The Pharmacology of Physiologically Difficult Airway Management and Impact on Hemodynamics: A Review

Abstract

Critically ill patients have a physiologically difficult airway (PDA), wherein tracheal intubation (TI) and transition to positive pressure ventilation may lead to cardiorespiratory and other complications. Medications administered during the management of a PDA, have an impact on peri-intubation hemodynamics, and may influence patient outcomes. Appropriately choosing, and dosing medications, such as anesthetic induction agents, neuromuscular blocking agents (NMBAs) etc. are thus important considerations that clinicians should be aware of. However, despite significant awareness, and research in this area, there remains ambiguity in the choice of such drugs. This review provides an update on the pharmacology of airway management in patients with a PDA, discussing medications administration strategies widely used in this patient population. We review the current evidence related to the use of anesthetic induction agents, neuromuscular blocking agents, vasopressors, inotropes, and adjunctive agents and provide updated guidance on appropriate medication selection in the context of airway management in patients with a PDA.

How to cite this article

Karamchandani K, Khawaja A, Chaney W, Bangalore R, Myatra SN. The Pharmacology of Physiologically Difficult Airway Management and Impact on Hemodynamics: A Review. Indian J Crit Care Med 2026;30(1):68–76.

Introduction

Tracheal intubation (TI) is one of the most performed procedures in critically ill patients and is associated with significant morbidity and mortality. A recent international multi-institutional observational study reported that almost 45% of critically ill patients undergoing TI had a major peri-intubation adverse event, of which hemodynamic instability was the most common, observed in 43% of the patients, followed by hypoxia in 9%.¹ Cardiac arrest was reported in 3% of the patients. Overall intensive care unit (ICU) mortality was 33%, and the occurrence of adverse events was associated with an increased risk of ICU and 28 days mortality. Similar findings were also observed in a multicenter study evaluating TI practices in the emergency department.² Among 2,846 patients, major adverse events were associated with 32% of intubations, most frequently new hemodynamic instability (20.0%), followed by severe hypoxemia (12.5%) and cardiac arrest (3.5%). Patients experiencing any major adverse event had a significantly higher 28 days mortality (58 vs 39%). In addition to the anatomic and logistical challenges associated with airway management in the critically ill, these patients tend to have significant physiological alterations that predispose them to complications associated with TI and initiation of positive pressure ventilation, thus leading to what has been described as a physiologically difficult airway (PDA).^3–5

Medications administered during the management of a PDA may have an impact on patient outcomes. In a secondary analysis of the INTUBE study, it was reported that the use of propofol for induction of anesthesia was an independent modifiable risk factor associated with cardiovascular instability or collapse (OR: 1.23; 95% CI: 1.02–1.49).⁶ In addition to the anesthesia induction drugs, which may affect hemodynamics and lead to cardiovascular collapse, other drugs, such as neuromuscular blocking agents (NMBA), may also have an impact on patient outcomes.^7,8 There remains ambiguity in the ideal choice of anesthesia induction agent as well as NMBA in these vulnerable patients. Similarly, the ideal choice and mode of administration of vasopressor and inotropic drugs for hemodynamic support during airway management in patients with a PDA remains unclear. In this narrative review, we discuss the pharmacology of various medications used during airway management in patients with a PDA, review the existing literature on the impact of their administration, and provide guidance based on updated evidence on the appropriate selection of these medications.

Methods

Studies were identified from the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Google Scholar, MEDLINE, and EMBASE databases. Additional literature was gathered using the reference lists of existing citations. Studies published between January 1st, 1970 and December 31st, 2024, that examined outcomes of medications administered during the management of a PDA were included.

Our search strategy combined three categories of keywords to fully answer our review question. The first category was pharmacology, with keywords including various induction drugs, neuromuscular blockers, and vasopressors/inotropes. The second category was outcomes (intubation), and the third was the study population (critically ill patients, PDA). This search strategy was applied and adjusted for each database using appropriate medical subject headings (MeSH) and keywords.

