Nonopioid and Atypical Agents

The use of nonopioid medications is best approached from the perspective of differentiating neuropathic pain for which anticonvulsants, antidepressants, and other agents play a primary role versus non-neuropathic pain for which opioids are the first line of therapy and other agents are used to reduce opioid dosage and reduce side effects. There is compelling evidence that the addition of oral gabapentin or carbamazepine to opioids provides superior pain relief for neuropathic pain in ICU patients when compared to opioids alone,82,83 and this use is strongly recommended in this setting in the 2012 SCCM guidelines.⁶ Pharmacotherapy for neuropathic pain has been extensively studied in randomized controlled trials (RCTs) in non-ICU patients, and medications including tricyclic antidepressants, selective serotonin receptor inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, tramadol, dextromethorphan, ketamine, topical capsaicin, lidocaine patch or gel, cannabinoids, and other agents have shown efficacy, albeit often in trials with small sample size and with associated side effects.⁸⁴

Nonopioid adjuvant therapy in non-neuropathic pain can help reduce the quantity of opioids administered and potentially decrease the incidence and severity of opioid-related side effects. Such agents have been extensively studied in various non–critically ill populations—primarily postoperative patients, with efficacy demonstrated in meta-analyses of RCTs for corticosteroids, NSAIDs, acetaminophen, ketamine, and others.85–88 There is relatively limited research in ICU patients and most of the RCTs performed with ICU patients have been in the postoperative setting. Best studied in the ICU population are IV (intravenous) acetaminophen, cyclooxygenase inhibitors, and ketamine.^89–91 As a result of the limited evidence base in ICU patients, the 2012 SCCM guidelines generally support this approach as a weak recommendation for the addition of nonopioids for non-neuropathic pain.⁶ The potential benefits as well as risks of nonopioids for ICU use are further discussed in reviews published in 2009.^9,55

Regional Anesthesia and Analgesia

Although systemic administration of opioids for pain management in the ICU is typically by the IV route, regional approaches can offer advantages in selected cases.⁹ Options for regional anesthesia and analgesia (RAA) include continuous epidural analgesia (CEA) and anesthesia (central neuraxial techniques) and continuous peripheral nerve or plexus block. With medication delivery in close proximity to the spinal cord or nerves, these techniques can promote parenteral opioid sparing, which is associated with less respiratory depression and gastrointestinal hypomotility and conveys other benefits. However, these techniques introduce new issues related to needle and catheter placement and maintenance, as well as physiologic alterations related to local anesthetic block and epidural drug delivery. Critically ill patients are often at higher risk for complications due to coagulopathy, thrombocytopenia, sepsis, and hemodynamic instability. Peripheral nerve blocks are particularly useful for anatomically localized pain such as limb injury or operation. However, of all the various RAA techniques, the greatest experience in ICU patients is with CEA.

Similar to other pain management issues, there is more published research to support the use of RAA in noncritical care settings, and most ICU studies focus on patient who are postoperative or have sustained injury. The recent evidence-based review undertaken to develop the 2012 SCCM guidelines provides the most relevant and current basis for use of RAA in ICU patients.⁶ Specific patient populations were examined, and only thoracic epidural anesthesia/analgesia for postoperative analgesia in patients undergoing abdominal aortic surgery received a strong recommendation as a superior alternative to IV opioids.⁹² Interestingly, high-level evidence was also available to compare lumbar epidural analgesia to IV opioids in the same population and no benefit was demonstrated.⁹³ Patients with traumatic rib fractures are the other population for which benefit from RAA was demonstrated for ICU patients. Specifically, use of thoracic epidural analgesia was associated with superior pain control and reduced incidence of pneumonia—but more hypotension—compared to parenteral opioids,^94,95 and its use is supported as a weak recommendation in this setting.⁶ The evidence was insufficient to recommend thoracic epidural analgesia for intrathoracic or nonvascular abdominal surgical procedures.⁶ Similarly, the lack of high-quality research prevented a recommendation regarding the use of RAA for medical ICU patients.⁶

Complementary Techniques

Nonpharmacologic interventions such as music, relaxation, and provision of information can provide complementary pain relief and can be considered.9,55,96–98 However, although they are low cost, easy to provide, and safe, they have a relatively weak body of evidence to support their routine use, and they are not “high impact,” providing only limited opioid-sparing or pain intensity reduction capability.^9,55,96

Sedative Drug Therapy

Sedative medications are widely used in the ICU setting and although various agents can be administered by other routes, most are given IV—either by continuous infusion or intermittent bolus. Traditionally, benzodiazepines have formed the cornerstone of ICU sedation,⁵ but recent clinical trial results and meta-analyses suggest that nonbenzodiazepines such as propofol and dexmedetomidine may be associated with better results such as less delirium and shorter ventilator time.⁶ Benzodiazepines activate γ-aminobutyric acid (GABA) A receptors, producing anxiolytic, amnestic, sedating, and hypnotic effects.^6,120 Benzodiazepines cause respiratory depression and systemic hypotension—problems that are particularly prominent in the elderly. Although diazepam, midazolam, and lorazepam have been employed for ICU sedation over the years, diazepam is now used infrequently. Key pharmacokinetic and clinical features of midazolam and lorazepam are displayed in Table 19.7. Delayed offset of action is relatively common with these drugs for a variety of reasons including tissue saturation after prolonged administration, impaired metabolism due to hepatic dysfunction, and in the case of midazolam, accumulation of active renally cleared metabolites.^6,120,121 Continuous infusion of lorazepam can lead to accumulation of the diluent vehicle, propylene glycol, causing toxicity that is characterized by metabolic acidosis and acute kidney injury, and accompanied by development of an increased osmolal gap.^122,123

Propofol is perhaps the most widely utilized agent administered for continuous IV sedation in the United States.¹²⁴ Propofol binds to GABA receptors as well as glycine, nicotinic, and muscarinic receptors producing effects similar to those from benzodiazepines.^6,125 Like benzodiazepines, propofol has no analgesic effects. Propofol is highly lipid soluble, quickly crossing the blood-brain barrier and rapidly redistributing into peripheral tissues. These features result in rapid onset and offset of action (see Table 19.7). However, prolonged administration can result in tissue saturation that can ultimately produce delayed offset of action. Similar to benzodiazepines, propofol commonly causes respiratory depression as well as systemic hypotension. Because propofol is dissolved in a lipid emulsion, higher rates of propofol infusion can produce hypertriglyceridemia and acute pancreatitis. Each milliliter of propofol solution contains 1.1 kcal of nutrition, and thus an infusion rate of about 40 mL/hour results in more than 1000 kcal of nutrition in 24 hours. Propofol infusion syndrome (PRIS) is an uncommon complication that is typically associated with prolonged infusion of high-dose propofol (i.e., >70 µg/kg/minute), although cases are reported at lower infusion rates or briefer administration. PRIS is characterized by metabolic acidosis, hypotension, cardiac arrhythmias, hypertriglyceridemia, and less commonly with acute kidney injury, rhabdomyolysis, liver dysfunction, and hyperkalemia.^6,126,127

Dexmedetomidine is a selective α₂-receptor agonist with sedative properties similar to benzodiazepines and propofol, but has a number of unique features. In contrast to other sedatives, dexmedetomidine has analgesic properties and can be opioid-sparing; is sympatholytic, potentially producing prominent bradycardia as well as hypotension at higher doses; is associated with a more alert state relative to anxiolytic properties; and has minimal effect on respiratory drive.128,129 It does not bind GABA receptors. Selected pharmacokinetic and clinical characteristics are displayed in Table 19.7. The most common adverse effects are hypotension and bradycardia. Hypotension can be particularly prominent when a loading dose is used—although hypertension can also occur. Clinical trial results suggest that when compared directly to midazolam, dexmedetomidine may be associated with lower prevalence of delirium.¹³⁰ The 2012 SCCM guidelines suggest that dexmedetomidine may be preferred over benzodiazepines in mechanically ventilated patients who have delirium and require continuous IV infusion of sedative medications.⁶

