Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary

Practice Parameters for Intravenous Analgesia and Sedation for Adult Patients In the Intensive Care Unit: An Executive Summary Practice Parameters for Intravenous Analgesia and Sedation for Adult
Patients In the Intensive Care Unit: An Executive Summary

Barry A. Shapiro, MD, FCCM; Jonathan Warren, MD, FCCM; Andrew B. Egol, DO,FCCM; Dennis M. Greenbaum, MD, FCCM; Judith Jacobi, PharmD, FCCM; Stanley A.
Nasraway, MD; Roland M. Schein, MD, FCCM; Antoinette Spevetz, MD; James R.
Stone, MD, FCCM Objective: The development of practice parameters for intravenous analgesia and
sedation for adult patients in the intensive care unit (ICU) setting for the purpose of
guiding clinical practice.
Participants: A task force of more than 40 experts in disciplines related to the use of
analgesic and sedative agents in the ICU was convened from the membership of the
American College of Critical Care Medicine (ACCM) and the Society of Critical Care
Medicine (SCCM).
Evidence: The task force members provided the personal experience and determined the
published literature (MEDLINE articles, textbooks, pharmacopeias, etc.) from which
consensus would be sought. Published literature was reviewed and classified into one of
four predetermined categories, according to study design and scientific value.
Consensus Process: The task force met several times as a whole, and numerous times
in smaller groups by teleconference, over a 1-yr period to identify the pertinent literature
and arrive at consensus recommendations for the whole task force to discuss.
Consideration was given to the relationship between the weight of scientific information
and the experts’ viewpoints. Over the next year, draft documents were composed by a
task force steering committee and debated by the task force members until consensus
was reached by nominal group process. The task force draft was then reviewed,
assessed, and edited by the Board of Regents of the ACCM. After steering committee
approval, the draft document was reviewed and approved by the SCCM Council.
Data Synthesis: To facilitate rapid communication of the six recommendations contained
within the complete and unabridged practice parameter document, an executive summary
was prepared for publication by the ACCM Board of Regents, and this executive summary
was approved by the task force steering committee and the SCCM Executive Council.
file:///D|/X. SOLER/BIBLIO2/guide_body_p02.htm (1 de 6) [18/09/2001 20:49:01] Practice Parameters for Intravenous Analgesia and Sedation for Adult Patients In the Intensive Care Unit: An Executive Summary Conclusions: A consensus of experts provided six recommendations with supporting
data for intravenous analgesia and sedation in the ICU setting: a) morphine sulfate is the
preferred analgesic agent for critically ill patients; b) fentanyl is the preferred analgesic
agent for critically ill patients with hemodynamic instability, for patients manifesting
symptoms of histamine release with morphine, or morphine allergy; c) hydromorphone can
serve as an acceptable alternative to morphine; d) midazolam or propofol are the
preferred agents only for the short-term (<24 hrs) treatment of anxiety in the critically ill
adult; e) lorazepam is the preferred agent for the prolonged treatment of anxiety in the
critically ill adult; f) haloperidol is the preferred agent for the treatment of delirium in the
critically ill adult. This executive summary selectively presents supporting information and
is not intended as a substitute for the complete document. (Crit Care Med 1995;
Key Words: analgesia; sedation; intensive care unit; morphine sulfate; fentanyl;
hydromorphone; midazolam; propofol; lorazepam; haloperidol
The American College of Critical Care Medicine of the Society of Critical Care Medicine has
developed practice parameters to assist healthcare providers in prescribing sedation and analgesia
in the intensive care unit (ICU) setting. These practice parameters are limited to adult patients
requiring sustained analgesia/sedation of longer than several hours duration, and do not consider
one-time therapy, nonsystemic analgesic therapies such as epidural techniques, or patients who
are <12 yrs of age. To assist the practitioner in determining the relative scientific authority of the
The unabridged document makes six specific recommendations, and each recommendation has
) that reflects the weight of scientific evidence, expert
opinion, and clinical practice experience upon which the recommendation was based.
