Management of Sedation and Paralysis

Management of Sedation and Paralysis Michael A. Fierro, MD*, Raquel R. Bartz, MD, MMCi KEYWORDS  Mechanical ventilation  Sedation  Paralysis  Patient ventilator dyssynchrony (PVD)

KEY POINTS  Minimizing sedation in mechanically ventilated patients, which can be facilitated by using validated scales and or protocols, has been linked with improved intensive care outcomes.  Benzodiazapines are associated with adverse effects when used as a sedative in mechanically ventilated patients and the routine use should be abandoned in most cases.  Patient–ventilator dyssynchrony (PVD) is a common, but harmful, occurrence in sedated patients and can be decreased with increasing doses of opioids and/or propofol.  Muscle relaxants have a survival benefit in acute respiratory distress syndrome and can also play a role in managing PVD in the mechanically ventilated patient.

invaluable in ensuring synchronous patient–ventilator interactions, especially in patients with cases of severe acute respiratory distress syndrome (ARDS).10–16 This review discusses the advantages and disadvantages of the various sedative and paralytics drugs and provides an outline of when and how these medications should be administered.

PRINCIPLES OF SEDATION AND ANALGESIA Sedatives and analgesics are administered to mechanically ventilated patients to decrease discomfort associated with endotracheal intubation, protect against self-injury, minimize pain during procedures and care in the intensive care unit (ICU), decrease inadvertent removal of supportive lines or tubes, or to improve patient–ventilator interactions. To achieve these objectives, analgesics and sedatives are administered either individually or in combinations and titrated to targets based on patient assessment or according

Funding: NIH K08 GM087429 (R.R. Bartz). Conflicts of Interest: The authors have nothing to declare. Duke University Medical Center, DUMC Box 3094, Durham, NC 27710, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med - (2016) -–http://dx.doi.org/10.1016/j.ccm.2016.07.012 0272-5231/16/Ó 2016 Elsevier Inc. All rights reserved.

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Endotracheal intubation and mechanical ventilation can lead to significant patient anxiety and agitation, which are associated with adverse outcomes.1–3 These symptoms were prevented previously with the routine use of sedatives in most mechanical ventilated patients, whereas paralysis was limited to patients with severe hypoxemic respiratory failure or significant patient–ventilator dyssynchrony (PVD). However, based on more recent evidence suggesting improvement in patient outcomes with lighter degrees of sedation, the use of sedative drugs has assumed a more limited and specific role in the mechanically ventilated patient.2,4–6 This review discusses the goals of sedation and paralysis in the mechanically ventilated patient, the evidence behind these goals, as well the pharmacologic characteristics impacting the selection of frequently used agents. Although it is now recommended that sedation and paralysis should be used as sparingly as possible based on recent clinical trials,4,5,7–9 in selected patients sedatives and paralytics can be

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Fierro & Bartz to a protocol that has been shown to reduce duration of mechanical ventilation and ICU length of stay (LOS), although definitive data are still needed.2,5,17–21 The shift to lighter sedation targets gained traction with data in 1998 and 2000 suggesting that increased durations of mechanical ventilation with continuous sedation and reduction in ventilator days by the use of daily sedation interruptions (DSI) in mechanically ventilated patients.8,22 In Kress and associates’ landmark trial, DSIs lead to a decrease in use of sedative medications and duration of mechanical ventilation and ICU LOS.8 However, in 2014 a Cochrane Review of the subject was unable to identify outcome benefits when pooling 9 trials comparing sedation strategies with and without DSI.23 Their negative results may reflect a trend toward fewer sedatives being administered in mechanically ventilated patients, because drug administration was not significantly different in the 2 arms of the review. This finding suggests that the initial benefit of DSIs may have been in their ability to prompt reduction of depth of sedation compared the amount of drug administered.23 Although physician and nurse perceptions of DSIs, which are often not evidence based, frequently dictate their use,24 deference of daily DSIs should certainly be considered in situations where they may cause harm, for example, in patients with increased intracranial pressure, refractory seizures, or severe PVD, and should not be performed on paralyzed patients. Although the use of continuous sedatives for the majority of mechanically ventilated patients is often considered standard of care in some institutions, current practice is highly variable by region and institution,25 and the alternative strategy of intermittent bolus sedation may be an equivalent or even superior strategy.26–28 A clinical trial in Denmark randomized 140 patients and found that patients given only intermittent sedatives, analgesics, or antipsyhcotics (unless continuous agents were determined essential to prevent patient injury, or to control PVD or agitation) had a shorter duration of mechanical ventilation than those randomized to receive continuous sedation with daily awakening trials; a larger, multicenter trial is currently ongoing.26,27 A similar study, however, failed to identify any patient-oriented benefits of intermittent versus continuous sedation, although patients in the intermittent group received fewer opioids and sedatives.28 Further on-going research will reveal how the practice of intermittent sedation compares to the use of protocol-based targeted to light sedation goals.

