Management of a critically ill child poses a special challenge to the clinician. Most children admitted to an intensive care unit (ICU) have multisystem involvement. The clinician must not only be aware of age-related changes in pharmacokinetics and pharmacodynamics but also be cognizant of various drug–drug and drug–disease interactions. Because of the ongoing pathophysiologic changes, the physician must also deal with changes in volume of distribution and elimination kinetics during the clinical course. A critically ill child is often exposed to 20 or more medications during his or her hospital stay. Practically, every organ system and disease entity is represented in the pathophysiologic derangements of the patients in the ICU. A comprehensive discussion of management of an individual disease entity is beyond the scope of this chapter. Instead, we offer a working outline of management of most commonly encountered disease processes in critically ill children.

Management of intracranial hypertension is the cornerstone of modern neurointensive care. Primary brain injury results from a direct insult from the initial event such as trauma, infection, metabolic derangement, and ischemia. Secondary brain damage results from pathophysiologic alterations in response to the primary event. Increased intracranial pressure (ICP) is one of the most important factors which further aggravate the brain damage.

Status epilepticus is defined as continuous or repeated convulsive or nonconvulsive seizures lasting 30 minutes or more. In children, causes include infections, trauma, toxic ingestions, and metabolic disturbances such as hyponatremia and hypocalcemia, brain tumors, epilepsy, and subtherapeutic levels of antiepileptic drugs. Status epilepticus is one of the most common disorders in children requiring ICU admission. Within the first 30 minutes of status epilepticus, sympathetic overactivity results in hypertension, tachycardia, and increased cardiac output. Increased catecholamine activity produces hyperglycemia. A combined respiratory and metabolic acidosis is a result of lactic acidosis and CO₂ retention. Excessive muscle activity can lead to rhabdomyolysis and acute tubular necrosis. The increase in cerebral metabolism often outstrips cerebral blood flow and eventually this discrepancy leads to depletion of brain glucose and oxygen. Status epilepticus should be considered an emergency, and treatment and determination of the etiology should be instituted immediately (Fig. 23.1).

Myasthenia gravis is an autoimmune disease caused by autoantibodies directed against the nicotinic receptors in the neuromuscular junction. Neonatal myasthenia gravis results from transplacental passage of maternal antibodies to the fetus. Medical therapy of myasthenia gravis consists of inhibition of acetyl cholinesterase inhibitors, immune suppression, and immune modulation. Acetyl cholinesterase inhibitors that are quaternary ammonium compounds (edrophonium, neostigmine, etc.) do not cross the BBB and are therefore appropriate for the management of myasthenia gravis. Tertiary amines such as physostigmine cross the BBB and are not appropriate in this setting.

Edrophonium is used mainly to establish the diagnosis but may also be used to distinguish between myasthenic crisis and cholinergic crisis in children receiving anticholinesterase therapy. An IV dose of 0.04 mg per kg over 1 minute is followed by 0.16 mg per kg (maximum 10 mg) given within 45 seconds if no response is observed. Objective evidence of motor function such as muscle strength and forced vital capacity should be documented. The onset of action is within seconds and duration of action is a few minutes. As with other anticholinesterase agents, severe bradycardia, hypotension, and other cholinergic effects can occur with the use of edrophonium. Atropine (0.01 mg per kg IV, minimum 0.1 mg, maximum 2 mg) should be available at the patient’s bedside to counteract serious cholinergic effects if they should occur.

Neostigmine is used both as a diagnostic agent as well as for ongoing therapy. It can be given IM in a dose of 0.025 to 0.04 mg per kg as a diagnostic tool. For ongoing therapy, 0.04 mg per kg can be given IM every 3 to 4 hours. Neostigmine bromide given orally in a dose of 0.4 mg per kg every 4 to 6 hours is preferred for prolonged use. For patients with significant dysphagia, neostigmine should be administered about 30 minutes before meals. Pyridostigmine is slightly longer acting than neostigmine. It is administered orally in a dose of 5 mg per kg per day in 4 to 6 divided doses. The doses of both neostigmine and pyridostigmine may have to be adjusted every 48 hours.

Corticosteroids: Long-term therapy may be necessary for immune suppression. A single oral daily dose of prednisone (0.5 to 1 mg per kg per day) is recommended. In resistant cases, combined steroid and azathioprine therapy is utilized to minimize the side effects of steroids. Thymectomy should be considered for patients with high titers of antiacetylcholine-receptor antibodies.

Intravenous immunoglobulin (IVIG): For immune modulation, plasmapheresis and IVIG are sometimes beneficial. IVIG is administered as 2 g per kg as a single dose over 10 to 12 hours or 400 mg per kg daily for 4 days. Relative benefits of immune modulation are still unconfirmed by randomized controlled studies. Several case series report short-term benefit from plasmapheresis particularly in myasthenic crisis (28).

In addition to sedative agents, critically ill children may require neuromuscular blocking agents (NMBAs) to facilitate various mechanical ventilatory modes such as high frequency oscillation, inverse ratio ventilation, and slow rates, all of which can induce significant discomfort and agitation. The addition of neuromuscular blockade may help improve respiratory system compliance and reduce barotrauma by preventing the patient from “fighting” the ventilator. Occasionally, neuromuscular blockade may also be necessary in children following laryngotracheoplasty, or those with extensive facial injuries or following facial reconstructive surgery where movement has to be kept at a minimum to maintain the artificial airway. NMBAs exert either depolarizing or nondepolarizing (competitive) effects on the neuromuscular junction.

