Achieving Optimal Patient Comfort in the ICU One of the primary goals of caring for patients in the ICU is to achieve optimal patient comfort. The basis for patient comfort is adequate analgesia and adequate sedation. Sedation is divided into 3 primary components: anxiolysis, hypnosis, and amnesia.
The Fine Balance in Patient Comfort The challenge in achieving patient comfort is to find the right balance between undersedation and oversedation.
The Fine Balance in Patient Comfort: Undersedation When patients are undersedated, they will experience anxiety. Left untreated, anxiety may progress to agitation, which may lead to wound disruption and patient injury. In this state, patients are also at risk for a number of potential complications, including hypertension, tachycardia, arrhythmias, and myocardial ischemia. Shelly MP, Wang DY. The assessment of sedation: a look at current methods and possible techniques for the future. Br J Intensive Care . May/June 1992:195-203.
The Fine Balance in Patient Comfort: Oversedation If a patient is oversedated, depersonalization may occur, wherein the patient is treated more like an object than a person. Oversedation may culminate in delayed emergence from the effects of medication and delayed weaning from the mechanical ventilator. These possibilities could expose the patient to pressure injury, venous stasis, and muscle atrophy. All of these factors have tremendous cost implications. Ultimately, the goal is to achieve a balance between undersedation and oversedation through regular assessment. Shelly MP, Wang DY. The assessment of sedation: a look at current methods and possible techniques for the future. Br J Intensive Care . May/June 1992:195-203.
Opioids The chemical structures of fentanyl and morphine sulfate — the 2 most commonly used opioids in the ICU — vary considerably. Fentanyl is more potent than morphine, has a more rapid mechanism of action, and has a shorter duration. Fentanyl can accumulate during prolonged use. It also releases less histamine than morphine and has less effect on cardiac dynamics. Crippen DW. The role of sedation in the ICU patient with pain and agitation. Crit Care Clin . 1990;6:369-392.
Opioids: Clinical Effects In clinical settings, opioids have various effects. They are primarily associated with analgesia, and they can be used as an adjunct when additional sedation is required. 1 Tolerance to these agents can develop. 1 Primary side effects include respiratory depression, withdrawal symptoms following prolonged exposure, hypotension when combined with benzodiazepines, and bradycardia, which are associated to a greater extent with morphine than fentanyl. 1,2 All opiates are associated with constipation. 1 1. Harvey MA. Managing agitation in critically ill patients. Am J Crit Care . 1996;5:7-16. 2. Wagner BKJ, O’Hara DA. Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin Pharmacokinet . 1997;33:426-453.
Sedation/Analgesia: Opioids The opioids are analgesic agents with a secondary effect of anxiolysis. These agents are useful for patients who require pain medication and are agitated as a result of their pain. These agents do not promote hypnosis or amnesia. Harvey MA. Managing agitation in critically ill patients. Am J Crit Care . 1996;5:7-16.
Benzodiazepines: Chemical Structures The chemical structures of the benzodiazepines are different. Diazepam is a lipid soluble agent with active metabolites. The fraction of unbound drug is increased in patients with cirrhosis, renal failure, and burns. Its elimination is decreased by cimetidine and omeprazole. It is no longer commonly used in the ICU. Midazolam is water-soluble and has some active metabolites. The half-life of midazolam, typically 2 hours in healthy adults, can be prolonged in patients who have undergone surgery and those who are older than 50. Lorazepam is a water-soluble agent with no active metabolites. The pharmacokinetics of lorazepam do not change appreciably as a result of aging or critical illness. 1. Wagner BKJ, O’Hara DA. Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin Pharmacokinet . 1997;33:426-453.
Benzodiazepines In summary, there are clear advantages to using benzodiazepines. They cause sedation, anxiolysis, and amnesia in ICU patients. 1 The limitations of these agents include prolonged weaning, 2,3 polyethylene glycol toxicity, 2 respiratory depression, 2,3 hypotension 3 (especially when combined with opioids), lack of analgesia, 4 a tendency toward oversedation or deep sedation, 3 a potential for dependence/tolerance, 3 and paradoxic agitation, especially among elderly patients. 3 1. Pepperman M. Sedation in the intensive care unit: the benzodiazepines and the benzodiazepine antagonist flumazenil (Anexate). Care of the Critically Ill . 1989;5:195- 199. 2. Lerch C, Park GR. Sedation and analgesia. Br Med Bull. 1999;55:76-95. 3. Harvey MA. Managing agitation in critically ill patients. Am J Crit Care . 1996;5:7-16. 4. Crippen DW. The role of sedation in the ICU patient with pain and agitation. Crit Care Clin . 1990;6:369-392.
Sedation/Analgesia: Amnesia, Hypnosis, Anxiolysis With Benzodiazepines When selecting an appropriate agent to achieve optimal sedation, the goals should be broken down into their components: amnesia, hypnosis, and anxiolysis. Depending on patient status, agents may be selected to meet each patient's needs. For instance, some patients require less anxiolysis than others. In some, amnesia is not important; in others, it is. Thus, an appropriate agent can be selected for each circumstance. Benzodiazepines are potent anxiolytics. 1,2 If given in a large enough dose, these agents will induce hypnosis. 2 In terms of sedation, the benzodiazepines are effective for amnesia, hypnosis, and anxiolysis. 1,2 However, they lack analgesic properties. In fact, attempts to use the benzodiazepines without pain medication could disinhibit cortical control and cause agitation. 2 1. Pepperman M. Sedation in the intensive care unit: the benzodiazepines and the benzodiazepine antagonist flumazenil (Anexate). Care of the Critically Ill . 1989;5:195- 199. 2. Harvey MA. Managing agitation in critically ill patients. Am J Crit Care . 1996;5:7-16.
Sedative/Hypnotics: Propofol Propofol, or 2,6-di-isopropylphenol, is metabolized rapidly. Its clearance exceeds hepatic blood flow. Propofol’s metabolites are inactive, so accumulation is not problematic, even among patients experiencing liver or renal failure. 1 This agent is useful when weaning patients from mechanical ventilation and is often used in the ICU for that purpose. 2 1. Lerch C, Park GR. Sedation and analgesia. Br Med Bull . 1999;55:76-95. 2. Harvey MA. Managing agitation in critically ill patients. Am J Crit Care . 1996;5:7-16.
