Pretreatment medications for rapid sequence intubation in adults for emergency medicine and critical care

INTRODUCTION — The first priority for managing an acutely unstable patient is to ensure that there is a patent and functioning airway. When endotracheal intubation is indicated, emergency clinicians often use rapid sequence intubation (RSI) to accomplish this task.

RSI is the recommended method for emergency airway management for intubations that are not anticipated to be of sufficient difficulty as to make laryngoscopy or intubation likely to fail. RSI involves the use of a sedative and a neuromuscular blocking agent to render a patient rapidly unconscious and flaccid for emergency endotracheal intubation and to minimize the risk of aspiration.

Manipulation of the airway during laryngoscopy and endotracheal intubation causes physiologic responses that may be harmful to patients with specific medical conditions. Pretreatment agents may be incorporated into RSI protocols to blunt such physiologic responses and protect patients from their potentially harmful effects.

The use of pretreatment medications for RSI in adults is reviewed here. The performance of RSI, including the use of induction and neuromuscular blocking agents, management of patients at high risk for adverse responses to RSI, and other aspects of emergency airway management in adults and children are discussed separately.

●RSI in adults (see "Rapid sequence intubation in adults for emergency medicine and critical care" and "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care" and "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care")

●RSI in children (see "Rapid sequence intubation (RSI) in children for emergency medicine: Approach" and "Rapid sequence intubation (RSI) in children for emergency medicine: Medications for sedation and paralysis" and "Technique of emergency endotracheal intubation in children")

●Emergency airway management in adults (see "Overview of advanced airway management in adults for emergency medicine and critical care" and "Approach to the difficult airway in adults for emergency medicine and critical care" and "Approach to the failed airway in adults for emergency medicine and critical care" and "Basic airway management in adults")

●Emergency airway management in specific clinical settings

PHYSIOLOGIC RESPONSES TO LARYNGOSCOPY AND INTUBATION — The pharynx, larynx, and carina of the trachea are highly innervated with sympathetic and parasympathetic nerves. The innervation of the upper and lower airways is discussed elsewhere. (See "Neuronal control of the airways".)

Performing laryngoscopy and placing an endotracheal tube stimulate these nerves and cause reflexive actions to protect the airway, such as gagging and coughing. Other reflexive responses to airway manipulation include parasympathetic stimulation in infants that can cause profound bradycardia, sympathetic stimulation in adults that can cause significant increases in heart rate, blood pressure, and intracranial pressure, and parasympathetically mediated bronchospasm.

Studies demonstrate that laryngoscopy causes a mean increase in systolic blood pressure of approximately 20 mmHg [1-5]. Studies looking directly at the effect of laryngoscopy upon intracranial pressure are lacking [6], but endotracheal suctioning causes a minimum of a 5 mmHg elevation [7,8].

PRETREATMENT MEDICATIONS AND THEIR INDICATIONS

Principles for the use of pretreatment agents — Pretreatment medications have the potential for both benefit and risk. Emergency airway management involves a series of sequential steps that must be performed in a specific and timely sequence. Thus, any steps and medications that have not been shown to provide a clear benefit are often best omitted, thereby reducing clinician anxiety and the risk of cognitive error. This is particularly true in pediatric resuscitations. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach" and "Emergency airway management in children: Unique pediatric considerations".)

To be effective, pretreatment agents generally must be administered at least 3 minutes prior to laryngoscopy. However, in critical cases, it may not be possible or worthwhile to delay intubation in order to allow pretreatment agents to take effect. In such cases, the pretreatment agents may be given less than 3 minutes before planned laryngoscopy, or omitted entirely. Pretreatment should be distinguished from physiologic optimization in critically ill patients who require emergency airway management but are at risk for adverse responses to RSI. (See "Rapid sequence intubation in adults for emergency medicine and critical care", section on 'Physiologic optimization'.)

For these reasons, pretreatment should be viewed as a supplementary (ie, non-essential) step in rapid sequence intubation (RSI). Proper sedation and neuromuscular blockade take priority when considering the medications for RSI. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care" and "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care".)

