CONTENTS

• Pharmacology of paralytic agents:
  • Pancuronium, vecuronium, rocuronium (aminosteroids)
  • Cisatracuium, atracurium (benzylisoquinoliniums)
  • Succinylcholine
• When to use paralytics
  • Indications for paralysis
    • Ventilator synchrony
    • Other indications
  • Management of ventilator dyssynchrony & avoiding unnecessary paralytic infusions
• Prolonged paralysis
  • BIS monitor
  • Target paralysis & train of four monitor
  • Eye care
  • Other risks & their mitigation
• Sugammadex
• Paralytic allergy

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aminosteroid paralytics (pancuronium, vecuronium, rocuronium)

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contraindications/cautions

• Potential side-effects of ciatracurium: bradycardia (0.4%), hypotension (0.2%), flushing (0.2%).
• Pancuronium has vagolytic effects that may cause tachycardia.

dosing

• ED95 (dose that decreases the twitch by 95% from baseline):
  • Pancuronium: 0.07 mg/kg.
  • Vecuronium: 0.05 mg/kg.
  • Rocuronium: 0.3 mg/kg.
• Initial dose:
  • Pancuronium: 0.1 mg/kg.
  • Vecuronium: 0.1 mg/kg.
  • Rocuronium: 0.6-1 mg/kg
    • RSI: Standard dose is 1.2 mg/kg. (34178382) However, some limited evidence dose support the use of higher doses of rocuronium (≧ 1.4 mg/kg). Higher doses may be reasonable in patients with shock who may experience delayed onset of paralysis. If higher doses are used, practitioners must expect and plan for a prolonged duration of paralysis. (33837951)
    • In morbid obesity, non-depolarizing paralytics may be dosed based on lean body weight. Lean body weight rarely exceeds 70 kg in women or 100 kg in men. (25950621) 
      • Lean body weight calculator: 🧮
• Onset:
  • Pancuronium: 2-3 minutes.
  • Vecuronium: 3-4 minutes.
  • Rocuronium: 1-2 minutes (shorter with higher dose).
• Duration of therapeutic paralysis:
  • Pancuronium: ~90-100 minutes.
  • Vecuronium: ~35-45 minutes.
  • Rocuronium: ~30 minutes.
• Time until full recovery:
  • Pancuronium: ~120-180 minutes.
  • Vecuronium: ~45-60 minutes.
  • Rocuronium: ~60-70 minutes (longer in hepatic dysfunction).
• Half-life:
  • Pancuronium: ~120 minutes.
  • Vecuronium: ~30-80 minutes.
  • Rocuronium: ~1.4-2.4 hours.
• Infusion dose:
  • Pancuronium: 0.8-2 ug/kg/min (not recommended).
  • Vecuronium: start at 1 ug/kg/min, titrate between ~0.8-2.3 ug/kg/min. (27842752)
  • Rocuronium: start at 10-12 ug/kg/min, titrate between ~4-16 ug/kg/min. Dose requirement often drops by 40% after 6-9 hours (tissue redistribution accounts for 80% of initial metabolism). (27842752, Irwin & Rippe 9e)

pharmacology

• Renal interactions:
  • Pancuronium: 45-70% renal excretion; may prolong effect and cause metabolite accumulation.
  • Vecuronium: 50% renal excretion; may prolong effect and cause metabolite accumulation.
  • Rocuronium: 30% renal excretion; minimal effect.
• Hepatic interactions:
  • Pancuronium: mild increase in hepatic dysfunction.
  • Vecuronium: mild increase in hepatic dysfunction.
  • Rocuronium: 70% hepatobiliary metabolism; moderate increase in hepatic dysfunction.
• Active metabolites:
  • Pancuronium: 3-OH (50% potency of parent compound) and 17-OH pancuronium.
  • Vecuronium: 3-desacetyl vecuronium.
  • Rocuronium: None.
• Prolonged block:
  • ⚠️ More likely with pancuronium or vecuronium (possibly related to active metabolites).
  • Less likely with rocuronium. (Irwin & Rippe 9e)

clinical utilization

• Rocurinum is the drug of choice for intubation among critically ill patients.
• Vecuronium is commonly utilized among intubated patients to cause short-term paralysis (lasting ~1 hour).
• Pancuronium is not generally used in critical care. However, in a medication shortage, pancuronium could be substituted for other aminosteroid paralytics (with the caveat that its duration of action is longer).

