1600 SECTION XIV Pediatric Critical Care Anesthesia Principles in the Pediatric Intensive Care Unit endocrine functions This explains cannabis use in chronic and neuropathic pain control,129 muscle sp[.]
1600 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit endocrine functions This explains cannabis use in chronic and neuropathic pain control,129 muscle spasticity, anorexia, sleep disorder, and some complex seizure disorders, such as Dravet syndrome, Doose syndrome, and Lennox-Gastaut syndrome.171–174 In a study investigating the use of cannabidiol-enriched cannabis in pediatric patients with treatment-resistant epilepsy, 84% of patients were reported to have reduction or complete cessation of seizure activity while taking cannabis.175 More than two-thirds of the subjects were reported to have better mood, increased alertness, and better sleep.175 In a recent prospective, open-label, expanded-access trial at 11 independent epilepsy centers in the United States, Devinsky et al.176 enrolled 214 patients (age 1–30 years) with severe, intractable, childhood-onset, treatmentresistant epilepsy to receive oral cannabidiol at to mg/kg per day There was a reduction in seizure frequency in many patients, with an adequate safety profile reported in this patient population with highly treatment-resistant epilepsies The study reported baseline median monthly frequency of motor seizures of 30.0 (IQR 11.0–96.0) with a decrease to 15.8 (5.6–57.6) over the 12week treatment period The median change in monthly motor seizures from baseline was –36.5% (IQR –64.70 to 0).176 It is believed that cannabidiol has anticonvulsive properties without demonstrating any proconvulsive effect that THC has.177 A recent case series from Germany reported few benefits, including reduction of muscle spasticity and improvement of dystonia, after using D9-THC in patients with neurodegenerative disease, mitochondriopathy, hypoxic ischemic encephalopathy, epilepsy, and posttraumatic reaction.178 These patients are frequently seen in PICUs for status epilepticus or breakthrough seizures The use of cannabis in these patients may potentially reduce the need for frequent hospitalization and thus reduce the risk of all possible adverse events that could be related to the critical care environment.179 Peripherally, CB1 receptors have been identified in the GI tract (intestine and liver), adipose tissue, and skeletal muscles Cannabis has been used to control nausea in patients with and without cancer.180 The presence of CB1 receptors in the GI tract and its antiemetic effect could suggest a role for cannabis in the treatment of certain GI diseases, such as irritable bowel syndrome Medical use of cannabis is legal in Canada and some US states Further research is needed to understand the mechanism of actions of D9-THC and the nonpsychoactive compound cannabidiol, and their interaction for optimizing potential therapy with the least adverse effects Dexmedetomidine Dexmedetomidine (Precedex) is a selective a2-adrenergic agonist It acts centrally in the locus ceruleus (sedation), in the spinal cord (analgesia), and in autonomic ganglia Stimulation of the a2receptor decreases the release of norepinephrine, inhibits sympathetic activity, and produces sedation, anxiolysis, and analgesia It is 1600 times more active at the a2-receptor than at the a1-receptor and thus eight times more selective than clonidine In adults, it has a redistribution phase of minutes and an elimination halflife of hours The pharmacokinetics appears to be similar in the pediatric patient, even after a 24-hour infusion.181 Dexmedetomidine is almost completely metabolized in the liver by uridine-5diphosphate-glucuronyltransferase and, to a lesser extent, by cytochrome P450 pathway to inactive metabolites It is highly lipophilic and has a large volume of distribution Clearance is reduced in neonates and infants possibly due to immaturity of the elimination pathways Clearance in term neonates is 42.2% of adult values but reaching 84.5% by the end of the first year of age In patients with renal failure, the pharmacokinetics did not show any prolongation of the terminal half-life However, these patients were sedated longer after the infusion was terminated compared with the control group.182 The prolonged sedation may be related to reduced protein binding of this normally highly protein-bound drug (94%) and thus higher free drug levels in the patient with renal failure In patients with hepatic dysfunction, reduced clearance has been reported With patients in severe hepatic failure, extension of the half-life to almost three times longer than normal was reported.183 Dexmedetomidine has proved to be effective for sedation in the adult intensive care setting,184 and its use in PICUs has gained popularity Several reports mostly have shown it to be safe and efficacious in critically ill infants and children.185–190 Dexmedetomidine is commonly used as a single sedative agent in patients receiving noninvasive mechanical ventilation.185 It is used as an adjunct sedative agent with opioids and/or BZDs in intubated patients while on mechanical