Succinylcholine acts similarly to acetylcholine and induces membrane depolarization. Because it is resistant to degradation by acetylcholinesterase, administration of succinylcholine produces initial fasciculations resulting from repetitive excitation, followed by flaccid paralysis. The recommended dose in children is 1 mg per kg per dose. Paralysis occurs in 1 minute after IV injection. Effects dissipate quickly as the drug is metabolized by butyrylcholinesterase in the blood and liver. However, during depolarization induced by succinylcholine, significant amounts of potassium are released, and succinylcholine is therefore contraindicated in conditions that can potentiate hyperkalemia. These include crush injuries, burns, and rhabdomyolysis. It is also contraindicated in patients with ICP, spinal cord injuries, muscular dystrophies, and known or family history of malignant hyperthermia.

Nondepolarizing or competitive NMBAs include pancuronium, vecuronium, atracurium, and mivacurium. These drugs block acetylcholine from binding to receptors on the motor endplate, thereby inhibiting depolarization. Elimination of nondepolarizing NMBAs varies, and this characteristic should be taken into account when using these drugs in critically ill children (Table 23.1).

In using NMBAs, a number of potential complications should be taken into account. It is important to ascertain adequacy of sedation to prevent the frightening consequence of paralyzing a child who has total awareness. The paralysis induced by agents with steroid rings such as pancuronium and vecuronium can result in a myopathy and prolonged paralysis when the patient is on corticosteroids as well (29). There are a number of drugs frequently used in children in the ICU that can potentiate the effects of NMBAs resulting in prolonged paralysis. These include antibiotics such as aminoglycosides; antiarrhythmics such as
β-adrenergic blockers; and other drugs such as furosemide, magnesium, and cyclosporine. Abnormalities in renal function and electrolyte disorders such as hypocalcemia and treatment modalities such as hypothermia can all prolong neuromuscular blockade and weakness. Unlike vecuronium or rocuronium, 80% of cisatracurium is metabolized to laudanosine via Hoffman elimination, with less than 20% of unchanged drug excreted in the kidneys, making it the more appropriate NMBA to use in patients with renal insufficiency. In addition, a study comparing vecuronium and cisatracurium in infants after congenital heart surgery showed more rapid spontaneous recovery of neuromuscular function with cisatracurium (30). Occasionally, there may be a need for continuous or frequent neuromuscular blockade. In such patients, the depth of neuromuscular blockade should be monitored. Clinical parameters such as handgrip strength may be used but may not be applicable in infants or those children who are sedated. Stimulating the ulnar nerve and assessing the evoked response of the adductor pollicis can provide a more objective measurement. Monitoring of neuromuscular function with the train-of-four ratio is useful in judging the response to therapy. Train of four is a modality whereby peripheral motor nerve stimulation is applied followed by the observation of muscle movement in response to the stimuli. Nondepolarizing agents such as vecuronium decrease the size of single twitches and both the strength and duration of the response to repetitive stimulation. The train of four consists of four stimuli given at 2 per second and is commonly used to determine the degree of neuromuscular blockade and the number of receptors occupied. If three twitches are observed, approximately 75% to 80% of receptors are occupied; and if one twitch is observed, 90% to 95% of receptors are occupied. One to two twitches indicate approximately 75% to 90% receptor occupancy and are thought to provide the optimum level of neuromuscular relaxation. Monitoring of the train of four in patients who are receiving frequent or continuous dosing of NMBAs helps prevent overdosing and prolonged paralysis.

The injection of aminosteroidal nondepolarizing NMBAs such as rocuronium and vecuronium stimulates the C-nociceptors in the peripheral veins, causing severe pain (31,32). The pain, as indicated by localized withdrawal response, is significant even after loss of consciousness during anesthesia induction. Ahmad et al. assessed the efficacy of fentanyl or lidocaine in the prevention of rocuronium injection–associated pain and found that fentanyl was more effective than lidocaine (33).

Rapid reversal of neuromuscular blockade is sometimes necessary in ICU patients who have received nondepolarizing agents. Neostigmine, 0.05 to 0.07 mg per kg IV (maximum of 5 mg), can be used for this purpose and has a peak action within 5 to 8 minutes. Atropine may have to be administered to counteract excessive muscarinic effects of bradycardia, increased secretions, and bronchospasm.

Sugammadex is a drug-specific modified #979;-cyclodextrin that is a selective relaxant binding agent. Unlike neostigmine, which increases cholinergic activity, the selective relaxant binding agent rapidly encapsulates steroidal NMBAs such as rocuronium, thereby directly preventing the pharmacologic actions of NMBAs. Studies have shown that sugammadex is effective and safe (34). The drug has been approved for use in Europe but not in the United States.

Sedation is often necessary in critically ill children because of the need to maintain endotracheal tubes, facilitate mechanical ventilation, and to ensure that chest tubes, central venous, arterial, and bladder catheters are not pulled out by an agitated child. The ICU environment is often a stressful one. Endotracheal tubes prevent children from crying or communicating. Frequent monitor and ventilator alarms and harsh lighting prevent normal sleep. Pain from catheters and procedures may add to the discomfort. However, despite the routine use of sedative agents in ICUs, there are few sedation scales that are designed for, and validated for use in children. A number of scales have been designed to assess sedation, including the Ramsay scale, the Comfort scale, Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS), visual analogue scale, and the Riker sedation–agitation scale. More commonly, caregivers use physiologic parameters such as heart rate and blood pressure, or movement to determine a child’s need for sedation. Children therefore can be subject to both undersedation and oversedation. The complications of oversedation include hemodynamic instability, severe withdrawal syndromes, and prolongation of mechanical ventilation and ICU stay.