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cisatracurium & atracurium

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contraindications/cautions

• Atracurium may cause dose-dependent histamine release with hypotension.

dosing

• ED95 (dose that decreases the twitch by 95% from baseline):
  • Cisatracurium: 0.05 mg/kg.
  • Atracurium: 0.25 mg/kg.
• Initial dose:
  • Cisatracurium: 0.1-0.2 mg/kg
    • 0.1 mg/kg loading dose for ventilator synchrony.
    • 0.2 mg/kg may be used for RSI.
  • Atracurium: 0.4-0.5 mg/kg.
    • 0.6 mg/kg may be used for RSI; this may provoke histamine release, causing tachycardia, hypotension, bronchospasm, and skin flushing. (34178382, 32483489)
• Onset:
  • Cisatracirum: 2-3 minutes.
  • Atracurium: 3-5 minutes.
• Duration of therapeutic paralysis:
  • Cisatracurium: ~45-60 minutes.
  • Atracurium: ~25-35 minutes.
• Time until full recovery:
  • Cisatracurium: ~60-90 minutes (range 20-270 minutes). (27842752)
  • Atracurium: ~60 minutes.
• Half-life:
  • Cisatracurium: 22-31 minutes.
  • Atracurium: 20 minutes.
  • Clearance may be prolonged due to hypothermia and acidosis since Hofmann elimination depends on pH and temperature.
• Infusion dose:
  • Cisatracurium:
    • Start at 3 mcg/kg/min.
    • Titrate in the range of ~0.5-10 mcg/kg/min. (27842752) Typically titrate by one mcg/kg/min every two hours.
    • ACURASYS used a fixed 15 mg bolus followed by a 37.5 mg/hr infusion (625 mcg/min, which is ~9 mcg/kg/min). This isn't recommended but rather is intended merely to provide some context.
  • Atracurium: start at 11-13 ug/kg/min, titrate in the range of ~4.5-30 ug/kg/min. (2784275); Irwin & Rippe 9e)

pharmacology

• Cisatracurium is an enantiometrically purified version of atracurium (which is a racemic mixture). As such, cisatracurium is generally preferable to atracurium.
• Metabolism is via Hoffman elimination (with minimal alteration in renal or hepatic dysfunction).
• Active metabolites: Laudanosine (less so with cisatracurium; probably not clinically relevant; renally excreted).
• Prolonged block: Rare.

clinical utilization

• Cisatracurium is generally preferred as the paralytic infusion of choice for prolonged sedation.
  • Its metabolism is more reliable, avoiding accumulation (especially in patients with renal and/or hepatic dysfunction).
  • Cisatracurium may cause fewer neuromuscular side effects than aminosteroid paralytics. (23062076)
• Atracurium isn't generally utilized, but it could be a substitute for cisatracurium in a medication shortage.

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succinylcholine

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succinylcholine contraindications/cautions

• Hyperkalemia.
• Malignant hyperthermia (personal or family history).
• Major burns or crush injuries.
• Immobilization >14 days.
• Neuromuscular disorders causing denervation for >2 days, including:
  • Stroke, encephalitis, amyotrophic lateral sclerosis.
  • Spinal cord disease.
  • Neuropathies (e.g., Guillain-Barre syndrome).
  • Muscular dystrophies.
• Myasthenia gravis (resistance to succinylcholine).
• Bradycardia (relative contraindication; rarely succinylcholine may cause bradycardia).

