Introduction
Pharmacologic agents are often used during mechanical ventilation of newborn infants to achieve various therapeutic goals including sedation and analgesia, neuromuscular paralysis, maintenance of fluid balance, and treatment of ventilator-associated inflammatory injury. Dosing, frequency, duration of use, and adverse effect profiles have not been studied well for most drugs used in neonates. Neonatal pharmacokinetics and pharmacodynamics exhibit considerable interindividual variability among neonates, and also differ considerably from those of adults, so extrapolation of animal and adult studies to this age group is often fraught with errors. Because of the limited data from studies, many of these drugs are used off-label as they have not undergone the rigorous testing in this age group required by the U.S. Food and Drug Administration (FDA). This chapter deals with several pharmacologic adjuncts to neonatal mechanical ventilation that are not covered in more detail elsewhere in the book.
Steroids
Maternal antenatal steroid administration for pregnancies at risk for preterm delivery to improve fetal lung maturity has become a well-established practice and has led to interest in using steroids postnatally for mechanically ventilated preterm infants at risk for bronchopulmonary dysplasia (BPD). Prolonged mechanical ventilation and its associated complications of volutrauma and biotrauma are some of the most important etiologic factors in the initiation and augmentation of the inflammatory processes that contribute to BPD. As potent anti-inflammatory agents, corticosteroids can potentially play a role in reducing its incidence and severity; indirect evidence for such a role is seen in infants with adrenal insufficiency, who have been shown to be at higher risk for developing BPD. Steroids act through several mechanisms to reduce inflammation. They increase the synthesis of annexin-1, a protein that inhibits phospholipase A2-induced release of arachidonic acid, the source of eicosanoid inflammatory mediators such as prostaglandins and leukotrienes. Steroids also inhibit other enzymes such as cyclooxygenases 1 and 2, which are also involved in eicosanoid synthesis and the influx of innate immune cells such as eosinophils into the pulmonary epithelium, thereby reducing inflammation and the concentration of inflammatory cytokines such as interleukin-1 in bronchoalveolar lavage. Steroids accelerate lung maturation by promoting alveolar wall thinning and microvascular maturation and promote surfactant production, especially when given during the first week after birth. They decrease elastase activity and collagen formation in the developing lung and increase antioxidant status and activity. Postnatal steroid regimens have been categorized as early (less than 8 days, postnatal age) or late (greater than or equal to 8 days of life) depending on the timing of their initiation.
Early Postnatal (<8 Days) Steroid Therapy for Prevention of Bronchopulmonary Dysplasia
Though adopted enthusiastically by many clinicians in the late 1980s, early steroid therapy has become more controversial today, with the results of several studies raising concern for neurodevelopmental sequelae. The vast majority of these studies evaluated dexamethasone, which is a more potent steroid compared to hydrocortisone. In a large trial, 384 infants of less than 30 weeks’ gestation were randomized to receive an early short course (two doses beginning at 12 hours of age) of dexamethasone or placebo. This trial showed that a short course of early dexamethasone reduced later prolonged dexamethasone treatment and ventilator and/or oxygen use but did not reduce death or BPD at 36 weeks of gestation. The largest trial that evaluated early dexamethasone was conducted in 2001 by the Vermont Oxford Network. In this multicenter trial, 542 extremely low birth-weight (ELBW) infants on mechanical ventilation soon after birth were randomized to receive either dexamethasone or placebo for 12 days with the first dose administered at 12 hours of age. The trial had to be stopped early before the completion of the predetermined sample size because of an increased incidence of complications including gastrointestinal perforation, hyperglycemia, poor weight gain, and hypertension in the early dexamethasone group. Furthermore, this trial also showed that early dexamethasone therapy increased periventricular leukomalacia and did not decrease the risk for BPD or death. Studies of early hydrocortisone therapy to prevent BPD were also carried out around this time. A multicenter trial randomized 360 mechanically ventilated ELBW infants at 12 to 48 hours of life to receive either hydrocortisone or placebo for 15 days. This trial, which was also stopped early as the authors discovered increased incidence of gastrointestinal perforation in the hydrocortisone group, found that survival without BPD and mortality were similar between the two groups.
A recent Cochrane Collaboration systematic review that identified 29 such trials of the early use of postnatal steroids for preterm infants at risk for developing BPD concluded that early (<8 days) steroid treatment (either hydrocortisone or dexamethasone) decreases BPD at 36 weeks’ postmenstrual age and facilitates extubation but also increases the risk for complications including intestinal perforation, hypertension, gastrointestinal bleeding, hyperglycemia, cardiomyopathy, and growth failure. More important, the meta-analysis also found that long-term follow-up studies of infants from the early steroid trials showed an increased risk for abnormal neurologic examination and cerebral palsy. Based on these findings the authors concluded that routine use of early steroids cannot be recommended for preterm infants at this time. However, because only a small number of trials reported follow-up data the authors of the meta-analysis also felt there was a compelling need for more extensive follow-up data regarding long-term neurodevelopmental outcomes from these studies.
Late (≥8 Days) Postnatal Steroid Therapy for Prevention or Therapy of Bronchopulmonary Dysplasia in Preterm Infants
The Cochrane Collaboration systematic review that included 21 trials with a total of 1424 infants who were randomized to receive steroids or placebo when older than a week concluded that steroid regimens initiated on or after 8 days of life reduced neonatal mortality rate at 28 days’ and at 36 weeks’ postmenstrual age (PMA) and decreased BPD at 36 weeks’ PMA in addition to facilitating earlier extubation. Although there was a trend toward an increase in cerebral palsy rates, there was also an opposing and larger trend for decreased mortality in the steroid group at the latest follow-up. The review concluded that corticosteroid therapy should be restricted to infants who are unable to be weaned off mechanical ventilation and that such exposure be limited to minimal dosing and duration of treatment. The Canadian Pediatric Society has also taken a similar stand on the use of postnatal corticosteroids, by recommending against the use of routine dexamethasone or hydrocortisone therapy for ventilated infants. These authors suggest short-term low-dose dexamethasone therapy as an alternative for infants with BPD who are on maximal ventilator and oxygen therapy, and further, that such therapy be initiated only after providing parents of such infants with information about the known short-term and long-term risks of such therapy. As of this writing, a large multicenter trial of a 10-day course of hydrocortisone for infants who are less than 30 weeks’ gestational age (GA) and unable to wean off mechanical ventilation at 14 to 28 days’ postnatal age is being conducted by the Neonatal Research Network. The primary outcome of this trial is survival without BPD as well as survival without neurodevelopmental impairment at 22 to 26 months’ corrected age.
