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Pain and Sedation Management of the Mechanically Ventilated Infant

Julie Williams, MS CRNP NNP-BC

Mechanical ventilation and the need for pain or sedation management are everyday components in the care of the sick neonate in the neonatal intensive care unit (NICU). Information obtained from studies of the adult population suggests that an endotracheal tube is uncomfortable and that the routine use of analgesia, sedation, or both is common (Coleman, Solarin, & Smith, 2002). Routine administration of sedatives or pain medication in the mechanically ventilated preterm infant is not recommended, though it is common in some practices. Even when the practice is common, however, a great variability from one practitioner to another can be seen.

Neonatal pain and discomfort are real phenomena. During the mid to late portion of the second trimester, nociceptive (pain) pathways become anatomically mature. A disruption in the development of this pathway (as may occur in premature birth) can cause neurological remodeling with repeated noxious stimuli (Taddio, Shah, Atenafu, & Katz, 2009). If pain is encountered late in gestation, later pain responses are enhanced; meanwhile, pain encountered early in gestation can dampen the pain response (Menon & McIntosh, 2008). Despite the long-term consequences associated with neonatal pain and discomfort, no consensus exists on a safe and effective approach to controlling pain in neonates.

The physiological signs of pain—which include elevation of heart rate, respiratory rate, and blood pressure; crying; and hyperkinesis—can be very dangerous for the extremely preterm infant. These physiological responses can affect oxygenation and metabolic demands and contribute to brain hemorrhages. Short-term consequences of pain include restlessness and changes in feeding and interaction patterns; long-term outcomes include altered responses to pain (Coleman et al., 2002).

Opioid and sedative use has been known to increase physiologic stability, improve ventilator synchrony, and decrease biochemical markers for pain and distress (Coleman et al., 2002). However, they are also known to cause respiratory depression, hypotension, and bradycardia (Coleman et al., 2002). Two opioids commonly used for analgesia and even sedation in the neonate are morphine and fentanyl.

Morphine is used more commonly than other pain medications (Anand, 2019). In addition to its analgesic effects, it can be used for its sedative property. It can be administered as a continuous drip or intermittently. According to the Thomson Reuters Clinical Editorial Staff (2011), adverse effects of morphine include respiratory distress, hypotension, bradycardia, transient hypertonia, ileus and delayed gastric emptying, urine retention, drug tolerance, and even seizures.

The Neonatal Outcome and Prolonged Analgesia in Neonates (NOPAIN) trial evaluated the effect of morphine on acute brain injury in the mechanically ventilated preterm infant. The study noted a decrease in the incidence of severe intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), and death compared to the group receiving midazolam and placebo (Anand et al., 1999).

The follow-up full-scale multicenter randomized double-blind placebo-controlled study titled “The Neurological Outcomes and Pre-emptive Analgesia in Neonates (NEOPAIN) Multicenter Trial” explored the question of whether the beneficial effects of routine morphine infusions in the ventilated preterm outweighed the associated risks. Eight hundred ninety-eight ventilated preterm neonates between 23 and 32 weeks gestation were enrolled. The enrolled neonates were randomized and received either morphine or placebo from a short period after birth and throughout the period of mechanical ventilation. The neonates received a loading dose of 100 mcg/kg of morphine, followed by an infusion of 10, 20, or 30 mcg/kg/hr for infants at 23–26, 27–29, and 30–32 weeks gestation, respectively, or placebo. Both groups were also allowed to receive open-labeled morphine if the infant was perceived to be in pain. Although the NEOPAIN trial showed no benefit in neurological outcome or mortality with the routine use of morphine in ventilated preterm infants, it did note an association between routine use of morphine and a higher incidence of hypotension and other adverse effects, demonstrating that risk is associated with morphine administration (Boyle, Freer, Wong, McIntosh, & Anand, 2006).

