Pain, agitation, delirium, and coma are not uncommon in the intensive care unit (ICU). They are secondary to the patient’s underlying disease or to the multiple interventions, such as medications, procedures, mechanical ventilation, wound care, and bed rest. They can also be a marker of critical illness, which is associated with catabolism, immune dysregulation, hypercoagulable states, increased myocardial workload, impaired wound healing, and ischemia.

An ideal individualized approach should be identification of pain, agitation, and alertness, followed by the use of nonpharmacologic and pharmacologic treatment. Nonpharmacological strategies to improve patient’s comfort include lighting adjustment, music therapy, massage, verbal reassurance, optimized sleep hygiene, and involvement of family members in the care of the patient. Often, critically ill patients are unable to report pain, and the behavioral pain scale and critical care observation tool have been shown to have inter-rater reliability and best internal consistency.^1,2 Clinical scales have been used to evaluate the agitation or alertness and degree of sedation of critically ill patients regardless of their requirements for mechanical ventilation. These scales include Adaptation to the Intensive Care Environment (ATICE), the Minnesota Sedation Assessment Tool (MSAT), the Motor Activity Assessment Scale, and the Vancouver Interactive and Calmness Scale (VICS). The most commonly used are the Ramsey Sedation Scale, the Richmond Agitation Sedation Scale^1,2 (RASS; Table 14-1), and the Sedation Agitation Scale (SAS; Table 14-2).^3,4 All the scales have been validated, through correlations with other sedation scales, bispectral index (BIS), electrocardiography (EEG), actigraphy, and different investigators. According to the guidelines of the Society of Critical Care Medicine (SCCM), RASS and SAS are the most validated tools (Level of Evidence [LOE] B).^5–7

Nonopioids Versus Opioids

Uncontrolled pain can result in psychologic and physiologic consequences such as posttraumatic stress disorder; increased catecholamine leading to arteriolar vasoconstriction and impaired tissue perfusion; catabolic hypermetabolism leading to hyperglycemia, lipolysis, and muscle breakdown; impaired wound healing; suppression of natural killer cell activity; and chronic neuropathic pain.^8-13 Despite the availability of non-opiod analgesics, their safety profile has not been completely studied in critical care; therefore, opioids are the primary analgesics in the critically ill⁵ (LOE). Non-opioid analgesics (Table 14-3) may be used as an adjunct or to decrease the amount of the opioid being administered.

Opioids are lipophilic, crossing the blood-brain barrier to act on μ, κ, and δ receptors in the central nervous system (CNS). Some, such as morphine, are hydrophilic in nature, thus exhibiting more peripheral effects (Table 14-4).

Fentanyl is 100 times more potent than morphine. It is considered as the first-line agent for pain management in the ICU, due to its quick onset, quick offset, easy titration, lack of an active metabolite, and less hemodynamic variability. Initial administration of fentanyl begins with a 25- to 50-μg bolus; this can be repeated every 15 to 30 minutes. If the patient requires more than 2 boluses within an hour, infusion at 25 to 700 μg/h or 0.7 to 10 μg/kg/h can be started. Dose adjustment is not required in renal impairment, but reduction should be considered in patients with severe hepatic impairment. Complications include stiff chest wall syndrome and serotonin syndrome when used with monoamine oxidase inhibitors (MAOI).

Remifentanil¹⁴ is an ultra-rapid-acting opioid that binds to stereospecific μ-opioid receptors within the CNS, increasing the pain threshold, altering pain perception, and inhibiting ascending pain pathways. Recommended dosing is 1.5 μg/kg followed by 0.5 to 15 μg/kg/h.

Morphine is considered the gold standard among opioids when dose adjustment or opioid rotation is being considered. It can cause hypotension from histamine release, which causes nitric oxide–related vasodilatation. It is metabolized into active and inactive metabolites that depend on the renal system for elimination. One of its metabolites, morphine 3-glucuronide, can accumulate and cause seizures. Continuous infusion of morphine should be avoided in patients with severe renal impairment. Usual dose is 2 to 4 mg given every 3 to 4 hours with infusion ranging from 2 to 30 mg/h.¹⁵

Hydromorphone has a metabolite, 3-glucuronide, which can accumulate in renal impairment and cause neuroexcitation. It has a low volume of distribution, high water solubility, low protein binding, and low molecular weight; this suggests that it can be removed by hemodialysis. Doses range from 0.2 to 0.6 mg every 1 to 2 hours with continuous infusion at 0.5 to 3 mg/h.¹⁵ Complications include serotonin syndrome with MAOIs and hypotension.

