While pain is certainly a cause for anxiety in most ICU patients, many patients suffer from anxiety despite adequate analgesia. It is obvious that a state of critical illness and dependence on others for care can invoke anxiety. Accordingly, sedation strategies must recognize and respond to this problem.
Assessing Adequacy of Sedation
Assessing adequacy of sedation can be difficult because of its subjective nature. Several sedation scales such as the Ramsay Sedation Score37 (Table 14-1), the Sedation Agitation Scale (SAS),38 and most recently, the Richmond Agitation-Sedation Scale (RASS)39 (Table 14-2) have been developed. The Ramsay scoring system is the most frequently referenced in clinical investigations of sedation. While it has the benefit of simplicity, it does not effectively measure quality or degree of sedation with regard to the goals outlined earlier40 and has never been validated objectively.41 Sedation scales such as the Sedation Agitation Scale and the Richmond Agitation-Sedation Scale have been tested extensively for validity and reliability.38,39,42 The RASS is perhaps the most extensively evaluated scale. It has been validated for ability to detect changes in sedation status over consecutive days of ICU care, as well as against constructs of level of consciousness and delirium. Furthermore, this scale has been shown to correlate with doses of sedative and analgesic medications administered to critically ill patients. As such, the RASS and SAS are preferable over the traditional Ramsay Sedation Score.
Table 14–1. Ramsay Sedation Score ||Download (.pdf)
Table 14–1. Ramsay Sedation Score
|1. Patient anxious and agitated or restless or both|
|2. Patient cooperative, oriented, and tranquil|
|3. Patient responds to commands only|
|4. Patient asleep, shows brisk response to light glabellar tap or loud auditory stimulus|
|5. Patient asleep, shows sluggish response to light glabellar tap or loud auditory stimulus|
|6. Patient asleep, shows no response to light glabellar tap or loud auditory stimulus|
Table 14–2. Richmond Agitation-Sedation Scale ||Download (.pdf)
Table 14–2. Richmond Agitation-Sedation Scale
|+4||Combative||Overtly combative/violent; danger to staff|
|+3||Very agitated||Pulls/removes tubes or catheters; aggressive|
|+2||Agitated||Nonpurposeful movement; not synchronous with ventilator|
|+1||Restless||Anxious, but movements not aggressive/violent|
|0||Alert and calm|
|−1||Drowsy||Sustained awakening (>10 s) with eye contact, to voice|
|−2||Light sedation||Briefly awakens (<10 s) with eye contact, to voice|
|−3||Moderate sedation||Movement to voice, but no eye contact|
|−4||Deep sedation||No response to voice; movement to physical stimulation|
|−5||Unarousable||No response to voice or physical stimulation|
|Observe patient. Calm? (score zero) Does patient have restless or agitated behavior? (1 to 4)|
The evaluation of sedation adequacy remains an individual bedside maneuver. The nurse's input is critical because he or she often will notice changes from an optimal level of sedation. Armed with validated sedation scales, clinicians may strive to administer sedatives and analgesics to more concrete, reportable levels. Ideally, one would prefer a patient whose indications for sedation as outlined earlier are met yet who remains fully communicative with bedside caregivers. Such a state of sedation correlates with a Ramsay score of 2 or 3, a Sedation Agitation Scale score of 3 or 4, or a RASS score of 0 or –1.37–39 This state of being awake and communicative while sedatives are still infusing is achievable in some patients. However, in many patients the stress of critical illness precludes such a condition, and patients may require sedation and analgesia to a point where constant communication is not possible.
