Comparison of older and newer sedation agents in bronchoscopy

Abstract

Flexible bronchoscopy is an important diagnostic and therapeutic modality in pulmonary medicine. Appropriate sedation is essential for patient safety and comfort. Several agents, such as benzodiazepine and opiates (fentanyl, Midazolam, and morphine), have been used for conscious sedation and anxiolytics. Lately, there has been an influx of newer sedation agents that have been valuable in bronchoscopy because of their beneficial properties. For example, Ketamine, a dissociative anesthetic, has been used during bronchoscopic procedures as an alternative to conventional sedatives or as an adjunct to them. Its bronchodilatory effects, minimal respiratory depression, sympathomimetic effect leading to hemodynamic stability, and analgesic properties make it particularly valuable in high-risk populations, including patients with respiratory compromise. Besides Ketamine, Esketamine, Dexmedetomidine, and other agents are also being used. This minireview explores the role of older and newer agents in bronchoscopy, highlighting their efficacy, safety profile, and potential advantages.

Key Words: Bronchoscopy; Sedative agents; Fentanyl; Midazolam; Ketamine; Esketamine; Dexmedetomidine; Sedation; Procedures

Core Tip: Bronchoscopy is a diagnostic and therapeutic tool. However, adequate sedation is necessary to ensure patient comfort and safety. The newer agents, such as Ketamine and Dexmedetomidine offer potential advantages in terms of reducing complications, maintaining hemodynamic stability, and improving procedural comfort compared to traditional agents like benzodiazepine and opioids. Exploring the benefits and side effects of these medications can enhance sedation strategies in bronchoscopy.

INTRODUCTION

Bronchoscopy is an essential tool in pulmonary medicine for diagnostic and therapeutic procedures. Due to its versatility and minimally invasive approach, flexible bronchoscopy (FB), a technique introduced by Shigeto Ikeda in 1966, is the most widely used modality of bronchoscopy[1]. FB minimizes the limitation of rigid bronchoscopy (RB) in procedures such as bronchoalveolar lavage and transbronchial lung biopsy[2]. However, FB has limited use in certain therapeutic interventions, such as silicone stent placement or management of massive hemoptysis[3].

RB was first introduced by Gustav Killian in the 1870s. It is used for both diagnostic and therapeutic procedures such as lung biopsy, cryotherapy, and endobronchial stent placement[4]. Endobronchial ultrasound, another bronchoscopy technique, is used with ultrasound to locate anatomical structures like lymph nodes, for example, which then can be biopsied to rule out infection or malignancy[5]. Electromagnetic navigational bronchoscopy and Robotic bronchoscopy, a newer bronchoscopy technique, uses electromagnetic sensors to navigate the bronchoscope toward the target lesion[6]. Irrespective of the technique, bronchoscopy could be performed without sedation. However, this would be very uncomfortable for the patients and is not advisable.

Most inadequately sedated patients during FB endorse discomfort. This lowers the chances of the patient repeating the procedure[7,8]. The goal of sedation in bronchoscopy is to provide analgesia, minimize anxiety, protect reflexes, and allow patients to follow commands[9].

Traditionally, benzodiazepines and opioids have been the preferred sedation in bronchoscopy. However, there has been growing interest in newer anesthetic combinations that might deliver better outcomes. Ketamine, Dexmedetomidine, and other newer agents have the potential to reduce complications by improving procedural comfort and safety, such as airway reflexes and hemodynamic stability while maintaining adequate sedation and analgesia[10]. In this paper, we will compare the newer and traditional agents.

LITERATURE SEARCH

A literature search was conducted using major medical databases such as PubMed, Google Scholar, etc. For accuracy and the most updated pricing of the medications, Medscape, meta-analyses on each medication, and other online websites such as Drugs.com were used. This minireview focused on systematic reviews, meta-analysis, randomized control trials (RCTs), retrospective studies from peer-reviewed journals that involve traditional, newer sedative agents, and combination regimens when used in bronchoscopies. The studies were critically interpreted and assessed for accuracy from other studies prior to being included in this minireview.