Another randomized controlled trial performed by Simons and colleagues (2003) evaluated the effects of continuous intravenous morphine on pain response, the incidence of IVH, and poor neurological outcomes, including severe IVH, PVL, and death. One hundred fifty neonates were randomized, and a loading dose of morphine 100 mcg/kg was given, followed by an infusion of 10 mcg/kg/hr. The study found that the continuous infusion of morphine in preterm newborns receiving mechanical ventilation did not lessen pain or protect against negative neurological outcomes. However, the author did note that preemptive administration of morphine did decrease the incidence of IVH but required further long-term follow-up for neurobehavioral outcomes.

Fentanyl is another opioid that can be used for analgesic and sedative purposes in the neonate. This synthetic opioid is 50–100 times more potent than morphine (Thomson Reuters Clinical Editorial Staff, 2011). It offers rapid onset of pain relief and promotes hemodynamic stability (Anand, 2019). Fentanyl relaxes the pulmonary vessels and can be used in neonates with persistent pulmonary hypertension. The downside to fentanyl is the tendency of patients to develop a tolerance to the medication very quickly (in contrast to morphine) and also the development of chest wall rigidity when it is administered too quickly (Lexicomp, 2019).

One double-blind placebo-controlled randomized trial evaluated the effects of a continuous infusion of fentanyl versus placebo in preterm ventilated infants less than 32 weeks gestation on neuroprotection over the first 72 hours of the ventilation (Qui et al., 2018). The premature infant pain profile (PIPP), cerebral blood flow velocity, neuron-specific enolase (NSE) concentrations in plasma samples, and recordings of the cerebral function monitoring (CFM) were evaluated. The fentanyl group had lower NSE levels, lower PIPP scores, and higher total CFM scores compared to the control group. The study concluded that a continuous fentanyl infusion had a possible protective effect on preterm infants.

Another double-blind randomized control study explored the use of a continuous infusion of fentanyl plus open-label administration of fentanyl boluses versus placebo plus open-label administration of fentanyl boluses in the ventilated preterm infant at ≤ 32.6 weeks gestation (Ancora et al., 2013). The study evaluated analgesic efficacy using the Echelle Douleur Inconfort Nouveau-Ne (EDIN) and the PIPP scale. The study concluded that a continuous fentanyl infusion plus open-label boluses of fentanyl did not reduce prolonged pain but did decrease acute pain and increase side effects compared to open-label boluses of fentanyl alone.

Even though research has demonstrated that opioids like morphine and fentanyl decrease physiologic instability in neonates, the evidence does not show a neurological benefit or lower mortality when the baby is routinely administered opioids for analgesia or sedation (Anand et al., 1999; Boyle et al., 2006). Given the demonstrated side effects of these pharmacologic agents, providers are concerned about administering them. Reinforcing this concern, a Cochrane review has concluded that there is insufficient evidence to recommend the routine use of opioids in the mechanically ventilated neonate (Bellu, de Waal, & Zanini, 2005)

The smallest and the most medically fragile infants generally undergo the greatest number of noxious stimuli throughout their care. Although the long-term effects of repeated painful stimuli are still being investigated, it can be surmised that there is a potential for negative end results, including altered pain sensitivity and neuroanatomic and behavioral abnormalities (American Academy of Pediatrics Committee on Fetus and Newborn et al., 2006). The prevention of pain, whether it is acute or chronic, should be the goal of all healthcare practitioners and the expectation of all parents.

Mechanical ventilation can be painful, and prolonged pain and stress can be harmful. The assessment of this prolonged pain and ways to adequately manage it can present a problem. The NEOPAIN trial echoed the common view that the assessment of pain and distress in the ventilated preterm patient presents specific challenges. The inability of the infant to self-report, the limited knowledge about the assessment of ongoing pain and distress in the neonate, and the difficulty in assessing persistent pain create an arena for subjective and variable pain assessments. This situation creates the possibility of inconsistent pain management.

Although the routine use of an opioid analgesic in the ventilated neonate cannot be recommended on the basis of the existing research, the research findings do not discount the notion that neonates do experience pain. They also do not discount the notion that some ventilated babies may require analgesic administration because of their individual ailments.

