Pediatric Annals

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Sedation and Analgesia in the Pediatric Intensive Care Unit

Joseph D Tobias, MD

Abstract

Admission and subsequent care in the pediatric intensive care unit (PICU) can be a frightening and painful experience for children of all ages. Pain may be caused by the primary medical illness, a surgical procedure, invasive procedures such as placement of central venous or arterial cannulae, or the ongoing presence of an endotracheal tube for mechanical ventilation. In addition to physical pain, emotional distress and anxiety may result from separation from parents, disruption of the day-night cycle, unfamiliar people, the noise of monitoring devices, fear of death, and loss of self-control. Although nonpharmacologic comfort measures such as open communication, reassurance, parental presence, and psychological interventions may decrease the effects of many of these factors, pharmacologic intervention frequently is necessary.

Before discussing the various pharmacologic agents available for providing sedation and analgesia in the PICU setting, it should be recognized that, while these agents are beneficial and mandatory in the majority of PICU patients, they can result in devastating and potentially life-threatening complications. General guidelines include appropriate monitoring of the patient's physiologic function in accordance with standards set forth the American Academy of Pediatrics;1 the ruling out of treatable and potentially life-threatening causes of agitation such as hypoxemia, hypercarbia, cerebral hypoperfusion, necrotic bowel, or a compartment syndrome; titration of the sedative and analgesic agent to achieve the desired level of sedation; and monitoring the patient's response using a formal sedation scale.

The barbiturates' effects on cardiorespiratory function are similar to those of propofol. In healthy patients, sedative doses have limited effects on cardiovascular function, respiratory drive, and airway protective reflexes, while larger doses result in respiratory depression, apnea, and hypotension, especially in patients with co-existing myocardial dysfunction. Hypotension results from both peripheral vasodilation and a direct negative inotropic effect. These agents should be used cautiously, if at all, in patients with cardiovascular dysfunction.

The barbiturates' greatest role in the PICU is in the treatment of increased ICP or refractory status epilepticus. These agents decrease the cerebral metabolic rate of oxygen, which results in reflex cerebral vasoconstriction, a decrease in cerebral blood volume followed by a decrease of ICP.

The role of barbiturates in PICU sedation is as a second-line agent when first-line agents, either alone or in combination, fail or result in untoward side effects. Despite the wealth of information with some of the other agents reviewed in this article, there is only limited published information regarding the use of pentobarbital infusions for sedation in the PICU setting. A retrospective report described the use of pentobarbital for sedation during mechanical ventilation in 50 infants and children ranging in age from 1 month to 14 years.37 Pentobarbital was used when sedation was inadequate despite the combination of a benzodiazepine (midazolam in doses of 0.4 mg/kg per hour) and an opioid (either fentanyl in doses of 10 µg/kg per hour or morphine in doses of 100 µg/kg per hour). With the administration of pentobarbital, effective sedation was achieved, and the other agents (benzodiazepine and opioid) were weaned. Additionally, there was no longer a need for direct-acting vasodilators to treat hypertension, and neuromuscular blocking agents were able to be discontinued. The cohort also included seven nonneonatal ECMO patients in whom pentobarbital provided effective sedation. Six of the 36 patients who had received pentobarbital for more than 4 days manifested signs and symptoms of withdrawal.

Another retrospective report outlined a contrary opinion in a cohort of eight PICU patients.38 Although pentobarbital provided effective sedation and allowed the discontinuation of neuromuscular blocking agents, the authors noted adverse effects in five of the eight (62.5%), including blood pressure instability, oversedation, and withdrawal phenomena. These adverse effects led…

Admission and subsequent care in the pediatric intensive care unit (PICU) can be a frightening and painful experience for children of all ages. Pain may be caused by the primary medical illness, a surgical procedure, invasive procedures such as placement of central venous or arterial cannulae, or the ongoing presence of an endotracheal tube for mechanical ventilation. In addition to physical pain, emotional distress and anxiety may result from separation from parents, disruption of the day-night cycle, unfamiliar people, the noise of monitoring devices, fear of death, and loss of self-control. Although nonpharmacologic comfort measures such as open communication, reassurance, parental presence, and psychological interventions may decrease the effects of many of these factors, pharmacologic intervention frequently is necessary.

