Morphine

Morphine is an opiate, and its primary therapeutic actions are sedation and analgesia; anxiolysis and euphoria also may occur. These four therapeutic effects may be exploited to the benefit of the patient. These actions are mediated through the periaqueductal gray matter, the ventromedial medulla, and the spinal cord. The reduction of nociceptive reflexes occurs all over the body, even below a completely transected spinal cord. In addition to increasing the sensory threshold for pain, morphine may decrease the hurting aspect (or unpleasantness) of pain. A patient given morphine may say something such as, “I have just as much pain, but it doesn’t distress me as much.” It blunts most types and intensities of pain, although some forms of neuropathic pain are relatively resistant. The resulting analgesia may be potent enough to abolish diagnostic symptoms and signs. The sedative effects reduce higher cortical function, cause difficulty in concentration, and cause a sense of drowsiness and dream-filled sleep. Higher doses will cause a state of unconsciousness or coma. The rate of respiration is reduced with a resultant fall in minute ventilation despite an accompanying increase in depth of breathing. This effect is associated with a decreased responsiveness to carbon dioxide (CO₂) and is additive to the decreased CO₂ response seen during sleep. In some circumstances respiratory drive may be restricted to hypoxic stimulation of the carotid chemoreceptors; this is the most serious dose-related adverse effect of morphine. It can occur at doses used clinically for analgesia. In general, all opiates produce the same degree of respiratory depression when given in equipotent doses and for any given level of analgesia. Opioids do not have anticonvulsant properties, whereas meperidine (and its metabolite normeperidine) may lower the seizure threshold.

Another CNS effect of morphine is pupillary constriction due to a central effect on the oculomotor nucleus. Nausea results from stimulation of the chemotrigger zone; however, opioids also depress the vomiting center, so the final effect is unpredictable. Nausea and vomiting are much more frequent in ambulatory patients than in patients confined to a hospital bed. Stress-related endocrine responses can be modified by morphine. It decreases the release of several hormones including adrenocorticotropic hormone, antidiuretic hormone, prolactin, growth hormone, and epinephrine. The neuroendocrine stress response that is normally seen with trauma and surgery may be blunted. Itching may be caused by histamine release, but it also may be due to opiate receptor activation in the spinal cord.²²

Morphine’s effects on smooth muscle cause constipation. It reduces the intestinal propulsion activity through its central and peripheral effects. The central effects may be mediated by the vagus nerve. The direct smooth muscle relaxation and the increased local cholinergic transmission can be partly reversed by naloxone. This decreased motility is the basis of several over-the-counter antidiarrheal preparations including diphenoxylate, a μ-agonist that does not cross the blood-brain barrier and thus acts as a peripheral opioid agonist. Morphine also causes an increase in biliary tract tone, which may cause biliary colic, as well as increased tone in the bladder detrusor muscle and vesical sphincter. Urinary retention is common with opioids and occurs in 55% of children receiving spinally administered opioid and 20% receiving intravenous (IV) opioid.²³

Morphine has been studied extensively in term and preterm neonates. Glucuronidation is present in term babies and in many preterm ones. The half-life of morphine, however, is 2 hours in children, 6.5 hours in term neonates, and 9 hours in the preterm child because of reduced clearance. Volume of distribution did not vary with age.²⁴ Morphine causes histamine release and can cause peripheral vasodilatation. Infused at analgesic doses, it has little effect on the cardiovascular system, but skin flushing is not uncommon with rapid IV administration. The histamine-releasing potential should be considered in patients with asthma, especially during an acute exacerbation, and in patients with unstable cardiovascular systems for whom safer alternatives, such as fentanyl, exist.

Dosing recommendations in the ICU include a bolus dose of 0.05 to 0.1 mg/kg and an infusion of 0 to 30 μg/kg/h. Fifty percent of these doses should be used if the patient is younger than 3 months of age. The pharmacokinetics of various opiates is outlined in Table 123-4. All opiates are weak bases and are moderately ionized at pH 7.4. Oral morphine is effective but undergoes hepatic first-pass metabolism, which is variable among patients. The oral dose for acute pain is two to five times the IV dose, while with long-term use the oral dose is 1.5 to 2.5 times the IV dose.

Morphine is metabolized to morphine-3-glucuronide (M3G) and M6G in the liver. M3G is the major metabolite and has little morphine-like activity, although some research has suggested that M3G may be associated with an antinociceptive effect, accounting for failure of analgesia during long-term use.²⁵ In contrast, M6G is many times more potent than morphine itself.

Morphine undergoes significant first-pass hepatic metabolism, whereby after a single parenteral dose, only morphine is initially active. After a single dose by mouth (PO), both morphine and M6G are active. With long-term oral use, M6G accumulates until its analgesic effect is greater than that of morphine. A similar effect can be anticipated with long-term morphine infusion in the patient in the PICU. The glucuronides are excreted by the kidney, together with only a small amount of free morphine. Ninety percent of total urinary excretion occurs within 24 hours.

Tolerance, defined as an increase in the dose required to create the same response, is a potential problem with all opiates. Tolerance is mainly limited to the depressant actions of morphine, including analgesia, respiratory depression, anxiolysis, and drowsiness. Tolerance of morphine’s inhibition of bowel motility and pupillary constriction is minimal. The mechanism of tolerance appears to involve the degree and duration of both μ- and κ-receptor occupancy. It appears more rapidly after continuous infusion, and cross-tolerance to other opiates is common, although anecdotal evidence suggests that when opioids are switched, a dose reduction may be possible because cross-tolerance sometimes appears incomplete.²⁶ Receptor downregulation also may occur, as well as altered metabolism with an increased M3G/M6G ratio. Simultaneous blockade of N-methyl-D-aspartate receptors has been shown to be effective in reducing the development of tolerance.²⁷ Clinical tolerance appears uncommon with an exposure of less than 3 days, but after prolonged administration, doses 10 to 20 times that which would cause respiratory arrest in nontolerant patients may be tolerated.

Meperidine

Meperidine has one tenth the potency of morphine. Compared with other common opioids, meperidine has more CNS excitatory effects including tremors, muscle spasm, myoclonus, psychiatric changes, and seizures. These effects may be due to a central serotoninergic effect.²⁸ It is metabolized by the liver to normeperidine, which is twice as toxic as meperidine and has a longer half-life (15 hours). Normeperidine accumulation is enhanced in patients with an induced cytochrome P450 system. Meperidine has a shorter duration of action (2 to 3 hours) and has a more rapid onset because of its increased lipid solubility compared with morphine. Meperidine is unique among opioids because of its local anesthetic properties, which are capable of providing surgical spinal analgesia.²⁹ A small dose (0.125 to 0.25 mg/kg) of meperidine may be used to treat postoperative shivering.

Fentanyl

Fentanyl is one of the most commonly used opiates in the ICU. It is a synthetic derivative of meperidine without many of its unwanted side effects. It is a potent μ-agonist and is 100 times more potent than morphine. It has a rapid onset and cessation because of its high lipid solubility (Figure 123-2). Fentanyl may be administered by several routes, including IV, intramuscular (IM), transmucosal,³⁰ and subcutaneous (SC) when venous access is inadequate. Skeletal muscle rigidity (which can occur with all synthetic opiates) is well described in the literature. It is mediated through the CNS and is an idiopathic response usually associated with a large bolus dose (≥5 μg/kg). It improves with the administration of NMBAs and is reversible with naloxone. Fentanyl has limited cardiovascular effects. Moderate bradycardia is the most common hemodynamic effect. Fentanyl does not cause histamine release. Dosing in the ICU is either by bolus (1 to 2 μg/kg) or infusion (1 to 4 μg/kg/h with higher doses as tolerance develops). The short duration of effect of a single dose of fentanyl is not due to metabolism but rather to rapid redistribution. Maximum brain concentration after a bolus is achieved within 90 seconds. Then, because of rapid redistribution, the plasma level falls by 50% in 30 minutes, and the result is a clinical duration of effect of a single dose of approximately 30 minutes. Fentanyl then accumulates in fat, where it is stored and slowly released with a longer elimination half-life of about 4 hours (longer than morphine). Marked respiratory depression occurs within 120 seconds, and a single dose of 5 μg/kg will cause apnea in 50% of patients. Also, fentanyl is metabolized by the liver to nor-fentanyl and hydroxy fentanyl derivatives, both of which are thought to be inactive. In the operating room, high-dose fentanyl is commonly used for cardiac anesthesia and for anesthetization of other unstable patients. A loading dose of 50 μg/kg, followed by 0.5 μg/kg/min, will occupy all opioid receptors and produce a state of anesthesia. Many cases of awareness with patients under anesthesia have been documented, however, even when these high doses of fentanyl were used.

Figure 123–2 Initial fentanyl redistribution.

Sufentanil

Sufentanil is another synthetic opiate that has actions and therapeutic effects that are similar to those of fentanyl. It is five to ten times more potent than fentanyl and is the most potent opioid in clinical practice, posing a high risk of apnea with bolus administration. Dosing recommendations include bolus dosing of 0.2 to 0.4 μg/kg or an infusion of 0.2 to 1 μg/kg/h.