Recently, the Bispectral Index Monitor, a device that processes the raw electroencephalogram (EEG) signal into a discreet scaled number from 0 (absence of cortical activity) to 100 (fully awake), has been evaluated as a tool to monitor sedation in the ICU setting. Some have found this device to reliably detect a patient's level of consciousness under general anesthesia,43 although others have questioned the overall utility of this device for preventing awareness.44 Preliminary data suggest a reasonable correlation between the bispectral index and the sedation agitation scale,45 as well as the RASS42; however, this device has not been evaluated extensively in the ICU and awaits more extensive validation before its role in the critical care setting is established.6
Recently, the occurrence of delirium in mechanically ventilated ICU patients has been shown to be associated with higher six-month mortality even after adjusting for severity of illness and the use of sedatives or analgesic medications.45a How to decrease the risk of delirium in critically ill patients, and the impact of such a strategy on overall outcome, is not known. The Confusion Assessment Method for diagnosing delirium has been modified for the ICU (the CAM-ICU) and has been validated (see Chapter 62).45b
Strategies for Administering Sedatives in the ICU
Since no single drug can achieve all the indications for sedation and analgesia in the ICU, a combination of drugs, each titrated to specific end points, is a more effective strategy. This may allow lower doses of individual drugs and reduce problems of drug accumulation. In the ICU, sedatives and analgesics almost always are administered by the intravenous route. Both continuous infusion and intermittent bolus techniques have been advocated. While continuous infusions of sedatives may reduce rapid fluctuations in the level of sedation, accumulation of drugs resulting in prolongation of mechanical ventilation and ICU stay has been described.46 Intermittent administration of sedatives and analgesics may increase demands on nursing time, potentially distracting attention away from other patient care issues. Other perceived benefits of continuous sedative infusions include a more consistent level of sedation with greater levels of patient comfort. The convenience of this strategy for both patients and caregivers is likely the greatest reason for its popularity.
Ideally, strategies for sedation and analgesia in critically ill patients should adhere to pharmacokinetic and pharmacodynamic principles. Unfortunately, ICU patients frequently exhibit unpredictable alterations in pharmacology,47 so precise guidelines for drug administration are not possible. For instance, when “short acting” benzodiazepines48,49 such as midazolam and lorazepam are administered in the ICU, these drugs accumulate in tissue (especially adipose) stores with a resulting prolonged clinical effect.24,46,50–52 Other circumstances that confound prediction of the pharmacologic behavior of sedatives and analgesics include altered hepatic and/or renal function,53 polypharmacy in the ICU with complex drug-drug interactions, altered protein binding, and circulatory instability. The multicompartmental pharmacokinetics typical in critically ill patients defy simple bedside pharmacokinetic profiling. As such, titration of sedatives and analgesics against discernible clinical end points, while imprecise, is the only tool available. Further confounding administration of sedatives in the ICU is the dramatic difference between extremes of sedation. Frequently, oversedated patients are easier to manage than undersedated patients, and in an effort to avoid unmanageable agitation, clinicians may be heavy handed when sedating agitated patients. In the initial stages of critical illness, such as the period immediately following intubation and mechanical ventilation, this may be appropriate; however, maintaining deep levels of sedation after patients are stabilized on mechanical ventilation can lead to the problems of prolonged sedation alluded to earlier.
It is not uncommon for some critically ill patients to require extraordinarily high doses of sedatives to achieve tranquility; such doses may be much greater than quoted in the literature and recommended by drug manufacturers.54 Indeed, occasional patients may even require pharmacologic paralysis to achieve synchrony with mechanical ventilation.55
Recently, evidence-based treatment strategies for many common conditions seen in critical illness have emerged. In the last decade, improved outcomes for critically ill patients with acute respiratory distress syndrome (ARDS),56 sepsis,57,58 acute renal failure,59 status asthmaticus,60 and cancer61 all have been reported. As sicker patients continue to demonstrate improved outcomes in the ICU, more aggressive levels of sedation and analgesia may be necessary. This is particularly likely for patients managed with unconventional ventilator strategies (e.g., permissive hypercapnia, low tidal volumes, prone positioning, and pressure-controlled ventilation) because these strategies may be inherently distressing to many patients. For selected patients, deep sedation may be the only practical option.
