing Endotracheal Suctioning

Pharmacolog

Waiting 2 minutes after sucrose administration-unnecessary?

Background Worldwide, oral sucrose is standard of care in many neonatal intensive care units to relieve procedural pain in neonates. This study aims to determine if time interval between sucrose administration and heelstick correlates with pain scores. Methods Neonates were prospectively studied with variable time intervals and assessed with the Premature Infant Pain Profile-Revised (PIPP-R). Results 150 neonates were included with a median gestational age of 30+6 (IQR 27+6-33+2) weeks and a median time interval of 72 (IQR 39-115) seconds between sucrose administration and heelstick. In multiple regression analysis, this time interval was not significantly related to the PIPP-R (B=0.004, 95% CI -0.005 to 0.013, p=0.37). Providing non-nutritive sucking combined with sucrose was significantly related to lower PIPP-R scores (B=-3.50, 95% CI -4.7 to -2.3, p<0.001). Conclusions Our study suggests that there is no need to wait 2 min after sucrose administration before a painful procedure. Sucrose-induced non-nutritive sucking shows a fast pain-relieving effect in neonates

Ibuprofen treatment after the first days of life in preterm neonates with patent ductus arteriosus

Aim: Patent ductus arteriosus (PDA) is treated with ibuprofen and it is known that the clearance of ibuprofen increases with postnatal age. We aimed to study whether postnatal age-adjusted ibuprofen dosages improve the effectiveness of treatment compared to standard ibuprofen dosages after the first days of life. Methods: A historical cohort of 207 preterm neonates treated with standard ibuprofen dosages (Group A; 2011–2015) was compared to a prospective cohort of 66 preterm neonates treated with postnatal age-adjusted ibuprofen dosages (Group B; 2015–2016). Results: Both groups had comparable background characteristics. Treatment was started after median 6 (25–75th percentile: 4–11) and 5 (25–75th percentile: 4–11) days and effectiveness was 33.2 and 44.7% (p =.17) in groups A and B, respectively. No hemodynamically significant PDA was found in 23/49 (46.9%) of the patients born before 28 weeks after adjusted ibuprofen dosages compared to 48/162 (29.6%) after standard ibuprofen dosages (p =.04). There were significantly more reversible side effects with the postnatal age-adjusted ibuprofen dosages (p =.04). Conclusions: There seems to be a trend to higher effectiveness with the adjusted ibuprofen dosages in preterm neonates before 28 weeks, but it is associated with more reversible side effects