EMERGENCY SEDATION AND PAIN MANAGEMENT - PART 10 ppsx

central venous return, and decreases in both intracerebral blood flow and intracerebral pressure. These systemic effects are exacerbated in hypovolemic, dis- tributive shock patients. Benzodiazepines bind to benzodiazepine receptors, enhancing GABA effects. Similar to barbiturates, benzodiazepines are negative inotropes with sedative hypnotic properties and no analgesic effect. They are useful adjuvants for induction of intubation and are often combined with opioids during RSI. Benzodiazepines are lipophilic. This is particularly true of midazolam, which has become the most commonly used benzodiazepine for induction. Midazolam is not a tissue irritant and can be given via intramuscular administration. Benzodiazepines potentiate respiratory depression and hypotension effects when used in combination with opioids. Benzodiazepines produce amnesia, are anxio- lytic, and are potent muscle relaxants. They have the unique advantage, compared to other induction agents, of being reversible with flunazemil. Opioids, specifically Fentanyl, may also be useful for anesthesia induction, in addition to premedication. A large dose of fentanyl is used for induction, ranging from 3 to 25 mcg/kg, depending on the adjuvant medications used and the rate of infusion. Hypotension and respiratory depression are associated with fentanyl use in this setting. Chest wall rigidity has been associated with rapidly infused fentanyl at high doses. Opioids also have the advantage of being reversible with naloxone. Propofol is an alkylphenol with an unknown mechanism of action. Propofol is believed to have an inter- action with GABA receptors resulting in effects as a sedative hypnotic with no analgesic effect. Propofol produces amnesia similar to benzodiazepines. Similar to barbiturates, propofol is a myocardial and respiratory depressant that causes hypotension by a reduction in systemic vascular resistance and negative inotropy. Fluid boluses have been shown to mediate this dro p in blood pressure. Propofol causes decreases in ICP, intraocular pressure (IOP), and cerebral perfusion pressure (CPP). It also acts as an anticonvulsant and antiemetic. Owing to its cerebroprotective effects, propofol has been touted as the induction agent of choice in isolated head trauma or status epilepticus. The hypotension and negative ionotropic effects limit its use in multitrauma patients and other clinical scenarios commonly associated with hemodynamic instability. Ketamine is a phenylcycline derivative. It is a dissociative agent that selectively inhibits the cortex and thalamus w hile stimulating the limbic system. These effects produce a catecholamine release, specifically endogenous norepinephrine. The resultant cumulative outcome is an anesthetic dissociative state accompanied by bronchodilation, tachycardia, laryngospasm, hypertension, and bronchorrhea. Ketamine has been found to increase ICP and IOP, and is therefore contraindicated in patients in whom elevations in ICP or IOP would be deleterious. There is clinical evidence to suggest that ketamine increases cardiac output and blood pressure, thereby increasing myocardial oxygen consumption and poten- tiating cardiac ischemia. These effect may, however, be advantageous in the hemorrhagic or septic shock patient. Ketamine is noted for its lack of inhibition of sponta- neous ventilation or laryngeal/pharyngeal reflexes. These properties, along with its bronchodilation and bronchorrhea, have prompted suggestions that ketamine is a useful induction agent in asthma and chronic obstructive pulmonary disease. No patient outcome studies have been performed to substantiate these applications. Etomidate is an imidazole derivative, sedative hypnotic. The mechanism of action for etomidate as an induction agent is unclear. Etomidate is believed to have GABA-like effects and is known to activate alpha 2b adrenoreceptors. Etomidate has no analgesic effects. The use of etomidate is associated with no increase in ICP or cerebral oxygen consumption, making it an ideal agent for head injured patients and others where cerebroprotective properties are valued. Etomidate has minimal effects on the cardiovascular system making it an excellent choice for patients with suspected or known hemodynamic instability. Adrenal suppression is a known effect of etomidate administration. This effect has been associated with increased mortality in the setting of continuous infusion for prolonged sedation. As a consequence, etomidate is primarily restricted to its use as a single dose induction agent as well as, more recently, procedural sedation. Adrenal axis suppression has been reported in etomidate studies considering a single induction dose. 264 Special Considerations for Emergency Procedural Sedation and Analgesia This effect is dose dependent and appears to last less than 12 hr. Given this