Pretreatment medications are used to avert the potentially harmful consequences of the physiologic responses to airway manipulation during laryngoscopy and endotracheal intubation described above. Such responses can be particularly harmful in young children (ie, bradycardia from vagal stimulation) and in patients with high airway resistance (eg, severe asthma), elevated intracranial pressure (eg, intracranial hemorrhage), cardiovascular conditions exacerbated by sudden increases in heart rate or blood pressure (eg, acute coronary syndrome, aortic dissection), as well as the patient in shock.

The mnemonic "ABC" has been proposed to help practitioners recall the conditions under which these medications may be used: high airway resistance ("asthma"), high intracranial pressure ("brain"), and specific cardiovascular conditions ("cardiovascular") [9].

Potential pretreatment agents include the following:

●Lidocaine to reduce the likelihood of bronchospasm when beta-2 agonist therapy has not been given.

●Short-acting opioid (eg, fentanyl) to decrease the cardiovascular effects of sympathetic nervous system stimulation in patients for whom a rapid rise in blood pressure is undesirable (eg, patients with elevated intracranial pressure or significant cardiovascular disease).

●Alpha-adrenergic agents (eg, epinephrine, phenylephrine) to increase systemic vascular resistance and thereby maintain blood pressure in selected patients who are in distributive, anaphylactic, neurogenic, or some forms of cardiogenic shock.

Each of these agents is discussed below.

In the past, a small (ie, defasciculating) dose of a nondepolarizing neuromuscular blocking agent was frequently given as pretreatment when succinylcholine was used for RSI. Such pretreatment was thought to blunt the potential rise in intracranial pressure caused by the fasciculations that accompany succinylcholine administration. However, this approach is not supported by high quality evidence [10]. In addition, evidence does not support the use of defasciculating pretreatment in patients with elevated intraocular pressure. Defasciculation for patients with elevated ICP or intraocular pressure is no longer recommended. Side effects associated with succinylcholine are reviewed separately. (See "Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults for emergency medicine and critical care".)

A number of other medications have been proposed for use as pretreatment agents, including beta blockers and calcium channel blockers. However, there is insufficient evidence to support the use of calcium channel blockers, and beta blockade usually is not desirable in patients requiring emergency intubation.

Beta-2 agonists — Selective beta-2 agonists (eg, albuterol) are widely accepted as standard initial therapy for patients presenting with acute bronchospasm [11,12]. Beta-2 agonists selectively result in bronchodilation through bronchial smooth muscle relaxation. Initial resuscitative measures for acute dyspnea with bronchospasm routinely employ beta-2 agonists to reduce the need for ventilatory support and supplementary oxygen. For patients who do require further resuscitative measures, continued beta-2 agonist therapy optimizes ventilatory assistance and improves conditions for RSI. Patients who have received treatment with a beta-2 agonist for bronchospasm within the last 30 minutes do not need pretreatment with lidocaine as part of RSI.

Lidocaine — Lidocaine may attenuate the rise in airway resistance and intracranial pressure that occur during laryngoscopy and intubation. Thus, lidocaine may be used as a pretreatment agent for patients undergoing RSI who are at risk for increased airway resistance (ie, asthma) or increased intracranial pressure (eg, intracranial hemorrhage). However, available evidence suggests that lidocaine does not further reduce reactive bronchospasm in patients who have received adequate doses of a beta-2 agonist (eg, albuterol), while studies of its effectiveness for attenuating intracranial pressure increases are inconsistent.

The lidocaine dose is 1.5 mg/kg intravenously (IV), given 2 to 3 minutes before intubation. Broad clinical experience suggests that lidocaine pretreatment is safe when given in this dose. Its onset of action is 45 to 90 seconds, and its effects last for 20 minutes. Lidocaine is metabolized by the liver and excreted in the urine. If there is not sufficient time to allow for lidocaine administration 3 minutes before intubation, lidocaine can be given in a shorter interval, immediately after intubation, or not at all.