The use of deep sedation carries a heavy price because the neurologic examination is severely limited in these patients. Ideally, a head-to-toe daily assessment for the presence of organ failure should be routine for every critically ill patient. This is particularly so during resuscitative phases of ICU care, when assessing the adequacy of end-organ perfusion and function is of paramount importance. The mental status examination is an important gauge of brain perfusion. Since brain injury is a devastating complication of critical illness, acute cerebral dysfunction must be detected quickly and corrected, if possible, before permanent injury takes place. The veil of sedation severely handicaps a clinician's ability to serially follow a patient's neurologic condition. Communication and thorough physical examination may detect problems early on and obviate urgent diagnostic studies and therapeutic interventions after a problem has advanced.
A protocol-driven approach to sedation has been shown to alleviate many of the problems mentioned earlier. A protocol directed by bedside nurses can shorten the duration of mechanical ventilation, ICU and hospital length of stay, and the need for tracheostomy62 (Fig. 14-1). Such protocols ensure adequate analgesia and sedation using frequent assessments of patient needs with goal-directed titration of analgesics and sedatives. Alternatively, a routine protocol of daily interruption of continuous sedative infusions can reduce many of the complications of sedation in the ICU setting, including duration of mechanical ventilation and ICU length of stay24,24a (Figs. 14-2 and 14-3). Such a strategy allows patients to spend a substantial portion of their ICU time awake and interactive, potentially reducing the amount of sedative and opiate given, as well as reducing the need for diagnostic studies (e.g., brain CT scan) to evaluate unexplained alterations in mental status.
Protocol for nursing management of sedation during mechanical ventilation. (Used with permission from Brook et al.62)
Kaplan—Meier analysis of the duration of mechanical ventilation, according to study group. After adjustment for base-line variables (age, sex, weight, APACHE II score, and type of respiratory failure), mechanical ventilation was discontinued earlier in the STOP group than in the control group (relative risk of extubation, 1.9; 95 percent confidence interval 1.3 to 2.7; P <0.001).
Kaplan—Meier analysis of the length of stay in the intensive care unit (ICU), according to study group. After adjustment for base-line variables (age, sex, weight, APACHE II score, and type of respiratory failure), discharge from the intensive care unit (ICU) occurred earlier in the STOP group than in the control group (relative risk of discharge, 1.6; 95 percent confidence interval, 1.1 to 2.3; P = 0.02).
Such protocol-driven sedation strategies allow a focused downward titration of sedative infusion rates over time, streamlining administration of these drugs and minimizing the tendency for accumulation. Protocol-driven sedation may allow the depth of sedation to be decreased without compromising the stated goals of sedation. This strategy may allow clinicians to minimize sedative accumulation. Initially, the thought of decreasing or stopping sedatives in a critically ill patient who has been agitated may be unsettling. As such, clinicians may sedate patients aggressively early in their ICU course and maintain the same level of deep sedation indefinitely. A daily holiday from sedatives can eliminate the tendency to “lock in” to a high sedative infusion rate, which—while appropriate early in ICU care—may be unnecessary on subsequent days. When sedative infusions are decreased or stopped, tissue stores can redistribute drug back into the circulation. The interruption of sedative infusions sometimes may lead to abrupt awakening and agitation. This must be anticipated by the ICU team to avoid complications such as patient self-extubation; if excessive agitation is noted, sedatives should be restarted. Although the attempt at waking and communicating with a patient may fail on a given day, this does not portend inevitable failure on all subsequent days. When awakening patients from sedation, one need only bring patients to the brink of consciousness—able to follow simple commands (i.e., open eyes, squeeze hand, track with eyes, open mouth/stick out tongue) without precipitating excessive agitation. Once objective signs of consciousness are demonstrated, restarting sedatives as needed is recommended. If after discontinuing the sedative infusion the patient requires resedation, we recommend restarting the infusion at 50 percent of the previous dose. Adjustments from this starting point can be individualized to patient needs.