Propofol Infusion syndrome Case reports suggest that propofol infusion for sedation in the ICU may cause a syndrome that can lead to the development of progressive myocardial failure and death. 1-4 A review of the literature by Kang found that propofol infusion syndrome can occur in adults as well as children. 1 Common clinical features are: hyperkalemia, hepatomegaly, lipemia, metabolic acidosis, myocardial failure, and rhabdomyolysis. The author cautions against the use of high dose (>5 mg/kg/h) and long-term (>48 h) propofol in adults in the ICU. In children, the evidence for propofol infusion syndrome can be found in published and unpublished reports. Five case reports of metabolic acidosis and fatal myocardial failure in 5 children receiving propofol were published in 1992 2 ; since then, several serious events related to propofol in children have been published. 3 In an unpublished US trial, death rates among 327 children who received propofol infusions for sedation in the ICU were 11% for those who received 2% propofol (n=113), 8% for those who received 1% propofol (n=109), and 4% for those receiving other sedatives (control group; n=105). 4 1. Kang TM. Propofol infusion syndrome in critically ill patients. Ann Pharmacother. 2002;36:1453-1456. 2. Cremer OL. Lancet . 2001;13:117-118. 3. Stelow EB. Clin Chem . 2000;46:577-581. 4. Parke TJ, Stevens JE, Rice AS, et al. Metabolic acidosis and fatal myocardial failure after propofol infusion in children: five case reports. Br Med J. 1992;305:613-616. 5. Bray RJ. Propofol infusion syndrome in children. Paediatric Anaesth. 1998;8:491-499. 6. AstraZeneca. Letter to healthcare providers. March 26, 2001. 7. Markovitz BP, Feuer P, Cox P. Rare events often happen infrequently: propofol complications revisited. Crit Care Med . 2000;28:2178-2179.
Sedation/Analgesia: Propofol Propofol is an effective anxiolytic agent that induces sleep. 1,2 Its amnestic effect, however, is different from that of the benzodiazepines. With propofol, amnesia occurs at a superhypnotic level 2 ; to ensure amnesia, the patient must be asleep. Thus, the patient taking propofol may remember preoperative instructions as well as any unpleasant events that occurred before the administration of propofol. Like the benzodiazepines, propofol does not have analgesic effects. 2 1. Harvey MA. Managing agitation in critically ill patients. Am J Crit Care . 1996;5:7-16. 2. Wagner BKJ, O’Hara DA. Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin Pharmacokinet . 1997;33:426-453.
2 Agonists: Chemical Structures These are the chemical structures of the two 2 agonists, the older agent clonidine and the newer agent dexmedetomidine.
2 Agonists Dexmedetomidine and clonidine are both 2 agonists; however, dexmedetomidine has an 2 : 1 adrenoreceptor ratio of approximately 1600:1. This is 7 to 8 times higher than clonidine. 1 The elimination half-life of dexmedetomidine is 2 hours versus 8 hours for clonidine. 1 While clonidine is available in tablet, patch, and epidural form, dexmedetomidine is only available as an IV infusion. 2 Clonidine has been used primarily as an antihypertensive agent, but has recently been used as an analgesic adjunct. 1 Dexmedetomidine, on the other hand, is used primarily as a sedative, and also has analgesic-sparing properties. 1 The IV formulation of clonidine is not available in the United States, whereas dexmedetomidine is only available in the United States in an IV formulation. 1. Kamibayashi T, Maze M. Clinical uses of 2 adrenergic agonists. Anesthesiology . 2000;93:1345-349. 2. Khan ZP, Ferguson CN, Jones RM. Alpha-2 and imidazoline receptor agonists: their pharmacology and therapeutic role. Anaesthesia . 1999;54:146- 165.
2 -Receptor Subtypes This figure shows the responses that can be mediated by 2 receptors. The sedative action of these agents originates in the locus ceruleus of the brain stem. The analgesic action is believed to originate in the spinal cord, as well as at peripheral loci. In the heart, these agents decrease tachycardia and promote bradycardia. Sustained vasodilation through sympatholysis and transient vasoconstriction from direct action at smooth-muscle cell receptors occur peripherally. The mechanisms for diuresis and antishivering are not yet clear. Kamibayashi T, Maze M. Clinical uses of 2 adrenergic agonists. Anesthesiology . 2000;93:1345-1349.
Mechanism for 2 -Induced Sedation/Hypnosis in the Rat Locus Ceruleus The effects of the 2 agonist dexmedetomidine in a noradrenergic neuron in the locus ceruleus are shown in this slide. In the cell membrane of the noradrenergic neuron, dexmedetomidine activates the 2 -adrenergic receptor. 1 The receptor couples via 2 G proteins to either inhibit the influx of calcium through voltage-sensitive calcium channels, or to promote the efflux of potassium through potassium channels. 1,2 The net effect is a decrease in cell membrane potential. The hyperpolarized membrane is less likely to fire; thus, the noradrenergic neuron does not release norepinephrine and the events that follow produce a hypnotic response by inhibiting release of histamine. 2 This pattern more or less resembles the natural sleep pathway. 1. Bhana N, Goa KL, McClellan KJ. Demedetomidine. Drugs . 2000;59:263-268. 2. Kamibayashi T, Maze M. Clinical uses of 2 -adrenergic agonists. Anesthesiology . 2000;93:1345-1349.
Cardiorespiratory and Neural Effects The cardiorespiratory and neural effects of the agents are significantly different in several important areas. Although all of the agents decrease blood pressure and heart rate, only the benzodiazepines, propofol, and dexmedetomidine offer cerebral protection. 1-3 Ventilatory depression, an important adverse effect of many of these agents, is not produced by dexmedetomidine or haloperidol. 4,5 1. Wagner BKJ, O’Hara DA. Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clin Pharmacokinet . 1997;33:426-453. 2. Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs . 2000;59:263-268. 3. Maze M. Clinical uses of 2 agonists [white paper]. Stanford, Calif; 2000. 4. Aantaa R, Kallio A, Virtanen R. Dexmedetomidine, a novel 2 - adrenergic agonist: a review of its pharmacodynamic characteristics. Drugs of the Future . 1993;18:49-56. 5. Harvey MA. Managing agitation in critically ill patients. Am J Crit Care . 1996;5:7-16.