Before discussing the various pharmacologic agents available for providing sedation and analgesia in the PICU setting, it should be recognized that, while these agents are beneficial and mandatory in the majority of PICU patients, they can result in devastating and potentially life-threatening complications. General guidelines include appropriate monitoring of the patient's physiologic function in accordance with standards set forth the American Academy of Pediatrics;1 the ruling out of treatable and potentially life-threatening causes of agitation such as hypoxemia, hypercarbia, cerebral hypoperfusion, necrotic bowel, or a compartment syndrome; titration of the sedative and analgesic agent to achieve the desired level of sedation; and monitoring the patient's response using a formal sedation scale.

Suggested starting guidelines for sedative and analgesic agents are listed in the Table (see page 638). The need to titrate the medications based on the patient's response is of extreme importance, as variabilities in their pharmacokinetics and pharmacodynamics may result from drug-drug interactions, end-organ (ie, hepatic, renal) failure or dysfunction, malnutrition, low plasma proteins with altered drug binding, alterations in drug distribution (due to alterations in cardiac output), and changes in the volume of distribution. The effect of these factors is illustrated by the study of Katz and Kelly,2 which noted variations in the fentanyl infusion rate required during mechanical ventilation of 0.47 to 10.3 µg/kg per hour to achieve a similar effect.

In our PICU, the incremental increase or decrease in the amount of medication administered is based on the use of formal sedation scores, along with the nurse's assessment of the patient's vital signs.3-6 Sedation scores should be considered the fifth vital sign and should be assessed and documented every time the other routine vital signs are recorded. These sedation scores generally include a combination of physiologic parameters such as heart rate and blood pressure, combined with an observation of the patient's general comfort level either at rest or in response to a physical stimulus.

Table

TABLE.Agents for PICU Sedation and Analgesia

TABLE.

Agents for PICU Sedation and Analgesia

Once these practice parameters are in place, the healthcare provider is ready to provide pharmacologic control of pain and anxiety for the infant, child, or adolescent in the PICU setting. Numerous medications have been used to provide sedation and analgesia in the ICU setting; each has inherent advantages and disadvantages. Because none of these agents will be effective in each patient or every scenario, the healthcare provider should become familiar with several agents to allow transition from one agent to another based on the clinical features of the patient.

As a comprehensive review of all of the agents used for sedation in the PICU is not feasible due to space constraints, this article reviews the most commonly used agents, including the benzodiazepines (midazolam and lorazepam), the opioids (morphine and fentanyl), ketamine, propofol, and the barbiturates (pentobarbital). Additionally, a brief discussion is provided regarding a potentially valuable new agent, the a2 adrenergic agonist dexmedetomidine. Although this agent is not approved by the Food and Drug Administration for use in pediatric patients, preliminary results in children combined with an increasing experience in the adult population suggest it may be an effective agent in the PICU setting.

AGENTS FOR SEDATION

Benzodiazepines

The benzodiazepines are the most commonly used agents for PICU sedation. They bind to the ct-subunit of the receptor for the inhibitory amino acid, gamma-aminobutyric acid (GABA). This interaction increases the binding of the GABA molecule to the ß-subunit, which facilitates chloride conduction across the neuronal membrane, resulting in hyperpolarization. This primary mechanism of action via the GABA system is shared by many sedative agents used in the PICU, including the benzodiazepines, propofol, and the barbiturates. The benzodiazepines provide amnesia, sedation, and anxiolysis but have no intrinsic analgesic properties.

Midazolam is a water-soluble benzodiazepine with a rapid onset of action and a short elimination half-life following single bolus dose administration. A significant amount of clinical experience and years of use have demonstrated the efficacy of continuous midazolam infusions for sedation in the PICU patient at starting doses ranging from 0.05 to 0.2 mg/kg per hour.7"10 In addition to its efficacy, the availability of generic forms of midazolam makes this a cost-effective form of sedation.

Rosen and Rosen8 demonstrated that midazolam administered as a bolus dose of 0.25 mg/kg followed by a continuous infusion of 0.4 to 4 µg/kg per minute (0.02 to 0.2 mg/kg per hour) provided effective sedation during mechanical ventilation without adverse hemodynamic effects. Jacqz-Algrain et al.10 compared midazolam with placebo for sedation during mechanical ventilation in 46 infants. The midazolam infusion was started at 0.06 mg/kg per hour and then decreased after 24 hours to 0.03 mg/kg per hour in infants born at less than 33 weeks gestation. Midazolam provided effective sedation, with only 1 of 24 patients who received midazolam being withdrawn from the study for inadequate sedation, compared with 7 of 22 infants in the placebo group. The authors noted significant variation of the plasma concentrations between patients despite using the same infusion rate. Two infants with gestational ages of less than 32 weeks had plasma concentrations greater than 1,000 ng/mL, demonstrating the expected decreased clearance in patients of shorter gestational age related to immaturity of the hepatic microsomal enzymes.

