#90180: Agitation, Sedation, and Delirium in Adult ICU Patients

Non-opioid analgesics, such as acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, ketorolac), may be used in adult ICU patients as part of multimodal pharmacotherapy [3]. These can be considered adjuncts and most appropriate for the treatment of less severe pain. They are recommended for use in addition to opioids to help reduce opioid requirements (i.e., opioid-sparing) and opioid-related side effects, improve pain control, and improve patient-centered outcomes [3,6].

The Society of Critical Care Medicine suggests using nefopam (if feasible) either as an adjunct or replacement for an opioid to reduce opioid use and their safety concerns for pain management in critically ill adults.

(https://www.sccm.org/Clinical-Resources/Guidelines/Guidelines/Guidelines-for-the-Prevention-and-Management-of-Pa Last Accessed: January 25, 2024)

Level of Evidence: Very low

Acetaminophen should be avoided in patients with significant liver dysfunction. Further, clinicians should exercise caution with NSAIDs in patients with kidney dysfunction, heart failure, cirrhosis, gastrointestinal bleeding, or platelet abnormalities [14].

Various medications (e.g., tricyclic antidepressants, gabapentin) are recommended for the treatment of neuropathic pain [3]. Monotherapy with IV opioids is not recommended in the treatment of neuropathic pain [3]. In some cases, gabapentin, pregabalin, and carbamazepine are used as opioid-sparing agents in critically ill adults.

Ketamine

Ketamine may be a safe and effective option in select ICU patients [14]. Ketamine seems to work as well as opioids for acute pain. (Note that pain doses are much lower than those used for sedation/anesthesia.) However, there are still potential side effects, such as nausea, mild hallucinations, and confusion. In addition, limited safety data exist for higher-risk patients, including those with schizophrenia or with decompensated heart failure, as ketamine may increase heart rate or blood pressure. Clinicians may consider using ketamine to reduce opioid needs or to consider ketamine as an alternative if opioid use may not be safe [15,16].

It is important to adhere to hospital protocols for ketamine use, including contraindications, as these may vary among facilities. Examples of contraindications include:

Emergence reactions with ketamine appear to be rare, especially with the lower doses used for pain. Reactions may involve anxiety, delirium, dream-like states, nightmares, illusions, or visual hallucinations [15,16].

Clinicians should consider warning patients about the potential for emergence reactions; this may improve acceptance [15,16]. Emergence reactions may not be as common with lower doses or in those older than 65 years of age, but caution is still warranted. Patients who are given ketamine should be provided with an appropriate environment and minimal stimuli during recovery to minimize emergence reactions. This may include dim lighting, limited noise, and have a comforting person present.

Lidocaine

Intravenous lidocaine is also sometimes an option for refractory acute and chronic pain syndromes, such as renal colic, neuropathic pain, and headaches. In addition, lidocaine is used perioperatively to limit opioids and hasten recovery [17].

However, lidocaine is not appropriate in all patients. For example, IV lidocaine should not be combined with regional anesthesia due to the increased risk for local anesthetic systemic toxicity [17]. IV lidocaine is contraindicated in patients with cardiac conduction abnormalities (including Adams-Stokes or Wolff-Parkinson-White syndromes) and severe sinoatrial, atrioventricular, or intraventricular block [17]. It should also be avoided in patients with seizure disorders, due to seizure risk with supratherapeutic blood levels of lidocaine [17].

Opioids are recommended as first-line agents for treating non-neuropathic pain in adult ICU patients due to their combined analgesic and sedative properties [2,3,6]. Respiratory depression from opioids is common, as well as hypotension secondary to a decrease in sympathetic tone or vasodilation from histamine release. Opioids can also cause decreased gastrointestinal mobility, pruritus, flushing, urinary retention, and delirium [6]. The adverse effects of opioids can increase a patient's length of stay in the ICU and worsen post-ICU outcomes. Efforts should be made to use non-opioid analgesics as well as nonpharmacologic methods to reduce opioids to the lowest effective dose for the shortest period of time [3].

All IV opioids are considered equally effective when titrated to achieve similar pain intensity endpoints [3]. The appropriate agent should be chosen based on its pharmacokinetics, metabolism, and adverse effect profile. Also consider if the patient is opioid tolerant.

Potential adverse effects to consider when using opioids in patients in an ICU include:

The primary opioids used in critically ill adult patients are fentanyl, morphine, and hydromorphone (Table 1) [3,6]. Meperidine is not generally recommended due to the risk for neurologic toxicity (e.g., reduction of seizure threshold) [9].