Pharmacological Goals of Airway Management in Patients with a PDA

Rendering the patient unconscious, facilitating laryngoscopy and TI through skeletal muscle relaxation, maintaining hemodynamic stability during the peri-intubation period, and ensuring patient comfort during and after TI are the general pharmacologic goals in airway management. As described above, patients with a PDA are susceptible to hemodynamic alterations both during and after TI. While laryngoscopy and intubation may cause significant blood pressure and heart rate elevations in healthy individuals, the physiologic response in patients with a PDA may be different.^9,10 In such patients, amelioration of hypoxia- and hypercarbia-mediated sympathetic drive, as well as the vasodilation and myocardial depression caused by administration of anesthetic induction drugs, may in turn lead to hemodynamic instability. This may require the administration of vasopressors and inotropic drugs either preemptively or for treatment. Figure 1 highlights some of the common causes of hemodynamic collapse with TI in patients with a PDA.

Fig. 1.

Common causes of hemodynamic collapse with tracheal intubation in patients with a PDA. SVR, systemic vascular resistance

Anesthesia Induction Agents

Anesthesia induction drugs are used during TI to provide adequate intubating conditions as well as hypnosis. Most patients receive NMBA during the process, and the use of a sedative-hypnotic drug as an induction agent prevents awareness while being paralyzed. The main induction drugs used in critically ill patients include etomidate, ketamine, and propofol, along with the drug admixtures “ketofol” (a combination of ketamine and propofol) and “propadate” (a combination of propofol and etomidate). Drugs used for induction of anesthesia can increase the risk of hemodynamic complications, and hence, appropriate choice and dosing of such agents is critical to prevent peri-intubation cardiovascular collapse.⁶

Propofol

Propofol is the most used induction agent for TI in critically ill patients across the world.¹ It exerts its effects by potentiating the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABA-A receptor and readily crosses the blood-brain barrier, resulting in a rapid loss of consciousness.¹¹ In addition, it has a rapid terminal half-life time. While propofol provides superior conditions for TI and is widely used as an induction agent in the operating room, it may not be suitable in most critically ill patients. A post hoc analysis of the INTUBE study showed that the use of propofol for induction of anesthesia was an independent predictor of cardiovascular collapse in critically ill patients undergoing TI (OR: 1.23; 95% CI: 1.02–1.49).⁶ However, there are inconsistencies in the reported association between propofol administration during TI and clinical outcomes. In a study exploring peri-TI complications, the use of propofol was not independently associated with cardiovascular instability (OR: 0.72; 95% CI: 0.51–1.01) after adjusting for relevant risk factors.¹² Similarly, in a study comparing propofol, ketamine, and etomidate for TI in critically ill patients, propofol use was associated with better outcomes.¹³ Another retrospective study observed hypotension (defined as systolic blood pressure < 70 mm Hg) in only 4% of critically ill adults that received propofol for TI.¹⁴ It is unclear if the dose of propofol used during the procedure has an impact on the antecedent hemodynamic collapse, considering that the dose used during the INTUPROS study [0.91 (0.60–1.23) mg/kg], was significantly lower than the standard anesthesia induction dose.¹² In the analysis of the INTUBE dataset, a dose-dependent effect was not evaluated. Taken together, it seems prudent to avoid standard anesthetic induction doses of propofol in patients with a PDA to decrease the risk of peri-intubation cardiovascular collapse. This was also suggested in the PDA Delphi consensus study.¹⁵

Etomidate

Etomidate is a sedative-hypnotic drug that increases the potency at which GABA activates the GABA-A receptors, as well as directly activates the GABA-A receptors in the absence of GABA.¹⁶ Considering its rapid onset of action and stable hemodynamic profile, it has been recommended as an induction agent of choice for TI in critically ill patients.^15,17 However, concerns about its use remain because of its suppression of adrenocortical steroid synthesis by inhibiting 11β-hydroxylase. In the study by Jabre et al. comparing ketamine and etomidate for RSI in critically ill patients, the percentage of patients with adrenal insufficiency was significantly higher in those that received etomidate compared to ketamine (OR: 6.7, 95% CI: 3.5–12.7).¹⁸ However, there was no significant difference in mortality. A 2011 meta-analysis comparing etomidate vs non-etomidate induction agent use in critically ill patients found a higher relative risk for adrenal insufficiency (RR = 1.64, range 1.52–1.77, p < 0.00001) and mortality (RR = 1.19, range 1.10–1.30, p < 0.0001) in the etomidate group.¹⁹ A re-analysis of the data found that the increase in mortality remained significant in trials with sepsis but not in those without sepsis. Considering that sepsis frequently results in relative adrenal insufficiency due to dysregulation of the HPA axis and alterations in cortisol metabolism, etomidate's inhibition of cortisol synthesis in patients with sepsis could further worsen adrenal insufficiency and may explain the increased mortality.²⁰