This executive summary is not intended to be, and must not be used as, a substitute orreplacement for the unabridged practice parameters document. Rather, this executive summary isintended to facilitate communication of the document’s six specific recommendations and thefundamental information upon which these recommendations were based.
Table 1.
Rating systems for citations and recommendations
Rating System for Recommendations (a), Randomized, prospective, controlled investigations
(b), Nonrandomized, concurrent, or historical cohort
(c), Peer-reviewed state-of-the-art articles, review articles,
(d), Nonpeer-reviewed published opinions, such as textbook
statements or official organizational publications Rating System for Recommendations Level 1: Convincingly justifiable on scientific evidence alone
Level 2: Reasonably justifiable by available scientific evidence and
strongly supported by expert critical care opinion file:///D|/X. SOLER/BIBLIO2/guide_body_p02.htm (2 de 6) [18/09/2001 20:49:01] Practice Parameters for Intravenous Analgesia and Sedation for Adult Patients In the Intensive Care Unit: An Executive Summary Level 3: Adequate scientific evidence is lacking but widely supported
by available data and expert critical care opinion ANALGESIA
Analgesia connotes the absence of sensibility to pain or noxious stimuli in the conscious patient.
Pain has consequences in the critically ill patient that can lead to clinically significant physiologic
responses such as tachycardia, increased myocardial oxygen consumption, hypercoagulability,
immunosuppression, and persistent catabolism (1). ICU patients commonly experience pain from
pathology as well as from diagnostic and therapeutic procedures, for which intravenous opiates are
the mainstay of analgesic therapy. The opiates are central nervous system µ opioid receptor
agonists that invoke analgesia, sedation, respiratory depression, constipation, urinary retention,
nausea, and confusion. Opiates have little, if any, amnestic properties.
Some critically ill patients receive inadequate analgesia due to unwarranted concerns aboutinducing opiate addiction. More commonly, inadequate analgesia in the ICU results fromattempting to avoid certain side effects of opiate analgesics that are prominent in the ICUpopulation, such as: a) respiratory depression in spontaneously breathing patients and in patientsreceiving partial ventilator support; b) hypotension, which is most likely to occur in patients withhypovolemia; and c) gastric retention and ileus, which are common in critically ill patients andenhanced by opiates. Despite these legitimate concerns, adequate analgesia must remain aprimary goal in the care of the critically ill.
Recommendation 1—Level 2: Morphine Sulfate Is the Preferred Analgesic Agent for Critically Ill
In the United States, morphine sulfate is the most frequently used intravenous analgesic
agent in the ICU, mainly because of low cost, potency, analgesic efficacy, and euphoric effect.
Morphine has a half-life of 1.5 to 2 hrs after intravenous administration in normal subjects. In the
ICU patient, distribution volume and protein binding may be abnormal, resulting in either an
exaggerated or diminished response. Morphine may induce histamine release, causing
hypotension and other adverse effects.
Morphine sulfate should be administered intravenously and titrated to effect. Therapy shouldgenerally start at a loading dose of 0.05 mg/kg, administered over 5 to 15 mins. Most adults require4 to 6 mg/hr after receiving an adequate loading dose. With bolus therapy, redosing should beaccomplished every 1 to 2 hrs; with continuous infusion therapy, one or more loading doses arerequired.
Recommendation 2—Level 2: Fentanyl Is the Preferred Analgesic Agent for Critically Ill PatientsWith Hemodynamic Instability, for Patients Manifesting Symptoms of Histamine Release WithMorphine, or Morphine Allergy. Fentanyl (Sublimaze®, Janssen Pharmaceutica, Titusville, NJ) is asynthetic opiate with greater potency and lipophilic properties than morphine, resulting in a fasteronset of action. Fentanyl does not cause histamine release, which may explain the reducedfrequency of hypotension compared with morphine. Intravenous fentanyl has a relatively shorthalf-life of 30 to 60 mins due to rapid redistribution to peripheral compartments (2). However,prolonged administration leads to accumulation in peripheral compartments that results in aprogressive increase in half-life to 9 to 16 hrs (3). Fentanyl has little euphoric effect, no activemetabolites, and does not cross-react in patients with morphine allergy.