Continuous opioid infusions may be used for ongoing pain, as well as for moderate or severe pain that is not relieved by intermittent injections. Intermittent, or bolus, injections are also useful for moderate pain and for preprocedure analgesia prior to and during painful procedures such as dressing changes. If a patient is conscious, they may be able to use patient-controlled analgesia (PCA) to control their pain by self-administering bolus injections as needed, with or without an underlying continuous infusion. All infusions and doses should be monitored closely and titrated as needed to give optimal pain relief while avoiding oversedation and unwanted adverse effects.

Fentanyl is commonly used for continuous pain control. It has a relatively short half-life (two to four hours), which makes it easily titrated when given as a continuous infusion [6]. Fentanyl is metabolized in the liver, has no active metabolites, and may accumulate in patients with liver impairment [9]. Fentanyl is lipophilic and may accumulate in fat and muscle with prolonged infusions, increasing the half-life in patients with obesity [6]. The accumulated drug may be released after the infusion is stopped, leading to prolonged activity. However, fentanyl is often preferred because it does not undergo elimination via the kidney. Fentanyl also causes less hypotension than morphine.

Morphine and hydromorphone can be used as continuous infusions but may be chosen for intermittent IV injections because their half-lives are longer than fentanyl [6]. Morphine and hydromorphone are metabolized by the liver, and the metabolites are excreted by the kidneys. Their effects can be prolonged in patients with liver or kidney impairment [6,9].

Morphine has a half-life of 3 to 5 hours, with an onset of analgesia of 5 to 10 minutes. It has a moderate volume of distribution, and its effects can be prolonged in obese patients [6]. Morphine causes histamine release, which can result in hypotension, itching, flushing, and bronchospasm [6,7,19].

Hydromorphone is much more potent than morphine. It has an inactive metabolite that may cause neuroexcitatory symptoms, especially for patients with kidney impairment, in which there can be accumulation with repeated doses [18].

Remifentanil is a derivative of fentanyl. It is metabolized by blood and tissue esterases and does not accumulate in patients with kidney or liver impairment. Remifentanil has a very short half-life (shorter than fentanyl) of 3 to 10 minutes and should not be used for bolus dosing alone [6]. It may be preferred for patients who need prompt reversal of action (e.g., requirement for frequent neurologic assessments). Remifentanil should be dosed on ideal body weight, or adjusted body weight in obese patients [3,6]. Fentanyl and remifentanil are equal in terms of achieving sedation goals with no difference found in a patient's duration of mechanical ventilation [6]. However, the use of remifentanil in the ICU setting seems limited by its high cost and its association with hyperalgesia following discontinuation of infusions [6,7]. Despite the theoretical advantages of remifentanil, more evidence is needed to solidify its place in therapy for analgesia and sedation in critically ill patients [2].

Sufentanil has a quick onset of one to three minutes, similar to fentanyl. It should not be used for bolus dosing alone. Sufentanil has no active metabolites, and its clearance is not affected in patients mild or moderate kidney impairment [9]. The dose should be based on ideal body weight if the patient's actual weight is more than 120% of ideal body weight [21]. For patients without IV access, sufentanil is also available in a sublingual formulation that is administered by trained staff. However, it is more expensive than other opioids and there are not data to prove it is more effective. For patients without IV access, hospital protocols should be followed for other opioid administration routes; for example, fentanyl injection can be given intranasally.

Constipation Management

All patients receiving opioids should be on an effective bowel regimen. It is important to initiate bowel regimens when the opioid is started instead of waiting for symptoms to develop. Bowel regimens typically include a scheduled osmotic (e.g., polyethylene glycol [PEG] 3350) or stimulant laxative (e.g., bisacodyl). These two can be combined if necessary. Other medications, such as magnesium citrate, glycerin suppositories, or enemas, can be added on if these are not effective. Although adding a stool softener (e.g., docusate) to a stimulant laxative is widely recommended, small studies show that this approach is not beneficial [59; 60].