ventilation; it allows for a reduction in dosing of other sedatives and analgesics within 24 hours in as many as 40% of the patients.185 Dexmedetomidine has also been used to facilitate extubation Dexmedetomidine has been approved by the FDA as a shortterm sedative (24 hours of sedation), although more prolonged off-label use is widespread and currently pending approval The recommended dosage for dexmedetomidine is a loading dose of 0.5 to 1.0 mg/kg over 10 minutes followed by an infusion of 0.2 to 0.7 mg/kg per hour It appears that in pediatric patients, a higher end of the dose range is required Doses higher than 1.5 mg/kg per hour have not been shown to provide any further sedative action Advantages of dexmedetomidine include minimal respiratory depression and predictable hemodynamic effects Because of the reduced sympathetic activity, blood pressure and heart rate fall slightly Clinical sedation trials have shown a decrease in heart rate of 7% and blood pressure by 10% It has been infused before, during, and after the extubation process Hypotension and bradycardia are more likely to occur during the loading phase, which may need to be prolonged or interrupted Dexmedetomidine cannot be given by rapid IV bolus because severe bradycardia and hypertension may occur from the direct stimulation of a1-adrenergic receptors Mild transient hypertension is sometimes noted in adults during the loading phase, although this effect was not common in pediatric patients Long-term use of dexmedetomidine (160 hours) also has now been reported, with no evidence of accumulation.191 The concern about rebound hypertension after long-term a2-adrenergic agonist treatment, such as that occurring with clonidine, has not been reported Since prolonged use of dexmedetomidine is now common, withdrawal from dexmedetomidine must be considered.192,193 Agitation, tremor, and sleep disturbances have been reported; however, many of the patients were also exposed to other sedative agents It appears prudent to either wean the dexmedetomidine slowly if the infusion has lasted days or more or substitute a small dose of oral clonidine or the clonidine patch (harder to wean dose) It is worth noting that clonidine has been reported as a sedative in the PICU.194 Clonidine given enterally mg/kg times per day was compared with placebo in 50 children There was no difference in the opiate requirement, BZD requirement, sedation scores, or withdrawal between the placebo group and clonidine group In this small study, it is not clear whether the clonidine dose was sufficient; further studies are required.194 CHAPTER 132 Sedation and Analgesia Dexmedetomidine use in the PICU has been associated with a shorter duration of mechanical ventilation; the potential reduced opioid use and its ability to preserve the respiratory drive are possible factors.186 This is similar to what has been shown in critically ill children after cardiac and thoracic surgery in which dexmedetomidine is effective as a primary agent that may enable earlier extubation.187 It is possible to extubate children on a reduced dose of dexmedetomidine that may prevent postextubation agitation The drug can then continue to be weaned during the rest of the child’s ICU stay.188,189 Sedation from dexmedetomidine often results in a patient who is tranquil yet easily aroused Reduced opioid analgesic requirements have been reported with its use.190 The easy arousal makes it a useful agent for when repeat neurologic examinations are required In a retrospective review of 121 patients from a mixed medical and surgical population in the PICU, a decrease of 20% in the dose of BZD or opioids was documented in 80% of the children who received dexmedetomidine.195 Bradycardia (12%) and hypotension (16%) requiring intervention have been described In burn patients,196 the overall quality of sedation was improved by the addition of dexmedetomidine Many patients were able to be weaned from other sedatives during the dexmedetomidine infusion Dexmedetomidine use in the pediatric cardiac ICU is gaining popularity A retrospective review of dexmedetomidine use (infused 36 hours) in 35 postoperative pediatric cardiac patients did not show any significant changes in cardiovascular parameters, but a reduction in postoperative opioid requirements occurred with an equivalent level of sedation.197 Another study demonstrated less delirium in the postoperative cardiac patients receiving dexmedetomidine.198 Many of these patients had pulmonary hypertension, and there appeared to be no concerns with the use of dexmedetomidine Dexmedetomidine also has antiarrhythmic effects that can treat and prevent arrhythmias in children, especially in the postoperative period.199 Further studies are still required to address questions regarding the metabolism, efficacy, and adverse effects of dexmedetomidine in the PICU population This agent also has been safely used for a variety of noninvasive sedation procedures, such as MRI, and several cases have been reported of its use as an adjunct to general anesthesia for pediatric patients It is a useful agent in the management of opioid