Arousability From Sedation During Dexmedetomidine Infusion Patients who were infused with placebo or 1 of 2 doses of dexmedetomidine were monitored with bispectral electroencephalogram (EEG) analysis. Bispectral Index System (BIS) measurements were taken before stimulation and immediately after patients were asked to perform various tasks, such as talking, ratings of alertness, a written cognitive test, a memory test, and a cold pressor test. With either infusion of dexmedetomidine, patients could be completely aroused from sedation with a mild stimulus. Hall JE, Uhrich TD, Barney JA, Arain SR, Ebert TJ. Sedative, amnestic, and analgesic properties of small-dose dexmedetomidine infusions. Anesth Analg . 2000;90:699-705.
Arousal and Task Performance During Equisedative Doses of Benzodiazepine or 2 Agonist in Humans When equisedative doses of a benzodiazepine and an 2 agonist were administered in head-to-head trials, levels of arousal and the performance of specific tasks were impaired by benzodiazepines and relatively unimpaired by 2 agonists. These results were found in response to tests of focused attention, 1 learning, 2 memory, 2-4 performance of specific tasks, 4 and the critical flicker fusion test, 5,6 suggesting a higher level of arousal in patients receiving 2 agonists. 1. Coull JT, Sahakian BJ, Middleton HC, et al. Differential effects of clonidine, haloperidol, diazepam and tryptophan depletion on focused attention and attentional search. Psychopharmacology. 1995;121:222-230. 2. Coull JT, Middleton HC, Robbins TW, Sahakian BJ. Clonidine and diazepam have differential effects on tests of attention and learning. Psychopharmacology. 1995;120:322-332. 3. Hanks GW, O’Neil WM, Simpson P, Wesnes K. The cognitive and psychomotor effects of opioid analgesics: II. A randomized controlled trial of single doses of morphine, lorazepam and placebo in healthy subjects. Eur J Clin Pharmacol. 1995;48:455-460. 4. Coull JT, Middleton HC, Robbins TW, Sahakian BJ. Contrasting effects of clonidine and diazepam on tests of working memory and planning. Psychopharmacology. 1995;120:311-321. 5. Kamibayashi T, Maze M. Clinical uses of 2 -adrenergic agonists. Anesthesiology . 2000;93:1345-1349. 6. Maddock RJ, Casson EJ, Lott LA, Carter CS, Johnson CA. Benzodiazepine effects on flicker sensitivity: role of stimulus frequency and size. Prog Neuropsychopharmacol Biol Psychiatry. 1993;17:955-970.
Mechanisms for Analgesic Effect Analgesic agents act at several levels of the pain pathway to suppress the sensation of pain. At the level of the peripheral nociceptors, opioids inhibit inflammation caused by the release of bradykinin and other kinins, and 2 agonists inhibit sympathetically mediated pain. At the level of the primary afferent neuron, both agents inhibit release of substance P and glutamate, and both directly inhibit the firing of second-order neurons that ascend to the cortex. At the subcortical and cortical levels, both agents decrease the emotive aspects of pain, causing the individual to experience less conscious distress about the pain. On the descending inhibitory pathways, the opiates activate the periaqueductal gray, which gives rise to the descending noradrenergic pathways. The 2 agonists disinhibit the A5 and A7 noradrenergic pathways in the spinal cord. 1 1. Guo T-Z, Jiang J-Y, Butterman AE, Maze M. Dexmedetomidine injection into the locus coeruleus produces antinociception. Anesthesiology . 1996;84:873-881.
Sleep Deprivation Pain, noise, light, and other factors all contribute to the problem of sleep deprivation in the ICU. Patients are continually disturbed for diagnostic, therapeutic, and nursing procedures. As a result, the average amount of sleep per patient in the ICU is 1 hour, 51 minutes during a 24-hour period. Lack of sleep may be detrimental to recovery and may disturb normal mental function. 1. Aurell J, Elmqvist D. Sleep in the surgical intensive care unit: continuous polygraphic recording of sleep in nine patients receiving postoperative care. Br Med J . 1985;290:1029-1032. 2. Freedman N, Kotzer N, Schwab. Patient perception of sleep quality and etiology of sleep disruption in the intensive care unit. Am J Respir Crit Care Med. 1999;159:1155-1162. 3. Gabor JY, Cooper AB, Hanly PJ. Sleep disruption in the intensive care unit. Curr Opin Crit Care. 2001;7:21-27. 4. Brown G, Scott W. An assessment of a sedative algorithm for sleep in an intensive care unit. Off J Can Assoc Crit Care Nurse. 1998;9:20-24.
Sleep Deprivation: Cognitive Function Sleep deprivation is harmful to cognitive function. 1 In patients with 36-hour sleep deprivation, memory was impaired 1 and communication skills became flawed, with an impairment in word generation and verbal fluency. 2 Individuals have difficulty making decisions after 36 hours without sleep, experiencing more rigid thinking and an inability to appreciate updated information. 3 Lack of sleep also may cause a confusional state. These patients are more likely to experience apathy and intensive care unit (ICU) delirium. 4 1. Harrison Y, Horne JA. Sleep loss and temporal memory. Q J Exp Psychol . 2000;53I:271-278. 2. Harrison Y, Horne JA. Sleep deprivation affects speech. Sleep. 1997;20:871-877. 3. Harrison Y, Horne JA. One night of sleep loss impairs innovative thinking and flexible decision making. Organ Behav Hum Decis Proc . 1999;78:128-145. 4. Krachman SL, D'Alonzo GE, Criner GJ. Sleep in the intensive care unit. Chest. 1995;107:1713-1720.
Restorative Properties of Sleep Sleep has restorative powers that aid in the body’s ability to heal itself. 1-3 During sleep, anabolism is predominant over catabolism. Anabolism facilitates the release of growth hormone, which is critical for a positive nitrogen balance and stimulates protein synthesis, enhancing the synthesis of bone and the formation of red blood cells. 1-3 While it promotes anabolism, sleep counteracts catabolism, thus inhibiting the release of cortisol and catecholamines, hormones that are typically found as a product of infection, surgical stress, or trauma. 1 1. Adam K, Oswald I. Sleep helps healing. BMJ . 1984;289:1400-1401. 2. Adam K, Oswald I. Protein synthesis, bodily renewal and the sleep-wake cycle. Clin Sci. 1983;65:561-567. 3. Krachman SL, D'Alonzo GE, Criner GJ. Sleep in the intensive care unit. Chest. 1995;107:1713-1720.