MONITORING SEDATION AND PROTOCOLS Over 40 years ago, Ramsay and coworkers29 introduced the use of a standardized scale as a tool to monitor a patient’s level of consciousness during ICU sedation with alphaxalone and alphadolone. Since their initial publication, multiple scales have been introduced and prospectively validated29–36; however, the Richmond Agitation– Sedation Scale (RASS) and Sedation–Agitation Scale have emerged as the most frequently used tools in literature for assessing and guiding depth of sedation.2 Whichever scale is implemented, it should be easy to use within a multidisciplinary group, have clear and discrete criteria for each level, contain a sufficient number of levels to allow for drug titration, include a mechanism to assess for agitation, and be designed with interuser reliability and prospective validation.37 The ability of a sedation scale to assess for agitation is of paramount importance, because up to 46% of critically ill patients exhibit severe or potentially dangerous agitation at some point in their ICU stay.1,38 Separate from these scales should be a delirium assessment, because it is an often misidentified condition that can worsen if managed with delivering more sedatives.39,40 Algorithm-based systems of assessment and management of sedation, which are typically multidisciplinary, have been demonstrated to decrease the amount of sedative medications administered, while being cost effective.17,41,42 For instance, the I-SAVE group reported a savings of $750 USD per patient after the deployment of multidisciplinary sedation– agitation–delirium protocol in their tertiary ICU, while decreasing ICU LOS and ventilator days, and improving pain scores.41

CHOICE OF SEDATION Sedative agents used in the ICU can be classified based on their pharmacodynamic properties such as amnestic, anxiolytic, analgesic, antipsychotic, and hypnotics. Many drugs have multiple properties and overlapping effects depending on the dosage used (Table 1). Amnestic agents, such as some benzodiazepines, inhibit anterograde memory formation. Anxiolytic drugs, including benzodiazepines and barbiturates, induce a state of calmness through activation of l-aminobutyric acid (GABA) receptors. Many classes of drugs hold analgesic properties; however, opioids are the most widely used class of pain-relieving drugs in the ICU and can also be administered for their sedative properties.46,52 Antipsychotic drugs, such as haloperidol, risperidone, ziprasidone, and quetiapine, which are primarily used for the

Table 1 Sedatives commonly used in the ICU Propofol

Dexmedetomidine

Midazolam

Lorazepam

Fentanyl

Loading dose

5 mg/kg/min over 5 min

1 mg/kg over 10 min

0.01–0.05 mg/kg

0.044 mg/kg (2 mg max)

Infusion dosing

0.007 mg/kg/h, typical Increase by 5–10 mg/kg/min 0.2–0.7 mg/kg/h, doses up to 0.02–0.1 mg/kg/h maintenance dose q5-10 min; typical range 1.5 mg/kg/h used clinically43 0.02–0.16 mg/kg/h44,45 5–50 mg/kg/min, or higher Distribution to fat and Hepatic via glucoronidation P450 CYP 3A4 metabolism to Hepatic conjugation, muscle (short-term and P450 metabolism active metabolite followed renal elimination of dosing only); hepatic by conjugation, urinary inactive metabolite conjugation exertion of inactive metabolite

1 mg/kg/min for 10 min 1–8 mg/kg/h, often used at 1–2 mg/ kg/h46

Metabolism

Pregnancy category Duration of action

B

C

C

D

Extensive liver metabolism primarily mediated by CYP3A4, with high first-pass metabolism C

This table represents a summary of manufacturer provided data on the dosing and pharmacokinetics of sedatives used in ICU sedation, unless otherwise noted. Abbreviations: CHF, congestive heart failure; ESRD, end-stage renal disease; FDA, US Food and Drug Administration; ICU, intensive care unit. Data from Refs.47–51

Management of Sedation and Paralysis

Terminal elimination With dose titration, 6-min distribution half-life for 1.2–2.4 h, prolonged with Terminal half-life is 9– awakening in can occur bolus dosing, 2-h terminal critical illness, CHF, hepatic 19 h, 261  189 min for half-life is 219 min in 10–15 min, even with half-life in steady state dysfunction mental status to return prolonged dosing to baseline after Terminal half-life after 10 d infusion44 infusion is 1–3 d Dose No changes required in Reduce dosage in patients Reduce dose in patients with No dose reduction Decrease dose with adjustment chronic hepatic or kidney with liver dysfunction or severe hepatic or renal required in hepatic hepatic in organ dysfunction age >65, no renal dosing dysfunction, CHF, dysfunction; terminal dysfunction and to failure adjustment hypovolemia, hypothermia, half-life prolonged a lesser extent with vasopressor dependence, 55% in renal renal dysfunction and critical illness dysfunction and 125% in ESRD Contraindications Can cause allergic reaction Can potentiate bradycardia, Decrease dose with CYP3A Avoid in acute narrowDecrease dose with and warnings in patients with soy or vasodilators and negative inhibitors, patients with angle glaucoma CYP3A4 inhibitors egg allergies inotropes, FDA warnings of narrow-angle glaucoma increased adverse effects and tachyphylaxis after 24 h

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Fierro & Bartz treatment of delirium, also have sedative effects and play an important role in the broader management of sedation, pain, agitation, and delirium.2 Hypnotic drugs, such as propofol, induce sleep through central nervous system depression and can be used as a bolus for induction of general anesthesia, intubation, or procedural sedation or as a continuous infusion for sedation in the ICU. Most sedative drugs, with the exception of dexmedetomidine, induce respiratory depression through a blunting of the respiratory response to carbon dioxide, which can be a valuable characteristic of these agents in promoting patient– ventilator synchrony (Table 2).