brief period, as well as the heightened cortisol levels routinely present in critically ill patients, there does not appear to be an adverse clinical effect associated with this adrenal suppression. However, recent studies demonstrating adrenal suppression in many septic patients have caused many clinicians to question the potential for harm with eto - midate induction in this population. No controlled or definitive studies have been performed to date to address this question. Given the current evidence, etomidate use should likely be removed from practice in those patients with a high clinical likelihood of sepsis. Alternatively, adjunctive treatment with a steroid, such as dexamethasone, at the time of etomidate induction can also serve to offset this concern in septic patients. Scopolamine is an anticholinergic muscarinic agent that acts by blocking acetylcholine (ACh) at muscarinic receptors. Scopolamine has both a sedative and amnesic effect, but no analgesia. Scopolamine use may cause tachycardia and resultant increased myocardial oxygen consumption, but is otherwise unremarkable for significant hemodynamic effects. For this reason, scopolamine has been used as an induction agent in uncompensated shock. A significant side effect to scopolamine use is the development of acute psychotic reactions. These events appear to be dose related and have limited its routine use for induction. Neuromuscular Blocking Agents/Paralytics Neuromuscular blocking agents, when added to induction agents, have been found to greatly increase the ease and success of tracheal intubation by optimizing visu- alization and patient muscle relaxation. Paralytics have a site of action at the motor endplate of the ACh receptor. There are two classes of paralytics: depolarizing agents and nondepolarizing agents (Table 38-3). Depolarizing neuromuscular blocking agents bind ACh receptors noncompetitively, leading to prolonged de- polarization and muscle paralysis. Succinylcholine is a dimer of acetylcholine molecules. First, it causes sodium channels to open leading to cell membrane depolariza- tion, which manifests as muscle fasciculation. Succinyl- choline then blocks synaptic transmission by blocking the ACh receptor with the resultant effect of muscular paralysis. Succinylcholine degradation occurs in plasma and the liver by pseudocholinesterases. Succinylcholine is the time-honored and most commonly used short-acting paralytic agent for RSI. The main complicating factors associated with the use of succinylcholine as a neuromuscular blocking agent are hyperkalemia, cardiac dysrhythmias, and malignant hyperthermia. The change in potassium levels induced by succinylcholine appears to range from –0.04 to 0.6 mmo l/l. Elevations in potassium associated with succinylcholine appear to peak at 5 min postinjection and resolve within 15 min. The hyperkalemia response appears to be the most significant in patients with large total body surface area burns greater than 24 hr old, patients with crush injuries (typically greater than 7 days old), paralysis, tetanus, myopathies, acute rhabdomyolysis, and sepsis. Ther e have been reported deaths secondary to succinylcholine-induce d hyperkalemia, though most Table 38-3. Neuromuscular blocking agents for consideration during RSI Medication Dose Onset Duration Indications Adverse reactions Adults Pediatrics Succinylcholine 1.5–2.0 mg/kg IV 0.1–0.15 mg/kg IV 1–2 min 8–11 min Any emergent RSI where not contraindicated Hyperkalemia, cardiac dysarrhythmias, malignant hyperthermia, prolonged paralysis Rocuronium 1.0 mg/kg IV 0.6 mg/kg IV 2–3 min 60 min When succinylcholine is contraindicated Apnea, bronchospasm Induction Agents for Sequence Intubation 265 of these cases have been children with undiagnosed myopathies. It has been suggested that caution be exercised with the use of succinylcholine in renal patients. A recent literature review has revealed that succinylcholine appears to be safe if there are no other risk factors for hyperkalemia present at the time of induction. Succi- nylcholine-associated dysrhythmias are typically char- acterized as bradyarrhythmias with rare reports of asystole and ventricular tachyarrhythmias. These arrhythmias typically occur in the pediatric population or in adults who receive more than a single dose of succinylcholine. For this reason, a dose of atropine is routinely administered in children as pretreatment and prior to repeat dosing of succinylcholine in adults. A history of malignant hyperthermia existing in the patient or the patient’s family is a contraindication to the use of succinylcholine. Studies have found that patients who have a masseter spasm with induction using thiopental or fentanyl are also at increased risk of a succinylcholine-induced hyperthermic event. Prolonged apnea can occur whenever succinylcholine is administered, and preparations for this event should be made