The COMFORT scale

The COMFORT scale is a subjective physiologic and behavioral scoring system that requires no disturbance of the patient and incorporates six behavioral and two physiologic measures ( Table 1 ). A bedside nurse using the tool observes a patient for 2 minutes and scores the patient on five behavioral items: alertness, degree of calmness or agitation, respiratory response, physical movement, and facial expression. The nurse also observes and records data obtained from the cardiorespiratory monitor (heart rate and blood pressure). The readings are rated and compared with the frequency of elevations above or below the values for the patient’s vital signs recorded during the previous 12 to 24 hours. At the end of the 2-minute period, the nurse assesses the patient’s muscle tone in relation to normal muscle tone for that child by flexing and extending a noninstrumented extremity (such as an elbow or knee without an intravenous or arterial line). Marx and colleagues determined the target range for the COMFORT scale score to be 17 to 26. Patients who have scores between 17 and 26 are considered optimally sedated, defined as “somnolent, responsive to the environment but untroubled by it, (with) no excessive movement.” The investigators determined the target range by comparing COMFORT scale readings to a pediatric intensivist–assigned sedation adequacy category. The COMFORT scale was more consistent than the assessment of the intensivist and between intensivists. The COMFORT scale is intended for use as an assessment tool during routine nursing care, not to evaluate response to procedural stress. In addition, the COMFORT scale cannot be used during administration of neuromuscular blocking agents (NMBAs).

Bedside staff should frequently identify and reassess the desired level of sedation for individuals, adjusting the target level according to the underlying pathophysiologic processes and the need for diagnostic and therapeutic procedures. They should titrate doses and infusion rates of sedative agents in light of these fluctuating requirements to ensure that the desired level of sedation is provided.

The bispectral index

Given the difficulties of assessment of sedation during deep levels of sedation and especially during the administration of NMBAs, objective measures of sedation using neurophysiologic techniques have been investigated. The bispectral index (BIS) is a measure of the processed electroencephalogram (EEG) using a digital scale ranging from 100 (completely awake) to 0 (isoelectric EEG). In general, a BIS score of 40 to 60 indicates hypnosis (unconsciousness), whereas values greater than 65 and less than 35 signify possible awareness and excessive sedation, respectively. Unfortunately, correlation between BIS and COMFORT scores during prolonged PICU admission are less than optimal and the impact of concomitant administration of multiple sedative and analgesic agents and variability on physiologic parameters remains poorly defined . The BIS does not accurately predict level of sedation in children under the age of 5 years. At present, there is insufficient evidence to support the routine use of BIS monitors in PICUs .

The FLACC scale

Pain is a subjective experience and patient report of pain is the most reliable indicator and considered the gold standard for guiding analgesic therapy. In preverbal infants and children, however, including those below age 3, behavioral observational scales are the primary tools for pain assessment. The FLACC scale is a behavioral tool validated for assessment of postoperative pain in children between the ages of 2 months and 7 years ( Table 2 ) . The acronym, FLACC, represents five categories: f ace, l egs, a ctivity, c ry, and c onsolability. Responses in each category are scored between 0 and 2, for a maximum total score of 10. Analgesic agents generally are administered for a score of 4 or greater. Pain assessment in patients under age 3 is particularly challenging. In all cases wherein communication skills are impaired, consideration must be given to the underlying pathophysiologic states and interventions that are associated with pain. In addition, reports of pain from a patient’s family and other caregivers should be integrated into the assessment.

Faces scales

In children between ages 3 and 12, self-reporting techniques, such as faces scales, may be used. These scales use photographs or drawings of faces depicting a range of comfort/discomfort graded in increasing intensity between “no pain” and “worst pain possible” . When presented with a faces scale, children are asked to point to the face that best shows how much pain they currently are experiencing. Faces scales, unlike other self-report measures, are believed easily understood by children in that they do not require the child to translate their pain experience into a numeric value.

Verbal rating, visual analog, and numeric rating scales

Older children usually can use unidimensional tools, such as the verbal rating scale, visual analog scale (VAS), and numeric rating scale (NRS), in the same way as adult patients. The NRS is a 0 to 10 scale wherein a patient chooses a number that describes the pain, with 10 representing the worst possible pain. The NRS has been validated against the VAS and, because it can be completed by writing or speaking, has potential advantages in critically ill patients.

