Discussion

In this case series, sedative effectiveness and safety of intranasal dexmedetomidine for echocardiography sedation in the most haemodynamically vulnerable group of complex cyanotic CHD patients was demonstrated. A one-time dose of 3 mcg/kg intranasal dexmedetomidine resulted in successful study completion for all five infants with shunt-dependent pulmonary blood flow. While the majority of patients (80%) demonstrated changes in procedural vitals, there were no significant haemodynamic or major adverse events.

Transthoracic echocardiography is one of the most commonly performed diagnostic procedures requiring sedation in uncooperative children. The optimal regimen has not been established, leading to wide institutional variation in not only the choice of sedative agent but also the dose and route of administration. Drugs like pentobarbital, propofol or some combination of narcotics, benzodiazepines, inhaled anaesthetics, and etomidate have demonstrated improved image quality without serious adverse events; however, they are not easily administered. ^{Reference Staudt and Eagle17–Reference Miller, Ding and Gunter18} Intranasal dexmedetomidine, intranasal ketamine, oral chloral hydrate, and intranasal midazolam have been described as perhaps more suitable options. ^{Reference Alp, Elmacı, Alp and Say9,Reference Sun, Liu and Yu12,Reference Saudek, Walbergh and Bartz14–Reference Panda, Pujara and Chauhan16,Reference Miller, Ding and Gunter18}

Dexmedetomidine is a highly selective alpha-2 agonist that provides anxiolysis, mild analgesia, and cooperative sedation without respiratory depression. ^{Reference Hayden, Breatnach and Doherty19} It decreases central nervous system sympathetic outflow in a dose-dependent manner and can be administered intranasally for procedural sedation which is ideal when attempts to minimise traumatic administration via intravenous or intramuscular routes are taken into consideration. ^{Reference Hayden, Breatnach and Doherty19–Reference Poonai, Spohn and Vandermeer23} Oral chloral hydrate has previously been the drug of choice for moderate sedation in uncooperative infants and toddlers requiring complete echocardiogram for decades. ^{Reference Hill, Walbergh and Frommelt24–Reference Fett, Hackbarth and Boville26} However, chloral hydrate is no longer commercially available in the United States. ^{Reference Miller, Divanovic, Hossain, Mahmoud and Loepke2} Prior studies have established good sedative features of intranasal dexmedetomidine with short half-life, faster recovery time, and effective sedation. ^{Reference Schwartz, Twite, Gulack, Hill, Kim and Vener1,Reference Banasch, Dersch-Mills, Boulter and Gilfoyle3}

intranasal dexmedetomidine has been safely and effectively used for sedation in children undergoing transthoracic echocardiography, but little has been published on its use in infants with complex and/or cyanotic heart disease. ^{Reference Gu, Song and Bai10–Reference Williams, Raees and Sunthankar13,Reference Miller, Ding and Gunter18} Our institutional experience has documented tolerance of intranasal dexmedetomidine in patients with significant complex heart disease and cyanotic heart disease; however, this had previously excluded single ventricle heart disease. ^{Reference Saudek, Walbergh and Bartz14} Virtually no published data exist regarding intranasal dexmedetomidine use in infants with single ventricle physiology and shunt-dependent pulmonary blood flow who are more at risk for complications related to changes in afterload and heart rate. While intranasal dexmedetomidine has emerged as an attractive option for procedural sedation in paediatrics, the downside to intranasal dexmedetomidine use includes dose-dependent hypotension and bradycardia that may limit its use amongst interstage infants who have a potentially unstable circulation. ^{Reference Yang, Li and Shi20–Reference Yu, Liu and Sun21}

Doses of 1.5–4 mcg/kg/dose intranasal dexmedetomidine have been described for procedural sedation with higher doses resulting in longer duration of adequate sedation. ^{Reference Yang, Li and Shi20–Reference Yu, Liu and Sun21,Reference Tug, Hanci and Turk27} Based on institutional experience, our practice was to administer 3 mcg/kg as an initial dose of intranasal dexmedetomidine with an adjunct 1 mcg/kg/dose if not sedated after 25 minutes. As previously published, the initial dose of 3 mcg/kg intranasal dexmedetomidine resulted in high rates of echocardiogram completion with over 98% study completion without need for adjunct dose at our institution’s echo lab. ^{Reference Saudek, Walbergh and Bartz14} This same initial intranasal dexmedetomidine dose resulted in adequate sedation defined as successful study completion in all five inpatient interstage patients without the administration of a rescue adjunct dose. Two patients (40%) briefly awoke during the echocardiogram but were able to fall back asleep without additional sedation.