In addition to management of BPD, steroids have also been used in attempts to facilitate and improve success rates of extubation for mechanically ventilated preterm infants. Studies have used up to three doses of 0.25 to 0.5 mg/kg dexamethasone given intravenously for this purpose. Infants included in these studies weighed at least 1 kg, had a mean GA greater than 30 weeks, and had been intubated for at least 7 days. A Cochrane Collaboration systematic review that analyzed these studies concluded that because dexamethasone use for facilitating extubation has not been adequately evaluated in ELBW infants and is associated with adverse effects such as hyperglycemia, its use can be approved only for infants at high risk for airway edema and obstruction such as those with repeated or prolonged intubations.
As an alternative to systemic steroid therapy, inhaled corticosteroids (ICS) offer the advantage of minimal or limited adverse systemic effects. A survey found that ICS therapy has been utilized for infants with BPD in 25% of U.S. children’s hospitals. However, variable and inefficient drug delivery and deposition in the lower airways of premature infants, secondary to factors such as small endotracheal tube diameters, short inspiratory times, and device limitations (type and placement of nebulizer used, particle size, aerosol flow, and other factors) have been serious limitations to the use of ICS for preterm infants. Although previously available data ( Table 34-1 ) suggested that the use of ICS does not prevent BPD, either compared to placebo or with systemic steroid use, a large multinational clinical trial in which infants were randomized to receive either inhaled budesonide or placebo has found that ICS therapy does reduce BPD incidence in ELBW infants. However, this study also found an increased rate of mortality, albeit statistically nonsignificant, in the inhaled steroid group compared to the placebo group. Further follow-up of the neurodevelopmental outcomes of infants enrolled in this study is being conducted as of this writing. More evidence regarding the effectiveness and safety of such early and prolonged use of ICS is required before their routine use can be recommended for the ELBW infant population.
| Reference | Sample Size | Dosage | Recruitment Criteria | Delivery Method | Placebo | Positive Results in Steroid-Treated Infants |
|---|---|---|---|---|---|---|
| Laforce et al. | 13 | Beclomethasone 3 × 50 mg for 28 days | >14 days, CXR BPD, VLBW | Nebulization through ventilator circuit or face mask | No blinded placebo | CRS; R(aw); no difference in infection |
| Geip et al. | 19 | Beclomethasone 1000 mg daily for 7 days or until extubated | >14 days, VLBW CXR BPD | MDI + spacer | Double blind | Extubation |
| Arnon et al. | 20 | Budesonide 600 mg twice daily for 7 days | 14 days, BW <2000 g, IPPV | MDI + spacer | Double blind | Significant PIP; no difference in serum cortisol levels |
| Ng et al. | 25 | Fluticasone propionate 1000 mg per day for 14 days | First 24 hr, <32 weeks’ GA, VLBW | MDI + spacer | Double blind | Basal and poststimulation plasma ACTH and serum plasma cortisol concentrations significantly suppressed |
| Fok | 53 | Fluticasone 500 mg bid for 14 days | <24 h, VLBW MDI + spacer IPPV | Double blind | 17/27 vs 8/26 extubated at 14 days; CRS | |
| Cole et al. | 253 | Beclomethasone 40 mg/kg/day, decreasing to 5 mg/kg over 4 weeks | 3-14 days, <33 weeks’ GA, ≤1250 g, IPPV | MDI + spacer neonatal anesthesia bag + ET tube (even when extubated) | Double blind | Rescue dexamethasone, RR 0.6 (0.4-1.0); IPPV at 28 days, RR 0.8 (0.6-1.0) at 28 days |
| Jangaard et al. | 60 | Beclomethasone (250 μg/puff), 1-2 puffs every 6-8 hr depending on birth weight | 28 days | Inline in respiratory limb of ventilator circuit with Medilife spacer via aerochamber with mask | Double blind | Similar incidence of growth failure, IVH, infection as well as long-term outcomes including NDI compared to placebo |
| Bassler et al. | 863 | Budesonide (200 μg/puff), 2 puffs every 12 hr for first 14 days, followed by 1 puff every 12 hr from day 15 until enrolled infant no longer required PPV or reached 32 weeks’ PMA | <12 hr, ELBW requiring PPV | MDI + spacer, inserted into ventilator circuit or face mask | Double blind | Reduced BPD incidence in the inhaled steroid group, RR 0.74 (0.6-0.91), p < 0.05, accompanied by increased mortality, RR 1.24 (0.91-1.69), p > 0.1 |
Sedation and Analgesia
About 20% of all infants and 50% of all ELBW infants admitted to tertiary neonatal intensive care units (NICUs) receive endotracheal intubation and/or mechanical ventilation. Sedation and analgesia may be important for the management of pain in neonates receiving respiratory support. In a 1997 survey neonatologists and nurses rated their assessment of pain for intubation and endotracheal suctioning in neonates at 2 on a scale of 4 (not painful to very painful). Consequences of episodic pain related to procedures like intubation include physiologic responses such as hypoxemia; pulmonary and systemic hypertension; release of stress hormones like cortisol, catecholamines, and glucagon; and increased markers of oxidative stress such as malondialdehyde. In addition, agitation during endotracheal intubation can cause increased intracranial pressures that can lead to intraventricular hemorrhage; trauma to gingival, orolabial, and glottic structures; and increased number of attempts required for any provider irrespective of their level of training and experience.