Midazolam is metabolized by the hepatic P450 enzyme system to 1-OH (hydroxy) midazolam, which is equipotent with the parent compound. It undergoes further hepatic metabolism via the glucuronyl transferase system to 1-OH midazolam-glucuronide, a water-soluble metabolite that is excreted renally. With metabolism dependent on the hepatic P450 system, clearance increases and half-life decreases from infancy to adulthood. Renal dysfunction can lead to the accumulation of 1-OH midazolam-glucuronide, with potentiation of the effects of midazolam.

Several other factors, including age and underlying illness, also may alter midazolam pharmacokinetics. Midazolam clearance in PICU patients ranging in age from 3 to 10 is significantly longer (5.5 ±3.5 hours) than that reported in healthy age-matched children (1.2 ±0.3 hours).11 These data show that midazolam does not demonstrate a short elimination half-life in PICU patients. Because its average half-life is 5.5 hours in the PICU setting, a steady state serum concentration will not be achieved for approximately 20 hours after initiating an infusion (4 to 5 half-lives of the medication). Therefore, sedation should be initiated with a bolus dose before the start of the continuous infusion.

Lorazepam is a water-soluble benzodiazepine that is metabolized by glucuronyl transferase to pharmacologically inactive metabolites. Medications known to alter the P450 system (eg, anticonvulsants, rifampin, Cimetidine) do not alter lorazepam's pharmacokinetics. In advanced liver disease, phase ? reactions (glucuronyl transferase) are better preserved than phase I reactions (P450 system) so that the pharmacokinetics of lorazepam remain unchanged. The Society of Critical Care Medicine, in its guidelines for ICU sedation for adults, has recommended the use of lorazepam as the preferred sedative for prolonged sedation.12

However, in comparison with midazolam, there is far less clinical experience with the use of lorazepam in the PICU setting. Pohlman et al.13 compared lorazepam with midazolam for sedation in 20 adult ICU patients. Adequate sedation was achieved with mean infusion rates of lorazepam at 0.06 mg/kg per hour and midazolam at 0.15 mg/kg per hour. The maximum and mean infusion rates (mg/kg per hour) for the study were 0.1 and 0.06 for lorazepam and 0.29 and 0.24 for midazolam. Fewer infusion rate adjustments per day were required with lorazepam than with midazolam (1.9 for lorazepam versus 3.6 for midazolam). The mean time to return to baseline mental status was also shorter with lorazepam (261 minutes with lorazepam versus 1,815 minutes with midazolam). Three of six surviving patients in the midazolam group required more than 24 hours to return to their baseline mental status, while all seven patients in the lorazepam group returned to baseline in less than 12 hours.

To date, there are no formal pediatric trials comparing lorazepam with midazolam for sedation in the PICU setting. Lugo et al.14 used enteral lorazepam to decrease intravenous midazolam dosing requirements and drug costs during mechanical ventilation in a cohort of 30 infants and children. Sedation was provided by a continuous midazolam infusion until the requirements were stable for 24 hours. Enteral lorazepam, administered per nasojejunal tube in divided doses every 4 to 6 hours, was then started at a dose of one-sixth of the total daily intravenous midazolam dose. On day 1, the midazolam requirements were significantly reduced, and by day 3, the midazolam infusion was discontinued in 24 of 30 patients. In the remaining six patients, the daily midazolam infusion requirements were reduced by 52%. When considering acquisition costs during the late 1990s, before the availability of generic midazolam preparations, the projected savings were more than $40,000 for the 30 patients. Given the availability of midazolam in a generic form and its current cost efficacy, it is unlikely that there will be any cost advantage with lorazepam compared with midazolam.

