Icu Neuromuscular Blockade

University of Maryland Medical Center ICU NEUROMUSCULAR BLOCKADE Guidelines for Use Neuromuscular blocking agents (NMBAs) may facilitate various medical interventions, to include mechanical ventilation. NMBAs should be used only after all other measures/therapies are attempted (ie, sedation, new ventilator technologies). The following guidelines were designed for the long-term use of NMBAs ( ≥ 24 hours) in the ICU. These guidelines are not intended for patients receiving NMBAs for short-term or occasional use. NMBAs provide no analgesia or sedation. All patients receiving NMBAs must receive a concurrent, around-the-clock benzodiazepine to provide sedation and amnesia. Pediatric patients receiving NMBAs must concurrently receive a benzodiazepine or chloral hydrate for sedation. Concurrent opiate administration will be indicated for those patients with pain (post-op, trauma, etc.), but is not a substitute for an amnestic sedative agent. Appropriate sedation/analgesia should be evaluated by assessment of changes in parameters that may indicate stress or pain. Unexplained elevations in heart rate or blood pressure, diaphoresis, or tearing may indicate anxiety or wakefulness in the patient receiving NMBAs. Drugs such as beta blockers should not be employed to control undefined tachycardia in patients receiving NMBAs. A. INDICATIONS: Neuromuscular blocking agents to produce muscle paralysis in the ICU are indicated, but not limited to the following situations: 1) difficult mechanical ventilation (ie, hypoxia with maximal ventilatory support, high airway pressures) 2) elevated intracranial pressure 3) post-operative “open chest” 4) procedures requiring no movement of the patient such as tracheal intubation, bronchoscopy, etc. 5) extraordinary life support modalities such as ECMO, ECLA, LVAD, RVAD, or IABP 6) acute pulmonary hypertension in pediatric patients 7) high frequency, oscillatory ventilation B. DEFINITIONS: For the purpose of these guidelines, short-term and long-term paralysis shall be defined as: 1. Short-term paralysis < 24 hours 2. Long-term paralysis ≥ 24 hours

C. AGENTS OF CHOICE FOR PROLONGED (≥ 24 hours) ICU PARALYSIS: For most adult and pediatric patients, the neuromuscular blocking agents of choice are pancuronium or doxacurium. The preferred method of administration for pancuronium and doxacurium is scheduled bolus dosing. However, both agents may be administered by continuous infusion. Bolus doses should be administered by slow IV push to minimize any histamine-related side effects. Atracurium and cisatracurium use should be restricted to patients with renal and hepatic failure. Atracurium will be considered therapeutically equivalent to cisatracurium for long-term ICU paralysis. Atracurium and cisatracurium should be administered by continuous infusion. NMBA orders should be written to titrate the agent to a certain number of twitches on train-of-four (TOF) monitoring (ie, titrate to 1-2 twitches out of four on TOF). 1) Pancuronium: ADULTS=>

Loading dose: Maintenance:

0.05-0.1 mg/kg i) 0.02-0.05 mg/kg IV q2hr (2mg IV q2hr- usual initial dose) or ii) 0.02-0.03 mg/kg/hr infusion if dosing interval becomes shorter than every 2 hours (usual initial rate1-2mg/hr). NOTE: Extended intervals (ie, q 3hr) or decreased infusion rates may be necessary for patients with significant renal or hepatic insufficiency. PEDIATRICS=>

Load/bolus: 0.1-0.15mg/kg/dose q 1-2 hours Infusion: 0.1mg/kg/hr NOTE: May cause tachycardia, increase in SBP and cardiac output. 2) Doxacurium: ADULTS=>

Loading Dose: 0.04 mg/kg Maintenance: initial- 0.025 mg/kg IV q 2 hr ( 2mg IV q 2hr- usual initial dose) NOTE: Renal dysfunction- extend dosing interval (ie, q3-4hr). Infusion generally not needed, but is available. PEDIATRICS=> NOTE:

Load: 0.03-0.1mg/kg Maintenance: 0.03-0.15mg/kg/dose q 2-4 hours Doxacurium contains benzyl alcohol. Use with caution in infants.