It is clear that sedatives may have an impact on the duration of mechanical ventilation.24,62 Protocolized sedation strategies may reduce the duration of mechanical ventilation by allowing earlier recognition of patient readiness to undergo a spontaneous breathing trial. Others have reported previously an important link between a successful spontaneous breathing trial and subsequent liberation from mechanical ventilation.63,64 The use of a daily spontaneous waking trial, followed, when possible, by a daily spontaneous breathing trial, should be implemented widely in the care of critically ill patients requiring mechanical ventilation.
Drugs for Sedation of Mechanically Ventilated Patients
Opiate receptors are found in the central nervous system, as well as in peripheral tissues. There are several classes of receptors, but the two most clinically important are the mu and kappa receptors. The mu receptors have two subtypes, mu-1 and mu-2. Mu-1 receptors are responsible for analgesia, whereas mu-2 receptors mediate respiratory depression, nausea, vomiting, constipation, and euphoria. The kappa receptors are responsible for such effects as sedation, miosis, and spinal analgesia. Table 14-3 presents a summary of the pharmacologic properties of the opiates.
Table 14–3. Properties of Commonly Used Opiates ||Download (.pdf)
Table 14–3. Properties of Commonly Used Opiates
|Typical starting dose||2–5 mg||20–50 mg||25–50 μg||5–10 mg|
|Onset||10 min||3–5 min||0.5–1 min||10–20 min|
|Duration after single dose||4 h||1–4 h||0.5–1 h||6–24 h|
|Hypnosis||No reliable effect||No reliable effect||No reliable effect||No reliable effect|
|Amnesia||No reliable effect||No reliable effect||No reliable effect||No reliable effect|
|Sz threshold||No effect||May decrease||No effect||No effect|
|Common side effects||N/V, ileus, itching||Seizure, N/V, ileus, itching||N/V, ileus, itching||N/V, ileus, itching|
The following discussion applies to the intravenous opiates used most commonly in the ICU.
Intravenous morphine has a relatively slow onset of action (typically 5 to 10 minutes) owing to its relatively low lipid solubility, which delays movement of the drug across the blood-brain barrier. The duration of action after a single dose is approximately 4 hours. As the drug is given repeatedly, accumulation in tissue stores may prolong its effect. Morphine undergoes glucuronide conjugation in the liver and has an active metabolite, morphine-6-glucuronide. Elimination occurs in the kidney, so effects may be prolonged in renal failure.
Meperidine's greater lipid solubility leads to more rapid movement across the blood-brain barrier and a more rapid onset of action, typically 3 to 5 minutes. Because of redistribution to peripheral tissues, its duration of action after a single dose is less than that of morphine (1 to 4 hours). Meperidine undergoes hepatic metabolism and renal elimination. A major problem with the use of meperidine is its metabolite normeperidine, a CNS stimulant that can precipitate seizures, especially with renal failure and/or prolonged use. Since meperidine offers no apparent advantage over other opiates, its side effect of CNS toxicity largely should preclude its use in critically ill patients.
Fentanyl is very lipid soluble, thereby rapidly crossing the blood-brain barrier and exhibiting very rapid onset of action. Its duration of action after a single dose is short (0.5 to 1 hour) because of redistribution into peripheral tissues; however, as with all opiates, accumulation and prolongation of effect can occur when this drug is given for extended periods. Inactive products of hepatic metabolism are excreted by the kidney.
The onset of action is similar to morphine. The duration of action is likewise similar to that of morphine when given as a single dose. However, the absence of active metabolites makes the duration of effect typically shorter than that of morphine when administered for extended periods.