before the use of the drug. Succinylcholine breakdown occurs in the liver by pseudocholinesterases. This metabolism can be decreased by a variety of conditions including hepatic disease, anemia, renal disease, pregnancy, extremes of age, cancer, cocaine intoxication, or a genetic pseudocholinesterase deficiency. Nondepolarizing neuromuscular blocking agents com- petitively block ACh receptors without stimulating the receptor. These agents are typically used in the emergent RSI setting when succinylcholine is contraindicated. Nondepolarizing agents have fewer side effects and may also be reversed with cholinesterase inhibitors such as neostigmine and edrophonium. Nondepolarizing neuromuscular blocking agents may be divided into long-acting and intermediate-acting agents with a varying time of onset. Pancuronium has the longest onset time and longest duration of action among nondepolarizing agents, specifically with cumulative do sing. Pancuronium has complications of vagolytic effects (tachycardia, hypertension, and increased cardiac output), prolonged paralysis, and histamine release that can lead to bronchospasm or even anaphylaxis. Pancuronium has for the most part been abandoned as an RSI medication owing to these adverse effects and its long onset time and duration. It has been replaced by the intermediate-acting depolarizing agents. The intermediate-acting, nondepolarizing neuromuscular blocking agents include Atracurium, Miva- curium, Vercuronium, and Rocuronium. Rocuronium has the shortest onset time and has shown the most promise as an emergent RSI selection agent in clinical scenarios where the use of succinylcholine is contraindicated or considered inappropriate. These agents all have longer durations of action than succinylcholine. The ability to successfully bag-valve mask ventilate a patient should be assured prior to their administration. SUMMARY Rapid sequence induction has become a necessary and frequent procedure for the emergency physician. A working knowledge of RSI medications and techniques is essential to the provision of emergent airway skills. BIBLIOGRAPHY 1. Dronen S. Rapid-sequence intubation: A safe but ill– defined procedure. Acad Emerg Med 1999;6:1–2. 2. Sakles JC, Laurin EG, Rantapaa AA, Panecek EA. Airway management in the emergency department: A one-year study of 610 tracheal intubations. Ann Emerg Med 1998;31:325–332. 3. Thompson JD, Fish S, Ruiz E. Succinylcholine for endotracheal intubation Ann Emerg Med 1982;11:526–528. 4. Dufour DG, Larose DL, Clement SC. Rapid-sequence intubation in the emergency department. J Emerg Med 1995;12:705–710. 5. Sivilotti MLA, Filbin MR, Murray HE, Slasor P, Walls RM. Does the sedative agent facilitate emergency rapid sequence intubation. Acad Emerg Med 2003;10:612–620. 6. Miller RD, Anesthesia, 5th edn. New York: Churchill Livingstone, 2000. 7. Robinson N, Clancy M. In patients with head injury undergoing rapid sequence intubation, does pretreatment with intravenous lignocaine/lidocaine lead to an improved neurological outcome? A review of the literature. Emerg Med J 2001;18:453–457. 8. Levitt MA, Dresden GM. The efficacy of esmolol versus lidocaine to attenuate the hemodynamic response to intubation in isolated head trauma patients. Acad Emerg Med 2001;8:19–24. 9. Clancy M, Halford S, Walls R, Murphy M. In patients with head injuries who undergo rapid sequence intubation using succinylcholine, does pretreatment with a 266 Special Considerations for Emergency Procedural Sedation and Analgesia competitive neuromuscular blocking agent improve outcome? A literature review. Emerg Med J 2001;18:373–375. 10. Brucia JJ, Owen DC, Rudy EB. The effects of lidocaine on intracranial hypertension. J Neurosci Nurs 1992;24: 205–214. 11. Koenig KL. Rapid–sequence intubation of head trauma patients: Prevention of fasciculations with pancuronium versus minidose succinylcholine. Ann Emerg Med 1992;21:929–932. 12. Bergen JM, Smith DC. A review of etomidate for rapid sequence intubation in the emergency department. J Emerg Med 1997;15:221–230. 13. Perry J, Lee J, Wells G. Are intubations conditions using rocuronium equivalent to those using succinylcholine? Acad Emerg Med 2002;9:813–823. 14. Perry J, Lee J, Wells G. Rocuronium versus succinylcholine for rapid sequence induction intubation. Cochrane Data- base Syst Rev 2003;1:CD002788. Induction Agents for Sequence Intubation 267 39 Sedation and Analgesia for the Critical Care Patient Richard Riker and Gilles Fraser SCOPE OF THE PROBLEM CLINICAL ASSESSMENT PAIN AND SEDATION CONSIDERATIONS PAIN AND SEDATION MANAGEMENT Opiates Opiate choices Controversial issues Opiate-based ‘‘sedation.’’ Benzodiazepines Controversial issues Propylene glycol toxicity. Benzodiazepine-induced delirium Propofol Controversial issues Bradycardia, acidosis, propofol infusion syndrome (pris) Propofol as a preferred long-term sedative option? Haloperidol Controversial issues Haloperidol improves outcomes? Atypical Antipsychotic Agents Dexmedetomidine Controversial issues Long-term dexmedetomidine use SUMMARY BIBLIOGRAPHY SCOPE OF THE PROBLEM Despite our best efforts to provide a humane environment for cri tically ill patients, up to 74% become agitated during their intensive care unit (ICU) stay, and as many recall unpleasant memories of their ICU stay including unrelieved pain, slee p deprivation, anxiety, nightmares, and hallucinations. All of these experiences may be associated with development of adverse outcomes, including posttraumatic stress disorder. In addition, agitation is commonly associated with unplanned patient removal of endotracheal tubes or other devices such as vascular catheters and enteral feeding tubes. These events may contribute to increased patient morbidity and additional hospital expense. Clearly inadequate sedation and analgesia are clini- cally detrimental, but excessive sedation is also unde- sirable because it may lead to prolonged mechanical ventilatory support, ICU length of stay, and increased neurodiagnostic testing. These factors extend the eco- nomic burden of sedating medications beyond the estimated $1 billion spent yearly for the purchase of this group of drugs. Finding a balance between the provision of patient comfort and oversedation has been difficult. Agitated ICU patients offer many unique challenges to clinicians. 268 They often suffer from multiple organ dysfunction, require prolonged periods of therapy, and may not be able to communicate their needs. Recently published ICU sedation and analgesia guidelines provide a framework for choosing appropriate therapeutic strategies designed to maximize the provision of patient comfort. The foundation for these recommendations is based on three issues: (a) the iden- tification of the cause of agitation whenever possible, (b) specific patient comorbidities, and (c) drug pharmacokinetics, pharmacodynamics, and side-effect profile (Table 39 -1 ). It should be emphasized that although appropriate drug selection is important, accurate dose titration of sedatives and analgesics may be a more vexing and clin- ically relevant concern for physicians caring for a critical care patient. The use of validated scoring tools embedded in protocols has been recommended by the Society of Critical Care Medicine along with a daily evaluation of underlying mental status and depth of sedation. These strategies have been shown to markedly improve clinical outcomes (Table 39-2). CLINICAL ASSESSMENT Critical care practitioners easily recognize pain resulting from trauma, chest tube placement, pancreatitis, or from surgic al incisions. Despite this, as many as 30% of patients report that their analgesic needs were not met during their ICU stay. When surveyed about the causes of discomfort, patients suggest that the more mundane aspects of critical care are very troubling and are neither acknowledged nor treated by their caregivers. The mere presence of an endotracheal tube or various vascular or drainage catheters, and even repositioning are significant stressors for the critically ill patient. Adding to the dilemma is the fact that these patients are often unable to communicate their needs to clinicians. As a result, clinicians must rely on physiologic and behavioral clues such as moaning, grimacing, splinting, and the presence of elevated blood pressure and heart rates for evaluation of pain. PAIN AND SEDATION CONSIDERATIONS Owing to the difficulties in identifying pain or discomfort in many patients and because oligoanalgesia is the most prominent cause of ICU agitation, analgesic medications are often thought to be an appropriate initial therapeutic option when the etiology of agitation is uncertain. Caregivers can evaluate the contribution of pain to these patient behaviors by intravenously administering a bolus dose of a rapid-acting opiate such as fentanyl and assessing patient response. As this strategy has evolved, many now consider that the initial provision of opiates, with supplemental sedation as needed, represents the most humane strategy to a lleviate agita tion in many IC U patients (Figur e 39-1 ). This approach is effective for initial patient management and may result in reduced mechanical ventilatory require- ments and ICU length of stay. PAIN AND SEDATION MANAGEMENT Opiates Sir William Osler once referred to morphine as ‘‘God’s own medicine.’’ Indeed it is difficult to overstate the impact of this medication and the other opiates for relief of pain and suffering. All opiates share similar pharmacology by interacting with various opiate receptors in the body. Although relief of pain is generally the most desired pharmacologic effect of the opiates, other aspects of opiate treatment are just as prominent (albeit in a less positive way) in the critically ill patient, including respiratory depression, gastrointestinal dysmotility, tolerance, and drug withdrawal. Opiate choices Distinctions among the opiates can help guide the choice of medications in a particular patient (Table 39-3). The liver metabolizes all opiates except remifentanil, and some have active metabolites that can accumulate in the setting Table 39-1. Essential factors for choosing appropriate ICU therapeutic strategies designed to maximize the provision of patient comfort  Define the cause of agitation whenever possible  Consider specific patient comorbidities  Consider analgesic and sedative drug pharmacokinetics, pharmacodynamics, and side-effect profiles Sedation for the Critical Care Patient 269 of renal disease. For instance, accumulation of the glu- curonide salts of morphine may lead to excessive narcosis whereas normeperidine, the metabolite of meperidine, may cause neurotoxicity. As a result, the opiates of choice in patients with a reduced glomerular function include fentanyl and hydromorphone. Selecting between these two agents is determined by the need for a more rapid onset (fentanyl) or prolonged duration (hydromorphone). Another pharmac ologic distinction between the opiates is the tendency of morphine to cause histamine release. The resultant vasodilatation may represent a therapeutic advantage when preload reduction is desirable. On the other hand, hypotension and bronchospasm associated with histamine release may represent a risk to the patient with unstable hemodynamics and reactive airways disease. Fentanyl may be a better option for these patients. Methadone is a unique opiate because it acts as a mu receptor agonist and an N-methyl-D-aspartate (NMDA) antagonist. This agent can often restore analgesic activity to patients tolerant to standard opiates and at doses that are only 10–15% of expected ‘‘equivalent’’ doses. The long half-life of this agent, good bioavailability, and low cost make methadone a reasonable analgesic espe- cially for patients who require high doses of standard opiates or who are transitioning from an intravenous opiate infusion to an enteral for mulation. Methadone Table 39-2. Studies that have evaluated the impact of analgesia and sedation assessment on ICU patient outcomes Author Tool Study design Number of patients Patient type Benefits Kress Ramsay with protocol target ¼ wakefulness and daily sedation interruption RCT 128 MICU Reduced ventilatory time by 33%, ICU stay by 35%, neurodiagnostic testing by 67% Schweickert Ramsay with protocol target ¼ wakefulness and daily sedation interruption Blinded, retrospective review of RCT 126 MICU Reduced ICU complications (VAP, bacteremia, barotrau- mas, VTE, cholestasis, sinusitis) by 50% De Jonghe ATICE with algorithm target ¼ wakefulness Prospective controlled study 102 MICU Reduced ventilator time by 57%, ICU stay by 47%, pressure sores by 50% Kress Ramsay with protocol target ¼ wakefulness and daily sedation interruption RCT with follow-up psychologic evaluation 32 MICU Reduced incidence of PTSD (31% vs 0%, p ¼ 0.06) Brook Ramsay with protocol target ¼ wakefulness RCT 321 MICU Reduced ventilator time by 28%, ICU stay by 30%, tracheostomies by 53% Brattebo MAAS with protocol to ‘‘avoid excessive sedation’’ Before-after 285 SICU Reduced ventilatory time by 28% Chanques Systematic BPS, NRS, RASS evaluations Two-phase prospective controlled 230 Mixed Reduced incidence of pain by 33% and agitation by 59% Notes: For all results except where noted, p < .05. RCT, randomized controlled trial; MICU, medical ICU; SICU, surgical ICU; VAP, ventilator-associated pneumonia; VTE, venous thromboembolic disorder; ATICE, adaptation to the intensive care environment; MAAS, motor activity assessment scale; PTSD, posttraumatic stress disorder; BPS, behavioral pain scale; NRS, numerical rating scale; RASS, Richmond agitation sedation scale. 270 Special Considerations for Emergency Procedural Sedation and Analgesia is also unique in that it can prolong the QTc on the electrocardiogram. The current literature strongly suggests that methadone-associated QTc interval prolongation may heighten the risk of torsades des pointes. In addition to QT prolongation, bradycardia has also been linked to high-dose methadone use in ICU patients. Meperidine remains a less desirable medication to treat p ain in the ICU patient because of its neurotoxic potential and its association with delirium. Meperidine may stimulate central serotonin release and, in con- junction with other serotonin active agents (mono- amine oxidase inhibitors, selegiline, and possibly the selective serotonin reuptake inhibitors), may be associated with the potentially lethal serotonin syndrome – confusion, restlessness, tremor, myoclonus, hyperreflexia, ataxia, tachycardia, hypertension, fever, and rhabdomyolysis. Remifentanil is a recently approved ultra short- acting parenteral opiate with a half-life of 3–10 min. It is metabolized by blood and tissue esterases. Use of remifentanil in the critical care setting is supported by a number of studies. It may offer an advantage over standard opiates because it is easily titratable as a continuous infusion and may not adversely affect intracranial pres- sures. A potential disadvantage of remifentanil is the rapid development of tolerance with a relative loss of analgesic activity. Controversial issues OPIATE-BASED ‘‘SEDATION.’’ Mounting evidence sup- ports the contention that ICU agitation may be effec- tively treated with opiates alone or in combination with traditiona l sedativ es (Ta ble 39-4 ) This therap eutic strategy acknowledges that the source of agitation is Yes Reassess goal daily, Titrate and taper therapy to maintain goal, Consider daily wake-up, Taper if > 1 week high-dose therapy & monitor for withdrawal No Set Goal for Analgesia Hemodynamically Unstable Fentanyl 25 - 100 mcg IVP Q 5-15 min, or Hydromorphone 0.25 - 0.75 mg IVP Q 5 - 15 min Hemodynamically stable Morphine 2 - 5 mg IVP Q 5 - 15 min Repeat until pain controlled, then scheduled doses + prn Set Goal for Sedation Acute Agitation # Midazolam 2 - 5 mg IVP Q 5 - 15 min until acute event controlled Ongoing Sedation # Lorazepam 1 - 4 mg IVP Q 10-20 min until at goal then Q 2 - 6 hr scheduled + prn, or Propofol start 5 mcg/kg/min, titrate Q 5 min until at goal Set Goal for Control of Delirium Haloperidol 2 - 10 mg IVP Q 20 - 30 min, then 25% of loading dose Q 6hr IVP Doses more often than Q 2hr? Consider continuous infusion opiate or sedative > 3 Days Propofol? (except neuro pt.) Convert to Lorazepam Yes Benzodiazepine or Opioid: Taper Infusion Rate by 10-25% Per Day Yes Doses approximate for 70kg adult Rule out and Correct Reversible Causes Use Non-pharmacologic Treament, Optimize the Environment ALGORITHM FOR SEDATION AND ANALGESIA OF MECHANICALLY VENTILATED PATIENTS Use Pain Scale * to Assess for Pain Use Sedation Scale ** to Assess for Agitation/Anxiety Use Delirium Scale *** to Assess for Delirium Is the Patient Comfortable & at Goal? 1 2 3 4 Lorazepam via infusion? Use a low rate and IVP loading doses Figure 39-1. Algorithm for sedation and analgesia of mechanically ventilated patients. Sedation for the Critical Care Patient 271 often unrecognized patient discomfort and focuses on analgesia therapy while reserving sedatives for refractory cases. This strategy also recognizes that traditional modes of sedation carry avoidable risks – benzodiazepines and delirium, propofol and cardiovascular impairment. Comparative studies have demonstrated a reduction in the need for mechanical ventilation as well as ICU stay with opiate-based ‘‘sedation.’’ It should be noted that a range of patients, 30–74%, will require benzodiazepine or propofol sedative rescue with this strategy. Benzodiazepines Benzodiazepines are gamma-aminobutyric acid (GABA) agonists that offer anxiolysis and amnestic effects that may be useful for ICU patients. The benzodiazepine agents most commonly used are midazolam and lorazepam. Pharmacokinetic and pharmacodynamic distinctions will direct the choice of one benzodiazepine agent over another. In the physiologic milieu of blood pH, midazolam becomes a highly lipid soluble moiety resulting in a more rapid onset of action than lorazepam. Mid- azolam is metabolized in the liver by cytochrome P450 3A4 with a half-life of approximately 3 hr. The uncon- jugated alpha-hydroxy metabolite of midazolam has nearly two-thirds the activity of the parent drug and accumulates in renal failure. Formatio n and accumulation of the active metabolite, accumulation of the parent drug in adipose tissue, and altered midazolam clearance resulting from a number of CYP 3A4 mediated drug interactions help to explain the consistent finding of prolonged sedation with long-term midazolam use (>3 days). Controversial issues PROPYLENE GLYCOL TO XICITY. Lorazepam is relatively insoluble in aqueous media requiring the inclusion of the diluent propylene glycol (PG) to permit parenteral administration. Although the Food and Drug Admin- istration (FDA) regards PG as ‘‘generally recognized as Table 39-3. Opiate considerations for analgesia and sedation in the critically ill patient – agents listed by descending duration of clinical activity (for dosing refer to Figure 39-1). Drug Site of metabolism Considerations Methadone Liver Effective at mu and NMDA receptors Long half-life May prolong QTc interval Meperidine Liver Neurotoxic metabolites Associated with delirium Morphine Liver Histamine release Longer acting than short-acting agents Hydromorphone Liver Longer acting than short-acting agents Good selection with impaired renal function Fentanyl Liver Rapid onset Short half-life Good selection with impaired renal function Remifentanil Esterases in blood and body tissues Rapid onset Ultra short half-life Relatively rapid development of tolerance Note: GFR, glomerular