D. SECOND-LINE AGENTS: Atracurium and cisatracurium should be limited to patients with multiorgan dysfunction (renal and hepatic) when the other NMBAs are unacceptable. Atracurium will be considered therapeutically equivalent to cisatracurium for longterm ICU paralysis. The preferred agents (pancuronium and doxacurium) may be used in multiorgan failure with appropriate train-of-four monitoring and close titration of dose. 1. Atracurium: ADULTS & PEDIATRICS= Load: 0.4-0.5 mg/kg Maintenance: 2-15 mcg/kg/min continuous infusion (usual dose 7-8 mcg/kg/min) 2. Cisatracurium: ADULTS & PEDIATRICS= Load: 0.1mg/kg Maintenance: 0.5-10 mcg/kg/min infusion (usual dose 3mcg/kg/min) E. MONITORING DURING NEUROMUSCULAR BLOCKADE i) Methods of monitoring degree of paralysis: 1) peripheral nerve stimulator (train-of-four)- Train-of-four (TOF)/ peripheral nerve stimulation is the standard of care to monitor level of neuromuscular blockade. Appropriate paralysis using TOF monitoring is generally considered 8590% blockade as indicated by 1-2 twitches out of four via the TOF monitoring. The consistent use of TOF will minimize drug accumulation, but may not prevent prolonged paralysis/prolonged weakness seen in some patients after discontinuation of NMBAs. The physician should write the NMBA orders specifying the number of twitches desired (ie, Doxacurium 2-3mg IV q2-3hr, titrate to 1-2 twitches out of 4 on TOF). 2) compliance with ventilatory support- Appropriate neuromuscular blockade is indicated clinically by the patient accepting ventilation without overbreathing or dysynchrony, and with reduced airway pressures, absent gag/cough reflex during tracheal suctioning, and no visible extremity movements. ii) Procedures for monitoring patient during prolonged paralysis (≥24 hours): 1. All patients receiving around-the-clock neuromuscular blockade should be monitored with a peripheral nerve stimulator in addition to the clinical assessment of ventilator compliance. 2. Train-of-four must be assessed at least every 12 hours, and 4 hours after each

dosage change. 3. Results of train-of-four monitoring will be recorded on the nursing flowsheet along with any dose adjustments. 4. Train-of-Four Procedures: a) TOF may be performed at the ulnar or facial nerve. Ulnar nerve stimulation may become difficult if there is significant peripheral edema. Facial nerve stimulation may be more appropriate in this situation. In addition, the facial nerve may correlate better with paralysis of the diaphragm. b) Place 2 standard EKG electrodes along the ulnar nerve approximately 2-3 inches apart. c) Attach alligator clips to the electrodes (polarity unimportant). d) Explain to the patient what you are going to do (ie, “checking your muscle response”, “you’ll feel 4 tingles in your arm”, etc.). e) Prior to initiation of NMBA, when possible, a baseline TOF should be performed to determine the minimum stimulus (mAmps needed to produced 4 strong twitches). 1. Set the peripheral nerve stimulator to 20-30 mAmps and depress TOF pad on the stimulator. 2.Watch for twitches or feel for twitches in the thumb or hand. 3. Increase the mAmps until 4 strong twitches are seen/felt. f) Once NMBA is started, check TOF in same location and start with the same current (mAmps) that produced twitches the last time TOF was checked. Increase the current until twitches are seen or until maximum on nerve stimulator. g) If no twitches are seen/felt, perform troubleshooting procedures (ie, reverse alligator clips, check electrode placement, check batteries). If no technical problems are discovered, hold NMBA until 1-2 twitches return, then restart at a decreased dose. h) A goal level of paralysis for most ICU patients is 1-2 twitches. See TOF chart for interpretation of twitches and example dose adjustments.

TRAIN-OF-FOUR # of Degree of Paralysis Twitches 0 100%- complete blockade

1

Drug accumulation or electrical current during nerve stimulation not transmitted. 90% blockade

2

Goal for paralysis of diaphragm. ≈ 85% blockade

3

Acceptable goal for most patients. ≈ 80% blockade

4

Acceptable for some patients. < 75% blockade Residual blockade may be present.

Suggested Dose Adjustments Hold dose until 1 out of 4 twitches returns on TOF and restart at a decreased rate or extend the interval. (ie, 10% less on infusion rate or extend interval from q2hr to q3-4hr) Continue current dose. Continue current dose or rebolus and increase maintenance dose if 1:4 twitches is desired. (ie, increase rate/dose by 10%) Continue current dose or rebolus and increase maintenance dose for more paralysis (ie, increase by 10%). Rebolus, and increase rate/dose (ie, increase by 10-20%). If patient is recovering from the NMBA, may use a 5 second headlift to check for residual paralysis.