One issue that must be considered with lorazepam, especially at higher doses or in the neonatal population, is related to the diluent used in the intravenous formulations, propylene glycol. Each milliliter of the lorazepam solution (2 mg lorazepam per milliliter of solution) contains 0.8 mL, or 800 mg, of propylene glycol. Signs and symptoms of propylene glycol toxicity include metabolic acidosis, renal failure or insufficiency, mental status changes, hemolysis, and an elevated osmolar gap. Propylene glycol is metabolized in the liver to lactic acid and pyruvic acid, accounting, in part, for the lactic acidosis that occurs. Propylene glycol also is excreted unchanged in the urine, making toxicity more likely in patients with renal insufficiency. Calculation of the propylene glycol infusion rate and periodic measurement of the osmolar gap (measured minus calculated serum osmolarity) may be indicated during high-dose or prolonged lorazepam infusions.

An increasing osmolar gap has been shown to be predictive of increasing serum propylene glycol levels.15 Because neonates and especially preterm infants are unable to handle propylene glycol related to hepatic and renal immaturity, continuous infusions of lorazepam are not recommended in this population.

Chicella et al.16 followed propylene glycol concentrations at baseline, 48 hours, and the end of therapy in 1 1 PICU patients ranging in age from 1 month to 15 months. Lorazepam infusion doses ranged from 0.1 to 0.33 mg/kg per hour and were administered for 3 to 14 days. The propylene glycol concentration increased from 86 ±93 pg/mL at baseline to 763 ±660 µ/mL at the completion of the infusion. Although there was a correlation between the cumulative dose of lorazepam and the plasma propylene glycol concentrations, there was no endorgan toxicity related to the increased propylene glycol concentration. The authors concluded that no toxicity occurred in their patient population because the doses that they used were significantly less than doses that had been previously associated with toxicity and renal function was normal in their patients.

Opioids

Opioids as a group represent the second most commonly administered sedative/analgesic agents in the ICU setting. Although generally used for analgesia, opioids also possess sedative properties, especially those with agonistic effects at the K-opioid receptor. These agents provide analgesia and sedation, but amnesia is not ensured even with high doses (50 to 75 pg/kg of fentanyl). Alternative agents are required in situations that demand amnesia, such as the patient who is receiving a neuromuscular blocking agent.

In the PICU setting, the majority of the clinical experience is with fentanyl or morphine. Fentanyl is used frequently in the PICU because of its limited effects on the cardiovascular system, even in high doses, as well as its beneficial effects on pulmonary vascular resistance and effective blunting of the sympathetic stress response. Given these properties, it is used often in the pediatric patient following surgery for congenital heart disease. Due to its rapid redistribution and resultant short plasma half-life following bolus administration, fentanyl generally is administered by a continuous infusion to maintain plasma concentrations adequate to provide analgesia. Despite this short half-life when administered as a single bolus dose, like midazolam, fentanyl demonstrates a context-sensitive half-life so that the duration of its effect is prolonged when administered over an extended period of time.

One adverse effect specific to the synthetic opioids is chest wall rigidity.17 Its incidence is related to the dose, the rate of administration, and, perhaps, the age of the patient. It is a centrally mediated, idiosyncratic reaction that, when severe, can interfere with effective respiratory function. It can be reversed with naloxone or interrupted with neuromuscular blocking agents. Although a rare phenomenon, its occurrence should be considered if respiratory dysfunction is noted following the use of synthetic opioids. In most cases, the synthetic opioids provide analgesia and sedation resulting in improved ventilatory function.

Morphine is the other opioid used frequently for sedation and analgesia in the PICU setting. Its cardiovascular effects include dilation of the venous capacitance system and a modest decrease in blood pressure, especially in patients with decreased intravascular volume. Morphine is metabolized by the hepatic microsomal enzymes to an active metabolite, morphine-6-glucuronide (M6G), which then undergoes renal excretion. Due to its dependence on renal excretion, alterations in renal function can result in M6G accumulation and potentiation of the sedative, analgesic, and respiratory depressant effects of morphine. Prospective trials have demonstrated no effect on future intelligence, motor function, or behavior when morphine is administered during the neonatal period.18

Following surgery for congenital heart disease, morphine infusions of 10 to 30 pg/kg per hour provide effective analgesia and sedation without impairing the ability to wean mechanical ventilatory support.19 Morphine infusions blunt the sympathetic response and reduce epinephrine levels in neonates requiring mechanical ventilation for hyaline membrane disease.20 When compared with fentanyl in a cohort of infants requiring sedation and analgesia during extracorporeal membrane oxygenation (ECMO), morphine provided equivalent levels of sedation while decreasing the need for supplemental bolus doses of opioid.21 Infants receiving morphine had a lower incidence of withdrawal (13 of 27 with fentanyl versus 1 of 11 with morphine; P < .01) and were hospitalized for fewer days after discontinuation of ECMO (31.1 ±14 versus 21 .5 ±7.0 days; P = .01).