OPIOIDS m-Opioids are administered to mechanically ventilated patients either solely for their sedative effects or as a method to provide a single agent for patients who require both analgesia and sedation.46,52,53 The most commonly used opioids in the ICU include fentanyl, hydromorphone, and morphine. In a 100-patient retrospective review, Tedders and colleagues53 found no difference in duration of mechanical ventilation or ICU LOS among patients sedated with a fentanyl intravenous continuous infusion versus a propofol intravenous continuous infusion. However, the

Table 2 Advantages and disadvantages of the commonly used sedatives during mechanical ventilation

Propofol

Dexmedetomidine

Advantages

Disadvantages

Consistent dose-dependent sedative response Short-acting for procedural sedation and intubation Less delirium than benzodiazepines Rapid awakening after discontinuation of infusion Depresses respiratory drive during management of PVD Minimal respiratory depression Less delirium than benzodiazepines Rapid awakening after discontinuation of infusion Can be used in nonventilated patients

Hypotension Cardiac depression Respiratory depression Hypertriglyceridemia Propofol-related infusion syndrome High caloric content of lipid emulsion Lacks analgesic properties Causes burning sensation on peripheral extremity infusion Hypotension Bradycardia Unreliable in providing deep sedation Can trigger withdraw after prolonged infusion Tachyphylaxis may occur after 24 h Limited efficacy in treating PVD Respiratory depression Unpredictable elimination in critically ill patients Increased delirium Increases duration of mechanical ventilation Potential for propylene glycol toxicity Respiratory depression Unpredictable elimination in critically ill patients Increased delirium Increases duration of mechanical ventilation Respiratory depression Causes ileus and gastric dysmotility No amnestic or anxiolytic effects Minimal evidence-based support as primary sedative Itching is common side effect Bradycardia

Midazolam

Anticonvulsant Can treat delirium tremens Amnestic activity Minimal effect on blood pressure

Lorazepam

Lower cost than midazolam Anticonvulsant Can treat delirium tremens Amnestic activity Minimal effect on blood pressure

Fentanyl

Provides both analgesia and sedation as a single infusion Depresses respiratory drive during management of PVD Can be given as boluses without need for continuous infusion Minimal hypotensive effect

Abbreviation: PVD, patient–ventilator dyssynchrony. Data from Refs.47–51

Management of Sedation and Paralysis patients receiving fentanyl required fewer rescue boluses, suggesting that the technique may promote better analgesia and sedation than the control group that provided continuous propofol and as-needed opioids.53 Data comparing continuous fentanyl infusions with other sedatives are limited, with slightly more investigative focus placed on the ultrashort-acting m-opioid remifentanil.46 Remifentanil is metabolized by tissues and plasma esterases independent of hepatic and renal function, with a context-sensitive half-life of approximately 3 minutes, which has been hypothesized to lead to reduced duration of ventilation and ICU LOS versus other opioid-based sedation techniques.46,54,55 Although remifentanil has a higher drug cost than fentanyl, with ideal use it may be effectively cost neutral or even cost saving when compared with other sedative drugs owing to its potential to decrease LOS.55,56 Using opioids for sedation is not without limitations, including side effects such as respiratory depression, pruritus, hypotension, ileus, and hallucinations.46,57 Because opioids lack inherent amnestic, hypnotic, or anxiolytic effects, recall of unpleasant ICU events is potentially greater for patients receiving opioids compared with those given benzodiazepines or propofol-based sedation.46 Additionally, the ultrashort-acting opioids such as remifentanil may cause hyperalgesia after discontinuation of the infusion, although the link remains controversial.58,59 Randomized studies comparing opioids with propofol or dexmedetomidine would assist in defining the role of these agents as a primary sedative in mechanically ventilated patients.

BENZODIAZEPINES Benzodiazepines are a class of drugs that act on the central nervous system as agonists to GABA-A neuronal receptors. Their effects include anterograde (but not retrograde) amnesia, anxiolysis, sedation, hypnosis as well as anticonvulsive properties. Class-specific side effects include dose-dependent respiratory depression, especially in patients with chronic obstructive pulmonary disease, and especially when used in conjunction with opioids, withdrawal symptoms including seizures after abrupt discontinuation in chronic users, and precipitation of delirium.60–63 They may also contribute to a dose-dependent increase in posttraumatic stress disorder when used in the ICU.64 Midazolam, a short-acting benzodiazepine used frequently in the ICU as a sedative, is oxidized in the liver by the CYP450 system to form a1-hydroxymidazolam, which is an active metabolite, and the clinically insignificant 4-hydroxymidazolam, both of which are conjugated in the liver and