Effect of Sedative Agents on “Repair” Mechanisms During natural sleep, growth hormone is increased, cortisol and catecholamine levels are decreased, and protein synthesis is increased. The sedative agents propofol, the benzodiazepines, and the 2 agonists have an effect on the repair mechanisms associated with sleep. The administration of these sedative agents has the following effects on growth hormone: Propofol has no effect; benzodiazepines may cause a modest decrease, although some studies show otherwise; and 2 agonists increase growth hormone levels. 1-4 All 3 groups of agents decrease cortisol and catecholamine levels. 2,4,5 Propofol has no effect on protein synthesis, 6 and benzodiazepines cause a decrease. 7 A positive nitrogen balance was found in patients who had undergone surgery, suggesting that 2 agonists increase protein synthesis. 2 Agents appear to most closely match the effects of natural sleep on these repair mechanisms. 1. Gottardis M, Fessler R, Luger TJ, Mutz N, Kornberger R. Behavior of human growth hormone after induction of anesthesia using propofol [in German; abstract in English]. Anaesthesist . 1988;37:690-693. 2. Aantaa R, Kallio A, Virtanen R. Dexmedetomidine, a novel 2 -adrenergic agonist: a review of its pharmacodynamic characteristics. Drugs of the Future . 1993;18:49-56. 3. Luger TJ, F ä ssler R, Gottardis M, Koller W, Mutz N. The behavior of hGH (human growth hormone) and somatomedin C after induction of anaesthesia with propofol compared with diazepam and thiopental [in German; abstract in English]. Anasth Intensivther Norfallmed . 1989;24:226-239. 4. Steiger A, Guldner J, Lauer CJ, Meschenmoser C, Pollm ä cher T, Holsboer F. Flumazenil exerts intrinsic activity on sleep EEG and nocturnal hormone secretion in normal controls. Psychopharmacology . 1994;113:334-338. 5. Mitchell P, Smythe G, Torda T. Effect of the anesthetic agent propofol on hormonal responses to ECT. Biol Psychiatry . 1990;28:315-324. 6. Schricker T, Klubein K, Carli F. The independent effect of propofol anesthesia on whole body protein metabolism in humans. Anesthesiology . 1999;90:1636-1642. 7. Heys SD, Norton AC, Dundas CR, Eremin O, Ferguson K, Garlick PJ. Anaesthetic agents and their effect on tissue protein synthesis in the rat. Clin Sci . 1989;77:651-655.
How Closely Do Sedative Agents Mimic Nature? In summary, the 3 groups of sedative agents mimic natural sleep in the following manner: Like natural sleep, 2 agonists promote tissue repair. Benzodiazepines have the opposite effect and propofol has no effect. In terms of immune function, the 2 agonists share the immune effects of natural sleep, while propofol and the benzodiazepines have the opposite effects. And finally, the 2 agonists use the same endogenous neural pathway that produces sleep in rodents, while the benzodiazepines converge on that pathway but not at the level of the locus ceruleus. Although propofol is a GABA-mimetic compound, its mechanism of action is unclear. It appears that, in rodent studies, 2 agonists affect the neural substrates and follow the same endogenous hypnotic pathway that occurs with natural sleep.
Choosing the Right Drug Achieving this balance requires the ability to evaluate the patient’s needs and to choose the right drug.
Drug Combinations Most of the time, achieving patient comfort requires use of more than 1 agent. By using a combination of agents with complimentary clinical effects, all of the components of patient comfort can be achieved in most patients.
Drug Coadministration Administering drugs in combination has several advantages. The doses that are needed to achieve sedation and analgesia are reduced. 1 The development of tolerance to the agents is decreased. Tolerance to opiates is problematic when these agents are used alone. Using lower doses of each drug reduces the side effects that might be caused by larger doses of either agent alone. For example, fentanyl can suppress gastrointestinal motility, 2 but when it is used in low doses with an agent like midazolam, which doesn’t share this side effect, the effect is reduced. The combination of agents can increase the risk of side effects, however, when the side effect is shared by both agents. For example, both fentanyl and midazolam cause respiratory depression and hypotension 3 ; therefore, these agents should only be used in combination in patients who are intubated and mechanically ventilated. 1. Harvey MA. Managing agitation in critically ill patients. Am J Crit Care . 1996;5:7-16. 2. Duke P, Maze M, Morrison P. Dexmedetomidine: a general overview. In: Maze M, Morrison P, eds. Redefining Sedation . London, UK: The Royal Society of Medicine Press Ltd; 1998:11-13. 3. Murray MJ, DeRuyter ML, Harrison BA. Opioids and benzodiazepines. Crit Care Clin . 1995;11:849-873.
Sedation/Analgesia: Patient Comfort In the ICU, the ultimate goal of sedation is to achieve patient comfort. This is attained through adequate analgesia and sedation, including amnesia, hypnosis, and anxiolysis.
Opioid + Sedative Combination An effective clinical strategy is to use the combination of an opioid like fentanyl to achieve analgesia and an agent like midazolam or propofol to produce amnesia, anxiolysis, and hypnosis.
Where Dexmedetomidine Fits In Where does the 2 agonist dexmedetomidine fit in?
Sedation/Analgesia: 2 Agonists The 2 agonists cover the spectrum of patient needs, including analgesia, anxiolysis, hypnosis, and, to some extent, amnesia. 1 The dexmedetomidine-treated patient, when aroused, is less confused and disoriented than the benzodiazepine-treated patient. Indeed, the quality of dexmedetomidine sedation offers several advantages in ICU sedation. 2 When patients are sedated with dexmedetomidine, they appear to be asleep. When aroused, they are alert, but when left alone, they return to a sleeping state. 2 1. Aantaa R, Kallio A, Virtanen R. Dexmedetomidine, a novel 2 -adrenergic agonist: a review of its pharmacodynamic characteristics. Drugs of the Future . 1993;18:49-56. 2. Mantz J, Singer M. Importance of patient orientation and rousability as components of intensive care unit sedation. In: Maze M, Morrison P, eds. Redefining Sedation . London, UK: The Royal Society of Medicine Press Ltd; 1998:23-29.