Despite the potential for adverse effects of pain during respiratory support, the management of procedural pain and sedation during endotracheal intubation remains an area of controversy and debate. For example, in a survey, only 44% of U.S. neonatal units reported routine use of premedication for elective intubations. First, pain assessment in the neonate is imperfect, and there is a poor correlation between individual tools that are used to attempt to objectively estimate pain. Facial expressions of pain, high activity levels, poor response to routine care, and poor ventilator synchrony were associated with inadequate analgesia in one study of preterm ventilated infants. Second, there are limited safety data regarding most drugs used for sedation and analgesia, especially regarding long-term neurodevelopmental outcomes when such medications are used for extremely premature infants. An American Academy of Pediatrics guidance statement published in 2010 recommends routine administration of premedication, including sedatives and analgesics, for infants that undergo nonemergent intubations but also recognizes these and other knowledge gaps and stresses the importance of continued research before such practice can become routine in all facilities that take care of such critically ill neonates.
Invasive mechanical ventilation in infants appears to be associated with chronic pain and/or stress, as supported by the increased serum levels of β-endorphins. Stress can lead to long-term consequences such as impaired motor and cognitive development at 8 and 18 months of corrected GA, lower IQ at 7 years, as well as internalizing behaviors at 18 months of age and decreased pain thresholds in adult life. These outcomes are thought to be secondary to frontoparietal cortical thinning, reduced development of white matter and subcortical gray matter, and increased activation of the somatosensory cortex associated with repeated or prolonged exposure to painful stimuli, especially in the early neonatal period. On the other hand, prolonged or repeated analgesic exposure can lead to excessive and prolonged need for ventilation, hypotension, and enhanced neuronal cell death. Current evidence indicates that the use of sedatives and analgesic agents for premature neonates should be a carefully considered decision that takes into account the safety and effectiveness of such agents. Nonpharmacologic interventions such as administration of oral sucrose, swaddling, containment, kangaroo care, facilitated tucking, and reduction of environmental stressors such as light and noise along with intermittent music therapy are variously effective for reducing stress associated with acutely painful procedures such as endotracheal suctioning and can be attempted as adjuncts or as first-line measures prior to the use of pharmacologic agents. However, there are limited data regarding the utility of these nonpharmacologic interventions for infants on mechanical ventilation. Typical dosages for sedatives and analgesics used in neonates are listed in Table 34-2 . Individual drugs are discussed below.
| Agent | Bolus Dose | Dose Frequency | Infusion Dose |
|---|---|---|---|
| Sedation | |||
| Lorazepam | 0.05-0.1 mg/kg | 4-12 hr | Not recommended |
| Midazolam | 0.05-0.15 mg/kg | 2-4 hr | 10-60 mg/kg/hr |
| Analgesia | |||
| Morphine | 0.05-0.2 mg/kg | 2-4 hr | 10-15 μg/kg/hr |
| Fentanyl | 1-4 mg/kg ∗ | 2-4 hr | 1-2 mg/kg/hr |
Opioids
From the time it was first isolated from Papaver somniferum in 1803, the alkaloid opioid morphine and its related drugs have been the standard against which all other agents with analgesic effects have been measured. The analgesic effect of opioids is due to their activation of the endorphin μ, κ, and/or δ receptors in the central nervous system, which initiates signal transduction and activation of inhibitory G proteins and reduction of cyclic adenosine monophosphate (cAMP) levels, leading to reduced neuronal excitability and decreased neurotransmitter release. Spinal and supraspinal activation of these pathways inhibits ascending nociceptive pathways, reduces pain thresholds, and alters the individual’s perception of pain.
Morphine
Morphine is one of the first-line agents for analgesia in adults and is also one of the most frequently used agents for this purpose in neonates. Morphine is a strong agonist of the μ opioid receptor (MOR) through which it mediates effects such as analgesia and respiratory depression. Tolerance of and dependence on morphine are also mediated through this receptor. Morphine acts as a weak agonist of the κ and the δ opioid receptors, unlike naturally occurring endorphins, which mediate most of their effects through these receptors rather than the MOR. The major effects of morphine are on the central nervous system (CNS) and organs containing smooth muscle such as the gastrointestinal and urinary tracts.
While morphine can be administered through oral, subcutaneous, and rectal routes, intravenous administration is the most common route of use for premature infants. Morphine has a quick onset of action and peaks at about 1 hour after injection. Its duration of action in neonates may be 2 to 4 hours. After an initial loading infusion of 100 mcg/kg over the first hour, standard doses used for continuous infusion range between 5 and 15 mcg/kg/h. Analgesia, the primary therapeutic indication for morphine, is achieved with morphine plasma concentrations of 15 to 20 ng/mL; some studies, however, suggest that the effective plasma morphine concentration to produce analgesia may be variable in preterm neonates. However, respiratory depression is often noted at levels not much more than this range in young infants ages 2 to 570 days. Respiratory depression, which is due to effects on respiratory centers in the brain stem, may be marked but is not usually of clinical significance in ventilated infants unless weaning from the ventilator is anticipated. Sedation, another therapeutic effect of morphine, occurs at much higher plasma levels (125 ng/mL), so morphine does not provide sedation at doses that are used to provide analgesia.
Rapid morphine bolus infusions can induce histamine release from mast cells, a common effect seen with other opioids as well, leading to vasodilation, hypotension, and bradycardia. Morphine infusions can be used safely for most preterm infants, but caution is required for infants of 23 to 26 weeks’ gestation, especially those with preexisting hypotension (Hall et al.). There are both interindividual and intraindividual variations in the effects of morphine. The metabolism of morphine matures with increasing GA; therefore, morphine infusion should be carefully titrated to the effect in preterm infants. Other effects of morphine include bronchoconstriction, decreased gastric motility, and increased anal sphincter tone and urinary tract smooth muscle tone. With prolonged morphine administration, some degree of tolerance develops, necessitating an increase in dosage. Following extended use, a weaning regimen that reduces the dose by 10% to 20% per day is recommended to prevent withdrawal symptoms. Morphine effects can be reversed by a naloxone dose of 0.1 mg/kg. Hepatic UDP-glucuronosyl transferase 2B7 converts morphine into morphine 6-glucuronide (responsible for both the analgesic and the respiratory depressant effects of morphine) and morphine 3-glucuronide (M3G), which acts as an antagonist to morphine and contributes to morphine tolerance. Both metabolites are eliminated through urinary and biliary excretion. Data suggest that preterm neonates metabolize morphine to form the M3G derivative predominantly, because of which accelerated development of tachyphylaxis to continuous morphine infusion may be noted. Morphine clearance reaches adult rates only at 6 to 12 months corrected postconceptual age. Morphine is not highly protein-bound even in adults, so its metabolism is relatively unaffected by plasma protein levels, but whether this is also true in preterm infants, who often have decreased albumin levels, remains unclear.