Similar findings were seen in a 2023 meta-analysis, in which etomidate was found to increase mortality compared to non-etomidate controls (RR = 1.16; 95% CI: 1.01–1.33; p = 0.03; I² = 0%; number needed to harm = 31), in addition to increased rates of adrenal insufficiency.²¹ It is unclear if etomidate should be avoided in patients with sepsis, and if adrenal insufficiency should be specifically looked for in patients who receive etomidate for induction of anesthesia for TI. Prophylactic administration of corticosteroids in critically ill patients without septic shock receiving etomidate for induction of anesthesia for TI has not been shown to reduce the duration of mechanical ventilation, ICU length of stay, or 28 days mortality.²²

Ketamine

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist and decreases the release of the excitatory neurotransmitter glutamate. Ketamine has sympathomimetic properties, causing transient increases in blood pressure, heart rate, and cardiac output. However, in catecholamine-depleted states, it is a direct myocardial depressant. Considering the relative cardiovascular stability associated with ketamine, it has been recommended as a preferred sedative-hypnotic, along with etomidate, for TI in critically ill patients.^15,17 While concerns have been raised that sympathetic activation associated with ketamine can lead to increased cerebral oxygen consumption and increased cerebral perfusion, which can lead to increased intracranial pressure (ICP), this has not been proven in clinical trials.^23,24

Ketamine vs Etomidate

Randomized controlled trials (RCT) comparing patient outcomes with the use of etomidate and ketamine for TI in critically ill patients have been inconclusive.^18,25,26 In the study by Jabre et al., which included 655 critically ill patients needing sedation for emergency intubation, there was no difference in any of the outcomes between the etomidate and ketamine groups.¹⁸ Similarly, a single-center RCT comparing the effects of a single dose of ketamine vs etomidate for RSI on maximum sequential organ failure assessment (SOFA) score and incidence of hypotension in critically ill patients did not find any difference between the two groups on any of the outcomes.²⁶ The etomidate vs ketamine (EvK) trial, which included over 800 critically ill patients undergoing emergency TI, reported that the primary outcome of day 7 survival was greater in patients that received ketamine, but there was no significant difference in survival by day 28 in both groups.²⁵ Retrospective cohort studies and meta-analyses, on the other hand, suggest that ketamine might be a better alternative in these circumstances. In a retrospective cohort study of critically ill patients that received invasive mechanical ventilation (IMV) and received etomidate on the day of IMV initiation, the authors reported that receipt of etomidate was associated with greater hospital mortality relative to ketamine (21.6 vs 18.7%; absolute risk difference, 2.8%; 95% CI: 2.1–3.6%; aOR: 1.28, 95% CI: 1.21–1.34).²⁷ Similarly, a recent Bayesian meta-analysis showed a moderate probability that the use of ketamine was associated with a reduced risk of mortality when compared to etomidate (probability = 83.2%; RR: 0.93; 95% CI: 0.79–1.08), with no difference in secondary outcomes such as SOFA score, vasopressor/ventilator-free days, post-induction mean arterial pressure, and successful first-pass intubation.²⁸ In contrast, a more recent meta-analysis demonstrated that ketamine probably results in more hemodynamic instability during the peri-intubation period as compared to etomidate and appears to have no effect on successful intubation on the first attempt or mortality.²⁹ The recently published randomized trial of sedative choice for intubation (RSI) did not report a significant difference in mortality at day 28 between the use of ketamine or etomidate (28 vs 29%) to induce anesthesia for TI in critically ill adults. Cardiovascular collapse during intubation occurred in 260 of 1,176 patients (22.1%) in the ketamine group and in 202 of 1,189 patients (17.0%) in the etomidate group (risk difference, 5.1% points; 95% CI: 1.9–8.3).³⁰ Considering this new evidence, the choice between these two drugs should be based on individual patient characteristics as well as local practices. Both ketamine and etomidate have been recommended as the preferred sedative-hypnotic drugs for TI in critically ill patients.¹⁵