Sedation/Analgesia: Dexmedetomidine (Primary), Midazolam (Adjunct Sedation) Dexmedetomidine can be used as a primary sedative/analgesic agent. Patients may receive dexmedetomidine as first-line therapy. Depending on the pharmacodynamic variability, some patients will require further sedation and analgesia, while others will not. When dexmedetomidine is used as primary therapy, midazolam may be given adjunctively as a small bolus if needed.
Sedation/Analgesia: Dexmedetomidine (Primary), Propofol (Adjunct Sedation) Similarly, propofol may be given adjunctively during primary therapy with dexmedetomidine if additional sedation is needed. In these cases, propofol may be administered either as a low-dose infusion or a bolus.
Sedation/Analgesia: Dexmedetomidine (Primary), Fentanyl (Adjunct Analgesia) Dexmedetomidine may be given as the primary analgesic agent as well. In this case, therapy is initiated as a continuous infusion and fentanyl is given as an adjunct as needed.
Sedation/Analgesia: Dexmedetomidine (Primary), Morphine (Adjunct Analgesia) Similarly, when dexmedetomidine is used as the primary analgesic, morphine may be given adjunctively as needed for pain relief.
Head Injury: Sedation Patients with brain injury can be agitated or combative and therefore must be sedated Moreover, they must be cooperative so that neurologic assessments can be conducted Dexmedetomidine is beneficial because it can be used as a primary agent or in combination to provide cooperative sedation It must be titrated to the desired effect
Dexmedetomidine Protocol for Trauma Initiate dexmedetomidine as a loading dose only in patients who are very hyperdynamic Gradually increase the dose and titrate to one of the sedation scales Lower doses (<0.7 mcg/kg/hr) are adequate for patients who are not neurologically injured Patients who are agitated due to neurologic injury require higher dosing of <2.0 mcg/kg/hr The higher dose is also appropriate for trauma patients experiencing withdrawal from alcohol or other drugs Patients can be kept on dexmedetomidine through weaning from mechanical ventilation; in some cases, dexmedetomidine therapy may be required for several days or longer
Preoperative Infusion: Protocol Start infusion preoperatively in the holding area. Consider a volume preload of 500 to 1000 cc saline if the patient is hypotonic The loading dose is 1 mcg/kg over 10 minutes. A slow loading dose is important to avoid bradycardia/tachycardia or hypertension Assess sedation after 5 minutes and add on sedation at reduced dosages if needed, typically 1 to 2 mg midazolam (half the dose regularly needed) Monitor BP/HR throughout If bradycardia occurs, treat with atropine After the loading dose, begin the dexmedetomidine infusion at 0.2 to O.7 mcg/kg/hr (typically 0.4 to 0.5 mcg/kg/hr) Transport to the OR with infusion
2 Agonists: Pharmacodynamics The pharmacodynamic properties of 2 agonists include numerous effects. These agents are associated with sedation/hypnosis, anxiolysis, and analgesia. 1 They reduce the sympathetic outflow from the CNS, decreasing blood pressure and heart rate as well as the release of norepinephrine. 1 Shivering, a problem that occurs during certain types of surgery, can be eliminated by administration of 2 agonists. 2 Evidence has shown that these agents have a neuroprotective effect and may potentially reduce the effects of intracranial pressure. 3 Unlike the other sedative agents, 2 agonists do not cause respiratory depression. 1 1. Aantaa R, Kallio A, Virtanen R. Dexmedetomidine, a novel 2 -adrenergic agonist: a review of its pharmacodynamic characteristics. Drugs of the Future . 1993;18:49-56. 2. Kamibayashi T, Maze M. Clinical uses of 2 adrenergic agonists. Anesthesiology . 2000;93:1345-1349. 3. Maze M. Clinical uses of 2 agonists [white paper]. Stanford, Calif; 2000.
Cain dex peds board review
DexmedetomidineJames G. Cain, MD, MBA, FAAPJames G. Cain, MD, MBA, FAAPPast President, International Trauma Anesthesia and Critical Care SocietyPast President, International Trauma Anesthesia and Critical Care SocietyPast President, West Virginia State Society of AnesthesiologistsPast President, West Virginia State Society of AnesthesiologistsDirector, Perioperative Medical Services, Children’s Hospital of Pittsburgh of UPMCDirector, Perioperative Medical Services, Children’s Hospital of Pittsburgh of UPMCDirector, Trauma Anesthesiology, Children’s Hospital of Pittsburgh of UPMCDirector, Trauma Anesthesiology, Children’s Hospital of Pittsburgh of UPMCVisiting Associate Professor, University of PittsburghVisiting Associate Professor, University of Pittsburgh
DisclosuresDisclosures Drug Safety Monitoring BoardDrug Safety Monitoring Board HospiraHospira Off label uses will be discussedOff label uses will be discussed No labeled uses for pediatrics!No labeled uses for pediatrics!3
Dexmedetomidine Labeling:Dexmedetomidine Labeling:Pediatric UsePediatric Use The efficacy, safety, and pharmacokineticsThe efficacy, safety, and pharmacokineticsof Precedex in pediatric patients less thanof Precedex in pediatric patients less than18 years of age have not been established.18 years of age have not been established. Therefore, Precedex should not be used inTherefore, Precedex should not be used inthis population.this population.4
