Introductory Chapter: Pharmacology of Airway Management in Emergency Medicine

1. Introduction

Definite airway management in the majority of emergency cases means tracheal intubation. Yet, both laryngoscopy and intubation can provoke a series of physiological reflex responses due to posterior pharynx’s afferent receptors (innervated by IX and X cerebral nerve). Central nervous system (CNS), cardiovascular system, and respiratory system responses to these stimuli vary in intensity; thus, it may potentially negatively affect patients’ outcome.

Anesthesia is used to attenuate those responds and ease the procedure. A combination of different drugs and dosage regimens is used. Knowledge of efficacy, toxicity, therapeutic ratio, and special consideration of those drugs is essential in order to achieve optimal conditions in any given case [1].

2. Hypnosis

2.1 General considerations

An ideal induction anesthetic induction agent should be acting rapidly, yet smoothly without or with minimal respiratory and cardiovascular depression, and act protectively for brain circulation. Recovery should be rapid, with minimal or zero adverse effects and absence of any pain on injection.

Despite the tremendous progress in pharmacology development, we are still far from such a drug. Thus, the advantages and the limitation of the available drugs, in combination with the status of the patient, will determine the final choice [2].

2.1.1 Etomidate

Since its introduction in clinical practice in 1970, etomidate remains a valuable choice for emergency airway management due to its fast onset of action and minimal cardiovascular effects. It is mainly used in cases of hemodynamically fragile patients. Its main drawbacks are nausea and prolonged suppression of adrenocortical steroid synthesis. Like propofol, etomidate interacts with GABA A receptors in a stereoselective way. Of all intravenous anesthetics used clinically, etomidate shows the greatest selectivity for GABA A receptors and has the fewest number of ionic interactions.

After intravenous injection, etomidate is tightly bound to plasma proteins such as albumin; plasmatic levels of cortisol, cortisone, and aldosterone are reduced, while those of 11-deoxycorticosterone, 11-deoxycortisol, and 17-hydroxyprogesterone are increased. Free drug is highly lipophilic, rapidly penetrating the blood-brain barrier; peak brain levels are reached 2 minutes after injection. Etomidate undergoes a hepatic metabolism (ester hydrolysis) to an inactive metabolite.

Etomidate central nervous system’s effects are alike to those of propofol and barbiturates. During unconsciousness transmission (induction), loss of cortical inhibition may provoke myoclonus (that can be confused with generalized tonic-clonic seizures). Etomidate has anticonvulsant activity in several experimental models, yet smaller than propofol and thiopental. Despite its favorable hemodynamic profile, it should be noted that patients with elevated sympathetic tone, such as those suffering from shock, intoxication, or drug withdrawal, may experience an abrupt drop in blood pressure, even when the drug is used only to induce anesthesia [3, 4].

2.1.2 Thiopental

Thiopental is a thiobarbiturate that facilitates the GABA (an inhibitory neurotransmitter) transmission, thus causing reticular activating system depression. It is supplied as a sodium salt that requires preparation to solution before use. It is noncompatible with acidic solution (e.g., pancuronium or rocuronium—it will precipitate), and accidentally intra-arterial injection can cause less water solubility (forming crystals in the arterioles) leading to tissue necrosis.

Induction dose depends to volemic status (3 to 5 mg/kg in healthy euvolemic adults, 1 to 3 mg/kg in cases of hypovolemia). Onset is fast (30 seconds), and the duration of effect is 5 to 10 minutes. It is an ideal choice for patients with increased intracranial pressure (ICP), since it results a dose-dependent decrease in cerebral metabolic rate and cerebral blood flow. However, it has no analgesic effects, can induce bronchospasm (histamine release), has negative intropic effects, and may precipitate hypotention and venodilatation, thus making it a poor choice in sepsis. It has been shown to suppress white blood cell recruitment, activation, and activity in vitro and in vivo, but there are no reports of increased mortality in septic patients receiving a thiopental induction [5, 6].

2.1.3 Ketamine

Clinical effects observed after ketamine administration include elevations in blood pressure and muscle tone, eye opening (often accompanied by nystagmus), increased myocardial oxygen consumption, and minimal respiratory depression. Ketamine has no effect on laryngeal or pharyngeal reflexes, so the airways of the patient remain intact. It is also a potent bronchodilator and can be used to treat refractory bronchospasm.

The commercially available preparation is a racemic mixture. The S+ isomer has more potent anesthetic and analgesic properties, which reflects a fourfold higher affinity for N-methyl-D-aspartate (NMDA) receptor binding sites. Hepatic biotransformation of the S+ isomer is faster, contributing to a faster return of cognitive function.