After a single bolus, sufentanil has kinetics similar to that of fentanyl with a short duration of clinical effect of approximately 30 minutes. However, with prolonged use, sufentanil accumulates less and is associated with a more rapid recovery after infusion because of its smaller volume of distribution and similar clearance. When the patient is receiving high doses of fentanyl, sufentanil is useful to conserve infusion volume.

Alfentanil

Alfentanil is another synthetic opiate with a rapid onset. It is five times less potent than fentanyl. Although it is less lipid soluble than fentanyl because of its low pKa (negative logarithm of the acid ionization constant), a higher percentage of the drug is present in the active unionized form, which results in a rapid onset. Because of its low volume of distribution, alfentanil has a short elimination half-life, which results in a short duration of action (5 to 10 minutes). Dosing regimens include boluses of 5 to 10 μg/kg if there is spontaneous respiration or 20 to 50 μg/kg if the patient’s lungs are ventilated. Alfentanil is a useful agent for preventing the hypertensive or increased intracranial pressure (ICP) response to intubation. As with all synthetic opiates, there is a risk of muscle rigidity with the higher dosing. Infusion dosing includes 0.2 to 1 μg/kg/min for patients receiving mechanical ventilation. Postinfusion recovery is quicker with alfentanil than with fentanyl. It is useful by infusion and safe to use in patients with hepatic or renal failure.

Codeine

Codeine has a chemical structure and effects that are similar to those of morphine and is commonly used as an oral medication for cough suppression or mild to moderate pain relief. A large part of its effects are due to the metabolism of codeine to morphine. Ten to twenty percent of patients lack a metabolic pathway to convert codeine to morphine, which results in an unpredictable effect. Dosing is 0.5 to 1 mg/kg. Constipation is a major adverse effect, and some patients report having a vague peculiar or unpleasant feeling when they take codeine. This drug can be habit-forming. It can be given orally, IM, or rectally. Rapid IV use may result in cardiovascular collapse. Rectally administered codeine has been shown to have as rapid an onset as IM codeine, but it yields lower peak levels in children.³¹ Codeine has been the analgesic of choice by neurosurgeons because of the belief that pupillary signs are maintained with use of this drug. Morphine has been shown to be a more effective analgesic, however, in patients with head injuries.³²

Remifentanil

Remifentanil is one of the newest synthetic opiates available. It was designed to be metabolized by plasma esterases to provide a short half-life. It is a potent μ-agonist with mild κ and δ effects. It is substantially more potent than fentanyl. It is supplied as a white lyophilized powder that contains glycine (it should not be used for epidural or spinal analgesia). The metabolism is by nonspecific esterases not affected by pseudocholinesterase deficiency. The metabolite, a weak μ-agonist, is excreted by the kidney. The kinetics of remifentanil is different from those of most opiates used in the ICU. It has a short half-life that is due to metabolism rather than to redistribution. Therefore remifentanil has what is known as a context-sensitive half-life. The elimination half-life for remifentanil is about 8 minutes. With an infusion of remifentanil, the half-life does not increase but remains constant. With opiates such as fentanyl and alfentanil (Figure 123-3), the clinical effect half-life increases with time until it reflects the elimination half-life of between 2 and 4 hours.

Figure 123–3 Context-sensitive half-life.

Kinetics reported for neonates are similar to those reported for adults. The continuous infusion rate depends on the degree of sedation/analgesia required (0.1 to 0.5 μg/kg/min for sedation; 0.75 to 2 μg/kg/min for balanced anesthesia; 4 μg/kg/min for loss of consciousness). Remifentanil has effects on the cardiovascular system that are similar to those of fentanyl. Remifentanil causes a mild bradycardia and a slight decrease in blood pressure,³³ which may be prevented with glycopyrrolate. No histamine release occurs. Remifentanil is a potent respiratory depressant. For spontaneous respiration, a low continuous infusion dose (without a bolus) should be used (0.1 μg/kg/min). Sedation can be effectively managed by continuous infusion without the need for a bolus because of the short half-life. An increase or decrease of infusion rate is rapidly reflected by a change in the degree of sedation, which is important to note. Most other opiate sedatives require bolus dosing to achieve a rapid change in effect. This type of dosing is neither appropriate nor needed for remifentanil.

Remifentanil has the usual opiate adverse effects; however, because of the short half-life, they have only brief clinical effect. Remifentanil may prove to be a safe and effective choice for PICU sedation in patients with severe renal or hepatic disease; however, the potential exists for glycine accumulation in patients with renal failure. It is an option only for those who require overnight ventilation or for those patients in whom a rapid awakening may be required for neurologic assessment. Remifentanil has been shown to reduce cerebral oxygen use and reduce cerebral blood flow if the CO₂ is maintained in a normal range.³⁴ Remifentanil is currently an expensive option and should not be considered for every patient. Also, because of its short duration, the postoperative patient may need an alternative analgesic after extubation. Rapid development of opiate tolerance with remifentanil has been described in healthy volunteers³⁵ and also when used in the ICU setting. This rapid tolerance has also been described in postoperative scoliosis patients³⁶; however, the increased morphine requirements described probably reflect the initial postoperative need to achieve an adequate morphine blood level rather than any acute tolerance.

Hydromorphone

Hydromorphone is a hydrogenated ketone of morphine. It is seven times as potent as morphine with a similar onset and duration of action. It causes less histamine release than morphine and may be used in patients who report pruritus due to morphine. Like morphine, hydromorphone undergoes hepatic metabolism; however, there are no active metabolites that are dependent on renal excretion. As such, it may be an effective alternative in patients with renal insufficiency or failure.

Tramadol

Tramadol is an opiate analgesic that relieves pain by binding to opiate receptors and by inhibiting the reuptake in the CNS and spinal cord of norepinephrine and serotonin, two pain-modifying neurotransmitters. Tramadol does not have antiinflammatory effects. Its use is indicated in cases of moderate to severe pain.³⁷ Despite being a narcotic-like agent, the Food and Drug Administration (FDA) has not classified tramadol as a controlled substance. Dosage (not FDA approved for patients younger than 16 years) is an initial oral dose of 1 to 2 mg/kg every 6 hours and should not exceed 6 mg/kg/day. An IV preparation is available outside of the United States. Patients with a creatinine clearance less than 30 mL/min should not receive a dose more often than once every 12 hours, with a maximum dose of 3 mg/kg/day. The dose for patients with cirrhosis or hepatic dysfunction is 1 mg/kg every 12 hours. Patients undergoing dialysis can receive their dose on the day of dialysis because only 7% of the drug is removed by the process. The adverse effects of tramadol most often involve the CNS and the GI tract. Patients may become dependent on tramadol. Abuse is possible, and it should not be given to opiate-dependent patients. Seizures have been seen in patients receiving high single oral doses of 10 mg/kg; this danger is even greater in patients with epilepsy and in anyone taking monoamine oxidase inhibitors and neuroleptic agents that lower the seizure threshold. Respiratory depression may occur if the recommended dosage is consistently exceeded or if another centrally acting depressant drug (e.g., alcohol) or an anesthetic is given concurrently. Because of the possibility of withdrawal symptoms, patients should not abruptly discontinue use of tramadol. Tramadol is not a useful drug for sedative action.

Table 123-5 provides conversion doses for some commonly used oral opiates. A summary of IV doses of different opiates is provided in Table 123-6.

Table 123–5 Dose Equivalents: Short Acting

Incidental Pain Syndromes in the Pediatric Intensive Care Unit

In addition to the techniques used to sedate children to facilitate their PICU management, many children will have pain related to their underlying condition. Many different options are available for controlling pain in the pediatric patient (Box 123-1). The pharmacologic management of pain should follow the traditional World Health Organization analgesic ladder, which begins with a nonopioid analgesic such as a nonsteroidal antiinflammatory drug or acetaminophen, followed by a weak opioid such as hydrocodone added to the nonopioid, and then moves on to a strong opioid such as morphine or hydromorphone as needed. When taken orally, a sustained-release preparation is often useful once the dose requirement has been determined. The dose requirement of a strong opioid is variable in the patient taking opioids for a prolonged period, and failure to appreciate this variability is a common cause for therapeutic failure. In addition, once a dose requirement is known, the analgesic should be given to preempt pain rather than to relieve pain as required. At each level of analgesic use, the addition of adjuvant medications should be considered. Adjuvant drugs fall into six groups: antidepressant, anticonvulsant, neuroleptic, steroid, stimulant, and local anesthetic. Of the tricyclic antidepressants, nortriptyline is available in a liquid form. The tricyclic antidepressants are indicated for neuropathic pain, particularly when the patient describes a burning pain. Also useful for neuropathic pain are the anticonvulsant agents gabapentin, pregabalin, and carbamazepine. These drugs often work best when the pain is described as shooting or lancinating. Neuropathic pain may result from tumor invasion, vincristine therapy, cytomegalovirus infection, or human immunodeficiency infection. Neuroleptic drugs, including chlorpromazine and trimeprazine, may be useful in the management of nausea, anxiety, and pruritus. Steroids benefit mood, inflammation, nausea, appetite, nerve swelling/entrapment, and vasculitis. When opioid sedation is interfering with quality of life, a stimulant such as an amphetamine may restore energy and alertness while allowing ongoing analgesia from the opioid. Sometimes pain can be managed by local anesthetic, placed by peripheral nerve block, topically, or as a neuraxial block.