Dexmedetomidine labeled prescribingDexmedetomidine labeled prescribing IndicationsIndications Sedation of initially intubated and mechanically ventilated patients during treatment inSedation of initially intubated and mechanically ventilated patients during treatment inan intensive care setting.an intensive care setting. Administer Precedex by continuous infusion not to exceed 24 hoursAdminister Precedex by continuous infusion not to exceed 24 hours Sedation of non-intubated patients prior to and/or during surgical and otherSedation of non-intubated patients prior to and/or during surgical and otherproceduresprocedures Dosage and administrationDosage and administration Individualize and titrate Precedex dosing to desired clinical effect.Individualize and titrate Precedex dosing to desired clinical effect. Administer Precedex using a controlled infusion device.Administer Precedex using a controlled infusion device. For Intensive Care Unit Sedation:For Intensive Care Unit Sedation: Generally initiate at one mcg/kg over 10 minutes, followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hrGenerally initiate at one mcg/kg over 10 minutes, followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hr For Procedural Sedation:For Procedural Sedation: Generally initiate at one mcg/kg over 10 minutes, followed by a maintenance infusionGenerally initiate at one mcg/kg over 10 minutes, followed by a maintenance infusioninitiated at 0.6 mcg/kg/hr and titrated to achieve desired clinical effect with dosesinitiated at 0.6 mcg/kg/hr and titrated to achieve desired clinical effect with dosesranging from 0.2 to 1 mcg/kg/hr.ranging from 0.2 to 1 mcg/kg/hr. Alternative doses recommended for patients over 65 years of age and awake fiberopticAlternative doses recommended for patients over 65 years of age and awake fiberopticintubation patientsintubation patients.. Precedex™ [package insert].5
Dexmedetomidine labeled prescribingDexmedetomidine labeled prescribing ContraindicationsContraindications NoneNone Adverse reactionsAdverse reactions Incidence greater than 2%Incidence greater than 2% hypotension, bradycardia, and dry mouthhypotension, bradycardia, and dry mouth Associated with infusions greater than 24 hoursAssociated with infusions greater than 24 hours ARDS, respiratory failure, andARDS, respiratory failure, andagitationagitation Drug interactionsDrug interactions Anesthetics, sedatives, hypnotics, opioids: Enhancement of pharmacodynamic effects.Anesthetics, sedatives, hypnotics, opioids: Enhancement of pharmacodynamic effects.Reduction in dosage of Precedex or the concomitant medication may be requiredReduction in dosage of Precedex or the concomitant medication may be required Disease effecting clearanceDisease effecting clearance Clearance is lower in patients with hepatic impairmentClearance is lower in patients with hepatic impairmentPrecedex™ [package insert].6
Hypotension, bradycardia, andHypotension, bradycardia, andsinus arrestsinus arrest Young, healthy volunteers with high vagal tone or rapidYoung, healthy volunteers with high vagal tone or rapidintravenous or bolus administration.intravenous or bolus administration. Potential to augment bradycardia induced by vagal stimuliPotential to augment bradycardia induced by vagal stimuli IV anticholinergic agents may be consideredIV anticholinergic agents may be considered Caution in patients with advanced heart block and/or severeCaution in patients with advanced heart block and/or severeventricular dysfunction.ventricular dysfunction. Hypotension and/or bradycardia may be expected to be moreHypotension and/or bradycardia may be expected to be morepronounced in patients with hypovolemia, diabetes mellitus, orpronounced in patients with hypovolemia, diabetes mellitus, orchronic hypertension and in elderly patients.chronic hypertension and in elderly patients.7Precedex™ [package insert].
Traumatic Brain InjuryTraumatic Brain InjuryPossible Spine InjuryPossible Spine Injury 16 year old male16 year old male Frequently agitatedFrequently agitated Frequently combativeFrequently combative Requires intubationRequires intubation Requires sedationRequires sedation Requires neuroRequires neurocheckschecks Desire cooperativeDesire cooperativepatientpatientChildren’s Hospital of Pittsburgh of UPMC8
What are your concerns? Hemodynamic stabilityHemodynamic stability Existing medications’ limitationsExisting medications’ limitations RespiratoryRespiratory IntubationIntubation ICUICU NeuroNeuro Agitation/delirium concernsAgitation/delirium concerns Ability to do “wake-up” neuro checksAbility to do “wake-up” neuro checks Rapid examRapid exam NeuroprotectiveNeuroprotective9
ConsiderationsConsiderations What is tWhat is the underlying processhe underlying processrequiring treatment?requiring treatment? How does drug/technique addressHow does drug/technique addressunderlying problemunderlying problem RectifyRectify IgnoreIgnore ExacerbateExacerbate15
Airway managementAirway management Asleep vs. sedatedAsleep vs. sedated FOB?FOB? PIV placedPIV placed Standard monitorsStandard monitors MedicationsMedications OOptions?ptions?16
PropofolPropofolAdvantagesAdvantages• SedationSedation11• HypnosisHypnosis11• AnxiolysisAnxiolysis11• Muscle relaxationMuscle relaxation11 ICPICP11 Cerebral metabolicCerebral metabolicraterate11• Relief of bronchospasmRelief of bronchospasm11LimitationsLimitations• Respiratory depressionRespiratory depression(enhanced by opioids)(enhanced by opioids)11• HypotensionHypotension11• Decreased contractilityDecreased contractility22• Lack of analgesiaLack of analgesia33• HypertriglyceridemiaHypertriglyceridemia11• Preservative issuesPreservative issues44• Potential for infectionPotential for infectionnecessitates need fornecessitates need forregular changing of linesregular changing of lines551. Harvey. Am J Crit Care.1996;5:7-16. 2. Lerch, Park. Br Med Bull. 1999;55:90. 3. Wagner,O’Hara. Clin Pharmacokinet. 1997;33:435. 4. Propofol [package insert]. 5. Prielipp et al. CritCare Clin. 1995;11:986. 25
