RTs should be familiar with sedative and analgesic agents routinely used in critical care areas. A multidisciplinary approach including physicians, nurses, clinical pharmacists, and RTs will optimize the use of these agents and produce satisfactory health care outcomes.

Sedation and analgesia are often required for patients who need mechanical ventilation in critical care areas. The primary concern of the RT is the impact that these agents have on the pulmonary system, including their effects on weaning from mechanical ventilation. Prolonging weaning may have deleterious effects, including greater risk of nosocomial pneumonia and spontaneous pneumothorax.

Case Report
The patient, a 64-year-old, 60-kg female, presented to the emergency department of Crozer-Chester Medical Center, Upland, Pa, on June 14, 2003, with acute shortness of breath that progressed in intensity over 48 hours. The patient had a medical history of chronic obstructive pulmonary disease, hypertension, and renal insufficiency. The patient was immediately transferred to the medical intensive care unit (ICU). On admission to the ICU, the patient’s blood pressure was 110/65 mm Hg, her heart rate was 88 beats per minute, her respiratory rate was 28 breaths per minute (with labored breathing), and her oral temperature was 38.7°C. Arterial blood gas analysis using a sample obtained while the patient breathed room air identified a pH of 7.23, a PaCO2 of 72 mm Hg, a PaO2 of 58 mm Hg, and a bicarbonate level of 32 mEq/L. Because of her deteriorating clinical course, the patient required intubation and initiation of mechanical ventilation. The ventilator was set to provide synchronous intermittent mandatory ventilation (SIMV) at a rate of 14 breaths per minute, a tidal volume (VT) of 500 mL, and a fraction of inspired oxygen (FIO2) of 50%. Chest radiographs after intubation determined proper endotracheal tube placement and detected a left lower lobe pneumonia.

The next 3 days of the patient’s ICU stay were uneventful. The patient was progressing in weaning from mechanical ventilation, but began to require greater analgesic control, including morphine sulfate, with 2 mg administered intravenously (IV) every 3 hours (16 mg /24 hours). The ventilator was set to provide pressure support of 10 cm H2O and an FIO2 of 40% during the day and SIMV at a rate of 6, a VT of 500 mL, and an FIO2 of 35% during sleeping hours. Over the next 2 days, the patient’s neurological status deteriorated, with decreases in her Glasgow Coma Score and in the ability to respond to questions. Weaning from mechanical ventilation was discontinued. The patient’s SIMV was reinstituted while the cause of her change in mental status was investigated.

The clinical pharmacist was consulted; as a result, morphine sulfate was discontinued and replaced by fentanyl citrate (25 mg IV every 3 hours as needed for pain). The rationale for this change included possible accumulation of morphine and morphine’s active metabolite (morphine-6-glucuronide) due to the patient’s history of renal insufficiency. The patient improved over the next 48 hours, responding to commands. She was successfully extubated and was transferred out of the ICU.

Analgesia
Pharmacological agents commonly used for analgesia include opioids, non-steroidal anti-inflammatory agents, and acetaminophen. It is common, in the ICU environment, for the mechanically ventilated patient to require IV opioids due to their quick onset of action, potency, and ease of dose titration. Opioids currently prescribed have physiological activity at a variety of central and peripheral chemoreceptors, although the m and k receptors are most important for analgesia. Analgesics such as opioids can be administered on a continuous or intermittent schedule, with supplemental doses given as required.¹ If a continuous infusion is used, a specific analgesic protocol should be incorporated to allow for daily awakenings of the patient. Analgesic protocols have been associated with lower total doses of opioids and with decreased days of ventilatory support.² Unfortunately, some patients may not qualify for daily awakenings due to their degree of critical illness. Sudden cessation of analgesia to allow for daily awakenings may progress to ventilator dysynchrony, severe hypoxemia, and hemodynamic instability. All opioid narcotics are directly associated with respiratory depression. It is imperative to apply a therapeutic plan of opioid use to the care of patients selected for weaning from mechanical ventilation. Indiscriminate use of narcotics may lead to failure to wean and may promote other complications associated with prolonged intubation and mechanical ventilation. Opioids commonly used in the ICU are shown in Table 1.

Morphine sulfate is a phenanthrene-derivative opiate agonist. The agent is considered the gold standard of opioids. Morphine may be administered in various formulations, but the IV route is the most common in the ICU environment. Repeated higher doses may induce respiratory depression, including decreases in respiratory rate, VT, and minute ventilation. In the presence of renal insufficiency, repeated doses may lead to prolonged sedation and respiratory depression due to an active metabolite (morphine-6-glucuronide). The agent, due to its sympatholytic activity, may also induce hypotension and vagally mediated bradycardia in euvolemic patients.³ Morphine is the preferred agent for intermittent therapy because of its longer duration of effect.

