Download choice of sedation for critically ill patients: a rational approach

PROCEEDINGS
CHOICE OF SEDATION FOR CRITICALLY ILL PATIENTS:
A RATIONAL APPROACH*
—
Louis Brusco, Jr, MD
ABSTRACT
Because no single, ideal sedative exists, the
clinician must take care to select the best agent
to ensure effective sedation while minimizing
side effects and maintaining a good cost-effectiveness profile. This article discusses the most
commonly used sedatives and assesses their
usefulness and effectiveness in the clinical setting, citing the latest guidelines provided the
Society of Critical Care Medicine.
(Advanced Studies in Medicine 2002;2(9):343-349)
Since there is no ideal sedative, evidence-based
medicine must be used to determine or choose a sedative regimen for patients; however, this can be difficult. Few randomized control studies have been
conducted comparing different sedative agents. In
some cases, the results of these studies have been
unconvincing, as pharmacology of the drugs tends to
change with duration of infusion, and studies may not
reflect actual clinical use. Additionally, sedatives are
frequently used in conjunction with analgesics; choice
of analgesic agent is based on the patient’s individual
needs and must be considered in the sedative selection.
The recently revised guidelines by the American
College of Critical Care Medicine (ACCM) provide
parameters for the use of analgesics and sedatives in
the ICU.
he ideal intensive care unit (ICU) sedative
would reduce stress and provide anxiolysis, analgesia, and amnesia, as well as
improve tolerance of ventilatory support
and nursing interventions. In addition, it
would have little effect on cardiovascular function; fast
onset; fast offset with minimal respiratory depression,
if possible; and have no active metabolites. This drug
would have no interactions with other medications; no
pain on injection; no tolerance or withdrawal; be safe
for all ages and have no age-related changes in pharmacokinetics; and be cost effective. Unfortunately, this
ideal sedative does not exist.
The ACCM guidelines define analgesia as “the
blunting or absence of sensation of pain or noxious
stimuli.” Inadequate pain relief can have a number of
consequences, including agitation, and can evoke a
stress response that is characterized by tachycardia,
increased myocardial oxygen consumption, hypercoagulability, immunosuppression, and persistent catabolism. The concomitant use of analgesics and sedatives
can relieve agitation and lessen the stress response.1
Opioid analgesics commonly used in the ICU include
fentanyl, morphine, and hydromorphone.
*This article is based on a presentation given by
Dr Brusco at a satellite symposium held at the Society of
Critical Care Medicine, January 27, 2002.
Address correspondence to: Louis Brusco, Jr, MD, St. Luke’sRoosevelt Hospital Center, Department of Anesthesiology,
1111 Amsterdam Avenue, New York, NY 10025.
OPIOIDS
Selection of an opioid is based upon its pharmacology and potential for adverse events.
Characteristics of an ideal agent would include rapid
onset, ease of titration, lack of accumulation, and
low cost.
T
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ANALGESICS
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Adverse events as a result of the use of opioids
occur frequently in the ICU and may include negative
effects on respiratory rate, hemodynamic function, the
central nervous system, and the gastrointestinal system. Hypotension may occur in patients who are
hemodynamically unstable, hypovolemic, or those
with elevated sympathetic tone. Myoclonus and muscle rigidity may occur with high-potency opioids and
may affect ventilatory efforts.1,2
FENTANYL
Fentanyl is a synthetic opioid with a rapid onset
and short duration of action. It may be delivered by
intermittent intravenous administration, continuous
infusion, or transdermal administration. It has no significant metabolites. Transdermal use is not recommended for acute relief due to a 12- to 24-hour delay
to peak effect.
Repeated dosing of a drug may cause accumulation
and prolonged effects.1,2 With prolonged infusion, the
half-life increases dramatically from 30 to 60 minutes
to 9 to 16 hours.3 Fentanyl also exhibits tachyphylaxis, with larger volumes of the drug necessary over time,
which may result in an increased recovery period following prolonged infusions.4 Fentanyl is more hemodynamically stable than morphine; however, it still
may result in hypotension due to suppression of
endogenous catecholamines.5
MORPHINE
Morphine sulfate is a prototypical opioid with a
longer duration of action than fentanyl. It is administered in intermittent doses. Significant metabolites
include morphine-3 and morphine-6 glucuronides.
