RSI Pharmacology New Hampshire Division of Fire Standards & Training and Emergency Medical Services

RSI Medications Protocol meds Oxygen Lidocaine Atropine Etomidate Succinylcholine Lorazepam Fentanyl Rocuronium Vecuronium

Medication Information Parameters Class Pregnancy Risk Category Preparation Action Onset Duration Drug Interactions Side Effects Reversal Agent(s)

Lidocaine Dose: 1.5 mg/kg IVP When: At least 2 minutes prior to intubation Why: May prevent a rise in ICP in TBI patients Suspicion of increased ICP Patient in respiratory distress with reactive airway disease or COPD Onset: immediate Duration: 10-20 minutes Mixed results regarding efficacy in decreasing ICP spike Standardized therapy at present – primarily for patients with suspected traumatic brain injury Also decreases the cough reflex and may decrease the incidence of post-laryngoscopy hypertension and tachycardia associated with intubation May also be give directly squirted into the posterior pharynx and trachea – may produce as much ICP spike, etc. as direct laryngoscopy Studies show ET suctioning and laryngeal manipulation cause an average ICP rise of 22 mmHg

Lidocaine Antidysrhythmic with anesthetic properties that blunt transient increases in ICP that result from laryngoscopy. Also blunts cough/gag reflex during laryngoscopy

Atropine Dose: 0.5 mg IVP When: Prior to intubation for bradycardic adults Why: Given to prevent worsening bradycardia From Succs, vagal stimulation during direct visualization, and hypoxia Atropine Onset: Immediate Duration: 4-6 hours

Etomidate Class – sedative/hypnotic used for general anesthesia induction Dose dependent Rapid onset/offset Minimal hemodynamic and respiratory effects compared to other induction agents Imidazole derivative unrelated to any other agent

Etomidate Pregnancy Risk Category – C No human studies and animal studies show adverse effect Transmission to breast milk uncertain – likely – but not a significant concern in an RSI situation Pediatrics – not approved for patients under 10 – however RSI protocol only for age 12 and above.

Etomidate Preparation – 2 mg/ml 20 and 40 mg vials (10 and 20 cc) Propylene glycol 35% Single use ampules Abboject Shelf life – 1 year Does not need refrigeration

Etomidate Action Enhances GABA, the principal inhibitory neurotransmitter Action at the GABA-A receptor complex Able to produce light sleep to deep coma Dose dependent EEG changes in anesthesia similar to barbiturates

Etomidate Indication: as an induction agent before the administration of a neuromuscular blockade agent. Contraindications: Known hypersensativity

Etomidate Onset Rapid onset of loss of consciousness Within one arm-brain circulation time Rapid distribution to CNS Then rapid clearance from the CNS and redistribution

Etomidate Dose: 0.3 mg/kg IV (maximum 40 mg) Duration of action With doses of 0.3 mg/kg Duration of hypnosis is 3-5 minutes Metabolized in liver to inactive metabolites Then metabolite excreted through urine Elimination half-life – 1.25-5 hours 75% excreted in urine within 24 hours 10% in bile and feces

Etomidate Drug Interactions Sedatives and Hypnotics – increased effect Opiates – increased effect No interaction with any neuromuscular blocker

Etomidate Side Effects Elderly patients sensitive Hypotensive patients sensitive Pain at injection site Muscle twitching 30% Myoclonic jerks Variable, Facial

Etomidate Side Effects Decreased plasma cortisol concentrations Last up to 8 hours after injections “Legal Laundry List” – hyper and hypoventilaiton apnea (5-90 seconds) laryngospasm hiccups / snoring hyper and hypotension Nausea / Vomiting after emergence

Etomidate Reversal Agents NONE

Neuromuscular Blockers HOW DO THEY WORK ???? WHAT DO THEY DO ?????

Neuromuscular Blockers Work by blocking the natural transmission of nerve impulses to skeletal muscles. No direct effect on: Heart, Digestive system, Brain, Pupillary Response, Smooth Muscle or other organ systems. No effect on level of consciousness or pain perception. No direct effect on seizure activity.