filtration rate; QTc, corrected Q-T interval. Table 39-4. Commonly utilized agents for sedation in the critically ill patient (for dosing refer to Figure 39-1). Lorazepam Midazolam Propofol Haloperidol Dexmedetomidine 272 Special Considerations for Emergency Procedural Sedation and Analgesia safe,’’ many accounts describing PG toxicity have been published in the medical literature. Acute tubular necrosis was noted in 15%, metabolic acidosis in 70% , and hyperosmolality in 50% of these patients. Risk factors for developing PG toxicity from parenteral lorazepam therapy include long-term use, high doses , renal and hepatic derangement, pregnancy, age less than 4 years, and treatment with metronidazole. The osmol gap correlates with PG concentrations and represents a widely available, inexpensive surrogate marker to identify possible PG toxicity. Monitoring the osmol gap 2–3 times weekly when daily lorazepam doses exceed 50 mg or approach 1 mg/kg/day is suggested. An osmol gap greater than 10–15 may be associated with toxic PG levels, and this threshold may help clinicians avoid the adverse events associated with PG toxicity. BENZODIAZEPINE-INDUCED DELIRIUM Recent data suggests that the use of lorazepam (and probably midazolam) is an independent risk factor for the development of delirium in ICU patients. One study found that 20 mg lorazepam resulted in the transition to delirium in the following 24 hr in 100% of patients. The most concerning aspect of these data is that the medications that are often administered to patients for anxiety may result in the development of another psychological issue – delirium. Propofol Propofol is popular for short-term sedation in critical patients because it is eminently titratable with a unique consistency in onset and offset. The pharmacology of this agent has not been well described, but it is thought to affect GABA receptors at a site distinct from the benzodiazepines. It has no analgesic activity and its amnestic effects may be less pronounced than that of the benzodiazepines (although this finding is contentious). Propofol is administered as an emulsion in a phospho- lipid vehicle, which contributes 1.1 kcal/ml to the patient’s total caloric intake. Propofol has been associated with a variety of adverse events including (in the order of strength of association) decreases in vascular tone, respiratory depression, hypertriglyceridemia, pancreatitis, interference with myocardial contractility, and neuroexcitatory symp- toms. It has only recently been discovered that propofol may inhibit CYP 3A4 function, leaving open the potential for a myriad of drug interactions. Controversial issues BRADYCARDIA, ACIDOSIS, PROPOFOL INFUSION SYNDROME (PRIS) First described in association with the deaths of five children in 1992, PRIS has now been reported in adults as well. The common aspects in children and adults include sustained (usually longer than 48 hr) high-dose propofol (>75 mcg/kg/min or 4.5 mg/kg/h) with elevated triglycerides, metabolic acidosis, rhabdomyolysis (myoglobinuria and/or elevated serum creatine kinase), hypotension, and bradycardia leading to asystole and death. Variants of these criteria (i.e., isolated metabolic acidosis or bradycardia) have also been reported with prolonged ICU use and more recently during short-term, high-dose, intraoperative propofol use. In the largest adult PRIS case series, Cremer identified PRIS in 7 (10%) of 67 brain-injured patients, 5 occur- ring after changing to 2% propofol. As with other reports, those with PRIS received higher doses of propofol (108 mcg/kg/min) compared to the 60 patients that did not develop PRIS. Recent reviews identify other potential factors in the development of this often-lethal syndrome, including corticosteroi d therapy, sepsis, and systemic inflammatory response syndrome, catecholamine use, and brain injury. Several potential mechanisms have emerged sup- porting the biologic plausibility of this syndrome. Mitochondrial cytochrome oxidase enzyme deficiencies were identified on muscle biopsy from two children with PRIS, and abnormal fatty acid metabolism was associated with PRIS in several pediatric cases, suggesting acquired metabolic disorders result in mitochondrial skeletal and myocardial myopathy. Additional cell cul- ture work has identified a potential connection between propofol and nitric oxide metabolism via the interme- diary nitrosopropofol that interferes with mitochondrial energy metabolism in a concentration-dependent man- ner; this may explain the association with sepsis or systemic inflammatory response in some cases. Although a causal relationship between propofol and this syndrome is not proven, extreme caution and a heightened sensitivity should be applied when administering doses of propofol greater than 75–80 mcg/kg/ min (4.5 mg/kg/hr), monitoring closely for components of the syndrome (creati ne kinase, liver function tests, triglyceride concentrations, evolving metabolic acidosis, Sedation for the Critical Care Patient 273 [...]