Ketamine produces dose-dependent depression in the CNS, leading to the situation known as the “dissociative anesthetic state,” which is characterized by inhibition of the thalamocortical system (deep analgesia and amnesia) and activation of the limbic system (delusional dreams).

Its use is recommended for induction of anesthesia in patients with asthma because of its ability to produce bronchodilation.

The renewed interest in ketamine is related to the use of lower doses (100–200 μg/kg) as an adjunct to anesthesia. Subanesthetic doses (0.1–0.5 mg/kg IV) produce analgesic effects. Ketamine’s anesthetic (sedative) and opioid analgesic-sparing effects reduce ventilatory depression. Unlike barbiturates, which act on the reticular activating system in the brainstem, ketamine acts on receptors in the cortex and limbic system. The activity on NMDA receptors may be responsible for the analgesic action as well as the psychiatric effects (psychosis). Ketamine also has sympathomimetic activity, which results in tachycardia, hypertension, increased myocardial and cerebral oxygen consumption, cerebral blood flow, and intracranial and intraocular pressure.

Ketamine has a distribution phase about 45 minutes (highly perfused tissues>muscle>peripheral tissue>fat) and easily crosses the placenta. Ketamine’s half-life is about 2 hours to 3 hours and has a primarily renal metabolism—kidneys (90%) and feces (5%), with 4% of an administered dose excreted unchanged in the urine.

When ketamine is administered intravenously, a sensation of dissociation is seen within 15 seconds, and anesthesia occurs within 30 seconds. Anesthesia lasts from 5 minutes to 10 minutes for intravenous administration. Ketamine’s analgesic effects last from 20 minutes to 45 minutes. Anesthetic effects are eliminated by a combination of redistribution and hepatic biotransformation to a metabolite with only 30% of its activity.

Usage for anesthesia is 1 to 4.5 mg/kg of ketamine infused over approximately 60 seconds. On average, 2 mg/kg will produce 5 minutes to 10 minutes of surgical anesthesia. If a longer effect is desired, additional increments can be administered to maintain anesthesia without producing significant cumulative effects [7].

2.1.4 Propofol

Propofol (1,3-diisopropylphenol) is a non-barbiturate intravenous anesthetic that is chemically unrelated to other intravenous anesthetics. It is used to induce and maintain anesthesia and can be infused continuously until the end of the procedure. When administered into small-caliber peripheral veins, it causes pain in most patients.

Anesthesia with propofol has a rapid induction, similar to thiopental, but emergence from anesthesia is 10 times faster and is associated with minimal confusion postoperative. Only desflurane has a faster recovery time than propofol, but it is associated with nausea/vomiting.

The initial distribution half-life is 2 minutes to 4 minutes, and the elimination half-life is 1 hour to 3 hours. For a tricompartmental model, the initial distribution half-life is from 1 minute to 8 minutes and the slow distribution half-life is from 30 minutes to 70 minutes. The elimination half-life is dependent on the drug infusion time and ranges from 2 hours to 24 hours. Despite this long elimination half-life, the context-sensitive half-life of propofol is 40 minutes for infusions longer than 8 hours. Propofol is metabolized by the liver, forming inactive compounds, and is eliminated by the kidneys. Because it has a clearance greater than hepatic blood flow, it is believed to have other sites of metabolism in addition to the liver, possibly the lungs. The induction dose in adults is 1.5 to 2.5 mg/kg, and the plasma levels to reach unconsciousness are 2 to 6 μg/ml. The dose is higher in children and lower in the elderly and in patients with comorbidities. It will also be reduced with the administration of adjuvant drugs and/or opioids. The infusion rate for the maintenance of hypnosis ranges from 100 to 200 μg and for sedation from 25 to 75 μg/kg/min, at plasma concentrations of 1 to 1.5 μg/ml, usually when the plasma concentration drops by 50% of the initial one [8].

3. Analgesia

3.1 Opioids

Although it is not recommended as part of the classic rapid sequence induction technique, use of opioids will attenuate the cardiovascular responses to laryngoscopy and intubation. This may be particularly valuable if intracranial pressure is raised or the patient has a history of coronary artery disease. Usually, opioid administration decreases the dose of an induction agent.

In case of apnea due to respiratory depression and a “cannot intubate” situation, reversal with naloxone may be required.