Neuromuscular Blockers Depolarizing Neuro Muscular Blockers Succinylcholine (Anectine, Quelicin) Non-Depolarizing Neuro Muscular Blockers Pancuronium (Pavulon), Vecuronium (Norcuron) Classified depending upon the effect they have on the neuromuscular endplate

Neural Transmission When a nerve impulse arrives at the synaptic knob of the presynaptic neuron calcium flows in and causes the release of neurotransmitters. The neurotransmitters diffuse across the synaptic cleft and attach to the dendrites of the postsynaptic neuron. This allows the current to flow from one neuron to the next. More than 30 neurotransmitter in the human body. Neurotransmitter acetylcholine is essential to understanding the function NMB

Motor Neuron Dendrites Neuron Cell Body Axon Telondendria

Acetylcholine Produced within neurons by combining molecules of acetylcoenzyme A and choline Rapidly broken down in the synaptic cleft into acetate and choline by the enzyme acetylcholinesterase which is found on the outer surface of the cell membranes. The broken down choline is taken up by the axon terminal and used in the synthesis of new acetylcholine

Anectine (Succinylcholine) SCh or “Succs” The only depolarizing paralytic in clinical use Benefits: Rapid onset Short duration Will cause “fasciculations” Succs attaches to the acetylcholine receptors of nerves and causes the nerves to depolarize – seen as muscle fasciculations. It remains until it is metabolized.

Succinylcholine Class Pregnancy Risk Category – C: Lactation - ?Safe Depolarizing Neuromuscular Blocker Pregnancy Risk Category – C: “Risk cannot be ruled out – Human studies are lacking and animal studies are either positive for fetal risk or lacking as well. However potential benefits may justify the potential risk.” Lactation - ?Safe Metabolism – in plasma Excretion - kidney

Succinylcholine Effect 2 phases to blocking The first block is due to the prolonged stimulation of the acetylcholine receptor results first in disorganized muscle contractions (fasciclations), as the acetylcholine receptors are stimulated. On stimulation, the acetylcholine receptors becomes a general ion channel, so there is a high flux of potassium out of the cell, and of sodium into the cell, resulting in an endplate potential less than the action potential. So, after the initial firing, the celll remains refractory. Bellise, Martha. “Chaz Higgs leaves jail”, Reno Gazette-Journal, March 27, 2007.

Succinylcholine Effect - continued The 2nd Block Phase On continued stimulation, the acetylcholine receptors become desensitized and close. This means that new acetylcholine signals do not cause an action potential; and the continued binding of sux is ignored. This is the principal paralytic effect of sux, and wears off as the sux is degraded and the acetylcholine receptors return to their normal configuration. Bellise, Martha. “Chaz Higgs leaves jail”, Reno Gazette-Journal, March 27, 2007.

Succinylcholine Dose: 1.5mg/kg IV (maximum 150 mg) When: Immediately after Etomidate Onset: rapid, usually 30-90 secs Duration: short acting, 3-5 mins

Succinylcholine Action Binds to nicotinic “M” receptors usually acted upon by Acetylcholine Initial Depolarization of muscle membrane Block further binding

Succinylcholine Drug interactions Potentiation of effects Oxytocin, Beta Blockers, Organophosphate insecticides Reduced duration of action Diazepam Other effects Cardiac Glycosides – dysrhythmias

Succinylcholine Indication: Immediate severe airway compromise in the context of trauma, drug overdose, status epilepticus, etc. where respiratory arrest is imminent.

Contraindications Severe burns > 24 hours old Massive crush injuries >8 hours old Spinal cord injury >3 days old Penetrating eye injuries Narrow angle glaucoma Hx of malignant hyperthermia patient or family Pseudocholinesterase deficiency Neuromuscular disease Hyperkalemia May precipitate fatal hyperkalemia! K+ may rise up to 1mEq (Typical rise: 0.5-1.0) {study: 46% increased, 46% decreased, 8% no change} Increased risk in chronic disease states & acute injury SEVERAL DAYS after the insult (perists for several weeks) Generally safe to administer within 24 hours of injury High incidence of undiagnosed muscular dystrophy in peds makes Succs use “relatively contraindicated” in “elective” peds RSI (esp. males <8)

Succinylcholine Adverse Effects: Fasciculations Hyperkalemia Bradycardia Prolonged Neuromuscular Blockade Malignant Hyperthermia

Succinylcholine – Adverse Effects Fasciculations: Associated with increased ICP, IOP, IGP ICP only clinically important Cause and Effect – unknown If needed pre-treat with Lidocaine, and a defasciculating dose of a non-depolarizing neuromuscular blocker – Rocuronium 0.06 mg/kg

Succinylcholine – Adverse Effects Hyperkalemia Normal rise in serum K+ is up to 0.5 meq/L Pathological rise may occur in Rhabdomyolysis Receptor upregulation May be life-threatening 4-5 days post injury most critical Any ongoing neuro/muscular process is at risk