succinylcholine dosing for RSI

• 1 mg/kg IV (with some sources listing 1-1.5 mg/kg, so its OK to round up).
• 3-4 mg/kg IM.
• Morbid obesity: based dosed on actual weight (plasma cholinesterase activity is increased in obesity). (34178382)
• Waiting 30 seconds after the onset of fasciculation should provide optimal timing for intubation. (32483489)

unique side-effects of succinylcholine

• [1] Hyperkalemia. This effect is usually moderate but may be more pronounced among patients who experienced denervation, leading to increased sensitivity to acetylcholine.
• [2] Malignant hyperthermia:
  • Usually occurs shortly after administration (e.g., <1 hour).
  • Initial features may include tachycardia, cyanosis, and muscle rigidity (especially the masseter).
  • Further discussion of malignant hyperthermia: 📖
• [3] Bradycardia rarely occurs due to increased vagal activity.
• [4] Prolonged paralysis due to pseudocholinesterase deficiency. This may be genetic, or it may be associated with malnutrition, liver disease, uremia, pregnancy, burns, plasmapheresis, or oral contraceptives.

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indications for paralysis

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paralysis to promote ventilator synchrony

potential benefits

• Paralysis reduces metabolic activity, which reduces CO2 production and O2 consumption. This could help slightly in patients with severely impaired gas exchange.
• Complete avoidance of ventilator dyssynchrony, which may help limit peak pressures and reduce the risk of barotrauma (e.g., pneumothorax).
• May facilitate prone positioning (although paralysis is not mandatory for prone patients).
• May promote accurate measurement of plateau pressures.

potential risks

• Listed below: ⚡️

data regarding paralysis in ARDS

• The ACURASYS trial in France evaluated early paralysis with cisatracurium for 48 hours among patients with PaO2/FiO2 <150 mm. The study purported to show a mortality benefit, but this was only statistically significant within an adjusted analysis (not based on the raw data). (20843245)
• The larger ROSE 🌹 multi-center RCT subsequently found no benefit from routine cisatracurium paralysis (compared with a strategy of as-needed paralysis, which resulted in 15% of patients in the control arm receiving paralytic). (31112383) There was an increased rate of cardiovascular events among patients treated with paralysis. (31433931) 
• Considering the totality of evidence, it's likely that routine paralysis never improved mortality (as implied by the adjusted results of the ACURASYS trial).
• Meta-analyses have shown that paralysis is associated with improvement in oxygenation. (32483489)

summary of evidence-based medicine on paralysis to promote ventilator synchrony

• Routine application of paralysis doesn't improve mortality in ARDS.
• Indications for paralysis may include:
  • Refractory hypoxemia.
  • Persistent ventilator dysynchrony posing a threat to lung-protective ventilation that is refractory to other interventions (further discussion of therapies that can be deployed to avoid paralysis below: ⚡️).
• Cisatracurim is arguably the preferred agent:
  • Cisatracurium is supported by a greater evidentiary basis in terms of safety (e.g., ACURASYS and ROSE trials).
  • Cisatracurim likely produces a reduced risk of ICU-related weakness than aminosteroid paralytics.
• If a paralytic is used, the lowest possible dose should be utilized for the shortest possible duration of time. This hasn't been proven in a rigorous, prospective fashion, but there is data correlating the duration of paralysis with escalating risk.

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other indications for paralysis

hyperthermia

• Paralysis will immediately shut down all thermal energy generation from muscles.
• Short-term paralysis may be required to treat hyperthermia due to various intoxications (e.g., serotonin syndrome).

shivering

• Paralysis is a treatment of last resort for managing shivering (e.g., in the context of therapeutic temperature monitoring status post-cardiac arrest).
• Before paralysis, a multimodal package of shivering-suppressive therapies should be instituted as described here: 📖

abdominal compartment syndrome or ICP elevation

• Rarely, paralysis may be required to prevent pressure fluctuations caused by coughing or bucking the ventilator.

refractory shock

• Rarely, it may be desirable to eliminate the work of breathing entirely.  Paralysis will reduce blood flow to the diaphragm, allowing it to be shunted to vital organs.
• Note, however, that eliminating the respiratory drive with deep sedation may similarly reduce the work of breathing.

procedures or MRI scanning (short-term paralysis)

• Short-term paralysis may improve the safety of delicate procedures.
• Paralysis is often desirable before MRI scanning to obtain a high-quality scan and avoid self-extubation in the MRI (patients can tongue out the tube, even if their hands are restrained).