withdrawal Furthermore, dexmedetomidine is useful for patients who are difficult to sedate, for the treatment of postoperative shivering, and for postanesthesia agitation Procedural sedation with intranasal (IN) dexmedetomidine also has been reported (IN dexmedetomidine mg/kg, along with IN sufentanil, mg/kg) Dexmedetomidine is not without adverse effects, the most common being bradycardia and hypotension.190 They usually are not life-threatening and improve with lowering the infusion rate or stopping the medication It is contraindicated in patients with heart block, and bradycardia has been reported in an infant treated with digoxin who received dexmedetomidine during the infusion phase.200 It is prudent to avoid its use with other drugs that can reduce arteriovenous node function such as b-blockers and calcium channel blockers It should be avoided also in patients with severe ventricular dysfunction or hypovolemia because reduction in sympathetic tone may cause a profound decrease in blood pressure There are now several reports on the use of dexmedetomidine for toxidromes such as anticholinergic syndrome201 as well as baclofen withdrawal in the PICU.168 1601 Propofol Propofol is a rapid-acting IV anesthetic agent As a highly lipidsoluble 2,6-diisopropylphenol, it is an oil and is insoluble in water It is formulated as a 1% aqueous emulsion (1.2% egg phosphatide, 10% soybean oil, 2.25% glycerol) with a propofol concentration of 10 mg/mL Recovery from propofol is rapid because of its short redistribution half-life, and it is rapidly cleared by hepatic metabolism in healthy patients after short infusions, making it ideal for short procedures The elimination half-life is hours (Table 132.9), but the half-life is context sensitive and has been reported to be between and days after a 10-day infusion because of significant body accumulation The kinetics follows a three-compartment model The dose for induction of anesthesia in children is 2.5 to 3.5 mg/kg; higher doses are required for infants and toddlers Anesthesia also can be maintained by an infusion The depth of sedation/anesthesia can be easily titrated, and an infusion rate of 25 to 150 mg/kg per minute usually provides adequate sedation As with most sedative agents, propofol has adverse effects It often causes hypotension in the critically ill child In patients dependent on high sympathetic tone to maintain normal blood pressure, even small doses of propofol may significantly decrease blood pressure The hypotension is mainly caused by vasodilation; there is little direct myocardial depression Bradycardia can occur upon the induction of anesthesia Propofol anesthesia can prevent the induction of known atrial tachycardias in the electrophysiology laboratory; cases have been reported of conversion of atrial tachycardia to sinus rhythm upon induction of propofol anesthesia Propofol is a potent respiratory depressant; again, this is more likely if propofol is bolus dosed Infusions of 250 to 300 mg/kg per minute can be tolerated if no other sedative agents are used and the airway is carefully positioned and monitored.202 Propofol has a useful depressant effect on airway reflexes and pharyngeal tone, which may facilitate endotracheal intubation in the absence of muscle relaxants The injection of propofol through a peripheral vein often causes pain; thus, strategies to minimize this effect are useful in the alert patient Most commonly, lidocaine—either mixed with propofol or injected immediately before the injection of propofol—will markedly reduce the pain Propofol sedation in the ICU has several advantages It acts rapidly and produces an easily controllable level of sedation Unlike barbiturates, it provides rapid clinical recovery, even after prolonged infusion It has antiemetic properties and can provide transient deep sedation if required for procedures It also has been shown to facilitate sedative synergy with BZDs.203 In the adult ICU population, propofol has been compared with midazolam for long-term sedation Both agents provide good sedation, but TABLE Pharmacokinetics of Intravenous Anesthetic 132.9 Agents Elimination Half-Life (h) Volume Distribution (SS; L/kg) Clearance (mL/kg/min) Protein Binding (%) Etomidate 2.9 2.52 17.9 76.9 Ketamine 3.1 3.10 19.1 12.0 Propofol 1.9 2.30 30.0 96.8 Drug SS, Steady state 1602 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit propofol has the advantage of being more titratable with a faster recovery.204 Despite propofol being more expensive than midazolam, the use of propofol can reduce overall ICU costs because of a reduction in ventilator weaning time.205 In a study of 500 children, propofol significantly reduced the time to extubation in children ventilated for or more days when compared with midazolam There was no difference in mortality between the groups.206 Propofol has been used in the ICU as an anticonvulsant for patients with refractory status epilepticus.207 In a comparison with pentobarbital, both drugs were equally effective in achieving burst suppression Propofol was much more rapid in effect; no difference was found in outcome or ICU