5. Drug holidays (discontinuation of the infusion or holding of a scheduled dose for several hours) should be considered after 5 days of continuous administration, or after 48 hours if the patient is receiving concurrent steroids. The purpose of the drug holiday is: 1) to assess if the indication for the NMBA still exists; and 2) to assess the time necessary for the patient to recover from the neuromuscular blockade. In general, if it takes a time equal to or greater than 4 half-lives of the NMBA to recover 3-4 twitches after the NMBA is held, then the dose and/or interval should be adjusted prior to restarting the NMBA. If the indication for neuromuscular blockade no longer exists after withdrawal, the NMBA should be discontinued. Example drug holiday procedure: 1. Consider a drug holiday for stable patients. 2. Hold NMBA if patient has received ≥ 5 days of NMBA therapy without other interacting medications or if patient has received ≥ 2 days of therapy with concurrent steroids. 3. Start checking TOF beginning 1 hour after the end of the last dosing interval or 1 hour after stopping an infusion. Check TOF every hour until 3-4 twitches are recovered.

Pancuronium or Doxacurium -If interval is q 2 hr, start checking TOF 3 hours after last dose. -Check TOF q 1 hr, until 3-4 twitches. -If time to recover 3-4 twitches is ≥ 6-8 hours, and the patient still requires paralysis (ie, desaturates or ICP increases), then restart at an extended dosing interval (ie, q3-4 hr) or 10% decrease in the infusion rate.

Atracurium or Cisatracurium -Start checking TOF 1 hour after infusion is stopped. -Check TOF q 1 hr, until 3-4 twitches. -If time to recover 3-4 twitches ≥2 hours, and patient still requires paralysis, then restart at 10% less.

F. ADVERSE EFFECTS: 1. Histamine release: generally, insignificant clinically but may occur with all the NMBAs in large bolus doses, administered rapidly. 2. Cardiovascular: tachycardia (vagolytic), bradycardia, mild hypotension (least common with doxacurium and cisatracurium) NOTE: The tachycardia associated with pancuronium is usually not clinically significant in adults, with an average increase of 10 beats/minute. 3. Tachyphylaxis: therapeutic resistance may occur with all NMBAs due to up regulation of the receptors; may occur less with bolus dosing 4. Prolonged neuromuscular blockade from accumulation: minimized with regular TOF monitoring 5. Post-paralytic syndrome: occurs with all agents, unpredictable. All of the common NMBAs (vecuronium, pancuronium, atracurium, doxacurium) have been implicated with post-paralytic syndrome/prolonged weakness. This weakness is caused by denervation of muscle and/or a result of NMBA interaction with various medications. Patients at high risk for prolonged weakness, in whom use of NMBAs should be avoided, include those receiving concurrent corticosteroids, aminoglycosides, and/or immunosuppressives. The occurence of prolonged paralysis is unpredictable and may take weeks-months to reverse. The severity of this syndrome can range from mild weakness to quadraplegia. The use of corticosteroids appears to be a risk factor for development of postparalytic syndrome/prolonged weakness regardless of the chemical structure of the NMBA (even nonsteroidal NMBAs). 6. Other concerns: -Skin breakdown (frequent turning needed) -Corneal drying (scheduled lacrilube to prevent) -Deep vein thrombosis (consider compression device or SQ heparin) -Inadequate sedation and analgesia (monitor for increases in HR,BP,

diaphoresis, and tearing during times of potential stress- see attached UMMS sedation score for more information) -Aspiration risk (elevate head of bed if enteral feedings are used) -Secretion removal G. DESIRED OUTCOMES: 1) Achieve optimal ventilation without adverse effects. 2) Achieve appropriate paralysis while minimizing NMB dose. 3) Prevent delays in ventilator weaning due to prolonged paralysis. 4) Provide cost-effective therapy. Bibliography: 1. Shapiro BA, et al. Practice parameters for sustained neuromuscular blockade in the adult critically ill patient: an executive summary (SCCM guidelines). Crit Care Med 1995;23:1601-1605. 2. Davidson JE. Neuromuscular blockade: indications, peripheral nerve stimulation, and other concurrent interventions. New Horizons 1994;2:75-84. 3. Watling SM, Dasta JF. Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: a review of the literature. Crit Care med 1994;22:88493.