The effectiveness and safety of morphine as a continuous infusion in ventilated infants remain to be established. The Neurologic Outcomes and Preemptive Analgesia in Neonates (NEOPAIN) trial was a large multicenter study that randomized 212 infants undergoing mechanical ventilation to receive placebo or morphine infusions (ranging from 10 to 30 mcg/kg/h), along with open-label intermittent morphine used for additional analgesia based on physician discretion. Reduction of pain score and smaller increases in heart rate and respiratory rate were noted in the morphine group. However, these infants took longer to tolerate full enteral feeds, had significant hypotension more often, and required mechanical ventilation for longer duration than infants in the placebo group. Mortality rates, the primary outcome of the NEOPAIN study, and morbidities related to prematurity such as intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) were similar between the two groups. Neurologic outcomes also did not differ between the infants given morphine (up to 10 mcg/kg/h) or placebo in another study of 150 ventilated term and preterm infants. A systematic meta-analysis of 13 studies (1505 infants) found that the reduction in pain scores achieved with continuous morphine infusion was clinically insignificant. This analysis also found that very preterm infants who received morphine took longer to achieve full enteral feeds and had more hypotensive episodes that required treatment. Other outcomes such as mortality, duration of mechanical ventilation, BPD, IVH, and PVL did not differ between infants who received morphine and those who received placebo. Overall, the systematic review concluded that there was insufficient evidence to recommend routine use of continuous morphine infusions for infants undergoing mechanical ventilation.
Preclinical animal studies have provided evidence that morphine can alter hippocampal development in the developing brain. Data regarding the impact of routine morphine use for preterm infants with regard to their long-term neurodevelopmental outcomes have shown that while overall intelligence may not be affected, effects on other neurodevelopmental outcomes may be of concern. A follow-up study of 19 infants who were part of the NEOPAIN trial showed that while there were no differences in IQ or school performance between the groups, head circumference was lower for infants who received morphine compared to those who received placebo. Infants from the morphine group also required longer time to complete tasks compared to those from the placebo group. A 5-year follow-up of mechanically ventilated preterm infants who were randomized to receive continuous morphine infusion or placebo also found that overall IQ scores, executive function, visual–motor integration, and intelligence did not differ between the morphine and the control groups, but the visual analysis subtest component score was noted to be lower for infants from the morphine group. Other studies have also highlighted subtle adverse effects on long-term motor development and neurobehavior when morphine was routinely used for analgesia for preterm infants.
Thus, based on the currently available data, morphine administration, especially as a continuous infusion, should not be considered routine for mechanically ventilated infants. Instead, opioids such as morphine should be used judiciously, either as intermittent doses or as continuous infusions, appropriately titrated for each infant to measurements of pain based on well-validated scales.
Fentanyl
Fentanyl is a synthetic opioid with higher lipophilicity compared to morphine. This higher lipid solubility allows fentanyl to cross the blood–cerebrospinal fluid barrier more rapidly and produce analgesic effects more quickly than morphine. In addition, the analgesic effects of fentanyl are 80 to 100 times more potent than the morphine effects. Fentanyl is oxidized by hepatic microsomal cytochrome P450 into norfentanyl, an inactive metabolite that is then renally excreted. Fentanyl clearance matures quickly after birth, reaching 70% of adult levels by 2 weeks’ postnatal age in term infants. Clearance of fentanyl can be reduced secondary to decreased hepatic blood flow. Owing to faster redistribution and an elimination half-life of 4 hours, fentanyl also has a shorter duration of action (30 to 40 min) than morphine, making it ideal for scenarios like intubation that require rapid induction and recovery from sedation and analgesia. Fentanyl also has reduced propensity to cause histamine release from mast cells, as well as decreased activity on the vasomotor center. These advantages of fentanyl make it theoretically less likely to cause significant hypotension compared to morphine. In addition, when used prior to endotracheal suctioning fentanyl blunts increases in pulmonary arterial pressure, as shown in a study of infants recovering from cardiac surgery, who are often prone to such crises. In contrast to morphine, studies of fentanyl pharmacodynamics also show that its therapeutic effects may be more predictable using serum levels. Because of these advantages, fentanyl has emerged as the most commonly used synthetic opioid for procedural analgesia in neonates.
Continuous fentanyl infusion is also often used to achieve more prolonged analgesia for mechanically ventilated infants. Currently available data suggest that fentanyl offers analgesia equivalent to that produced by morphine, as shown in a trial of 163 mechanically ventilated newborn infants between 29 and 37 weeks’ gestation at birth randomized to receive continuous infusions of either fentanyl or morphine in the first 2 days of life. Adverse effects such as decreased gastrointestinal motility were also less commonly observed in the fentanyl group. However, similar needs for vasopressors to treat hypotension were observed in both groups. Another important, though rare, disadvantage that appears to be more common with fentanyl use than with morphine is chest wall rigidity, especially when it is administered as a rapid bolus infusion. In addition, when used as a continuous infusion the serum half-life of fentanyl is prolonged in preterm infants. This may be secondary to the high lipid solubility of fentanyl that allows it to accumulate in adipose and other lipid-rich tissue. When discontinued after prolonged use, redistribution of fentanyl from such stores can prolong respiratory depression and delay the recovery from sedation. Severe gastrointestinal adverse effects can also be seen with fentanyl, showing that the choice of fentanyl over morphine for analgesia may not be as advantageous as is sometimes believed.