Management of Sedation

Sedative drug therapy is an important component of sedation and analgesia management as discussed earlier and outlined in Box 19.2. Careful selection and titration of sedative drugs are critical to achieve optimal patient comfort while avoiding the adverse impact of excessive or unnecessarily prolonged sedation. The use of structured approaches to sedation and analgesia via algorithms and protocols has achieved a prominent place in ICU practice. There are several common themes. One theme is to tailor the sedation to the specific patient, including medication selection based upon sedation goals (such as rapid arousal), avoidance of side effects (such as hypotension), and consideration of elimination issues (such as avoiding midazolam in a patient with impaired renal function). Although all of the sedative drugs listed in Table 19.7 have a role in ICU sedation management, emerging evidence appears to favor using propofol or dexmedetomidine in preference to benzodiazepines in patients for whom continuous infusion sedation is needed—as suggested in the 2012 SCCM guidelines.⁶ A recent meta-analysis limited to moderate or high-quality RCTs demonstrated slightly longer ICU LOS with benzodiazepines, in comparison to propofol or dexmedetomidine.⁶ In a 2008 meta-analysis of 16 RCTs that compared propofol to alternative agents for moderate to long duration sedation (i.e., >2 days), propofol was associated with shorter duration of mechanical ventilation and shorter ICU LOS.¹³¹ In a 2010 meta-analysis of 24 RCTs comparing dexmedetomidine to alternative agents, ICU LOS was shorter with dexmedetomidine and duration of mechanical ventilation was not significantly different.¹³² Two recent studies deserve additional comment. A multicenter RCT comparing dexmedetomidine to midazolam by Riker and colleagues demonstrated that dexmedetomidine was associated with shorter time to extubation, lower prevalence of delirium, and fewer infections but no difference in ICU LOS, mortality rate, or sedation quality. Dexmedetomidine was less potent than midazolam and was associated with more bradycardia but less hypertension.¹³⁰ Jakob and coworkers recently reported two phase-3 multicenter RCTs that compared dexmedetomidine to midazolam and to propofol.¹³³ Patients randomized to dexmedetomidine had shorter duration of mechanical ventilation than with midazolam, but not with propofol. Patient interaction (communication, arousability, cooperation) was better with dexmedetomidine than with either other agent, but hypotension and bradycardia were more common.

A second major theme is to focus first on analgesia, as discussed earlier. The 2012 SCCM guidelines suggest that analgesia-first sedation be used in mechanically ventilated adult ICU patients.⁶ Asking first about pain, before the patient has been sedated and cognitively impaired, is advantageous. Additionally, several RCTs have demonstrated analgesia-based sedation to be associated with shorter duration of mechanical ventilation in comparison to hypnotic-based sedation.^134–136 Finally, Strom and associates randomized mechanically ventilated adult ICU patients to bolus morphine (analgesia-based, limited sedation) versus morphine plus propofol for the first 48 hours, then midazolam (sedation + analgesia), and found shorter duration of mechanical ventilation and ICU LOS but threefold more agitation when sedative drugs were minimized.¹⁶

A third major theme is to strive for a light level of consciousness and to avoid accumulation of medications and their active metabolites, thus reducing the likelihood of delayed awakening. This approach is strongly recommended in the 2012 SCCM guidelines,⁶ based in part on studies like those of Strom and associates.¹⁶ The underlying rationale for this approach arises from the observation by Kollef and colleagues that use of continuous IV sedation and analgesia is associated with delayed recovery from respiratory failure and longer LOS.¹³ Although a variety of sedation management strategies have been demonstrated to shorten the duration of mechanical ventilation, the most robust data support the use of a sedation protocol or the implementation of daily interruption of sedation.^6,20 In an early RCT, Brook and coworkers found the use of a nurse-implemented protocol that emphasized intermittent therapy to be associated with shorter duration of mechanical ventilation, reduced ICU and hospital LOS, and fewer tracheostomies compared to usual management.¹⁴

The following year, Kress and colleagues showed in an RCT that daily interruption of IV sedation (DIS) until the patient was alert or agitated and then restarting the medications at 50% of the original dose was accompanied by more rapid recovery from respiratory failure, as well as performance of fewer tests for unexplained altered mental status.¹⁵ Interestingly, not all of the benefit could be attributable to reduced accumulation of medications or active metabolites because total propofol dosage was similar between groups although significantly less midazolam was used with daily interruption.¹⁵ This prompted speculation that the DIS might also permit earlier identification of sufficient respiratory reserve for ventilator weaning—“wake up and breathe.”¹³⁷ Girard and colleagues subsequently demonstrated that the strategy of combining DIS with performance of a spontaneous breathing trial (SBT) led to faster recovery from respiratory failure as well as reduced all-cause 1-year mortality rate compared to SBT alone.¹³⁸ Abrupt withdrawal of sedative (and sometimes analgesic) medications is accompanied by severalfold increases in circulating catecholamines as well as tachycardia and hypertension.⁴⁶ Experts have expressed concern that this unmasked stress response might be associated with cardiac ischemia.¹³⁹ In a prospective study, DIS was not accompanied by electrocardiographic or cardiac enzyme evidence of myocardial ischemia in at-risk patients.⁴⁶ Questions have also been raised as to potential impact of this abrupt withdrawal of medications designed to provide comfort on downstream neuropsychological disturbances such as posttraumatic stress disorder (PTSD).¹³⁹ An additional study by Kress and colleagues demonstrated no increase in subsequent PTSD and, actually, trends for better neuropsychological health months after daily interruption,¹⁴⁰ perhaps as a result of the added opportunities to establish concrete memories during awakening.¹⁴¹ There are populations for whom complete cessation of IV sedatives and analgesics is probably unwise. Girard and colleagues incorporated a safety screen into their protocol and avoid performing DIS in patients (a) receiving sedative infusion for active seizures or alcohol withdrawal, (b) receiving escalating doses due to ongoing agitation, (c) receiving NMBA, (d) having evidence of myocardial ischemia within the past 24 hours, or (e) having elevated ICP.¹³⁸ It may be that alcoholic patients are at particular risk for poor tolerance of daily interruption because patients randomized to this intervention had worse outcomes compared to a protocol approach in an RCT conducted in an ICU with a high prevalence of patients with alcohol use disorders.¹⁴²

A variety of other structured approaches have been examined in prospective trials, although many have utilized a less robust two-phase approach. Protocols that utilize an evidence-based nurse-implemented algorithm that seeks to minimize medication doses has been linked to shorter duration of mechanical ventilation,143–148 shorter ICU and hospital LOS,^144,147,148 lower direct drug costs,^144,146 less opioid medication,¹⁴⁸ less medication-induced coma,¹⁴⁸ and lower 30-day mortality rate.¹⁴⁸ These interventions appear to be less effective in Australian ICUs, perhaps as a result of higher nurse : patient ratios.^149,150 Other algorithms apply active pharmacist input,¹⁵¹ or focus on pain and agitation.¹¹⁵ There are few multicenter RCTs that compare several approaches—more are needed. In a preliminary study,¹⁵² Mehta and associates found DIS to be equivalent to a sedation protocol, setting the stage for a larger Canadian RCT. Carson and colleagues found continuous infusion propofol with DIS to be superior to intermittent lorazepam.¹⁵³