Ketofol

Ketofol, a drug admixture of ketamine combined with propofol, has been considered for use as an induction drug in critically ill patients undergoing TI.³¹ “Ketofol” has been proposed as an ideal induction agent and a go-to solution for preserving hemodynamics in patients with a PDA.³² However, evidence is lacking on the use of this admixture in critically ill patients, and the limited data available is unable to show better hemodynamics with the use of “ketofol” vs etomidate.³¹ Considering that ketofol lacks a standardized ratio for the two drugs and is not a pre-mixed combination, the lack of improvement in patient hemodynamic outcomes when compared to etomidate may restrict the use of ketofol during emergency intubations.³³

Propadate

Propadate is a drug admixture of propofol and etomidate and has been proposed as an induction agent in patients with a PDA, considering a better hemodynamic profile compared to propofol alone and a potential reduction in the risk of adrenal suppression reported with etomidate.^33,34 Little data regarding the efficacy and safety of propadate exists, with one meta-analysis reporting that the combination of propofol and etomidate for sedation in gastroscopies resulted in a beneficial hemodynamic profile compared to propofol.³⁵ Currently, the propofol and etomidate admixtures comparisons (PEAC) trial is underway to evaluate the hemodynamic and adverse effect profiles of different ratios of propofol and etomidate in the admixture (NCT05358535).³⁶ A problem with drug admixtures is the concerns of stability of the admixture as an emulsion, with the potential of breaking down when mixed with other agents. While this has been reported with parenteral nutrition formulations, there is a lack of data on drug admixtures such as ketofol and propadate.³⁷

Midazolam

Midazolam is a fast-acting benzodiazepine that acts as a GABA agonist to cause sedation and amnesia. Since it is the most lipophilic benzodiazepine, it rapidly crosses the blood-brain barrier, but it has a very short half-life due to being rapidly redistributed.

Benzodiazepines as a class are not commonly used in these critically ill patients, because of the high risk of delirium associated with their use in this patient population.³⁸ However, recent evidence suggests that benzodiazepines, and specifically midazolam are, being used as sedative-hypnotic agents for TI in critically ill patients.^1,12 The INTUPROS trial reported that midazolam was used in 66% of critically ill patients undergoing TI, whereas the INTUBE study found that 36% of patients received benzodiazepines.^1,12 While benzodiazepines do provide hemodynamic stability, further studies are needed to assess the impact of this one-time dose of benzodiazepines to facilitate TI in critically ill patients on delirium and other patient outcomes.

Dosing of Anesthesia Induction Agents and the Risk of Awareness

Considering that most anesthesia induction agents impact patient hemodynamics, it has been observed that lower doses of these drugs are often used for TI in critically ill patients.^1,12,39 While this may prevent hemodynamic perturbations, it perhaps increases the risk of patient awareness under paralysis. Accidental awareness is a significant risk following administration of long-acting NMBAs for TI, with a reported frequency of 2–8%.^40–42 Patients who receive NMBAs to facilitate TI should receive a sedative-hypnotic infusion to prevent awareness during neuromuscular blockade.¹⁵ The use of clinical assessment of depth of sedation, rather than processed electroencephalogram (EEG), should be used to assess the depth of sedation.

Neuromuscular Blocking Agents

Neuromuscular blocking agents are frequently used to facilitate optimal conditions for TI and are one of the core medication components of rapid sequence intubation (RSI).⁴³ The use of NMBA during TI has been associated with improved intubating conditions, and is recommended. Working directly at the neuromuscular junction, NMBA exert their effects by binding to the nicotinic acetylcholine receptors (AChRs) on the postsynaptic muscle endplate, which blocks acetylcholine from binding, inhibits further depolarization, and ultimately leads to skeletal muscle paralysis. Neuromuscular blocking agent can be divided into two groups: Depolarizing and nondepolarizing. Depolarizing NMBA resemble and act similarly to acetylcholine by binding to the AChR and causing initial depolarization of the motor end plate. The initial depolarization causes fasciculations, which is followed by flaccid paralysis as the agent continues to block the receptors for its duration of action. Succinylcholine is the only available depolarizing NMBA in the modern era. Nondepolarizing NMBA are competitive antagonists that bind to the receptors without activating them, thus inhibiting depolarization and subsequent muscle contraction.