Absolute contraindications to pretreatment with lidocaine include a known lidocaine allergy and high grade heart block (Mobitz type II or third degree) in a patient without a functioning pacemaker. Lidocaine can cause cardiac arrest in the setting of a high grade heart block.

Multiple randomized trials have demonstrated that 1.5 mg/kg IV of lidocaine can suppress cough reflexes when administered 1 to 3 minutes prior to intubation [13-21]. Evidence that lidocaine reduces bronchospasm is less clear. Studies in healthy volunteers suggest that pretreatment with lidocaine mitigates bronchial reactivity induced with inhaled histamine [22-24]. However, in a small randomized trial of asthmatic patients undergoing general anaesthesia, pretreatment with lidocaine did not prevent an increase in airway resistance during intubation [25].

Although lidocaine was formerly used routinely for patients with elevated ICP, there is no high quality evidence that directly addresses whether pretreatment with lidocaine effectively reduces the rise in intracranial pressure (ICP) caused by laryngoscopy and endotracheal intubation [10,26-28]. What little evidence exists consists of small trials that have reached contradictory conclusions. Two small randomized trials found that lidocaine minimized the rise in ICP in patients undergoing neurosurgical procedures [29] or endotracheal suctioning [30]. In contrast, three other randomized trials found no benefit from pretreatment with lidocaine in blunting ICP rise during intubation [31,32] or endotracheal suctioning [33]. The largest of these trials involved 124 patients undergoing general anaesthesia and endotracheal intubation in preparation for neurosurgery [31].

Given these conflicting studies, we do not recommend that lidocaine be used as a pretreatment agent for patients with elevated intracranial pressure undergoing RSI. Patients with asthma who are undergoing RSI may benefit from a single dose of lidocaine, 1.5 mg/kg, given 3 minutes before induction, if it is not possible to give an aerosolized beta-2 agonist.

Short-acting opioid — Short-acting opioids blunt the sympathetic response to laryngoscopy. Only if time permits and the patient's blood pressure is already elevated, clinicians may use a short-acting opioid (eg, fentanyl, alfentanil, sufentanil) as pretreatment for RSI of a patient with elevated intracranial pressure (ICP) or cardiovascular disease that may be exacerbated by sudden, further elevations in blood pressure. Short-acting opioids should not be given to patients with shock or significant hemodynamic instability.

Fentanyl is used most often in the emergency setting. The dose is 3 mcg/kg IV given over 30 to 60 seconds to minimize the likelihood of respiratory depression. It is given approximately three minutes before the induction medication is administered and should be the last pretreatment drug given.

Fentanyl is an opioid receptor agonist. Its effects begin within two to three minutes of administration; its duration of action is 30 to 60 minutes. Fentanyl can cause respiratory depression and hypotension [34]. In patients with tenuous hemodynamic status, fentanyl should be avoided or given in lower doses (1 mcg/kg) [35].

Several randomized trials found fentanyl to be effective at attenuating rises in blood pressure and heart rate during RSI [36-38]. However, subsequent studies have reported either no significant difference compared with placebo [39] or hypotension [34,40-42]. Data pertaining to the effects of fentanyl on the ICP of patients with acute head injuries undergoing RSI are limited to low-quality studies with conflicting results [43,44].

In rare instances fentanyl causes a "rigid chest" syndrome, in which the patient becomes apneic and cannot be ventilated or oxygenated with a bag mask. Rigidity is abolished by the administration of paralyzing doses of succinylcholine (SCh) [45] or a nondepolarizing NMBA [46]. Reported cases generally involve a single, rapidly administered, large dose of fentanyl, many-fold higher than the doses used for emergency RSI. (See "Perioperative uses of intravenous opioids in adults: General considerations", section on 'Prevention and management of adverse opioid effects'.)