Perhaps nonpharmacological measures, including decreasing environmental stimuli and modifying ventilator setting, are ways to decrease pain and distress in the ventilated infant. Measures like containment, decreasing noxious noise and light, and grouping procedures and care to allow for longer periods of undisturbed time may also be ways to successfully soothe the infant.

Pain management in the ventilated neonate is a complicated subject because multiple factors influence the decision to treat. Similarly, multiple factors can influence the decision not to treat. More research must be done before the routine administration of an opiate or sedative can be recommended. At this time the decision will have to be based on the practitioner’s best judgment.


American Academy of Pediatrics Committee on Fetus and Newborn, American Academy of Pediatrics Section on Surgery, Canadian Paediatric Society Fetus and Newborn Committee, Batton, D. G., Barrington, K. J., & Wallman, C. (2006). Prevention and management of pain in the neonate: An update. Pediatrics, 118(5), 2231–2241. doi:10.1542/peds.2006-2277

Anand, K. (2019). Prevention and Treatment of Neonatal Pain. In R. Martin & M. Kim (Eds.), Uptodate. Retrieved April 23, 2019, from

Anand, K., Barton, B., McIntosh, N., Lagercrantz, H., Pelausa, E., & Young, T. (1999). Analgesia and sedation in preterm neonates who require ventilatory support: Results from the NOPAIN trial. Neonatal Outcome and Prolonged Analgesia in Neonates. Archives of Pediatrics and Adolescent Medicine, 153(4), 331-338.

Ancora, G., Lago, P., Garetti, E., Pirelli, A., Merazzi, D., Mastrocola, M., . . . Faldella, G. (2013). Efficacy and safety of continuous infusion of fentanyl for pain control in preterm newborns on mechanical ventilation. The Journal of Pediatrics, 163(3), 645–651.

Bellu, R., de Waal, K. A., & Zanini, R. (2005). Opioids for neonates receiving mechanical ventilation. Cochrane Database of Systematic Reviews (Online), (1)(1), CD004212. doi:10.1002/14651858.CD004212.pub2

Boyle, E. M., Freer, Y., Wong, C. M., McIntosh, N., & Anand, K. J. (2006). Assessment of persistent pain or distress and adequacy of analgesia in preterm ventilated infants. Pain, 124(1–2), 87–91. doi:10.1016/j.pain.2006.03.019

Coleman, M. M., Solarin, K., & Smith, C. (2002). Assessment and management of pain and distress in the neonate. Advances in Neonatal Care: Official Journal of the National Association of Neonatal Nurses, 2(3), 123–136; quiz 137–139.

Lexicomp. (2019). Fentanyl: Pediatric drug informationUpToDate. In UpToDate. Lexicomp Inc.

Menon, G., & McIntosh, N. (2008). How should we manage pain in ventilated neonates? Neonatology, 93(4), 316–323. doi:10.1159/000121458; 10.1159/000121458

Simons, S. H., van Dijk, M., van Lingen, R. A., Roofthooft, D., Duivenvoorden, H. J., Jongeneel, N., . . . Tibboel, D. (2003). Routine morphine infusion in preterm newborns who received ventilatory support: A randomized controlled trial. JAMA: The Journal of the American Medical Association, 290(18), 2419–2427. doi:10.1001/jama.290.18.2419

Taddio, A, Shah, V, Atenafu, E, & Katz, J. (2009). Influence of repeated painful procedures and sucrose analgesia on the development of hyperalgesia in newborn infants. Pain,144(1–2),43–48. doi: 10.1016/j.pain.2009.02.012

Thomson Reuters Clinical Editorial Staff. (2011). Neofax 24th Edition. Thomson Reuter.

Qui, J., Zhao, L., Yang, Y., Zhang, J., Feng, Y., & Cheng, R. (2018). Effects of fentanyl for pain control and neuroprotection in very preterm newborns on mechanical ventilation. The Journal of Maternal-Fetal & Neonatal Medicine. Retrieved from