Morphine has a half-life of 2 to 3 hours in healthy
adults, but is increased in patients with severe cirrhosis or burns. Septic shock and renal disease decrease
clearance, and end-organ disease significantly affects
metabolism of the drug.1,2
Vasodilation may result in hypotension and the
active metabolites may result in prolonged sedation in
patients with renal insufficiency.1 A morphine-stimulated histamine release may result in allergic reactions
and cardiovascular instability.2
HYDROMORPHONE
Hydromorphone is a high-potency, semisynthetic
opioid that may be administered in oral, rectal, and
parenteral forms. It is inexpensive, has a half-life of
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approximately 2 to 3 hours, and is commonly used for
patients with severe long-term pain. Hydromorphone3-glucuronide is the active metabolite, but it is not
clinically significant.1,2
While the duration of action is similar to morphine, it does not stimulate histamine release.
Hydromorphone is a potent respiratory depressant
Table 1. Characteristics of the Ideal Sedative
" Rapid onset of action
" Easily titratable level of adequate sedation
" Short acting, allowing patient assessment, rapid recovery following discontinuation, easy weaning from mechanical ventilation, and early extubation
"
"
"
"
"
No or few adverse effects
"
"
"
"
"
"
Minimal respiratory depression
"
"
"
"
"
"
"
"
Ease of administration
No anaphylaxis or allergic reaction
No nausea, vomiting, or phlebitis
No or minimal interaction with other drugs
Minimal metabolism; not dependent on normal hepatic, renal,
or pulmonary function
Minimal effect on cardiovascular function
No pain on injection
No active or toxic metabolites
No suppression of cortisol production by the adrenal cortex
No or minimal interactions with other commonly prescribed
ICU drugs
Lack of accumulation with prolonged administration
Does not promote growth of pathogens
No tolerance and withdrawal symptoms
Cost effective
Easily prepared and long shelf life
Safe for all ages with no age-related changes in pharmacokinetics
Provides facilitation of ventilator synchrony and the performance of various procedures and nursing interventions
" Lack of abuse potential
Data from references 6-9.
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and may accumulate in cases of renal failure, resulting
in neuroexcitation and cognitive impairment.
Literature states it is less effective and has greater toxicity than other opioids.1,2
Propofol is a negative inotrope, a vasodilator that can
cause dose-related hypotension and carries a risk of infection and hyperlipidemia. Long-term or high-dose infusions may result in hypertriglyceridemia. Other adverse
effects may include bradycardia and pain upon injection.1
SEDATIVE HYPNOTICS
Efforts to reduce anxiety in the ICU may include
frequent reorientation, maintenance of patient comfort, provision of adequate analgesia, and optimization
of the environment.1 Sedative therapy often is used as
an adjunct to these measures and frequently is essential
as a part of the care plan in order to maintain patient
safety and comfort. Sedation of mechanically ventilated patients frequently is medically necessary. Table 1
outlines characteristics of the ideal sedative.
Unfortunately, the ideal sedative does not exist,
and therapeutic choice should be based upon individual patient needs.
PROPOFOL
Propofol is ultra short acting following a bolus dose
and short-term infusion. Its rapid onset and offset of
action is particularly useful for the short-term sedation
of 3 classes of patients:
• Short-term intubated patients, including:
– Surgical patients
– Asthmatics
– Drug overdose patients
– Any patient with an anticipated quick extubation
• Patients with changing neurologic status requiring frequent neurological evaluation
• The elderly
MIDAZOLAM
Midazolam has a rapid onset of action (generally 2 to
5 minutes) and a short duration of action following
bolus dose (approximately 15 minutes). Its duration of
action extends to 1 to 2 hours following short-term infusion. Studies have shown that duration following prolonged infusion (>72 hours) can range from 3 to 15
hours. Swart et al found an average elimination half-life
of 8.9 hours, with a large interpatient variability (3 to 15
hours; standard deviation of 4.4 hours).13
Erratic recovery times after usage are common with
benzodiazepines. Other possible adverse events
include ventilatory depression, tolerance, and tachyphylaxis after prolonged therapy (≥3 days); a predisposition to chemical dependence has been associated
with long-term use.10,14
LORAZEPAM
Lorazepam is a benzodiazepine with a slow onset of
action (10-20 minutes), an intermediate half-life (6
Figure. Comparisons of Half-lives of Lorazepam,
Midazolam, and Propofol
Propofol is a complex drug with 3 half-lives. The α
half-life, or distribution of the drug from the blood to
the tissues following administration, is 2 to 3 minutes.
The β half-life, or the elimination half-life, ranges
from 30 to 60 minutes (Figure). The γ half-life, or terminal half-life during which the drug is eliminated
from tissue fat, ranges from 300 to 700 minutes.10
Wake-up time following short-term administration is
approximately 15 minutes; however the duration of
action is prolonged after infusion exceeding 72
hours,11 resulting in a wake-up time of 30 to 60 minutes. It has been found that daily wake-ups for neurological assessments can reduce wake-up time following
prolonged propofol infusion.12
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hours) following bolus dose, and a longer duration of
action (12-32 hours) after 72 hours of infusion.
