ICU Sedation, Anxiolysis, and Neuromuscular BlockadeRichard C. Prielipp, M.D., M
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Minneapolis, Minnesota
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LEARNING OBJECTIVES:
· Recognize the need for sedation, analgesia, and/or anxiolytic therapy in ICU patients· Understand how to utilize assessment scale(s) to monitor and control depth of sedation· Be familiar with kinetic properties of standard ICU sedatives, and their untoward side-effects· Understand the potential utility of
α
2
-agonists in the OR and transition to the ICU· Identify the limitations and appropriate application of NMB drugs in the ICU
Introduction
The physiological response initiated during surgery and continuing into the ICU is characterized by increasedcatecholamines, cortisol, growth hormone, antidiuretic hormone (ADH), renin-angiotensin, and other neuroendocrine responseswhich increase oxygen consumption, exacerbate hyperglycemia, increase myocardial wall tension, disrupt electrolytehomeostasis, and initiate other potentially counterproductive physiologic reactions. Therefore, intensivists strive to providesedation and analgesia to ameliorate these responses as well as to optimize patient comfort. The ideal level of sedation variesfrom patient to patient and in different situations, but most intensivists maintain a patient who is tranquil and sleepy, but stillresponsive. Deeper sedation should be reserved for select patients, such as those receiving neuromuscular blocking drugs or thosewith inadequate ventilation and oxygen delivery. Unfortunately, providing excess anxiolysis to the intubated, mechanically-ventilated ICU patient may produce a state of “suspended animation” where the patient is immobile and unresponsive. This pharmacologic-induced ICU coma renders patients vulnerable to increased edema, thromboemboli, pressure ulcers, gastricregurgitation and aspiration, hemodynamic alterations, and ultimately, sepsis. Indeed, evidence suggests that ICU patients arefrequently over-sedated, which delays weaning of mechanical ventilation, and increases the cost and duration of the ICU stay(1,2). Several authors now advocate a regular daily interruption of sedative infusions in ICU patients to expedite ventilator weaning, even when using agents such as propofol (1,2). Furthermore, a univariate analysis found excess sedation (i.e., RamsayScore
≥
4) was an important extrinsic risk factor for nosocomial pneumonia in ICU patients (3). On the other hand, intensivistsalso recognize that inadequate sedation frequently results in complications such as unplanned extubations. These events occur in
≈
9% of intubated ICU patients, after 3-4 days of mechanical ventilation, and often require immediate reintubation. Theseunplanned extubations result in serious complications in 6% of patients, including aspiration, arrhythmias, bronchospasm, andsevere bradycardia. Thus, clinicians must be familiar with a large array of sedative drugs, including barbiturates, benzodiazepines(BZ), butryophenones, opioids, and even inhaled anesthetics to sedate and optimize ICU patient care. This will explore currentissues of ICU sedation including utilization of bedside scoring systems, titration to appropriate endpoints, review the commonlyused sedative drugs, including the
α
2
-agonist, dexmedetomidine.
Issues Related To Sedative Use: Currently, half of all ICU patients report fear or anxiety during periods of mechanicalventilation. Even years afterward, 90% of these patients recall this experience as unpleasant (
adapted from Rotondi et al,CCM 2002)
ICU Event(s) % Recall Event% with Moderate to ExtremeDistress about ICU Events
OET: intubated 78% 83%Invasive Procedures 70% 43%“not in control” 55% 83% Noise 51% 55%Use of restraints 45% 86%Pain 39% 87%Terror or Panic Attack 32% 90%The causes of anxiety in critically ill patients include an inability to communicate, continuous stimulation with noise (e.g.,equipment alarms), and inability to control physical interventions (frequent vital signs, repositioning, lack of mobility, andextremes of temperature). In addition, sleep deprivation may increase patient anxiety, affecting up to 50% of ICU patients. Sleepdeprivation and inadequate anxiolysis probably contributes to the (increasingly recognized) evidence that survivors of criticalillness often suffer long term psychiatric morbidity such as post-traumatic stress disorder (4) and even reduced health-relatedquality of life (HRQL) parameters, especially in the domains of physical functioning and pulmonary problems (5).Therapeutically, the use of sedatives may reduce the ICU stress response, improve tolerance to routine ICU procedures, andreduce long term adverse psychological sequelae. Appropriate sedation may require the
combination
of two or more drugs (e.g.,midazolam + fentanyl) to optimize care which allows the patient to remain in a calm, but communicative state (6).Acute side effects from sedatives include alterations in respiratory drive, inability to maintain and protect the airway,cardiovascular instability, induction of hepatic enzyme pathways, and drug-drug interactions. Specific classes of drugs such asanti-psychotic agents have uncommon, but unique deleterious effects such as tardive dyskinesias, neuroleptic malignantsyndrome, and even
torsades de pointes
ventricular tachycardia. In addition, rapid discontinuation of most sedative drugs after prolonged or continuous infusion may be associated with a withdrawal syndrome. These include physical withdrawal, agitation,
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hypertension, CNS excitation, and seizures. Most clinicians therefore recommend a gradual titration to discontinue sedatives after long term use.