Prolonged opioid use can lead to the development of tolerance, tachyphylaxis, and withdrawal symptoms when such use is discontinued. In one study of infants on extracorporeal membrane oxygenation, fentanyl infusion was associated with more rapid development of tolerance and requirement for higher doses over time, along with increased incidence and severity of withdrawal effects, leading to significantly longer hospital stay compared to continuous morphine infusion. Fentanyl use is also associated with more severe tachyphylaxis compared to morphine. In another study, a fentanyl total dose greater than 415 mcg/kg predicted withdrawal with 70% sensitivity and 78% specificity, whereas a fentanyl infusion duration greater than 8 days predicted withdrawal with 90% sensitivity and 67% specificity. Both fentanyl and morphine require weaning from the total daily dose by 10% to 20% per day to prevent such withdrawal.
As an analgesic agent, fentanyl is associated with disadvantages as shown in several trials that compared it to placebo. Fentanyl was noted to be associated with a need for higher, rather than lower, ventilator support in a randomized trial of 20 infants with respiratory distress syndrome, possibly secondary to decreased chest wall compliance due to fentanyl-induced chest wall rigidity. In a multicenter trial of 131 mechanically ventilated infants between 22 and 32 weeks’ GA at birth randomized to receive either fentanyl or placebo, short-term pain scores were lower for infants who received fentanyl, but there were no long-term differences in either the pain scores or the need for open-label fentanyl use, which was also similar between the two groups. Fentanyl use also prolonged the duration of mechanical ventilation and the time to first meconium passage in this study. Data available from a randomized placebo-controlled trial of 27 preterm ventilated infants regarding the impact of fentanyl infusion on mortality or the incidence of short-term adverse neurologic effects such as IVH indicate it has no advantages over placebo; as of this writing there are no data regarding its effects on long-term neurodevelopmental outcomes.
Dexmedetomidine
As an analgesic agent with additional anxiolytic and sedative properties and the additional advantage of very minimal potential to cause respiratory depression, dexmedetomidine has been extensively used in adults, often beyond the 24 hours of use that it has been approved for by the FDA. Dexmedetomidine is an imidazole derivative and the active isomer of medetomidine. It is a selective central α 2 -adrenergic receptor agonist. α 2 -Adrenergic receptors are found in a number of supraspinal and spinal neuronal sites in the central and peripheral nervous systems where they modulate both presynaptic and postsynaptic sympathetic output. One of the areas of the CNS with a high density of this receptor is the locus coeruleus, the primary site of norepinephrine synthesis in the brain, with functions that include maintenance of sleep–wake cycle, attention, memory, and arousal. Blocking sympathetic outflow from the locus coeruleus is the primary mechanism behind the sedative and analgesic effects of dexmedetomidine. This area is also the origin of several descending spinal nociceptive pathways that converge on the substantia gelatinosa in the dorsal horn of the spinal cord. At this level, dexmedetomidine stimulates α 2 receptors to inhibit release of substance P, a nociceptive mediator. While other drugs that act on α 2 -adrenergic receptors such as clonidine exist, dexmedetomidine is unique in its high specificity for the α 2A subtype of this receptor which is primarily responsible for its very effective sedative and analgesic effects.
Dexmedetomidine is increasingly being used in the pediatric population, especially in the postoperative cardiac intensive care environment. In the first-ever study of its use in preterm infants a study with historic controls (for whom fentanyl had been used as analgesic) assessed the use of dexmedetomidine in 24 preterm infants with a mean GA of 25 weeks. This study showed that dexmedetomidine use was associated with less need for adjunctive sedation, shorter duration of mechanical ventilation, and lower incidence of culture-positive sepsis episodes compared to fentanyl use. The lower incidence of sepsis noted with dexmedetomidine is believed to be secondary to its promotion of macrophage activity and reduction of inflammatory mediators such as tumor necrosis factor-α and interleukin-6 that has been noted in animal studies. This anti-inflammatory effect of dexmedetomidine, if confirmed in large randomized trials, may be a significant advantage for mechanically ventilated preterm infants who are very often prone to developing BPD. Another difference was the lack of signs of withdrawal for infants in the dexmedetomidine group, whereas infants in the fentanyl group often required slower weaning.
Other potential advantages of dexmedetomidine use in preterm mechanically ventilated infants may include its minimal potential to cause respiratory depression and gastrointestinal dysmotility. Adverse effects associated with dexmedetomidine also are a result of its α 2 -adrenergic agonist activity. Like clonidine, which has similar receptor activity albeit with lesser specificity, dexmedetomidine can cause hypotension, bradycardia, decreased secretion, bowel motility, and excessive diuresis. In the study of dexmedetomidine use in preterm infants, the incidence of significant hypotension or bradycardia was similar between the dexmedetomidine group and the control group (fentanyl), indicating that dexmedetomidine may not be inferior to other currently used sedatives and analgesics with respect to this adverse effect. While no differences were noted between the two groups with respect to short-term neurologic outcomes such as IVH, large randomized trials that include long-term neurodevelopmental outcomes of its use need to be conducted before dexmedetomidine can be recommended for use in premature infants without reservation.
Benzodiazepines
As sedative–hypnotics, the benzodiazepines cause CNS depression to reduce anxiety, produce drowsiness, and maintain a state of reduced awareness. Benzodiazepines are widely used for such purposes in the NICU. However, benzodiazepines do not possess analgesic effects. By increasing the affinity of γ-amino butyric acid (GABA) binding to the GABA-A receptors, benzodiazepines increase neuronal inhibition at various levels of the nervous system including the cerebral cortex, hypothalamus, hippocampus, and substantia nigra. Side effects of benzodiazepine use include respiratory depression and, especially in infants with hypovolemia or impaired cardiac function, hypotension. The most commonly used benzodiazepines in the NICU are discussed here.