Succinylcholine

Succinylcholine is commonly used for RSI due to its ideal pharmacokinetic parameters, including a rapid onset of action and the shortest duration of action of 5–10 minutes among NMBAs. Administration of succinylcholine should be avoided in patients with known decreased plasma cholinesterase activity, recent burns or trauma within 24–72 hours, and muscle myopathies.⁴⁴ Succinylcholine can cause acute hyperkalemia in susceptible patients due to depolarization of the upregulated muscle nicotinic AChRs, leading to efflux of intracellular potassium into the plasma.⁴⁵ It should be used with caution in patients with disuse atrophy or those who have been bedridden for the risk of succinylcholine-induced hyperkalemia.⁴⁶ Succinylcholine has also been associated with bradycardia and transient increases in intraocular and ICP, the clinical significance of which is unclear.⁴⁷

Rocuronium

The onset of action of rocuronium is dose-dependent, and at higher doses (1.2 mg/kg or greater), rocuronium can create good intubation conditions in approximately 60 seconds.⁴⁷ The duration of action is longer and also dose-dependent, ranging from 30 to 120 minutes. In addition to its long half-life, pharmacodynamic considerations for rocuronium include its affinity for vagal receptors; inhibition of vagal activity can lead to tachycardia.⁴⁸ Vecuronium may also be used for TI; however, due to its slower onset of action (2–3 minutes), it is less ideal for use in RSI. Like rocuronium, it also has a longer duration of action, with effects lasting for about 45–65 minutes after administration of an intubation dose.⁴⁷ Both rocuronium and vecuronium undergo some degree of hepatic metabolism and renal clearance, so increased time to clearance may be seen in patients with hepatic or renal dysfunction. Due to the longer half-lives of nondepolarizing NMBA, consideration must be given to the potential increased risk of awareness when the effects of the hypnotic drugs used during induction of anesthesia wear off.

While there is limited data published looking specifically at how the use of NMBA affects outcomes in patients with PDA, the use of NMBA has been shown to increase first-pass intubation success rate, and decrease peri-intubation complications.^49,50 A prospective observational study evaluating out of operating-room TI in 556 hospitalized patients in two tertiary care centers reported lower rates of hypoxia (10.1 vs 17.4%, p = 0.022) and lower rates of airway-related complications (3.1 vs 8.3%, p = 0.012) in the patients that received NMBA.⁵⁰ Further, no difference in the incidence of hypotension was noted between the two groups. In another study, evaluating TI in a medical ICU observed that first-pass success was significantly higher in patients who did receive NMBA, 80.9% (95% CI: 77–84%), compared to 69.6% (95% CI: 62–76%), p = 0.003. No significant difference was seen in rates of complications, including hypotension, desaturations, or aspiration. Pooled data from several observational studies show similar rates of respiratory and cardiovascular collapse when NMBA are used compared to when they are not, with trends toward less complications in patients who receive NMBA (0–7.5% vs 3–24%).⁵¹ Despite the available data being limited by study design (mostly observational studies) and significant heterogeneity in the setting and patient population, NMBA may be utilized to improve first-pass success and optimize conditions during TI in patients with a PDA. Guidelines also recommend the use of NMBA for RSI.^17,51,52 It might be appropriate to withhold NMBA in patients who would benefit from maintaining spontaneous respiratory drive, such as those with severe metabolic acidosis.

