Sedation, Analgesia, and Related Topics

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Chapter 4 Sedation, Analgesia, and Related Topics

In this chapter the indications, contraindications, and adverse effects of drugs used for sedation and analgesia in the intensive care unit (ICU) are reviewed. In addition, practical tools for the measurement of depth of sedation and quality of analgesia are outlined. The related topics of neuromuscular-blocking drugs and antiemetics are also discussed.

PHARMACOKINETIC CONSIDERATIONS

The term pharmacokinetics refers to the handling of a drug by the body and includes the distribution and elimination of a drug. The term pharmacodynamics refers to the effect of a drug on the body and includes the concepts of efficacy, adverse effects, and potency described under the subsequent heading Analgesic Drugs.

Duration of Effect

The elimination half-time is the time taken for the amount of drug in the body to decrease by 50%. This parameter is often quoted when describing the pharmacokinetic properties of a drug. However, elimination half-time only rarely reflects the duration of effect. When a drug is given intravenously, it is rapidly distributed to a central “virtual” compartment consisting of plasma, interstitial fluid, and organs with high blood flow (brain, heart, liver, kidneys). This central compartment is in equilibrium with the effect site and with the organs of elimination—the liver and the kidneys. Drugs with low lipid solubility, high ionization, and high protein binding tend to be confined to this central compartment and typically have a small steady-state volume of distribution (VSS; Fig. 4-1). Such drugs can be described using a one-compartment model (V1). For drugs that obey one-compartment kinetics, the duration of effect may be related to the elimination half-time. Examples include aminoglycosides and neuromuscular blocking drugs. However, highly lipid-soluble drugs, including most sedative-hypnotics and opioid analgesics, display multicompartment kinetics in which drugs are redistributed from the central compartment to one or two peripheral compartments (V2, V3; see Fig. 4-1).

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Figure 4.1 Pharmacokinetic models. The top panel shows one- and three-compartment models. With a one-compartment model, drug is delivered to the central compartment, which has an apparent volume of distribution (V). Drug is eliminated from the body by the liver and the kidneys (or plasma enzymes). The clearance of a drug (CL) is the volume of plasma from which the drug is completely eliminated per unit time; it is usually reported in ml/min. For a one-compartment model, the volume of distribution and the clearance of the drug determine the elimination half-time (T1/2elim):T1/2elim = Ln(2)V/CL, where Ln(2) is the natural logarithm of 2(0.692). For drugs that obey one-compartment kinetics, the elimination half-time is an important determinant of the duration of effect of the drug. The central compartment is in equilibrium with the effect-site compartment (Ve). Keo is the rate constant for equilibrium between the central compartment and the effect site. The time taken for the effect-site concentration to increase to half the central compartment concentration is the effect-site half-time (T1/2keo); it is related to Keo as T1/2keo = Ln(2)/Keo. Effect-site half-time is an important determinant of the speed of onset of a drug.

For a three-compartment model, drug equilibrates between the central compartment (V1) and two peripheral compartments (V2 and V3). The steady-state volume of distribution (VSS) is given by: VSS = V1 + V2 + V3. Rate constants and distribution half-times between the central and peripheral compartments can be calculated. The bottom panel shows plasma-concentration-time curves for a drug that displays three-compartment kinetics. Following a single intravenous (IV) dose (curve A), the concentration initially falls very rapidly due to redistribution from the central compartment; the clinical effect is relatively short. Following multiple intravenous bolus doses (curve B), or prolonged infusion (curve C), the peripheral compartments become progressively saturated with drug. With each dose, the rate of decline of the plasma concentration decreases until the peripheral compartments are fully saturated. Once drug administration ceases, the plasma concentration slowly falls, and the clinical effect is prolonged.

In a three-compartment model, the drug is delivered to the central compartment and then distributed to two peripheral compartments: the second compartment is composed of tissues with intermediate blood flow (e.g., muscle); and the third compartment is composed of tissues with low blood flow, principally fat. For highly lipid-soluble drugs, this third compartment can provide a huge reservoir into which drug molecules slowly equilibrate. For example, the VSS of propofol, a highly lipid-soluble drug, is more than 400 l, a volume much greater than the volume of a human being, implying that the drug is concentrated in the lipid-rich V3. This compares with a VSS of just 15 l for pancuronium, a poorly lipidsoluble drug that is confined mainly to the extracellular fluid. The offset of highly lipid-soluble drugs, such as fentanyl, midazolam, and propofol, is not due to their elimination from the body but to redistribution from the central compartment to peripheral compartments. However, following prolonged infusion, the peripheral compartment can become saturated with a drug. Once the infusion has stopped, as the concentration in the central compartment falls due to hepatic metabolism, the drug moves back into the central compartment from the peripheral compartments, prolonging the clinical effect.

