Description of the condition

Neonates, especially when preterm, are more sensitive to nociceptive stimuli than older children; this is because the functional ascending pain pathways capable of transmitting noxious impulses are present by 24 weeks' gestation, whilst the neurotransmitters that modulate the ascending impulse are absent until approximately 48 weeks' gestation (Anand 2000a; Hatfield 2014). Neuronal and synaptic organization may be permanently altered by repetitive painful experiences in preterm neonates. The cerebral cortex is affected by multiple mechanisms of neonatal pain and stress. Pain causes neuronal cells to die, and indirectly causes changes to the set‐point of stress‐sensitive endocrine systems. Pain, when treated inadequately, results in the immature pain system predisposing preterm infants to greater clinical and behavioral sequelae (Anand 2000a). Both in animal experiments and human studies, it has been shown that the immature nervous system is highly responsive to tactile and noxious stimuli. Neurophysiological recordings in newborn infants undergoing clinically required skin‐breaking procedures reveal strong spinal nociceptive reflex activity and distinct nociceptive cortical potentials in response to these procedures (Cornelissen 2013; Fabrizi 2011; Slater 2010). The younger the postnatal age of the infant, the more prolonged this noxious evoked activity is (Fitzgerald 1984; Hatfield 2014).

With advances in perinatal services and neonatal intensive care technology, the survival of extremely premature and compromised infants has increased substantially (Glass 2015). However, despite medical advances, a considerable number of these infants have long‐term sequelae, such as cerebral palsy, neurosensory impairments, learning disabilities and respiratory diseases (Glass 2015; Younge 2017). In neonatal intensive care units (NICUs), preterm infants are repeatedly and persistently exposed to noxious stimuli, which results in profound and long‐lasting changes in nociceptive neural pathways (Slater 2010). Preterm infants are exposed to these noxious stimuli during a critical window, towards the end of human gestation, where the relatively mature fetus undergoes an important period of brain development, peak rates of brain growth, exuberant synaptogenesis and the developmental regulation of specific receptor populations (Anand 2000b; Bhutta 2002; Brummelte 2012).

Nearly two‐thirds of infants born at less than 29 weeks' gestation require mechanical ventilation for some duration during the newborn period (Giaccone 2014). These neonates are endotracheally intubated and require repeated endotracheal suctioning (Cignacco 2009). Endotracheal suctioning is identified as one of the most frequent and most painful procedures in premature infants (Hadian 2013; Ward‐Larson 2004). It causes moderate to severe pain. Endotracheal suctioning still causes mild pain in premature neonates, despite improving nursing performance and performing a standard procedure based on neonatal need (Hadian 2013).

To assess pain in neonates validly and reliably, pain assessment is necessary. Many multidimensional pain assessment tools are available, yet pain remains insufficiently recognized and often under‐treated (Manworren 2016; Walker 2014). Not only is there a need to reduce acute behavioral responses to pain in neonates, but also to protect the developing nervous system from persistent sensitization of pain pathways and avoid potential damaging effects of altered neural activity on central nervous system development (Walker 2014).

Description of the intervention

The most obvious and effective strategy to reduce pain from repeated endotracheal suctioning is to reduce the frequency of suctioning. In addition, many different non‐pharmacological interventions aimed at reducing stress during painful procedures have been described and studied (Attarian 2014; Riddell 2015).

Although the neurodevelopmental outcomes of neonates may be affected by pain, concerns have also been raised about adverse short‐ and long‐term neurodevelopmental outcomes related to the use of pharmacological interventions, such as opioids, in preterm neonates (Anand 2004; Bellù 2008; Bellù 2010).

If minimizing frequent procedures and non‐pharmacological interventions are unsuccessful, analgesic medications could be administered. Management of neonatal pain often includes opioid therapy. Morphine and fentanyl are the most commonly used opioids in the NICU (Attarian 2014). Paracetamol is the most commonly prescribed analgesic for the treatment of acute pain in adults and children and is a widely accepted treatment for moderate pain in neonates (Meek 2012; Ohlsson 2016).

Included interventions

1. Non‐opioid analgesia: acetaminophen and nonsteroidal anti‐inflammatory drug agents. Because the mechanism of action includes inhibition of prostaglandin formation, these drugs have limited adverse effects in regards to respiratory depression. They are used as adjuncts to opioid analgesia for moderate to severe pain (Bhalla 2014).

   1. Paracetamol: paracetamol is defined by the National Library of Medicine as "a derivative of acetanilide with analgesic, antipyretic and weak anti‐inflammatory properties. It is a common analgesic in all age groups but may cause liver, blood cell and kidney damage" (National Library of Medicine 2013). A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain. The effect lasts for approximately four hours. It is associated with few, mainly mild, adverse events (Ohlsson 2016; Toms 2009). There is insufficient evidence to establish its role in reducing the effects of painful procedures in neonates (Ohlsson 2016; Walker 2014).

   2. Non‐steroidal anti‐inflammatory drugs (NSAIDs): these drugs have the ability to inhibit cyclooxygenase. There are limited studies investigating the analgesic effect of NSAIDs in neonates. Adverse effects, such as alterations in cerebral blood flow, intraventricular hemorrhage, platelet dysfunction and decreased Glomerular Filtration Rate (GFR) are described in this population (Bhalla 2014).