Historically, succinylcholine has been the most used NMBA for RSI; however, the contraindications, side effect profile, and drug availability have led to increased interest in the use of non-depolarizing NMBA. Several studies comparing succinylcholine and rocuronium for TI in critically ill patients have failed to demonstrate any clinically meaningful difference between the two drugs. A prospective, RCT evaluating the two drugs for RSI in medical and surgical ICU patients found no difference in oxygen desaturations, intubating conditions, or hemodynamic changes during TI.⁵³ Among adults undergoing TI in an out-of-hospital emergency setting, rocuronium was non-inferior to succinylcholine.⁷ A more recent secondary analysis of the direct vs video laryngoscope (DEVICE) trial and the pragmatic trial examining oxygenation prior to intubation (PREOXI) trial also concluded that the incidences of first pass success and severe complications were not significantly different between patients who received succinylcholine and patients who received rocuronium. It is important to consider that the dose of rocuronium used may have an impact on intubating conditions, as was observed in a Cochrane review comparing the two drugs for RSI.⁵⁴ For the primary outcome of intubation conditions, succinylcholine was found to be more likely to create excellent conditions [RR (95% CI) 0.86 (0.81–0.92)];, however, it was observed that intubating conditions with higher doses of rocuronium (0.9–1.0 mg/kg) were not significantly different than with succinylcholine, while lower doses were associated with worse intubation conditions.

A large database review using the vizient clinical database compared the use of succinylcholine and rocuronium for TI in patients with myocardial infarction, and observed that the rocuronium group had higher in-hospital mortality, included after adjusting for comorbidities and hospital characteristics (odds ratio, 1.40 [95% CI: 1.23–1.59]).⁸ While this study is limited by its observational and retrospective nature, as well as limited information on demographics and background characteristics, it highlights the need for further studies in different patient populations that may be more affected by side effect profiles of the different NMBA. It has been recommended that either drug may be used for TI in patients with a PDA, with caution advised when using succinylcholine in certain situations.¹⁵

Vasopressors and Inotropes

Hemodynamic instability is common during TI in critically ill patients, with the most recent data suggesting an incidence varying from 27 to 46% in large multicenter observational studies.^1,12 This results from a combination of pharmacologically induced vasodilation and myocardial depression, conversion from negative-pressure to positive-pressure ventilation, as well as the amelioration of the hypoxia- and hypercarbia-associated sympathetic drive.⁴⁴ Both peri-intubation hypotension and hemodynamic instability after intubation are associated with significant morbidity and mortality.^1,12,55,56 Administration of fluids preemptively to prevent these hemodynamic perturbations associated with TI has not been shown to be effective in large multicenter RCTs.^57,58 This is because a “one size fits all” approach may not work in these situations, and it may be important to assess fluid responsiveness using point-of-care ultrasound (POCUS) prior to fluid administration, time and resources permitting.⁵⁹ Vasoactive agents, specifically vasopressors, are also commonly used to maintain hemodynamic stability during airway management in critically ill patients. Inotropic support is also often utilized to counter any direct myocardial depression effect of the anesthetic induction drugs, pre-existing myocardial dysfunction, or critical illness-associated cardiomyopathy. While there is insufficient evidence at the current time to recommend preemptive fluid bolus administration to prevent cardiovascular collapse in critically ill patients undergoing TI, the PDA Delphi recommends that vasopressor and/or inotrope infusion administration can help prevent and/or minimize peri-intubation cardiovascular collapse.^15,51 Two ongoing international trials (NCT05318066 and NCT05014581) are investigating the effectiveness of preemptively administering vasopressors in preventing cardiovascular collapse in critically ill adults undergoing TI.

A recent meta-analysis observed decreased odds of peri-intubation hypotension with the administration of prophylactic vasopressors in patients undergoing TI in the operating room with propofol.⁶⁰ However, the support of the same in critically ill patients could not be established by this analysis due to multiple confounding variables in this population. The strategies of vasopressor administration, i.e., push-dose pressors vs infusion of pressors in effectively restoring blood pressure during the peri-intubation period, have been heavily debated. For example, while a protocolized use of push-dose epinephrine was found to be effective in temporarily correcting hemodynamic compromise associated with intubation of critically ill patients during transport, non-protocolized use of push-dose pressors was ineffective at correcting hypotension in a similar setting.^61,62 In the latter study, most patients either required repeat dosing of push-dose pressors or were initiated on infusion of vasopressors to treat refractory hypotension.⁶² The choice between push-dose vs continuous infusion of vasopressors to prevent peri-intubation cardiovascular instability is also unclear. A retrospective cohort study evaluating the effects of push dose phenylephrine vs continuous infusion of norepinephrine within 30 minutes of TI on peri-intubation hypotension showed no difference.⁶³ Overall, even though the safety of push-dose vasopressors during the peri-intubation period is established, there is no clear data on the direct comparison of the efficacy of push-dose and infusion-dose delivery of individual vasopressors. Some of the commonly used vasopressors-inotropes and their use during TI in critically ill patients are briefly described below.