OLDER AGENTS

Midazolam

Mechanism: Midazolam is a benzodiazepine approved in 1980s provides an enhancing effect on the gamma-aminobutyric acid (GABA) receptor, the primary inhibitory neurotransmitter in central nervous system[11]. The presence of fused imidazole ring in Midazolam enhances its water solubility compared to other benzodiazepines[11]. In addition to the enhancing effect, Midazolam binds to benzodiazepine receptors located on GABA receptor complex (α and γ subunits) resulting in increased frequency of chloride channel opening. The influx of chloride ion results in reduced neuronal firing that produces effects such as sedation, anterograde amnesia, and anxiolysis[11]. Amongst many benzodiazepines, Midazolam is one of the most frequent benzodiazepines of choice due to its favorable pharmacokinetics, which includes rapid onset of action (30 seconds-1 minute), rapid time to peak effect (5-10 minutes) and relatively short duration of action (2 hours). Elimination half-life is reported at 1.6-3.2 hours as illustrated in Table 1[12]. As mentioned previously, Midazolam provides sedative, hypnotic, and anxiolytic effects but at higher dosages is reported to have dissociative properties[12,13]. In addition, it is reported that Midazolam is superior in terms of potency compared to Diazepam due to its high affinity towards benzodiazepine receptor[11]. Of note, older population tend to achieve sedation at a lower dose and experience longer recovery time with benzodiazepine. In contrast, individuals with history of stem cell, lung transplant or drug dependence are observed to require higher dose to achieve the desired sedative effect with Midazolam[11,12].

Table 1 Pharmacokinetics, advantages and disadvantages of sedatives used in bronchoscopy.

Medication	Pharmacokinetics	Metabolic pathway	Advantages	Disadvantages	Adverse effects
Midazolam	Onset: 30–60 seconds; duration: 2 hours	Primarily hepatic	Reversal agent (Flumazenil), amnesia, cerebral protection	Risk of liver disease	Respiratory depression, hypotension, nausea, pain/swelling at injection
Diazepam	Onset: 1–5 minutes; duration: 6–8 hours; half-life: Approximately 100 hours	Hepatic	Long-acting, Flumazenil antidote, large therapeutic window	Less potent, long-duration	Sedation, dizziness, hypotension, respiratory depression, dependency
Propofol	Onset: 30 seconds; duration: 3–10 minutes	Hepatic	Fast onset, anti-emetic, bronchodilator, less cough	Poor amnesia, complex recovery	Hypotension, respiratory depression, bradycardia, pain, infection risk, high mortality risk in pediatric population
Fentanyl	Onset: 1–2 minutes; duration: 30–60 minutes	Hepatic CYP3A4	Strong analgesic, rapid onset	High respiratory depression, bradycardia	Nausea, vomiting
Ketamine	Onset: 10–30 seconds; duration: 5–15 minutes	Hepatic	Dissociative, bronchodilator, airway reflex preserved	Hallucinations, long recovery	Elevated blood pressure, hallucinations, worsens psychosis
Ketofol	Onset: 30 seconds; duration: 5-10 minutes1	Hepatic	Synergistic sedation, combines benefits	No standard ratio, and there remains risk of apnea	Hallucinations, nausea, secretions, respiratory depression
Remifentanil (Ultiva)	Onset: 1–2 minutes; duration: 5–10 minutes	Tissue esterases and blood	Very fast onset/offset, ideal for short procedures	Expensive, needs close monitoring	Respiratory depression, bradycardia, hypotension, nausea
Dexmedetomidine	Onset: 10–15 minutes; duration: 1–2 hours	Hepatic	No respiratory depression, less nausea/vomiting/delirium	Long onset, Prolonged recovery, liver clearance impacted	Hypotension bradycardia
Esketamine (Spravato)	Onset: 5–10 minutes; duration: 20–40 minutes; half-life: 7–12 hours2	Hepatic	Fast, stable hemodynamics, fast recovery, less desaturation	Expensive, limited data	Dissociation, elevated BP, nausea, dizziness3, psychiatric/visual symptoms3

¹Duration varies depending on Ketamine-Propofol ratio.

²Based on intramuscular nasal formulation due to lack of clinical studies.

³Specifically in the pediatric population based on studies.

