Pharmacologic Management of Rapid Sequence Intubation (RSI) James Gibson, PharmD PGY1 Pharmacy Practice Resident

Learning Objectives List the six P’s of RSI. Discuss historical rationale for “LOADing” patients undergoing RSI. Understand the rationale for use of one induction agent over another. Identify the contraindications to succinylcholine administration and how to manage patients who are not candidates.

Rapid Sequence Intubation (RSI) Induction of a patient using simultaneous Sedatives Rapid-acting paralytic agent Goal: to avoid assisted ventilation due to elevated risk of aspiration Un-fasted patient Pharyngeal/laryngeal manipulation

The Six P’s of RSI Preparation Pre-oxygenation Pretreatment and induction Paralysis Placement of the tube Post-intubation management

Preparation Assess patient—difficult airway? IV access Monitor (tele, pulse ox) Gather: Equipment for intubation Post-intubation medication(s) Pertinent patient history Supplies for surgical airway (just in case!!) Difficult airway: trauma, cervical collar, can you visualize the oral pharynx or just hard palate?; obstruction/obesity, neck mobility

Pre-Oxygenation Goals: Methods: Establish O2 reservoir Maximize time for intubation Prevent need for bag-mask ventilation Methods: 3-5 minutes of 100% O2 via face mask 4 (or 8) vital capacity breaths on 100% O2 100% O2 for 3 minutes = acceptable O2 sats for ~8 min 4 vital capacity breaths = acceptable O2 sats for ~6 min

Pre-Oxygenation Pre-oxygenation is complicated by comorbidities, body habitus (pregnancy), agitation or patient cooperation, and availability of equipment to deliver 100% oxygen. http://www.ncsrc.org/2_newsletters_2008_2.shtml

Pretreatment Goal: Mitigate adverse physiologic reactions to intubation Sympathetic “pressor response” Bronchospasm Increased intracranial pressure (ICP) Muscle fasciculation Begins 2-3 minutes PRIOR to induction/paralysis “LOAD” Not routinely done in practice Pressor response—manipulation of airway increase BP and HR small effect from succinylcholine administration

Pretreatment Lidocaine Opioid Atropine Defasciculating agent Dose: 1.5 mg/kg IV To prevent rise in ICP by Preventing cough Blunting pressor response May reduce reactive bronchospasm in asthma Lidocaine lowers ICP by: preventing coughing, and Blunts pressor response—though less effective than fentanyl However, paralyzed patients cannot cough, so benefit is likely insignificant Lidocaine may be added to albuterol to prevent bronchospasm in asthmatics—the added benefit of lidocaine is uncertain

Pretreatment Lidocaine Opioid Atropine Defasciculating agent Fentanyl 3 mcg/kg IV Provides analgesia Lessens pressor response Limits ICP increase More effective than lidocaine

Pretreatment Lidocaine Opioid Atropine Defasciculating agent Dose: 0.02 mg/kg To prevent bradycardia caused by airway manipulation and succinylcholine Historically used in pediatrics May be more beneficial with repeated doses of succinylcholine (i.e. OR setting) Laryngoscopy and intubation thought to cause vaso-vagal reflexbradycardia Review found that bradycardia in RSI is usually clinically insignificant (i.e. with single doses of succinylcholine) Benefit was mostly described in case series involving the OR setting where multiple doses of succs were given Atropine may predispose to arrhythmias (i.e. not benign drug)

Pretreatment Lidocaine Opioid Atropine Defasciculating agent Fasciculations occur in >90% of patients given succinylcholine Muscle pain Increase intragastric pressure  emesis Increase ICP (?) Prevention Higher doses of succs (1.5 mg/kg vs 1 mg/kg) Non-depolarizing NMB (1/10th of paralytic dose)

Induction Agent(s) Given as rapid IV push immediately before paralyzing agent Ideally provides: Rapid loss of consciousness Analgesia Amnesia Stable hemodynamics Induction agents also provide relaxation, which is additive to that of NMBA’s

Induction Agents Drug Dose Thiopental 3-5 mg/kg IV Methohexital Fentanyl 5-15 mcg/kg IV Midazolam 0.1 mg/kg IV Ketamine 1-2 mg/kg IV Etomidate 0.3 mg/kg IV Propofol 2 mg/kg IV