Norepinephrine

Norepinephrine or noradrenaline is a catecholamine that functions as both a hormone and a neurotransmitter. In a recent review, norepinephrine was recommended as the first-choice vasopressor to treat hemodynamic instability associated with TI, and peripheral administration of norepinephrine was also favored.⁶⁴

Vasopressin

Vasopressin is a neurohormone that maintains plasma volume by balancing plasma osmolality and aids in vasoconstriction. Its role specifically in the management of peri-intubation hypotension has not been well studied, but push-dose vasopressin was found to increase blood pressures effectively and safely in trauma patients who underwent RSI.⁶⁵

Epinephrine

Epinephrine, an endogenous catecholamine released by the adrenal medulla in response to stress, enhances cardiac function by increasing effective blood volume and contractility. Given its affinity to cardiac receptors and the ability to restore diastolic blood pressure and improve coronary perfusion, synthetic epinephrine is used as the standard first-line therapy in cardiopulmonary resuscitation of patients suffering cardiac arrest. The use of epinephrine has been extended to non-cardiac arrest patients with sepsis, trauma, and other critically ill patients in the pre-hospital setting, where much lower doses have been used to effectively correct hypotension.⁶⁶ Similarly, during RSI of critically ill patients in the emergency room, a case series showed that push-dose epinephrine can effectively increase blood pressure in the peri-intubation period.⁶⁷ A comparison of push-doses of epinephrine and phenylephrine in reversing hypotension in the emergency department showed that epinephrine was superior to phenylephrine in increasing systolic blood pressure without a concomitant increase in heart rate, demonstrating a combined inotropic and vasopressor benefit.⁶⁸ The role of push-dose epinephrine in preventing and treating peri-intubation hypotension needs further evaluation.

Phenylephrine

Phenylephrine is a pharmacological agent often used to treat vasoplegia associated with anesthesia induction drugs via its action on the alpha-1 agonist receptors. The use of phenylephrine in airway management has expanded beyond the scope of the operating room to other critical care settings, including the emergency room and ICU. A retrospective chart review has shown that push-dose phenylephrine can improve hemodynamics in the peri-intubation period safely.⁶⁹

Fluid Loading

The administration of a fluid bolus has been suggested as an intervention to reduce the incidence of cardiovascular collapse during TI.^70,71 Two randomized multicenter trials conducted compared the administration of a 500 mL intravenous saline bolus vs no fluid bolus in critically ill adult patients prior to TI. The first, the PrePARE study, was conducted in an unselected patient, while the second, the PrePARE II study, included patients who received positive pressure ventilation between induction and laryngoscopy (e.g., NIV, gentle mask ventilation during RSI).^57,58 Both studies showed no reduction in the overall incidence of cardiovascular collapse following intubation. These studies suggest that routine use of a fluid bolus prior to TI may not be beneficial to reduce the incidence of cardiovascular collapse in these patients, suggesting that a fluid bolus should be considered on a case-by-case basis, potentially guided by an assessment of fluid responsiveness, if feasible. In the meantime, expert consensus supports hemodynamic optimization prior to TI in this high-risk population. This includes the use of fluids and vasopressors/inotropes alone or in combination to reduce the risk of cardiovascular collapse during TI in this high-risk group.¹⁵

