1595CHAPTER 132 Sedation and Analgesia Midazolam Midazolam is an imidazobenzodiazepine It has a short elimina tion half life of 2 hours and is water soluble, which means that IV injection is nonirrita[.]
CHAPTER 132 Sedation and Analgesia 1595 Midazolam Lorazepam Midazolam is an imidazobenzodiazepine It has a short elimination half-life of 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 proved to be as effective at controlling febrile seizures as IV diazepam (0.3 mg/kg).103 Intramuscular midazolam can be as safe and effective as IV lorazepam in managing patients with status epilepticus.104 Midazolam has extensive first-pass metabolism and provides less reliable results when given PO Despite that, 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 hour of adequate anxiolysis, although residual hangover effects may persist.105 Rectal and sublingual administration have also been described Midazolam is considered one of the mainstays of continuous infusion therapies in the management for refractory status epilepticus in pediatric patients A bolus dose of midazolam ranging from 0.1 to 0.5 mg/kg is used at the start of treatment followed by a continuous infusion rate of 0.06 to 0.5 mg/kg per hour (up to 1.5 mg/kg per hour) or 1.0 to 8.3 mg/kg per minute (up to 25 mg/kg per minute) Higher infusion rates of midazolam are used to treat EEG seizure activity in comparison to clinical convulsive seizure activity.106–108 Significantly higher dosing rates are used when burst suppression is the chosen end point IV and nasal midazolam have been successfully and safely used for imaging procedural sedation.109 The success rate is higher for shorter imaging procedures, such as for computed tomography scan versus MRI Midazolam is about eight times more potent than diazepam, with sedation starting dose recommendations of a bolus dose of 0.05 to 0.1 mg/kg and an infusion of to µg/kg per minute.110 Midazolam is metabolized by the cytochrome P450 system subfamily IIIA (nifedipine oxidase), polypeptide (CYP3A4), to hydroxymidazolam (63% potency) and hydroxymidazolam glucuronide (9% potency).111 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.112 The half-life of midazolam in patients in the ICU may be prolonged compared with that in healthy patients.113 With short-term infusions (,12 hours), it retains a rapid recovery; however, with increased duration of use, recovery becomes prolonged Its clearance may be reduced by several commonly used ICU drugs, including calcium channel blockers, erythromycin, and triazole antifungal agents.114 Midazolam clearance can also be reduced by mechanical ventilation, possibly due to reduced cardiac output.115 There appears to be no correlation between day-night cycle and midazolam pharmacokinetics in critically ill children Critical illness itself can have a major effect on midazolam clearance Using pharmacokinetics modeling, midazolam clearance was found to be lower in critically ill patients when compared with healthy infants admitted for postoperative monitoring This is believed to be owing to reduced cytochrome P450 3A4/5 (CYP3A4/5) activity as a result of inflammation, reduction in liver blood flow as a result of mechanical ventilation or acute illness, and the reduction of total albumin that is frequently reported in critically ill patients.104 Lorazepam is an alternative water-soluble agent that is well absorbed after both oral and IM administration.116 It produces sedation for to 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 cytochrome P450, and there are no active metabolites This metabolism is unaffected by cimetidine or phenobarbital, which affects only oxidative metabolic pathways Sodium valproate may inhibit its metabolism.117 In patients 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, recovery characteristics were found to be significantly different In patients receiving lorazepam, it took an average of 260 minutes to return to baseline; in patients receiving midazolam, it took more than six times longer to return to baseline Lorazepam may be administered by bolus (0.05–0.10 mg/kg every to hours) or by infusion (0.05 mg/kg per hour) Lorazepam is slightly less expensive than midazolam.117 It has been recommended as the BZD of choice for long-term sedation because of its more predictable recovery profile in patients in the ICU Lorazepam for IV use has propylene glycol as a diluent; thus, there is risk of metabolic lactic acidosis with prolonged use or high daily doses Several other potential ICU drugs may use propylene glycol as a carrier, including some IV preparations of phenytoin and phenobarbital, nitroglycerin, digoxin, and etomidate Propylene glycol toxicity has been reported in adults who received infusions of multiple medications containing propylene glycol.118 Thus, care should be taken when lorazepam