Patient controlled analgesia (PCA) has become the mainstay of postoperative pain relief in children because of its efficacy and safety. However, its use is limited by the child’s ability to understand how to use the PCA pump. Proxy PCA (PCA-P) has been used for younger children or those with cognitive impairment.³⁹ The use of the PCA by the nurse or the caregiver may override the “safety net” that the PCA has. The use of PCA-P has been associated with greater need for rescue interventions; however, it is often used in sicker children. When PCA-P is used, careful evaluation and rigorous monitoring is needed.

Sickle Cell Crisis

Sickle cell disease differs from cancer and acquired immune deficiency syndrome in that intermittent episodes of severe pain occur, requiring urgent intensive treatment. A good review of this subject has been published.⁴⁰ Chronic pain also may be present because of long-term tissue and bone damage from periods of ischemia during past crises, including persisting myocardial ischemia. Patients may be receiving long-acting opioids or may have had repeated exposure to opioids with past crises. Patients with a sickle cell disease crisis that involves the chest or brain are likely to be admitted to the PICU. Chest crises result from the sickling of erythrocytes in the pulmonary vasculature and result in hypoxia to the rest of the body and local lung damage. The systemic hypoxia worsens the crisis and is thus self-perpetuating. Chest radiograph changes may be late, and an associated paralytic ileus may be present. Poor pulmonary function may discourage the practitioner from using adequate opioid analgesics out of concern for worsening the hypoxia. However, it is important not to underestimate the need for pain relief and to appreciate that past opioid exposure may have resulted in tolerance to opioids. If IV access is difficult to obtain, morphine may be given subcutaneously or orally. Anecdotal success also has been reported with nebulized morphine.⁴¹

Rapid Opiate Detoxification

Reports have been made of rapid opiate detoxification in the ICU. These procedures have used a form of deep sedation (often with use of propofol or another anesthetic agent) to facilitate opioid withdrawal in patients addicted to the recreational use of opiates.⁴⁸ The patients are given high doses of opiate antagonists to displace all opiates from the receptors and then heavy sedation is initiated to reduce the occurrence and effects of the sympathetic stimulation observed with short-term opiate withdrawal. These procedures have been safely performed in the ICU; however, there have been several reports of complications⁴⁹ when these procedures were not performed with full ICU support. Currently the effectiveness and safety of 1-day opiate detoxification is still an area of debate.⁵⁰ If used, however, it should be combined with an established long-term support plan to optimize long-term success.

In the PICU, deep sedation with propofol has been used to facilitate rapid opiate weaning of ventilator-dependent patients.⁵¹ The use of propofol for up to 3 days allowed a reduction of fentanyl dosing from 24 to 9 μg/kg/h (a 65% reduction). No signs or symptoms of opiate withdrawal were noted, and metabolic acidosis did not develop. Opiate antagonists were not used for this rapid weaning process. However, concern has been raised regarding the long-term administration of propofol, especially in the PICU patient, given the development of the propofol infusion syndrome.

Diazepam

The first widely used BZD in the ICU was diazepam. Because of its low solubility in water, it is available in the IV or IM form dissolved in propylene glycol. This formulation causes a significant amount of pain and thrombophlebitis with peripheral IV use. A lipid emulsion that has fewer adverse effects is available in the United Kingdom. Diazepam is inexpensive and is effective for short-term sedation; in such cases, accumulation is less of a concern. Diazepam may be given orally because it has good absorption, but absorption tends to be erratic when it is given rectally or intramuscularly. It is highly lipid soluble with a long half-life (24 hours). Metabolism by oxidative biotransformation generates several hypnotically active metabolites with an elimination half-life that may be longer than diazepam, including oxazepam (half-life, 10 hours) and n-dimethyldiazepam (half-life, 93 hours). Delayed recovery has been reported in neonates after they received diazepam, possibly because of the long half-life of dimethyldiazepam.⁶⁵ Prolongation of effects occurs in patients when clearance is reduced because of hepatic dysfunction and when metabolism is inhibited by drugs such as cimetidine and omeprazole.

Midazolam

Midazolam is an imidazobenzodiazepine. It has a short elimination half-life of 2 hours and is water soluble, which means that IV injection is nonirritating. Because of these factors, it has become popular in ICUs for sedation by infusion. Intranasally (0.2 mg/kg), midazolam has proven to be as effective at controlling febrile seizures as IV diazepam (0.3 mg/kg).⁶⁶ It has extensive first-pass metabolism and provides less reliable results when given PO, although this route is often successfully used for premedication of children before general anesthesia in doses of 0.5 to 0.75 mg/kg (maximum, 20 mg). It is available in a pleasant-tasting cherry syrup and is effective in 10 to 15 minutes, providing up to 1 hour of adequate anxiolysis, although residual hangover effects may persist.⁶⁷ Rectal and sublingual administration has been described.

Midazolam is about eight times more potent than diazepam, with starting dose recommendations of a bolus dose of 0.05 to 0.1 mg/kg⁶⁸ and an infusion of 1 to 6 μg/kg/min. Midazolam is metabolized by the cytochrome P450 system subfamily IIIA (nifedipine oxidase), polypeptide 4 (CYP3A4),⁶⁹ to hydroxymidazolam (63% potency) and hydroxymidazolam glucuronide (9% potency). Because of the high degree of protein binding (94% protein bound), the free level can be significantly changed with interactions because of the protein binding, which also may occur with heparin. Hepatic or renal failure increases the free fraction by two to three times, and its effect also can be prolonged by the accumulation of active metabolites.⁷⁰ The half-life of midazolam in patients in the ICU may be prolonged compared with that in healthy patients.⁷¹ With short-term infusions (<12 hours), it retains a rapid recovery; however, with increased duration of use, the recovery becomes prolonged. Its clearance may be reduced by several commonly used ICU drugs, including calcium channel blockers, erythromycin, and triazole antifungal agents.⁷²

Lorazepam

Lorazepam is an alternative water-soluble agent that is well absorbed after both oral and IM administration.⁷³ It produces sedation for 4 to 8 hours after a single dose. Lorazepam has a slower onset than does midazolam. The elimination half-life is about 14 hours. Metabolism is by glucuronyl transferase, not the cytochrome P450, and there are no active metabolites. This metabolism is unaffected by cimetidine or phenobarbital, which only affects oxidative metabolic pathways. Sodium valproate may inhibit its metabolism.⁷⁴ In persons with advanced liver disease, these phase II glucuronidation reactions are better preserved, and the increased half-life seen is due to increases in the volume of distribution rather than to reduced clearance. In patients with renal failure, prolonged half-life is also due to reduced protein binding because clearance is unchanged. No change in metabolism occurs with aging or critical illness. In a comparison of infusions of midazolam and lorazepam, the recovery characteristics were found to be significantly different. In patients receiving lorazepam, it took an average of 260 minutes to return to baseline, whereas in patients receiving midazolam, it took more than six times longer to return to baseline. Lorazepam may be administered by bolus (0.05 to 0.1 mg/kg every 2 to 4 hours) or by infusion (0.05 mg/kg/h). Lorazepam is slightly less expensive than is midazolam.⁷⁵ It has been recommended as the BZD of choice for long-term sedation because of its more predictable recovery profile in sick patients in the ICU. Lorazepam for IV use has propylene glycol as a carrier. Risk of a metabolic lactic acidosis exists because of the metabolism of this carrier. Cases of fatal metabolic acidosis from propylene glycol have been reported in neonates taking a particular vitamin preparation. Several other potential ICU drugs may use propylene glycol as a carrier, including some IV preparations of phenytoin and phenobarbital, nitroglycerin, digoxin, and etomidate. Reports of propylene glycol toxicity in adults who received multiple propylene glycol infusions have been made.⁷⁶ Care should be taken when lorazepam is infused in patients who receive these other medications. In patients in the PICU, propylene glycol levels have been shown to correlate with the dose of lorazepam received; however, no metabolic abnormalities were detected.⁷⁷ Hemodialysis has been used successfully in the management of the lorazepam-associated propylene glycol toxicity.⁷⁸

The metabolisms of different BZDs are intertwined with each other. Most of the agents require an oxidative process first with potentially active compounds before glucuronidation and excretion. The pharmacokinetics for different BZDs is shown in Table 123-8.

Tolerance and Dependence to the Benzodiazepines

Tolerance for and dependence on BZDs can occur as with opiates in the PICU.⁷⁹ This effect is not all due to receptor number downregulation.⁸⁰ Withdrawal symptoms may be avoided with a slow taper of the medication of 10% per day or by substituting a long-acting oral agent such as diazepam. Acute withdrawal symptoms may include anxiety, insomnia, nightmares, seizures, psychosis, and hyperpyrexia. A postmidazolam infusion phenomenon has been described that includes poor social interaction, decreased eye contact, and a decreased interest in the surroundings. The patient may exhibit choreoathetotic movements with dystonic posturing that can persist for 2 to 4 weeks but will resolve with no sequelae.