Midazolam
Because of its pH-dependent water and lipid solubility, midazolam combines decreased incidence of thrombophlebitis or discomfort during intravenous administration with rapid onset of action (less than 3 minutes) and time to peak sedative effects (less than 20 minutes) compared to other benzodiazepines, making it a preferred drug for use in emergent situations in which rapid onset and termination of sedative effects may be required. It is also frequently used as a continuous infusion for sedation of mechanically ventilated neonates. Midazolam is converted by hepatic cytochrome P450 3A4 hydroxylation to form active and inactive metabolites. Owing to relatively lower levels of this enzyme at birth, midazolam has a longer elimination half-life (6.3 hours) and lower clearance rate (1.8 mL/kg/min) in healthy neonates. In a study of 187 neonates between 26 and 42 weeks’ GA who underwent mechanical ventilation, the midazolam elimination half-life was 1.6-fold greater than normal. Preterm infants have a longer elimination half-life compared to term infants, indicating that midazolam clearance increases with postnatal age and is decreased by critical illness as well as mechanical ventilation. Oral midazolam use in neonates is rare and associated with reduced clearance; bioavailability via the oral route was estimated to be around 50% in one study. Midazolam is highly protein bound; low serum albumin concentrations may lead to increased fractions of unbound midazolam available to enter the CNS and potentiate its therapeutic as well as adverse effects.
The adverse effects of midazolam in neonates include respiratory depression, hypotension, hypotonia, hypertonia, dyskinetic movements, myoclonus, and paradoxic agitation. The decreased number of GABA-A receptors seen in the neonate is believed to be the cause of the hyperexcitability instead of sedation that is often seen with midazolam use. Young age, female gender, and reduced serum albumin levels have been reported to be risk factors for the development of such adverse short-term neurologic effects. Withdrawal associated with discontinuation of midazolam use has been noted in rodent studies and may be the cause of the neurologic adverse effects seen in older infants, children, and adults. Finally, the usual parenteral preparation contains 1% benzyl alcohol as a preservative; this may need to be taken into consideration when dosing this drug. Use of the more concentrated 5 mg/mL preparation will reduce exposure to benzyl alcohol per milligram of midazolam used. Newer preparations of midazolam are preservative-free.
A randomized trial of the use of continuous midazolam infusion as sedation for mechanical ventilation in 46 preterm infants found that while midazolam was an effective sedative compared to placebo, it did not reduce duration of ventilation, supplemental oxygen use, or incidence of severe lung disease or mortality compared to placebo. In addition, midazolam use prolonged NICU stay and tended to increase the incidence of hypotension and bradycardia in preterm infants when its use was continued beyond 48 hours. Another multicenter study of sedation in the NICU randomized 67 mechanically ventilated infants between 24 and 32 weeks’ GA to receive morphine, midazolam, or dextrose placebo infusions for up to 14 days (the Neonatal Outcome and Prolonged Analgesia in Neonates trial). In addition to finding results similar to those of the previous study, this trial also found that midazolam use led to increased incidence of neurologic adverse effects such as IVH and PVL compared to morphine or placebo use. A meta-analysis of such studies by Ng et al. concluded that in light of the currently available evidence, the increased risks of adverse neurologic effects seen with midazolam use outweigh any benefits and therefore preclude its recommendation for use as a continuous infusion for sedation in the preterm infant.
Lorazepam
Lorazepam is a longer acting, highly lipophilic benzodiazepine compared to midazolam with a serum half-life of 24 to 56 hours and a duration of action of 8 to 12 hours in critically ill neonates. Lorazepam is metabolized by hepatic glucuronidation into inactive metabolites, which are then eliminated through biliary excretion. Apnea, somnolence, and stereotypic movements are complications associated with lorazepam use in neonates. In adults and older children, prolonged administration or continuous infusion of lorazepam causes metabolic acidosis secondary to accumulation of toxic alcohols such as propylene glycol, an agent that is used to increase the solubility of lorazepam in currently available lorazepam formulations. Therefore, lorazepam cannot be recommended for administration as a continuous infusion in neonates. As lorazepam is a longer acting agent, prolonged sedation can be achieved with intermittent dosing to achieve sedation in mechanically ventilated infants. However, like other benzodiazepines, routine use of lorazepam for sedation in preterm infants has not been adequately characterized with respect to its long-term neurodevelopmental effects and cannot be recommended at this time.
Diazepam
Diazepam has anxiolytic, hypnotic, anticonvulsant, muscle relaxant, and amnesic effects that are characteristic of benzodiazepines and, like other benzodiazepines, has no analgesic properties. Diazepam is absorbed rapidly after oral administration but irregularly after intramuscular administration. The elimination half-life approximates 75 hours in preterm infants and 30 hours in term infants. Diazepam is metabolized in the liver and, along with its metabolites, is slowly excreted in the urine. Simple correlations do not exist between plasma level and clinical response. Diazepam can cause respiratory depression, which may actually help infants to “settle” on the ventilator. Diazepam can be useful as a long-acting sedative when given in doses ranging from 0.10 to 0.25 mg/kg every 6 hours.
Other Sedative Agents
Propofol is an intravenous alkylphenol sedative–hypnotic without analgesic effects. It is a rapid-acting agent with short half-life and low propensity to cause respiratory depression. A study of 63 neonates that compared a combination of succinylcholine, atropine, and morphine to the use of only propofol for sedation prior to intubation found that propofol use led to shorter time required for successful intubation and less associated oral/nasal trauma as well as shorter recovery times. Infants in the propofol group also experienced less hypoxemic events during the endotracheal intubation attempts. Despite these advantages, the use of propofol in neonates as an induction agent for endotracheal intubation has been associated with a high incidence of hypotension. In addition, continuous infusion of propofol has been associated with fatal complications secondary to metabolic acidosis, bradycardia, rhabdomyolysis, and renal failure (the propofol infusion syndrome) when used in children and adults. Thus, continuous infusion of propofol for sedation is strongly discouraged.
Chloral hydrate , a commonly used sedative agent, has the major advantages of excellent oral bioavailability and minimal respiratory depression. While it is well suited to procedural sedation, particularly for radiologic procedures, electroencephalography, and echocardiography, with prolonged use accumulation of trichloroethanol leads to life-threatening arrhythmias, hypotension, and paradoxic CNS stimulation. This disadvantage of chloral hydrate, along with its tendency to displace various drugs and bilirubin from their protein-bound sites, as well as its propensity to cause direct hyperbilirubinemia, preclude its use for sedation in neonates.