is infused in conjunction with those drugs In critically ill children, propylene glycol levels correlate well with the dose of lorazepam administered; however, no metabolic abnormalities were detected.119 Hemodialysis has been used successfully in the management of the lorazepam-associated propylene glycol toxicity.120 All of these BZDs have been commonly used as the first-line treatment for pediatric patients with status epilepticus.121 The use of the longer-acting lorazepam may preclude the need for additional dosing for recurrent seizures However, there may be an increased risk of respiratory depression, especially if redosing is required Some earlier studies have indicated the safety of lorazepam over diazepam, and one study suggested that the use of IV lorazepam (0.1 mg/kg) is as safe and efficacious as IV diazepam (0.2 mg/kg) in pediatric patients with status epilepticus.122 IM lorazepam can be an ideal choice in children with complex medical and physical disabilities when IV access is a challenge A recent retrospective descriptive study reported resolution of status epilepticus in 68.5% of episodes after one dose of IM lorazepam 0.05 to 0.1 mg/kg in this patient population in a single institution.123 The majority of children at that facility did not have IV access, requiring the use of alternative routes of administration of BZDs for acute seizure management The pharmacokinetics for different BZDs is shown in Table 132.7 Tolerance for and Dependence on Benzodiazepines Tolerance for and dependence on BZDs can occur as with opiates in the PICU.124 This effect is not all due to receptor number 1596 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit downregulation.125 The incidence of IWS secondary to BZDs ranges from 17% to 35% in pediatric critical care units.126–128 Risk of IWS increases once continuous BZD/opioid infusion time lasts longer than days and warrants close monitoring for signs and symptoms Monitoring for IWS should start as early as after days of continuous infusion; a midazolam infusion rate greater than 0.35 mg/kg per hour is predictive of IWS.129 Withdrawal symptoms may be avoided with a slow taper of the medication of 10% per day or by substituting with a long-acting oral agent, such as diazepam or lorazepam Acute BZD 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 to weeks but resolves without sequelae As would have been anticipated, the longer the duration and higher the cumulative dose of BZDs, the higher the chance that withdrawal symptoms will occur Flumazenil Flumazenil is an imidazobenzodiazepine and is a specific competitive antagonist of the BZD receptor It has no effect on other drugs such as barbiturates, ethanol, or other GABA-mimetic agents Flumazenil reverses the hypnotic and sedative effects of BZDs It is primarily used to reduce the residual effects of BZD, including sedation, amnesia, respiratory depression, and muscle relaxation Flumazenil was also reported to act as an antagonist of sevoflurane, isoflurane, and propofol to shorten anesthesia emergence This effect was also considered to be related to competitive binding to the GABA receptor.130,131 It has a half-life of approximately hour after a single IV bolus In patients with hepatic impairment, its half-life and clearance are prolonged, and a significant increase (.50%) of free drug occurs because of reduced plasma protein binding Renal failure has little effect on the pharmacokinetics of flumazenil It is indicated for the complete or partial reversal of the central sedative effects of BZDs Contraindications include patients who have a known hypersensitivity to BZDs, patients with epilepsy who are receiving treatment with BZDs, and patients who have overdosed with a tricyclic antidepressant Flumazenil use often is associated with mild to moderate tachycardia and hypertension In cases of multiple-drug overdose, the use of flumazenil remains controversial It often is overused in the emergency setting without due concern for potential adverse reactions because of the potential toxic effects (e.g., cardiac arrhythmias or convulsions) of other psychotropic drugs ingested.132 The toxicity of tricyclic antidepressants may become apparent as the effects of BZDs are antagonized Patients should be evaluated for the signs and symptoms of a tricyclic antidepressant overdose An electrocardiogram (ECG) may be helpful in determining the risks involved Flumazenil dosing information for pediatric patients is limited The initial suggested dose is 0.01 mg/kg (maximum, 0.2 mg) with incremental doses of 0.005 to 0.010 mg/kg (maximum, 0.2 mg) given every minute up to a maximum cumulative dose of mg The lower doses are suggested for sedation reversal and the higher doses for BZD overdose Infusions at 0.05 to 0.1 mg/kg per hour have been used.133 The use of flumazenil in