The bowel regimen should be individualized based on patient characteristics and special considerations. Unique considerations include [22]:

Addressing Opioid Tolerance

Treating acute pain in patients taking chronic opioids can be challenging. For example, postsurgical or trauma patients often need large doses to control pain, which can be outside of some clinician's comfort zone [23]. When selecting or evaluating pain regimens, ensure surgical patients continue their usual maintenance regimen before surgery to prevent withdrawal and uncontrolled pain and verify that as-needed doses are adequate based on the scheduled regimen [23]. The oral route is preferred, but if the patient cannot take their usual maintenance regimen (e.g., post-operatively), consider converting it to basal rate PCA. It is important to avoid escalating the patient's long-acting opioid regimen and to avoid long-acting opioids or fentanyl patch for acute pain. When selecting doses, consider potency differences among opioids [23].

Opioid-Induced Hyperalgesia

Opioid-induced hyperalgesia is defined as "a state of nociceptive sensitization caused by exposure to opioids" [24]. Patients with opioid-induced hyperalgesia experience a sensitivity to pain that could be the same as their original, underlying pain or could originate from a different source [25]. Opioid-induced hyperalgesia can present in a way that is often mistaken for opioid tolerance. Tolerance to the analgesic effects of opioids can develop and requires escalating doses of opioids to maintain the same level of pain control. If a patient has tolerance to an opioid, pain will decrease when the opioid dose is increased. If the patient has opioid-induced hyperalgesia, increasing the opioid makes the pain even worse and a decrease in the opioid dose relieves the pain [24]. Switching opioids can also help relieve hyperalgesia [26]. Opioid-induced hyperalgesia should be considered in the differential diagnosis when opioid therapy fails [25].

Opioid Allergy

Opioid allergy is a common patient complaint. However, less than 2% of opioid reactions are "true allergies" and may be more appropriately categorized as pseudoallergies. A pseudoallergy is a side effect of opioids that can resemble an allergy but is usually caused by histamine release from mast cells. Symptoms of a pseudoallergy often include flushing, itching, rash, or hives. Opioids most associated with pseudoallergies include codeine, morphine, and meperidine. True allergies are more likely with symptoms such as severe hypotension; breathing, speaking, or swallowing difficulties; or swelling of the face, lips, mouth, tongue, pharynx, or larynx. Patients allergic to one opioid are thought to be less likely to react to an opioid in a different structural class (Table 2). Because true allergy is rare, there is not enough information to assess the chance of cross-reactivity. In addition, several opioids' product labeling contraindicates their use in patients with true allergies to any opioid.

Opioid Stewardship Considerations

Long-term opioid use, which is associated with the development of opioid use disorder, overdose, and other risks, often begins with opioid use for acute pain [28]. Clinicians and facilities should take steps to ensure prescribers and patients are on the same page regarding opioid risks and benefits. For example, before surgery, educate patients about postoperative pain. Tolerable pain and improved function are goals; complete pain relief is not always realistic. Organizational strategies to reduce unnecessary or unsafe opioid prescribing include [28]:

Opioid safety is also a consideration at transitions of care. Patients taking medications for opioid dependence should be identified on admission, as there are special considerations for managing acute pain in these patients. Inpatient opioid use should be reviewed to help assess the need for a discharge opioid prescription. In all cases, caution should be exercised when switching patients between opioids to ensure equianalgesic doses are properly considered [28].

Propofol is an anesthetic and gamma-aminobutyric acid (GABA) agonist [6,7]. It has sedative, hypnotic, anxiolytic, amnestic, antiemetic, and anticonvulsant properties; it does not have analgesic properties [2,3]. Its amnestic properties are less than with benzodiazepines in adult ICU patients at light levels of sedation [9]. Propofol has a rapid onset of action (one to two minutes) and a short duration (as short as three minutes with short-term use) [6,9]. This is an advantage for rapid sedation as well as rapid awakening [7]. However, long-term administration of propofol (more than 48 hours) can lead to a prolonged duration of action [9].

Propofol is given as a continuous infusion, not by intermittent dosing, due to its short half-life and dose-dependent hypotension. It is metabolized mainly in the liver to inactive metabolites that are excreted in urine [18].

Side effects of propofol include hypotension (occurring in up to 25% of patients), bradycardia, respiratory depression, neuroexcitatory effects, pancreatitis, and hypertriglyceridemia [2,6,7]. Propofol is supplied as a lipid emulsion. Triglycerides should be monitored in patients at risk for hypertriglyceridemia and during prolonged therapy. In addition, calories from propofol should be counted toward a patient's caloric goals [2]. The 10% lipid emulsion of many propofol formulations has approximately 1.1 kcal (0.1 g of fat) per mL of propofol [32].

It is important to be careful about look-alike errors with propofol. Propofol has a similar milky-white appearance to liposomal bupivacaine or clevidipine.