Propofol Infusion SyndromePropofol Infusion Syndrome Propofol infusion in the ICUPropofol infusion in the ICU Associated with serious adverse events and death in severalAssociated with serious adverse events and death in severalcase reportscase reports1-41-4 Propofol infusion syndrome in adultsPropofol infusion syndrome in adults1-31-3:: Associated with high-dose (>5mg/kg/hAssociated with high-dose (>5mg/kg/h 83 mcg/kg/min),83 mcg/kg/min),long-term (>48 h) infusionlong-term (>48 h) infusion Clinical features: metabolic acidosis, hyperkalemia,Clinical features: metabolic acidosis, hyperkalemia,hepatomegaly, lipemia, myocardial failure, rhabdomyolysishepatomegaly, lipemia, myocardial failure, rhabdomyolysis Propofol infusion syndrome in childrenPropofol infusion syndrome in children4-64-6:: Published and unpublished reports of fatal propofol infusionPublished and unpublished reports of fatal propofol infusionsyndrome in pediatric ICUssyndrome in pediatric ICUs1. Kang TM.1. Kang TM. Ann Pharmacother.Ann Pharmacother. 2002;36:1453-1456; 2. Cremer OL.2002;36:1453-1456; 2. Cremer OL. LancetLancet. 2001;13:117-118.. 2001;13:117-118.3. Stelow EB.3. Stelow EB. Clin ChemClin Chem. 2000;46:577-581. 4. Parke TJ et al.. 2000;46:577-581. 4. Parke TJ et al. Br Med JBr Med J. 1992;305:613-616.. 1992;305:613-616.5. Bray RJ.5. Bray RJ. Paediatric Anaesth.Paediatric Anaesth. 1998;8:491-499. 6. AstraZeneca. Letter to health care providers.1998;8:491-499. 6. AstraZeneca. Letter to health care providers.March 26, 2001. 7. Markovitz BP et al.March 26, 2001. 7. Markovitz BP et al. Crit Care MedCrit Care Med. 2000;28:2178-2179.. 2000;28:2178-2179. 26
αα22 AgonistsAgonistsClonidineClonidine Selectivity:Selectivity: αα22::αα11 200:1200:111 tt1/21/2 ββ 10 hrs10 hrs11 PO, patch, epiduralPO, patch, epidural22 AntihypertensiveAntihypertensive11 Analgesic adjunctAnalgesic adjunct11 IV formulation not availableIV formulation not availablein USin USDexmedetomidineDexmedetomidine Selectivity:Selectivity: αα22::αα11 1620:11620:133 tt1/21/2 ββ 2 hrs2 hrs33 IntravenousIntravenous33 Sedative-analgesicSedative-analgesic33 Primary sedativePrimary sedative Only IVOnly IV αα22 available foravailable foruse in the USuse in the US1. Maze. White paper; 2000. 2. Khan et al. Anaesthesia. 1999;54:150. 3. Kamibayashi, Maze.Anesthesiology. 2000;93:1345-1349.29
Peds dex pharmacokineticsPeds dex pharmacokinetics 93% protein binding93% protein binding Near complete hepatic metabolism to inactiveNear complete hepatic metabolism to inactivemetabolitesmetabolites 85% glucuronidation85% glucuronidation 15% cytochrome P45015% cytochrome P450 7 min redistribution half life7 min redistribution half life Volume of distribution is 118 LVolume of distribution is 118 L Clearance 15 ml/kg/minClearance 15 ml/kg/min 2 hour elimination half life2 hour elimination half life May be doubled in severe liver failureMay be doubled in severe liver failure Urinary excretionUrinary excretion30
α-2-adrenoreceptors Pre and Post synaptic locations Central and peripheral nervous system Vascular smooth muscle Heart Other organs Presynaptic activation reduces norepinephrine release Postsynaptic activation hyperpolarizes neuralmembranes Acts as a feedback loop, further reducing norepinephrine release Activation in locus ceruleus produces hypnotic/anxiolyticaction Analgesic properties at pre-synaptic sites in spinal cord31
α2A??α2Aα2Cα2Aα2AAnxiolysisα2Bα2BXXα2BXReprinted with permission from Kamibayashi, Maze.Anesthesiology. 2000;93:1346. 32
Mechanism forMechanism for αα22-induced sedation/-induced sedation/hypnosis in the locus ceruleushypnosis in the locus ceruleusCa++Ca++Ca++–– +Decrease ininflux of Ca++Decrease in actionpotential due tohyperpolarizationα2Aα2ARGo Gk K+K+K+33
No significant ECG changesNo significant ECG changes Congenital heart diseaseCongenital heart disease 101 post op patients101 post op patients Pre dexmedetomidine ECGPre dexmedetomidine ECG Post dexmedetomidine ECGPost dexmedetomidine ECG Trend toward lower heart rateTrend toward lower heart rate No other significant ECG changesNo other significant ECG changes34
Rapid bolus dexRapid bolus dexCardiac effectsCardiac effects Routine cath for 12 post cardiac transplantRoutine cath for 12 post cardiac transplantpatientspatients 0.25 or 0.5 mcg/kg over 5 sec0.25 or 0.5 mcg/kg over 5 sec Hemodynamics pre-bolus, 1 and 5 minuteHemodynamics pre-bolus, 1 and 5 minute HR & CO decreasedHR & CO decreased SBP, DBP, SBP, sPAP, dPAP, wPAP increasedSBP, DBP, SBP, sPAP, dPAP, wPAP increased Only value not at baseline at 5 minutes was HROnly value not at baseline at 5 minutes was HRwith 0.5 mcg/kg boluswith 0.5 mcg/kg bolusJooste, et al. Acute Hemodynamic Changes Following Rapid Intravenous BolusDosing of Dexmedetomidine in Pediatric Heart Transplant Patients UndergoingRoutine Cardiac Catheterization, Accepted Anesthesia & Analgesia 2010,Manuscript Number: AA-D-09-01438R4
No ventilation effectNo ventilation effect Minimal change in minute ventilationMinimal change in minute ventilationeven at high doseseven at high doses No change in CO2 responseNo change in CO2 response37
Arousability From Sedation DuringArousability From Sedation DuringDexmedetomidine InfusionDexmedetomidine Infusion406080100BISPlacebo 0.2 0.6During cognitive and cold pressor testingJust prior to cognitive and cold pressor testingDexmedetomidine Infusion(µgkg-1hr-1)Adapted from Hall et al. Anesth Analg. 2000;90:701.39
Arousal and Task Performance DuringArousal and Task Performance DuringEqui-sedative Doses of BenzodiazepineEqui-sedative Doses of Benzodiazepineoror αα22 Agonist in HumansAgonist in Humans α2 AgonistBenzodiazepineFocused attentionLearningWorking memoryTask performanceCritical flicker fusion test40
Dexmedetomidine for pediatricsDexmedetomidine for pediatrics Enhances post op T&A comfortEnhances post op T&A comfort11 Enhances post op LTR sedationEnhances post op LTR sedation22 No significant effect on upper airwayNo significant effect on upper airwaymorphologymorphology3,43,4 Beats propofol for OSA spontaneous ventilationBeats propofol for OSA spontaneous ventilation55 Well tolerated, predictable hemodynamics withWell tolerated, predictable hemodynamics withbolusbolus66 No effect on ECGNo effect on ECG77 Extensive safety in ICUExtensive safety in ICU IV, nasal, buccal, oralIV, nasal, buccal, oral42