sedated patients in the ICU should be tempered by the potential for an unrecognized BZD dependence, which would increase the risk of adverse effects If its use is required, a carefully titrated dose would be appropriate The half-life of flumazenil is much shorter than that of some of the BZDs it may be counteracting (see Table 132.7) The use of an infusion may be necessary because re-sedation has been reported after single-bolus use.134 However, this requirement should not preclude the use of flumazenil in an ICU setting.135 Flumazenil has been used for the reversal of moderate sedation The onset is usually within to minutes, with an expected peak effect at to 10 minutes after IV injection.136 Both the plasma concentration of BZDs and the flumazenil IV dose determine the duration of drug reversal Although well tolerated in the pediatric population, flumazenil was not shown to significantly reduce recovery time.137 Because flumazenil has a limited duration with the potential for re-sedation after discharge from medical care, an appropriate period of observation is required A study in which researchers monitored the effects of flumazenil after sedation indicated that some of the residual effects of midazolam were still present after reversal.138 Flumazenil has been used to treat a paradoxical midazolam reaction139,140 and shown to be effective in the management of hepatic encephalopathy or hyperammonemia.141 In addition to the IV route, flumazenil has been administered by rectal, nasal, IM, and oral routes Higher doses are required for rectal (50 mg/kg) and intranasal (40 mg/kg) routes Oral flumazenil is not a good option because of slow onset and poor bioavailability (16%) owing to the first-pass effect in the liver.142 Other Agents for Sedation in the Pediatric Intensive Care Unit Chloral Hydrate Chloral hydrate is a widely used oral hypnotic/sedative agent It has been used for sedation in radiographic procedures, EEGs, and many healthcare locations It was first synthesized in 1832 and used in 1869 as a hypnotic agent Shortly after, reports of acute and chronic toxicity were published.143 In 1910, it was labeled as the most dangerous of hypnotics, even though heroin and opium were in common use at that time The addition of ethanol potentiates its effect (street name “Mickey Finn”) It has been used to control agitation in the intensive care nursery and to treat sleep difficulties in older patients Chloral hydrate is rapidly and completely absorbed from the GI tract and is immediately converted into the active component trichloroethanol (TCE) by alcohol dehydrogenase.144 The plasma level peaks at 30 to 60 minutes TCE is 45% protein bound TCE undergoes glucuronidation with some oxidation to trichloroacetate (TCA) The half-life of TCE is to 12 hours, whereas that of TCA is 67 hours In infants and neonates, this may be increased by a magnitude of three to four With multiple dosing, a significant potential exists for accumulation TCA can displace bound bilirubin from albumin Its actions include CNS depression with drowsiness and sleep in less than an hour With an overdose, the patient falls into a deep stupor or coma, and the pupils change from constricted to dilated At therapeutic levels, the blood pressure and respiratory rate are unaffected Chloral hydrate has little hangover effect It has several effects on the cardiovascular system, including decreased myocardial contractility, a shortened refractory period, and an increased sensitivity of the heart to catecholamines It also has effects on mucous membranes Irritation can cause gastritis, nausea, and vomiting With overdose, a severe hemorrhagic gastritis with gastric necrosis and esophagitis has been described Chloral hydrate and ethanol CHAPTER 132 Sedation and Analgesia interfere with one another’s metabolism through competition for alcohol dehydrogenase Also, ethanol inhibits the conjugation of TCE and TCE inhibits the oxidation of ethanol Coumadin activity may be increased by chloral hydrate Chloral hydrate is synergistic with other sedative agents In children receiving amphetamine-based medication, chloral hydrate is contraindicated because there have been rare reports of arrhythmias The reversal of chloral hydrate with flumazenil has been described; however, a report of ventricular tachycardia with this combination also has been made Chloral hydrate is available as capsules, syrup (50 mg/mL), and suppositories The sedative dose is 25 to 50 mg/kg (PO/by way of the rectum), whereas up to 100 mg/kg can be safely used in children younger than years with a maximum dose of g Because of an increased half-life, neonatal dosing should be lower (25 mg/kg) In preterm babies, toxicity resulted when chloral hydrate was used for days In term babies, toxicity resulted when it was used for days The therapeutic level for TCE