There were no significant adverse events. Procedural vitals showed reductions in heart rate, pulse oxygen saturation and blood pressure when compared to baseline in all but one patient, however these haemodynamic trends were considered minor as they did not require escalation in care or interruption of echo and ultimately, self-resolved. Consistent with its mechanism of action, most patients receiving intranasal dexmedetomidine had a transient lower heart rate during sedation, but this did not cause circulatory compromise. We detected no concomitant hypoperfusion or decreased contractility on echocardiogram in any of these patients. There were no episodes of haemodynamic instability, and importantly, there was no requirement for any additional inotropy to maintain haemodynamic stability.

Our institutional practice has favoured intranasal dexmedetomidine for echocardiographic sedation as it has several advantages over other commonly used and comparable agents by avoiding unpleasant side effects while maintaining ease of administration, good efficacy, and low-risk profile. Midazolam, a benzodiazepine, is the most commonly studied procedural sedation drug and can be administered either intranasally or orally; however, it provides no analgesia and is associated with adverse events such as post-operative behavioural changes, cognitive impairment, paradoxical reactions, and respiratory depression. ^{Reference Alp, Elmacı, Alp and Say9,Reference Panda, Pujara and Chauhan16} Additionally, intranasal midazolam is known to provide nasal irritation and burning. ^{Reference Sheta, Al-Sarheed and Abdelhalim28} On the contrary, intranasal ketamine is used for its pain controlling aspect and may provide less bradycardia than dexmedetomidine but is not devoid of adverse events such as gastrointestinal tract stimulation, excessive salivation, nystagmus, an increased incidence of emergence agitation, and an unpleasant bitter taste. ^{Reference Lewis and Bailey4–Reference Fantacci, Fabrizio and Ferrara5,Reference Alp, Elmacı, Alp and Say9,Reference Sun, Liu and Yu12,Reference Goyal, Singh, Bangi and Singh15} Finally, an important factor when choosing a sedative medication in children is their potential effect on the developing brain. ^{Reference Lewis and Bailey4,Reference Berkenbosch6,Reference Staudt and Eagle17} Neurotoxic effects of GABAergic agonists, such as midazolam, and NMDA receptor antagonists, such as ketamine, have been established in animal studies, whereas dexmedetomidine has demonstrated neuroprotective effects in rodent models and primates. ^{Reference Jevtovic-Todorovic, Absalom and Blomgren29–Reference Koo, Oshodi, Meschter, Ebrahimnejad and Dong31}

This study did have several limitations. The sample size of our study was small, and further study in a larger cohort is needed to truly evaluate both efficacy and safety. Although comprehensive echo studies were completed in all subjects using a one-time dose of 3 mcg/kg intranasal dexmedetomidine, while adequate sedation was achieved, uninterrupted sedation was not achieved. Prior investigations do suggest that when selecting intranasal dexmedetomidine dose for echo sedation, consideration for cyanotic CHD is important as the effective dose for sedation is higher in children with cyanotic CHD. ^{Reference Miller, Ding and Gunter18,Reference Yang, Li and Shi20–Reference Yu, Liu and Sun21} Our study did not investigate different dosing strategies for sedation in interstage infants nor the intranasal dexmedetomidine dose-response relationship since our target was achieving sedation. Also, our study did not establish an objective sedation scale which is a consideration for future studies. Future investigation should consider the haemodynamic risk of a higher intranasal dexmedetomidine dose balanced with the potential benefits of longer depth and duration of sedation. Finally, it has been well-established that circulatory compromise during the interstage period can be reflected using near-infrared spectroscopy-derived somatic/renal regional saturations as a non-invasive measure of systemic venous oxygen delivery and can allow for earlier identification of low cardiac output early after initial palliation of hypoplastic left heart syndrome. ^{Reference Hoffman, Ghanayem and Scott32} Due to the retrospective nature of this study, complete near-infrared spectroscopy data on all patients were not available. Additional study in patients with single ventricle physiology and shunt-dependent pulmonary blood flow during the interstage period using regional oximetry to fully describe the haemodynamic effects of intranasal dexmedetomidine is warranted.