Dexmedetomidine spares opioidsDexmedetomidine spares opioids1. Data on file, Integrated Summaries of Efficacy and Safety.2. Martin E, Ramsay G, Mantz J, Sum-Ping STJ. The role of the alpha2-adrenoceptor agonistdexmedetomidine in postsurgical sedation in the intensive care unit. J Intensive Care Med.2003;18:29-41.46
Effect of dex on caudal withEffect of dex on caudal withbupivicainebupivicaine50
Dexmedetomidine and deliriumDexmedetomidine and delirium Perioperative infusion of 0.2 Perioperative infusion of 0.2 μμg/kg/hg/kg/h Decreases incidence and frequency ofDecreases incidence and frequency ofemergence deliriumemergence delirium No prolongation in time to extubate orNo prolongation in time to extubate ordischargedischarge No prolongation in time to dischargeNo prolongation in time to dischargeShukry, Mathisen, et al., Pediatric Anesthesia; 15:12, 1098-1104, 2005Shukry, Mathisen, et al., Pediatric Anesthesia; 15:12, 1098-1104, 200551
Sleep DeprivationSleep DeprivationAverage amount of sleepAverage amount of sleepin the ICU isin the ICU is1 hour, 51 minutes1 hour, 51 minutesper 24 hoursper 24 hoursAurell, Elmqvist. Br Med J. 1985;290:1031.52
Sleep Deprivation: CognitiveSleep Deprivation: CognitiveFunctionFunction Impaired memoryImpaired memory11 Impaired communication skillsImpaired communication skills22 Impaired decision-makingImpaired decision-making33 Confusional stateConfusional state44 ApathyApathy DeliriumDelirium1. Harrison, Horne. Q J Exp Psychol. 2000;53I:271. 2. Harrison, Horne. Sleep.1997;20:871-877. 3. Harrison, Horne. Organ Behav Hum Decis Proc. 1999;78:128-145.4. Krachman et al. Chest. 1995;107:1713-1720.53
Restorative Properties of SleepRestorative Properties of Sleep Increased rate of healingIncreased rate of healing Promotes anabolismPromotes anabolism Facilitates growth hormone releaseFacilitates growth hormone release Counteracts catabolismCounteracts catabolism Inhibits cortisol releaseInhibits cortisol release Inhibits catecholamine releaseInhibits catecholamine releaseAdam, Oswald. BMJ. 1984;289:1400-1401. Adam, Oswald. Clin Sci. 1983;65:561-567.Krachman et al. Chest. 1995;107:1715.54
How Closely Do SedativeHow Closely Do SedativeAgents Mimic Nature?Agents Mimic Nature?α2 AgonistsPropofol BenzodiazepinesTissue repairImmunefunctionNeuralsubstratesOppositeOpposite SameSameOppositeOpposite SameSameDifferentDifferent SameSameOppositeOppositeUnknownUnknown56
No rebound withNo rebound withdexmedetomidinedexmedetomidine 136 patients at 10 institutions136 patients at 10 institutions 1/3 of patients received > 24 hours of dex1/3 of patients received > 24 hours of dex Ave 54 hoursAve 54 hours Range 24.5-123.5 hourRange 24.5-123.5 hourDasta, et al. Ann Pharmaco 38; 1130-5; 2004
ChoosingChoosingthe Right Drugthe Right Drug58
Decreased dose of both drugsDecreased dose of both drugs Decreased incidence of toleranceDecreased incidence of tolerance Decreased individual side effectsDecreased individual side effects Increased risk of combined side effectsIncreased risk of combined side effects Respiratory depressionRespiratory depression HypotensionHypotensionDrug CoadministrationDrug Coadministration60
Dexmedetomidine for airwayDexmedetomidine for airwayanesthesiologyanesthesiology Critical airway with local anestheticCritical airway with local anestheticallergyallergy11 Difficult airway due to odontogenicDifficult airway due to odontogenicinfectionsinfections22 Awake trachAwake trach33 Anterior mediastinal massAnterior mediastinal mass44 No respiratory depressionNo respiratory depression5569
Dexmedetomidine sedationDexmedetomidine sedationfor our TBI patientfor our TBI patient Can be used as primary agentCan be used as primary agent Cooperative sedationCooperative sedation Titrate to effectTitrate to effect Blunt hyperadrenergic responseBlunt hyperadrenergic response Dex 0.5mcg/kg/Dex 0.5mcg/kg/hourhour May require up to 2 mcg/kg/hourMay require up to 2 mcg/kg/hour Narcotic supplemented prnNarcotic supplemented prn70
Dexmedetomidine sedationDexmedetomidine sedation Initiation of dexmedetomidineInitiation of dexmedetomidine Loading dose: when appropriateLoading dose: when appropriate Gradual step-up in dose based on heart rateGradual step-up in dose based on heart rate Titrate to sedation scaleTitrate to sedation scale Lower doses (<0.7 mcg/kg/hr)Lower doses (<0.7 mcg/kg/hr) Adequate for non-CNS injuryAdequate for non-CNS injury Higher doses (<2.0 mcg/kg/hr)Higher doses (<2.0 mcg/kg/hr) Agitation associated with CNS injuryAgitation associated with CNS injury Withdrawal from alcohol or other drugsWithdrawal from alcohol or other drugs71
Dexmedetomidine InfusionDexmedetomidine InfusionStrategyStrategyAssess volume status of patientAssess volume status of patientDex loading dose: 1 mcg/k/hour infusion for 10 minutesDex loading dose: 1 mcg/k/hour infusion for 10 minutesHypovolemicHypovolemicConsider adjunctmedications?Consider adjunctmedications?Consider increaseConsider increaseAssess effectAssess effectMonitor BP/HRthroughoutIf bradycardia,consideratropineMonitor BP/HRthroughoutIf bradycardia,consideratropineDex continuous infusion: 0.5 to 1.5 mcg/kg/hrDex continuous infusion: 0.5 to 1.5 mcg/kg/hrVolume preloadVolume preloadEuvolemicEuvolemicDex=dexmedetomidine.InadequateInadequate AdequateAdequate72
αα22 Agonists:Agonists:PharmacodynamicsPharmacodynamics Sedation/hypnosisSedation/hypnosis11 AnxiolysisAnxiolysis11 AnalgesiaAnalgesia11 Sympatholysis (decrease BP, HR, NE)Sympatholysis (decrease BP, HR, NE)11 Reduces shiveringReduces shivering22 Neuroprotective effectsNeuroprotective effects33 No effect on ICPNo effect on ICP33 No effect on SSEPNo effect on SSEP No respiratory depressionNo respiratory depression111. Aantaa et al. Drugs of the Future. 1993;18:49-56. 2. Kamibayashi, Maze. Anesthesiology.2000;93:1348. 3. Maze. White paper; 2000.73