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management of ventilator dyssynchrony & how to avoid a paralytic infusion for ventilator synchrony

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The most common indication for a paralytic infusion in the ICU is the management of ventilator dyssynchrony. Paralysis will make patients look beautiful but carries substantial risks (as outlined below ⚡️). Consequently, paralysis should be avoided when possible (especially in asthmatic patients, who may be at increased risk of myopathy). Below are several strategies to avoid paralysis when able, which, as always, must be tailored to any specific patient. It's usually possible to sedate the patient enough that they're passive on the ventilator – in which case, it's doubtful that adding a paralytic will cause clinical benefit.  

[1/6] adjust the ventilator to improve patient comfort

• The classic adage is “fit the ventilator to the patient, don't fit the patient to the ventilator.”
• Maximal efforts should always be made to improve patient comfort by adjusting the ventilator before instituting chemical paralysis. For example:
  • If there is evidence of flow-starvation in volume-cycled ventilation modes, the flow rate may be increased. Alternatively, switching to pressure-support ventilator modes may often improve patient comfort.
  • Small increases in tidal volume (e.g., from 6 cc/kg to 8 cc/kg) may improve dyssynchrony. (33381233)

[2/6] permissive hypercapnia

• Most patients will tolerate hypercapnia very well (in the absence of right ventricular failure).
• IV bicarbonate may help improve the pH and allay concerns about acidemia (discussed further below).
• pH and pCO2 targets are wholly arbitrary, so instituting a paralytic infusion due to failure to meet some arbitrary threshold is usually misguided (e.g., “the pH was below 7.15 so we needed to paralyze the patient”).

[3/6] suppress the respiratory drive

• Respiratory drive suppression is the single most potent approach to avoiding paralysis. This may be achieved with a multi-modal combination of several interventions.  
• Medications:
  • [1] Opioids.
  • [2] Propofol.
    • Propofol blunts the respiratory drive.
    • Propofol may reduce oxygen consumption and CO2 production. (27842752)
  • [3] Benzodiazepines, when combined with opioids (when given alone, benzodiazepines have little effect on respiratory drive). (27842752)
  • [4] IV bicarbonate +/- loop diuretics to improve the serum bicarbonate (thereby reducing the respiratory drive). (5933194, 8718911, 16695940, 889648, 29307724)  Remember that metabolic acidosis will increase the respiratory drive (in an effort to mount a compensatory respiratory alkalosis), making the patient feel more air-hungry.
  • [5] Phenobarbital. 💉
• Reduce endogenous CO2 production (e.g., temperature control, treatment of agitation).

[4/6] it's OK if the patient doesn't look perfect

• Paralysis will make patients appear peaceful, but paralysis doesn't necessarily improve the patient's experience of mechanical ventilation (in fact, paralysis may make their experience infinitely worse by creating a risk of awareness while paralyzed).
• We need to be mindful of precisely what we are aiming for here: our perception of the patient's comfort versus the patient's actual comfort.
• Some patients may look bad during mechanical ventilation (e.g., with retractions or a shallow “guppy breathing” pattern). However, if the patient is deeply sedated and unconscious, it's perfectly acceptable to tolerate this (provided that the ventilator pressures and volumes are within a safe range). The patient may appear outwardly uncomfortable, but if the patient is unconscious, they aren't experiencing it. Paralyzing the patient may alleviate our discomfort as providers while making the patient more uncomfortable (by merely masking their discomfort).

[5/6] consider reducing trigger sensitivity on the ventilator

• For a deeply sedated patient, reducing the trigger sensitivity is one way to minimize ventilator-induced lung injury:
  • For an asthmatic patient, tachypnea may drive dynamic hyperventilation.
  • In ARDS, tachypnea may increase mechanical power delivery to the lung.
• Reducing trigger sensitivity may be achieved in various ways, depending on the clinical context. For example, in an asthmatic patient this could be achieved simply by decreasing the PEEP to 5 cm in patients with significant autoPEEP.
• Reducing trigger sensitivity could cause dyspnea and air hunger, so this should only be done in a deeply sedated patient (but by the time you get here, all the patients will be deeply sedated).