Despite their overall beneficial effects, some data suggest the opioids may affect immune function. Although the clinical significance of such effects in the PICU setting remains to be determined, these preliminary data should be acknowledged. Opioid receptors are present on immune cells that participate in the inflammatory response. Binding of opioids to these receptors decreases inflammation and may play some role in the control of acute pain by opioids. However, in specific circumstances, this effect may be deleterious. Increased viral loads have been noted in patients with HTV infection who are receiving methadone.22 Opioids also modulate cytokine production and in an animal model, morphine administration led to reduced reticuloendothelial cell function, phagocytic count, phagocytic index, lcilling properties, and superoxide anion production.23"24

Ketamine

Ketamine is a phencyclidine (PCP) derivative that produces a state known as dissociative anesthesia, in which the patient may keep his or her eyes open and yet be amnestic and unresponsive to painful stimuli. Ketamine's clinical effects are thought to result from interactions at several sites, including agonism at opioid receptors and antagonism at the N-methyl-D-aspartate (NMDA) receptors. A unique attribute of ketamine, which separates it from the other agents discussed in this article, is that it provides both amnesia and analgesia.

The preparation currently in clinical use in the United States is a racemic mixture of the two optical isomers [S(+) and R(-)]. Preliminary trials are underway with the S(+) enantiomer, which may limit the potential adverse effects of ketamine including emergence phenomena. Metabolism occurs by hepatic N-methylation to norketamine, which is further metabolized via hydroxylation pathways with subsequent urinary excretion. Norketamine retains approximately one-third of the analgesic and sedative properties of the parent compound.

Beneficial properties of ketamine include preservation of cardiovascular function, limited effects on respiratory mechanics, and maintenance of central control of ventilation in the majority of patients. In most clinical situations, ketamine administration results in an increase in heart rate and blood pressure, effects that are mediated through the release of endogenous catecholamines.25 Ketamine also has been shown to have limited effects on several respiratory parameters including functional residual capacity, minute ventilation, and tidal volume.26 Release of endogenous catecholamines results in improved pulmonary compliance, decreased resistance, and prevention of bronchospasm.

Issues related to ketamine that may limit its use in the ICU setting are theoretical effects on pulmonary vascular resistance (PVR) and intracranial pressure (ICP). Although these two areas remain controversial, recent literature suggests ketamine's effects on these two vital physiologic areas is of limited clinical significance provided that ventilation is controlled and there are no increases in PaC02,which would secondarily increase PVR and ICP.

There are a limited number of reports regarding the use of a ketamine infusion for sedation of the PICU patient.27·28 Hartvig et al.28 used a ketamine infusion to provide sedation and analgesia following cardiac surgery in 10 pediatric patients who ranged in age from 1 week to 30 months. Five patients received ketamine at 1 mg/kg per hour, and five received a dose of 2 mg/kg per hour. Supplemental doses of midazolam were administered as needed. The two groups had similar and acceptable levels of sedation. No adverse effects were noted.

A final caveat concerning ketamine is that it is commercially available in three different concentrations: 100 mg/mL, 50 mg/mL, and 10 mg/mL. Therefore, inadvertent overdosing or underdosing may occur. Although it should not be considered a first-line agent for sedation in the PICU patient during mechanical ventilation, ketamine may be useful in various PICU scenarios including patients who develop adverse cardiovascular effects with opioids or benzodiazepines, sedation with the preservation of spontaneous ventilation when using noninvasive ventilation techniques, patients with status asthmaticus in whom the release of endogenous catecholamines following ketamine administration may provide some therapeutic effect, low-dose administration in an attempt to delay or prevent the development of tolerance to opioids related to its effects at the NMDA receptor, and during the performance of brief, painful invasive procedures in the spontaneously breathing patient.

Propofol

Propofol is a sedative/amnestic agent with no analgesic properties. Its chemical structure (alkyl phenol) is distinct from that of other intravenous anesthetic agents, including the barbiturates and etomidate, although its mechanism of action is similar, acting through the GABA system. Propfol was initially introduced into anesthesia practice for the induction and maintenance of anesthesia, but its rapid onset, rapid recovery time, and lack of active metabolites led to its evaluation as an agent for ICU sedation.