Benzodiazepines

The benzodiazepines, midazolam (Versed) and lorazepam (Ativan), are the drugs used most commonly for sedation in PICUs. They produce sedation by binding to the α subunit of the γ-aminobutyric acid (GABA) receptor in the CNS. This interaction causes an influx of chloride ions into the nerve cell, hyperpolarizing the neuron and rendering it relatively more refractory to depolarization. The benzodiazepines produce amnesia, sedation, and anxiolysis but do not have analgesic properties. Benzodiazepines may cause hypotension as a result of relaxation of vascular smooth muscle and cardiac depression.

Midazolam is a parenteral benzodiazepine with sedative, amnestic, anxiolytic, and anticonvulsant properties. Midazolam has a faster onset and shorter duration of action than other benzodiazepines, such as diazepam (Valium) and lorazepam. Midazolam is water soluble in the commercially prepared formulation but becomes lipid soluble at physiologic pH and can cross the blood-brain barrier rapidly. It is metabolized in the liver by the cytochrome P450 system and its chief metabolite is 1-hydroxymidazolam. The latter compound has significant pharmacologic activity and may accumulate in patients who have renal failure. 1-Hydroxymidazolam ultimately is conjugated to the glucuronide form, and this compound has only minimal biologic activity. The metabolites of midazolam are excreted in the urine.

Midazolam has a relatively rapid onset and offset due to redistribution after a single dose. The clinical onset of sedation is approximately 1 to 1.5 minutes, with a peak effect within 5 minutes. The elimination half-life (t _1/2β ) of midazolam in children is similar to that in adults, approximately 2 to 2.5 hours. The t _1/2β is prolonged to approximately 6 hours in neonates because of slow clearance, probably the result of delayed development of hepatic microsomal oxidative enzymes. By contrast, the t _1/2β is 10 to 20 hours for lorazepam and 20 to 70 hours for diazepam. As a result of its prolonged t _1/2β , diazepam is used infrequently in PICUs. The t _1/2β of midazolam and its primary metabolite are prolonged in patients who have renal failure and congestive heart failure. In addition, the t _1/2β of midazolam increases during prolonged infusion or repeated dosing. This phenomenon is known as the context-sensitive half-life (ie, the t _1/2β increases in the context of prolonged administration) and is an important concept in drug dosing in PICUs (discussed later).

The sedative potency of midazolam is approximately half that of lorazepam and three to four times that of diazepam. Midazolam can be dosed intermittently, as continuous infusion, or as a combination. The optimal dosing varies from patient to patient according to clinical circumstances, age of the patient, co-existing diseases, and other medications concurrently administered. Data for infants up to 6 months old are limited. The initial intravenous dose for children 6 months to 5 years is 0.05 to 0.10 mg/kg ( Table 3 ). Doses up to 0.5 mg/kg may be needed to achieve adequate sedation. For children aged 6 to 12 the initial dose is 0.025 to 0.05 mg/kg. The total dose may be as high as 0.4 mg/kg, generally not exceeding 10 mg. A continuous infusion usually is preceded by a loading dose to achieve a steady state concentration more rapidly. The initial doses above may be followed by an infusion at a rate of 0.025 to 0.05 mg/kg per hour. The infusion rate then is titrated to effect. The infusion rate should be diminished in the presence of excessive somnolence (ie, no eye opening with verbal and tactile stimulation) and hypotension. Alternatively children receiving long-term dosing (intermittent or continuous) may develop tolerance to midazolam, resulting in the need to increase the infusion rate. These phenomena may account for substantial intrapatient and interpatient variability in dosing and underscore the need for regular, objective assessment of the degree of sedation (ie, use of scoring tools).

The most serious adverse events associated with midazolam in children include hypotension and, in nonmechanically ventilated patients, hypoventilation, decreased oxygen saturation, and apnea.

Lorazepam is an intermediate-acting benzodiazepine that is relatively water-soluble and is metabolized by glucuronyl transferase to pharmacologically inactive metabolites (unlike midazolam and diazepam). Because lorazepam has a slower entry into the CNS, its onset is slower than midazolam and diazepam. Significantly less published information exists regarding the pharmacology of lorazepam in infants and children than for midazolam. No studies compare the two agents in the PICU setting.