[6/6] trial PRN short-term paralytics

• Before committing the patient to a day of paralytic infusion, try a few bolus doses of paralytic (e.g., vecuronium 10 mg IV, repeated up to 2-3 times as needed).
• Many patients only require a few hours of paralysis to facilitate adaptation to mechanical ventilation and allow time to institute the above treatments.
• 💡 If end-tidal capnography is available, pay attention to changes in volumetric CO2 clearance before and after paralysis. A large shift may indicate significant oxygen consumption by skeletal muscles.

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prolonged paralysis

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BIS monitor

• Prior to paralysis, ensure that the patient is well sedated clinically (e.g., sternal rub).
• While paralyzed, monitor sedation using a BIS monitor (a system that monitors cerebral EEG waves to measure arousal).
  • Target a BIS level 40-60.
  • If BIS >60, the patient is too awake – add sedation.
  • If BIS < 40, the patient is over-sedated.
• A similar strategy should be used for any other ICU patient (e.g., multimodal therapy with control of pain, anxiety, and delirium). The target level of arousal is measured using the BIS monitor, but other principles are generally the same.
• One limitation of BIS monitoring is that it may not work well for ketamine (e.g., patient may be entirely dissociated, yet have a relatively high BIS score, suggesting that they are inadequately sedated).

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targeting the appropriate level of paralysis

The ideal level of paralysis and how to achieve this is unknown. To promote ventilator synchrony, 100% total paralysis isn't required. 

titrate to the desired clinical efficacy

• The most logical strategy might be to titrate paralytic to the lowest dose that achieves the desired clinical effect. Although there is no high-quality, prospective data supporting this, it would make sense, given that this is how we titrate other medication infusions (e.g., sedatives). (Irwin & Rippe 9e)
• For example, if paralysis is indicated to patient-ventilator synchrony, the lowest dose required to achieve this goal should be utilized (even if that dose doesn't cause complete paralysis).

peripheral nerve stimulator (train-of-four)

• Degree of paralysis should be clinically monitored by measuring the number of twitches elicited by sequential stimulation of the muscle with four sequential shocks (“train of four”).
  • 0 twitches: excess paralytic.
  • 1-2 twitches: therapeutic paralysis without excessive risk of toxicity.
  • 3-4 twitches: partial paralysis.
  • Even with four twitches, fading intensity of subsequent twitches reveals the presence of some paralytic. (32483489)
• Serial monitoring of the train-of-four may help avoid excessive dosing of paralytics.
• Limitations:
  • Different muscle groups have varying sensitivity.
  • Tissue edema may decrease the current experienced by the patient.
  • Different providers may assess twitches visually or tactilely. (32483489)
  • Incorrect positioning.
  • ⚠️ Peripheral nerve stimulators alone should not be used as the sole tool for paralytic titration.
• Before extubation, train-of-four monitoring may help confirm the absence of neuromuscular blockade. (34178382)

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eye care

• ICUs should have protocols regarding the administration of eye lubrication and eyelid closure.
• Before ICU admission, gently taping the eyes closed should prevent dessication or ulceration.

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other risks of paralysis to consider & mitigate

risks/drawbacks of paralytic infusion

• Elevated DVT risk (possibly the strongest independent risk factor among ICU patients). (32483489)
• Pressure ulceration.
• Nerve injury.
• ICU-acquired weakness (including critical illness neuropathy and/or myopathy).
• Unintended awareness during paralysis.
• Requirement for deep sedation (in efforts to avoid awareness). Deep sedation may promote delirium.
• Reduced diaphragmatic activation may reduce recruitment of the lung bases (especially relevant with APRV, which is more effective among non-paralyzed patients).
• Inability to evaluate the patient neurologically. (32483489)