Fentanyl should be administered by continuous intravenous infusion. Most patients will beadequately treated with 1 to 2 µg/kg/hr. One or more loading doses of 1 to 2 µg/kg are generallyrequired when therapy is initiated.
Recommendation 3—Level 3: Hydromorphone Can Serve as an Acceptable Alternative toMorphine. Hydromorphone (Dilaudid®, Knoll Pharmaceutical, Whippany, NJ) is a semisynthetic file:///D|/X. SOLER/BIBLIO2/guide_body_p02.htm (3 de 6) [18/09/2001 20:49:01] Practice Parameters for Intravenous Analgesia and Sedation for Adult Patients In the Intensive Care Unit: An Executive Summary morphine derivative with more potent analgesic/sedative properties than morphine and significantlyless euphoria. The dosage should be initiated at 0.5 mg and titrated by 0.5 mg increments, withmost patients requiring 1 to 2 mg every 1 to 2 hrs.
Meperidine (Demerol®, Sanofi Winthrop Pharmaceuticals, New York, NY) has an active
metabolite, normeperidine, that may accumulate and produce central nervous system excitation
(4). Opiate agonist-antagonists (nalbuphine, butorphanol, buprenorphine) are available for the
relief of mild-to-moderate pain and may reverse other opiate agents. Agonist-antagonists are not
recommended for routine use in critically ill patients (5). Nonsteroidal anti-inflammatory drugs have
no analgesic advantages over opiates and have potential risks of gastrointestinal bleeding,
bleeding secondary to platelet inhibition, and the development of renal insufficiency (6).
Sedation (calming or allaying excitement) is indicated in the ICU setting for the primary treatment of
anxiety (psychophysiologic response to the anticipation of real or imagined danger) and agitation
(excitement accompanied by motor restlessness). The prototype intravenous sedative agent is
diazepam (Valium®, Roche Laboratories, Nutley, NJ, and others), a long-acting lipophilic
benzodiazepine that rapidly penetrates the central nervous system, allowing for the sedative effect
to be seen within 2 to 3 mins and peak effect within 3 to 5 mins. All parenteral benzodiazepines
reliably cause anterograde amnesia (inability to form new memory) and have no analgesic activity.
The effects of a single diazepam dose abates rapidly as the drug redistributes to peripheral tissues,
while a more sustained effect is achieved with repeated administration due to the saturation of
peripheral compartments and central nervous system binding sites (7). Diazepam is no longer
recommended for routine use in the ICU for the following reasons: a) pain and thrombophlebitis are
common when administered by peripheral vein injection; b) a scheduled intermittent dosing
regimen may lead to excessive sedation unless an objective monitor of the level of sedation is
utilized before each dose; and c) dilution is required for continuous infusion, which demands large
volumes of fluid administration.
Recommendation 4—Level 2: Midazolam or Propofol Are the Preferred Agents Only for the
Short-Term (<24 Hrs) Treatment of Anxiety in the Critically Ill Adult.
The greater cost of these drugs
is balanced by the rapidity with which their pharmacologic effects abate with short-term therapy.
Midazolam (Versed®, Roche Laboratories) is a short-acting, water-soluble benzodiazepine thatbecomes a lipophilic compound in the blood and that rapidly penetrates the central nervous systemto produce an onset of sedation (2 to 2.5 mins) similar to diazepam. Midazolam is similar todiazepam in all respects, except for its brief duration of clinical effect due to rapid redistribution, afactor that favors continuous infusion for maintaining sedation in the critically ill. Long-termadministration results in a prolongation of the clinical effects of the drug. A maintenance midazolamdosage of 0.03 mg/kg/hr serves well as a starting point, with dosage titrated to effect over time.
One or more bolus loading doses (0.03 mg/kg) are generally required when therapy is initiated.
Propofol (Diprivan®, Stuart Pharmaceuticals, Wilmington, DE) is an intravenous, generalanesthetic agent that has sedative, hypnotic, anxiolytic, and anterograde amnestic properties atsubanesthetic dosages. When propofol is utilized in subanesthetic dosages, it produces anxiolysisand possesses some anterograde amnestic effects. When propofol infusion is compared withmidazolam infusion in critically ill patients, the two drugs are equally effective sedative agents (8).