excreted in the urine.65 Although the half-life of midazolam is approximately 3 hours, significant accumulation of the active metabolite, a1-hydroxymidazolam glucuronide can occur in critically ill patients as well as patients with coadministered CYP3A4 inhibitors, liver dysfunction, advanced age, or obesity.65,66 Lorazepam is metabolized primarily in the kidneys, with a similar pharmacologic effect, but greater potency than midazolam, with 10 mg of midazolam being equivalent to approximately 0.7 mg of lorazepam.67 Lorazepam is also conjugated in the liver to an active metabolite, but hepatic metabolism plays a minimal role in drug elimination with dose reduction only required with severe hepatic dysfunction. Although the half-life of lorazepam has been cited as 12 hours, its use as an infusion has been associated with a quicker return of baseline mental function after discontinuation when compared with patients receiving midazolam.44 Studies have demonstrated conflicting results when comparing the efficacy of achieving and maintaining patients’ targeted sedation goals with midazolam versus lorazepam, but cost analyses consistently favor the use of lorazepam.45,67–69 Ultimately, the clinical usefulness of continuous benzodiazepine infusions is decreasing in favor of dexmedetomidine, propofol, and to a lesser extent opioids, given the link between benzodiazepine use with prolonged duration of mechanical ventilation and increased rates of ICU delirium.2,43,70–75 Given the quality and quantity of comparative studies, it has become apparent that benzodiazepine infusions should not be routinely selected for ICU sedation, but should instead be reserved for selected patients or specific indications such as alcohol withdrawal, delirium tremens, and refractory seizures.2,76–78 Although benzodiazepines were considered classically the most hemodynamically stable sedative, they still may cause hypotension, especially in hypovolemic patients, and multiple studies have demonstrated no difference in vasopressor requirements when midazolam is compared with propofol sedation.79

DEXMEDETOMIDINE Dexmedetomidine is a highly specific agonist of central a2a-adrenergic receptors with minimal a1 receptor activity, causing sedative effects related to the depression of norepinephrine release in neurons of the locus ceruleus.80 Unlike benzodiazepines and propofol, these neurons are not fully inhibited, which allows the patient to be sedated, but interactive, while maintaining respiratory drive and airway reflexes.81,82 In addition to sedation,

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Fierro & Bartz dexmedetomidine has analgesic properties and an opioid-sparing effect.83 Clonidine shares similar properties with dexmedetomidine, and can be administered orally; however, the data supporting its use as a sedative in the ICU are sparse.84 The most commonly reported side effects of dexmedetomidine when compared with other sedatives are first-degree heart block, bradycardia, and hypotension, which are mediated by the dorsal motor nucleus and the motor complex, structures unrelated to the sedative effect.69,74,81 Paradoxically, the loading dose of dexmedetomidine can be associated with an abrupt increase in sympathetic discharge and caution should be maintained in patients with significant pulmonary hypertension or who require tight blood pressure control.85,86 Multiple randomized trials have demonstrated superiority of dexmedetomidine-based sedation regimens compared with the use of continuous benzodiazepines.43,69,74,81 In 2007, the MENDS study (Maximizing Efficacy of Targeted Sedation and Reducing Neurologic Dysfunction) compared patients receiving dexmedetomidine infusions with those receiving lorazepam infusions. Sedation with dexmedetomidine lead to more days alive without coma, less delirium, and increased time in the goal range of sedation.43 In 2009, the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared to Midazolam) study group identified that patients sedated with dexmedetomidine required fewer ventilator days and had a decreased incidence of delirium, while achieving a comparable level of sedation.69 In 2015, a Cochrane Review analyzed 7 studies including 1624 patients comparing dexmedetomidine with traditional sedatives (propofol, midazolam, and lorazepam) and found that sedation with dexmedetomidine reduced the mean duration of mechanical ventilation by 22% and the ICU LOS by 14% without a difference in mortality.81 A recent, 183-patient trial also demonstrated a reduced incidence of delirium with dexmedetomidine sedation compared with propofol sedation in cardiac surgical patients; however, this study is difficult to extrapolate to the general critical care population because the median mechanical ventilation time was only 5.9 hours.87 Although dexmedetomidine is associated with higher drug costs than benzodiazepines, it ultimately has been demonstrated to save money given its impact on shortening the duration of mechanical ventilation and reducing ICU delirium.88 Although a Cochrane review of 1624 patients was unable to associate dexmedetomidine use with a decreased incidence of delirium, the authors acknowledged that may be owing to a high

degree of variability and bias in the included studies.81 Dexmedetomidine is currently approved by the US Food and Drug Administration (FDA) for ICU sedation using dosages up to 0.7 mg/kg/h for a period limited to 24 hours. However, it is frequently used for longer durations and at doses of up to 1.5 mg/kg/h or higher.69 It is unclear if higher doses of dexmedetomidine improve quality of sedation or outcome; a retrospective review points out that, although safe, patients receiving doses higher than 0.7 mg/kg/h, are less likely to meet sedation goals than those who are within the FDAapproved range.89 These findings suggest that increasing doses of dexmedetomidine may have a plateauing effect in sedative response compared with drugs such as propofol and fentanyl, with failure to achieve even light sedation goals in 1 in every 8 to 10 patients.81 Although the FDA reports tachyphylaxis occurring after 24 hours of dexmedetomidine infusion, which may impact achievement or maintenance of sedation goals, its clinical occurrence and significance is controversial.90 It has also been found that dexmedetomidine is inferior to propofol in its ability to achieve sedation levels of RASS-4.75