Fentanyl citrate is a synthetic phenylpiperidine-derivative opiate agonist that is structurally related to meperidine and is routinely used in anesthesiology as an adjunct to general anesthesia. Based on its unique pharmacodynamic profile, this agent is considered by some clinicians to have the most potent onset, the shortest duration of action, and the shortest recovery time. Fentanyl is the preferred agent for patients who do not tolerate morphine and require rapid analgesia, are hemodynamically unstable, or have a history of renal insufficiency.

Meperidine is also considered a phenanthrene-derivative opiate agonist. The agent is similar to morphine in its pharmacological profile, but is not as potent as morphine and has a shorter duration of action. The use of this agent for chronic analgesia in most ICU settings has been limited because its known metabolite (normeperidine) has been associated with neurological sequelae, including tremors, seizures, and delirium.⁴ The active metabolite is a concern when the agent is administered in high or repeated doses to patients with renal failure. Meperidine may be considered for patients who require opioid intervention, but have a documented allergy to morphine, fentanyl, or hydromorphone (or are unable to tolerate any of these agents due to other adverse effects).

Hydromorphone is very similar to morphine in its pharmacological effect, but is considered more potent than morphine. Advantages of hydromorphone over morphine include that it does not produce an active metabolite or contribute to histamine release. Hydromorphone would be indicated for patients who cannot tolerate morphine, are hemodynamically unstable, or have a history of renal insufficiency.

Sedation
The causes of anxiety and agitation in the mechanically ventilated patient may be numerous, including underlying medical illness; the inability to communicate due to endotracheal intubation; continuous stimuli, including alarms, nursing activities, and other health care interventions; and sleep deprivation. The optimal way to assess the degree of sedation is to use a sedation scale, such as the Ramsey Sedation Scale, Riker Sedation-Agitation Scale, or the Motor Activity Assessment Scale.^5-7 Due to the variability of physicians’ practices for sedating the mechanically ventilated patient, practice parameters were developed to assist with and to maintain a continuity of care.⁸ These guidelines were recently updated, based on a review of scientific literature, clinical practice, and expert opinion.⁹ Table 2 (page 22) lists the most common agents used in clinical practice.

Benzodiazepines have both sedative and hypnotic properties. The mechanisms of action of benzodiazepines include the inhibition of neurotransmitter action and the depression of central nervous system activity.¹⁰ Benzodiazepines are effective in producing an anterograde amnesia and preventing patients from remembering their ICU experiences. The most commonly used agents for IV continuous infusion in the ICU setting are lorazepam and midazolam. Because of its longer half-life, lorazepam is the preferred benzodiazepine for patients requiring more than 3 days of mechanical ventilatory support. Midazolam would be considered for patients likely to need less than 3 days of ventilatory support. For acute agitation, as an intermittent dose, midazolam would be the optimal selection because its onset of action is quicker than that of lorazepam. Agents such as diazepam are administered as scheduled doses throughout the day. Diazepam’s long-acting metabolite and potential for excessive sedation with repeated doses cause some clinicians to avoid its use.

Propofol is considered a general anesthetic primarily indicated for use as a sedative during procedures in the operating room, but it has gained popularity as a continuous-infusion sedative/hypnotic for mechanically ventilated patients. Its mechanism of action is not clearly defined. The agent is a lipid-based product that has sedative, hypnotic, and amnestic properties. Unlike the benzodiazepines, propofol is unique in its chemical composition and pharmacodynamic properties. Because of its rapid onset of effect and short elimination half-life, a propofol infusion can be interrupted daily for a quick neurological assessment. The drug is recommended when short-term mechanical ventilation is expected, usually lasting less than 3 days (as for status asthmaticus, status epilepticus, or drug overdose). Neurosurgical patients, however, may benefit from long-term propofol infusion because it lowers intracranial pressure.¹¹ The drug has been used by some clinicians as an alternative for pharmacological paralysis (using vecuronium or pancuronium) for patients who may require pressure-control or inverse-ratio ventilation. The drug should be avoided in patients allergic to eggs, lecithin, or soybeans because of its lipid emulsion composition.

Haloperidol is a neuroleptic agent indicated for the treatment of numerous disorders, including psychosis, Tourette disorder, and delirium. Its mechanisms of action include the blocking of both dopaminergic receptors in the brain, which initiates a stabilizing effect and causes a flat cerebral affect.¹⁰ Delirium can occur up to 80% of ICU patients.⁹ The Confusion Assessment Method is the most widely used diagnostic tool in the ICU and has demonstrated its validity in the medical literature.¹²

Conclusion
The initiation and maintenance of analgesia and sedation will continue to have a direct impact on the roles of RTs in the critical care environment, particularly because of their effects on weaning from mechanical ventilation. A therapeutic plan that includes the use of assessment tools for both analgesia and sedation must be implemented with the assistance of a multidisciplinary team if we are to provide optimal care.

Michael J. Cawley, PharmD, RPh, RRT, CPFT, is associate professor of clinical pharmacy, Philadelphia College of Pharmacy/University of the Sciences in Philadelphia, and critical care clinical pharmacist, medical/surgical intensive care unit, Crozer-Chester Medical Center, Upland, Pa.

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