Benefits: One of the benefits of Midazolam is noted to be cerebral protection as it reduces cerebral hypoxia and ischemia in a dose-dependent manner. The reduction in cerebral metabolic rate for oxygen and cerebral blood flow is said to benefit patients with impaired intracranial compliance or increased intracanal pressure[11]. Furthermore, overall heart function, which includes heart filling pressure, is said to remain stable even though there is a small decrease in blood pressure and a slight elevation in heart rate noted at 0.15mg/kg IV[11]. The availability of a reversal agent, Flumazenil, allows quick reversal of Midazolam if a complication arises[12]. In comparable dosage, Midazolam can produce significantly greater anterograde amnesia than Propofol[14].

Side effects: Midazolam has relatively low side effects. Nonetheless, the most common side effects are noted to be restlessness (5.6%), coughing (1.5%), nausea, and vomiting (36.8%). Furthermore, pain and swelling at injection site occur in 10%-78% of cases[11]. There is a risk of prolonged sedation in patients with liver dysfunction as Midazolam is metabolized via the liver. It should also be noted that Midazolam can cause some respiratory depression compared to other benzodiazepine like Diazepam[11].

Cost: Midazolam is available in injectable solution (1 mg/mL) and 5 mg/mL with the cost of $14.58 for 50 mL and 14.56 for 20 mL respectively Table 2[15].

Table 2 Year of introduction and pricing of sedatives used for bronchoscopy.

Medication	First use in bronchoscopy	Price (approx)1
Midazolam	1980s	1 mg/mL: $14.58 5 mg/mL: $14.56
Diazepam	1960s	2 mL: $8.29–$14.60/mL (10 vial minutes) 10 mL: $3.84–$4.72/mL (10 vial minutes)
Propofol	1980s	20 mL: $5, 50 mL: $10, 100 mL: $20
Fentanyl	1968	2 mL: $1.49/vial, 20 mL: $13.89/vial
Ketamine	1970s	20 mL: $18, 10 mL: $6, 5 mL: $10
Ketofol	2000s	Based on Ketamine and Propofol concentrations used
Remifentanil (Ultiva)	1996	1 mg: $36.21–$62.5, 12 mg: $103.83–$141.57, 5 mg: $219.33–$286.49
Dexmedetomidine	1999 (FDA-approved)	$45.21 per 2 mL vial (100 μg/mL)
Esketamine (Spravato)	2010s (FDA: 2019)	56 mg dose: $440.08; 84 mg dose: $438.54

¹Prices fluctuate with overall marketing supply and demand, supply chain considerations, and hospitals’ overall storage, handling, and administration costs.

FDA: Food and Drug Administration.

Diazepam

Starting in 1963, Diazepam was introduced as a sedative in which its use then expanded for bronchoscopies in the late 1960s. In 1973, a study that pioneered bronchoscopy, albeit RB, used Diazepam for sedation. It evaluated its initial use as a premedication during general anesthesia to assess for awareness during bronchoscopy and laryngoscopy. Even though the findings were insignificant, this paved the way for further investigation with Diazepam for these procedures[16].

Mechanism: Diazepam is another benzodiazepine that also works on the GABA receptor and was initially approved by the Food and Drug Administration (FDA) for alcohol withdrawal and febrile seizures[17]. Like Midazolam, Diazepam binds to the benzodiazepine receptor which results in increased influx of chloride ions[18]. Diazepam has a similar onset of 1-5 minutes as other benzodiazepines, but a much longer duration of action of 6-8 hours. Peak onset ranges from 1 hour to 1.5 hours[18]. The medication half-life of the active metabolite N-desmethyldiazepam is up to 100 hours, which is excreted through the urine[18].

Benefits: In one study, the efficacy and safety of Midazolam, Diazepam, and Propofol were compared in patients undergoing bronchoscopy. The study found that while the side effects of hypotension and respiratory depression were similar between Diazepam and Midazolam, these effects appeared to be more pronounced with Propofol[19]. It also found that Midazolam caused more profound amnesia as compared to Diazepam[20]. Overall, the therapeutic index of Diazepam is remarkably high, allowing it to be used safely. However, the risk becomes more profound when combined with other sedatives such as opiates, alcohol, barbiturates, and other centrally acting agents[18]. The antidote, Flumazenil, provides extra safety in the event of an overdose.

Side-effects: Like most sedating agents' Diazepam can cause hypotension and respiratory depression. Other side effects include suicidal ideation, dependency, and syncope[18]. Additionally, more prolonged sedation was observed with Diazepam compared to the other sedatives. Although Diazepam is effective for sedation during bronchoscopy, it may not be the best choice for short procedures requiring rapid recovery[19] as noted in Table 1.