Butyrophenones and Phenothiazines

Special Issue Regarding Long-Term Infusion of Propofol

Several important problems may occur when propofol is used in the PICU. With long-term propofol infusions, a significant amount of lipid may be infused into the patient, with the same consequences as lipid infusions used for hyperalimentation. Hyperlipidemia and triglyceridemia have been reported in up to 10% of patients receiving propofol in the ICU. Pseudohyponatremia or the inability to do routine plasma electrolyte analysis has been described. It is important that the propofol calorie (20 mL/h = 528 kcal/day)¹¹⁶ and lipid load be included in the nutrition plan for the patient. It may be necessary to reduce enteral feeds or avoid intralipids in selected patients. With high propofol dosing, respiratory acidosis has been reported.¹¹⁷ The emulsion used for propofol administration is an excellent culture medium at room temperature; cases have been reported of patients with systemic infection caused by propofol during operative procedures.¹¹⁸ This infection is due to poor aseptic technique in the preparation and use of the propofol syringes and infusion lines. Unusual infective organisms were detected in several patients, and an epidemiological study by the Centers for Disease Control and Prevention found propofol to be the common element.¹¹⁹ Certain precautions should be followed when propofol is used in the PICU. The staff should be educated to the potential dangers of infection from propofol. The ampule neck should be wiped with alcohol. There are no multidose vials of propofol. Syringes should be disposed of when they are more than 6 hours old, and lines should be changed every 12 hours. Filters are available that can remove many of the potential pathogens, and they are compatible with the lipid-based propofol infusion.

A few episodes of allergy to propofol have been reported; immune reactions, involve both anaphylactic and anaphylactoid types of reactions, are estimated at 1:45,000.¹²⁰ Although clinically indistinguishable, the anaphylactic response involves prior exposure to a component of the propofol suspension. Egg allergy has been considered a contraindication to its use. However, the egg phosphatide component found in propofol is not related to the major egg allergen protein ovalbumin.¹²¹ In fact, intradermal testing with propofol in 25 patients allergic to eggs was negative; therefore, current evidence suggest that anaphylaxis is not more likely to develop in patients who are allergic to eggs when they are exposed to propofol. Propofol does not release histamine and is an acceptable agent for use in patients with asthma.

Several new generic formulations of propofol are available. These formulations include different antioxidants, such as metabisulfites, which may have an increased risk of allergic reaction. However, this increased risk has not been borne out.¹²² They appear to be equal in efficacy and adverse effects to the propofol solution known by the brand name Diprivan. A new water-soluble prodrug, fos-propofol, has been approved by the FDA and is due for release soon. The onset of action of fos-propofol is significantly slower than for propofol (5 minutes), which may reduce the incidence of hypotension and respiratory depression. A few patients who receive propofol may have dark-green urine due to phenol metabolites; this effect is not a clinical concern.¹²³

Propofol Infusion Syndrome

One of the most important concerns is the development of a refractory metabolic acidosis in children who had received propofol sedation in the ICU. This effect was first described in 1992 as a series of five cases¹²⁴ with fatal myocardial failure in children with respiratory illnesses requiring ventilation and sedation. Five young patients from different ICUs had croup and went on to have a refractory cardiac failure, bradycardia, and acidosis. A lipemic serum had developed in all patients. They had all received propofol at an average rate of about 8 mg/kg/h for more than 70 hours.

In review, the case reports were not as simple or as complete in their reporting, with several published letters¹²⁵ from physicians involved with these patients showing incomplete data in the reporting. Several other case reports of an apparently similar clinical course were then subsequently described in the literature, which was enough evidence for the Committee on Safety of Medicines in the United Kingdom to issue a warning on propofol and its use in pediatric patients. At that time the FDA could not find a causal link between propofol and the deaths in children and did not issue a warning.

This reaction to propofol came to be known as the propofol infusion syndrome (PRIS).¹²⁶ It is the sudden or relatively sudden onset of a marked bradycardia resistant to treatment with a least one of the following signs: lipemia, enlarged liver, severe metabolic acidosis, or rhabdomyolysis.

PRIS is unlikely to be due to the carrier emulsion because intralipid has been used extensively in severely ill patients without problems. The propofol metabolites are acidic, highly water soluble, and have a short half-life.

A steady number of case reports of this syndrome have appeared in the literature since the initial description, as well as a couple of studies involving several hundred patients^127,128 who have not shown any problem with propofol in the PICU. In these studies, lower doses of propofol (4 mg/kg/h) were used, with regular monitoring of the acid base status and triglyceride levels. “Propofol bashing” became popular.¹²⁹ There are few drugs that are licensed specifically for the PICU, however, and proper trials are needed to avoid drugs being condemned as hearsay. Subsequently, a randomized, controlled trial of propofol was begun, and after its use in 327 patients, it was reviewed by the FDA.¹³⁰ The study was never published, but researchers found that, despite similar pediatric risk of mortality scores, patients who had received either 1% or 2% propofol preparations had a two to three times greater risk of death compared with the control sedative group. This finding led to a letter from AstraZeneca reminding health care workers that propofol was not approved for sedation of pediatric patients.¹³¹

Much debate still occurs regarding whether there is a safe infusion rate or duration of infusion for propofol in the PICU setting. It has been estimated that a study to show a significant increase in death would require 7000 patients, which would be difficult to accomplish.

PRIS has also now been described in adult patients.¹³² These patients had similar cardiac and metabolic findings, often associated with the management of intracranial hypertension. PRIS appeared to be a higher risk if the 2% formulation was used. Patients with raised ICP require deeper levels of sedation and require higher doses of propofol; they also are receiving vasopressor support to maintain the CPP, which puts a further stress on a myocardium that is already failing.

The pathophysiologic cause of PRIS is still poorly understood, but it appears to mimic mitochondrial myopathies. Such patients are generally well until stressed. Rhabdomyolysis and cardiac and hepatic failure then develop in these patients.¹³³ Case reports have shown some metabolic abnormalities that may be the cause of the cardiac failure and acidosis. One report describes a 10-month-old child who had the syndrome and was successfully treated with hemofiltration and plasmapheresis.¹³⁴ Muscle and liver biopsy specimens showed changes consistent with a toxic insult. Analysis also showed a reduction in the cytochrome C oxidase activity in the muscle, with a normal activity in skin fibroblasts, excluding an underlying respiratory chain defect. Profound acidosis with lactic acidosis is found in different types of genetically acquired cytochrome oxidase deficiency. It was postulated that the hemofiltration removed a water-soluble metabolite of propofol that had caused a reversible reduction in the oxidase activity. A second case report¹³⁵ also showed a metabolic abnormality. Elevated levels of malonylcarnitine and C5-acyl carnitine were found in a patient with PRIS. This patient was also treated successfully with hemofiltration. These findings are consistent with impaired fatty acid oxidation due to impaired entry of long chain fatty acids into the mitochondria and a failure of the respiratory chain. A review of the pathophysiologic function of the syndrome¹³⁶ suggested that propofol increases the activity of malonyl coenzyme A, which inhibits the carnitine palmityl transferase I, so long chain fatty acids cannot enter the mitochondria. Propofol also uncouples oxidation, so the short and medium chain fatty acids cannot be used, even though they have entered the mitochondria and also may inhibit the respiratory chain. Low energy production leads to cardiac and peripheral muscle necrosis.

In pediatric patients it has been suggested that an inadequate calorific intake coupled with a high metabolic demand requires a fully active fatty acid oxidation capacity. Propofol may inhibit this pathway and cause a cellular metabolic failure syndrome to develop. Children have lower glycogen stores and often require higher doses of sedative agents; thus the syndrome is more likely to occur in pediatric patients. A carbohydrate intake of 6 to 8 mg/kg/min should be enough to suppress fat metabolism in the critically ill child. Also, concerns have been raised about the influence of catecholamines and steroids in the development of the syndrome, especially in the adult population.

Propofol is still frequently used for procedural and short-term sedation,¹³⁷ but in a recent case report, researchers describe a patient who had PRIS.¹³⁸ The patient had received a propofol infusion for 15 hours at 20 mg/kg/h. After a 13-hour propofol-free period, an 8-hour infusion of propofol at 4 mg/kg/h was given, after which the patient had intractable bradycardia and acidosis. This report raises concerns about high-dose, short-term propofol use in the PICU.