support measurements or length of stay.208 In patients with raised ICP, propofol has the same effects as barbiturates on ICP, CBF, and cerebral metabolic rate of oxygen It requires a similar level of hemodynamic support to maintain appropriate blood pressure and cerebral perfusion pressure (CPP) It can produce the same degree of burst suppression that is required for uncontrolled intracranial hypertension It also allows rapid changes in the level of sedation to facilitate neurologic examination In this regard, it is a superior agent As described later, however, the use of large doses of propofol in the ICU setting may be associated with worse outcomes protein ovalbumin.214 In fact, intradermal testing with propofol in 25 patients allergic to eggs was negative; therefore, current evidence suggests that anaphylaxis is not more likely to develop in patients who are allergic to eggs when 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 include different antioxidants, such as metabisulfites, which may have an increased risk of allergic reaction However, this increased risk has not been borne out.215 They appear to be equal in efficacy and adverse effects to the propofol solution known by the brand name Diprivan A few patients who receive propofol may have dark green urine due to phenol metabolites; this effect is not a clinical concern.216 A new water-soluble prodrug, fospropofol, has been cleared by the FDA and is approved for sedation procedures in adult patients Fospropofol is hydrolyzed by alkaline phosphatases to propofol, phosphate, and formaldehyde The half-life of fospropofol is minutes.217 The onset of action is significantly slower than for propofol (5 minutes), which reduces the incidence of hypotension and respiratory depression The dose is about 6.5 mg/kg as a bolus218 and is not recommended for infusion However, fospropofol requires the same standards of care as propofol Special Issue Regarding Long-Term Infusion of Propofol Propofol Infusion Syndrome Several important problems may result from propofol use 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 routine plasma electrolyte analysis, has been described It is important that the propofol calorie (20 mL/h 528 kcal/day)209 and lipid load be included in the patient’s nutrition plan It may be necessary to reduce enteral feeds or avoid intralipids in selected patients With high propofol dosing, respiratory acidosis has been reported.210 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.211 This infection is due to poor aseptic technique in the preparation and use of the propofol syringes and infusion lines Unusual infective organisms have been detected in several patients; an epidemiologic study by the Centers for Disease Control and Prevention found propofol to be the common element.212 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 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, both anaphylactic and anaphylactoid types, are estimated at in 45,000.213 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 One of the most important concerns in children treated with propofol sedation in the PICU is the development of a refractory metabolic acidosis This effect was first described in 1992 as a series of five cases with fatal myocardial failure in children with respiratory illnesses requiring ventilation and sedation.219 Five young patients from different ICUs had croup and went on to have refractory cardiac failure, bradycardia, and acidosis A lipemic serum developed in all patients, and all received propofol at an average rate of about mg/kg per hour for more than 70 hours In review, these cases were not as simple or as complete in their reporting, with several published letters from physicians involved with these patients showing incomplete data.220 Several other case reports of an apparently similar clinical course were 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 Eventually, this reaction to propofol came to be known as the propofol infusion syndrome (PRIS).221 It is the sudden or relatively sudden onset of a marked bradycardia resistant to treatment, with at 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 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, including studies involving several hundred patients who have not shown any problem with propofol in the PICU.222,223 In these studies, lower doses of propofol (4 mg/kg per hour) were used, with regular monitoring of the acid-base status and triglyceride levels Propofol bashing became popular.224 Subsequently, a randomized controlled trial of propofol was initiated and, after the use of this drug in 327 patients, it was reviewed by the FDA.225 The study was never published However, researchers found that, despite CHAPTER 132 Sedation and Analgesia 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 healthcare workers that propofol was not approved for the sedation of pediatric patients 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.227 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 higher doses of propofol; they also receive vasopressor support to maintain the CPP, which puts a