Muscle Relaxants
Neuromuscular blockade is sometimes required for the care of critically ill infants, especially during procedures that often require their immobilization. Such blockade can be achieved either through excessive depolarization at the neuromuscular junction (depolarizing agents) or through a blockade of transmission at the neuromuscular junction achieved by acetylcholine antagonists (nondepolarizing agents). The use of muscle relaxants is not routinely indicated during mechanical ventilation of neonates, but muscle relaxants are sometimes used as part of premedication regimens and in certain patient populations such as infants with persistent pulmonary hypertension of the newborn (PPHN). Although paralysis may improve oxygenation and ventilation of severely hypoxemic term infants with PPHN, it may have adverse effects on preterm infants with respiratory distress syndrome. The use of synchronized ventilation using ventilator rates above the spontaneous rate of the patient frequently will accomplish the goals of paralysis (see Chapter 18 ). Muscle relaxants may be useful in selected preterm infants whose own respiratory efforts interfere with ventilation and may reduce the incidence of pneumothorax in these infants.
Perlman et al. demonstrated that the elimination of fluctuating cerebral blood flow velocity by muscle paralysis reduced the incidence of IVH in selected preterm infants with respiratory distress syndrome (RDS), but this has not been tested in a large trial and is not practiced commonly. As muscle paralysis may reduce oxygen consumption, paralysis may be advantageous to infants with compromised oxygenation. Prolonged paralysis of greater than 2 weeks’ duration has been associated with disuse atrophy and subsequent skeletal muscle growth failure. Importantly, in terms of pulmonary mechanics, Bhutani et al. have shown a decrease in dynamic lung compliance and an increase in total pulmonary resistance only after more than 48 hours of continuous paralysis with pancuronium. Both parameters improved by 41% to 43% at 6 to 18 hours after discontinuation of paralysis.
Spontaneous respiratory efforts appear to contribute little to minute ventilation in the severely ill preterm infant with very low lung compliance. These infants are at risk of decreased functional residual capacity after paralysis, possibly through loss of upper airway braking mechanisms. In infants with lung compliance that is less compromised and in larger infants, spontaneous respiratory efforts contribute markedly to total ventilation. Thus, ventilator adjustments (usually increases in rate) are necessary to prevent significant hypoventilation when paralysis is instituted. Monitoring gas exchange is recommended. Although loss of intercostal muscle tone may lead to an increase in intrathoracic pressure, this does not appear to cause an increase in respiratory resistance.
The primary hazard during paralysis appears to be accidental inconspicuous extubation. The paralyzed neonate is entirely dependent on mechanical ventilation, and careful observation is required. Also, paralysis obscures a variety of clinical signs whose expression depends on muscle tone and movement, such as seizures. Finally, paralysis does not alter the sensation of pain; thus, analgesics should be administered under circumstances in which their use would be indicated in a nonparalyzed infant.
In practice, the decision to administer a muscle relaxant is most often based on clinical observation of an infant in combination with arterial blood gas measurements. Muscle relaxants are used frequently to facilitate hyperventilation therapy (see Chapter 18 and the section entitled Persistent Pulmonary Hypertension of the Newborn in Chapter 23 ). Analysis of ventilator or esophageal pressure waveforms is a more objective method of assessing whether an infant is in phase with the ventilator and whether mean intrathoracic pressure is increased. However, there is no reliable way of predicting which infants in this circumstance will benefit from paralysis. Thus, muscle relaxants should be administered as a therapeutic trial and their use continued if blood gas values improve during the trial, if nursing care is greatly simplified, or if there is obvious improvement in patient synchrony with the ventilator and comfort. If the complications of prolonged paralysis are to be prevented, periodic assessment of the infant in the nonparalyzed state is essential. The short-acting depolarizing muscle relaxant succinylcholine is infrequently used in the care of neonates, except when paralysis for intubation is necessary; therefore, only the commonly used nondepolarizing agents are discussed in this section. Recommended dosages are listed in Table 34-3 .
| Agent | Initial Dose (mg/kg) | Dose Frequency | Infusion Dose (mg/kg/hr) |
|---|---|---|---|
| Pancuronium | 0.04-0.15 | 1-4 hr | Not recommended |
| Vecuronium | 0.03-0.15 | 1-2 hr | 0.05-0.10 |
| Rocuronium | 0.3-0.6 | 0.5-1 hr | 0.4-0.6 |
Pancuronium
Pancuronium bromide, a long-acting, competitive neuromuscular blocking agent, is the muscle relaxant most frequently used in neonates. Gallamine and d -tubocurarine are seldom used because of significant cardiovascular effects, sympathetic ganglionic blockade, and, in the case of the former, obligatory renal excretion. All of these agents block transmission at the neuromuscular junction by competing with acetylcholine for receptor sites on the postjunctional membrane. Pancuronium has vagolytic effects, and an increase in heart rate is commonly observed during its use. Administered intravenously, pancuronium produces maximum paralysis within 2 to 4 minutes. The duration of apnea after a single dose is variable and prolonged in neonates and can last from one to several hours. Incremental doses increase the duration of respiratory paralysis. In addition, the duration of paralysis is prolonged by acidosis, hypokalemia, use of aminoglycoside antibiotics, and decreased renal function. Alkalosis can be expected to antagonize blockade. Although renal excretion is the major route of elimination of pancuronium, hepatobiliary excretion and metabolism may account for the elimination of a significant portion of an administered dose.
The recommended dosage of pancuronium in neonates varies from 0.06 to 0.10 mg/kg. Although it is customary to administer repeat doses that are of the same magnitude as the initial dose, subsequent doses of half the initial dose may be effective in prolonging paralysis when muscular activity or spontaneous respiration returns. Continuous infusion of pancuronium in neonates is associated with the potential for accumulation because of these patients’ slow rate of excretion; thus this method of administration is best avoided unless electrophysiologic monitoring is available.