... 167 Food and Drug Administration (FDA), 99, 116, 272 fracture and joint reduction, 185 procedural sedation clinical assessment, 185–86 follow-up/consultation considerations, 189 pain /sedation considerations, 188–89 pain /sedation management, 186–88 Index regional anesthesia, 230 clinical assessment, 230–31 follow-up/consultation considerations, 236 pain /sedation considerations, 231 pain /sedation management, ... considerations, 76–77 pain /sedation considerations, 76 pain /sedation management, 76 patient-controlled analgesia (PCA), 83–85 pediatric emergency departments (EDs), in PSA, 11 clinical assessment, 11–12 presedation assessment, 12 follow-up/discharge considerations, 16 pain /sedation considerations assessment, 12 distraction method, 12–14 personnel and training, 14 preprocedural fasting, 14–15 special health-care needs,... ischemia-related chest pain, 106 carisprodol, 116 cartridge, 241 cauda equina syndrome, 110 celecoxib, 48, 49, 143 central sensitization system, 137 cerebral perfusion pressure (CPP), 85 cetacaine, 262 chest pain, 103 causes, 104 clinical assessment, 103 cardiovascular etiologies, 104 –5 gastrointestinal etiologies, 105 musculoskeletal etiologies, 105 psychological etiologies, 105 pulmonary etiologies, 105 ... etiologies, 105 follow-up/consultation considerations, 107 pain management cardiovascular etiologies, 106 –7 gastrointestinal etiologies, 107 musculoskeletal etiologies, 107 pulmonary etiologies, 107 from somatic nerve fibers, 106 treatment, 104 from visceral nerve fibers, 106 chloral hydrate, 176 cholelithiasis, 131 chronic pain, 3, 135 clinical assessment, 135–36 considerations, 137–38 follow-up/consultation... 80–81 pain /sedation considerations, 81–82 pain /sedation management analgesic and sedation agents, 82–85 nonpharmacological approaches, to analgesia, 82 regional and local anesthesia, 85 myoclonus, 177, 186 280 nalmefene, 165–67 naloxone, 23, 131, 165 narcotic analgesia, 94, 99, 106 , 107 , 142 narcotic-sparing regimen, 142, 144 nasogastric (NG) tube placement, 200 clinical assessment, 200 follow-up/consultation... comparing analgesia-based sedation using reminfentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: A randomized trial Crit Care 2005;9:R200–R 210 9 Barnes BJ, Gerst C, Smith JR, et al Osmol gap as a surrogate marker for serum propylene glycol concentrations in 276 10 11 12 13 14 15 16 Special Considerations for Emergency Procedural Sedation and Analgesia patients... clinical assessment, 141 follow-up considerations, 144 pain considerations, 141–42 pain management, 142–44 acute myocardial infarction, 104 acute orthopedic injury, 87 clinical assessment, 87–88 follow-up/consultation considerations, 90 pain considerations, 88 pain management, 88–90 acute otitis media (AOM), 92, 91–92 acute pain, 1, 3, 49, 75, 135 acute pericarditis, 104 alfentanil, 188, 262 allodynia,... 206 Neonatal Infant Pain Scale (NIPS), 19 neostigmine, 266 neurogenic claudication, 110 neuromuscular blocking agents, for RSI, 265 neuropathic pain, 137 mechanisms and therapeutic possibilities, 138 neurophysiology, of pain, 44 nitric oxide, 137 nitroglycerin, 106 NitronoxÒ, 82, 257 nitrous oxide, 82, 165, 171, 182, 257–58 N-methyl-d-aspartate (NMDA) antagonist, 138, 270 nociceptive pain, 18–19, 137... oxygenation, 153 pain, dimensions of, 58 pain assessment, 55, 56 clinical assessment, 55–56 clinical significance vs statistical significance, 56–57 multidimensional pain scales BPI-SF, 63–66 CRIES Scale, 62 MPAC, 63 M-PEPPS, 60–62 SF-MPQ, 62–63 vs unidimensional pain scales, 57 reliability, of pain scale, 56 unidimensional pain scales, 57–60 FACES Pain Scale, 59–60 vs multidimensional pain scales, 57... mivacurium, 266 moderate sedation, 6, 8 moderate/large abscess, 196, 197 Modified Pre-Verbal, Early Verbal Pediatric Pain Scale (M-PEPPS), 60–62 morphine, 1, 23, 50–52, 52, 200, 258, 270 morphine sulfate, 106 , 107 MPQ – Short Form (SF-MPQ), 62–63 mu receptor, 49, 270 mucosal administration device (MAD), 170 multidimensional pain scales BPI-SF, 63–66 CRIES Scale, 62 MPAC, 63 M-PEPPS, 60–62 SF-MPQ, 62–63 multimodal . OF THE PROBLEM CLINICAL ASSESSMENT PAIN AND SEDATION CONSIDERATIONS PAIN AND SEDATION MANAGEMENT Opiates Opiate choices Controversial issues Opiate-based ‘ sedation. ’’ Benzodiazepines Controversial. etiologies, 105 follow-up/consultation considerations, 107 pain management cardiovascular etiologies, 106 –7 gastrointestinal etiologies, 107 musculoskeletal etiologies, 107 pulmonary etiologies, 107 from. 188–89 pain /sedation management, 186–88 278 Index regional anesthesia, 230 clinical assessment, 230–31 follow-up/consultation considerations, 236 pain /sedation considerations, 231 pain /sedation management,

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