Succinylcholine Adverse Effects - Hyperkalemia Receptor upregulation in Burns – especially 5 days post burn Denervation or neuromuscular disorders Crush injuries Intra-abdominal infections Myopathies Renal failure – controversial Use a non-depolarizer instead (Roc)

Succinylcholine Adverse Effects – Malignant Hyperthermia (MH) Very rare condition – 1:15,000 Patient experiences a rapid increase of temperature, metabolic acidosis, rhabdomyolysis, and DIC Treatment includes administration of Dantrolene and external means of temp. reduction Malignant hyperthermia is a rare complication with an autosomal dominant inheritance pattern. It occurs in approximately 1 in 15,000 children and 1 in 50,000 adults. The clinical syndrome consists of high fever, tachypnea, tachycardia, cardiac arrhythmias, hypoxia, acidosis, myoglobinuria, and impaired coagulation. Unabated muscle contractions mediated by abnormal calcium channels are believed to be the physiologic basis for this condition. Treatment includes aggressive cooling measures, volume replacement, and correction of hypoxia and acid-base and electrolyte abnormalities. Dantrolene sodium, a direct-acting skeletal muscle relaxant, has been shown to be effective in reducing the muscle hypermetabolism that causes the fever.

Succinylcholine Adverse Effects - MH Absolute contraindication Acute loss of intracellular calcium control Results in: Muscular rigidity (masseter) Autonomic instability Hypoxia Hypotension Hyperkalemia Myoglobinemeia DIC Elevated temperature a late finding

MH - Treatment If the diagnosis of MH is seriously being considered – Contact medical control immediately and divert to the CLOSEST facility Once in the hospital Dantrolen 2.5 mg/kg IV q 5 minutes until muscle relaxation or maximum dose of 10mg/kg. www.mhaus.org http://medical.mhaus.org/NonFB/Slideshow_eng/SlideShow_ENG_files/frame.htm

Succinylcholine Dose: 1.5 mg/kg IV (maximum 150 mg), following Emotidate Administration of a neuromuscular blocker does not alter mentation or the ability to feel pain

Succinylcholine Onset < 1 Minute Slightly slower in hypotension

Succinylcholine Duration 5-10 minutes Beware acetylcholinesterase deficiency Rare Prolonged action

Succinylcholine Reversal Agent Neostigmine 0.5-2 mg IV This is given if the patient does not loose their paralysis. This would not be given pre-hospital. +/- atropine 05.-1 mg IV to prevent side effects such as bradycardia

Succinylcholine Special Considerations Consider atropine in bradycardic adults Pre-medicate with Lidocaine because fasciculations can lead to increased ICP LETHAL in the wrong hands Constant attendance Have BVM ready to go before administering drug Has no effect on consciousness

Midazolam & Lorazepam Benzodiazepines Provide sedation, amnesia, and anticonvulsant properties No analgesia Midazolam: Faster onset, shorter duration than lorazepam Lorazepam: may be the preferred agent due to its longer action duration Midazolam: 2x as potent as diazepam *Induction dose: benzo of choice. In the well-premedicated, healthy patient, 0.2 mg/kg over 5-15 seconds – induction occurs in 28 seconds The stresses of intubation are not blocked by midazolam – so adjuvant anesthetics, usually opioids, are often combined with benzos (but combo of versed + fentanyl or sufentanyl produces greater decreases in systemic BP than each drug alone) (there is evidence that midazolam and diazepam decrease catecholamine – use with caution in certain pt populations who are surviving on catecholamines…) Decrease in SVR results in a slight decrease in arterial BP (12-26% reduction in MAP) More than the other benzos “despite the hypotension, midazolam, even in doses as high as 0.2 mg/kg, is safe and effective for induction of anesthesia…” – Miller, anesthesia book In pts with elevated left ventricular filling pressures, midazolam produces a “NTG-like” effect by lowering the filling pressure and increasing CO. Study: 0.1 mg/kg v. 0.1 mg/kg with a max of 5mg for RSI. 219 patients. Results: statistically significant relationship between versed use and hypotension and SBP decrease following RSI Sign/symptoms: Movement, Increase in heart rate Pay close attention to the patient’s level of consciousness. Signs/symptoms of discomfort may include movement, increase heart rate, increased blood pressure.

Midazolam (Versed) Dose: 0.05-0.1 mg/kg IVP Rapid onset – 1-2 minutes Single dose duration: 15-20 minutes In the prehospital setting, hypotension with midazolam was found to be dose related and thus should be used cautiously in patients with hypovolemia or traumatic brain injury, or both.