Induction Agents Etomidate Ultrashort-acting non-barbiturate hypnotic Rapid onset—30 to 60 secs Hemodynamic stability Hydrolyzed in liver and plasma  ICP with minimal effects on cerebral perfusion NO analgesia ADE: Myoclonic jerks,  cortisol production Myoclonic jerks can be confused with seizure activity, but just disinhibition of subcoritcal activity. Prevented by NMB, thus rarely seen in RSI. No treatment needed; can use benzo if persistent. Infusions of etomidate have been associated with adrenal suppression and strongly linked to increased mortality in critically ill patients. Suppression after single dose has been inconsistently demonstrated, and significance of mild cortisol suppression in septic shock is uncertain.

Induction Agents Fentanyl Short-acting, potent Minimal histamine release Hemodynamically stable Sedation is rate- AND dose-dependent Combined with other induction agents for analgesia ADE: muscle rigidity, grand mal seizures (rare) No histamine release = no hypotension or emesis Chest wall rigidity  difficult bag ventilation. But NMBA obviates clinical significance of this.

Induction Agents Midazolam Sedative, amnestic, muscle relaxant NOT analgesic Less cardiorespiratory depression vs. other benzos BP; HR Use lower dose in hypovolemic, elderly, or traumatic brain injury patients (0.05 mg/kg) Does NOT contain propylene glycol Propylene glycol toxicity  acute renal failure, lactic acidosis, osmol gap Solubilizing agent in lorazepam IV

Induction Agents Ketamine NMDA-antagonist  dissociative anesthesia Analgesic, amnestic, anesthetic Dissociation occurs at threshold of 1-1.5 mg/kg IV 4-5 mg/kg IM (more emesis) Catecholamine reuptake inhibition ( HR, BP, CO, ICP) Maintains respiration and airway reflexes ADE: Emergence delirium (30%)—Premed: midazolam 0.07 mg/kg Emesis (highest in adolescents ~9yo) CI: schizophrenia (schizoaffective); <3 months (relative): Asthma exacerbation; CVD Produces a cataleptic-like state; dissociated from the surrounding environment by direct action on the thalamocortical and limbic systems. Noncompetitive NMDA receptor antagonist that blocks glutamate. Eyes often remain open, and patient may make spontaneous, non-purposeful movements CV effects may make it useful in patients w/ hemorrhagic shock ~1/3 of patient have emergence reaction. Less common in children + midaz does not seem to decrease incidence in children. Annals of Emergency Medicine. 57.5 (2011): 449-461

Neuromuscular Blocking Agents (NMBAs) Quaternary ammonium compounds that mimic structure of ACh Depolarizing vs non-depolarizing Allow complete airway control Higher success (100% vs 82%) Less aspiration and airway trauma Enable lower doses of sedative Better hemodynamic stability Acetylcholine Succinylcholine Roberts: Clinical Procedures in Emergency Medicine. 5th. Philadelphia, PA: Elsevier, 2010. 99-109

Succinylcholine Depolarizing NMBA Paralysis in ~60 sec. DOA: 3-5 min Non-competitively binds ACh receptors  initial membrane depolarization Longer degradation time than ACh Paralysis in ~60 sec. DOA: 3-5 min Prolonged in pseudocholinesterase deficiency (genetic, hepatic/renal failure, pregnancy, cocaine) Repeat doses prolong paralysis May increase bradycardia/hypotension DOC for RSI Duration varies by resource—some state up to 6-10 minutes. Pseudocholinesterase deficiency may prolong to 23 minutes in severe cases

Succinylcholine Dose: 1.5 mg/kg IV (infants: 2 mg/kg IV) ADEs: Use ACTUAL body weight Rapid bolus; follow w/ 20-30 mL saline flush ADEs: Muscle fasciculation  myalgias Hyperkalemia,  CPK Bradycardia/hypotension Mild increase in ICP Malignant hyperthermia Malignant hyperthermia: rare, hereditary complication—autosomal dominant Fever, tacypnea, tachycardia, arrhythmias, acidosis, muscle rigidity, impaired coagulation Treat with cooling, volume repletion, and Dantrolene sodium (1-2 mg/kg IV)