For drugs that display multicompartment kinetics, distribution and context-sensitive half-times are more useful concepts than elimination half-time. The distribution half-time is the time taken for the concentration within the central compartment to fall by 50%. Following a single intravenous dose, the distribution half-time determines the duration of effect of the drug (see Fig. 4-1). The context-sensitive half-time is the time taken for the effect-site concentration to fall by 50% following discontinuation of an intravenous infusion.1 Because a drug accumulates in the peripheral compartments over time, the context-sensitive half-time changes depending on the duration of infusion (Fig. 4-2). The context-sensitive half-time provides some indication of the duration of effect of the drug following both short- and long-term infusions (or repeated bolus doses). The percentage of decrease in concentration required for recovery from a drug’s effect is not necessarily 50%.

Highly lipid-soluble drugs typically undergo extensive hepatic metabolism to produce water-soluble metabolites that are then excreted by the kidney. For a number of sedative and analgesic drugs, these metabolites are pharmacologically active and can prolong the clinical effect, particularly in the presence of renal dysfunction.

Multicompartment kinetics, prolonged infusion, the presence of active metabolites, and concomitant hepatic and renal dysfunction collectively explain why the duration of effect of many sedative and analgesic medications is greatly prolonged in critically ill patients.

Onset of Action

The speed of onset of a drug depends on multiple factors; two that are of clinical importance for intravenously administered sedatives and analgesics are (1) the speed with which the drug is distributed within the central compartment and (2) the half-time for equilibration between the central and effect-site compartments (T1/2keo; see Fig. 4-1). Low cardiac output slows drug distribution within the central compartment and can greatly prolong the onset time. Thus, when administering potent sedative or analgesic medications to patients with low cardiac output, it is essential to give a small initial dose and wait a longer than normal time for the clinical effect to occur. Values for T1/2keo vary among drugs. For instance, the T1/2keo for morphine, fentanyl, and remifentanil are 17 minutes, 6.6 minutes, and 1.16 minutes, respectively. Therefore, morphine will have a slower onset of action than fentanyl and remifentanil.

SEDATION

Sedation is part of a continuum of central nervous system (CNS) depression that ranges from anxiolysis through sedation, hypnosis (sleep), unconsciousness, and coma. Most sedative-hypnotic drugs produce anxiolysis at subhypnotic doses. Certain drugs, notably the benzodiazepines, also produce antegrade (i.e., following drug administration) amnesia at low doses. Some sedativehypnotics are anticonvulsants (e.g., benzodiazepines, barbiturates, and propofol). Anxiolysis is not the same as sedation. Antipsychotic drugs produce a state of outward calm but can increase feelings of anxiety and apprehension.

Indications for Sedation

Ventilated patients require sedation to tolerate endotracheal intubation and mechanical ventilation, facilitate nursing care, minimize the stress response, reduce oxygen consumption, diminish recall of unpleasant experiences, and prevent the development of posttraumatic stress disorder.2,3 Less commonly, sedation is indicated in extubated patients for the treatment of anxiety or delirium.

Mechanical ventilation, particularly using lungprotective strategies with long inspiratory times and permissive hypercapnia, is poorly tolerated by nonsedated patients and can result in ventilator dysynchrony (Chapter 29) and the sensation of dyspnea. Distressed patients may become tachycardic and hypertensive, which can exacerbate or provoke myocardial ischemia and bleeding. Such patients may also self-extubate or pull out their intravascular lines and surgical drains. A critically unwell patient commonly benefits from deep sedation, occasionally accompanied by neuromuscular blockade, during the acute phase of an illness. However, most patients do not require paralysis, only a level of sedation sufficient to allow tolerance of endotracheal intubation. Sedation of agitated patients should be commenced only after providing adequate analgesia and treating reversible physiologic causes.3

