Introduction

Pain and sedation are controversial topics in the world of neonatology.Despite significant clinical trial data, there is still no definitive evidence regarding the best method for assessment or management of pain and sedation needs in critically ill infants.

Principles of Sedation

Neonates lack the ability to communicate pain and discomfort; therefore, the healthcare team is responsible for identifying the need for adequate sedation and providing it. Previous research examining preterm births have determined that, at the time of birth, neonates are undergoing critical nervous system development. Disruption or prolonged exposure to noxious stimuli may lead to neurologic remodeling.¹ The American Academy of Pediatrics (AAP) strongly recommends the use of protocols for the management of sedation in the neonatal population; however, the AAP acknowledges the need for further studies before it can establish treatment guidelines.^2–4

Assessment

Sedation of neonates can be a deleterious task. It is imperative to find a balance by ensuring the infant is appropriately sedated while monitoring for over-sedation. The N-PASS—Neonatal Pain, Agitation, and Sedation Scale—may be utilized for this purpose. N-PASS is a reliable tool for assessing neonatal pain and sedation. Patients are assessed based on crying irritability, behavior state, facial expression, extremities tone, and vital signs; they are scored on a scale of −2, meaning well-sedated to +2, in which the neonate is experiencing pain and agitation. This scale may be utilized in neonates receiving all types of sedatives.⁵

In neonates receiving neuromuscular blocking agents (NMBA), healthcare professionals may utilize train-of-four (TOF) in monitoring effectiveness. TOF monitoring consists of peripheral nerve stimulation that produces four stimuli over 2 seconds. Patients display zero to four twitches. Paralysis is indicated by a decrease in the number of twitches. Although this tool is highly utilized in the adult and some pediatric populations, it is generally not used in neonatal patients. Due to the size of the electrodes and fragility of the neonates, it is possible to stimulate the muscle itself, leading to movement, regardless of whether the neuromuscular junction is blocked. Thus, clinical monitoring—observation of visual and tactile stimulation on muscle movement and breathing patterns—is often utilized.⁶

Nonpharmacologic Modalities

Although there is not much research available on nonpharmacologic sedation methods, limiting environmental light and noise may aid in decreasing agitation. Neonates may potentially have a reduced need for sedative medications by limiting their exposure to interruptions and stimuli.⁷

Pharmacologic Agents for Sedation

GABA Modulators

Barbiturates

Phenobarbital—a depressant used for seizure control in neonates (see Chapter 17). Phenobarbital may also be used in combination with opioids for sedation; however, there is a lack of evidence proving its effectiveness.⁸

Benzodiazepines

Midazolam—a short-acting benzodiazepine that acts on gamma-aminobutyric acid (GABA) receptors, which are present in the fetus around week 7 of gestation. Midazolam, which is highly water-soluble and rapidly cleared, is the preferred benzodiazepine for sedation. Although midazolam is short acting, reduced hepatic function in neonates results in a longer duration of action.⁹

Midazolam may be administered orally, intranasally, or parenterally. Because the bioavailability of oral midazolam is half of intravenous (IV) midazolam, the dose of oral (PO) midazolam should be double the IV dose.⁸ Due to its rapid onset of action, intranasal midazolam is often used in neonates requiring surfactant in the delivery room.¹⁰ Studies in ventilated patients have demonstrated that better sedation is achieved when midazolam is coadministered with morphine.

Lorazepam—a benzodiazepine with a long duration of action used in neonates unresponsive to phenobarbital for both sedation and seizure prevention (see Chapters 17 and 18).⁸

Propofol

Propofol is a short-acting lipophilic anesthetic that rapidly penetrates the blood−brain barrier.³ Although propofol is commonly used in the adult and pediatric populations, research in neonates is lacking. When compared to morphine, atropine, and succinylcholine for intubation, propofol reduced intubation times, increased oxygen saturations, and incurred less trauma compared to the combination regimen in neonates.¹¹

All neonates receiving propofol should be closely monitored throughout therapy. Propofol should be used with caution in neonates because

clearance is inversely related to neonatal and postmenstrual age.

intermittent bolus or continuous administration can lead to accumulation in neonates, causing toxicity.⁸

postnatal age, concurrent medications, and the presence of cardio-myopathy may also affect clearance.³