further stress on a myocardium that is already failing The pathophysiology of PRIS is still poorly understood, but it appears to mimic mitochondrial myopathies Patients are generally well until stressed Rhabdomyolysis and cardiac and hepatic failure then develops.228 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.229 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 lactic acidosis is found in different types of genetically acquired cytochrome C oxidase deficiency It was postulated that hemofiltration removed a water-soluble metabolite of propofol that could cause a reversible reduction in oxidase activity A second case report of PRIS230 also showed a metabolic abnormality in the form of elevated levels of malonylcarnitine and C5-acyl This patient was also treated successfully with hemofiltration These findings are consistent with reports of 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 pathophysiology of the syndrome231 suggested that propofol increases the activity of malonyl coenzyme A, which inhibits carnitine palmityl transferase I; thus, long-chain fatty acids cannot enter the mitochondria Propofol also uncouples oxidation; thus, 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 inadequate caloric 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 to mg/kg per minute 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 in the PICU for procedural and short-term sedation.232 However, in a case report, researchers described a patient who had PRIS.233 The patient had received a propofol infusion for 15 hours at 20 mg/kg per hour After a 13-hour 1603 propofol-free period, an 8-hour infusion of propofol at mg/kg per hour was given, after which the patient had intractable bradycardia and acidosis.233 This report raises concerns about high-dose, shortterm propofol use in the PICU In a report on the use of propofol for two cases of refractory status epilepticus, patients aged years and 17 years had features similar to PRIS.234 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 (18–27 mg/kg per hour) to achieve burst suppression for more than 48 hours Rhabdomyolysis and cardiac failure developed in both patients Neither lipid nor acid-base status was monitored, and practitioners with limited experience with this drug used propofol as the sole agent In light of the reports now appearing in the adult neurointensive care literature with the development of a propofol infusion–like syndrome in adult neurosurgical patients,235 it would appear that propofol is not the best choice for prolonged sedation for patients with intracranial hypertension An early indicator of 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.236 Propofol remains a useful agent for procedural sedation in the PICU When compared with midazolam and ketamine, propofol resulted in safe and effective sedation Patients sedated with propofol awakened almost twice as fast; thus, the efficiency of the sedation service was also improved.237 Propofol is also probably appropriate for overnight sedation, and higher doses should be avoided An adjuvant agent should be considered since tolerance appears to develop more rapidly when propofol is used alone If its use is required for a prolonged period, then careful consideration should be given to its risks and benefits; prevention of PRIS should include adequate caloric intake One study showed that some PICUs are still using long-term high doses despite the potential risks involved.238 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 over barbiturates There appears to be a significant mortality (50%) in neurosurgical patients who develop PRIS Regular monitoring of the cardiac function; ECG; and CPK, lipid profile, and acid-base status is warranted It has been suggested that daily CPK measurements may identify those at risk of developing PRIS and allow a change in sedation before the full-blown clinical effects become apparent.239 When more than 5000 U CPK was used as a screening tool, the incidence of PRIS in adult neurosurgical patients fell from 2.9% to 0.19% Of these patients, 7% screened positive for PRIS, and their sedation was changed with no reported mortality Although successful in this report, these steps may not necessarily prevent all mortality from the syndrome.240 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 and 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% involved pediatric patients.241 The features associated with PRIS are shown in Table 132.10 The predicted outcome from these scores is shown in Table 132.11 1604 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit TABLE Features Reported for Propofol Infusion 132.10 Syndrome, Incidence, and Score Feature % Incidence Score Cardiac 44 Hypotension 34 Rhabdomyolysis 27 Hepatic failure 24 Renal failure 24 Metabolic acidosis 20 Dyslipidemias 5 Rhabdomyolysis and hypotension Age ,18 y and renal failure –1 Rhabdomyolysis and renal failure –1 TABLE Predicted Outcome From Propofol Infusion 132.11 Syndrome Score Predicted Mortality Rate (%) 10 25 50 75 90 The debate as to the safety of propofol in the PICU continues Several reports state