Cost: Diazepam is available in two vials, 2 mL and 10 mL. A 2 mL vial runs between $8.29 and $14.60 per mL if buying 10 vials at a time, and the 10 mL vial runs between $3.84 and $4.72 per mL if buying 10 vials at a time[21].

Propofol

Mechanism: Introduced in clinical medicine in the 1980s, Propofol is currently well known for its use to provide anesthesia/sedation. Propofol (2,6-disoproplyphenol) is a lipophilic anesthetic medication that binds to the beta-subunit of GABA-A receptors[22]. It is metabolized via the liver and excreted through the urine. The onset of action is noted to be 30 seconds, peak effect at 5 minutes and duration of action around 3-10 minutes. In terms of half-life, Propofol exhibits rapid distribution phase of 2-4 minutes, slower elimination phase of 30-60 minutes and a terminal elimination phase of 3-12 hours that can be prolonged with extended administration[23].

Benefits: The advantage of Propofol is its quick onset of around 30 seconds compared to other agents, such as Midazolam, which results in faster recovery[23]. This characteristic makes Propofol ideal for short procedures. Furthermore, compared to a placebo, the use of Propofol for sedation resulted in fewer reports of cough, pain, and asphyxiation sensation during the procedure. Propofol also provides anti-emetic, antipruritic, anxiolytic, bronchodilator effect[23].

Side effects: Notable hemodynamic effects include decreased arterial blood pressure, vascular resistance, and cardiac contractility. Depending on the dose, this agent can cause respiratory depression and inhibit hypoxic ventilatory drive. Furthermore, other undesirable effects include local pain at the injection site[24]. Due to the lipophilic nature of Propofol, there is a risk of inflammatory response as well as healthcare-related infection which could potentially worsen clinical outcomes in critically ill patients[25].

In an unpublished RCT, significant mortality in pediatric population was observed among those receiving standard Propofol as sedative agent. Therefore, FDA recommends against using Propofol in this population along with pregnant women[25]. In comparison to Midazolam, Propofol is shown to have inferior efficacy in producing substantial anterograde amnesia[14].

Cost: The generic injection is available in three sizes. A 20 mL vial will cost around 5 dollars, a 50 mL vial will cost around 10 dollars, and a 100 mL vial will cost around 20 dollars[23].

Fentanyl

Originally FDA approved for use in sedation and pain control by the FDA in 1968, opiates have been used in bronchoscopies since the 1970s and 1980s.

Mechanism: These agents bind to the μ-receptor which then hyperpolarizes the cell causing a decrease in nerve cell excitability. When a ligand is bound to the μ-receptor, potassium flows into the cell causing hyperpolarization, thus inhibiting cell activation. While both opioids can be used in bronchoscopy, fentanyl is more suitable for shorter procedures due to its rapid onset of 1-2 minutes and shorter duration of action from 30 minutes to 60 minutes[12]. Drug half-life has a wide range between 3 hours and 7 hours, metabolized by the liver via the CYP3A4 system, and is predominately renally excreted[26].

Benefits: Given its rapid onset, fentanyl makes for a viable choice for shorter-term procedures like bronchoscopies. Many studies have compared fentanyl’s use as an adjunct sedative with favorable pain-related outcomes[12]. Morphine, due to its longer half-life, outperforms fentanyl on this endpoint[12].

Side effects: Opiates as a class are known for their respiratory depression, bradycardia, and hypotension which increases incidence in intubations[12]. Fentanyl, specifically, is one of the most potent opiates that is 100 × more potent than morphine[12]. Fentanyl is contraindicated in patient population with history of Chronic obstructive pulmonary disorder (COPD), asthma, sleep apnea[26].

Cost: Currently, fentanyl is sold in 2 mL vials and 20 mL vials which cost $1.49 and $13.89 per vial respectively[27,28].

Compared to the newer agents, the above-described medications remain cost-effective and widely available at hospitals across the United States.

NEWER AGENTS

Ketamine

A structural analogue of phencyclidine, Ketamine is a dissociative sedative mostly used in the pediatric population for bronchoscopy and endoscopy. Introduced in medicine in 1964, its use is widely seen in disaster medicine in developing world due to its high safety margin in terms of death from overdose[22,29].