Lorazepam is not easily titratable due to its longer halflife.1 It has a prolongation of effect, with severely
decreased drug requirements in the elderly. Because it
lacks active metabolites and has decreased lipophilicity, lorazepam may be a steady and predictable agent
for long-term sedation, but some literature states it
should not be used to treat seizures or acute anxiety.10
Besides other adverse effects associated with benzodiazepines, the solvents used with lorazepam have
been implicated in cases of reversible acute tubular
necrosis, lactic acidosis, and hyperosmolar states
after prolonged use.1
propofol (11 minutes); time from discontinuation
to extubation was greater with midazolam (391
minutes) than propofol (250 minutes). Propofol
patients were found to be more hypotensive.18
• In comparing the safety of the 2 drugs, Wahr et
al found no difference in postoperative
ischemia, non–Q-wave myocardial infarction
(MI), Q-wave MI, or cardiac death. Patients
receiving propofol were less tachycardic and
hypertensive, but more hypotensive.19
• Hall et al found time to extubation was greater with
midazolam (24.7 hours) than propofol (6.7 hours),
but length of stay in the ICU was shorter with
midazolam (64 hours) than propofol (94 hours).20
COMPARISON STUDIES: PROPOFOL, MIDAZOLAM,
AND LORAZEPAM
McCollam et al randomized 31 patients to receive
lorazepam, propofol, or midazolam. Using the Ramsay
scale, it was found that adequate sedation occurred
most frequently with midazolam; oversedation was
most common with lorazepam, and undersedation
with propofol. Midazolam required the fewest number of titrations. Initial time to adequate sedation was
shortest in the propofol group. Total drug cost was
significantly higher for propofol than either midazolam or lorazepam, and 18% of the total cost for
lorazepam was due to drug loss due to precipitation.
Researchers considered only acquisition cost, however, and did not investigate cost effectiveness based
upon cost of total care.15
Several studies compared propofol with midazolam
in patients following coronary artery bypass grafting
(CABG).
Ostermann et al conducted a review of 49 randomized controlled trials, reaching the following
conclusions6:
• McMurray et al found treatment with propofol
resulted in earlier extubation after discontinuation, decreased morphine requirements, and a
lower PaCO2 after extubation.16
• Snellen et al demonstrated a longer recovery time
with midazolam (66 minutes) versus propofol (24
minutes), and a longer time for weaning with midazolam (243 minutes) versus propofol (154 minutes)
following post-CABG sedation.17 The quality of
sedation between the 2 drugs was similar.
• Roekaerts et al found patients receiving midazolam required more adjustments and bolus doses;
time from discontinuation to responsiveness was
greater with midazolam (72 minutes) than
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• Propofol is at least as effective as midazolam.
• Propofol exhibits a faster time to extubation than
midazolam; it is not yet clear if this translates
into shorter time on mechanical ventilation or
length of stay in the ICU.
• Propofol results in a greater incidence of
hypotension.
• Propofol may offer an advantage when rapid
awakening is desired.
• Further study is necessary.
Table 2 summarizes the properties of propofol,
midazolam, and lorazepam.
PHARMACOECONOMICS
The high cost of drug therapy in the ICU has led
to pharmacoeconomic comparisons of commonly
used sedatives. A true pharmacoeconomic study evaluates not only acquisition cost of drugs, but considers
administration cost and impact of therapy on both
positive and negative outcomes, such as length of stay
and treatment of adverse events. Several studies have
undertaken a pharmacoeconomic evaluation of propofol and midazolam and/or lorazepam.
A 1999 study by Swart et al concluded that
lorazepam was a useful alternative to midazolam, with
easier management of sedative level and a significant
cost savings.13
Barrientos-Vega et al compared propofol and midazolam, and demonstrated a significantly shorter time
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to waking and significantly shorter time to weaning
among patients in the propofol group than the midazolam group. Total costs analyzed included acquisition
cost, cost of ICU stay during sedation, and cost during
weaning. Although the acquisition cost of propofol
was higher, the total care cost for the group receiving
propofol was $511 164, compared with $584 712 for
the group receiving midazolam.21
Since the completion of each of these studies, both
midazolam and propofol have had significant price
reductions, effectively reducing acquisition differentials
and possibly improving the cost effectiveness of propofol
when compared with midazolam and lorazepam.