that use for short duration at low doses has been proven to be safe,242,243 starting at a low dose of 0.5 mg/kg per hour and limiting the maximum dose to mg/kg per hour This approach, along with an infusion duration of 12 to 48 hours, has been reported as safe However, these are small studies; considering that the true incidence is unknown, a negative occurrence in a study of 200 patients still statistically means that the rate of PRIS could as high as 1.5%,244 consistent with data from the neurosurgical population This leaves the intensivist with a difficult conundrum: Does propofol need to be used, or are there suitable alternatives for this patient? Propofol Tolerance and Withdrawal Tolerance to propofol in the ICU setting can develop very quickly, resulting in high doses needed to maintain the desired level of sedation However, despite its widespread use, particularly in the adult ICU setting, reports of propofol withdrawal appear to be very limited in the literature In adults, dosing reduction has been associated with agitation, tremors, and tachycardia.245 A very slow wean of propofol (0.1 mL/h) managed to prevent these symptoms Data in children are limited to a few case reports The Drug Enforcement Agency has outlined the following symptoms as part of a propofol withdrawal syndrome: tachycardia, confusion, hallucinations, fever, agitation, and seizures Delirium associated with this syndrome can persist for a week and the syndrome has been described following only weeks of propofol use The symptoms appear to be quite similar to those of BZD withdrawal consistent with a GABA receptor effect from propofol In the ICU setting, the etiology of these nonspecific symptoms may be difficult to appreciate in a mixed sedation picture It is possible that a low dose of BZD may help with the GABA receptor withdrawal effect Ketamine Ketamine is a phencyclidine derivative that provides sedation and analgesia It works mainly as a noncompetitive antagonism of the N-methyl-D-aspartic acid (NMDA) receptor It provides hypnotic, analgesic, and amnesic (short-term memory loss) effects It targets other receptors, such as a-amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) receptors, and the s1-receptor It results in a state of dissociative (trancelike) anesthesia, which is mainly related to the high degree of phencyclidine site occupancy of NMDA receptors It is available in a variety of dilutions, such as 10, 50, and 100 mg/mL The latter is the most beneficial for IM use and the preparation of infusions For a state of general anesthesia to be induced, a dose of to mg/kg IV is required Onset takes to 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 to 10 mg/kg, although onset is slower (5–10 minutes) and duration of prolonged effect is 45 to 60 minutes Oral and intranasal routes are possible options, especially in pain management Oral dose of S-ketamine of to 15 mg/kg up to 500 mg as a maximum dose has been used for chronic pain A dose of 0.25 to 4.00 mg/kg can be used intranasally.246 It is metabolized by the hepatic cytochrome P450 through the N-demethylation of ketamine to norketamine Unmetabolized ketamine and its metabolites are excreted in the urine.247 The half-life is 3.1 hours (see Table 132.9) The side effects of ketamine include hypertension, tachycardia, increased ICP, and bronchodilation 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.248 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 sialagogue; the use of an anticholinergic agent such as glycopyrrolate may be helpful Its use is contraindicated in patients who cannot tolerate hypertension, have a history of cerebrovascular hemorrhage, have psychiatric disturbances, and have raised ICP It is a useful agent for sedation, 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 2.0 mg/kg per hour.249 After discontinuing its use, the patient should receive BZD to minimize the likelihood of hallucinations and recover in a quiet environment Ketamine cannot be assumed to preserve pharyngeal reflexes any better than other sedative agents; apnea and airway obstruction can still occur.250 Fasting guidelines should still be observed Ketamine has been shown to be effective for refractory status epilepticus (RSE).251 During RSE, there is downregulation of the GABAA receptors, limiting the effectiveness of the BZDs There is, however, an upregulation of NMDA receptors during RSE, which promotes excitotoxicity and further potentiates epileptogenicity.252 On review of the literature, ketamine was effective in ... from the neurosurgical population This leaves the intensivist with a difficult conundrum: Does propofol need to be used, or are there suitable alternatives for this patient? Propofol Tolerance... regarding the metabolism, efficacy, and adverse effects of dexmedetomidine in the PICU population This agent also has been safely used for a variety of noninvasive sedation procedures, such as MRI,... rhythm upon induction of propofol anesthesia Propofol is a potent respiratory depressant; again, this is more likely if propofol is bolus dosed Infusions of 250 to 300 mg/kg per minute can be tolerated