Mechanism: This sedative acts by inhibiting receptors in the central nervous system via non-competitive N-methyl-D-aspartate (NMDA) receptor and partially activating opioid receptors known as μ-receptor[30]. NMDA receptors (NMDARs) are glutamatergic signaling channels largely expressed in CNS which are activated by glutamate. This causes influx of sodium and calcium which causes depolarization and neuronal excitability. Ketamine alters glutamatergic signaling leading to dissociative state accompanied by analgesia and sedation[31,32]. Ketamine is metabolized via the liver and excreted through urine[30]. Ketamine has a rapid onset of 10-30 seconds along with a duration of action from 5 minutes to 15 minutes, and peak concentration is achieved in plasma peak concentration achieved within 1-3 minutes with a short elimination half-life of 2 hours[31,30].

Benefits: Ketamine provides analgesic and anesthetic properties, making it a valuable tool during bronchoscopy. The effect of analgesia is comparable to that of opioids but with a significantly lower risk of respiratory depression. Furthermore, an adequate analgesic effect is provided by Ketamine, even at subanesthetic doses[30,31]. The sympathomimetic effect, such as an increase in vascular tone and heart rate, makes Ketamine one of the better choices for the hemodynamically unstable patient population. In addition, the bronchodilator effect of Ketamine is useful in bronchoscopy, especially in counteracting airway reactivity and bronchospasm. Airway reflexes, as well as cough reflex, laryngeal reflex, and pharyngeal muscle tone are maintained during sedation with Ketamine which reduces the risk of aspiration[32].

Side effects: Ketamine can induce dissociative and psychotomimetic effects as they recover from anesthesia. The symptoms include but are not limited to an altered sense of self, time, and time-positive and negative symptoms such as hallucinations and emotional detachment, respectively. In addition, patients with underlying schizophrenia can have exacerbated psychotic symptoms[31]. Recovery time from Ketamine was also noted to be prolonged compared to Propofol[30].

Cost: The cost of generic Ketamine injection varies based on concentration and vial size: (1) A 10 mg/mL, 20 mL vial costs $18; (2) A 50 mg/mL, 10 mL vial costs $6; and (3) A 100 mg/mL, 5 mL vial is priced at $10, while a 100 mg/mL, 10 mL vial costs $14[33].

Ketamine + Propofol (Ketofol)

Mechanism: Ketofol is a combination of Ketamine and Propofol, used for balanced sedation, providing both analgesia and sedation. The mixture consists of a 1:1 ratio of Ketamine and Propofol[22].

Benefits: The combination of these agents counteracts each other’s adverse effects. Ketamine can cause vomiting, while Propofol’s anti-emetic effect balances this effect. Therefore, it reduces the propensity for vomiting[34]. Propofol causes cardiovascular depression, but the combination with Ketamine balances out this side effect[22]. The sedative effect of Ketofol is also noted to be additive, resulting in a lower total dose requirement[22,35]. In addition, recovery time is shorter with the combination compared to Ketamine or Propofol alone[22]. Median recovery time was noted to be 13 minutes for Ketofol and 16 minutes for Ketamine alone. Ketofol is slightly better in terms of total sedation time and recovery time[34]. Furthermore, the peak effect is 1-2 minutes, and the duration of action is often around 5-10 minutes. However, it must be noted that duration of medication varies depending on the Ketamine-Propofol ratio and dose resulting in inconsistent results[36].

Side effects: In clinical trials, Ketofol did not demonstrate significant reduction in apnea, airway obstruction, desaturation, and respiratory depression compared to other sedations[37]. Ketofol did not demonstrate lower incidence of adverse respiratory events compared to Propofol[37]. In most of the studies, an absence of standardized dosages/ratios used for Ketamine and Propofol combination appears to make it difficult to create an optimal dosage protocol resulting in inconsistent results across the trials[37].

Cost: The price of Ketamine ranges from $6 to $18 per vial, and Propofol is typically priced around $5-$20 per vial depending on the ampule[23,33].

Remifentanil (Ultiva)

Beginning in 1996 Remifentanil became available in the United States. Its popular use is attributable to its profile as a potent, ultra-short-acting synthetic opioid used for pain management and sedation in procedures like surgery and intensive care. It is an analog to fentanyl but differs greatly in part due to the ester side chain which affects pharmacokinetics.