In a report on the use of propofol for two cases of refractory status epilepticus, patients aged 7 and 17 years had features similar to the PRIS.¹³⁹ Status epilepticus itself can result in neurologic deficit, hypoxia, rhabdomyolysis, cardiac arrhythmias, hyperthermia, metabolic acidosis, acute renal failure, and death. However, these patients received high doses of propofol (18 to 27 mg/kg/h) to achieve burst suppression for more than 48 hours. Rhabdomyolysis and cardiac failure developed in both patients. No monitoring of lipid status or acid base was performed, and propofol was used as the sole agent by practitioners with limited experience with this drug. In light of the reports now appearing in the adult neurointensive care literature with the development of a propofol infusionlike syndrome in adult neurosurgical patients,¹⁴⁰ it would appear that propofol is not the best choice for prolonged sedation for patients with intracranial hypertension. An early indicator of the cardiac instability from PRIS may be changes in the ECG. It has been reported that the development of a right bundle-branch block with convex ST elevation was an early sign of this syndrome.¹⁴¹

Propofol remains a useful agent for procedural sedation in the PICU. When compared with midazolam and ketamine, propofol resulted in safe, effective sedation. The patients sedated with propofol awakened almost twice as fast; thus the efficiency of the sedation service was also improved.¹⁴² Propofol is also probably appropriate for overnight sedation, and higher doses should be avoided. It probably should not be used as a solo agent because in those cases tolerance appears to develop more rapidly. If its use is required for a prolonged period, then careful consideration should be given to its risks and benefits. A recent study showed that staff members of some PICUs are still using long-term high doses despite the potential risks involved.¹⁴³ Prevention of PRIS could include adequate calorific intake. The dose and duration of propofol should be carefully managed to minimize its use. It would appear from the reports of PRIS in the neurosurgical population that the desire for rapid awakening has propagated the use of propofol coma, rather than using barbiturates. Regular monitoring of the cardiac function, ECG, and CPK are warranted; lipid profile and acid base status may help in early detection. However, these steps may not necessarily prevent mortality from the syndrome.¹⁴⁴ Treatment should be immediate cessation of propofol. Cardiac support may be difficult because of unresponsiveness to conventional circulatory support. The use of pacing and extracorporeal membrane oxygenation has been reported. Hemodialysis or hemofiltration have been reported as having some success.

An outcome prediction table has been developed for PRIS based on more than 1000 reports from the FDA’s Medwatch program, of which 20% were pediatric patients.¹⁴⁵ The features associated with PRIS are shown in Table 123-12. In addition to the individual features, there were several additional scores depending on a combination of features (see Table 123-12). The predicted outcome from these scores is shown in Table 123-13. These predicted outcomes were very close to the actual reported mortality of the analyzed cohort. No independent verification exists at present. However, this article does highlight the variability in features of the PRIS and accounts for the differences in the reported mortality.

Table 123–12 Features Reported for PRIS, Incidence, and Score

Table 123–13 Predicted Outcome from PRIS

Types of Procedures and Preprocedure Evaluation

In many instances sedation may be beneficial in the PICU, such as for the placement of central lines and centesis tubes and during dressing changes. Sedation facilitates the procedure in uncooperative patients and allows long or uncomfortable procedures to be performed. Outside the ICU, both noninvasive and invasive radiologic examinations^151,152 often require sedation (Box 123-7).

Safety with moderate sedation is largely determined by careful assessment and management of the airway, together with precautions to prevent aspiration of gastric contents. Adequacy of sedation largely depends on appropriate patient selection, the combination of the patients’ known medical conditions, past sedation experience, and the nature (particularly pain) of the patients’ procedures, coupled with appropriate drug selection. Moderate sedation may be better tolerated than deep sedation or general anesthesia when hemodynamic stability is compromised because many sedative and anesthesia agents induce cardiovascular instability such as vasodilation or myocardial depression. Furthermore, the ability to monitor the patient’s neurologic status during the procedure through conversation or instruction may be helpful, especially during invasive neuroradiologic procedures. Moderate sedation may allow an earlier discharge because less sedative is being used and may make the procedure, which would usually require the full operating room environment, possible outside of the operating room.

All patients should be assessed before moderate sedation. Box 123-8 lists the elements that should be included in the assessment. The medical history should include evaluation of the cardiorespiratory system, any history of gastroesophageal reflux, and any previous sedation attempt that failed or any abnormal reaction to sedation. A recent asthmatic attack or respiratory tract infection, poorly controlled seizure disorder, or diabetes may require a change or postponement of the sedation plan. It is recommended that patients be classified according to the ASA preoperative patient classification (Table 123-16). In most circumstances it is generally recommended that patients in ASA class VI and some in class III are not suitable for moderate sedation.

Table 123–16 American Society of Anesthesiology Classification

It is prudent to adopt the same guidelines that are used before general anesthesia is administered, in case sedation that is deeper than anticipated occurs. These guidelines are age dependent, and current recommendations are shown in Table 123-17. Despite this, less caution is often reported regarding fasting, without any apparent worsening of outcome. For example, in a survey of 450 radiology departments, 35% had no nothing by mouth (NPO) status requirement for neonates, and 17% used a 2-hour NPO status requirement for infants. For oral contrast studies, most departments sedated the patient within 1 hour of the contrast being swallowed.¹⁵³ Consent should be obtained as with any medically indicated procedure or intervention. It should include discussion about the risks and benefits of the procedure and the sedation technique, as well as expectations of outcome and alternatives to the procedure and sedation.

Table 123–17 Presedation NPO Guidelines

NPO, Nothing by mouth.

∗ Milk, breast milk, pulp fruit juices.

† Clear fruit juices, water.

The presedation interview for outpatients or non-ICU patients also should involve giving instructions and information to a responsible person, including postsedation instructions, a 24-hour phone contact phone number, guidelines concerning limitations of activity, and expected postsedation behavior. If moderate sedation is provided for nonscheduled patients, a review of several aspects is important (Box 123-9).

Monitoring During the Procedure

Sedation provided outside the ICU should be performed in a facility/area with the appropriately trained support staff. The staff should have had appropriate training with respect to pharmacology, monitoring, resuscitation (basic and advanced life support), emergency drugs, and cardiac arrest protocols and medications. Advanced cardiac life support and pediatric advanced life support recommendations should be available to be followed.

Monitoring of patients undergoing moderate sedation is an important component of safe, effective sedation. Several different recommendations have been made by the Joint Commission on Accreditation of Healthcare Organizations,¹⁵⁴ the American Board of Anesthesiology, and the AAP. These recommendations have not yet been fully followed by persons providing sedation for children.¹⁵⁵ A study of pediatric dentists after publication by the AAP of its new recommendations found minimal monitoring and documentation of the sedation procedure. Obtaining baseline vital signs is important. Because of the possibility of oversedation, the level of consciousness should be assessed frequently, especially during titration of effect. This level of consciousness is best assessed with the Ramsay scale (see Table 123-1). A sedation record is important for documentation of the drugs used with times and doses and for the monitored measurements that are charted on a time-based record. Monitoring should include pulse oximetry for assessment of the degree of oxygenation and heart rate. The saturation should be maintained by supplemental oxygen. Breathing can be assessed either by monitoring the respiratory rate or by capnography. The blood pressure should be checked at regular intervals during the procedure. A study of 85 pediatric patients with complications after sedation showed that most severe complications resulted from a common pathway involving respiratory depression leading to respiratory arrest, cardiac arrest, and subsequent severe neurologic devastation. The most common causes for these complications are summarized in Box 123-10. There is no particular drug that is more likely to cause problems. Polypharmacy, especially with three or more drugs, has been shown to be a risk factor for pediatric sedation complications.¹⁵⁶ Dentists using nitrous oxide in combination with other agents appeared to have a higher incidence of problems. If long-acting drugs are used, the patient must be observed for an appropriate length of time. Several reports have been made of respiratory arrest occurring while the child was in the car seat on the way home. Any health care worker providing moderate sedation should be familiar with an emergency algorithm in case problems arise (Figure 123-4).

Figure 123–4 Sedation emergency airway algorithm. ETT, Endotracheal tube.

Many different pharmacologic options are available for moderate sedation in children. The oral route is commonly used in children; it has a slow onset time that avoids a rapid peak effect, but it also gives an unpredictable degree of sedation, which is not easy to titrate. IM administration is painful; however, it is useful in uncooperative patients. The rectal route is nearly always available and has found favor in the past for barbiturate sedation. More contemporaneously, rectal diazepam at 0.2 to 0.5 mg/kg has proved useful in the control of seizures when IV access is not available.¹⁵⁷ Onset can be fairly slow and the duration prolonged. The IV route offers a titratable effect but also adds the danger of acute overdose. The use of intranasal sedation administration has been reported for a variety of drugs. A disposable device such as the Mucosal Aerosol Device can be used. The Mucosal Aerosol Device attaches to a Luer lock syringe and has a soft cone insert for placement in the nares. It creates a fine spray that improves drug delivery and deposition onto the nasal mucosa. Another route of administration is transmucosal administration, such as the fentanyl “lollipop” (ACTIQ). Dosing recommendations are shown in Table 123-18. One must always keep in mind that BZD-opiate or barbiturate-opiate combinations are potent causes of respiratory depression, and extra monitoring and vigilance should be used. With IM and oral medications, adequate time should elapse to allow absorption before a further dose is given to avoid accidental overdose.

Table 123–18 Drug Dose Guidelines for Moderate Sedation

CM3, Catheterization mixture number 3; IM, intramuscular; IV, intravenous; PO, by mouth.