In summary, a variety of structured approaches to sedation management are effective for speeding recovery from respiratory failure and critical illness. Practical considerations for establishing a sedation protocol include multidisciplinary development, integrating published algorithms into the local environment, and sustaining a durable approach despite the challenges of insufficient time and resources.²⁰ Finally, emphasis on protocolized light sedation brings additional opportunities such as linkage to SBTs¹³⁸ and to early mobilization,¹⁵⁴ but new challenges such as managing patient agitation¹⁶ and consequences such as self-extubation.¹³⁸ The 2012 SCCM guidelines recommend using a multidisciplinary ICU team approach with provider education, preprinted protocols and order sets, and ICU rounds checklists to facilitate pain, agitation, and delirium management guidelines and protocols.⁶

Comparison of Agents (Table 19.8)

The neuromuscular junction consists of a prejunctional motor nerve ending separated from a postjunctional membrane—or motor endplate—of skeletal muscle by a synaptic cleft. Acetylcholine (ACh) is released from vesicles in the prejunctional motor ending and bind nicotinic cholinergic receptors of the motor endplate, producing a change in membrane potential as a result of influx of sodium and efflux of potassium. Calcium is released from the sarcoplasmic reticulum, producing muscle action potential. Depolarizing NMBAs such as succinylcholine bind the receptors and cause the ion channel to remain open, producing depolarization and potentially causing sufficient potassium efflux to produce hyperkalemia. Additional depolarizations cannot occur until the agent diffuses from the receptors. Succinylcholine is the prototypical paralytic for rapid sequence intubation, due to its rapid onset and short duration of action.¹⁶¹ However, it can precipitate malignant hypertension and can cause hyperkalemia, which can lead to fatal arrhythmias.¹⁶² The cause of this adverse event is thought to be up-regulation of ACh receptors along the skeletal muscle membrane. Stimulation of these additional receptors by succinylcholine results in potassium efflux, leading to hyperkalemia. Hence, caution should be used when succinylcholine is considered for patients at risk for up-regulation of ACh receptors such as upper or lower motor denervation, chemical denervation (by muscle relaxants, drugs, or toxins), immobilization, infection, direct muscle trauma, muscle tumor, muscle inflammation, and burn injury. Furthermore, succinylcholine should be avoided in patients with renal dysfunction, as hyperkalemia is potentiated in this population. Additionally, succinylcholine has been associated with increases in intracranial and intraocular pressure and should be used with caution in patients with acute ocular or traumatic brain injury.¹⁶³

The nondepolarizing agents are bulky molecules with ACh-like moieties that bind the ACh receptors without ion flow or depolarization. Broadly, the nondepolarizing NMBAs are divided into two structural classes, aminosteroidal and benzylisoquinolinium agents. The aminosteroidal NMBAs incorporate an ACh-like structure onto a steroid backbone.¹⁶⁴ Much like other steroidal drugs, elimination of the aminosteroidal agents is organ dependent. Pancuronium, the first aminosteroidal NMBA, antagonizes not only nicotinic ACh receptors, but also muscarinic receptors.¹⁶⁵ This results in vagal blockade and tachycardia, making it less ideal for patients with significant cardiac disease.³⁰ Compared to other aminosteroidal NMBAs, pancuronium has a long half-life, which allows for sustained neuromuscular blockade to be achieved with intermittent bolus dosing.³⁰ Because of the long half-life, organ-dependent metabolism, and production of active metabolites, pancuronium has a high propensity to accumulate in critically ill patients. Newer aminosteroidal NMBAs, such as vecuronium and rocuronium, offer advantages over pancuronium as they do not antagonize muscarinic receptors. Vecuronium is an intermediate-acting aminosteroidal NMBA with both renal and hepatic elimination. It offers utility both for procedural and sustained paralysis, but like pancuronium, can accumulate in patients with organ dysfunction. Rocuronium has the fastest onset and shortest duration of action of the aminosteroidal NMBAs, making it ideal for rapid sequence intubation in circumstances when succinylcholine is contraindicated. Like all aminosteroidal NMBAs, it exhibits organ dependent clearance; however, when used intermittently for procedural paralysis, this is rarely of clinical significance.

In contrast to the aminosteroidal NMBAs, benzylisoquinolinium agents are nonsteroidal agents that are degraded by plasma esterase and Hofmann degradation.164,165 Atracurium was the first benzylisoquinolinium NMBA and was advantageous in that it was an intermediate-acting paralytic with organ-independent clearance. However, atracurium causes significant histamine release and thus must be used with caution in patients with hypotension or shock. Additionally, patients with organ dysfunction are at increased risk of seizures when atracurium is used for sustained paralysis due to accumulation of a toxic metabolite, laudanosine.³¹ Cisatracurium is the cis-cis isomer of atracurium and represents approximately 15% of the atracurium conformation.¹⁶⁴ Like atracurium, cisatracurium undergoes clearance via plasma esterase and Hofmann degradation but is devoid of histamine release and toxic metabolites.

Monitoring

Monitoring of the patient during chemical paralysis is performed to ensure safety and effectiveness of the intervention. Goals of monitoring include achieving the targeted depth of sedation to accomplish therapeutic goals while reducing the likelihood of undesired prolonged paralysis or acute quadriplegic myopathy (AQM) and also avoiding other potential complications. Different targets for NMBAs may vary from merely reduced spontaneous movement or better synchronization of spontaneous breathing with mechanical ventilation to apnea for fully passive ventilation or complete cessation of all skeletal muscle activity. Accordingly, observation of limb and respiratory muscle activity as well as review of graphic display of ventilator data should be performed to confirm the therapeutic target is reached. Testing of deep tendon reflexes may be helpful as they disappear as 100% blockade is reached. Monitoring the depth and duration of paralysis is important in order to optimize neuromuscular blockade for each individual patient and to avoid complications of therapy.30,31,160,166 Such monitoring typically includes clinical evaluation as well as an objective measure of the extent of blockade using peripheral nerve stimulation (PNS) testing by evaluating the response to “train-of-four” (TOF) stimulation. In TOF testing, four equal brief electrical charges are delivered every 0.5 second from a nerve stimulator device that is attached to leads placed on the skin overlying a superficial nerve that innervates an easily observed muscle. The most common placement is over the ulnar nerve with observation of contraction of the adductor pollicis muscle or over the facial nerve with observation of contraction of the orbicularis oculi muscle. It is estimated that if less than 75% of receptors are blocked, the four muscular contractions are equal in intensity and that once more than 90% of receptors are blocked no contractions occur. A common safety goal is for titration of the NMBA so that one to three muscle contractions are present, thus potentially avoiding excessive dosing. It is worth considering, however, that clinical effectiveness (such as patient-ventilator synchrony) is sometimes achieved while TOF reveals all four contractions. In contrast, in order to achieve apnea or complete cessation of muscular activity, TOF of zero may be necessary. In this circumstance, periodically decreasing the NMBA infusion rate until TOF of one or more may be necessary to avoid excessive dosing.