Compared with midazolam for sedation in adult patients, propofol provides shorter recovery times, improves titration efficiency, reduces post-hypnotic obtundation, and allows for faster weaning from mechanical ventilation.29 Like the barbiturates and etomidate, propofol decreases the cerebral metabolic rate of oxygen, leading to reflex cerebral vasoconstriction and lowering of ICP.

Propofol's cardiovascular effects are similar to those of the barbiturates, with the potential for hypotension from peripheral vasodilation and negative inotropic properties. These effects are exaggerated following rapid bolus administration and in patients with compromised cardiovascular function. Propofol also may augment central vagal tone, leading to bradycardia and conduction disturbances. Neurological manifestations include opisthotonic posturing, myoclonic movements (especially in children), and seizure-like activity. Movement disorders including myoclonus and posturing have been attributed to propofol's antagonism at glycine receptors in subcortical structures. Although there are anecdotal reports with a temporal relationship between propofol and clinical seizure activity, no formal evidence exists to prove this association.

In a study evaluating the effects of propofol and thiopental on the surface electroencephalograms of 20 patients undergoing temporal lobe surgery, no difference in the rate of discharge or extension of the irritative zone was seen.30 Propofol remains an effective agent in various algorithms for treating patients with refractory status epilepticus.31

Despite its benefits and efficacy, the routine use of propofol for sedation in the PICU is not advocated because of reports of what has been termed the "propofol infusion syndrome," which was first reported in a cohort of five PICU patients by Parke et al.32 in 1992. The clinical signs and symptoms include metabolic acidosis, bradycardia, dysrhythmias, rhabdomyolysis, and fatal cardiac failure. Bray et al.33 reviewed the clinical course of 18 children with suspected propofol infusion syndrome. Risk factors included propofol administration for more than 48 hours, infusion rates greater than 4 mg/kg hour, and age. Thirteen of the 1 8 patients were 4 or younger, and only 1 of 18 was older than 10.

An animal model has provided some insight into a potential mechanism of the propofol infusion syndrome. In guinea pig cardiomyocytes, propofol has been shown to disrupt mitochondrial function.34 Clinical work has further confirmed this potential mechanism; biochemical analysis of a 2-year-old boy who developed the propofol infusion syndrome revealed an increase in the plasma concentration of C5-acylcarnitine, indicative of inhibition of mitochondrial function at complex ? of the respiratory chain, and an increased plasma concentration of malonyl -carnitine.35 This latter compound inhibits the transport protein necessary for the movement of long-chain fatty acids into mitochondria. Hemofiltration was used in the treatment of this patient, which resulted in reversal of the clinical manifestations and recovery of the patient.

Despite these concerns, the contention that we should abandon use of propofol for PICU sedation is not embraced universally by the medical community. There are reports in the literature demonstrating the safe and effective use of propofol for sedation of small cohorts of PICU patients. The decision to use propofol or not must be made in the context of a "Dear Healthcare Provider" letter issued in March 2001 by AstraZeneca, manufacturer of Diprivan® propofol injectable infusion. The letter reported the results of a clinical trial that compared propofol (either a 1% or 2% solution) to other agents used for PICU sedation. During the study period and the 28 day follow-up, there were 12 deaths (11%) in the 2% propofol group, nine deaths (8%) in the 1% propofol group and four deaths (4%) in the standard sedation group. Although formal review did not show a specific pattern to the deaths, the company issued a letter with the following statement: "Propofol is currently not approved for sedation in pediatric ICU patients in the United States and should not be used for this purpose."

Although these concerns have eliminated the prolonged use of propofol for sedation in our PICU regardless of the dose, we use short-term (6 to 12 hours) infusions of propofol to transition from agents such as fentanyl and midazolam, which display context-sensitive halflives, to allow for more rapid awakening for tracheal extubation. In specific circumstances, propofol may be used as a therapeutic tool in the treatment of refractory status epilepticus or increased ICP. In such cases, intermittent analysis of acid-base status and creatinine Phosphokinase levels (evaluating for rhabdomyolysis) is suggested. If a base deficit with an increasing serum lactate is noted, immediate discontinuation of propofol is recommended. Additionally, propofol is an effective agent in the provision of procedural sedation. Issues regarding the propofol infusion syndrome should not limit its use in the operating room arena or for procedural sedation.