The onset of action after a single subanesthetic intravenous dose of propofol is rapid (1 to 2 mins)and its effect is brief (10 to 15 mins) due to its rapid central nervous system penetration andsubsequent redistribution. For these reasons, propofol is administered only by continuous infusionwhen used for sedation. Long-term infusions result in accumulation within lipid stores, resulting in aprolonged elimination phase with a half-life of up to 300 to 700 mins. However, subtherapeuticplasma concentrations are maintained after discontinuation of the drug by rapid clearancemechanisms. Propofol is administered at an initial infusion rate of 0.5 mg/kg/hr and titrated rapidlyupward in increments of 0.5 mg/kg every 5 to 10 mins, according to clinical response. Typical file:///D|/X. SOLER/BIBLIO2/guide_body_p02.htm (4 de 6) [18/09/2001 20:49:01] Practice Parameters for Intravenous Analgesia and Sedation for Adult Patients In the Intensive Care Unit: An Executive Summary maintenance dosages are 0.5 to 3.0 mg/kg/hr. Propofol should be administered via a central vein.
Recommendation 5—Level 2: Lorazepam Is the Preferred Agent for the Prolonged Treatment ofAnxiety in the Critically Ill Adult. Lorazepam (Ativan®, Wyeth-Ayerst Laboratories, Philadelphia, PA,and others) is an intermediate-acting benzodiazepine that is less lipophilic than diazepam, whichdecreases its potential for peripheral accumulation (9). Compared with midazolam, lorazepam islonger acting, causes less hypotension, causes an equally effective anterograde amnesia, is lowerin cost, and with prolonged administration produces more rapid awakening (10). Lorazepam ismost conveniently administered by intermittent intravenous bolus injection, but continuousintravenous infusion is an equally acceptable method of administration. The usual starting dosageis 0.044 mg/kg every 2 to 4 hrs, as needed, but this requirement is highly variable. One or moreloading doses are generally required with continuous infusion therapy. Because lorazepam has aslightly delayed onset of action, a single dose of midazolam or diazepam may be utilized to initiatesedative therapy when rapid sedation is required.
Recommendation 6—Level 1: Haloperidol Is the Preferred Agent for the Treatment of Delirium inthe Critically Ill Adult. Delirium is a state of reduced ability to appropriately respond to externalstimuli, usually manifested as disorganized thinking (rambling, incoherent/irrelevant speech),decreased level of consciousness, altered sensory perception, disorientation, and/or altered levelof psychomotor activity. Delirium is frequent in the ICU and is often incorrectly termed "ICUpsychosis." Administration of opiates or benzodiazepines as initial therapy for delirium may causea paradoxical worsening of symptoms because of the further alteration in sensory perceptionproduced by these agents.
Haloperidol (Haldol®, McNeil Pharmaceutical, Raritan, NJ) is a butyrophenone neuroleptic drugwith proven efficacy in the treatment of delirium in the critically ill (11). Although haloperidol has notbeen approved by the U.S. Food and Drug Administration for intravenous administration, this routeof administration has been reported to be safe and effective (12) and is preferred in the critically illpatient to maximize bioavailability and predictability (11). Clinical effects are observed within 30 to60 mins after intravenous administration and may last 4 to 8 hrs. Haloperidol may cause QTprolongation on the electrocardiogram (13) and should be used with caution in conjunction withother drugs that may prolong the QT interval. The usual starting dosage is 2 to 10 mg administeredintravenously and the dosage is repeated every 2 to 4 hrs.
