Sedation, Analgesia, and Paralysis during Mechanical Ventilation of Premature Infants

Abstract

Objective To characterize administration of sedatives, analgesics, and paralytics in a large cohort of mechanically ventilated, premature infants. Study design Retrospective cohort study including all infants <1500 g birth weight and <32 weeks gestational age mechanically ventilated at 348 Pediatrix Medical Group neonatal intensive care units (NICU) from 1997–2012. The primary outcome is the proportion of mechanically ventilated days in which infants were administered drugs of interest. Multivariable logistic regression was used to evaluate the predictors of administration of drugs of interest. Results We identified 85,911 mechanically ventilated infants. Infants received a drug of interest (opioids, benzodiazepines, other sedatives, and paralytics) on 433,587/1,305,413 (33%) of mechanically ventilated infant-days. The administration of opioids increased during the study period from 5% of infant-days in 1997 to 32% in 2012. The administration of benzodiazepines increased during the study period from 5% of infant-days in 1997 to 24% in 2012. Use of paralytics and other drugs remained ≤1% throughout the study period. Predictors of drug administration included younger gestational age, small for gestational age status, male sex, major congenital anomaly, older postnatal age at intubation, exposure to high frequency ventilation, exposure to inotropes, more recent year of discharge, and NICU site. Conclusion Administration of opioids and benzodiazepines in mechanically ventilated premature infants increased over time. Because infant characteristics were unchanged, site-specific differences in practice likely explain our observations. Increased administration over time is concerning given limited evidence of benefit and potential for harm.

A Critical Review on the Relevance of Paracetamol for Procedural Pain Management in Neonates

“…In contrast, Simons et al (morphine maintenance infusion, 10 µg/kg/h) did not observe lower blood pressure in morphine-exposed preterm neonates nor in inotropic prescription practices, irrespective of the post-menstrual age, within their randomized, placebocontrolled study (12). Finally, morphine delayed the attainment of full enteral nutrition (secondary analysis) by 3 days [17 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) in the placebo arm compared to 20 (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) days in the morphine arm] in the NEOPAIN trial (13).…”

“…The reported short-term side effects associated to opioid exposure in preterm neonates include hypoventilation and apnea, low blood pressure, intestinal hypoperistalsis, and bladder dysfunction. Hypoventilation and apnea resulted in prolonged duration [7 (4-20) days in morphine-exposed group compared to 6 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) days in the placebo group, + 1 day of ventilation] (9). Along the same line, Hartley et al recently reported that morphine (single oral, 100 µg/kg dose) in non-ventilated preterm infants, used to facilitate the screening for retinopathy of prematurity (ROP) in the Procedural Pain in Premature Infants (POPPI study) and to blunt the pain response, resulted in a high incidence (8/15 vs. 3/15, relative risk 2.7, number needed to harm = 3) of either newly occurring apneic events or an increase in the number of such events in the morphine-exposed group (10).…”

“…Consequently, a balanced approach, considering both wanted and unwanted effects, is appropriate, and data on drug utilization of analgesics hereby provide us some insights in the epidemiology and trends of drug prescription practices, and this also includes paracetamol (14)(15)(16)(17).…”

Evidence‐based clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation

“…Prolonged pain has been shown to influence neonatal morbidity and have long-term adverse effects (8). However, there is still no consensus on the safety and efficacy of the drugs, especially opioids, used during neonatal mechanical ventilation (9). That is why our group decided to review the available evidence in the literature.…”

Morphine exposure in preterm infants correlates with impaired cerebellar growth and poorer neurodevelopmental outcome

“…However, guidelines caution against the routine use of opioids in common situations such as mechanical ventilation, given the potential for respiratory adverse effects 1. Despite this caution, opioid exposure for this indication remains common 2. Conflicting data exist regarding the impact of this exposure on the developing brain 3.…”