Despite the intuitive value of monitoring the depth of NMBA dosing, clinical trials that compare PNS monitoring to clinical monitoring alone have not consistently demonstrated added value. In one RCT, Rudis and coworkers demonstrated more rapid recovery to four of four TOF contractions and to spontaneous breathing as well as fewer episodes of delayed recovery when vecuronium infusion was titrated to achieve one of four TOF contractions in comparison to patients with clinical monitoring alone.¹⁶⁷ Patients with impaired renal function had the slowest recovery. In contrast, PNS monitoring did not lead to better outcomes in prospective trials of patients who received atracurium¹⁶⁸ or cisatracurium.¹⁶⁹ Further, intentional dosing of cisatracurium to achieve TOF of zero only marginally prolonged the recovery time.¹⁷⁰ Finally, no PNS monitoring was performed in the 2010 placebo-controlled RCT in which 178 patients received a 48-hour cisatracurium infusion and there was no difference in the rate of ICU paresis compared to the placebo group.³² Unfortunately, maintenance of TOF more than zero does not guarantee AQM will not occur. Most reported cases developed despite documented appropriate TOF results. Accordingly, although the 2002 SCCM guidelines recommended that all patients receiving NMBA should be assessed both clinically and by TOF monitoring (grade B recommendation) with a goal of adjusting the degree of NMBA to achieve 1 to 2 twitches (grade C recommendation), the validity of this recommendation is most compelling when vecuronium infusion is used but less so for atracurium or cisatracurium given subsequent published reports.³⁰ Monitoring of patients who are receiving NMBAs should also address prevention and early detection of venous thromboembolism (VTE), pressure ulcers, corneal ulcers, patient awareness, and inadequately controlled pain and anxiety.

Complications

The primary safety concerns with NMBAs are for prolonged paralysis due to persistent drug effect or from AQM. Both circumstances result in significant weakness and are considerations in the broad differential diagnosis of weakness in the ICU patient. Causes of weakness range widely from severe electrolyte disturbances like hypermagnesemia or hypophosphatemia to critical illness polyneuropathy, steroid myopathy, or Guillain-Barré syndrome. A variety of factors can increase the risk for prolonged recovery from NMBAs, including organ dysfunction and resulting impaired clearance of the parent compound, accumulation of active metabolites, drug-drug interactions, and other medical conditions. Drugs that potentiate or antagonize the actions of nondepolarizing NMBAs are listed in Box 19.4. There is also considerable variability in duration of effect among NMBAs. The aminosteroids are eliminated by a combination of renal clearance and hepatic metabolism to a number of compounds, some of which are active and are eliminated in the urine. Accordingly, dysfunction of liver or kidneys is associated with prolonged paralysis.^31,171 Resolution of paralysis is not predictable with vecuronium, particularly with prolonged infusion.^171,172 This contrasts sharply with the benzylisoquinoliniums with recovery times of about 1 hour, even despite prolonged infusion¹⁶⁹ and with higher doses.¹⁷⁰ Perhaps most instructive is a prospective head-to-head comparison of vecuronium and cisatracurium in ICU patients in which average recovery time was fivefold longer with vecuronium.¹⁷³ Close monitoring of depth of sedation using TOF PNS appears to reduce the incidence of prolonged paralysis with vecuronium¹⁶⁷ but is of less certain value with atracurium or cisatracurium.^168,169

AQM is a potentially devastating form of NMBA-related weakness in which the muscle weakness can be severe and quite protracted.³⁰ AQM is characterized by weakness of the limb and trunk muscles with sparing of the extraocular muscles as well as preserved sensory function and cognition. Understanding of the mechanisms underlying AQM have evolved from suspicion that myonecrosis alone was responsible to that of altered muscle membrane properties with loss of motor protein myosin and myosin-associated thick filament proteins. Work by Larsson and associates has demonstrated that a combination of myofibrillar protein degradation plus down-regulation of protein synthesis at the transcriptional level is prominent.¹⁷⁴ Key predisposing factors for ICU-acquired weakness appear to be functional denervation—such as from NMBAs and corticosteroids. The argument has been made that prolonged deep sedation may be another source of immobilization.³³ Additional risk factors for ICU-acquired polyneuropathy and myopathy include sepsis and other forms of systemic inflammation, hyperglycemia, malnutrition, and prolonged immobility. Although both aminosteroid and benzylisoquinolinium agents have been linked to AQM in case reports, it is noteworthy that in the relatively limited prospective clinical trial literature of NMBA in ICU patients, AQM is described in about 5% of patients who received vecuronium but none of the more than 200 patients who were administered atracurium or cisatracurium infusion.¹⁶⁹ Further, in the largest multicenter RCT of cisatracurium versus placebo, there was no difference in the incidence of ICU-acquired weakness.³² Finally, some experts consider the causality of NMBA—particularly short-duration NMBA—for producing ICU-acquired weakness to be far from certain.³³

Evolving Role in Acute Respiratory Distress Syndrome

NMBAs have been utilized for years to optimize gas exchange in patients with severe ARDS. Numerous RCTs demonstrate and other observational studies indicate that as many as one half of ARDS patients receive at least intermittent NMBA, with the most common indication being refractory hypoxemia. Sustained increases in PaO₂:FIO₂ ratio have been demonstrated in small RCTs.158,159 Interestingly, preliminary studies also have demonstrated lower levels of proinflammatory cytokines in bronchoalveolar lavage fluid and circulating blood in patients randomized to cisatracurium, in contrast to placebo.¹⁵⁹ In 2010, Papazian and coworkers published the results of a French multicenter RCT in which 340 patients with severe ARDS (PaO₂:FIO₂ < 150 mm Hg) were randomized to receive a 48-hour infusion of cisatracurium or placebo.³² Patients randomized to cisatracurium had better outcomes including lower rate of death at 28 days and trends for lower rates of death in the ICU and the hospital, more ventilator-free days and organ failure–free days, and fewer barotraumas. Post hoc analysis showed that the mortality rate benefit was limited entirely to the patients with most profound hypoxemia (PaO₂:FIO₂ < 120 mm Hg), although the relationship of other key outcomes to baseline oxygenation was not reported. Impressively, there was no difference in rates of ICU paresis, and limb weakness was identical for cisatracurium and placebo groups. A number of methodologic issues are worth noting, including no use of PNS for monitoring, use of very deep sedation (Ramsay Sedation Score = 6), use of ketamine for sedation in 20% of patients, open label use of cisatracurium in 56% of placebo patients, the use of very modest PEEP despite severe hypoxemia, and the high barotrauma for placebo patients. Clinicians are eager for additional RCTs to confirm the findings.

1. Puntillo, KA, Arai, S, Cohen, NH, et al. Symptoms experienced by intensive care unit patients at high risk of dying. Crit Care Med. 2010; 38:2155–2160.

2. Desbiens, NA, Wu, AW, Broste, SK, et al. Pain and satisfaction with pain control in seriously ill hospitalized adults: Findings from the SUPPORT research investigations. Crit Care Med. 1996; 24(12):1953–1961.

3. Puntillo, KA. Pain experiences of intensive care unit patients. Heart Lung. 1990; 19(5 Pt 1):526–533.

4. Novaes, MA, Knobel, E, Bork, AM, et al. Stressors in ICU: Perception of the patient, relatives and health care team. Intensive Care Med. 1999; 25(12):1421–1426.

5. Jacobi, J, Fraser, GL, Coursin, DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med. 2002; 30(1):119–141.

6. Barr, J, Fraser, GL, Puntillo, K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013; 41(1):263–306.

7. Sessler, CN. Comfort and distress in the ICU: Scope of the problem. Sem Respir Crit Care Med. 2001; 22(2):111–113.

8. Sessler, CN. Progress toward eliminating inadequately managed pain in the ICU through interdisciplinary care. Chest. 2009; 135(4):894–896.

9. Erstad, BL, Puntillo, K, Gilbert, HC, et al. Pain management principles in the critically ill. Chest. 2009; 135(4):1075–1086.

10. Arroliga, A, Frutos-Vivar, F, Hall, J, et al. Use of sedatives and neuromuscular blockers in a cohort of patients receiving mechanical ventilation. Chest. 2005; 128(2):496–506.