As noted in Table 123-15, different procedures require different qualities of sedation. These qualities are found in the array of drugs available to the intensivist (Table 123-19). It may be useful to choose the sedative agent or agents that best fit the particular requirements for the procedure being performed.

Opiate and BZD antagonists should be readily available wherever moderate sedation is being performed. Staff caring for these patients should understand the drug indications and dosing of these medications to reduce any potential delay in their appropriate use. They can quickly and effectively reverse the respiratory depression from excessive doses of sedation.

In some circumstances the services of the anesthesia department may be useful. The anesthesia department has access to other pharmacologic agents such as propofol and nitrous oxide, as well as the inhalational agents. The ability to use a deeper level of sedation if required is easily obtained with these rapidly acting, short-acting agents. In emergency procedures where the patient’s NPO status is unsafe or unknown, patients may need to undergo intubation to protect the airway.

Anesthesiologists have the ability to perform a “needleless” sedation technique using a gas induction with anesthetic agents; an IV drip may be placed if required when the patient is asleep. This technique is especially useful for repeat procedures in oncology patients. Also, anesthesia personnel are better able to sedate patients whose illness may contraindicate routine moderate sedation protocols (Box 123-11).

Postprocedure Care and Monitoring

Care of the patient during the recovery period after moderate sedation is important. The patients must be monitored during recovery to ensure adverse events are rapidly recognized and treated. The recovery area should be equipped with appropriate monitors and resuscitation equipment and have a trained individual in attendance. The monitoring should be performed to the same degree as during the actual procedure. Level of consciousness and vital signs should be recorded at regular intervals. A physician who is responsible for the patient must be identifiable and must be easy to contact if required urgently. Patients may be discharged home when they are alert and orientated or when they have returned to baseline if baseline initial mental status was abnormal. Vital signs should be stable and within acceptable limits. A sufficient time should have elapsed if a reversal agent was used (2 hours). Patients should be discharged in the presence of a responsible adult to accompany them home and report any complications. Written instructions should be given to the parent concerning diet, medications, and activities, and a 24-hour contact telephone number also should be given to the parent.

Moderate sedation is safe and frequently used; unconscious sedation is potentially hazardous, and patients who undergo it require careful monitoring. Hospital protocols are useful for a smoothly run, safe sedation policy.¹⁵⁸ Staff should be appropriately trained in sedation and resuscitation basic and advanced life support. When the ASA/AAP recommendations are followed, the risks of a sedation-related complication can be reduced.¹⁵⁹ Individual risk factors include deep sedation and the use of chloral hydrate. When all the recommendations for moderate sedation, including NPO, ASA class, avoidance of deep sedation, sedation level monitoring, and drug use were followed, the adverse event rate was zero.

Sedation for Magnetic Resonance Imaging

The PICU physician is often called upon to provide sedation for a patient in the ICU who is undergoing MRI. Also, many institutions rely on the PICU team to provide a sedation service for other inpatients or outpatients undergoing MRI. Deep sedation is often required for effective sedation of younger children undergoing an MRI scan. The same standards should be adhered to as with any other child undergoing sedation¹⁶⁰ with respect to patient selection, monitoring, and postimaging care.

MRI is an imaging modality that is being increasingly used to aid in the diagnosis of neuroanatomic disorders. The patient is required to lie still within a small space while multiple images are obtained. MRI scanning is performed less rapidly than computed tomography (CT) scanning. Movement by the patient causes degradation of the image quality, and a change in the patient’s position may affect the homogeneity of the magnetic field, which is optimized at the beginning of the scan. Studies can take from 45 minutes to more than 2 hours, with individual sequences taking 3 to 10 minutes. The scanner is noisy and the restriction on space and movement can induce claustrophobia in some patients. The patient also may experience a slight increase in temperature. Most adults and older children (older than 6 years) are capable of lying still for the scan. With the use of earplugs and music it is well tolerated. Several groups of patients, however, may require sedation¹⁶¹ for the scan to be performed (Box 123-12).

Because of the large magnetic field, several unique problems¹⁶² can occur during a scan. These problems include the potential risk of the magnet causing a ferromagnetic object to move or heat up or the induction of an electric current from the radio frequency pulses and switching magnetic gradients used in generating the images. This potential risk results in a significant list of contraindications to MRI (Box 123-13). Sedating these patients also entails several risk factors. The patient is in a remote location, with limited access to and visibility of the airway. Several equipment issues exist as well (Box 123-14). The monitors used must be suitable for use in the MRI suite.¹⁶³ They should be nonferromagnetic; the cables should be screened from electromagnetic interference (fiberoptic is ideal); and the signal should be filtered to avoid radio frequency interference (which interferes with image quality). Despite the specialized technology that is available, several problems remain. The ECG waveform is frequently altered, and analog information is often lacking during a scanning cycle. The ECG cables may cause burn injury, and special ECG electrodes are required to avoid burn injury. For pulse oximetry to be performed, a special probe is required. Heating of the usual probe may cause burn injury. Fiberoptic connection to the patient is best. Capnography requires long tubing, which results in a prolonged upsweep and delay in displaying real-time measurements. The respiratory rate and trends can still be useful. Any battery-powered monitor requires a nonmagnetic lithium battery. Exposure to the MRI shortens battery life. Most ICU ventilators are not MRI compatible (Servo i is available as an MRI compatible model). Some specialized MRI-safe anesthesia machines have a ventilator; however, their use should be restricted to the anesthesia staff who are familiar with the equipment. The IV poles and the equipment carts also should be nonferromagnetic. Any equipment with a transformer (e.g., syringe pumps and IV pumps) must be kept out of the magnetic field. Gas cylinders must be aluminum. The area around any magnet that generates a magnetic field stronger than 5 G should not contain any ferromagnetic items.

Any staff entering the MRI suite should remember to remove any ferromagnetic objects, including keys, watches, pens, and credit cards. Stethoscopes and laryngoscopes also are ferromagnetic. Infusion pumps should be outside the magnetic field, that is, outside the 5-G line. The electric motor in infusion pumps emits electromagnetic radiation and may run at an abnormal speed in the presence of a strong magnetic field. The pump is also a projectile risk. IV infusions through long tubing from outside the scanner can be useful so that the depth of anesthesia can be altered without having to enter the MRI suite. MRI-compatible infusion pumps are now also available. Some of these pumps allow changing infusion rates via electronic hand-held devices without entering the scanning room The ICU patient’s infusions can be changed over to these infusion devices while the patient is still in the ICU and then transported to the scanner.

The use of a cuffed endotracheal tube may affect the quality of the MRI image because of metal in the valve of the pilot balloon and reinforcement of the mask airway. With the patient in the ICU, special care must be taken to ensure that all cables and transducers that may be carefully screened and all ferromagnetic objects are removed (“hiding in the sheets”). For invasive vascular pressure to be measured, the transducer should be as far from the patient as is practically possible and separated with a saline-filled pressure line. If cardiac arrest occurs, the patient should be removed from the magnetic field. The defibrillator should be kept outside the magnetic field and checked regularly. A nonferromagnetic code cart is also advisable. It is essential that the code team follow the rules about removing any loose magnetic items before entering the MRI suite or else a lethal projectile may be released. Ventilating the lungs of the ICU patient is often performed by hand ventilation by ICU staff in the MRI suite. The sedation technique is often a continuation of that used in the ICU, especially for a patient who undergoes intubation. In some children single doses of fentanyl or midazolam may be sufficient for a adequate sedation. If deeper sedation is required for patient comfort/cooperation, then IV sedation with supplemental oxygen with propofol is useful. A bolus of 2 mg/kg and an infusion of 100 μg/kg/min is a good method for patients with few medical problems and an easily maintained airway. It results in a rapid recovery with little nausea or vomiting.

Ketamine

Ketamine is a phencyclidine derivative that provides sedation and analgesia. It results in a state of dissociative (trancelike) anesthesia. It is available in a variety of different dilutions, such as 10 mg, 50 mg, and 100 mg/mL. The latter is the most useful for IM use and the preparation of infusions. For a state of general anesthesia to be induced, a dose of 2 mg/kg IV is required. Onset takes 1 to 2 minutes with anesthesia lasting 10 to 15 minutes. Lower doses may be used for sedation. Anesthesia also can be induced by the IM route with a dose of 10 mg/kg, although onset is slower (5 to 10 minutes) and duration of prolonged effect is 45 to 60 minutes. It is metabolized by the liver and excreted by the kidneys. The half-life is 3.1 hours (see Table 123-11).