Muscle wall rigidity is an idiosyncratic response to opioids and is probably related to the dose and speed of opioid administration. In an observational study of 380 patients undergoing cardiac surgery, high dose fentanyl (100 mcg/kg, or approximately 30 times the dose used in RSI) caused approximately 8 percent of patients to develop extreme thoracic and abdominal rigidity [47]. There is a single case report of rigidity in a patient who received fentanyl at a dose of 2 mcg/kg while taking venlafaxine, a serotonin and norepinephrine reuptake inhibitor [48]. Fentanyl has been widely used for procedural sedation in doses similar to those used for RSI, and reports of muscle rigidity are virtually absent, even from large series [49,50].

Alpha-adrenergic agents — The patient in shock frequently requires cardiovascular support to maintain their blood pressure, including intravascular fluid and/or adrenergic agents to increase systemic vascular resistance. Evidence now demonstrates that pre- and post-intubation hypotension is associated with increased in-hospital mortality [51-53]. Some clinicians advocate using small doses of epinephrine (5 to 20 micrograms) or phenylephrine (50 to 200 micrograms) to optimize the hemodynamics of emergency patients with tenuous blood pressure, especially due to sepsis, who require emergency intubation [54,55]. No direct studies of such patients with sufficient size and power have been published to support or refute this practice, and the appropriate role of alpha adrenergic agents in this setting remains controversial [56]. Before considering pretreatment with an adrenergic medication, the clinician should administer appropriate treatments for hypotension, such as IV boluses of isotonic crystalloid for hypovolemia or blood products for hemorrhagic shock. (See "Rapid sequence intubation in adults for emergency medicine and critical care", section on 'Physiologic optimization'.)

Multiple choices affect the clinical status of a patient in or near shock once the intubation process begins. The decision to administer an adrenergic agent before intubation is a clinical one that the practitioner must make based upon the circumstances at hand. Assessment of the patient's vital signs, volume status, and cardiac function may lead the clinician to reduce the induction agent dose, change the induction agent, administer crystalloid to expand intravascular volume, or to administer a pre-induction adrenergic agent. A reasonable rule of thumb is to consider giving an alpha adrenergic agonist in a patient who will require vasopressors to treat hypotension following intubation, especially if ketamine is not to be used as the induction agent for RSI. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Shock'.)

CHOICE OF PRETREATMENT AGENTS

General approach — For reasons discussed above, pretreatment should be viewed as a supplementary (ie, nonessential) step in rapid sequence intubation (RSI). In appropriate clinical circumstances, the pretreatment approaches described here may be beneficial. (See 'Pretreatment medications and their indications' above.)

Asthma (elevated airway resistance) — To reduce airway resistance in adults requiring urgent intubation for reactive airway disease, we administer a beta-2 agonist such as albuterol during preparation for intubation. For the vast majority of patients, such treatment will already have been given and may be on-going. In patients for whom there is insufficient time to administer albuterol before intubation, and in whom no albuterol has been given within the last 30 minutes, we suggest pretreatment with lidocaine. The lidocaine dose is 1.5 mg/kg intravenously (IV), given 2 to 3 minutes before intubation. The management of acute, severe asthma exacerbations is summarized in the following table (table 1) and algorithm (algorithm 1), and discussed in detail separately. (See 'Lidocaine' above and "Acute exacerbations of asthma in adults: Emergency department and inpatient management".)

In severe exacerbations, IM epinephrine is advocated by some as a last-ditch treatment before intubation. (See "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Parenteral beta-agonists (epinephrine and terbutaline)'.)

Elevated intracranial pressure — A short-acting opioid (eg, fentanyl) may be given to patients who are hypertensive and require urgent intubation due to a condition that can be exacerbated by an elevation in intracranial pressure. Such conditions may include intracranial hemorrhage, meningitis or encephalitis with suspected ICP elevation, traumatic brain injury, cerebral edema, and hypertensive encephalopathy. (See "Evaluation and management of elevated intracranial pressure in adults".)

A short-acting opioid should not be given as a pretreatment agent to a patient with significant hemodynamic instability because of the risk of a further decline in blood pressure. The fentanyl dose is 3 mcg/kg IV given over 30 to 60 seconds approximately 3 minutes before the induction medication is administered. (See 'Lidocaine' above and 'Short-acting opioid' above.)