Sedation Scoring Systems
: Assessment of the degree of sedation facilitates titration of sedatives to appropriate, predeterminedend-points (7). The Ramsay score was developed specifically to assess drug-induced sedation. This consists of a six-point scoringsystem with three possible scales while awake, and three other scales when asleep. While the Ramsay score fails to account for the agitated or oversedated patient, it nevertheless has been utilized in most comparative sedation trials. By contrast, the Riker Sedation-Agitation Scale (SAS) uses a seven-point scale to more fidelity in gauging ICU patients exhibiting signs of agitation(8). The appropriate target level for sedation is a calm, cooperative patient that can be easily aroused with maintenance of thenormal sleep-wake cycle, if possible. Brain function monitoring may assist this titration in selective cases (9). Specific drugs toachieve these endpoints and their potential side-effects are discussed below.
Benzodiazepines (BZ)
: Sedation is a complex neurophysiologic condition consisting of anxiolysis, hypnosis, amnesia, andanticonvulsant actions, and the BZ drugs are unique in providing this full spectrum of effects. Therefore, BZ are a cost effective(10) and commonly used sedative option in the ICU. Benzodiazepines block the acquisition and encoding of new information(anterograde amnesia), but do not reliably provide any degree of retrograde amnesia. The BZ exert their anxiolytic, amnestic,anticonvulsant, and muscle relaxing effects through interaction at specific binding sites on neuronal gamma-amino butyric acid(GABA) receptors, whereas the hypnotic effect appears to be mediated elsewhere. The GABA
A
receptor is an protein complexthat forms a chloride permeable ion channel. Receptor activation leads to channel opening and increased chloride conductanceinto the cell, throttling neuronal firing and impulse transmission. The binding of BZ to the GABA receptor is stereospecific andsaturable, with potency of individual agents determined by their receptor affinity.Chronic administration of BZ can lead to receptor downregulation and drug tolerance. Acute tolerance appears to be acommon finding in ICU patients receiving BZ or other sedative agents for periods >24 hours. Withdrawal syndromes have beenreported with cessation of both midazolam and other BZ infusions. Risk factors for acute withdrawal include high infusion rates, prolonged duration, and abrupt cessation.The effects of BZ are dose dependent. However, various patient specific factors such as age, concurrent pathology, anddrug therapy affect the intensity and duration of activity. Elderly patients exhibit slower clearance of BZ and have a larger volume of drug distribution, contributing to a marked prolongation of clinical sedation. While BZ drugs possess high therapeuticto toxic ratios, acute clinical complications may include airway obstruction and respiratory depression (most commonly duringconcurrent administration of narcotics), and hypotension.
Midazolam
is a short-acting, water-soluble BZ often given by continuous infusion in the ICU (see structure in slideshown at lecture). As currently marketed, midazolam is buffered to a pH of 3.5, opening its imidazole (diazepine) ring andmarkedly increasing its water solubility. However, at physiologic pH, the diazepine ring closes rapidly and midazolam becomeslipid soluble. As a consequence, the BZ effects of midazolam are very rapid and occur within one or two circulation times withinthe CNS.One of midazolam’s two metabolites (1-hydroxymidazolam) is partially active, but its low receptor affinity and lipidsolubility minimize clinical psychoactivity, except when this metabolite accumulates during long infusions. Midazolam ismetabolized via hepatic microsomal oxidation. The oxidative pathway is susceptible to many factors including hepatic disease,advanced age, and drug inhibition. Significant inhibition of midazolam metabolism is reported with propofol, diltiazem,macrolide antibiotics (erythromycin), and other inhibitors of CYP3A4, and thereby increase its duration of effect.
Lorazepam
, a long-acting, slow-onset BZ, is among the most potent of this class of sedatives. Lorazepam isapproximately 90% protein bound, and while well absorbed orally, it is most commonly delivered by intermittent boluses in theICU. Peak effects are not observed for 30 min however. Lorazepam is metabolized to inactive products by hepaticglucuronidation, and this unique pathway renders lorazepam resistant to drug interactions, with one notable exception beinginhibition by valproic acid. The pharmacokinetics of lorazepam do not change significantly in the elderly or critically ill populations. The t
1/2
β
ranges from 10 to 20 hours (see Table below), but is prolonged by liver and end-stage kidney disease. Thesolvent for lorazepam contains polyethylene glycol 400 (PEG) and propylene glycol (PG), both of which have been implicated ascausing acute tubular necrosis, lactic acidosis, and hyperosmolar coma after prolonged, high dose lorazepam infusions. The toxicthreshold for this effect has not been defined, but is probably in the range of
≥
10 mg per hour. Moreover, a recent study by Elyand colleagues identified that lorazepam was an independent risk factor for transition of ICU patients to a delirium [odds ratio =1.2], a significant association shared only by other factors such as increasing age and Acute Physiology and Chronic HealthEvaluation II scores (11). The incremental risk of lorazepam was significant at doses of only 20 mg/day (i.e., less than 1 mg per hour by infusion).