is to 12 mg/L; toxicity occurs when the level is more than 25 mg/L Chloral hydrate provides successful moderate sedation in approximately 90% of patients, but it appears to be less effective in patients older than years A higher risk of failure with excessive effect can be seen in patients with a history of obstructive sleep apnea or encephalopathy A recent meta-analysis showed that the use of chloral hydrate in procedural and diagnostic sedation in children appears to be effective and fairly safe when administered in the appropriate settings with appropriate monitoring.145 Similar to any other procedural sedation, a thorough preprocedural patient assessment and appropriate patient monitoring—including pulse oximetry and heart rate both during the procedure and during recovery—are highly recommended However, newer, safer, reversible sedation medications are readily available, with shorter durations of effect that lower the risk for postprocedural oversedation In a randomized, prospective study of 150 children under the age of years with known or suspected congenital heart disease scheduled for transthoracic echocardiography with sedation, chloral hydrate was as effective as intranasal dexmedetomidine.146 Signs of chloral hydrate toxicity are usually noted within hours of dosing Paradoxical excitement also has been described in 6% of patients There is some evidence that chloral hydrate may be genotoxic and carcinogenic Mice studies have shown that a single-dose exposure can result in an increased risk of hepatic carcinomas and adenomas.147 Chloral hydrate overdose produces a clinical picture that is similar to acute barbiturate poisoning Ataxia, lethargy, and coma occur within to hours Also, a pear-like odor may be noted Cardiovascular instability poses the main threat to life Severe arrhythmias—including atrial fibrillation, supraventricular tachyarrhythmia, ventricular tachyarrhythmia, torsades de pointes, and ventricular fibrillation—have been described Chronic use can cause a dependence syndrome Also, chloral hydrate is not detectable in the blood TCE levels are measurable, but they are not useful for clinical management, although they can be helpful for retrospective forensic diagnosis The management of toxicity includes evaluation and monitoring at a medical facility if an amount greater than 50 mg/kg or an unknown amount has been ingested Charcoal with intubation should be considered if significant toxicity is suspected Standard antiarrhythmic management is often unsuccessful, although esmolol, overdrive pacing, and hemoperfusion have been tried 1597 Butyrophenones and Phenothiazines Haloperidol Butyrophenones belong to a group of major tranquilizers Haloperidol is a potent antipsychotic agent with nonspecific dopamine antagonist action It has little effect on the cardiovascular or respiratory systems It produces the appearance of calm with minimal hypnotic effect and reduces operant behavior (purposeful movement) The patient appears tranquil and dissociated from surroundings but is readily accessible if spoken to Haloperidol may mask actual feelings of mental restlessness It is a potent antiemetic agent (with action at the chemotrigger zone) and has no appreciable effect on the EEG It potentiates analgesics and other sedative agents Compared with less potent butyrophenones, it has fewer adverse effects Neuroleptanalgesia, a dissociative form of anesthesia, can be induced when haloperidol is combined with high-dose opiates This anesthetic state is useful for certain cardiac and neurosurgical procedures that require cardiovascular stability and a responsive patient Haloperidol is metabolized to inactive compounds with a half-life of 15 to 25 hours It is highly protein bound Hepatic dysfunction increases the half-life because of reduced clearance Adverse effects include extrapyramidal signs, although acute dystonia is rare Prolongation of the QT interval is possible, with the attendant risk of ventricular tachycardia.148 Hepatic toxicity can occur but is rare Haloperidol is indicated for the treatment of psychoses, Tourette disorder, and severe behavioral problems in children In the PICU, it is used as a treatment for agitation in patients who are unresponsive to other more commonly used agents It also has proved to be effective as part of a sedative withdrawal strategy The usual dosage for agitation in children younger than years is 0.01 to 0.03 mg/kg every hours The maximum daily dose is 0.15 mg/kg per day Haloperidol is available as syrup, tablets, and an IM preparation Two IM preparations are available: lactate is for repeated use and decanoate is a slow-release monthly formulation Although not approved by the FDA, the IM lactate form has been given intravenously without problems Haloperidol has been used to treat pediatric hyperactive delirium in