PROPOFOL Propofol is a drug with sedative, hypnotic, anticonvulsant, and antiemetic properties used for the induction of general anesthesia, continuous sedation in the operating room and ICU, and for procedural sedation. The presumed mechanisms of action are through activation of GABA-A and GABA-B receptors, inhibition of N-methylD-aspartate receptors, and modulation of calcium influx through slow calcium ion channels.91 In a large propensity-matched study, the use of continuous propofol infusion compared with benzodiazepine infusions was associated with reduced mortality, ICU LOS, and duration of mechanical ventilation.70 Multiple smaller studies also support decreased LOS when propofol is compared with benzodiazepines.71,73 In a multicenter trial comparing propofol with dexmedetomidine, patients sedated with propofol had no difference in duration of mechanical ventilation, ICU LOS, or mortality, but had a decreased ability to communicate pain using the visual analog scale.74 A unique side effect of propofol is the propofol infusion syndrome, a rare but potentially severe syndrome of hypotension, bradycardia, lactic acidosis, lipemia, rhabdomyolysis, and hepatomegaly occurring in patients with infusion rates of greater than 67 mg/kg/min lasting for more

Management of Sedation and Paralysis than 48 hours.92 Much of the description of propofol infusion syndrome is limited to case reports, but a recent review identified 37 adult cases in previously critically ill patients, of whom only 7 survived.93 In addition to cumulative propofol dose, probable risk factors for propofol infusion syndrome include critical illness, vasopressor use, glucocorticoid administration, carbohydrate malnutrition, and subclinical mitochondrial disease.93 In patients on infusions lasting longer than 48 hours, it is important to serially monitor for increasing triglyceride levels, which can lead to pancreatitis, although the condition is rare, and to consider the caloric intake from the lipid emulsion in which propofol is delivered.94–96 Last, propofol acts as a vasodilator causing hypotension, and has a cardiac depressant effect greater than benzodiazepines.97 However, this is mostly attenuated by use of lower dosages in patients with reduced ejection fractions. Although randomized trials have demonstrated outcome benefits of propofol over benzodiazepine infusions, head-to-head data comparing propofol with dexmedetomidine are sparse.81 A large prospective trial assessing the differences in duration of mechanical ventilation, ICU LOS, incidence of delirium, patient experience, and mortality between propofol and dexmedetomidine would be beneficial, but until then outcomes associated with the 2 drugs seems to be similar.74

NEUROMUSCULAR BLOCKING DRUGS Neuromuscular blocking drugs (NMBDs) are divided into depolarizing agents, which includes succinylcholine, and nondepolarizing agents, which are further classified as aminosteroids (vecuronium, rocuronium, and pancuronium) and benzylisoquinolones (atracurium and cis-atracurium; Table 3). Only nondepolarizing agents are used as continuous infusions for muscle relaxation in the ICU, whereas succinylcholine use is limited to establishing muscle relaxation for endotracheal intubation. Nondepolarizing agents act by competitively inhibiting nicotinic acetylcholine receptors at the motor end plate of striated muscles (smooth muscle and cardiac muscle are unaffected). Given the variability of pharmacokinetics in these drugs, especially the aminosteroids which rely on hepatic and renal metabolism, train of four monitoring, which assesses and grades neuromuscular response to electrical stimulus, should be implemented to clinically assess the degree of neuromuscular blockade in patients receiving NMBDs.4,104 When infusions are titrated to effect using train of four parameters, there is likely minimal difference in the incidence of

prolonged neuromuscular blockade or drug clearance among the different agents despite their variable pharmacokinetics and heterogeneity of patients.105,106 Notably, neuromuscular blockade can be potentiated by drugs, including volatile anesthetics, aminoglycosides, polymyxins, lithium, magnesium, procainamide, local anesthetics, and quinidine as well as clinical conditions such as acidemia, hypothermia, and hypokalemia.104 When muscle relaxants are used in the ICU, electroencephalogram-based monitoring, such as the bispectral index (Aspect Medical Systems, Newton, MA) should be used to assess depth of sedation and to titrate infusions to decrease the risk of awareness while paralyzed.2,107 Although ICU-specific data are lacking, a bispectral index level of 40 to 60 is generally accepted as a target level which minimizes both the risks of excess sedation and patient recall of muscle relaxation controlled ventilation alone in some patients.107–111 Although it is clear that all patients, with a possible exception of those with severe brain injury, require continuous sedation to prevent awareness during muscle relaxation, there are no data assessing individual sedatives. Clinical guidelines, last published in 2002, provide minimal direction, and do not incorporate the availability of bispectral index monitoring or the newly discovered adverse consequences of benzodiazepines.4 In their 2010 ARDS management study protocol, Papazian and colleagues11 used a combination midazolam and sufentanil for sedation in both arms, with propofol and ketamine serving as adjuvants. In practice, the use of NMBDs may be curtailed out of concern over increased risks of acute quadriplegic myopathy syndrome, critical illness polyneuropathy, and related neuropathy and myopathy syndromes, which are well-described in case reports; however, a definitive causal relationship between NMBDs and these syndromes has not been established.4,104,112 However, in patients with ARDS, Papazian and associates11 noted no increase in neuromuscular weakness in treated patients, which they attribute to the use of a benzylisoquinolone over an aminosteroid, and the relatively short duration of blockade needed to achieve survival benefit. A second potential adverse effect of muscle relaxants is ventilator-induced diaphragmatic dysfunction, in which the diaphragm undergoes both disuse atrophy and muscle injury at the molecular level.113 The incidence of myopathies seems to be reduced when coadministration of NMBDs with corticosteroids or during hyperglycemia is avoided.114 A class-specific side effect of benzylisoquinolones is the production of the inactive metabolite