Neuromuscular Blocking Agents

Vecuronium—an intermediate-acting NMBA and a structural derivative of pancuronium (no longer on the market). Compared to pancuronium, vecuronium is shorter acting and 1.2 to 1.5 times more potent. Vecuronium is cleared primarily through hepatic elimination, yet its metabolite, 3-descacetylvecuronium, is renally eliminated.^12,13 Studies demonstrated that on discontinuation of vecuronium, time to recovery ranged from 27 to 80 minutes. Evidence correlating with infusion and recovery times is conflicting. However, studies showed that vecuronium does not significantly change respiratory mechanics but does decrease hypoxemic episodes in neonates.¹³

Rocuronium—an intermediate-acting analog of vecuronium. Compared to vecuronium, it is approximately one-sixth as potent, and its onset of action is 2.5 times faster. Rocuronium is hepatically metabolized and renally eliminated. It has mild vagolytic activity, which increases the risk of tachycardia. Patients have developed tolerance to this agent, and a significant dose increase was noted after 5 days of therapy. On discontinuation of therapy, spontaneous recovery of neuromuscular function was observed within 24 to 44 minutes.¹² Rocuronium has been associated with an increase in pulmonary vascular resistance (PVR). This agent should be used cautiously due to the increased risk of bronchopulmonary dysplasia and lung injury in this population.

Atracurium—an intermediate-acting NMBA metabolized via Hoffman elimination. Hoffman elimination is dependent on pH and temperature; therefore, when those variables are altered, such as in hypothermia or acidosis, elimination may be reduced.¹²

Adverse effects related to histamine release on bolus injection include

hypotension

tachycardia, bronchospasm

erythema

rash

There is a potential seizure risk secondary to the formation of laudanosine, which is a long-acting metabolite produced by Hoffman elimination that is both hepatically and renally eliminated. In neonates with reduced hepatic and renal function, laudanosine has the ability to accumulate.¹²

Cisatracurium—an intermediate-acting NMBA and a derivative of atracurium. Cisatracurium is 4 times as potent as atracurium, has minimum histamine release, and has a higher neuromuscular blockade. It undergoes Hoffman degradation, resulting in a 5- to 10-time decrease in concentration of laudanosine as opposed to atracurium. In one prospective study, all patients required a statistically significant dose increase after 3 days of therapy, likely due to the development of tolerance.¹²

In comparison to vecuronium, the recovery time after discontinuing infusion was significantly greater for vecuronium-treated patients than for cisatracurium-treated patients. It has been suggested that the prolonged recovery time with vecuronium may be due to reduced clearance and accumulation of its active metabolite.¹²

Alpha Agonists

Dexmedetomidine

Dexmedetomidine is a new alternative agent used to prolong sedation in mechanically ventilated neonates. Dexmedetomidine, classified as an alpha-2 agonist, leads to sedation and anxiolysis.^5,14 A case control study showed that neonates who received dexmedetomidine required less adjunctive sedation and a shorter duration of mechanical ventilation as well as experienced fewer occurrences of culture-positive sepsis.^5,14 Unlike opioids, dexmedetomidine does not affect respiratory drive or gastrointestinal (GI) motility. A prospective study showed that patients had a significantly shorter duration of mechanical ventilation than patients who received fentanyl because they could be removed from mechanical ventilation prior to dexmedetomidine discontinuation. Patients also had a reduced time to first stool.¹⁴

Because dexmedetomidine is hepatically metabolized, neonates require lower doses compared to pediatric patients. Dexmedetomidine is also highly protein bound. Neonates typically present with lower albumin and a large volume of distribution (Vd). With the addition of an immature blood−brain barrier, dexmedetomidine’s sedative properties may be potentiated, leading to increased sedative and analgesic effects.⁵

Adverse effects are generally dose dependent and include hypotension and bradycardia. No respiratory side effects have been documented in Phase III trials; however, no long-term developmental studies have been performed.^5,15

NMDA Antagonists

Ketamine

Ketamine is a potent NMDA (N-methyl-D-aspartate) receptor antagonist that acts as both a sedative and analgesic agent.¹⁵ Unlike other sedatives, ketamine does not affect cerebral blood flow. It has the potential to cause bronchodilation and slight increases in blood pressure and heart rate, so it could be used for hypotensive neonates undergoing airway procedures such as mechanical ventilation.⁸ Although rare, research has found that use in neonates may lead to apnea, hypoxemia, and laryngospasm (phenomenon was likely procedure related rather than to ketamine use). However, some healthcare facilities prohibit the use of ketamine in infants less than 3 months of age.¹⁶ Additional studies are needed to determine its safety and efficacy as an anesthetic in neonates.⁸

Opioids

Research has demonstrated the therapeutic need for both morphine and fentanyl. For more information, see the following section.

Principles of Analgesia

Pain in the neonate was not accepted and acknowledged until the late 1980s.¹⁷

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