HALOPERIDOL
Haloperidol is a neuroleptic agent used to treat
delirium, and is not a sedative agent. It has a half-life
of 18 to 54 hours, with loading regimens given to
achieve a rapid response in acutely delirious patients.
When used for the control of agitated patients following a traumatic brain injury, it may prolong the duration of posttraumatic amnesia.1
DEXMEDETOMIDINE
Dexmedetomidine is an alpha2-agonist that provides both sedation and analgesia. It causes no respiratory depression and induces a unique type of
sedation that allows for easy arousal with preserved
respiratory drive, and a quick return to sedated state
is achieved without altering infusion rate. While the
usual dose range is 0.2 to 0.7 mg/kg/h, doses over the
maximum do not offer greater sedation. Currently,
dexmedetomidine is only approved for short-term
infusion, ≤24 hours. A common adverse effect is
hypotension, particularly with volume depletion.
Dexmedetomidine exhibits a ceiling on its sedative
effect, which limits its effectiveness as a single agent.
SCCM GUIDELINE RECOMMENDATIONS14
The recently revised guidelines from the Society
of Critical Care Medicine (SCCM) provide recommendations on choice of analgesics, sedatives, and
sedation monitoring. Following are some of the
recommendations:
ANALGESICS
If intravenous doses of an opioid analgesic are
required, fentanyl, hydromorphone, and morphine
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are the recommended agents.
Scheduled opioid doses or a continuous infusion is
preferred over an “as-needed” regimen to ensure consistent analgesia.
Fentanyl is preferred for a rapid onset of analgesia
in acutely distressed patients.
Fentanyl or hydromorphone is preferred for
patients with hemodynamic instability or renal
insufficiency.
Morphine or hydromorphone is preferred for intermittent therapy because of its longer duration of effect.
SEDATIVE THERAPY
Propofol is recommended when rapid wakening is
important (eg, for neurosurgical assessment or extubation). Triglyceride concentrations should be monitored after 2 days of infusion, and total caloric intake
from lipids should be included in the nutrition support prescription.
Midazolam or diazepam should be used for rapid
sedation of acutely agitated patients. Midazolam is recommended for short-term use only, as it produces
Table 2. Properties of Intravenous (IV) Sedatives
Propofol
Midazolam
Lorazepam
Bolus dose
2 mg/kg
1-5 mg
1-5 mg
Elimination half-life
30-60 minutes
1-4 hours
10-20 hours
Half-life of parent
compound
26-32 hours
3-11 hours
8-15 hours
Onset after IV dose
1-2 minutes
2-5 minutes
5-20 minutes
Lipophilicity
High
High
Moderate
Active metabolites
No
Yes
No
Continuous IV
Yes
Yes
Yes
Metabolic pathway
Oxidation
Oxidation
Glucuronidation
Unique adverse
events
Elevated triglyc- Benzodiazepine- Solventerides; pain on related adverse related acidosis/
injection
events only
renal failure in
high doses
Data from references 1 and 10.
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unpredictable awakening and time to extubation when
infusions continue longer than 48 to 72 hours.
Lorazepam is recommended for the sedation of
most patients via intermittent IV administration or
continuous infusion.
The titration of the sedative dose to a defined endpoint is recommended with systematic tapering of the
dose or daily interruption with retitration to maximize
prolonged sedative effects.
The use of sedation guidelines, an algorithm, or a
protocol is recommended.
SEDATION MONITORING
A sedation goal or endpoint should be established
and regularly redefined for each patient. Regular
assessment and response to therapy should be systematically documented.
The use of a validated sedation assessment scale is
recommended. Objective measures of sedation, such
as the Bispectral Index, have not been completely evaluated and are not yet proven useful in the ICU.
APPLYING THE GUIDELINES
At St. Luke’s-Roosevelt Hospital Center, choice of
sedative depends on individual patient needs and
anticipated duration of intubation.
• Propofol is used for immediate postintubation
and postoperative sedation. Use is generally limited to 72 hours, except in patients with head
trauma or neurosurgical indications, and the
elderly. Patients who have been sedated long term
with another drug, but are moving toward extubation, may be switched to propofol.
• Morphine, lorazepam, and haloperidol are used
for longer-term sedation.
CONCLUSIONS
Optimal care of the ICU patient consists of an
individualized treatment plan based upon relief of
pain, anxiety, and agitation. While there is no single
ideal sedative, lorazepam, midazolam, and propofol
each offer distinct benefits based upon individual
patient needs. In determining an appropriate sedative,
the SCCM guidelines recommend lorazepam for sedation of most patients, midazolam for short-term sedation, and propofol when rapid wakening for
348
assessment or extubation is desired, or in the elderly.