Remifentanil is a lipid-soluble drug with a rapid onset of action. This drug is unique in that it is metabolized rapidly by hydrolysis by nonspecific blood and tissue esterases. As such, its pharmacokinetic profile is not affected by hepatic or renal insufficiency. It must be given by continuous infusion because of its rapid recovery time. This rapid recovery, typically minutes after cessation of the drug infusion, may prove useful in the management of critically ill patients. To date, the drug has not been studied extensively in the critical care setting. Most studies have been performed in neurosurgical and cardiac surgical settings, and little data are available regarding long-term use of this drug. Remifentanil as a component of general anesthesia may have a role in reducing the need for ICU admissions by allowing extubation in the operating room and preventing the need for postoperative ICU care.65,66
All opiates have similar pharmacodynamic effects and will be discussed without reference to individual drugs except where important differences are present.
The primary effect of opioids is analgesia, mediated mainly through the mu and kappa receptors. Mild to moderate anxiolysis is also common, although less than with benzodiazepines. Opiates have no reliable amnestic properties.
Opiates lead to a dose-dependent centrally mediated respiratory depression, one of the most important complications associated with their use. Respiratory depression, mediated by the mu-2 receptors in the medulla, typically presents with a decreased respiratory rate but preserved tidal volume. The CO2 response curve is blunted, and the ventilatory response to hypoxia is obliterated. An important benefit of these drugs is the relief of the subjective sense of dyspnea frequently present in critically ill patients with respiratory failure.
Opiates have little hemodynamic effect on euvolemic patients whose blood pressure is not sustained by a hyperactive sympathetic nervous system. When opiates and benzodiazepines are given concomitantly, they may exhibit a synergistic effect on hemodynamics. The reasons for this synergy are not entirely clear. Meperidine has a chemical structure similar to atropine and may elicit a tachycardia, another reason its use is discouraged in the ICU. All other opiates usually decrease heart rate by decreasing sympathetic activity. Morphine and meperidine may cause histamine release, although it is rarely important in doses typically used in the ICU. Fentanyl does not release histamine.67
Remifentanil may cause bradycardia and hypotension, particularly when administered concurrently with drugs known to cause vasodilation, such as propofol.
Other side effects include nausea, vomiting, and decreased gastrointestinal motility. Methylnaltrexone, a specific antagonist of mu-2 receptors in the gut, has been reported recently to attenuate this side effect in humans.68 The utility of methylnaltrexone in the ICU has not been tested. Other side effects include urinary retention and pruritus. Muscle rigidity occasionally occurs with fentanyl and remifentanil. This is seen typically when high doses of these drugs are injected rapidly and may affect the chest wall muscles, making ventilation impossible. Neuromuscular blockade, typically with succinylcholine, reverses this problem.
Benzodiazepines act by potentiating γ-aminobutyric acid (GABA) receptor complex–mediated inhibition of the CNS. The GABA receptor complex regulates a chloride channel on the cell membrane, and by increasing the intracellular flow of chloride ions, neurons become hyperpolarized, with a higher threshold for excitability. Flumazenil is a synthetic antagonist of the benzodiazepine receptor that may reverse many of the clinical effects of benzodiazepines. Table 14-4 presents a summary of the pharmacologic properties of the benzodiazepines.
Table 14–4. Properties of Commonly Used Benzodiazepines ||Download (.pdf)
Table 14–4. Properties of Commonly Used Benzodiazepines
|Typical starting dose||1–2 mg||0.5–1 mg||5–10 mg|
|Onset||0.5–2 min||3–5 min||1–3 min|
|Duration after single dose||2 h||6–10 h||1–6 h|
|Metabolism||Hepatic||Hepatic (less influenced by age and liver disease)||Hepatic|
|Analgesia||No effect||No effect||No effect|
|Common side effects||Paradoxical agitation||Paradoxical agitation||Paradoxical agitation|
The three available intravenous benzodiazepines, midazolam, lorazepam, and diazepam, are discussed below.
The onset of action of midazolam is rapid (0.5 to 5 minutes), and the duration of action following a single dose is short (∼2 hours). All benzodiazepines are lipid soluble with a large volume of distribution and therefore are distributed widely throughout body tissues. For all benzodiazepines, the duration of action after a single bolus depends mainly on the rate of redistribution to peripheral tissues, especially adipose tissue. Midazolam undergoes hepatic metabolism and renal excretion. Alpha-hydroxy midazolam is an active metabolite but has a half-life of only 1 hour in the presence of normal renal function.