The inactive ingredients in these emulsion formulations can vary and may affect their appropriateness for different patients. For example, the emulsion formulations contain soybean oil and egg lecithin. Other formulations contain sulfites or benzyl alcohol. These are all ingredients that may cause allergic reactions in some patients [18].

High doses of propofol (more than 65–80 mcg/kg/minute) as well as prolonged infusions (more than 48 hours) are associated with propofol-related infusion syndrome (PRIS) [34]. This is a serious side effect that may involve arrhythmias, hypotension, hypertriglyceridemia, kidney dysfunction, severe metabolic acidosis, and rhabdomyolysis [7,9]. The incidence of propofol infusion syndrome is about 1% and mortality is up to 33% [9]. The minimally effective dose of propofol should always be used. Monitoring should include serum creatine kinase, serum triglycerides, and observation for any unexplained anion gap metabolic acidosis. Supportive care, including early recognition and prompt discontinuation of propofol, is essential, as there are no effective treatments available for propofol infusion syndrome [6].

Some patients may require higher sedative doses than expected even to achieve light sedation, such as those with COVID-19. There are no hard and fast rules when treating these patients, but certain strategies should be considered to ensure safe and appropriate use [3,21,33,34]. Generally, use propofol first. All patients should be monitored for hypotension and symptoms of the rare but fatal PRIS, unexplained metabolic acidosis, rhabdomyolysis, and bradycardia. There is no consensus on a maximum propofol dose, but PRIS risk goes up with higher doses and longer durations. Clinicians should consider allowing short-term use above the standard, such as up to 80 mcg/kg/min for a few days. With higher doses, triglycerides should be checked more frequently (e.g., a few times per week). Propofol is often stopped for triglyceride levels greater than 500 mg/dL, but a higher threshold should be considered, because pancreatitis is rare when triglyceride levels are less than 1,000 mg/dL. If giving high propofol doses for multiple days, other sedatives may be added; using lower doses of each medication may limit side effects.

Alternatives should be available when propofol is not an option due to issues such as shortages. Dexmedetomidine may be considered for light sedation. Patients administered dexmedetomidine should be monitored for bradycardia and hypotension. This agent does not provide deep-enough sedation to use with a paralytic. If deep sedation is needed, add or switch to a midazolam drip. It is important to limit use of midazolam when able, because benzodiazepines are linked to delirium risk. A ketamine drip may be considered as an add-on option, especially with hypotensive patients, because it can raise blood pressure, and those requiring additional analgesia. Ketamine use should be avoided in patients with decompensated heart failure, and all patients should be monitored for tachycardia and increased secretions.

Dexmedetomidine is a relatively selective, alpha-2 receptor agonist [35]. It has analgesic, anxiolytic, sedative, and opioid-sparing properties. Dexmedetomidine has no anticonvulsant activity and should never be used alone in alcohol withdrawal [2]. It can be used for sedation in non-mechanically ventilated patients due to its lack of significant respiratory depression [3,6,7]. Patients are easily arousable with dexmedetomidine but can remain sedated when undisturbed [2]. The use of dexmedetomidine is associated with reduced duration of mechanical ventilation and possibly a lower incidence of delirium in comparison with benzodiazepines [3,7].

Dexmedetomidine has an onset of action of 5 to 10 minutes, a peak effect at about 1 hour, and a short duration of action (with a half-life of 2 to 3 hours). It is administered as a continuous infusion, rarely with a bolus dose [3].

Bradycardia and hypotension are common side effects with continuous infusions of dexmedetomidine [6]. Hypotension can be significant and adverse effects are not always quickly reversed when the infusion is stopped. Hypertension can occur after the infusion is stopped and with bolus injections. The rapid administration of a bolus dose can cause cardiovascular instability, tachycardia, bradycardia, or heart block. For this reason, the initial bolus may be avoided in most patients [6,7].

Dexmedetomidine is metabolized in the liver. Lower doses should be used initially in patients with severe liver disease and titrated to effect [36]. Product labeling of dexmedetomidine warns of tolerance, tachyphylaxis, and increased adverse effects when used for more than 24 hours' duration [36]. However, several studies have shown safety and efficacy with longer durations [9].