Because sedatives account for a high percentage of
ICU drug resources, cost is a vital component of any
decision-making process. As generics become available, acquisition cost is constantly changing and
should not be the only factor considered. True cost
effectiveness is based upon total cost of care, including
both positive and negative outcomes.
Ultimately, a rational choice of sedative is a multifactorial decision, based upon individual patient
needs, desired effect of sedation, and cost effectiveness.
REFERENCES
1. Jacobi J, Fraser GL, Coursin DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the
critically ill adult. Crit Care Med. 2002;30:119-141.
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.
3. Shafer A, White PF, Schuttler J, Rosenthal MH. Use of fentanyl infusion in the intensive care unit: Tolerance to its anesthetic effects? Anesthesiology. 1983;59:245-248.
4. Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics,
and rational opioid selection. Anesthesiology. 1991;
74:53-63.
5. Flacke JW, Flacke WE, Bloor BC, Olewine S. Effects of
fentanyl, naloxone, and clonidine on hemodynamics and
plasma catecholamine levels in dogs. Anesth Analg.
1983;62:305-313.
6. Ostermann ME, Keenan SP, Seiferling RA, Shibbald WJ.
Sedation in the intensive care unit: A systematic review.
JAMA. 2000;283:1451-1459.
7. Cohen IL. Management of the agitated intensive care
patient. Crit Care Med. 2002;30:S97-S121.
8. Carrasco G, Molina R, Costa J, et al. Propofol vs. midazolam in short-, medium-, and long-term sedation of critically ill patients: A cost-benefit analysis. Chest. 1993;
103:557-564.
9. Chamorro C, de Latorre FJ, Montero A, et al. Comparative
study of propofol versus midazolam in the sedation of critically ill patients: Results of a prospective, randomized, multicenter trial. Crit Care Med. 1996;24:932-939.
10. Nasraway SA. Use of sedative medications in the intensive
care unit. Semin Respir Crit Care Med. 2001;22:165-174.
11. Albanese J, Martin C, Lacarelle B, Saux P, Durand A,
Gouin F. Pharmacokinetics of long-term propofol infusion
used for sedation in ICU patients. Anesthesiology. 1990;
73:214-217.
12. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;
342:1471-1477
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13. Swart EL, van Schijndel RJ, van Loenen AC, Thijs LG.
Continuous infusion of lorazepam versus midazolam in
patients in the intensive care unit: Sedation with lorazepam
is easier to manage and is more cost-effective. Crit Care
Med. 1999;27:1461-1465.
14. Shafer A. Complications of sedation with midazolam in the
intensive care unit and a comparison with other sedative
agents. Crit Care Med. 1998;26. Available at: http://
home.mdconsult.com/das/article/body/1/jorg=journal&s
ource=MI&sp=1023692&si. Accessed January 16, 2002.
15. McCollam JS, O’Neil MG, Norcross ED, Byrne TK, Reeves
ST. Continuous infusions of lorazepam, midazolam, and
propofol for sedation of the critically ill surgery trauma
patient: A prospective randomized comparison. Crit Care
Med. 1999;27:2454-2458.
16. McMurray TJ, Collier PS, Carson IW, Lyons SM, Elliott P.
Propofol sedation after open heart surgery: A clinical and
pharmacokinetic study. Anaesthesia. 1990;45:322-326.
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17. Snellen F, Lauwers P, Demeyere R, Byttebier G, Van Aken
H. The use of midazolam versus propofol for short-term
sedation following coronary artery bypass grafting.
Intensive Care Med. 1990;16:312-316.
18. Roekaerts PM, Huygen FJ, de Lange S. Infusion of propofol
versus midazolam for sedation in the intensive care unit following coronary artery surgery. J Cardiothorac Vasc Anesth.
1993;7:142-147.
19. Wahr JA, Plunkett JJ, Ramsay JG, et al. Cardiovascular
responses during sedation after coronary revascularization:
Incidence of myocardial ischemia and hemodynamic
episodes with propofol versus midazolam. Anesthesiology.
1996;84:1350-1360.
20. Hall RI, Sandham D, Cardinal P, et al. Propofol vs midazolam for ICU sedation: A Canadian multicenter randomized
trial. Chest. 2001;119:1151-1159.
21. Barrientos-Vega R, Mar Sanchez-Soria M, Morales-Garcia
C, Robas-Gomez A, Cuena-Boy R, Ayensa-Rincon A.
Prolonged sedation of critically ill patients with midazolam
or propofol: Impact on weaning and costs. Crit Care Med.
1997;25:33-40.
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