An additional problem with propofol is the lipid emulsion used as diluent. This is the same preparation that is used in Intralipid for parenteral alimentation solutions. Problems with the lipid component include anaphylactoid reactions (more likely in patients with a history of egg allergy), pain on injection, and elevated triglyceride levels with prolonged infusions; it also is a viable medium to support the growth of bacteria. The lipid content of propofol needs be considered when calculating the patient's daily caloric intake. A propofol infusion of 2 mg/kg per hour provides approximately 0.5 gm/kg per day of fat. Although not in widespread clinical use, there are preliminary trials evaluating a 2% solution of propofol (twice the amount of propofol with the same amount of lipid per milliliter as the 1% solution). Although the 2% propofol solution is less likely to cause hypertriglyceridemia, there may be alterations in propofol's bioavailability, as there may be an increased dose requirement, and more patients show inadequate sedation with the 2% solution compared with the 1% solution.36

Barbiturates

The classification of barbiturates can be based on their chemical structure or their duration of activity. The chemical structure varies in that it can contain a sulfur atom (thiobarbiturates such as thiamylal and thiopental) or an oxygen atom (methohexital) in their ring structure. Short acting agents such as methohexital, thiopental, and thiamylal have a clinical duration of action of 5 to 10 minutes. Long acting agents with halflives of 6 to 12 hours include pentobarbital and phénobarbital. The clinical effects of the short-acting agents dissipate rapidly due to their redistribution, although their hepatic metabolism may take hours. The short-acting barbiturates are used most commonly by intravenous bolus administration for brief procedures such as anesthetic induction and endotracheal intubation.

The barbiturates' effects on cardiorespiratory function are similar to those of propofol. In healthy patients, sedative doses have limited effects on cardiovascular function, respiratory drive, and airway protective reflexes, while larger doses result in respiratory depression, apnea, and hypotension, especially in patients with co-existing myocardial dysfunction. Hypotension results from both peripheral vasodilation and a direct negative inotropic effect. These agents should be used cautiously, if at all, in patients with cardiovascular dysfunction.

The barbiturates' greatest role in the PICU is in the treatment of increased ICP or refractory status epilepticus. These agents decrease the cerebral metabolic rate of oxygen, which results in reflex cerebral vasoconstriction, a decrease in cerebral blood volume followed by a decrease of ICP.

The role of barbiturates in PICU sedation is as a second-line agent when first-line agents, either alone or in combination, fail or result in untoward side effects. Despite the wealth of information with some of the other agents reviewed in this article, there is only limited published information regarding the use of pentobarbital infusions for sedation in the PICU setting. A retrospective report described the use of pentobarbital for sedation during mechanical ventilation in 50 infants and children ranging in age from 1 month to 14 years.37 Pentobarbital was used when sedation was inadequate despite the combination of a benzodiazepine (midazolam in doses of 0.4 mg/kg per hour) and an opioid (either fentanyl in doses of 10 µg/kg per hour or morphine in doses of 100 µg/kg per hour). With the administration of pentobarbital, effective sedation was achieved, and the other agents (benzodiazepine and opioid) were weaned. Additionally, there was no longer a need for direct-acting vasodilators to treat hypertension, and neuromuscular blocking agents were able to be discontinued. The cohort also included seven nonneonatal ECMO patients in whom pentobarbital provided effective sedation. Six of the 36 patients who had received pentobarbital for more than 4 days manifested signs and symptoms of withdrawal.

Another retrospective report outlined a contrary opinion in a cohort of eight PICU patients.38 Although pentobarbital provided effective sedation and allowed the discontinuation of neuromuscular blocking agents, the authors noted adverse effects in five of the eight (62.5%), including blood pressure instability, oversedation, and withdrawal phenomena. These adverse effects led to discontinuation of the drug in two of the patients.

An additional problem with pentobarbital is that the barbiturate solution is alkaline, leading to incompatibilities with other medications and parenteral alimentation solutions, thereby necessitating a separate infusion site. Because the pH of the barbiturate solution is high, local erythema and thrombophlebitis can occur with subcutaneous infiltration. The barbiturates possess no analgesic properties and therefore should be used with an opioid in situations requiring analgesia.