Adverse Effects of Sedation

Excessive sedation contributes to hypotension and delays awakening, needlessly prolonging the duration of mechanical ventilation.4 Sedation may also mask the development of intracranial, intrathoracic, or intraabdominal complications. The reduction in sympathetic tone that follows the administration of sedative and analgesic drugs can cause important hypotension. Hypotension is particularly marked in patients with high levels of endogenous catecholamines such as those that occur in the settings of hypovolemia and acute heart failure. Following prolonged administration of some sedatives (and opioid analgesics), tolerance may develop such that increased doses are required to elicit the same clinical effect. Abrupt discontinuation of certain sedatives, notably benzodiazepines, in a patient who has developed tolerance, may provoke a withdrawal syndrome (see discussion under subsequent heading Benzodiazepines). For these reasons, the need for sedation should be evaluated on an on-going basis and the depth of sedation regularly assessed.

Assessment of Sedation

If the clinical state allows, sedation should be stopped each day until the patient shows signs of awakening. Sedation can then be restarted if still indicated. A number of sedation scoring systems have been developed to quantify the depth of sedation and allow sedative drugs to be titrated to effect. Some commonly used scoring systems are shown in Table 4-1. Although primarily a system for monitoring neurologic function after trauma, the Glasgow Coma Scale (Table 4-2) may also be used to monitor sedation, although much information is lost in patients who are intubated and cannot respond verbally. One option in ventilated patients is to revise the Glasgow Coma Scale score to a maximum of 10, with the annotation that the patient is intubated.

Table 4-2 Glasgow Coma Scale

Verbal Response Motor Response Eye Response
5 = Appropriate 6 = Obeys commands 4 = Opens spontaneously
4 = Disorientated 5 = Localizes to pain 3 = Opens on command
3 = Unconnected words 4 = Withdraws from pain 2 = Opens with pain
2 = Sounds only 3 = Abnormal flexion to pain 1 = No response
1 = Nothing 2 = Extends to pain  
  1 = No response Total = V + M + E = 3-15

The Bispectral Index (BIS) monitor, a highly processed electroencephalogram, is widely used to assess depth of anesthesia during surgery and has been used on a limited basis to monitor depth of sedation in the ICU.5,6 A potential problem with this monitor in the ICU environment is that BIS recordings are increased—implying a reduced depth of sedation—by electromyographic activity.7 Thus, BIS recordings tend to be lower in paralyzed patients than in nonparalyzed patients for an equivalent depth of sedation. This phenomenon could potentially lead to paralyzed patients receiving inadequate sedation, resulting in unpleasant awareness.

Sedative Drugs

The ideal sedative agent would have a rapid onset and offset of action (i.e., a short and constant context-sensitive half-time); cause minimal respiratory and cardiovascular depression; and be inexpensive. No single agent fulfills all three criteria.

Propofol

Propofol is a hypnotic anesthetic agent that is administered intravenously by bolus or continuous infusion. At low doses, propofol causes amnesia and anxiolysis; at higher doses, general anesthesia. The mechanism of action of propofol is probably the enhancement of GABA (γ-aminobutyric acid) channel activity (see later discussion).

Propofol is a highly lipid-soluble drug that is formulated as a lipid emulsion. The solution supports bacterial growth and should be prepared using aseptic technique. Infusion lines and/or propofol bottles should be changed every 12 to 24 hours.

The onset of action following a bolus dose usually occurs within 30 seconds. Propofol has a distribution half-time of 2 to 4 minutes, which results in an offset of effect of 5 to 10 minutes following a bolus dose. There is minimal residual sedation. Propofol has a relatively stable context-sensitive half-time (see Fig. 4-2), and awakening is rapid even after prolonged infusion. In one study of cardiac surgery patients, extubation occurred after a mean time of 7.6 minutes after cessation of propofol infusion (mean dose of 82.8 mg/hr) following 17 hours of continuous sedation.8 The corresponding extubation time for patients given midazolam (mean dose 2.3 mg/hr) was 125 minutes. This rapid offset of clinical effect following prolonged infusion occurs because propofol has high hepatic and extrahepatic clearance (pharmacokinetic effect) and because subhypnotic concentrations of propofol cause minimal sedation (pharmacodynamic effect).

The dose range for sedation in the ICU is 0.3 to 3 mg/kg/hr. There is large interpatient variability in the required dose; higher doses are required in the young (because of increased clearance) and in those habituated to other sedative-hypnotics such as alcohol. As a bolus (0.5 to 3 mg/kg), propofol can be used to induce general anesthesia.