Etomidate (Amidate®, Abbott Laboratories, Abbott Park, IL) is an intravenous anesthetic/hypnotic
agent with minimal cardiovascular- and respiratory-depressant effects that is often used in the ICU
to provide anesthesia for short procedures. Long-term use for sedation has been associated with
adrenocortical suppression and increased mortality. Ketamine (Ketalar®, Parke-Davis, Morris
Plains, NJ) is an intravenous anesthetic/analgesic agent that is utilized in the ICU in conjunction
with specific procedures, such as painful dressing changes. Ketamine may induce increases in
blood pressure, heart rate, and intracranial pressure when used as a sedative agent. The
barbiturate agents thiopental (Pentothal®, Abbott Laboratories) and pentobarbital (Nembutal®,
Abbott Laboratories) are used in the ICU population primarily to control intracranial pressure or as
anticonvulsants. Utilizing subanesthetic doses, the barbiturates are effective sedative agents but
lack amnestic and analgesic properties, and produce myocardial depression and vasodilation that
commonly result in tachycardia and hypotension. Chlorpromazine (Thorazine®, SmithKline
Beecham, Pittsburgh, PA) and droperidol (Inapsine®, Janssen Pharmaceutica) are neuroleptic
agents that have been evaluated for the treatment of restlessness and delirium. Insufficient
experience exists to recommend either of these agents in critically ill patients.
1 *Lewis KS, Whipple JK, Michael KA, et al: Effect of analgesic treatment on the physiological
(c). consequences of acute pain. Am J Hosp Pharm 1994; 51:1539–1554
2 Mather LE: Clinical pharmacokinetics of fentanyl and its newer derivatives. Clin
(c). Pharmacokinet 1983; 8:422–446
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(c). Tolerance to its anesthetic effects. Anesthesiology 1983; 59:245–248
4 Kirwood CF, Edwards DJ, Lalka D, et al: The pharmacokinetics of meperidine in acute
(b). trauma patients. J Trauma 1986; 26:1090–1093
5 Acute Pain Management Guideline Panel: Acute Pain Management: Operative or Medical
(d). Procedures and Trauma. Clinical Practice Guideline. AHCPR Pub. No. 92-0032. Rockville,
MD, Agency for Health Care Policy and Research, Public Health Service, U.S. Department ofHealth and Human Services, February 1992 6 Brown CR, Moodie JE, Wild VM, et al: Comparison of intravenous ketorolac tromethamine
(b). and morphine sulfate in the treatment of postoperative pain. Pharmacotherapy 1990;
7 Ritz R, Elsaser S, Schwander J: Controlled sedation in ventilated intensive care patients.
(c). Resuscitation 1988; 16(Suppl):583–589
8 Roekaerts PMHJ, Huygen FJPM, de Lange S: Infusion of propofol versus midazolam for
(b). sedation in the intensive care unit following coronary artery surgery. Journal of Cardiothoracic
and Vascular Anesthesia 1993; 7:142–147 9 Greenblatt DJ, Ehrenberg BL, Gunderman J, et al: Kinetic and dynamic study of intravenous
(b). lorazepam: Comparison with intravenous diazepam. J Pharmacol Exp Ther 1989;
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(a). midazolam in the treatment of acute agitation syndromes during mechanical ventilatory
support. Crit Care Med 1994; 22:1241–1247 11 Fish DN: Treatment of delirium in the critically ill patient. Clin Pharm 1991; 10:456–466
12 Riker RR, Fraser GL, Cox PM: Continuous infusion of haloperidol controls agitation in
(c). critically ill patients. Crit Care Med 1994; 22:433–440
13 Huyse F, Van Schijndel RS: Haloperidol and cardiac arrest. Lancet 1988; ii:568–569
*For an explanation of these annotations, see Table 1.
These practice parameters have been developed by the Guidelines/Practice Parameters Committee of the American College ofCritical Care Medicine, Society of Critical Care Medicine, and thereafter reviewed by the Society’s Council. These guidelines reflectthe official opinion of the Society of Critical Care Medicine and should not be construed to reflect the views of the specialty boards orany other professional medical organization.
Editor’s Note: As with previous guidelines published in this journal, these guidelines have not undergone traditional peer review. SeeCrit Care Med 1991; 19:137 and 1992; 20:447.
Reproduced with permission from the Society of Critical Care Medicine. Copyright Society of Critical Care Medicine. All rightsreserved.
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