The kinetics of midazolam change considerably when it is given by continuous infusion to critically ill patients. After continuous infusion for extended periods, this lipid-soluble drug accumulates in peripheral tissues rather than being metabolized. On discontinuing the drug, peripheral tissue stores release midazolam back into the plasma, and the duration of clinical effect can be prolonged.69 Obese patients with larger volumes of distribution and elderly patients with decreased hepatic and renal function may be even more prone to prolonged effects.
Intravenous lorazepam has a slower onset of action than midazolam (∼5 minutes) because of its lower lipid solubility, which increases the time required to cross the blood-brain barrier. The duration of action following a single dose is long (6 to 10 hours) and is proportional to the dose given; however, most pharmacokinetic studies are done on healthy volunteers and may not apply to critically ill patients. Lorazepam's longer duration of action is due to lower lipid solubility with decreased peripheral tissue redistribution.
The onset of action of intravenous diazepam is short (∼1 to 3 minutes). Duration of action following a single dose also is short (30 to 60 minutes) owing to high lipid solubility and peripheral redistribution. Diazepam rarely is given by continuous infusion because it has a long termination half-life. Once the peripheral tissue compartment is saturated, recovery can take several days. Diazepam has several active metabolites that themselves have prolonged half-lives. The metabolism of diazepam depends on hepatic function and is prolonged in liver disease and in the elderly.
The benzodiazepines have similar effects and will be discussed without reference to individual drugs except where important differences are present.
All benzodiazepines cause a dose-dependent suppression of awareness along a spectrum from mild depression of responsiveness to obtundation. They are potent amnestic agents;70,71
lorazepam appears to produce the longest duration of antegrade amnesia. All are potent anxiolytic agents. A paradoxical state of agitation that worsens with escalating doses may occur occasionally, especially in elderly patients. All benzodiazepines have anticonvulsant properties.72
Benzodiazepines cause a dose-dependent, centrally mediated respiratory depression. This ventilatory depression is less profound than that seen with opiates; however, it may be synergistic with opiate-induced respiratory depression. In contrast to opiates (described earlier), the respiratory pattern of a patient receiving benzodiazepines is a decrease in tidal volume and an increase in respiratory rate. Even low doses of benzodiazepines can obliterate the ventilatory response to hypoxia.
Benzodiazepines have minimal effects on the cardiovascular system in patients who are euvolemic. They may cause a slight decrease in blood pressure without a significant change in heart rate. Clinically important hypotensive responses usually are seen only in patients who are hypovolemic and/or those whose increased endogenous sympathetic activity is maintaining a normal blood pressure.
Propofol is an alkylphenol intravenous anesthetic. The exact mechanism of action is unclear, although it is thought to act at the GABA receptor. It is an oil at room temperature and is prepared as a lipid emulsion.
Propofol is highly lipid soluble and rapidly crosses the blood-brain barrier. Onset of sedation is rapid (1 to 5 minutes) and depends on whether or not a loading dose is given. Duration of action depends on dose but is usually very short (2 to 8 minutes) owing to rapid redistribution to peripheral tissues.73,74 When continuous infusions are used, duration of action may be increased, but it is rare for the effect to last longer than 60 minutes after the infusion is discontinued. The drug is metabolized mainly in the liver with an elimination half-life of 4 to 7 hours. Propofol has no active metabolites. Because of its high lipid solubility and large volume of distribution, propofol can be given for prolonged periods without significant changes in its pharmacokinetic profile. The termination of its clinical effect depends solely on redistribution to peripheral fat tissue stores. When the infusion is discontinued, the fat tissue stores redistribute the drug back into the plasma, but usually not to clinically significant levels.