Cardiovascular emergencies — To prevent sudden increases in heart rate or blood pressure in patients requiring urgent intubation during a cardiovascular emergency (eg, acute coronary syndrome, aortic dissection), or for emergency intubation of patients with known severe cardiovascular disease (eg, recent myocardial infarction or episodes of angina pectoris), we suggest pretreatment with a short-acting opioid (eg, fentanyl). A short-acting opioid should not be given to a patient with shock or significant hemodynamic instability. The fentanyl dose is 3 mcg/kg IV given over 30 to 60 seconds approximately 3 minutes before the induction medication is administered. (See 'Short-acting opioid' above.)

Depending on the cause of shock, an alpha adrenergic agonist may be given 2 minutes prior to intubation to help prevent an exacerbation of hypotension following RSI. Potential agents include epinephrine (5 to 20 micrograms) or phenylephrine (50 to 200 micrograms). We suggest the use of an alpha agonist in carefully selected patients who are in shock and require support of systemic vascular resistance during RSI when alternative methods for maintaining blood pressure have not been or are not expected to be successful. Do not use alpha agonists as pretreatment in patients with an arrhythmogenic cause of shock, aortic dissection, or suspected valvular failure as the cause of shock, or in patients with acute angle closure glaucoma.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Airway management in adults".)

SUMMARY AND RECOMMENDATIONS

●Physiologic response to laryngoscopy and intubation – Performing laryngoscopy and placing an endotracheal tube stimulate the sympathetic and parasympathetic nerves of the upper airway, causing reflexive actions to protect the airway (such as gagging and coughing) as well as increases in blood pressure and intracranial pressure. (See 'Physiologic responses to laryngoscopy and intubation' above.)

●Pretreatment is not essential for rapid sequence intubation (RSI) – Pretreatment should be viewed as a supplementary (ie, nonessential) step in RSI, with the exception of addressing hypotension before and after intubation. (See 'Pretreatment medications and their indications' above.)

●Use of atropine – Atropine should be readily available as a rescue medication if bradycardia occurs but is not used for pretreatment in adults. Atropine pretreatment in young children is discussed separately. (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach".)

●Bronchospasm – A beta-2 agonist (eg, albuterol) should be administered before intubation to patients with evidence of bronchospasm or a history of reactive airway disease. In patients with demonstrable bronchospasm for whom there is not sufficient time to administer a beta-2 agonist, we suggest pretreatment with lidocaine (Grade 2C). (See 'Asthma (elevated airway resistance)' above and 'Beta-2 agonists' above and 'Lidocaine' above.)

●Elevated intracranial pressure – If time permits and the patient's blood pressure is elevated, pretreatment with a short-acting opioid (eg, fentanyl) may be given to a patient who requires urgent intubation due to a condition that can be exacerbated by an elevation in intracranial pressure. Such conditions may include stroke, intracranial hemorrhage, meningitis or encephalitis, traumatic brain injury, and hypertensive encephalopathy. Evidence about such pretreatment is equivocal. (See 'Elevated intracranial pressure' above and 'Short-acting opioid' above.)

●Cardiovascular emergency – We suggest pretreatment with a short-acting opioid (eg, fentanyl) to prevent sudden increases in heart rate or blood pressure in patients requiring urgent intubation during a cardiovascular emergency (eg, acute coronary syndrome, aortic dissection) (Grade 2C). A short-acting opioid should not be given to any patient with shock or significant hemodynamic instability. (See 'Cardiovascular emergencies' above and 'Short-acting opioid' above.)

For carefully selected patients in shock who require emergency intubation, pretreatment with an alpha agonist may help to prevent an exacerbation of hypotension following RSI. (See 'Cardiovascular emergencies' above and 'Alpha-adrenergic agents' above.)

●Pre-intubation hypotension – Pre-intubation hypotension should be managed with therapies aimed at the cause of hypotension before performing RSI whenever possible. (See "Rapid sequence intubation in adults for emergency medicine and critical care", section on 'Physiologic optimization'.)