11. Payen, JF, Chanques, G, Mantz, J, et al. Current practices in sedation and analgesia for mechanically ventilated critically ill patients: A prospective multicenter patient-based study. Anesthesiology. 2007; 106(4):687–695.

12. Mehta, S, McCullagh, I, Burry, L. Current sedation practices: Lessons learned from international surveys. Anesthesiol Clin. 2011; 29(4):607–624.

13. Kollef, MH, Levy, NT, Ahrens, TS, et al. The use of continuous IV sedation is associated with prolongation of mechanical ventilation. Chest. 1998; 114(2):541–548.

14. Brook, AD, Ahrens, TS, Schaiff, R, et al. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. 1999; 27(12):2609–2615.

15. Kress, JP, Pohlman, AS, O’Connor, MF, Hall, JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000; 342(20):1471–1477.

16. Strom, T, Martinussen, T, Toft, P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: A randomised trial. Lancet. 2010; 375(9713):475–480.

17. Fraser, GL, Riker, RR. Comfort without coma: Changing sedation practices. Crit Care Med. 2007; 35(2):635–637.

18. Martin, J, Heymann, A, Basell, K, et al. Evidence and consensus-based German guidelines for the management of analgesia, sedation and delirium in intensive care—short version. Ger Med Sci. 2010; 8:Doc02.

19. Sessler, CN, Varney, K. Patient-focused sedation and analgesia in the ICU. Chest. 2008; 133(2):552–565.

20. Sessler, CN, Pedram, S. Protocolized and target-based sedation and analgesia in the ICU. Crit Care Clin. 2009; 25(3):489–513.

21. Riker, RR, Fraser, GL. Altering intensive care sedation paradigms to improve patient outcomes. Crit Care Clin. 2009; 25(3):527–538.

22. Honiden, S, Siegel, MD. Analytic reviews: Managing the agitated patient in the ICU: Sedation, analgesia, and neuromuscular blockade. J Intensive Care Med. 2010; 25(4):187–204.

23. Patel, SB, Kress, JP. Sedation and analgesia in the mechanically ventilated patient. Am J Respir Crit Care Med. 2012; 185(5):486–497.

24. Ely, EW, Shintani, A, Truman, B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004; 291(14):1753–1762.

25. Girard, TD, Jackson, JC, Pandharipande, PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med. 2010; 38(7):1513–1520.

26. Morandi, A, Brummel, NE, Ely, EW. Sedation, delirium and mechanical ventilation: The “ABCDE” approach. Curr Opin Crit Care. 2011; 17(1):43–49.

27. Gunther, ML, Morandi, A, Ely, EW. Pathophysiology of delirium in the intensive care unit. Crit Care Clin. 2008; 24(1):45–65.

28. Bledowski, J, Trutia, A. A review of pharmacologic management and prevention strategies for delirium in the intensive care unit. Psychosomatics. 2012; 53(3):203–211.

29. Jones, SF, Pisani, MA. ICU delirium: An update. Curr Opin Crit Care. 2012; 18(2):146–151.

30. Murray, MJ, Cowen, J, DeBlock, H, et al. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med. 2002; 30(1):142–156.

31. Warr, J, Thiboutot, Z, Rose, L, et al. Current therapeutic uses, pharmacology, and clinical considerations of neuromuscular blocking agents for critically ill adults. Ann Pharmacother. 2011; 45(9):1116–1126.

32. Papazian, L, Forel, JM, Gacouin, A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010; 363(12):1107–1116.

33. Puthucheary, Z, Rawal, J, Ratnayake, G, et al. Neuromuscular blockade and skeletal muscle weakness in critically ill patients: Time to rethink the evidence? Am J Respir Crit Care Med. 2012; 185(9):911–917.

34. Wunsch, H, Kahn, JM, Kramer, AA, Rubenfeld, GD. Use of intravenous infusion sedation among mechanically ventilated patients in the United States. Crit Care Med. 2009; 37(12):3031–3039.

35. Sessler, CN, Grap, MJ, Brophy, GM. Multidisciplinary management of sedation and analgesia in critical care. Semin Respir Crit Care Med. 2001; 22(2):211–226.

36. Jaber, S, Chanques, G, Altairac, C, et al. A prospective study of agitation in a medical-surgical ICU: Incidence, risk factors, and outcomes. Chest. 2005; 128(4):2749–2757.

37. Woods, JC, Mion, LC, Connor, JT, et al. Severe agitation among ventilated medical intensive care unit patients: Frequency, characteristics and outcomes. Intensive Care Med. 2004; 30(6):1066–1072.

38. Fraser, GL, Prato, BS, Riker, RR, et al. Frequency, severity, and treatment of agitation in young versus elderly patients in the ICU. Pharmacotherapy. 2000; 20(1):75–82.

39. Sessler, CN, Glass, C, Grap, MJ. Unplanned extubation: Incidence, predisposing factors, and management. J Crit Illness. 1994; 9:609–619.

40. Carrion, MI, Ayuso, D, Marcos, M, et al. Accidental removal of endotracheal and nasogastric tubes and intravascular catheters. Crit Care Med. 2000; 28(1):63–66.

41. Mion, LC, Minnick, AF, Leipziq, R, et al. Patient-initiated device removal in intensive care units: A national prevalence study. Crit Care Med. 2007; 35(12):2714–2720.

42. Fraser, GL, Riker, RR, Prato, BS, Wilkins, ML. The frequency and cost of patient-initiated device removal in the ICU. Pharmacotherapy. 2001; 21(1):1–6.

43. Sessler, CN. Sedation scales in the ICU. Chest. 2004; 126:1727–1730.

44. Kong, KL, Willatts, SM, Prys-Roberts, C, et al. Plasma catecholamine concentration during sedation in ventilated patients requiring intensive therapy. Intensive Care Med. 1990; 16:171–174.

45. Lindenmayer, JP. The pathophysiology of agitation. J Clin Psychiatry. 2000; 61(Suppl 14):5–10.

46. Kress, JP, Vinayak, AG, Levitt, J, et al. Daily sedative interruption in mechanically ventilated patients at risk for coronary artery disease. Crit Care Med. 2007; 35(2):365–371.

47. Korak-Leiter, M, Likar, R, Oher, M, et al. Withdrawal following sufentanil/propofol and sufentanil/midazolam. Sedation in surgical ICU patients: Correlation with central nervous parameters and endogenous opioids. Intensive Care Med. 2005; 31(3):380–387.

48. Epstein, J, Breslow, MJ. The stress response of critical illness. Crit Care Clin. 1999; 15(1):17–33.

49. Schein, RM, Hazday, N, Pena, M, et al. Clinical antecedents to in-hospital cardiopulmonary arrest. Chest. 1990; 98(6):1388–1392.

50. de Wit, M, Jones, DG, Sessler, CN, et al. Alcohol-use disorders in the critically ill patient. Chest. 2010; 138(4):994–1003.

51. Li, SY, Wang, TJ, Vivienne Wu, SF, et al. Efficacy of controlling night-time noise and activities to improve patients’ sleep quality in a surgical intensive care unit. J Clin Nurs. 2011; 20(3-4):396–407.

52. Xie, H, Kang, J, Mills, GH. Clinical review: The impact of noise on patients’ sleep and the effectiveness of noise reduction strategies in intensive care units. Crit Care. 2009; 13(2):208.

53. van de Leur, JPO, van der Schans, CP, Loef, BG, et al. Discomfort and factual recollection in intensive care unit patients. Crit Care. 2004; 8(6):R467–R473.

54. Puntillo, KA, Morris, AB, Thompson, CL, et al. Pain behaviors observed during six common procedures: Results from Thunder Project II. Crit Care Med. 2004; 32(2):421–427.