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Benzylisoquinolines Cis-Atracurium Initial bolus dose

11

Atracurium

Rocuronium

Vecuronium

0.4–0.5 mg/kg

0.6 mg/kg, 1.2 mg/kg for rapid sequence intubation 10–12 mg/kg/min 4–16 mg/min; dose drops by 40% after 6–9 h98 Minimal effect on duration of activity Primarily hepatobiliary98 Tissue redistribution accounts for 80% of initial metabolism Elimination half-time 84– 144 min in general anesthesia; mean terminal half-time 337 min, 60 min (range, 15–155) to recovery of fourth twitch98 May increase pulmonary vascular resistance

0.8–0.1 mg/kg

0.15 mg/kg or 15 mg ; 20 mg may be given for PVD11 3 mg/kg/min 0.5–10.2 mg/kg/min

11–13 mg/kg/min 4.5–29.5 mg/kg/min

None

None

Hepatic metabolism Alternative metabolism

Trace Plasma: 80% Hoffman elimination

None Plasma: nonspecific esterases and Hoffman elimination

Elimination time

Elimination half-life is 20– 29 min, >75% TOF ratio regained in 50–55 min (range, 20–270)

Elimination half-life 20 min, >75% TOF ratio regained in 32–108 min (mean, 60)

Novel side effects

Laudanosine metabolite causes transient hypotension and possibly CNS excitation None

Laudanosine metabolite causes transient hypotension and possibly CNS excitation None

Side effects

Histamine release, bronchospasm, hypotension

Pregnancy category

B

Skin flushing, histamine release with doses >0.6 mg/kg C

Starting rate Typical steady-state rate Renal metabolism

Dose adjustment with organ dysfunction

Aminosteroids

Duration prolonged by 50% with liver dysfunction and minimally increased in ESRD Transient hypotension or hypertension, anaphylaxis C

1 mg/kg/min 1.26–2.27 mg/kg/min99 3%–35% urinary excretion 25%–50% biliary excretion N/A

Elimination half-time 65–75 min; in ICU, mean recovery of full neuromuscular function is 20–36 min99 —

Minimal prolongation in renal failure, prolonged duration in liver dysfunction and cholestasis Anaphylaxis

C

This table represents a summary of manufacturer provided data on the dosing and pharmacokinetics of muscle relaxants used in ICU sedation, unless otherwise noted. Abbreviations: CNS, central nervous system; ESRD, end-stage renal disease; ICU, intensive care unit; PVD, patient–ventilator dyssynchrony; TOF, train of four. Data from Refs.100–103

Fierro & Bartz

Table 3 Commonly used ICU muscle relaxants

Management of Sedation and Paralysis laudanosine, which can cause central nervous system excitation after prolonged infusion, but the clinical significance is limited.104 Anaphylaxis, which occurs more frequently with aminosteroids than benzylisoquinolones, is an important adverse effect to recognize and may occur in up to 1 in 2500 patients administered rocuronium.115–117 An increased incidence of deep vein thrombosis is also believed to occur in patients undergoing sustained muscle relaxation.4 Muscle relaxation also can lead to corneal ulceration, which can be prevented by taping the eyelids shut and or administering ocular lubrication.4

PATIENT–VENTILATOR DYSSYNCHRONY PVD can occur during triggering, flow delivery, or cycling phases of the respiratory cycle and causes high pressure loads on respiratory muscles, leading to patient discomfort, fatigue, and possibly muscle injury.14,118 PVD is important to recognize because muscle loads caused by dyssynchrony can meet or even exceed loads imposed by the patient’s underlying pathology, causing significant oxygen expense as well as potential for lung trauma.119 Once PVD is recognized, an alternative ventilator mode or adjustment of ventilation parameters such as positive end-expiratory pressure, triggering sensitivity, gas flow rates, inspiratory pressure, or cycle settings should be attempted.118,120,121 The use of emerging ventilation modes guided by esophageal pressure monitoring and/or diaphragmatic electromyography may prove to be valuable techniques to improve patient–ventilator interaction in the future.121,122 Once it is established that the patient–ventilator interaction cannot be improved effectively by the modification of ventilator settings, consideration should be made to increase sedation and potentially use NMBDs.

USE OF SEDATIVES TO FACILITATE VENTILATOR SYNCHRONY When sedatives are used to manage PVD, specifically propofol, opioids, and historically benzodiazepines, their primary benefit is in their ability to decrease the patient’s respiratory drive. As this is done, sedation should no longer be managed according to a scale or algorithm, but instead should be uptitrated until PVD resolves or until their use is limited by hypotension. Importantly, if the strategy of lung protection or management of PVD is in the transition of a patient from a controlled ventilation mode such as pressure or volume assist control to a setting that is based on spontaneous breathing, such as pressure