Propofol is a hypnotic agent that, like the benzodiazepines, provides a dose-dependent suppression of awareness from mild depression of responsiveness to obtundation. It is a potent anxiolytic as well as a potent amnestic agent.75 Its effect on seizure activity is controversial. Animal studies suggest that it is neither pro- nor anticonvulsant; however, there are case reports of propofol being used to treat seizures, as well as being associated with seizure activity. Propofol has no analgesic properties and should be accompanied by a separate analgesic agent in most, if not all, patients. Failure to recognize this may lead to difficulty keeping patients comfortable, and excessive doses of propofol may be administered.
The CO2 response curve is blunted, and apnea may be seen, especially after a loading dose is given. The respiratory pattern is usually a decrease in tidal volume and an increase in respiratory rate.
Propofol can cause significant decreases in blood pressure, especially in hypovolemic patients. This is mainly due to preload reduction from dilation of venous capacitance vessels. A lesser effect is mild myocardial depression.76,77 Care must be taken in giving this drug to patients with marginal cardiac function; however, since myocardial oxygen consumption is decreased by propofol and the myocardial oxygen supply-demand ratio is preserved, it may be useful in patients with ischemic heart disease.
Because it is delivered in an intralipid carrier, hypertriglyceridemia is a possible side effect.78,79 Therefore, triglyceride levels should be checked frequently. If hypertriglyceridemia occurs, the drug should be stopped. Intralipid parenteral feedings should be adjusted according to the propofol infusion rate because there is a significant caloric load from propofol. Strict aseptic technique and frequent changing of infusion tubing are essential to prevent iatrogenic transmission of bacteria and fungi because propofol can support their growth.80 Dysrhythmias, heart failure, metabolic acidosis, hyperkalemia, and rhabdomyolysis have been reported in both children and adults treated with propofol, especially at high doses (>80 μg/kg per minute in adults).81
Butyrophenones such as haloperidol and droperidol are used occasionally in the ICU for sedation. These drugs induce a state of tranquility such that patients often demonstrate a detached affect. Butyrophenones appear to antagonize dopamine, especially in the basal ganglia, although their exact site of action is not known.
After an intravenous dose, onset of sedation usually occurs after 2 to 5 minutes. The half-life is approximately 2 hours but is dose dependent. Dose requirements vary widely, starting at 1 to 10 mg and titrating to effect. Haloperidol undergoes hepatic metabolism.
Onset of action is usually 2 to 5 minutes, with a typical starting dose of 0.625 to 2.5 mg. Half-life is approximately 2 hours but is longer when higher doses are used. Droperidol, like haloperidol, is metabolized in the liver.
Both haloperidol and droperidol produce CNS depression, resulting in a calm, often detached appearance. These drugs are used most commonly in critically ill patients who are acutely agitated and hyperactive. Patients may demonstrate a mental and psychiatric indifference to the environment.82 Patients also may experience a state of cataleptic immobility. There is no demonstrable amnesia with these drugs. They have no effect on seizure activity. Analgesic effects are minimal with haloperidol; however, droperidol seems to have a significant potentiating analgesic effect when given concomitantly with an opiate. Indeed, droperidol and fentanyl are given occasionally in combination, producing a so-called neuroleptanesthesia. The butyrophenones are the drugs of choice for patients thought to be demonstrating psychotic behavior or agitation resistant to other pharmacologic interventions.
Neither haloperidol nor droperidol has any significant effect on the respiratory system when used alone. There are reports of attenuation of respiratory depression in the presence of opiates, but this effect is mild. Droperidol has been shown to maintain the hypoxic pulmonary drive.83
Haloperidol and droperidol may result in mild hypotension secondary to peripheral α1 blocking effects. Haloperidol also may decrease the neurotransmitter function of dopamine and lead to mild hypotension by this mechanism. Haloperidol may prolong the QT interval and has been reported to result in torsade de pointes,84 although this problem is quite rare.