Succinylcholine Hyperkalemia Typical K+ increase < 0.5 mEq/L Up to a 5 mEq/L K+ increase in certain settings: Contraindicated in: Conditions with up-regulation of ACh-receptors (see table) Known/suspected hyperkalemia Personal/family hx of malignant hyperthermia Hyperkalemia is NOT prevented by defasciculating doses of non-depolarizing NMBAs Clinically, safer to consider period of concern >72 hours (or 3 days) Myasthenia Gravis is NOT a contraindication—actually require higher doses of succinylcholine (2 mg/kg)

Non-Depolarizing NMBAs Competitive antagonists of ACh at neuromuscular junctions Higher doses = faster onset, longer duration Reversible Alternatives to succinylcholine Long-acting vs intermediate-acting Agent Dose (mg/kg) Onset (min) Duration (min) Succinylcholine 1.5 1 3-5 Rocuronium 1-1.5 30-110 Vecuronium 0.1 0.25 3 30-35 60-120 Pancuronium 2-5 (60-100) Neostigmine: 0.02-0.08 mg/kg IV; Max of 5 mg in adults (depending on reference) Will reverse NMBA’s action only after ~40% of effects have worn off (UpToDate) Give with atropine to block systemic cholinergic response (0.5-1mg) Sugammadex is an investigational agent for reversal of non-depolarizing agents Roberts: Clinical Procedures in Emergency Medicine. 5th. Philadelphia, PA: Elsevier, 2010. 99-109

Non-Depolarizing NMBAs Pancuronium Long time to onset  HR and BP (vagolytic effect) Histamine release  bronchospasm/anaphylaxis Active metabolites Accumulates Renal dosing required NOT recommended for RSI Binds muscarinic receptors in SA node and prevents uptake Renally cleared, so accumulates with renal insufficiency CrCl 10-50: 50% of dose CrCl <10: do not administer

Non-Depolarizing NMBAs Vecuronium Slower onset than rocuronium Non-vagolytic; no histamine release Active metabolites Often requires “priming” dose 0.01 mg/kg during pre-oxygenation phase, then 1.5 mg/kg given 3 min later for paralysis

Non-Depolarizing NMBAs Rocuronium Onset similar to succinylcholine Non-vagolytic; no histamine release No active metabolites Preferred alternative to succinylcholine in RSI

Post-intubation Care After endotracheal tube is placed: Provide continued sedation/analgesia Propofol drip (No analgesia) ≤ 120 kg begin infusion at 20 mcg/kg/min 121-150 kg begin infusion at 15 mcg/kg/min >151 kg begin infusion at 10 mcg/kg/min Bolus fentanyl and midazolam Fentanyl (analgesia): LD: 25-100 mcg IV q15 min PRN (max 300 mcg in first hr) MD: 25-100 mcg IV q30 min PRN (max 200 mcg/hr) Midazolam (sedation): LD: 1-4 mg IV q15 min PRN (max 16 mg in first hr) MD: 1-4 mg IV q1 hr PRN UWMC Form U2914

References Claudius, C, LH Garvey, J Viby-Mogensen, et al. "The Undesirable Effects of Neuromuscular Blocking Drugs." Anaesthesia. 64.1 (2009): 10-21. Print. Fleming, Bethany, Maureen McCollough, et al. "Myth: Atropine should be administered before succinylcholine for neonatal and pediatric intubation.." Can J Emerg Med. 7.2 (2005): 114-117. Print. Green, Steven, Mark Roback, et al. "Clinical Practice Guidelines for Emergency Department Ketamine Dissociative Sedation: 2011 Update." Annals of Emergency Medicine. 57.5 (2011): 449-461. Print. Hopson, Laura, and Richard Schwartz. Roberts: Clinical Procedures in Emergency Medicine. 5th. Philadelphia, PA: Elsevier, 2010. 99-109. Print. Martyn, Jeevendra, and Martina Richtsfeld. "Succinylcholine-induced Hyperkalemia in Acquired Pathologic States." Anesthesiology. 104. (2006): 158-69. Web. 8 Mar. 2012. Walls, Ron. Marx: Rosen's Emergency Medicine. 7th ed. Philadelphia, PA: Elsevier, 2010. 3-22. Print.