Midazolam Duration: 1-4 hours Hepatic clearance Decreased dose needed (longer half life) Obese Geriatric CHF Hepatic or renal insufficiency Midazolam HCl should only be administered IV or IM. Also available as versed syrup for PO use Don’t use in pregnancy – increased congenital malformations

Lorazepam Class – Benzodiazepine II Pregnancy Risk Category – D (Intermediate Acting) Pregnancy Risk Category – D (Positive evidence of human fetal risk. Maternal benefit may outweigh fetal risk in serious or life-threatening situations) Metabolism – liver Excretion - urine

Lorazepam (Ativan) Dose: 1-2 mg IV every 15 minutes as needed for sedation (maximum 10 mg) Onset: 5 minutes Duration: 6-8 hours, dose dependant Don’t use in pregnancy – increased congenital malformations

Lorazepam Enhances GABA – the primary neuro-inhibitor Amnesia, anxiolysis, central muscle relaxation, anticonvulsant effects, hypnosis Doesn’t release histamine Allergic reactions rare

Lorazepam - Metabolism Similar for all BNZ Lipid soluble – brain penetration Rapid onset – 60-120 sec t ½  - 3-10 min t ½  - 10-20 hours – 5 active metabolites

Vecuronium & Rocuronium Non-Depolarizing Paralytics Provide paralysis, but NO sedation, amnesia, or analgesia properties

Vecuronium (Norcuron) Considered safe without many contraindications May be used in most patients including cardiovascular, pulmonary, and neurological emergencies Must be reconstituted from powdered form Vial: 10 mg/10 ml Structural analog to pavulon – but not vagolytic

Vecuronium (Norcuron) Dose: 0.1mg/kg IVP Repeat/maintenance dose: 0.01 mg/kg Onset: 2-3 minutes Duration: approx. 20-30 minutes Repeat dose not part of NH EMS protocol Vec may be given with on-line medical consultation for continued paralysis

Vecuronium (Norcuron) Metabolized by the liver and kidneys Use with caution in patients with liver failure May have 2x the recovery time Patients with renal or hepatic failure will need less medication to maintain paralysis Does not cause hypotension or tachycardia Associated with prolonged blockade after med is DC’d – All steroid-based NMBAs have been associated with prolonged recovery time and myopathy – undergo extensive hepatic metabolism, producing active drug metabolites Vec produces 3 active metabolites – one as 80% as strong as Vec. Accumulates in pts with renal failure (hepatic elimination is decreased in pts with uremia) So, lessening in popularity in the ICU

Rocuronium (Zemuron) Very similar properties to Vecuronium Does not need to be mixed, can be stored at room temp for 60 days Less vagolytic properties

Rocuronium (Zemuron) Competitive blockade of ACH Reversed by ACHesterase inhibitors Degradation, liver metabolism and bile/kidney excretion Reversed by neostigmine

Rocuronium (Zemuron) No known contraindications Pregnancy class B (Animal Studies show no risk or adverse fetal effects but controlled human 1st trimester studies not available/ do not confirm. No evidence of 2nd or 3rd trimester risk. Fetal harm possible but unlikely) Lactation ?Safe “Back-up” paralytic agent.

Rocuronium (Zemuron) Onset: 30-60 seconds Dose: 1 mg/kg IVP Fastest onset of all non-depolarizing NMBs Dose related Dose: 1 mg/kg IVP Duration: 20-75 minutes Repeat/maintenance dose is the same as the initial dose Vial: 10mg/ml vials of 50 mg (or 10mg/ml vials of 100 mg) Repeat dose not part of NH EMS protocol Roc may be given with on-line medical consultation for continued paralysis *Raising the dose of Roc from 0.6 to 0.9 mg/kg nearly halves the time for suitable intubating conditions, but it also increases the duration. Nevertheless, most studies concur Roc 0.9 mg/kg or higher should be used for “crash” RSI conditions.

Prolonged Seizure Activity Neuromuscular Blockers cease motor activity but DO NOT stop seizure Anticonvulsant (diazepam) administration should precede neuromuscular blockers

Pregnant Patients and Neuromuscular Blockers Pregnancy = weight gain Larger breast may increase resistance during BVM Toxemia may cause edemotous airway Desaturate more rapidly due to reduced functional residual capacity and increased oxygen consumption Regurgitation more likely Decreased cardiac output Supine Hypotensive Syndrome Review complications to be anticipated with pregant patients.

Summary