Historically, benzodiazepines have been the most commonly used agents for sedation in the ICU setting [2]. However, guidelines now recommend benzodiazepines as second-line therapy, with dexmedetomidine, propofol, and analgesia-based sedation regimens being preferred [3,6]. Benzodiazepines seem to be associated with poorer patient outcomes, such as development of delirium, longer duration of mechanical ventilation, and longer duration of ICU stay in medical, surgical, trauma, and burn patients [2,6,7]. Still, the use of benzodiazepines remains important in critically ill patients for treatment of seizures and alcohol withdrawal. They also have a role in deep sedation (when indicated) or to reduce doses of other sedatives [3].

Benzodiazepines have anxiolytic, amnestic, sedative, hypnotic, and anticonvulsant effects, but no analgesic activity (Table 4) [3]. Adverse effects include respiratory depression and hypotension. These effects are more pronounced with concomitant cardiopulmonary depressants, especially opioids [3].

Lorazepam and midazolam are commonly used in the ICU setting [6]. They are given either by intermittent or, less commonly, by continuous infusion. Diazepam is also used occasionally and is given by intermittent infusions, not continuously [9]. Diazepam and midazolam have a quicker onset of action (2 to 5 minutes) than lorazepam (15 to 20 minutes).

Repeated dosing of benzodiazepines causes accumulation in adipose tissue [36]. This accumulation increases the duration of effect after they are stopped, particularly in obese patients. Both diazepam and midazolam are metabolized by the liver to active metabolites [2,6]. These active metabolites are eliminated via the kidneys, so the effects of diazepam and midazolam may be prolonged in patients with impaired kidney function [2,6,7]. Lorazepam is metabolized by the liver but does not have active metabolites [6]. Diazepam can cause phlebitis when injected into peripheral veins [9].

Note that injectable lorazepam and diazepam are formulated with a propylene glycol solvent, and some patients have allergies to this solvent. There have also been reports of toxicity (e.g., metabolic acidosis, hypotension) with higher-than-recommended doses of lorazepam. Patients with kidney impairment or using high doses of lorazepam (1 mg/kg/day or more) for prolonged periods of time may be at increased risk of toxicity [2,37].

Neuromuscular blocking agents (e.g., atracurium, vecuronium, cisatracurium) paralyze skeletal muscles but do not have sedative or analgesic properties. The use of paralysis via neuromuscular blockers in mechanically ventilated adult ICU patients has decreased considerably due to the potential for worse patient outcomes with this deep sedation. Within the ICU, neuromuscular blockade is still useful in certain mechanically ventilated patients, such as to facilitate breathing synchronization, to reduce the severity of muscle spasms associated with tetanus, and to decrease oxygen consumption [6,38,39].

In the ICU, the most commonly used neuromuscular blockers are succinylcholine and rocuronium, with rocuronium considered the preferred agent, particularly for rapid sequence intubation [57]. Rocuronium is the most recently developed neuromuscular blocking agent, introduced in 1992, and developed as a short- to intermediate-acting nondepolarizing agent with an extremely rapid, dose-based onset [64,65,66]. The usual intubating dose is 0.6–1.2 mg/kg. Its rapid onset (45 to 90 seconds) has placed it as a nondepolarizing alternative to succinylcholine; however, doses sufficient to speed onset to this degree come with long durations of action (60 to 90 minutes). In the patient whose airway is difficult and in whom the chance of failure to rapidly intubate may lead to a comorbid or mortal event, succinylcholine has been the criterion standard. This circumstance, however, has changed with the introduction of sugammadex to clinical practice in the United States. This novel reversal agent works by surrounding the molecules of rocuronium, precluding it from binding to the nicotinic acetylcholine receptor [67]. Following an intubating dose of rocuronium, administration of sugammadex allows the complete recovery of neuromuscular function in a shorter time than an equipotent dose of succinylcholine.

Succinylcholine is an older agent, but it is still used in some facilities. Upon injection, succinylcholine rapidly distributes throughout the body, binding to the acetylcholine receptors on the postsynaptic muscle tissue. Instead of preventing muscular contraction, it causes a random and uncoordinated firing of these receptors, resulting in the physical manifestation of anything from minor twitching to tonic contraction of major muscle groups. These fasciculations are an indicator that the drug is working. After the muscle groups tighten, they relax, but the presence of the drug on the receptors does not allow the muscle tissue to immediately repolarize [65].The effective dose is 0.5–0.6 mg/kg, and the usual intubating dose is 1.0–1.5 mg/kg. Doses in excess of 5 mg/kg are associated with a phase II block, which unpredictably prolongs the action of succinylcholine. The onset of action is 1 minute, with a return to normal typically seen after 9 to 13 minutes.