Mechanism: It is a μ-receptor agonist, like morphine or fentanyl. It is metabolized by tissue esterases and blood, independent of the liver or kidneys, making it particularly suitable for patients with liver or kidney impairment[38]. A total of 95% of the metabolites are renally excreted with the remainder removed via feces[39]. Remifentanil is frequently used in bronchoscopy due to its rapid onset of action (1-2 minutes), short duration (with a half-life of less than 10 minutes), and ease of titratability[38]. These characteristics, especially its short half-life, make Remifentanil ideal for short procedures.

Benefits: Remifentanil has been compared to a Midazolam/Propofol combination in patients undergoing flexible fiberoptic bronchoscopy and showed no significant difference in adverse outcomes, such as desaturation, hypotension, or arrhythmias[39]. However, patients receiving Remifentanil had a significantly shorter recovery time (6.4 minutes vs 11.6 minutes), indicating its effectiveness in facilitating rapid recovery after the procedure[39]. When compared to fentanyl alone, the recovery period is significantly reduced (3.8 minutes vs 10.4 minutes)[40]. Remifentanil does not seem to benefit much as an adjunctive in pain management during bronchoscopy[41]. Nevertheless, its rapid onset and minimal impact on liver or kidney function make Remifentanil a valuable option for sedation during bronchoscopy procedures[41].

Side effects: Like other opiates, common side effects include respiratory depression, nausea, vomiting, and bradycardia[12]. Although hemodynamic fluctuations are common for opiates as a class, Remifentanil does not release histamine when injected, unlike morphine, which allows for more predictable hemodynamic variations.

Cost: The effective dosage for anesthesia induction is 0.5-1 μg/kg/minute and due to the high elimination rate by tissue esterases, boluses with the same induction dose can be given every 2-5 minutes, which can become expensive even in short procedures[42]. Although promising, Remifentanil remains very expensive. It comes in 3 different powdered vial formulations 1 mg at $36.21-$62.51 per vial, 2 mg at $103.83-$141.57 per vial, and 5 mg at $219.33-$286.49 per vial[43].

Dexmedetomidine (Precedex)

Mechanism: Dexmedetomidine FDA approved in 1999 is a selective alpha-2 adrenergic agonist that provides sedation and analgesia[44]. It has been evaluated for safety and efficacy as a sedative during bronchoscopy extensively. Dexmedetomidine is primarily eliminated via the liver[44].

Half-life is reported to be around 2.1-3.1 hours in a healthy patient and in critically ill patients, it is reported to be 2.2-3.7 hours. The onset of action is around 5 minutes, and the peak effect occurs within 15 minutes[45].

Benefits: According to a systematic review and meta-analysis, Dexmedetomidine offers adequate sedation while maintaining spontaneous breathing and the ability to follow commands, making it a promising option for procedural sedation[46]. Compared to traditional sedatives like Midazolam or Propofol, Dexmedetomidine is associated with a significantly lower incidence of hypoxia[46]. When evaluating other key outcomes such as hypotension, hypertension, patient satisfaction, arrhythmia, and coughing, no significant difference was found between Dexmedetomidine and a placebo[46]. However, the advantages of Dexmedetomidine over older sedatives include its ability to avoid excessive sedation and respiratory depression, thus preserving airway reflexes and allowing patients to follow commands while being adequately sedating, i.e., conscious sedation is meaningfully achieved. Furthermore, it results in fewer side effects such as nausea, vomiting, and delirium[46].

Side effects: Despite these advantages, Dexmedetomidine induces dose-dependent bradycardia and hypotension. This has been associated with sympathetic depression from its action on the alpha-2 receptor[46]. Another disadvantage is the prolonged recovery time compared to Propofol[46]. It must also be noted that there is a recommendation to cautiously use Dexmedetomidine in patients with a medical history of heart failure. It can potentially worsen myocardial dysfunction[47].

Cost: A total of 100 μg/mL in a 2 mL glass vial is reported to cost $45.21 per vial[48].