55. Mularski, RA, Sessler, CN, Schmidt, GA. Pain management in the intensive care unit. In: Rathmell J, Ballantye J, Fishman S, eds. Bonica’s Management of Pain. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:1587–1602.

56. Willis, WD, Westlund, KN. Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol. 1997; 14(1):2–31.

57. Puntillo, KA, Wild, LR, Morris, AB, et al. Practices and predictors of analgesic interventions for adults undergoing painful procedures. Am J Crit Care. 2002; 11(5):415–429.

58. Puntillo, K, Pasero, C, Li, D, et al. Evaluation of pain in ICU patients. Chest. 2009; 135(4):1069–1074.

59. Jensen, MP, Karoly, P, Braver, S. The measurement of clinical pain intensity: A comparison of six methods. Pain. 1986; 27(1):117–126.

60. Chanques, G, Viel, E, Constantin, JM, et al. The measurement of pain in intensive care unit: Comparison of 5 self-report intensity scales. Pain. 2010; 151(3):711–721.

61. Payen, JF, Bosson, JL, Chanques, G, et al. and DOLOREA Investigators: Pain assessment is associated with decreased duration of mechanical ventilation in the intensive care unit: A post hoc analysis of the DOLOREA study. Anesthesiology. 2009; 111(6):1308–1316.

62. Puntillo, KA, Miaskowski, C, Kehrle, K, et al. Relationship between behavioral and physiological indicators of pain, critical care patients’ self-reports of pain, and opioid administration. Crit Care Med. 1997; 25(7):1159–1166.

63. Herr, K, Coyne, PJ, Key, T, et al. Pain assessment in the nonverbal patient: Position statement with clinical practice recommendations. Pain Manage Nurs. 2006; 7(2):44–52.

64. Ambuel, B, Hamlett, KW, Marx, CM, Blumer, JL. Assessing distress in pediatric intensive care environments: The COMFORT scale. J Pediatr Psychol. 1992; 17(1):95–109.

65. Merkel, SI, Voepel-Lewis, T, Shayevitz, JR, Malviya, S. The FLACC: A behavioral scale for scoring postoperative pain in young children. Pediatr Nurs. 1997; 23(3):293–297.

66. Li, D, Puntillo, K, Miaskowski, C. A review of objective pain measures for use with critical care adult patients unable to self-report. J Pain. 2008; 9(1):2–10.

67. Sessler, CN, Grap, MJ, Ramsay, MA. Evaluating and monitoring analgesia and sedation in the intensive care unit. Crit Care. 2008; 12(Suppl 3):S2.

68. Gelinas, C, Fillion, L, Puntillo, KA, et al. Validation of the critical-care pain observation tool in adult patients. Am J Crit Care. 2006; 15(4):420–427.

69. Payen, JF, Bru, O, Bosson, JL, et al. Assessing pain in critically ill sedated patients by using a behavioral pain scale. Crit Care Med. 2001; 29(12):2258–2263.

70. Chanques, G, Payen, JF, Mercier, G, et al. Assessing pain in non-intubated critically ill patients unable to self report: An adaptation of the behavioral pain scale. Intensive Care Med. 2009; 35(12):2060–2067.

71. Odhner, M, Wegman, D, Freeland, N, et al. Assessing pain control in nonverbal critically ill adults. Dimens Crit Care Nurs. 2003; 22(6):260–267.

72. Li, D, Miaskowki, C, Burkhardt, D, Puntillo, K. Evaluations of physiologic reactivity and reflexive behaviors during noxious procedures in sedated critically ill patients. J Crit Care. 2009; 24(3):472.

73. Puntillo, KA, Stannard, D, Miaskowski, C, et al. Use of a pain assessment and intervention notation (P. A. I. N. ) tool in critical care nursing practice: Nurses’ evaluations. Heart Lung. 2002; 31(4):303–314.

74. Gelinas, C, Johnston, C. Pain assessment in the critically ill ventilated adult: Validation of the critical-care pain observation tool and physiologic indicators. Clin J Pain. 2007; 23(6):497–505.

75. Desbiens, NA, Mueller-Rizner, N. How well do surrogates assess the pain of seriously ill patients? Crit Care Med. 2000; 28(5):1347–1352.

76. Bion, JF, Logan, BK, Newman, PM, et al. Sedation in intensive care: Morphine and renal function. Intensive Care Med. 1986; 12(5):359–365.

77. Wilhelm, W, Kreuer, S. The place for short-acting opioids: Special emphasis on remifentanil. Crit Care. 2008; 12(Suppl 3):S5.

78. Battershill, AJ, Keating, GM. Remifentanil: A review of its analgesic and sedative use in the intensive care unit. Drugs. 2006; 66(3):365–385.

79. Hagmeyer, KO, Mauro, LS, Mauro, VF. Meperidine-related seizures associated with patient-controlled analgesia pumps. Ann Pharmacother. 1993; 27(1):29–32.

80. Riker, RR, Fraser, GL. Adverse events associated with sedatives, analgesics, and other drugs that provide patient comfort in the intensive care unit. Pharmacotherapy. 2005; 25(5 Pt 2):8S–18S.

81. Ehret, GB, Voide, C, Gex-Fabry, M, et al. Drug-induced long QT syndrome in injection drug users receiving methadone—High frequency in hospitalized patients and risk factors. Arch Intern Med. 2006; 166(12):1280–1287.

82. Pandey, CK, Bose, N, Garg, G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: A double-blinded, placebo-controlled crossover study. Anesth Analg. 2002; 96(6):1719–1723.

83. Pandey, CK, Raza, M, Tripathi, M, et al. The comparative evaluation of gabapentin and carbamazepine for pain management in Guillain-Barré syndrome patients in the intensive care unit. Anesth Analg. 2005; 101(1):220–225.

84. Eisenberg, E, Peterson, D. Neuropathic pain pharmacotherapy. In: Rathmell J, Ballantye J, Fishman S, eds. Bonica’s Management of Pain. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:1194–1207.

85. De Oliveira, GS, Jr., Agarwal, D, Benzon, HT. Perioperative single dose ketorolac to prevent postoperative pain: A meta-analysis of randomized trials. Anesth Analg. 2012; 114(2):424–433.

86. Maund, E, McDaid, C, Rice, S, et al. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: A systematic review. Br J Anaesth. 2011; 106(3):292–297.

87. De Oliveira, GS, Jr., Almeida, MD, Benzon, HT, McCarthy, RJ. Perioperative single dose systemic dexamethasone for postoperative pain: A meta-analysis of randomized controlled trials. Anesthesiology. 2011; 115(3):575–588.

88. Laskowski, K, Stirling, A, McKay, WP, Lim, HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesthesia. 2011; 58(10):911–923.

89. Memis, D, Inal, MT, Kavalci, G, et al. Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting. J Cardiothorac Vasc Anesth. 2005; 19:306–309.

90. Maddali, MM, Kurian, E, Fahr, J. Extubation time, hemodynamic stability, and postoperative pain control in patients undergoing coronary artery bypass surgery: An evaluation of fentanyl, remifentanil, and nonsteroidal anti-inflammatory drugs with propofol for perioperative and postoperative management. J Clin Anesth. 2006; 18:605–610.

91. Guillou, N, Tanguy, M, Seguin, P, et al. The effects of small-dose ketamine on morphine consumption in surgical intensive care unit patients after major abdominal surgery. Anesth Analg. 2003; 97:843–847.

92. Nishimori, M, Ballantyne, JC, Low, JH. Epidural pain relief versus systemic opioid-based pain relief for abdominal aortic surgery. Cochrane Database Syst Rev. (3):2006.