2. Opioid analgesia: morphine or fentanyl are the most commonly used opioids in the neonatal population (Bhalla 2014). There are still substantial gaps in the knowledge surrounding sedation (e.g. midazolam) and analgesia (e.g. opioids, nonsteroidal anti‐inflammatory drugs, acetaminophen) during mechanical ventilation in neonates; and concerns remain about their safety, efficacy and short‐ and long‐term outcomes in mechanically ventilated neonates (Aranda 2005).

   1. Morphine: alleviates prolonged pain, reduces behavioral and hormonal stress responses and improves ventilator synchrony and sedation. However, despite its routine use in the NICU, morphine given as a loading dose followed by continuous intravenous infusions does not provide adequate analgesia for the acute pain caused by invasive procedures among ventilated neonates (Carbajal 2005). There are also concerns about adverse short‐ and long‐term neurodevelopmental outcomes related to the use of morphine infusions in preterm neonates (AAP 2016). Some side effects have been reported, such as hypotension, constipation, urinary retention, respiratory depression, duration of mechanical ventilation and development of dependence and tolerance (Walker 2014).

   2. Diamorphine: works more quickly than morphine, reduces the amount of histamine released and therefore causes fewer hypotensive effects than morphine (Wood 1998). Diamorphine was found to be effective in reducing stress response (reduction of plasma cortisol and catecholamines) in ventilated newborn infants; adverse events described were reduction of blood pressure, and when diamorphine was dosed high, retention of carbon dioxide along with a decrease in actual partial oxygen pressure (Barker 1995).

   3. Fentanyl: this drug is considered as a selective m‐receptor agonist and is almost one hundred times more potent than morphine. It has a rapid, predictable onset of action with a short duration of action, mostly due to its high lipid solubility. Fentanyl gives greater hemodynamic stability. Although fentanyl may be associated with rapid development of tolerance and chest wall rigidity, it is the preferred analgesic agent for critically ill patients. Fentanyl has been shown to prevent neonates from surgical stress responses and to improve postoperative outcomes (Maitra 2014; Walker 2014).

   4. Remifentanil: a novel opioid. It was found to be at least as effective as morphine‐midazolam for endotracheal intubation (Avino 2014). It gives intense analgesia and anesthesia, with a rapid recovery in various clinical scenarios (Kamata 2016). It is not dependent on hepatic metabolism and is eliminated by non‐specific esterases. The duration of action is not affected by the duration of infusion. It makes rapid awakening possible. Reported adverse events include: chest wall rigidity and decreased thoracic compliance associated with hypoventilation, oxygen desaturation, hypercarbia, decreased tidal volume causing profound hypoxemia, bradycardia and eventual asystole. Other adverse events that may occur are laryngospasm, hyperalgesia and tolerance (Bhalla 2014; Kamata 2016).

3. Other drugs with analgesic/sedative effects acting on the central nervous system.

   1. Ketamine: an N‐methyl‐D‐aspartate (NMDA) receptor antagonist that has analgesic and amnesic effects. It has the effect of maintaining stable respiratory and cardiovascular function. It has a rapid onset and the effect only lasts for a few minutes (Barois 2013). It might be a good choice for acute pain during short technical procedures. Reported adverse events include: transient respiratory depression, transient laryngospasm, increased secretions and emesis (Bhutta 2007; Hall 2012).

   2. Propofol: a highly lipophilic and a short‐acting analgo‐sedative. A great advantage of this drug is that it maintains spontaneous breathing. Reported side effects in neonates include: reduced propofol clearance with extensive interindividual clearance variability and hypotension resulting in cerebral blood flow alterations (Simons 2013; Smits 2017).

   3. Benzodiazepines: these are sedatives with amnesic effects. They are commonly used for seizure control, and preoperative and procedure‐related sedation in neonates (Gupta 2018). Up until recently they were used as a sedative in mechanically ventilated preterm infants (American Academy of Pediatrics 2006). Due to a lack of data demonstrating effect, and concerns about the increased risk of poor neurologic outcomes, there is insufficient evidence to promote the use of benzodiazepines such as midazolam (Ng 2017).

   4. Dexmedetomidine: a drug with sedative, anxiolytic and analgesic properties. It is currently used as an anesthetic in neonates (Sottas 2017). It provides sedation and analgesia without compromising respiratory function, and compared to narcotics it has less effect on gastrointestinal motility (O'Mara 2018).

How the intervention might work

Pharmacological interventions are commonly used for procedural pain but their usage is not evidence‐based (Lago 2009). Analgesics could reduce the transmission of noxious stimuli, reducing observed behavioral distress and signs of physiological instability (Moultrie 2017).

Why it is important to do this review

Review articles have reported the role of pharmacological interventions during procedural pain in neonates (Carbajal 2005; Cignacco 2007; Ohlsson 2016). These interventions are effective for many different acute procedures. The role of pharmacological interventions during endotracheal suction in ventilated neonates has not yet been appraised. Endotracheal suctioning is often administered by one nurse or a respiratory therapist (Gardner 2009). Although there is an increase of adherence to national or international pain guidelines, infant pain remains undertreated. Reducing painful stimuli and interventions, and identifying effective pain‐reducing pharmacological interventions, is an obligation of researchers and healthcare providers in the NICU. By performing this review, we hope to ascertain which types of pharmacological interventions are effective in pain management during endotracheal suctioning in mechanically ventilated neonates.