α2-adrenergic agonists

A recent addition to the potential armamentarium for sedation in the PICU patient is dexmedetomidine, an ^-adrenergic agonist. The sedative effects of the a2-adrenergic agonists are mediated via stimulation of central parasympathetic outflow and inhibition of sympathetic outflow from the brainstem. Decreased noradrenergic output from the locus cereleus allows for increased firing of inhibitory neurons, including the GABA system, resulting in sedation and anxiolysis. This effect is similar to that which occurs during non-REM sleep and is distinct from other agents commonly used for ICU sedation (eg, benzodiazepines, barbiturates, propofol). The lack of non-REM sleep with the prolonged use of other sedative agents is one of the mechanisms that is postulated to result in delirium.

The α2-adrenergic agonists also provide some degree of analgesia through the regulation of substance P release, resulting in primary analgesic effects as well as potentiation of opioid-induced analgesia. Dexmedetomidine has an affinity 8 times that of Clonidine for the a2-adrenergic receptor, a differential a? to ot2 agonism of 1:1,600, and a half-life of 2 hours, thereby allowing its titration by intravenous administration. Dexmedetomidine is approved by the FDA for short-term (24 hours or less) sedation of adult patients during mechanical ventilation. When compared with placebo, adult patients who received dexmedetomidine for sedation during mechanical ventilation following cardiac and general surgical procedures required 80% less midazolam and 50% less morphine.39

To date, there is only one prospective trial evaluating dexmedetomidine in pediatric patients requiring mechanical ventilation.40 Low-dose dexmedetomidine (0.25 pg/kg per hour) provided a level of sedation that was equivalent to midazolam at 0.22 mg/kg per hour, while a higher dose of dexmedetomidine (0.5 pg/kg per hour) was more effective than midazolam. The quality of sedation was assessed by noting the need for supplemental morphine and by objective sedation scores.

Dexmedetomidine was somewhat less effective in patients younger than 6 to 12 months; five of the six patients who exhibited inadequate sedation during dexmedetomidine use were younger than 12 months. The only noted adverse effect was bradycardia in one patient receiving dexmedetomidine who was also receiving digoxin.

Dexmedetomidine can have deleterious effects on ventilatory and cardiovascular function. Belleville et al.41 noted a depression of the slope of the CO2 response curve, a decrease in minute ventilation at an end-tidal carbon dioxide concentration of 55 mmHg, and episodes of an irregular breathing pattern with periods of apnea following a bolus dose of 2 pg/kg to adult volunteers. When dexmedetomidine was used during the postoperative period, 18 of 66 patients experienced adverse hemodynamic effects including hypotension (mean arterial pressure less than 60 mmHg, or a greater than 30% decrease from baseline) or bradycardia (heart rate less than 50 beats per minute).39 These hemodynamic effects occurred during the loading dose in 1 1 of the 18 patients.

SUMMARY

Various clinical situations may arise in the PICU that necessitate the use of sedation, analgesia, or both. Although there is a large clinical experience with midazolam in the PICU population and it remains the most commonly used benzodiazepine in this setting, lorazepam may provide an effective alternative, with a longer half-life and more predictable pharmacokinetics without the concern of active metabolites. However, there are limited reports regarding its use in the PICU population, and concerns exist regarding the potential for toxicity related to its diluent, propylene glycol. Although the synthetic opioid fentanyl frequently is chosen for use in the PICU setting because of its hemodynamic stability, preliminary data suggest morphine may have a slower development of tolerance and may cause fewer withdrawal symptoms than fentanyl. Morphine's safety profile includes longterm follow-up studies that have demonstrated no adverse central nervous system developmental effects from its use in neonates and infants. In the critically ill infant at risk following surgery for congenital heart disease, clinical experience supports the use of the synthetic opioids, given their ability to modulate PVR and prevent pulmonary hypertensive crisis.

Alternatives to the benzodiazepines and opioids include ketamine, pentobarbital, or dexmedetomidine. Ketamine may be useful for patients with hemodynamic instability or airway reactivity. There are limited reports regarding the use of pentobarbital in the PICU, with one study raising concerns of a high incidence of adverse effects associated with its use. Propofol has gained great favor in the adult population as a means of providing deep sedation while allowing for rapid awakening; however, its routine use is not recommended because of its potential association with "propofol infusion syndrome." As the pediatric experience increases, it appears that there will be a role for newer agents such as dexmedetomidine.

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TABLE.

Agents for PICU Sedation and Analgesia

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