In critically ill adults, lorazepam has advantages over midazolam. Pohlman and colleagues compared the two drugs for sedation in 20 adult ICU patients. Adequate sedation was achieved with mean infusion rates of lorazepam (0.06 mg/kg/h) and midazolam (0.15 mg/kg/h). Fewer infusion rate adjustments were required for lorazepam and the mean time to return to baseline mental status was shorter with lorazepam after discontinuation of therapy (261 minutes for lorazepam versus 1815 minutes for midazolam). Swart and colleagues also reported that the desired level of sedation was easier to achieve with lorazepam than with midazloam in critically ill adults; they found no difference in recovery 24 hours after discontinuation of infusions between the two agents. The Society of Critical Care Medicine deemed lorazepam the preferred agent for long-term sedation (>24 hours) in adult ICUs, in part because the context-sensitive half-life of midazolam was markedly longer than that of lorazepam . The relative time to offset of midazolam compared with lorazepam in the ICU setting remains controversial, however. Barr and colleagues performed a study to characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam administered as continuous intravenous infusions for postoperative sedation of surgical ICU patients. The investigators found significant delays in emergence from sedation with lorazepam as compared with midazolam when administered for ICU sedation.

The t _1/2β plays a minor role in determining the time-course of a single bolus dose of a sedative drug because termination of action is dependent on distribution out of the central compartment. The redistribution half-life (t _1/2α ) primarily determines the clinical offset of a drug after single dose administration. In traditional pharmacokinetic modeling, the t _1/2β was believed better predict clinical offset of a drug given as a continuous infusion. Recent work, however, has shown that the relationship between duration of clinical effect of sedatives and traditionally measured t _1/2β does not hold.

When an infusion is delivered over several hours, days, or even weeks (as can be the case in an ICU) and then discontinued, the context-sensitive half-time predicts the rapidity with which the drug concentration declines better than the t _1/2β . Although derived from traditional rate constants, the context-sensitive half-times depend largely on the duration of infusion. That is, the context (or duration) of the infusion directly influences the pharmacokinetic properties of the drug being administered. The context-sensitive half-time represents the time for the drug plasma concentration to decrease by 50% after the cessation of a prolonged continuous infusion. The protracted offset of lorazepam and midazolam after repeated dosing or continuous infusion compared with their reported t _1/2β suggests significant increases in their context-sensitive half-lives ( Fig. 1 ).

Context-sensitive half-times for lorazepam, midazolam, diazepam, and propofol. The context-sensitive half-times increase with the duration of drug infusion. ( From Young C, Knudsen N, Hilton A, et al. Sedation in the intensive care unit. Crit Care Med 2000;28:854–66; with permission.)

The delirium-inducing effect and the potential toxicity of lorazepam may prompt a reconsideration of the recommendation of its use as a first-line drug. The association between cognitive impairment and medication use (including routinely administered agents, such as benzodiazepines and opioids) is widely appreciated, but recently a link to delirium has been recognized. Establishing causality is difficult because these drugs often are given to treat pre-existing behaviors that may result from delirium. In an attempt to clarify this association, Pandharipande and colleagues evaluated 11 covariates to determine factors that may contribute to the development of delirium. They identified lorazepam as an independent risk factor for delirium (odds ratio 1.2; 95% CI, 1.1 to 1.4; P = .003). In this study, patients receiving more than 20 mg of lorazepam over 24 hours nearly always developed delirium. Too few patients were treated with midazolam to allow for a rigorous evaluation of its deliriogenic potential. These provocative data suggest that the medications traditionally used to calm and comfort patients actually may lead to impaired cognitive function and worse outcomes.

Another adverse effect of intravenous lorazepam is accumulation and potential toxicity from propylene glycol—a diluent used to facilitate drug solubility for parenteral administration . Toxicity from propylene glycol and its metabolites, lactate and pyruvate (generated by hepatic alcohol dehydrogenase), include hyperosmolarity, cellular toxicity, metabolic acidosis, and acute tubular necrosis. In addition to long-term and high-dose lorazepam therapy, other identified risk factors for propylene glycol toxicity include renal and hepatic derangement, pregnancy, age less than 4 years, and treatment with metronidazole. Monitoring propylene glycol serum concentrations is impractical in most institutions because these assays are rarely available and results from referral laboratories often are delayed. Data suggest that the serum osmol gap may be a reliable surrogate for propylene glycol concentrations, with an osmol gap greater than 10 to 15 indicating significant accumulation. Hemodialysis effectively removes propylene glycol and corrects hyperosmolar states, but discontinuing the parenteral formulation of lorazepam generally is all that is required .