The adverse effects of ketamine include hypertension, tachycardia, increased intracranial pressure, and bronchodilation. The bronchodilation is probably due to its sympathomimetic action. It is a direct myocardial depressant, but blood pressure is usually maintained by the sympathetic stimulation that ketamine causes. In critically ill patients who already are using their maximum sympathetic drive, ketamine may cause a decrease in cardiac output or even cardiac arrest. Hallucinations and other psychiatric symptoms are often reported during and after its use in adults, but they occur less frequently in children. Ketamine is a potent sialogogue, and the use of an anticholinergic agent such as glycopyrrolate may be helpful. Its use is contraindicated in patients who cannot tolerate hypertension,¹⁶⁴ have a history of cerebrovascular hemorrhage, have psychiatric disturbances, and have raised ICP. It is a useful agent for sedation for procedures, especially if there is no IV access. It has been used in patients with status asthmaticus as an adjunct bronchodilator both in intubated and nonintubated patients at an infusion rate of 0.5 to 2 mg/kg/h. After discontinuing its use, the patient should receive BZDs to minimize the likelihood of hallucinations and be nursed in a quiet environment. Ketamine cannot be assumed to preserve pharyngeal reflexes any better than other sedatives agents, and apnea and airway obstruction can still occur.¹⁶⁵ NPO guidelines should still be observed.

Etomidate

Etomidate is a carboxylated imidazole that is unrelated to other anesthetic agents. It is a rapidly acting IV anesthetic agent, which, like other rapid-onset anesthetic agents, partitions into the brain within one circulation time and redistributes out of the brain over the next few minutes. It is available dissolved in 30% propylene glycol as a 2 mg/mL solution. Like propofol, it causes pain on injection. The anesthetic dose is 0.2 to 0.3 mg/kg. It has a favorable adverse effect profile with minimal cardiovascular and respiratory depression. Etomidate is associated with a high incidence of nausea and vomiting after emergence from anesthesia. Its pharmacokinetics are shown in Table 123-11. The greatest disadvantage of etomidate in the intensive care setting is adrenocortical depression due to inhibition of adrenocortical mitochondrial 11-β-hydroxylase.¹⁶⁶ This effect is present in neonates and in adults.¹⁶⁷ The outcome of patients sedated with etomidate is worse than in those using alternative sedation, and steroid deficiency is thought to be the cause.¹⁶⁸

In the CNS, etomidate suppresses seizure activity, although patients may show excitatory movements not associated with cortical EEG changes suggestive of seizures. The intracranial and intraocular pressures are lowered. It is the drug of choice for patients who are undergoing emergency intubation, those who have head injuries, and those who have a compromised cardiovascular system, and it is safe for use in patients with asthma because there is no histamine release. Etomidate has the highest therapeutic index of any anesthetic agent.

Several case reports of the satisfactory use of etomidate for controlling refractory intracranial hypertension have been published; it is associated with fewer cardiovascular problems than are barbiturates. Nevertheless, caution must be taken concerning the development of a lactic acidosis due to the metabolism of propylene glycol.

Inhalational Anesthetic Agents

The inhalational agents remain the most widely used anesthetics in the operating room, although their mechanism of action is still poorly understood. The following agents are currently in clinical use: enflurane, isoflurane, sevoflurane, and desflurane. Sevoflurane and desflurane are newer agents that currently have limited use in the ICU. Isoflurane remains the most logical choice of inhalational anesthetic in the ICU based on its cost/benefit ratio. As with any drug used in the ICU, it is important to understand the pharmacology, the adverse effect profile, and, in this case, the technical aspects of delivering these agents to the patient. These drugs are all fluorinated hydrocarbons (Figure 123-5). Except for halothane, which is no longer in common clinical use, they are ethyl-methyl esters. Each agent has different physicochemical properties that are important to its properties (Table 123-20).

Figure 123–5 Structures of inhalational agents.

Nitrous oxide is frequently used by anesthesia personnel as an adjunct. In some institutions it is used as the basis of a hospital pediatric procedural sedation service for children. Patients on the hospital floor undergoing minor to moderately painful procedures are mildly sedated with 50% nitrous oxide (as routinely used in pediatric dentistry); this technique has a good safety profile. A newer anesthetic agent in use in Europe is xenon. This gas has anesthetic properties with very few cardiac adverse effects. It is very expensive to use and requires a specialized fully closed breathing circuit to minimize the amount of gas used. The rate at which a change in inspired concentration is reflected in the brain is determined mainly by the blood/gas solubility. The more soluble the gas is in blood, the slower is the change due to the gas dissolving into the blood and reducing the partial pressure available to equilibrate with the brain. Sevoflurane and desflurane are the least soluble and therefore have the most rapid onset and offset; halothane has the slowest onset. The potency of the agents is represented by the minimal alveolar concentration (MAC). The MAC is the percent of inhaled anesthesia agent required to prevent 50% of anesthetized patients from responding to a surgical incision. The lower the MAC, the more potent the agent is. Halothane is the most potent of the agents used and desflurane is the least potent. The MAC of anesthetic agents is not constant with age. For all the agents it is highest for those aged 1 to 12 months, and the MAC falls throughout childhood to reach adult levels. Neonates show a slightly reduced MAC compared with infants. The oil/water solubility determines the degree of accumulation of the agent within the body fat stores. A highly fat-soluble agent will have larger body stores; therefore recovery from the agent is delayed.

These agents all have significant effects on the cardiorespiratory systems. Although respiration can be controlled, the negative inotropic and vasodilator effects are pronounced and limit the concentrations that can be used. Halothane, the oldest of these agents, has the greatest degree of cardiac depression. Sevoflurane and desflurane have an adverse effect profile similar to that of isoflurane, except that sevoflurane is partly metabolized to a potentially toxic metabolite, compound A, from a reaction with the soda lime used in anesthesia circle systems. For accumulation of compound A to be minimized in the circuit, a fresh gas flow of greater than 2 L/m should be used. Thus sevoflurane is may not be not a good choice for prolonged ICU treatment with this type of circuit. Desflurane has some sympathomimetic effect, especially when the concentration is abruptly increased, and significant tachycardia and hypertension can occur.

Adverse effects of halothane include hypotension, which is due to direct myocardial depression. It also causes bradycardia because of effects on the sinoatrial node and vagal stimulation. Cardiac arrhythmias may occur, most commonly junctional rhythm. Halothane also sensitizes the myocardium to catecholamines, especially when the patient is hypercapnic or hypoxic. Because these physiologic changes are common in the intensive care patient, the potential for serious interactions with halothane abound. Halothane is metabolized approximately 20% by the liver, and a trifluoroacetic metabolite may cause an immune-mediated fatal hepatitis.¹⁶⁹ Isoflurane causes hypotension mainly because of vasodilation, while maintaining cardiac output. Concern has been expressed about a coronary steal phenomenon occurring in which blood is diverted from a partially obstructed coronary bed served by collateral arteries, due to vasodilation. The evidence for this phenomenon is weak, however, and ischemia is probably due to hypotension rather than a true steal phenomena. Isoflurane vapor is pungent and may cause airway irritation, coughing, and laryngospasm if the patient is not adequately sedated before its use. It is only minimally metabolized (0.2%), and a hepatitis reaction is extremely unlikely.

Malignant hyperthermia is a rare reaction that may occur whenever the halogenated inhalational anesthetics or succinylcholine is given to a patient. It involves the unrestrained entry of calcium into myocytes and consequential consumption of adenosine triphosphate, resulting in metabolic failure. Hypermetabolism, manifested by increased CO₂ production, and acidosis occur. Later the body temperature rises and death from hyperkalemia occurs. Correction of blood chemistry, aggressive cooling, and the administration of dantrolene are urgently indicated.

The metabolism of all the anesthesia agents can result in the production of free fluoride ions. Concentrations of fluoride greater than 50 μmol/L can cause renal dysfunction and a reduced concentrating capacity. This risk would appear to be higher for both halothane and sevoflurane because of their more extensive metabolism. It also may be exaggerated by patients who are prescribed drugs that induce the cytochrome P450 enzyme complex.

Inhalational agents may cause hepatotoxicity in two ways: (1) by metabolism to reactive intermediates that are directly hepatotoxic or (2) through the intermediates that form adducts to hepatic proteins. These new proteins are then recognized as foreign, and an immune response that causes hepatic injury occurs. This is thought to be the mechanism of halothane hepatitis. This form of hepatitis is most common after halothane use; even then it is rare, occurring in 1 of 100,000 cases. It is less common with isoflurane, sevoflurane, or desflurane, which are much less metabolized. This fulminant hepatic failure, which may be fatal, is most common after repeated administrations of halothane in older obese patients. The predominance of reductive halothane pathway metabolism results in a trifluoroacetic acid metabolite that forms a hapten. Halothane hepatitis is also less common in children.