critical care units149,150 once other measures, including managing the underlying critical illness and preventing possible iatrogenic factors (e.g., BZDs, sleep deprivation), have failed to alleviate the symptoms of delirium IV, oral liquid, oral tablet, and IM formulations/routes are available A dose of 0.05 mg/kg per day divided twice daily can be used For urgent use in children less than years of age, a dose of 0.025 mg/kg is used; for children age years or older, a dose of 0.5 to 1.0 mg every 15 to 20 minutes is used until agitation and symptoms of delirium are controlled A maintenance oral dose of 0.05 to 0.15 mg/kg per day divided every to 12 hours is suggested if needed.150 IV haloperidol may be considered for use to treat hyperactive delirium or if unable to give enteral medication It is important to note that IV dosing is twice as potent as enteral; thus, a lower dose must be used Droperidol Droperidol is a dopamine receptor antagonist that causes analgesic, sedative, and antiemetic effects It is faster acting than haloperidol, with a shorter duration of action and a half-life of hours It is available as an approved IV formulation With an IV bolus, mild hypotension occurs because of mild a-adrenergic receptor blockade Droperidol is more sedating than haloperidol and may be used as an adjunct to general anesthesia It also is used in low doses (0.05 mg/kg) as an antiemetic agent Concerns exist about 1598 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit the potential for droperidol to cause prolongation of the QT interval that may result in ventricular arrhythmias,151 but the QT prolongation can also be transient with no major sequelae.152 Recent reports suggest that droperidol can be safely used in children for acute behavioral disturbance as a sedative in the prehospital setting153 as well as in emergency departments for its analgesic, antiemetic, and sedative effects.154 Chlorpromazine Chlorpromazine is a weaker antipsychotic agent with general CNS depressant activity It has an antidopaminergic effect— including extrapyramidal adverse effects, lethargy, and apathy— with an EEG similar to that of normal sleep It also causes a decrease in the body’s ability to maintain temperature control, shivering is reduced, and it can be useful in patients in hypothermic-induced states Cardiovascular effects include a-adrenergic receptor blockade with hypotension and postural hypotension, but no effect is seen on the ECG Respiratory drive and depth are unaffected; however, some mucosal dryness may be noted In the GI tract, its anticholinergic effect causes decreased secretions and motility Liver effects include jaundice, which occurs in 0.5% (recurrence rate, 40%) independent of dose or duration of therapy It is also associated with a rash, fever, and eosinophilia This syndrome has a low mortality rate and usually resolves quickly upon discontinuation of chlorpromazine Other effects include antihistamine-like action; local analgesia; a temporary leukopenia; and, rarely, agranulocytosis Chlorpromazine also has antiemetic properties Indications include premedication, sedation as part of the lytic cocktail catheterization mixture number (CM3),155 intractable pain, antipsychosis, treatment of hiccoughs, prevention of succinylcholine pain, and induction of hypothermia (with other active measures) Dosing (0.05–1.00 mg/kg every hours) may be via the PO, IM, IV, or rectal routes Chlorpromazine has been used in critically ill children with delirium that is not responding to standard therapy A dose of 0.4 mg/kg IV every hours was reported to be safe and effective.156 Chlorpromazine is metabolized both in the gut wall and by the liver It yields more than 50 metabolites, most of which are inactive Other phenothiazine derivatives include prochlorperazine, which has mainly antiemetic properties Extrapyramidal adverse effects are more common in children younger than years Dosage is a PO or rectal dose of 0.40 mg/kg every hours and an IM or IV dose of 0.15 mg/kg Lytic Cocktail The lytic cocktail CM3 is a mixture of 25 mg/mL of meperidine, 6.5 mg/mL of promethazine, and 6.5 mg/mL of chlorpromazine Its recommended dose is 0.1 mL/kg of body weight, but significant institutional variations exist The CM3 was popular as sedation for cardiac catheterization However, it has been reported to have a high failure rate and lacks several important characteristics of an ideal sedative for children Dosing cannot be titrated easily and individually Onset of action is delayed (30 minutes), and duration of effect is protracted (5–20 hours) CM3 has no anxiolytic or amnestic properties Additional caution should also be exercised when this cocktail is used in children with seizure disorders The metabolite of meperidine and the lowered seizure threshold from chlorpromazine put the patient at risk