support, then continuous sedation should be minimized or discontinued to promote effective ventilation.123 In mechanically ventilated patients, respiratory drive can be affected by the pattern of mechanical ventilator support, but largely depends on chemical triggers including PaCO2, PaO2, and pH.124 In conscious, mechanically ventilated patients, respiratory drive and ultimately minute ventilation are tied closely to cerebral CO2 levels, but the response becomes blunted in the sedated patient. It has been demonstrated that a decrease in PaCO2 by as little as 3 to 4 mm Hg can result in apnea in sedated patients.124 In a combined human and animal study, the respiratory depressant effect of fentanyl was demonstrated to be linear and dose dependent as assessed by dose versus measured PaCO2 in both healthy volunteers and rats.125 Similar dose-dependent decreases in PaCO2, respiratory rate, and minute ventilation occurred in a series of 8 healthy male volunteers administered fentanyl and alfentanil.126 Propofol has a similar effect as demonstrated in a study where it was infused in 10 healthy volunteers, leading to progressive respiratory depression as measured by increasing PaCO2, with the most profound depression occurring with bolus dosing.127 Benzodiazepines also promote central respiratory depression, especially when combined with opioids, but again first-line use for this purpose is discouraged given their adverse effects.2,79 Dexmedetomidine does not induce a clinically significant reduction of respiratory drive in mechanically ventilated patients.81,82 Given the predictable, dose-dependent, respiratory depression induced by propofol and opioids, escalating doses of these drugs can be implemented to decrease respiratory effort in patients exhibiting PVD. Indeed, in an observation of 20 medical ICU patients, de Wit and coworkers14 identified a linear relationship between ineffective ventilator triggering and increasing levels of sedation measured by RASS. When sedatives alone are unable to reduce PVD, as may occur despite deep sedation15 or if their use is limited by refractory hypotension, consideration can be made for the addition of a muscle relaxant.

THE ADDITION OF MUSCLE RELAXANTS FOR ACUTE RESPIRATORY DISTRESS SYNDROME The use of muscle relaxants has regained enthusiasm over the past decade as a series of 3 studies demonstrated decreased mortality, decreased duration of mechanical ventilation, improved PaO2 to FiO2 ratios, and decreased barotrauma when used for 48 hours in patients in the initial

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Fierro & Bartz stage of severe ARDS.16 Effective use of NMBDs causes flaccid paralysis of the diaphragm and accessory respiratory muscles, eliminating a patient’s work of breathing, thus preventing the volutrauma and barotrauma caused by PVD.10 Additional benefits of these drugs may include an ability to improve thoracic wall compliance, functional residual capacity, and ventilation–perfusion mismatch, while decreasing shunt, overdistention of high compliance regions, and end-expiratory alveolar collapse.123 Lung protective ventilation, a ventilation strategy of low tidal volumes, high positive end-expiratory pressure, limited plateau pressures, and permissive hypercapnia, has been demonstrated to provide an up to 22% mortality benefit when used for ARDS, but often stimulates dyssynchronous ventilation.128 During lung protective ventilation, it has been demonstrated in an observational study that breathstacking events often occur multiple times per minute with resultant tidal volumes in excess of 10 mL/kg in sedated patients.15 Although deep sedation reduces their occurrence, with a mean of 0.4 PVD events per minute occurring in patients with a RASS score of 4, this illustrates a potential impact of NMBDs in the deeply sedated patient who has a preserved respiratory drive owing to permissive or unintentional hypercarbia.15 In patients with acute lung injury, muscle relaxants can also be used to prevent PVD during highly stimulating alveolar recruitment strategies, such as the use of high positive end-expiratory pressure or “open lung” ventilation modes.129 Continuous neuromuscular blockade also plays a role in selected patients being managed for increased intracranial pressure, refractory tetanus, shivering during therapeutic hypothermia, status asthmaticus, and abdominal compartment syndrome, and can be more generally used to reduce oxygen consumption in the critically ill.4,104,130 Given that 3 studies that included 431 patients and 2 subsequent metaanalyses identified an absolute in-ICU mortality benefit of 13.3% in ARDS patients treated with neuromuscular blockade (31.4% vs 44.7%; relative risk, 0.71; 95% confidence interval, 0.55–0.90), use of these drugs should be considered in all patients in the initial stage of severe ARDS patients, not just those with refractory PVD.10–13,16 The survival benefits, which persisted at 30 days, with a number needed to treat of only 9, may be owing to reduction of early volutrauma and barotrauma stemming from PVD.10,16 Although the ARDS data have been promising, nonrandomized studies have linked muscle relaxants with prolonged duration of mechanical ventilation and LOS, but may be subject to selection bias and reflect heterogeneous