93. Block, BM, Liu, SS, Rowlingson, AJ, et al. Efficacy of postoperative epidural analgesia: A meta-analysis. JAMA. 2003; 290:2455–2463.

94. Bulger, EM, Edwards, T, Klotz, P, et al. Epidrual analgesia improves outcome after multiple rib fractures. Surgery. 2004; 136(2):426–430.

95. Carrier, FM, Turgeon, AF, Nicole, PC, et al. Effect of epidural analgesia in patients with traumatic rib fractures: A systemic review and meta-analysis of randomized controlled trials. Can J Anaesth. 2009; 56:230–242.

96. Cepeda, MS, Carr, DB, Lau, J, Alvarez, H. Music for pain relief. Cochrane Database Syst Rev. (2):2006.

97. Kwekkeboom, KL, Gretarsdottir, E. Systematic review of relaxation interventions for pain. J Nurs Scholarsh. 2006; 38(3):269–277.

98. Suls, J, Wan, CK. Effects of sensory and procedural information on coping with stressful medical procedures and pain: A meta-analysis. J Consult Clin Psychol. 1989; 57(3):372–379.

99. Riker, RR, Fraser, GL. Monitoring sedation, agitation, analgesia, neuromuscular blockade, and delirium in adult ICU patients. Sem Respir Crit Care Med. 2001; 22:189–198.

100. Ramsay, MA, Savege, TM, Simpson, BR, Goodwin, R. Controlled sedation with alphaxalone-alphadolone. Br Med J. 1974; 2:656–659.

101. Olleveant, N, Humphris, G, Roe, B. A reliability study of the modified new Sheffield Sedation Scale. Nurs Crit Care. 1998; 3(2):83–88.

102. Chernik, DA, Gillings, D, Laine, H, et al. Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: Study with intravenous midazolam. J Clin Psychopharmacol. 1990; 10(4):244–251.

103. Binnekade, JM, Vroom, MB, de Vos, R, et al. The reliability and validity of a new and simple method to measure sedation levels in intensive care patients: A pilot study. Heart Lung. 2006; 35:137–143.

104. Devlin, JW, Boleski, G, Mlynarek, M, et al. Motor Activity Assessment Scale: A valid and reliable sedation scale for use with mechanically ventilated patients in an adult surgical intensive care unit. Crit Care Med. 1999; 27(7):1271–1275.

105. De Jonghe, B, Cook, D, Griffith, L, et al. Adaptation to the Intensive Care Environment (ATICE): Development and validation of a new sedation assessment instrument. Crit Care Med. 2003; 31(9):2344–2354.

106. Weinert, C, McFarland, L. The state of intubated ICU patients: Development of a two-dimensional sedation rating scale for critically ill adults. Chest. 2004; 126(6):1883–1890.

107. De Lemos, J, Tweeddale, M, Chittock, D. Measuring quality of sedation in adult mechanically ventilated critically ill patients: The Vancouver interaction and calmness scale. J Clin Epidemiol. 2000; 53:908–919.

108. Riker, RR, Picard, JT, Fraser, GL. Prospective evaluation of the Sedation-Agitation Scale for adult critically ill patients. Crit Care Med. 1999; 27(7):1325–1329.

109. Sessler, CN, Gosnell, MS, Grap, MJ, et al. The Richmond Agitation Sedation Scale: Validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002; 166:1338–1344.

110. Ely, EW, Truman, B, Shintani, A, et al. Monitoring sedation status over time in ICU patients: Reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003; 289(22):2983–2991.

111. Pun, BT, Gordon, SM, Peterson, JF, et al. Large-scale implementation of sedation and delirium monitoring in the intensive care unit: A report from two medical centers. Crit Care Med. 2005; 33(6):1199–1205.

112. Brandl, KM, Langley, KA, Riker, RR, et al. Confirming the reliability of the sedation-agitation scale administered by ICU nurses without experience in its use. Pharmacotherapy. 2001; 21(4):431–436.

113. Costa, J, Cabre, L, Molina, R, Carrasco, G. Cost of ICU sedation: Comparison of empirical and controlled sedation methods. Clin Intensive Care. 1994; 5(Suppl):17–21.

114. Botha, JA, Mudholkar, P. The effect of a sedation scale on ventilation hours, sedative, analgesic and inotropic use in an intensive care unit. Crit Care Resuscitation. 2004; 6:253–257.

115. Chanques, G, Jaber, S, Barbotte, E, et al. Impact of systematic evaluation of pain and agitation in an intensive care unit. Crit Care Med. 2006; 34(6):1691–1699.

116. Friedman, D, Claassen, J, Hirsch, LJ. Continuous electroencephalogram monitoring in the intensive care unit. Anesth Analg. 2009; 109:506–523.

117. Lu, CH, Man, KM, Ou-Yang, HY, et al. Composite auditory evoked potential index versus bispectral index to estimate the level of sedation in paralyzed critically ill patients: A prospective observational study. Anesth Analg. 2008; 107:1290–1294.

118. LeBlanc, JM, Dasta, JF, Kane-Gill, SL. Role of the bispectral index in sedation monitoring in the ICU. Ann Pharmacother. 2006; 40:490–500.

119. Vivien, B, DiMaria, S, Ouattara, A, et al. Overestimation of Bispectral Index in sedated intensive care unit patients revealed by administration of muscle relaxant. Anesthesiology. 2003; 99:9–17.

120. Young, CC, Prielipp, RC. Benzodiazepines in the intensive care unit. Crit Care Clin. 2001; 17:843.

121. Bauer, TM, Ritz, R, Haberthur, C, et al. Prolonged sedation due to accumulation of conjugated metabolites of midazolam. Lancet. 1995; 346(8968):145–147.

122. Yaucher, NE, Fish, JT, Smith, HW, Wells, JA. Propylene glycol-associated renal toxicity from lorazepam infusion. Pharmacotherapy. 2003; 23(9):1094–1099.

123. Barnes, BJ, Gerst, C, Smith, JR, et al. Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation. Pharmacotherapy. 2006; 26(1):23–33.

124. Wunsch, H, Kahn, JM, Kramer, AA, Rubenfeld, GD. Use of intravenous infusion sedation among mechanically ventilated patients in the United States. Crit Care Med. 2009; 37(12):3031–3039.

125. Marik, PE. Propofol: Therapeutic indications and side-effects. Curr Pharm Design. 2004; 10(29):3639–3649.

126. Fong, JJ, Sylvia, L, Ruthazer, R, et al. Predictors of mortality in patients with suspected propofol infusion syndrome. Crit Care Med. 2008; 36(8):2281–2287.

127. Diedrich, DA, Brown, DR. Analytic reviews: Propofol infusion syndrome in the ICU. J Intensive Care Med. 2011; 26(2):59–72.

128. Bhana, N, Goa, KL, McClellan, KJ. Dexmedetomidine. Drugs. 2000; 59(2):263–268.

129. Gerlach, AT, Murphy, CV, Dasta, JF. An updated focused review of dexmedetomidine in adults. Ann Pharmacother. 2009; 43(12):2064–2074.

130. Riker, RR, Shehabi, Y, Bokesch, PM, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: A randomized trial. JAMA. 2009; 301(5):489–499.

131. Ho, KM, JY, Ng. The use of propofol for medium and long-term sedation in critically ill adult patients: A meta-analysis. Intensive Care Med. 2008; 34(11):1969–1979.

132. Tan, JA, Ho, KM. Use of dexmedetomidine as a sedative and analgesic agent in critically ill adult patients: A meta-analysis. Intensive Care Med. 2010; 36(6):926–939.