Atracurium and cisatracurium are generally the preferred agents in patients with kidney or liver impairment, patients receiving systemic corticosteroids, and patients with acute respiratory distress syndrome, targeted temperature management, or traumatic brain injury [6,40]. Both undergo Hoffman elimination (independent of the liver or kidneys) to inactive metabolites. When neuromuscular blockade is used in mechanically ventilated ICU patients, attempts should be made to limit drug dose as well as duration of use [2].

Neuromuscular blockers are considered high-alert medications. It is important to develop and follow preparation and administration policies to ensure safety (e.g., application of auxiliary labels to IV bags, pharmacy and nursing double checks, specific placement on delivery to patient care units). Other ways to focus on safe use of neuromuscular blocking agents are to ensure the lowest doses for the shortest duration to minimize complications, such as myopathy, and to use clinical endpoints (e.g., ventilator synchrony) and train-of-four to monitor. Auxiliary medications (e.g., eye lubricants, venous thromboembolism prophylaxis) are necessary in many patients.

While mechanical ventilation is possible without the co-administration of neuromuscular blocking drugs, some forms of mechanical ventilation will be difficult for the patient to tolerate. For example, as the mechanical ventilator inflates the lungs, a volume will be reached that triggers the Hering-Breuer response [68]. This reflex ordinarily stops negative pressure inspiration in the normally breathing adult; however, in the mechanically ventilated patient, it may cause the patient to violently attempt to cough, more commonly known as "bucking" on the ventilator. This phenomenon may be attenuated by either sedation or narcotic analgesia, but the doses of such medications may result in prolonged inhibition of normal respiration and delay extubation. Further, in patients with either acute lung injury or acute respiratory distress syndrome (sometimes referred to as noncardiogenic pulmonary edema), the administration of neuromuscular blockade can decrease oxygen consumption [69]. In one study of 340 patients requiring mechanical ventilation secondary to acute respiratory distress syndrome, a group that received a 15-mg bolus dose of cisatracurium followed by an infusion of 37.5 mg/hour for 48 hours resulted in a 90-day mortality rate of 31.6%, compared with a mortality rate of 40.7% in those not receiving the protocol [70]. While the importance of the judicious use of neuromuscular blockers in the critically ill cannot be understated, one study provides clear and convincing evidence of the importance of a sufficient level of sedation that should also be given to these patients. In their study, patients were more likely to develop delirium in the absence of or inadequacy of sedation [71]. In their research, 64.4% of mechanically ventilated patients experienced delirium and had a 30-day mortality rate of 30.3%, compared with a rate of 11.9% in those not experiencing delirium [71]. Clinicians should always keep in mind the concept that neuromuscular blockers offer no diminution of central nervous system function whatsoever, and there can be few things as terrifying as being paralyzed and wide awake.

With the use of a peripheral nerve stimulator and the co-administration of sedation, the ICU staff can closely monitor a patient's degree of neuromuscular blockade [72]. Patients requiring prolonged neuromuscular blockade in the ICU are best treated with intravenous infusions of intermediate-acting agents. As with all hospitalized patients, the goal is to treat the underlying disease or injury as quickly as possible, and then wean the patient from the ventilator in a quick and efficient manner. While intermittent boluses of neuromuscular blockers will prevent patient movement, they may impede the reversal and weaning process. A large loading dose of neuromuscular blocking drug, given to ensure quick onset, has the disadvantage of exceeding the therapeutic dose levels and extinguishing the train-of-four response (no twitches). Until the dose begins to degrade, there is no way to determine the extent of neuromuscular blockade. Indeed, there may be a supramaximal dose, resulting in prolonged blockade. The infusion dose, though taking a bit longer to set up, stops at the desired point. The lack of peaks and nadirs ensures the correct dose throughout the administration of the drug, easing recovery from neuromuscular blockade.

Finally, the administration of large bolus doses of neuromuscular blocking agents in the ICU has been associated with prolonged blockade [72]. This is attributed primarily to those agents degraded by the liver and eliminated by the kidney. During the peak stages of the patient's illness or injury, hepatic and/or renal function may decrease. Agents such as pancuronium and vecuronium, with significant hepatic breakdown, active metabolites, and diminished renal excretion, have been associated with prolonged neuromuscular blockade lasting days or weeks after the cessation of administration [72]. This phenomenon appears especially linked to those patients presenting with sepsis. One group of researchers speculated the aggravating effects of neuromuscular blockers in these patients may also be due to degraded renal function [73].