practices in terms of management and duration of NMBDs.22

OXYGENATION AND NEUROMUSCULAR BLOCKING DRUGS The exact mechanism of improvement in oxygenation in ARDS patients given muscle relaxation is likely multifactorial, stemming from improved alveolar recruitment owing to ventilator synchrony, with associated decreases in shunting and improvement in lung compliance and gas exchange, combined with decreased oxygen use through elimination of the work of breathing.10,13,123 On a molecular level, Forel and colleagues12 demonstrated decreased levels of interleukin (IL)-6, IL-8, and IL-1b in patients given cisatracurium, and propose that decreased pulmonary inflammation resulting in improved gas exchange contributes to improvements in oxygenation. Deep sedation is a requisite for continuous muscle relaxation in the ICU and it can be difficult to separate the metabolic effects of muscle relaxants from those of sedatives. Continuous propofol infusion alone has been noted to decrease oxygen consumption, and resultantly CO2 production by approximately 15% when used for moderate sedation.127 Oxygen consumption can decrease to 30% when combined with an opioid during levels of sedation that are comparative with general anesthesia.127 It is unclear what the additive effect of NMBDs is in the deeply sedated patient on controlled ventilation without PVD. Freebairn and colleagues131 failed to demonstrate differences in VO2, oxygen delivery, gastric intramucosal pH, or oxygen extraction ratios in deeply sedated, mechanically ventilated, septic patients administered vecuronium versus those given placebo. In a study of healthy patients undergoing hand surgery, administration of rocuronium during tourniquet-induced ischemia did not impact regional tissue oxygenation as measured by near-infrared spectrometry.132 Importantly, neither of these studies assessed changes in energy metabolism in patients in whom the drugs were used to abolish PVD, spontaneous ventilation, or excessive muscle contraction in a sedated patient, where the benefit of NMBDs probably lies. Indeed, Manthous and associates133,134 determined that controlled ventilation with muscle relaxants decreased VO2 by 19% when compared with spontaneous ventilation with CPAP and that VO2 reduction associated with muscle relaxants was greater than the transition to controlled ventilation alone in some patients. In a series of mechanically ventilated patients with cardiopulmonary disease, the respiratory oxygen cost of breathing was on

Management of Sedation and Paralysis average 24% of total VO2.135 NMBDs may have particular benefit in the obese, in whom the work of breathing associated with spontaneous ventilation was measured in one study as 540 versus 227 kg*m/L in lean individuals.136 In a separate study assessing the change in VO2 after induction of anesthesia, intubation, and institution of mechanical ventilation without muscle relaxation, there was a 16% reduction in oxygen consumption in obese patients compared with a less than 1% reduction in lean patients.137 These studies, which measure oxygen demand, demonstrate that the work of breathing can remain significant during mechanical ventilation and illustrate a physiologic avenue for NMBDs to impact oxygenation. Because muscle relaxants will cause spontaneous ventilatory efforts to cease, thereby eliminating the work of breathing, the resulting decrease in oxygen consumption and CO2 production offered by these drugs can be profound, especially in cases of severe PVD and in obese patients.

USE OF SEDATIVES AND NEUROMUSCULAR BLOCKING DRUGS IN HIGH-FREQUENCY OSCILLATORY VENTILATION Although the use of high-frequency oscillatory ventilation in ARDS is controversial, with a major study by the OSCILLATE (The Oscillation for Acute Respiratory Distress Syndrome [ARDS] Treated Early) Trial Investigators identifying increased mortality with the ventilation mode, its use requires unique sedation goals and can serve as a model for the management of patients with severe PVD.138–141 In the OSCILLATE study, there was a significant increase in sedation and muscle relaxant requirements in the high-frequency oscillatory ventilation group versus the conventional ventilation group.140 Sedation was required to prevent PVD in nearly 100% high-frequency oscillatory ventilation patients, in whom spontaneous inspiratory effort can cause large intrathoracic pressure swings, atelectasis, hypoxemia, patient discomfort, and even ventilator dysfunction.142 In a retrospective review, Burry and colleagues142 found that the need for muscle relaxation to prevent deleterious PVD was reduced in patients given high-dose opioids to achieve deep sedation goals.

USE OF SEDATION AND NEUROMUSCULAR BLOCKING DRUGS WITH EXTRACORPOREAL MEMBRANE OXYGENATION Sedation goals for patients on extracorporeal membrane oxygenation (ECMO) will vary greatly by institution and type of ECMO, but should

ultimately reflect the individual patient requirements. Although it is imperative that cannulas do not become dislodged by an agitated patient, central cannulation strategies, especially the dual lumen internal jugular venovenous ECMO cannula allow patients to tolerate lesser degrees of sedation than conventional 2-cannula strategies.143 Multiple reports demonstrate the safety and probable benefit of both passive and active physiotherapy, including ambulation, while on ECMO using central venovenous and even venoarterial cannulation strategies.144–146 Importantly, lipophilic drugs such as fentanyl and midazolam may sequester in the tubing of ECMO circuits causing unpredictable drug delivery to the patient.147

SUMMARY Although sedatives are commonly administered for the management of patient discomfort and agitation during mechanical ventilation, an important and often underused indication is the maintenance of patient–ventilator synchrony. The current prevailing trend in ICUs throughout the world is to reduce the amount of sedatives used, which has been supported by reductions in duration of mechanical ventilation, delirium, LOS, and cost. A common tool to incorporate these changes is the titration of drug infusions to maintain a light degree of sedation according to protocols based on validated sedation scales. Although the benefits of minimizing sedation are clear, it is important to consider the potential benefits of using deeper levels of sedation to treat patients’ with refractory PVD, which causes lung injury through volutrauma and barotrauma. Because muscle relaxants have been demonstrated to improve survival from ARDS, their administration should be strongly considered at the time of diagnosis of severe ARDS. These drugs, when combined with deep planes of sedation, may also have more general benefits in the management of PVD and the reduction of oxygen consumption and carbon dioxide production in the critically ill. Although minimization and protocolization of sedation in the ICU has been demonstrated to improve costs and outcomes, it is important to set sedation goals on an individual basis, taking into consideration both patient comfort severity of illness, and patient–ventilator interactions.

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