Extrapyramidal effects are seen occasionally with these drugs but are much less common with intravenous than with oral butyrophenones. When these complications occur, treatment with diphenhydramine or benztropine may be necessary. Neuroleptic malignant syndrome (NMS) occurs rarely and is characterized by “lead pipe” muscle rigidity, fever, and mental status changes. The mechanism of NMS is not fully understood, although some data suggest a central dopaminergic blockade that leads to extrapyramidal side effects and muscle rigidity with excess heat generation. Bromocriptine, dantrolene, and pancuronium all have been used to treat NMS successfully.85
Droperidol is a potent antiemetic and sometimes is used for nausea and vomiting associated with general anesthesia or chemotherapy.
Other Drugs Used for Sedation in the ICU
86–88 is a selective α2 agonist approved for short-term use (<24 hours) in patients initially receiving mechanical ventilation. While patients remain sedated, when undisturbed, they arouse easily with stimulation. This drug is attractive because patients seem to transition from sedated to awake states rather easily, thus facilitating neurologic examinations. The drug has both analgesic and anxiolytic effects. Side effects include bradycardia and hypotension, especially with hypovolemia or high sympathetic tone. Unfortunately, dexmedetomidine has not been studied extensively as an agent for long-term administration to critically ill patients.
has a molecular structure similar to phencyclidine. Patients given this drug experience a profound dissociative state. They may keep their eyes open and maintain a protective cough reflex but appear unaware of their surroundings. It is recommended to give this drug slowly over a period of approximately 1 minute. Ketamine causes minimal respiratory depression. There may be amnesia, but this is not a reliable property of the drug. Coordinated but seemingly purposeless movements are seen often. Profound analgesia is seen with ketamine. The common side effect of emergence delirium and severe hallucinations has limited its usefulness for sedation of adult patients in the ICU. This phencyclidine derivative has gained popularity recently as an illicit drug of abuse.
Barbiturates such as thiopental and pentobarbital are potent agents that cause amnesia and unconsciousness. They have little use as sedatives in critically ill patients because of a propensity to cause hemodynamic instability. In addition to this, they are lipid soluble and thus accumulate in peripheral tissues after long-term infusions, leading to prolonged recovery from sedation. These drugs may be used to induce a pharmacologic coma in patients with severe brain injury.
Inhalational anesthetics such as
have been studied in critically ill patients and shown to be safe and effective.89 These drugs have analgesic, amnestic, and hypnotic properties and may be useful as single agents. Isoflurane undergoes only 0.2% metabolism, being eliminated almost exclusively through the lungs. Technical problems delivering the drug safely through the ventilator at accurate concentrations, as well as difficulty scavenging the exhaled gas, have limited the use of inhalational anesthetics for sedation in the ICU in the United States.
Table 14-5 summarizes pharmacologic properties of other commonly used sedative agents.
Table 14–5. Properties of Other Sedative Agents ||Download (.pdf)
Table 14–5. Properties of Other Sedative Agents
|Typical starting dose||1–2 mg/kg||0.5–1 mg||0.5–1.0 μg/kg over 10 min; 0.2–0.7 μg/kg/h infusion|
|Onset||0.5–1 min||2–5 min||5–10 min|
|Duration after single dose||2–8 min||2 h||30–60 min|
|Metabolism||Hepatic, renal, lungs?||Hepatic||Hepatic|
|Analgesia||No effect||No effect||++|
|Seizure threshold||??||No effect||No effect|
|Reducing dyspnea||+||No effect||No effect|
|CV effect||Venodilation, arteriolar dilation, myocardial depression||Venodilation, arteriolar dilation||Venodilation, arteriolar dilation, bradycardia, occasional hypertension|
|Respiratory effect||Hypoventilation||No effect||No effect|
|Common side effects||Increased triglycerides||Neuroleptic malignant syndrome (rare), extrapyramidal effects (rare)||Hypotension, bradycardia|