All of the inhalational agents cause cerebral vasodilation, which results in an increase in CBF (because of decoupling of the demand/flow ratio) and ICP. In pediatric patients with raised ICP, there was no difference among isoflurane, desflurane, and sevoflurane with respect to the increase in ICP and CBF.¹⁷⁰ In contrast, IV anesthetics maintain the demand/flow ratio, and CBF and ICP fall, with the exception of ketamine. In addition to an effect of CBF, the arterial blood pressure typically will decrease with anesthesia, and the effect of this on the CPP must be accounted for. In one study, the effect of the decrease in arterial pressure on CPP exceeded the effect of increasing ICP by a factor of 3.¹⁷¹ With these potential effects on CBF, the use of isoflurane should be carefully considered in patients who have or are at risk of raised ICP. Nevertheless, isoflurane has been safely used in neuroanesthesia with controlled ventilation to a normal PaCO₂ and an inspired concentration not exceeding 1 MAC.¹⁷²

Isoflurane has two main applications in the PICU: sedation and the management of refractory asthma. Only a few reports have been made of long-term sedative use of isoflurane in the ICU. In an adult study, 40 patients¹⁷³ who received an average of 96 MAC hours of isoflurane showed hemodynamic stability, less tachyphylaxis compared with other sedative agents, and a more rapid wean from the ventilator. No evidence was found of renal or hepatic dysfunction with serum fluorides less than 50 μmol/L. In a pediatric study, 10 patients¹⁷⁴ who had been receiving large doses of opiates or BZDs received an average of 130 MAC hours of isoflurane. The range of use was from 1 to 30 days. Fifty percent of the patients experienced a withdrawal-like phenomenon—most commonly, those who had received more than 70 MAC hours of isoflurane. Fluoride levels also were measured, and although they were correlated with the duration of treatment, none was greater than 30 μmol/L. The highest levels were in a patient who was taking both phenytoin and phenobarbitone. Hypotension only occurred in one patient. No hepatic or renal dysfunction occurred. The withdrawal was treated with a combination of BZDs and haloperidol with good effect. Isoflurane also has been used in patients with renal dysfunction, and fluoride levels were not elevated.¹⁷⁵ The starting dose for sedation should be 0.5%; this dose can then be titrated to effect by the ICU team. At levels above 1.5%, other sedative agents and paralytics often are not required.

Multiple case reports of the use of inhalational agents for status asthmaticus in both adults and children have been made. Because of its speed of onset and its bronchodilation effects, isoflurane is a useful adjunct to β₂-adrenergic agonists. If no improvement occurs, or if unacceptable adverse effects occur, then its effects rapidly wane on discontinuation. Isoflurane is recommended for use because of its safer adverse effect profile. No reports of renal or hepatic dysfunction have been made despite its use for often prolonged periods. Hypotension seems to be more common in patients sedated with isoflurane; it is possibly related to increased intrathoracic pressure and the potential for greater preload reduction with vasodilation. Fluid boluses and occasionally vasopressors are often required. Because isoflurane is not an analgesic agent, opiates may be needed for painful or uncomfortable procedures. Also, when the patient is weaned off the isoflurane, additional sedatives will be required. The isoflurane should be started at 0.5% and titrated for effect; doses of up to 2.5% have been reported as safely used.¹⁷⁶

The inhalational anesthetic agents are liquids at room temperature. A special delivery device called a vaporizer is required to deliver an accurate supply of the vapor. All vaporizers have several features in common. They provide a reservoir of the inhalational liquid with a level indicator and are capable of delivering a constant level of vaporization. Most newer vaporizers also have a color-coded keyed filler (e.g., purple for isoflurane and yellow for sevoflurane) that prevents the accidental filling of the vaporizer with the wrong agent. This error could result in overdosing the patient because the vaporizer calibration is drug specific. If two vaporizers are accommodated in series on the anesthesia machine back bar, then an interlocking system should be used to prevent the accidental use of both vaporizers. Otherwise, the results would be contamination of the second vaporizer by gas from the first vaporizer and an uncontrolled excess delivery of gas to the patient.

One of the main problems with using these inhalational agents in the PICU is how to deliver them to the patient. One technique is to use an anesthesia machine to deliver the gas to an ICU ventilator with the correct oxygen percentage and inhalational agent. This mixture is delivered from the fresh gas outlet of the anesthesia machine. It is selected by adjustment of the flow rotameters on the anesthesia machine to give the desired oxygen concentration and then selection of the desired inspired concentration of inhalational agent on the vaporizer. Unfortunately, most ICU ventilators will not accept this low-pressure gas supply as their driving gas. The Servo 900C is an exception because it has a low pressure inlet option for the driving gas. High flow rates are required to maintain filling of the bellows of the ventilator; the flow rates must be higher than the minute ventilation. This requirement sometimes results in a limitation of inspired oxygen because the maximum flow of oxygen from the rotameters of the anesthesia machine is 10 to 12 L/m. Also, this process consumes a lot of vapor.

Also available is another Servo ventilator, the 900D, that has a custom-fit vaporizer on the normal high-pressure input. This machine is similar to the 900C, but it has been modified for anesthesia use and also allows hand ventilation with inhalational agents. Often the only alternative is to deliver anesthetic with an anesthesia machine. Anesthesia machine ventilators are not as sophisticated as ICU ventilators, may not be able to deliver appropriate volumes for pediatric patients, and often have limited positive end-expiratory pressure capabilities. The anesthesia machine needs to be checked before use and its correct function should be continually assessed during its use, which requires an understanding of the setup and alarms on the machine and an understanding of the procedures of the appropriate tests. This understanding usually is not within the confines of a pediatric intensivist’s scope of practice, and an anesthesiologist should be involved to ensure the safe and effective use of this apparatus.

Whenever inhalational agents are used, the waste gases from the expiratory limb of the ventilator should be scavenged to avoid prolonged exposure of the health care worker to these agents. The Occupational Safety and Health Administration limits occupational exposure to 2 ppm halothane for health care workers.¹⁷⁷ The worker is at risk of becoming sedated, and potential teratogenic effects also exist. Several large studies about prolonged exposure to these agents have not shown any increase in risks for anesthesia personnel with respect to hepatic disease, teratogenesis, spontaneous abortions, psychological difficulties, infertility, neuropathy, or bone marrow depression.¹⁷⁸ Caution also should be taken when filling the vaporizer to avoid spilling the liquid during the process.¹⁷⁹ Two forms of scavenging are available. A passive system involves simply a tube connected to the expiratory limb connected to the outside. This system is at risk of occlusion because of kinking or someone standing inadvertently on the tubing, which will then occlude the expiratory limb of the ventilator. An active system involves an active suction to the expiratory limb, with a safety reservoir bag in series to prevent excess suction pressure from being exposed to the patient.

In the operating room it is routine to monitor the levels of anesthesia agents given with a gas analyzer. This monitoring provides an inspired and expired inhalational agent concentration and is helpful to ensure that the vaporizer is functioning correctly, that the vaporizer has not emptied without being detected, and that the concentration dialed on the vaporizer has reached its effect. When the end-tidal inhalational agent concentration equals the inspired agent, then steady state has been achieved. This steady state normally occurs rapidly with isoflurane, but in a patient with severe asthma due to the severe limitation in airflow gas exchange, achievement of steady state may be delayed.

If the PICU staff is unfamiliar with the delivery system being used for the isoflurane, then it would be appropriate to have staff from the anesthesiology department set up the equipment and ensure that it functions correctly. Failure to configure the delivery system correctly has the potential to cause considerable harm or death. Once the situation has stabilized, an anesthesiologist may not be required at the bedside. However, an anesthesiologist should be available by pager to help troubleshoot any difficulties. In these cases the inspired agent should be monitored continually.

The use of inhalational agents in the PICU involves the use of equipment that may be unfamiliar to pediatric intensive care physicians. Isoflurane appears to be the best choice,¹⁸⁰ and it offers several useful advantages, including the ability to deeply sedate patients (especially those difficult to sedate) without polypharmacy.¹⁸¹ Although they are currently poorly defined,¹⁸² tolerance and a withdrawal-like syndrome have been described; however, they appear to occur more slowly than with other sedative agents. It may be helpful to have a set of guidelines available for isoflurane use to facilitate its use in the PICU. These guidelines could include equipment use, monitoring requirements, dosing, and treatment of complications.¹⁸³ Caution should be used in patients who may have raised ICP because isoflurane may increase CBF. Isoflurane does allow for rapid arousal if neurologic examinations are required.

The Anaesthetic Conserving Device (AnaConDa) is a modified heat moisture exchanger that has been developed to allow the use of inhalational agents in the ICU without requiring high fresh gas flows or specialized ventilators.¹⁸⁴ It is placed in the breathing circuit between the ventilator Y circuit and the endotracheal tube. The liquid anesthesia agent is injected directly into the device using a syringe pump. The device membrane allows for the inhalational agent to be taken up by the inspired gas. On expiration much of the inhalational agent is deposited on the membrane, allowing for an efficient inhalational rebreathing technique. The inspired concentration of the inhalational agent is monitored from the device using a routine gas analyzer. It has been used in several adult ICU trials as well as in a series of three children. Some problems due to excess dosing have been experienced, and the 100 mL dead space of the device, as well as resistance to gas flow, may make its use inappropriate in children. Compared with an inhalational agent vaporizer, there is no percentage inhalational agent dial. The rate on syringe injection determines the percentage of the inhalational agent. This infusion rate is set according at a pre-recommended rate. Initially the inspired concentration is low because of dilution. Differences in minute ventilation and gas flows may make this pre-recommended rate inaccurate. The injection rate needs to be titrated to the monitored percent of the inspired inhalational agent, which can increase significantly with time, especially until equilibrium is reached. The AnaConDA device is not approved for use in the United States.