Opioid Conversion

Opioid rotation may be necessary in some patients due to the development of tolerance to the agent or due to changes in organ system and hemodynamic stability. The patient’s level of comfort must be assessed and the steps below must be taken into consideration when converting from 1 opioid to another. Calculate the total dose in milligrams taken in the previous 24 hours (Table 14-4). If pain is controlled on the current opioid, reduce the new opioid daily dose by 25% to 50% to account for cross-tolerance, dosing-ratio variation, and inter-patient variability. If pain is uncontrolled on the current opioid, increase the opioid daily dose by up to 50% to 100%. Consider adjuvant therapy as needed. Titrate liberally and rapidly to analgesic effect during the first 24 hours. Monitor for adverse events and effectiveness.

A reversal agent for opioid toxicity is naloxone. It is an antagonist that blocks the μ and κ opioid receptors. It reverses lipophilic opiates more readily than it does hydrophilic opioids (eg, fentanyl). The initial dose is 0.4 mg to 2 mg every 2 to 3 minutes, depending on the type and duration of action of the opioid used. For patients on long-acting opioids, a continuous infusion of naloxone may be needed for optimal response, since the half-life of the drug is relatively short. The onset of action is approximately 2 minutes with a duration of 30 to 120 minutes, depending on the route of administration. It is also used in patients with opioid-induced pruritus, although this is not a US Food and Drug Administration (FDA)-approved indication. Patients being treated for this condition should be monitored carefully for pain control. Commonly observed side effects with naloxone include abdominal cramps, vomiting, hypertension, tachycardia, seizures, chest pain, and arrhythmia. In certain patients, such as those with acute respiratory distress syndrome (ARDS) or congestive heart failure (CHF), naloxone can provoke pulmonary edema; this is likely a result of opiate-induced pulmonary vascular smooth muscle relaxation.

Complications and Treatment of Opioids

Opioid use is associated with side effects such as esophageal motility disorders, nausea and vomiting, gastroparesis, sphincter of oddi dysfunction, constipation, and narcotic bowel syndrome.¹⁶ The μ-opioid receptors are the principal mediators of analgesia but also cause sedation, dependence, respiratory depression, and bowel dysfunction.^16,17 Tolerance develops with these receptors secondary to desensitization. In the gastrointestinal (GI) tract, differential tolerance occurs so that all organs except the colon develop tolerance.¹⁶ Opioid induced constipation is defined as new or worsening symptoms of constipation, with initiation or change of opioid therapy, including 2 or more of the following: (1) straining during greater than one-third of bowel movements; (2) lumpy or hard stools; (3) sensation of incomplete evacuation; (4) sensation of anorectal obstruction/blockage with greater than one-third of defecations; (5) manual maneuvers to facilitate more than 25% of defecations; and/or (6) less than 3 spontaneous bowel movements per week.¹⁶ For constipation prophylaxis, patients should receive a bowel regimen consisting of a, laxatives and bowel stimulant (e.g. miralax, senna, bisacodyl) (Table 14-5).^16–20 The peripherally-acting μ-opioid antagonists (PAMORA) such as methylnaltrexone (subcutaneous or oral), naloxegol (oral), and naldemidine (oral) are indicated for the treatment of opioid-induced constipation (OIC) in patients when laxative therapy has produced insufficient response. It is recommended to discontinue all maintenance laxatives prior to starting these agents and re-initiate as needed if the response is suboptimal. Dose reduction is recommended in patients with renal impairment. Use of PAMORA is contraindicated in patients with known or suspected gastrointestinal obstruction due to the potential for GI perforation.¹⁸ The most common adverse drug events associated with PAMORAs include abdominal pain, diarrhea, headaches, abdominal distension, hyperhidrosis, anxiety, muscle spasms, rhinorrhea, and chills. These agents should be re-evaluated once the patient is no longer receiving opioids.