Esketamine (Spravato)

Esketamine is the S-enantiomer form of Ketamine that received FDA approval in 2019 for treating treatment-resistant depression[49]. It is available in the United States although it must be administered in a healthcare facility under supervision. Additionally, most research has focused on comparing Esketamine to Ketamine in the context of treatment-resistant depression. It is currently being used off-label in trials for its role in bronchoscopies in pediatric patients as combination therapy with other sedatives[50].

Mechanism: Also, compared to the full racemic Ketamine, Esketamine has been shown to bind to the NMDA receptor more potently, which can lead to stronger anesthetic and analgesic effects, including dissociative amnesia[51,50].

Benefits: The pharmacokinetics are like that of Ketamine, with metabolism primarily occurring in the liver, but Esketamine offers a faster onset of action, particularly with nasal formulations, while intravenous formulations exhibit similar onset times to Ketamine[49]. Additionally, Esketamine has a longer duration of action (30–60 minutes) compared to Ketamine’s shorter duration (15–30 minutes), making it a potentially longer-lasting sedative option[48]. Unfortunately, little accurate data exists for the half-life of the IV/IM formulation, but the intranasal formulation half-life is between 7-12 hours within the adult population[52]. Lastly, it is mainly metabolized by the liver and predominantly removed via renal excretion[49].

The sympathomimetic properties of Esketamine allow it to counteract the common adverse effects of respiratory depression and hemodynamic instability seen in other sedatives[50,53]. Stronger effects are evident at lower doses, making it potentially advantageous in certain clinical settings. A study compared Propofol/Esketamine (dose 0.2 mg/kg) to Propofol/Ufentanil (dose 0.2 μg/kg) and showed that Esketamine was able to counteract the effects of Propofol. Additionally, it showed reduced rates of cardiovascular and respiratory depression with opiates compared to other opiates[50,54]. Esketmine has shown efficacy in bronchoscopies with more stable hemodynamics, faster recovery time, longer duration of analgesia, and lower incidence of adverse reactions such as oxygen desaturation and injection site pain[55-57].

Side effects: Side effects are similar to Ketamine, although Esketamine has lower rates of cardiovascular stimulation due to its remarkable selectivity for the NMDAR, lower dosage, and shorter duration, causing less sympathetic stimulation[56]. Also, based on studies, there is an increase in psychiatric symptoms, and in children, there was an increase in visual disturbances and dizziness[56].

Cost: Outside of clinical trials, Esketamine is not available in IV formulations. The approved intranasal formulations are 28 mg/device (56 mg dose), nasal spray $440.08 per dose, and 28 mg/device (84 mg dose) $438.54 per dose[57].

CONCLUSION

Bronchoscopy remains an essential tool in pulmonary medicine for diagnosis and therapeutic procedures. Alongside bronchoscopy, sedation plays a critical role in providing comfort and procedural success. This minireview places emphasis on the advantage of newer agents such as Ketamine, Dexmedetomidine, Esketamine and combination therapies over traditional sedation strategies. The specific benefits such as bronchodilation, hemodynamic stability, patient-specific factors are highlighted as well.

Appropriate selection of sedative agent should include consideration of individualized patient–specific factors, safety and procedural requirements. Based on the review, patients with obstructive airway disease, such as COPD or asthma, would benefit from agents such as Ketamine, Propofol, or Esketamine due to their bronchodilator effect. Hemodynamically unstable or emergent endoscopy cases are best managed by Ketamine or Ketofol due to their supportive effect on cardiovascular system. Both Ketamine and Ketofol also seem to be appropriate choices for the pediatric population. At the other end of the spectrum, the geriatric population will require dosing consideration, especially with benzodiazepines.

Medical providers should utilize the recommended agents by focusing heavily on patient-oriented medical factors and procedural duration. This approach is more likely to improve patient safety and enhance patient comfort.

Although various choices for sedative agents are available for bronchoscopy, data heavily extracted from observational data fail to prove causation, and control of variables is highly limited. There remains a need for larger, randomized controlled trials to compare traditional sedatives (Midazolam, Propofol) with newer sedatives (Ketamine, Dexmedetomidine) in a heterogenous population. Such studies would further establish evidence-based guidelines for health providers.

Future research should evaluate individual agents and address the use of combinations of traditional and newer sedative agents. Agents such as Ketamine and Propofol (Ketofol) can offer synergistic benefits. However, limited controlled clinical trials exist. Once available, such data would provide a clear guideline regarding sedation practices in bronchoscopy.