133. Jakob, SM, Ruokonen, E, Grounds, RM, et al. Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: Two randomized controlled trials. JAMA. 2012; 307(11):1151–1160.

134. Breen, D, Karabinis, A, Malbrain, M, et al. Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: A randomised trial. Crit Care. 2005; 9(3):R200–210.

135. Park, G, Lane, M, Rogers, S, Bassett, P. A comparison of hypnotic and analgesic based sedation in a general intensive care unit. Br J Anaesth. 2007; 98(1):76.

136. Rozendaal, FW, Spronk, PE, Snellen, FF, et al. Remifentanil-propofol analgo-sedation shortens duration of ventilation and length of ICU stay compared to a conventional regimen: A centre randomised, cross-over, open-label study in the Netherlands. Intensive Care Med. 2009; 35(2):291–298.

137. Sessler, CN. Wake up and breathe. Crit Care Med. 2004; 32:1413–1414.

138. Girard, TD, Kress, JP, Fuchs, BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): A randomised controlled trial. Lancet. 2008; 371(9607):126–134.

139. Heffner, JE. A wake-up call in the intensive care unit. N Engl J Med. 2000; 342(20):1520–1522.

140. Kress, JP, Gehlbach, B, Lacy, M, et al. The long-term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care Med. 2003; 168(12):1457–1461.

141. Jones, C, Griffiths, RD, Humphris, G, Skirrow, PM. Memory, delusions, and the development of acute posttraumatic stress disorder-related symptoms after intensive care. Crit Care Med. 2001; 29(3):573–580.

142. de Wit, M, Gennings, C, Jenvey, WI, Epstein, SK. Randomized trial comparing daily interruption of sedation and nursing-implemented sedation algorithm in medical intensive care unit patients. Crit Care. 2008; 12(3):R70.

143. De Jonghe, B, Bastuji-Garin, S, Fangio, P, et al. Sedation algorithm in critically ill patients without acute brain injury. Crit Care Med. 2005; 33(1):120–127.

144. Mascia, MF, Koch, M, Medicis, JJ. Pharmacoeconomic impact of rational use guidelines on the provision of analgesia, sedation, and neuromuscular blockade in critical care. Crit Care Med. 2000; 28(7):2300–2306.

145. Brattebo, G, Hofoss, D, Flaatten, H, et al. Effect of a scoring system and protocol for sedation on duration of patients’ need for ventilator support in a surgical intensive care unit. Qual Safety Health Care. 2004; 13(3):203–205.

146. MacLaren, R, Plamondon, JM, Ramsay, KB, et al. A prospective evaluation of empiric versus protocol-based sedation and analgesia. Pharmacotherapy. 2000; 20(6):662–672.

147. Quenot, JP, Ladoire, S, Devoucoux, F, et al. Effect of a nurse-implemented sedation protocol on the incidence of ventilator-associated pneumonia. Crit Care Med. 2007; 35(9):2031–2036.

148. Skrobik, Y, Ahern, S, Leblanc, M, et al. Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates. Anesth Analg. 2010; 111(2):451–463.

149. Bucknall, TK, Manias, E, Presneill, JJ. A randomized trial of protocol-directed sedation management for mechanical ventilation in an Australian intensive care unit. Crit Care Med. 2008; 36(5):1444–1450.

150. Elliott, R, McKinley, S, Aitken, LM, Hendrikz, J. The effect of an algorithm-based sedation guideline on the duration of mechanical ventilation in an Australian intensive care unit. Intensive Care Med. 2006; 32(10):1506–1514.

151. Marshall, J, Finn, CA, Theodore, AC. Impact of a clinical pharmacist-enforced intensive care unit sedation protocol on duration of mechanical ventilation and hospital stay. Crit Care Med. 2008; 36(2):427–433.

152. Mehta, S, Burry, L, Martinez-Motta, JC, et al. A randomized trial of daily awakening in critically ill patients managed with a sedation protocol: A pilot trial. Crit Care Med. 2008; 36(7):2092–2099.

153. Carson, SS, Kress, JP, Rodgers, JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med. 2006; 34(5):1326–1332.

154. Schweickert, WD, Pohlman, MC, Pohlman, AS, et al. Early physical and occupational therapy in mechanically ventilated, critically ill patients: A randomized controlled trial. Lancet. 2009; 373(9678):1874–1882.

155. Arroliga, A, Frutos-Vivar, F, Hall, J, et al. Use of sedatives and neuromuscular blockers in a cohort of patients receiving mechanical ventilation. Chest. 2005; 128(2):496–506.

156. Mercat, A, Richard, JC, Vielle, B, et al. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: A randomized controlled trial. JAMA. 2008; 299(6):646–655.

157. Sessler, CN. Sedation, analgesia, and neuromuscular blockade for high-frequency oscillatory ventilation. Crit Care Med. 2005; 33(3 Suppl):S209–S216.

158. Gainnier, M, Roch, A, Forel, JM, et al. Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2004; 32(1):113–119.

159. Forel, JM, Roch, A, Marin, V, et al. Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Crit Care Med. 2006; 34(11):2749–2757.

160. Gehr, LC, Sessler, CN. Neuromuscular blockade in the intensive care unit. Semin Respir Crit Care Med. 2001; 22(2):175–188.

161. Walz, JM, Zayaruzny, M, Heard, SO. Airway management in critical illness. Chest. 2007; 131(2):608–620.

162. Martyn, JA, Richtsfeld, M. Succinylcholine-induced hyperkalemia in acquired pathologic states: Etiologic factors and molecular mechanisms. Anesthesiology. 2006; 104(1):158–169.

163. McManus, MC. Neuromuscular blockers in surgery and intensive care, Part 2. Am J Health Syst Pharm. 2001; 58(24):2381–2395.

164. Tuba, Z, Maho, S, Vizi, ES. Synthesis and structure-activity relationships of neuromuscular blocking agents. Curr Med Chem. 2002; 9(16):1507–1536.

165. Brunton LL, Goodman LS, Blumenthal D, Buxton I, eds. Goodman and Gilman’s Manual of Pharmacology and Therapeutics. New York: McGraw-Hill, 2007.

166. Sessler, CN. Train-of-four to monitor neuromuscular blockade? Chest. 2004; 126(4):1018–1022.

167. Rudis, MI, Sikora, CA, Angus, E, et al. A prospective, randomized, controlled evaluation of peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill patients. Crit Care Med. 1997; 25(4):575–583.

168. Strange, C, Vaughan, L, Franklin, C, Johnson, J. Comparison of train-of-four and best clinical assessment during continuous paralysis. Am J Respir Crit Care Med. 1997; 156(5):1556–1561.

169. Baumann, MH, McAlpin, BW, Brown, K, et al. A prospective randomized comparison of train-of-four monitoring and clinical assessment during continuous ICU cisatracurium paralysis. Chest. 2004; 126(4):1267–1273.

170. Lagneau, F, D’Honneur, G, Plaud, B, et al. A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients. Intensive Care Med. 2002; 28(12):1735–1741.

171. Segredo, V, Caldwell, JE, Matthay, MA, et al. Persistent paralysis in critically ill patients after long-term administration of vecuronium. N Engl J Med. 1992; 327(8):524–528.

172. Segredo, V, Caldwell, JE, Wright, PM, et al. Do the pharmacokinetics of vecuronium change during prolonged administration in critically ill patients? Br J Anaesth. 1998; 80(6):715–719.

173. Prielipp, RC, Coursin, DB, Scuderi, PE, et al. Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients. Anesth Analg. 1995; 81(1):3–12.

174. Larsson, L, Li, X, Edstrom, L, et al. Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: Mechanisms at the cellular and molecular levels. Crit Care Med. 2000; 28:34–45.