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DrugOnset(min)MetabolicPathwayActiveMetabolitePotential AdverseEffectsLoading Dose/IntermittentBolus DoseInfusionDoseRangeMidazolam 2-5 CYP3A4 yes† accumulates after prolonged infusions0.02-0.08 mg/kg 0.04-0.2mg/kg/hr Propofol 1-2 glucuron +sulfateconjug.no elevated TG; supportsmicrobial growth0.25-1.0 mg/kg 10-100
μ
g/kg/minHaloperidol 3-20 CYP3A4,CYP2D6yes EPS; QT prolongation; NMS30-150
μ
g/kg 40-150
μ
g/kg/hr Dexmedetomidine 20-30 glucuron +conjug.no Hypertension or hypotension NR 0.2-0.7
μ
g/kg/hr
Diazepam
is very lipid soluble, highly protein bound, distributes quickly into the brain, and is the oldest BZ used in theICU. It is available in both intravenous and oral preparations. The original propylene glycol (PG) intravenous formulation often produced thrombophlebitis, thrombosis, and even metabolic acidosis. These problems are reduced by the alternative formulationof diazepam in a sterile fat emulsion. The emulsion consists of fractionated soybean oil, fractionated egg yolk phospholipids,glycerin, and water. The pharmacokinetics and pharmacodynamics of the lipid emulsion preparation are reported to becomparable to the original propylene glycol based formulation.Diazepam is metabolized by hepatic microsomal enzymes to active compounds such as desmethyldiazepam, which hasa very long half-life (100-200 hours) and is dependent upon the kidneys for elimination. Diazepam metabolites are further converted to oxazepam (t
½
≅
10 hours), which is then conjugated prior to elimination. The elimination (t
1/2
β
) half-life of diazepamvaries widely and is increased in the elderly, neonates, and patients with liver disease. Age increases the t
1/2
β
linearly; the t
1/2
β
measured in hours is approximately equal to the patient’s age in years. Metabolism is also affected by genetics, endocrine status,nutritional status, smoking, sex, and concurrent drug therapy such as cimetidine.Diazepam administration reduces cerebral metabolic rate for oxygen consumption and decreases cerebral blood flow ina dose-dependent manner. Like other BZs, diazepam raises the seizure threshold. Diazepam alone has minimal cardiovascular and respiratory depressant effects. Modest reductions in tidal volume (20-30%) are compensated for by increasing respiratoryrate, with minimal net change in minute ventilation. However, opioid analgesics and other sedative-hypnotic drugs markedly potentiate the respiratory effects of diazepam.Complications with BZ are relatively rare, and are generally attributable to their primary psychological activity. BZalone produce minimal respiratory depression, with a minor decrease in tidal volume, compensated for by an increase inrespiratory rate. In higher doses, they blunt the response to hypoxia and hypercarbia, an affect most pronounced in the elderly or those with intrinsic lung disease. A reversible encephalopathy (movement disorders, depressed level of consciousness, poor visual tracking) has been associated with prolonged infusions of midazolam (and fentanyl) in children. In addition, an abstinencesyndrome can be precipitated in the ICU during rapid withdrawal from these agents, characterized by anxiety, agitation, andsymptoms of sympathetic stimulation (hypertension and tachycardia). All these symptoms may be treated by reinstituting BZtherapy, including the use of oral medications such as lorazepam, clonazepam, and oxazepam.
Propofol (Diprivan®)
: Propofol, 2,6-diisopropylphenol, is a unique sedative-hypnotic approved by the Food and DrugAdministration for ICU sedation in 1993 (12). Because of the high lipophilicity, it requires a phospholipid emulsion carrier (10%INTRALIPID®), which provides 1.1 kcal/ml as a (fat) nutrition source. Long term or high-dose infusions may result inhypertriglyceridemia, which may be associated with elevated pancreatic enzymes, and on occasion, pancreatitis. Propofol iscontraindicated in patients sensitive to soybean oil, egg lecithin, or glycerol.Propofol is administered as a continuous infusion, and the level of sedation adjusted by titrating the dose. Propofol istypically characterized by a more rapid recovery from its clinical sedative effects and EEG effects than midazolam (13, 14).Treatment with propofol may also permit more rapid titration and maintenance of patients in a state of adequate sedation for agreater proportion of the day. Propofol is associated with a short time to extubation after discontinuation of drug infusion, as propofol is cleared very rapidly due to redistribution to fatty tissue and hepatic metabolism to inactive metabolites. These properties are utilized in postoperative cardiac surgical patients, allowing titrated sedation for several hours while the patientcompletely rewarms, eliminates residual neuromuscular blockade, and improves cardiac function (12-14). After very longinfusions, plasma concentrations gradually increase unless the infusion rate is decreased over time, and current data are beginningto question the rapidity of recovery after greater than 12 hours of IV sedation. Thus, recent evidence by Carson et al appears toconfirm the need for a daily interruption of sedation therapy, even for infusions of a drug like propofol (2). One additional benefitof propofol is that kinetic parameters do not change in patients with renal or hepatic dysfunction. Two reviews summarize past,small comparison clinical trials of BZ and propofol, and are reviewed elsewhere (13, 14).
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