mitigation of these risks

• Aggressive DVT prophylaxis.
• ICU protocols to avoid pressure injury.
• Close attention to glycemic control may reduce the risk of ICU-acquired weakness.
• Consider avoiding dexamethasone (which may be especially likely to cause myopathy, as compared to other steroids). (33159530)
• Minimization of paralysis:
  • Wean paralytic infusions to the lowest effective dose.
  • 🏆 Attempt a paralysis vacation at least daily and discontinue paralysis as soon as possible. Short-term paralysis with cisatracurium under close supervision is reasonably safe. However, the odds of developing myopathy increase with each additional day of paralysis. (10378560)

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sugammadex

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basics

• Sugammadex is a reversal agent for rocuronium or vecuronium (its efficacy against pancuronium is unclear).

how sugammadex should be used

• [1] Sugammadex should not be used to reverse rocuronium in critically ill patients with difficult intubation.
• [2] Sugammadex may be utilized to rapidly eliminate rocuronium after RSI, thereby allowing a neurological examination (e.g., in a patient with status epilepticus or traumatic brain injury).
• [3] Occasional patients are encountered who have bizzarely prolonged paralysis following rocuronium (possibly related to older age or hepatic dysfunction). Sugammadex may be utilized in these patients.
• [4] Adjunctive treatment of anaphylaxis due to rocuronium or vecuronium.

details 💊

• Dose:
  • Moderate blockade: 2 mg/kg actual body weight.
  • Deep blockade: 4 mg/kg actual body weight.
  • Immediate reversal after 1.2 mg/kg rocuronium:  16 mg/kg actual body weight.
• Contraindications/complications:
  • Risk of allergic/anaphylactic reaction.
  • ⚠️ Risk of bradycardia and cardiac arrest (if patient starts developing bradycardia consider giving epinephrine without delay).
  • Not FDA approved for patients with GFR <30 ml/min, but several studies have reported successful use in this situation without complications. (34178382, 32483489)

re-intubation in a patient who recently received sugammadex

• Following administration of sugammadex, re-intubation may be a little challenging. Sugammadex will persist for a while (its half-life is 2 hours and may extend up to 19 hours in severe renal failure). Persistent sugammadex may render the administration of aminosteroid paralytic (e.g., rocuronium) ineffective.
• Options include the following:
  • [1] Cisatracurium ⚡️ would be an excellent option (RSI dose is 0.2 mg/kg).
  • [2] Succinylcholine ⚡️ may be an option in this scenario (in the absence of contraindications).
  • [3] If the patient received 2-4 mg/kg of sugammadex, this could be overcome by using a very high dose of rocuronium to over-saturate the sugammadex (e.g., 1.5-2 mg/kg). (20630888) However, paralysis will be delayed for up to several minutes. Therefore, this is not a preferred strategy.

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paralytic allergy

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• Many paralytics (e.g., atracurium) have the capacity to stimulate histamine release, so there is a potential to misdiagnose histamine release (an anaphylactoid reaction) as a much more dangerous, IgE-mediated anaphylactic reaction.
• Anaphylaxic reactions to paralytic agents are a real and problematic phenomenon, however. This seems to be more common in Europe and Australia, possibly related to antigenic exposures which increase cross-allergic responses.
• Sadlier et al. performed one of the most detailed studies evaluating anaphylactic reactions to paralytic agents.  In their study, the most common paralytics to cause anaphylaxis were: (23335568)
  • Rocuronium (56%).
  • Succinylcholine (21%).
  • Vecuronium (11%).
  • Atracurium (9%).
  • No episodes of anaphylaxis due to pancuronium or cisatracurium.
• There appears to be a low risk of cross-allergic reactions between aminosteroid paralytics (rocurinum, vecuronium) and cisatracurium. (23335568)
• If anaphylaxis occurs following exposure to rocuronium or vecuronium, sugammadex may be used to help treat this. However, the cornerstone of management remains standard therapies for anaphylaxis such as epinephrine (further discussion here: 📖).

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questions & discussion

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