The long-term benefits of respiratory paralysis need to be balanced with potential complications. Prolonged use of pancuronium bromide has been implicated in sensorineural hearing loss in childhood survivors of congenital diaphragmatic hernia. In a cohort study of head trauma patients in a pediatric intensive care unit setting, patients treated with and without pancuronium were compared. In the 15 patients with isolated intracranial pathology who received continuous paralysis, compliance progressively dropped by 50% over 4 days. Compliance normalized after discontinuation of paralysis. Compliance did not change in the patients who were ventilated but not paralyzed. The paralyzed patients required mechanical ventilation longer than the nonparalyzed patients, and 26% of these patients developed nosocomial pneumonia, a complication that was not seen in the nonparalyzed patients. Prolonged use of pancuronium has also been associated with weight gain and third-space accumulation from lack of movement and urinary retention.
Despite the reported complications, pancuronium is still frequently used in the NICU population. A systematic review summarized the literature by stating that in ventilated preterm infants with evidence of asynchronous respiratory efforts, neuromuscular paralysis with pancuronium seems to be associated with less IVH and possibly less pulmonary air leak. The authors went on to stress that long-term pulmonary and neurologic effects are uncertain.
The effects of pancuronium can be rapidly reversed with the use of the anticholinesterase agent neostigmine at 0.08 mg/kg intravenously, preceded by the administration of glycopyrrolate at 2.5 to 5 mcg/kg, which blocks the muscarinic side effects. Although rapid reversal is seldom needed for medical reasons in neonates receiving assisted ventilation, reversal may occasionally be useful diagnostically in infants considered to have suffered a CNS insult during paralysis.
Vecuronium
Vecuronium is a short-acting nondepolarizing muscle relaxant that is structurally related to pancuronium, with time to onset of action of 1.5 to 2.0 minutes after intravenous bolus infusion, with a duration of effect that lasts only 30 to 40 minutes. It has few cardiovascular side effects and is cleared rapidly by biliary excretion. Thus, it is safer than pancuronium in the presence of renal failure. Interference with excretion or potentiation of effect has been suggested when vecuronium is used in combination with metronidazole, aminoglycosides, and hydantoins. However, no problems have been observed in infants receiving these agents and vecuronium in its usual dosage. Acidosis can be expected to enhance the neuromuscular blockade provided by vecuronium and alkalosis to antagonize it.
Vecuronium usually is given by continuous intravenous infusion at a rate of 0.1 mg/kg/hr after an initial paralyzing bolus dose of 0.1 mg/kg. Intermittent bolus dosing would need to be so frequent (i.e., every 30 to 60 minutes) that this type of regimen usually is impractical. Continuous infusion is preferred for certain postoperative cardiac patients whose respiratory or other muscular movement may jeopardize the success of the repair. The effects of vecuronium can be reversed by neostigmine administration, as described earlier for pancuronium.
Rocuronium
Rocuronium is a rapid-acting but less potent desacetoxy analogue of vecuronium. Like other steroidal drugs it is mostly (70% to 90%) metabolized in the liver and excreted through the biliary tract, which accounts for its shorter duration of action, reported to be 20 to 35 minutes, compared to agents that are mostly excreted through the renal system. A trial of 44 intubations in preterm infants who were randomized to receive either atropine or fentanyl alone or rocuronium added to these agents found that infants in the latter group were more likely to be successfully intubated on the first attempt. Onset of paralysis was 22 to 106 seconds after administration of a 0.5-mg/kg dose of rocuronium. Complete paralysis was noted to last for 3 to 29 minutes after administration of the above dose. Adverse effects noted in this study included transient tachycardia (7%) and bronchospasm in one infant. Recommended dosages for rocuronium can be found in Table 34-3 .
Cisatracurium
Atracurium is an isoquinoline nondepolarizing neuromuscular blocker that is metabolized mostly by Hofmann elimination, a nonenzymatic spontaneous degradation process that occurs at physiologic pH and temperature. Cisatracurium is an enantiomer of atracurium that is four times more potent, slower in its onset of action, but similar to atracurium in its duration of action. Like atracurium it undergoes Hofmann elimination but is not hydrolyzed by plasma cholinesterase. Unlike atracurium, cisatracurium does not provoke histamine release, thereby minimizing adverse effects such as hypotension and bradycardia. Its metabolism also produces less laudanosine, a CNS stimulant that can provoke seizures. A study of continuous cisatracurium infusion for neuromuscular blockade compared to vecuronium in 19 infants recovering from cardiac surgery found that infants in the cisatracurium group recovered their neuromuscular function faster compared to infants in the vecuronium group. This study used doses of cisatracurium ranging between 0.75 and 4.5 mcg/kg/min. In these dosage ranges, cisatracurium had an elimination half-life between 15 and 468 minutes for the nine infants in this study. Routine use of cisatracurium in newborn infants, especially for ELBW premature infants, requires more evidence regarding its pharmacokinetic and pharmacodynamic profiles in this patient group.
Bronchodilators and Mucolytic Agents
Bronchospasm was long believed to play a minimal if any role in contributing to airway resistance in the newborn, especially in preterm infants. Anatomic studies that demonstrated lack of smooth muscle in the distal airways of premature infants strengthened this opinion. However, studies that confirmed the presence of airway smooth muscle even in the lungs of 23-week gestation infants have disproved such misconceptions. The airways of 25-week-old infants have smooth muscle relative to airway circumference that is similar to that of term infants, indicating that bronchospasm is possible in preterm infants within the first few days after birth. It is now known that mechanically ventilated infants with BPD have airway smooth muscle hypertrophy that often plays a significant role in increasing airway resistance. In addition to contributing to resistance to airflow, the tracheobronchial tree of preterm infants compared to term infants and adults also possesses a relatively higher number of goblet cells that express mucus and fewer ciliated airway cells to assist in the mobilization of airway secretions and mucus. In addition to effecting bronchodilation, some agents such as aminophylline improve diaphragmatic and inspiratory muscle contractility, which may result in both improved ventilation and a greater likelihood of successful and earlier extubation, the goals for which the clinician should be striving. Thus, bronchodilators to decrease airway resistance and mucolytic agents that promote mucin breakdown are often used as aids to mechanical ventilation of the neonate. Typical dosages for commonly used aerosolized medications are listed in Table 34-4 .