Fentanyl is a potent (100 times more potent than morphine) synthetic opioid with a relatively fast onset (2–5 min), short duration of action (30–60 min after a single dose), and minimal cardiovascular effects (still, a chance of bradycardia exists). A usual dose of 2–3 μg/kg IV will usually reduce the rise in blood and intracranial pressure, triggered by laryngoscopy and intubation. Alfentanil (usual dose 10–20 μg/kg iv) reaches its peak action after just 90 seconds (duration: 5–10 minutes), which make it a good alternative to fentanyl. Finally, remifentanil is even more potent opioid that can be used either as alternative to fentanyl (doses 0.5–1 μg/kg) or even as alternative to rapid-onset paralytic agents (succinylcholine or rocuronium) in higher doses (3–4 μg/kg) for rapid sequence intubation. Morphine, on the other hand, may be used in addition to, or instead of midazolam, ketamine or etomidate in cases of ventilatory difficulty secondary to combativeness in already intubated patients; yet it is not considered a useful agent for emergency airway management.

4. Neuromuscular blocking drugs (NMBs)

4.1 Suxamethonium (or succinylcholine)

Suxamethonium (1.5–2 mg/kg) is the only depolarizing agent in use, with fast onset (starting at 15 seconds and complete block in 45–60 sec, short duration (4–6 minutes), and high potency. It still—after more than 50 years since its introduction into clinical practice—remains the drug of choice for neuromuscular blockade during rapid sequence intubation (RSI), though rocuronium is gaining more and more popularity. It is metabolized by plasma pseudocholinesterase (T_1/2—47 sec) to succinylmonocholine and choline. Its main drawbacks are the side effects it may provoke:

• Hyperkalemia that increase by up to 0.5 mmol/l even in normal subjects. This increase in potassium concentration may be greatly in patients with certain pathological conditions, particularly demyelinating conditions, desquamating skin conditions, major trauma, burns, and several other pathologies (muscle myopathies) where loss of muscle excitation secondary to denervation, immobilization, or inflammation leads to up-regulation of immature acetylcholine (Ach) receptors throughout the whole muscle membrane.

• Bradycardia, which is especially if large or repeated doses are given, children are most at risk. Thus, atropine should be ready for administration. Children do not need to be pretreated with atropine routinely but draw up the correct dose (0.02 mg kg⁻¹) and be ready to give it whenever a child is anesthetized.

• Muscle fasciculation that can increase intracranial, intraocular, and intragastric pressure. The effect could be attenuated when proper dose of induction drug is given concurrently.

• Muscle pain that likely to occur 12–24 hours after giving suxamethonium to fit young patients and those who mobilize quickly after anesthesia.

• Histamine release that may cause significant hypotension in some patients

• Prolonged neuromuscular block, which is in patients with low or abnormal pseudocholinesterase activity or in cases with repeated doses of suxamethonium, paralysis may be prolonged. The action of suxamethonium may also be prolonged in the presence of organophosphate poisoning or cocaine use, when neuromuscular blockade may last from 20 to 30 minutes.

4.2 Non-depolarizing muscle relaxants (ndΝΜΒ)

ndNMB agents have several properties that may affect airway function (Table 1) There are two major categories: steroidal (rocuronium, vecuronium and pancuronium) and benzylisoquinolinium (cisatracurium, atracurium, and mivacurium). Though there are a lot of available ndNMB, the vast majority of them is used only for cases with no airway emergency. Of note also is the fact that these agents pose various effects, with the diaphragm and the adductor muscles of the larynx being more resistant to paralysis than some of the muscles affecting upper airway patency. The most common side effect is histamine release, which clinically includes hemodynamic instability (tachycardia and hypotension), bronchospasm, and urticaria. Several drug interactions should also be in mind when using ndNMB: drug-like antibiotics (aminoglycosides, clindamycin, and tetracycline), antiarrhythmics (quinidine and calcium channel blockers), dantrolene, ketamine, local and inhaled anesthetics, and magnesium sulfate augment their action, while anticonvulsants (phenytoin, valproic acid, and carbamazepine), cholinesterase inhibitors (neostigmine and pyridostigmine) inhibit their potency.

Muscle relaxants	Type	Typical induction dose (mg/kg)	Time to onset (minutes)	Duration to 25% recovery
Succinylcholine	Depolarizer	1–1.5	1–1.5	6–8
Rocuronium	Nondepolarizer	0.9–12	1–1.5	30–40
Vecuronium	Nondepolarizer	0.08–12	3–4	35–45
Cisatracurium	Nondepolarizer	0.1–0.15	5–7	30–45
Pancuronium	Nondepolarizer	0.08–0.12	2–4	60–120

Table 1.