Patients with congenital heart disease with physiologic conditions such as tetralogy of Fallot or left ventricular outflow obstruction may be put at risk because of systemic vasodilation that causes altered blood flow through shunts, a hypercyanotic spell, or decreased coronary blood flow due to diastolic hypotension • BOX 132.3 Signs and Symptoms of Neuroleptic Malignant Syndrome Elevated creatine phosphokinase (97%) Tachycardia (75%) Altered consciousness (75%) Tachypnea Hypertension Diaphoresis Leukocytosis Neuroleptic Malignant Syndrome Both the butyrophenones and phenothiazines have a rare but well-described adverse effect called the neuroleptic malignant syndrome It involves the development of hypertonicity, with autonomic instability, fever, and cognitive disturbance The incidence is 0.5% to 1.4% of patients exposed to neuroleptic agents The true incidence in children is unknown, however Several different diagnostic criteria are available Fever and rigidity present in all cases; other symptoms are shown in Box 132.3 A variety of therapies have been described, including supportive treatment and discontinuation of the neuroleptic agent, anticholinergics, amantadine, bromocriptine, dantrolene, L-dopa, and electroconvulsive therapy Several other rarer diagnoses may manifest this myriad of symptoms, such as paroxysmal sympathetic hyperactivity syndrome following traumatic brain injury, serotonin syndrome, and anti-NMDA receptor encephalitis.1572159 Baclofen Baclofen is a p-chlorophenol derivative of the GABA analog that has specific agonist activity at the GABAB receptor It has a halflife of to hours Baclofen has inhibitory effects on the brain and spinal cord At the spinal cord level, it suppresses spinal reflexes to result in muscle relaxation It is widely used as a skeletal muscle relaxant in patients with spasticity, such as cerebral palsy, spinal cord injury, and multiple sclerosis It is most frequently given PO Adverse effects include urinary retention, sedation, bradycardia, hypotension, respiratory depression, and apnea Weakness may limit patient compliance These side effects are sedative-like characteristics of the drug, which are not useful in clinical practice Therefore, abrupt cessation of long-term baclofen therapy resembles, in part, short-term sedative withdrawal Intrathecal baclofen (ITB) has been used with increasing frequency in children to treat spasticity Its use has been reported as effective in reducing oral baclofen and propranolol for refractory paroxysmal sympathetic activity after traumatic brain injury.159 This system allows delivery of the drug to the spinal cord and reduces the dose significantly (1% of oral requirements), limiting systemic adverse effects Baclofen inhibits the release of serotonin in the brainstem After long-term use, there is accommodation of the serotonin pathways to this long-term inhibition that is consistent with the usually observed increasing doses required for ITB during the first 12 to 18 months of treatment When this inhibition is abruptly removed, sudden excess release of serotonin occurs Acute overload of serotonin transmission, such as an overdose of serotonin reuptake inhibitors, can result in confusion, hyperthermia, myoclonus, and autonomic instability Baclofen also has anticholinergic and antihistamine effects that may result in drowsiness; paradoxical excitation has been reported in children CHAPTER 132 Sedation and Analgesia Multiple cases of ITB withdrawal have now been reported.160–165 ITB withdrawal seems to be more severe if the ITB treatment lasted more than year A review of ITB pumps in 100 patients at a single center has shown that problems with the delivery system are fairly common.163 A total of 24% of patients experienced a problem, with a follow-up period for a maximum of 5.6 years An average of two problems per patient was reported Disconnection of the catheter from the implanted pump was the most common problem Access ports on the pump seemed to increase the risk of problems (16% compared with a 2% disconnection rate); however, these ports make troubleshooting easier Causes of difficulty with ITB delivery are provided in Box 132.4 ITB withdrawal syndrome is interesting because it appears to have many similarities with neuroleptic malignant syndrome Prolonged muscle contraction caused by rebound spasticity results in thermogenesis, hyperthermia, and rhabdomyolysis.164 Patients with ITB withdrawal often are managed initially with broad-spectrum antibiotics as if they have sepsis and multisystem organ failure, with no improvement in the clinical situation.165 The differential diagnosis of the hypermetabolic state is listed in Box 132.5 The symptoms of ITB withdrawal can be classified into three categories (Table 132.8) Often, the first clinical signs are the development of itching