Patients with Neurologic Injury

There may be additional considerations in patients with neurologic injury where cerebral blood flow is more sensitive to changes in blood pressure, oxygenation, and ventilation. Tracheal intubation leads to a sympathetic response and potentially significant fluctuations in MAP and ICP. In severe traumatic brain injury (TBI), autoregulation of cerebral profusion may be lost and spikes in ICP will further decrease cerebral perfusion. Strategies thought to mitigate this during TI include pretreatment with anesthetic or analgesic, utilizing induction agent that is hemodynamically neutral, and using NMBA to blunt cough and gag reflex. Lidocaine use is not recommended as data has failed to show impact on changes in ICP or neurologic outcomes.⁷² Fentanyl has been shown to blunt the elevations in blood pressure and heart rate cause by the sympathetic response in RSI, which is thought to limit spikes in ICP, however data in TBI patients supporting this is sparse and adverse effects of hypotension must be weighed.⁷³ Etomidate is frequently favored as an induction agent in this population given neutral effects on hemodynamics and ICP. More recent data suggests that ketamine may be a reasonable alternative in this population as it has not been shown to increase ICP, although it may cause hypotension in some so future research is needed.⁷⁴ Selection of optimal NMBA remains controversial. Either succinylcholine or rocuronium may be used. Succinylcholine's short duration of action makes it ideal for obtaining earlier neurologic exam post RSI, however recent retrospective studies have suggested rocuronium may be safer for patients with more severe TBI.⁷⁵

Limitations of Current Evidence and Future Areas of Research

Although many studies individually assess induction, neuromuscular blocking, vasopressors, and inotropic agents, there is no clear consensus on guidelines for the combined usage of these agents in critically ill patients who require TI.

While propofol was shown to have a direct negative hemodynamic effect in ICU patients during TI, the same effects have not been consistently observed, making it difficult to advise for or against the use of propofol in these situations.³⁹ Additionally, the pharmacodynamics of propofol can negatively affect hemodynamics, and the dose-dependent effect of propofol has not been studied, which may be the reason for the varying results. While the use of ketamine has been associated with hemodynamic stability, and preliminary data may indicate its superiority over etomidate, there is lack of data on comparison between ketamine and propofol, the two most widely used induction agents.^21,25 Similarly, there is limited data on the use of other sedative agents, such as benzodiazepines, and the co-administration of opioids has also not been studied in this patient population.

The use of succinylcholine and rocuronium has been individually researched in various clinical settings, and both agents have been deemed safe, with no difference observed in first pass intubation, hemodynamic instability, or oxygenation between the two agents. However, there is a lack of a prospective data comparing the administration of depolarizing and non-depolarizing NMBA in patients with PDA, especially in the aftermath of introduction of sugammadex. The effects of push dose administration of some of the vasopressors have been compared during the induction of anesthesia for TI, which have been shown to treat the hemodynamic instability that often occurs. However, there is no direct comparison of all the vasoactive agents with variable administration, i.e., push vs continuous infusion.

There is a plethora of clinical scenarios in which TI is needed for critically ill patients who have varying physiological states depending on underlying pathology, creating a great challenge to study the effect of these medications effectively. Moreover, the variability of clinical practice, based on institutional guidelines, individual preferences, and the availability of these medications, all add to the complexity of studying these agents in this population.

Table 1 lists some of the areas of future research in this field.

Table 1.

Areas of future research

Appropriate choice and dosing of anesthetic induction agents, including drug admixtures.

Co-administration of opioids with induction drugs and midazolam to prevent peri-intubation cardiovascular collapse and other complications.

Use of succinylcholine and rocuronium for RSI in difference patient populations with PDA that may be more affected by side effect profiles of the different NMBAs.

Optimal strategy to prevent cardiovascular collapse (using a fluid bolus, or vasopressors or a combination prior to TI) during TI.

Appropriate choice of vasopressor (ephedrine, phenylephrine, and norepinephrine) and its use (dose, timing, dilution) to prevent cardiovascular collapse during TI.

Conclusion

Medications administered during the management of a PDA have an impact on peri-intubation hemodynamics and may influence patient outcomes. Ketamine or etomidate have been recommended as the preferred sedative-hypnotic drugs. Either rocuronium or succinylcholine may be used for RSI with caution advised when using succinylcholine in certain situations. Norepinephrine is recommended as the first-choice vasopressor to treat hemodynamic instability associated with TI in patients with PDA. The role of preemptive use of norepinephrine to prevent cardiovascular collapse needs to be determined. Future research is required to answer the remaining uncertainties.

Orcid

Kunal Karamchandani https://orcid.org/0000-0003-3089-8088

Asad Khawaja https://orcid.org/0000-0002-2215-6896

Whitney Chaney https://orcid.org/0000-0002-2445-4010

Raksha Bangalore https://orcid.org/0000-0001-6512-9401

Sheila N Myatra https://orcid.org/0000-0001-6761-163X