Commonly used non-depolarizing neuromuscular blockers [1].

^a Typical times to onset and recovery, and induction doses of common muscle relaxants are compared. Recovery time is defined as the time to regain 25% of baseline movement elicited by electrical stimulation.

Contraindications include cerebral palsy, burn injuries, hemiplegia, peripheral nerve injury, and severe chronic infections of botulism or tetani that induce resistance and conditions like advanced life support (ALS), autoimmune disorders, Guillain-Barre, Duchenne type muscular dystrophy, or myasthenia gravis which trigger hypersensitivity.

The only nNMB that is gaining interest and popularity for airway emergencies is rocuronium and 1.0–1.2 mg kg⁻¹ of rocuronium can be used for modified rapid sequence induction, and will enable intubation after 60 seconds, with duration of 45–60 min. Its use was further boosted with the introduction of suggamadex (see below). Yet, even then RSI is best performed by senior staff, and with an acceptance that timely progression to surgical airway may be required.

4.3 Sugammadex

Sugammadex is a steroidal nNMB binder, a cyclodextrin that works by binding NMB molecules in a 1:1 ratio and has designed to reverse steroidal ndNMBs, while the neostigmine/glycopyrrolate combination is still in use for the reversal of benzylisoquinolinium ndNMB. The complex formed is excreted by kidneys.

Usual dosing in 4–8 mg/kg (causing reversal in about 3 min) yet immediate reversal of rocuronium after RSI requires a large dose of sugammadex (i.e., 16 mg/kg). In the obese patient, the dose should be based on actual body weight. If decision of reintubation is made then a 30-min waiting time after sugammadex reversal appeared to be the cutoff to decrease the onset time to less than 2 min if an RSI dose of 1.2 mg/kg for rocuronium is used. Otherwise, benzylisoquinolinium ndNMB or succinylcholine should be used.

Sugammadex is costly, and its side effects include hypersensitivity, effects on hemostasis (with an increased risk of bleeding in some patient groups), and bradycardia. Furthermore, the use of sugammadex for immediate reversal of rocuronium in children and adolescents has not been investigated.

5. Others

5.1 Esmolol

Esmolol is a short-acting cardioselective beta-1 receptor antagonist effective in reducing the adrenergic response to various perioperative stimuli, including laryngoscopy for tracheal intubation and tracheal extubation. Several studies have demonstrated the beneficial effects of esmolol on analgesia, but the mechanism has not yet been fully elucidated. One hypothesis is that under physiological conditions, nociceptors are not activated by sympathetic stimulation. With inflammation after surgery, catecholamines sensitize nociceptors and modulate neurogenic inflammatory responses, important in primary and secondary hyperalgesia. Beta-adrenergic antagonists are possible blockers of the excitatory effects of noradrenaline [9]. Beta-adrenergic antagonists can also modulate central adrenergic activity and calcium and potassium channels in the central nervous system, generating some types of central analgesia [10, 11, 12]. During laryngoscopy for orotracheal intubation, the beneficial effects are more restricted to the attenuation of undesirable hemodynamic effects.

Studies have shown that esmolol, when used in continuous infusion, is effective in reducing undesirable hemodynamic effects such as hypertension and tachycardia during laryngoscopy maneuvers for orotacheal intubation [13, 14, 15]. Esmolol was also associated with lower intraoperative opioid consumption [16, 17].

Esmolol can also be a safe drug to be used at the time of extubation, especially in patients sensitive to hemodynamic effects such as tachycardia and hypertension. Mendonça et al. in 2021 demonstrated that in patients undergoing surgery during the extubation maneuver, esmolol was effective in attenuating these effects by not delaying extubation [15].

In this context, esmolol can be a safe option, sparing opioids, to be used both in orotracheal intubation, intraoperatively and postoperatively for most patients, and its short half-life brings yet another advantage, as it increases safety even more of this medication.

6. Regional and topical anesthesia of the airway

Though there are a lot of regional and topical techniques that may in reality provide conditions for awake endotracheal intubation (application techniques such as the McKenzie technique that uses a 20-gauge cannula attached to oxygen bubble tubing via a three-way tap or a mucosal atomization device for spraying local anesthetic, and glossopharyngeal nerve or superior laryngeal nerve or recurrent laryngeal or translaryngeal block), they are time-consuming, thus limiting their use in emergency situations.