Propofol

Like the benzodiazepines, propofol produces sedation and amnesia by interacting with the GABA receptor and may cause hypotension resulting from relaxation of vascular smooth muscle and direct cardiac depression. Its chemical structure (alkylphenol) is distinct from other sedative agents. Propofol has a rapid onset and offset even after prolonged infusion ( Fig. 2 ). Compared with midazolam in adult ICU patients, propofol is associated with shorter recovery times, improved titratability, and more rapid weaning from mechanical ventilation . Because of its desirable pharmacologic properties, propofol became used widely in pediatric intensive care during the 1990s. A disturbing report was published in 1992 describing deaths in mechanically ventilated children attributable to “propofol infusion syndrome” . Subsequent reports further described the features of this syndrome, including metabolic acidosis, bradycardia, arrhythmias, rhabdomyolysis, and cardiac failure . Risk factors include propofol administration for more than 48 hours and infusion rates exceeding 4 mg/kg per hour (67 μg/kg/min). In 2001, a “Dear Health Care Provider” letter was circulated by AstraZeneca, the manufacturer of propofol (Diprivan), emphasizing, “propofol is currently not approved for sedation in pediatric ICU patients in the United States and should not be used for this purpose.” This letter was predicated on the results of a clinical trial comparing propofol (1% or 2% solution) to other “standard agents” used for sedation during mechanical ventilation; the trial was terminated because of an excess mortality rate in the patients receiving propofol. Subsequent studies have suggested that the mechanism for propofol toxicity includes disruption of mitochondrial fatty acid oxidation and energy production . An additional problem associated with propofol administration is the diluent, which is a lipid emulsion similar to the intralipid solution used for intravenous nutrition. Elevated serum triglyceride concentrations may result from the concomitant administration of propofol and intralipid.

Context-sensitive half-time of propofol.

Despite the potential toxicity and medical-legal liability associated with the use of propofol in PICUs, its use is advocated under limited circumstances. A study published in 2002 reviewed the use of propofol in 142 PICU patients who received an infusion of up to 50 μg/kg per hour supplemented by intermittent doses of 1 mg/kg as needed up to once per hour . Propofol was not associated with metabolic acidosis or circulatory depression in this retrospective review, and the investigators speculated that propofol infusion is safe in dosages up to 67 μg/kg per minute. At present, the role of propofol in PICUs remains undefined. It may be prudent to limit the use of propofol infusions for PICU sedation to 12 to 24 hours at a dosage of 50 to 100 μg/kg per hour for specific indications. These include postoperative sedation for 2 to 4 hours to facilitate offset of NMB from muscle relaxants administered in an operating room, normalization of temperature in patients who have hypothermia induced in an operating room, and observation of cessation of bleeding from indwelling chest tubes and surgical drains before tracheal extubation. When infusions exceed 4 hours, laboratory surveillance should be performed to promptly identify unexplained metabolic acidosis and hypertriglyceridemia, in which case the drug should be discontinued immediately. In the context of LTR, propofol may be used to provide sedation pending tracheal extubation in patients having received prolonged infusions of benzodiazepines and opioids with long context-sensitive half-times (ie, to transition patients to spontaneous breathing and readiness for extubation after discontinuation of [or reduction in dosing of] these longer-acting agents). It is the opinion of this author that propofol should not be used as a primary sedative agent during mechanical ventilation of patients after LTR except under this specific circumstance.

Barbiturates and adjuvant sedative drugs

Like the benzodiazepines and propofol, barbiturates produce sedation/hypnosis, lack analgesic properties, have anticonvulsant effects, and may cause hypotension. Barbiturates, primarily pentobarbital, are used in PICUs primarily in the management of refractory status epilepticus and elevated intracranial pressure. The factors limiting the use of pentobarbital and other barbiturates include protracted offset (especially after prolonged infusion), hypotension, and its alkaline pH, precluding co-infusion of other medications and parenteral nutrition solutions through the same intravenous lumen. Pentobarbital is used as a second-line agent when benzodiazepines fail to produce adequate sedation. A retrospective report described the use of pentobarbital for sedation during mechanical ventilation in 50 patients between the ages 1 month and 14 years . The investigator reported effective sedation and subsequent weaning of benzodiazepines and opioids and discontinuation of muscle relaxants. Six of the 36 patients who had received pentobarbital for more than 4 days manifested signs of withdrawal. A high incidence of adverse effects was reported in a review of eight PICU patients receiving pentobarbital, including circulatory depression, oversedation, and withdrawal phenomena .