The main side effects of propofol relate to cardiac and respiratory depression. Hypotension due to vasodilation tends to be more marked than with other sedatives. Bolus doses must be used with extreme caution because as little as 20 mg can cause profound hypotension in critically unwell patients. Respiratory depression and apnea are also common, particularly following bolus doses. In extubated patients, equipment for bag-mask ventilation and endotracheal intubation should be immediately available. Doses in excess of 5 mg/kg/hr for prolonged periods have been associated with propofol infusion syndrome. This syndrome is characterized by metabolic acidosis and progressive hemodynamic collapse, and it is potentially fatal.9 Prolonged infusions may result in hyperlipidemia resulting from the intralipid emulsion.

Propofol is a very useful agent for short-term sedation following cardiac surgery. Once patients have been fully rewarmed and bleeding has settled, propofol can be discontinued in the expectation of rapid awakening.

Midazolam

Midazolam can be given enterally or parenterally and has an oral bioavailability of about 50%. For sedation in the ICU, midazolam is given by intermittent intravenous bolus or by continuous infusion. The usual dose range is 2 to 10 mg/hr, but much higher doses are occasionally required. Following a single intravenous dose, midazolam has a rapid onset of action and a short duration of effect. The distribution half-time is about 8 minutes. Bolus doses should be administered slowly (1 mg/min) and titrated to effect because the peak effect may be delayed for several minutes in patients with low cardiac output. Following prolonged infusion the context-sensitive half-time is increased (see Fig. 4-2), which results in a greatly prolonged duration of effect.

Midazolam undergoes hepatic metabolism by hydroxylation—by the cytochrome P-450 (CYP) 3A4 enzyme system—and conjugation. The 1-hydroxy metabolite is pharmacologically active and can contribute to the clinical effect. Drugs that inhibit the CYP3A4 enzyme system (Table 4-3) can prolong the effect of midazolam.

Table 4-3 Selected Substrates, Inhibitors, and Inducers of the CYP3A4 and 2D6 Hepatic Enzyme Systems

CYP3A4
Substrates Inhibitors Inducers
Calcium channel blockers Antiarrhythmics Rifamycins
Diltiazem Amiodarone Rifabutin
Felodipine Calcium channel blockers Rifampin
Verapamil Diltiazem Rifapentine
Benzodiazepines Verapamil Anticonvulsants
Midazolam Nicardipine Carbamazepine
Alprazolam Azole antifungals Phenobarbital
Immunosuppressives Itraconazole Phenytoin
Cyclosporine Ketoconazole Others
Tacrolimus Voriconazole St.
Sirolimus Macrolide antibiotics Anti-HIV agents
Statins Erythromycin  
Atorvastatin Clarithromycin  
Lovastatin Troleandomycin  
Macrolide antibiotics Others  
Erythromycin Grapefruit juice  
Clarithromycin Anti-HIV agents  
Others Metoclopramide  
Losartan    
Sildenafil    
Anti-HIV agents    
  CYP2D6  
Substrates Inhibitors  
β blockers Antidepressants and antipsychotics  
Alprenolol Chlorpromazine  
Bufuralol Haloperidol  
Carvedilol Fluoxetine  
Metoprolol Paroxetine  
Propranolol Clomipramine  
Timolol Doxepin  
Antiarrhythmics Antiarrhythmics  
Flecainide Quinidine  
Mexiletine Amiodarone  
Propafenone Antihistamines  
Antipsychotics H2 antagonists (ranitidine)  
Haloperidol H1 receptor antagonists  
Antidepressants    
Fluoxetine    
Paroxetine    
Venlafaxine    
Some tricyclic antidepressants    
Opioids    
Codeine    
Dextromethorphan    
Tramadol    

Substrate drugs’metabolisms or inhibitors of the relevant enzyme system. Two are enhanced or inhibited other important CYPenzyme systems are 2C9, which is involved in the metabolism of warfarin, and 2C19, which is involved in the metabolism of the proton pump inhibitors (omeprazole, pantoprazole, etc.)

(Modified from Wilkinson GR: Drug metabolism and variability among patients in drug response. N Engl J Med 352:2211, 2005.)48 HIV, human immunodeficiency virus.

Hypotension is less marked than with propofol but can still occur. Apnea and airway obstruction are common, particularly when midazolam is combined with an opioid. Midazolam is a useful sedative agent in patients who are hemodynamically unstable or require prolonged ventilation.

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