Stiff chest wall syndrome is more common in pediatrics and with lipophilic synthetic opioids such as fentanyl, alfentanil, remifentanil, and sufentanil. This rigidity decreases chest wall compliance and may result in ineffective spontaneous ventilation and impairs the effective use of ventilator support. Risk factors include neurological diseases, metabolic disorders, and medications modifying dopamine levels. Early recognition is imperative, and management with the use of ventilatory support and prompt reversal with either naloxone or a short-acting neuromuscular blocking agent should be implemented as soon as possible.

Opioid-induced hyperalgesia is increased nociceptive sensitization secondary to opioids. The type of pain may be similar to or different from initial sensation. Several mechanisms have been proposed, including the activation of N-methyl-D-aspartate (NMDA) receptors on the postsynaptic nerve terminal. Ways to manage this effect include adequate hydration, opioid dose reduction, addition of adjuvant medication, and opioid rotation to agents with effect on the NMDA receptors, such as methadone or ketamine.²¹

Benzodiazepines

The benzodiazepines act by stimulating specific receptors in the CNS. Stimulation of this receptor potentiates the inhibitory effects of gamma-aminobutyric acid (GABA) on GABA-A receptors, resulting in chloride influx, hyperpolarization, and decreased ability of the neuron to reach an action potential, thereby producing sedation and anxiolysis. They produce amnesia, have anticonvulsant activity but lack analgesic properties. The addition of benzodiazepines to opioids may potentiate the effect of opioids through the inhibition of opioid metabolism.^22,23 Benzodiazepines are weak competitive inhibitors of cytochrome P450 3A4 (CYP3A4). They are a pregnancy category D. Patients with renal failure may experience propylene glycol toxicity²⁴ from lorazepam infusion or a high dose of diazepam. Flumazenil is a benzodiazepine antidote. It is given in increments of 0.2 mg titrated to effect with a total dose of 1 mg in adults. The onset is within 1 to 2 minutes with peak effects within 10 minutes. Caution should be exercised in patients receiving long-term benzodiazepine therapy, as it may precipitate acute withdrawal and seizures. Its use is contraindicated in patients with known hypersensitivity to the drug or to benzodiazepines, and also in those who are receiving benzodiazepines to control a potentially life-threatening condition such status epilepticus or intracranial pressure. Further discussion on benzodiazepines is in Chapter 16.

Propofol

Propofol is an alkylphenol derivative compound prepared in a 10% lipid emulsion. It has sedative and amnestic properties but no analgesic properties. It has a rapid onset of action of less than 1 minute and a short duration of action (approximately 10 minutes, but it is dose dependent). Clearance of the drug is not affected by renal or hepatic dysfunction, and it is devoid of any active metabolites. Hypotension is a major cardiovascular effect in which a reduction in mean arterial pressure may occasionally exceed 30%; caution should be exercised when used in patients with hemodynamic instability, hypovolemia, or abnormally low vascular tone. It is administered as a continuous infusion starting at 5 to 10 μg/kg/min and then titrated to effect. Daily interruption with retitration or a light target level of sedation is recommended to minimize prolonged sedative effects. The dose ranges from 25 to 80 μg/kg/min.^25-27

Propofol-related infusion syndrome (PRIS) can occur with prolonged infusions greater than 48 hours and doses greater than 80 μg/kg/min. Propofol-related infusion syndrome is a potentially fatal condition and must be recognized early to avert detrimental outcomes.²⁸ It is associated with metabolic acidosis, cardiac failure, arrhythmias (eg, bradycardia), cardiac arrest, rhabdomyolysis, hyperkalemia, hypertriglyceridemia, refractory hypotension, and kidney failure. All patients should have a baseline triglyceride level, and this should be monitored every 3 to 7 days thereafter. A triglyceride level of 400 mg/dL or more is associated with increased risk of PRIS and pancreatitis; therefore, alternate sedative should be sought. A commonly observed effect from propofol infusion is the presence of green-colored urine, which usually resolves approximately 6 hours after the discontinuation of the drug. The main metabolic pathway of propofol is oxidation, reduction, and hydrolysis by cytochrome P450 and glucuronate conjugation in liver microsomes. The glucuronate conjugates propofol-glucuronide, 4-(2,6-diisopropyl-1,4-quinol)-sulphate, and 4-(2,6-diisopropyl-1,4)-glucuronide are thought to produce the urine discoloration.²⁹