Chloral hydrate is a sedative agent that is administered enterally and is considered safe and generally effective for short-term use. Repetitive dosing is of concern because of accumulation of the metabolites, trichloroethanol and trichloroacetic acid, which may produce excessive CNS depression, predispose newborns to hyperbilirubinemia, decrease albumin binding of bilirubin, and contribute to metabolic acidosis . Rarely, tachyarrhythmias may occur after repeated dosing of chloral hydrate . Other adjuvant drugs used for pediatric sedation include antihistamines (eg, diphenhydramine [Benadryl] and promethazine [Phenergan]). In a study comparing the efficacy of an intravenous infusion of midazolam (0.05 to 0.3 mg/kg/h) to a combination of enteral chloral hydrate (25 to 50 mg/kg every 6 hours) and promethazine (0.5 to 1.0 mg/kg every 6 hours) in PICUs, the latter was found more effective . In general, chloral hydrate and antihistamines are used in combination with benzodiazepines and opioids in mechanically ventilated infants and children who are refractory to these primary agents.

Benzodiazepines

The benzodiazepines, midazolam (Versed) and lorazepam (Ativan), are the drugs used most commonly for sedation in PICUs. They produce sedation by binding to the α subunit of the γ-aminobutyric acid (GABA) receptor in the CNS. This interaction causes an influx of chloride ions into the nerve cell, hyperpolarizing the neuron and rendering it relatively more refractory to depolarization. The benzodiazepines produce amnesia, sedation, and anxiolysis but do not have analgesic properties. Benzodiazepines may cause hypotension as a result of relaxation of vascular smooth muscle and cardiac depression.

Midazolam is a parenteral benzodiazepine with sedative, amnestic, anxiolytic, and anticonvulsant properties. Midazolam has a faster onset and shorter duration of action than other benzodiazepines, such as diazepam (Valium) and lorazepam. Midazolam is water soluble in the commercially prepared formulation but becomes lipid soluble at physiologic pH and can cross the blood-brain barrier rapidly. It is metabolized in the liver by the cytochrome P450 system and its chief metabolite is 1-hydroxymidazolam. The latter compound has significant pharmacologic activity and may accumulate in patients who have renal failure. 1-Hydroxymidazolam ultimately is conjugated to the glucuronide form, and this compound has only minimal biologic activity. The metabolites of midazolam are excreted in the urine.

Midazolam has a relatively rapid onset and offset due to redistribution after a single dose. The clinical onset of sedation is approximately 1 to 1.5 minutes, with a peak effect within 5 minutes. The elimination half-life (t _1/2β ) of midazolam in children is similar to that in adults, approximately 2 to 2.5 hours. The t _1/2β is prolonged to approximately 6 hours in neonates because of slow clearance, probably the result of delayed development of hepatic microsomal oxidative enzymes. By contrast, the t _1/2β is 10 to 20 hours for lorazepam and 20 to 70 hours for diazepam. As a result of its prolonged t _1/2β , diazepam is used infrequently in PICUs. The t _1/2β of midazolam and its primary metabolite are prolonged in patients who have renal failure and congestive heart failure. In addition, the t _1/2β of midazolam increases during prolonged infusion or repeated dosing. This phenomenon is known as the context-sensitive half-life (ie, the t _1/2β increases in the context of prolonged administration) and is an important concept in drug dosing in PICUs (discussed later).

The sedative potency of midazolam is approximately half that of lorazepam and three to four times that of diazepam. Midazolam can be dosed intermittently, as continuous infusion, or as a combination. The optimal dosing varies from patient to patient according to clinical circumstances, age of the patient, co-existing diseases, and other medications concurrently administered. Data for infants up to 6 months old are limited. The initial intravenous dose for children 6 months to 5 years is 0.05 to 0.10 mg/kg ( Table 3 ). Doses up to 0.5 mg/kg may be needed to achieve adequate sedation. For children aged 6 to 12 the initial dose is 0.025 to 0.05 mg/kg. The total dose may be as high as 0.4 mg/kg, generally not exceeding 10 mg. A continuous infusion usually is preceded by a loading dose to achieve a steady state concentration more rapidly. The initial doses above may be followed by an infusion at a rate of 0.025 to 0.05 mg/kg per hour. The infusion rate then is titrated to effect. The infusion rate should be diminished in the presence of excessive somnolence (ie, no eye opening with verbal and tactile stimulation) and hypotension. Alternatively children receiving long-term dosing (intermittent or continuous) may develop tolerance to midazolam, resulting in the need to increase the infusion rate. These phenomena may account for substantial intrapatient and interpatient variability in dosing and underscore the need for regular, objective assessment of the degree of sedation (ie, use of scoring tools).

Table 3

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