and some increase in spasticity If replacement baclofen is not given, the symptoms may progress to a severe hypermetabolic state that can be fatal if the cause is not • BOX 132.4 Causes of Interrupted Intrathecal Baclofen Delivery Pump malfunction Pump failure Battery failure Infections necessitating pump removal Catheter problems (e.g., kinks, holes, tears, dislodgement, disconnection, migration) • BOX 132.5 Differential Diagnosis of Intrathecal Baclofen Withdrawal Autonomic dysreflexia Neuroleptic malignant syndrome Malignant hyperthermia Sepsis Status epilepticus Toxic Metabolic Immune-mediated disorders 1599 • BOX 132.6 Management of Suspected Baclofen Withdrawal • • • • • • • • • • Suspicion in at-risk patients Administer antipyretics and other cooling techniques for fever Administer benzodiazepines for seizures or spasticity Rule out medical causes Oral baclofen therapy Contact patient’s intrathecal baclofen pump specialist to interrogate the pump and check the reservoir Abdominal radiographs (anteroposterior/lateral) to check for catheter integrity Neurosurgical consultation for possible surgical exploration and repair If catheter appears intact on plain radiographs, consider performing a contrast catheter study to check for catheter integrity If problem is unresolved, contact manufacturer recognized and treated Of 27 patients reported to the FDA, six deaths were documented.166 The management of ITB withdrawal requires early diagnosis It involves supportive ICU care and the onset of baclofen replacement therapy as soon as possible Box 132.6 provides a stepwise approach to evaluating patients with suspected baclofen withdrawal A definitive diagnosis may be obtained with measurement of cerebrospinal fluid baclofen levels, but the results probably are not going to be available in a timely manner Although the primary aim should be to replace baclofen, rapid replacement of ITB may not be possible The required oral baclofen replacement dose may be 50 to 100 times the intrathecal dose, and patients may not tolerate this dose very well because of adverse effects IV administration of a BZD should be the initial step in the treatment of baclofen withdrawal Dantrolene has been used as an adjunct therapy for the increased spasticity The use of the potent serotonin antagonist cyproheptadine has been proposed as an alternative treatment adjunct.167 It had improved fever, spasticity, and itching in adult patients with gout who had ITB withdrawal Dosages of cyproheptadine were in the range of 0.25 mg/kg per day every hours, either PO or IM In some patients, ITB withdrawal is an elective management problem due to pump removal for infection In these patients, if a replacement pump cannot be placed, the patient needs to be observed and managed in the ICU to recognize and treat the withdrawal syndrome More recently, there have been reports of dexmedetomidine use as part of the management strategy for both oral and intrathecal baclofen withdrawal.168 The monitoring of creatine phosphokinase (CPK) levels may be helpful in guiding therapy In the reported cases of ITB withdrawal, CPK levels have been in the range of 1800 to more than 40,000.169 Mild elevations in CPK (300–500) may be an early marker of inadequate treatment Cannabis TABLE 132.8 Severity of Intrathecal Baclofen Withdrawal Designation Description Mild Pruritic symptoms and increased spasticity Moderate High fever, altered mental status, seizures and profound rigidity, autonomic instability Severe Rhabdomyolysis, hepatic failure, renal failure, disseminated intravascular coagulation, brain injury, death The medical use of cannabis was first described in ancient Chinese history.170,171 The real breakthrough happened in the mid-1960s, when the psychoactive component of cannabis—D9-tetrahydrocannabinol (D9-THC)—was discovered This led to the formulation of other synthetic analogs of D9-THC and the discovery of the cannabinoids’ receptors CB1 and CB2.170,172 CB1 receptors are believed to regulate the neurotransmitters at the synaptic terminals both in the central and peripheral neurons Centrally, CB1 receptors play an important role in movement control, pain and sensory perception, appetite, emotions, and autonomic and ... use.134 However, this requirement should not preclude the use of flumazenil in an ICU setting.135 Flumazenil has been used for the reversal of moderate sedation The onset is usually within to minutes,... serotonin pathways to this long-term inhibition that is consistent with the usually observed increasing doses required for ITB during the first 12 to 18 months of treatment When this inhibition is... (TCA) The half-life of TCE is to 12 hours, whereas that of TCA is 67 hours In infants and neonates, this may be increased by a magnitude of three to four With multiple dosing, a significant potential