Procedural sedation is increasingly used to decrease anxiety, fear, or pain during diagnostic examinations and procedures. This is an essential aspect of clinical practice for pediatric patients who cannot cooperate. Intravenous (IV) anesthetics such as midazolam, ketamine, propofol, and dexmedetomidine can be used for pediatric sedation. However, most patients requiring procedural sedation attend outpatient clinics and IV access is not established [1]. For these patients, non-IV routes, such as oral, intramuscular, or intranasal administration, are used.

Historically, the most widely used non-IV sedative is oral chloral hydrate syrup. However, its use presents considerable challenges due to slow onset of action, prolonged sedation, and high incidence of gastrointestinal side effects (nausea and vomiting) that limit sedation success rate and result in complications such as respiratory depression, oxygen desaturation, and even death [2–5]. Chloral hydrate has not been produced in the United States since 2012.

Nevertheless, chloral hydrate is widely used for pediatric sedation in South Korea [6–9]. Despite the availability of alternative options [2,7,10–18], many hospitals continue to use oral chloral hydrate because of its low cost and its familiarity among medical staff [1,6]. If chloral hydrate is shown to have a low success rate or significant side effects in a given patient population or procedure, replacement of the sedative is appropriate. Therefore, to ensure safe and effective sedation, it is important to examine the success rate and side effects of chloral hydrate sedation based on patient characteristics and the procedures involved. To the best of our knowledge, such an analysis has not been previously conducted in South Korea.

This retrospective study aimed to analyze the success rate and incidence of side effects of pediatric chloral hydrate sedation in South Korea and identify the risk factors for procedural sedation failure and sedation-related complications.

A total of 6,773 pediatric procedural sedation during the study period (between January 1, 2021, and March 30, 2022) were identified. Of these, 82 patients were excluded due to incomplete data, with 6,691 patients included in the analysis. The incidence of sedation failure was 21.8% (1,457/6,691) with an initial dose of oral chloral hydrate (50 mg/kg).

Patient characteristics are shown in Table 1. There were significant differences in the proportion of age groups, patient weight, hospitalization status, presence of congenital syndrome or congenital heart disease, oxygen dependency, tracheostomy state, history of sedation failure or complications with chloral hydrate, procedure type or duration, and duration of sedation between the failed and the successful procedural sedation groups. Patient characteristics according to complications occurring after chloral hydrate are set out in supplemental Table 1.

Patients with failed procedural sedation had a higher overall complication rate (17.5% [225/1,457]) than those with successful sedation (6.2% [324/5,234]). Respiratory depression, desaturation, vomiting, and paradoxical excitation were more common in patients with failed sedation than in those with successful sedation. This trend was observed across all age groups (Table 2).

Using multivariable regression, the following were identified as factors associated with an increased risk of sedation failure: weight, inpatient status on a general ward or intensive care unit, congenital syndrome, oxygen dependency, a history of sedation failure or complications with chloral hydrate for the same procedure, procedure duration more than 60 min, angiography, computed tomography, lumbar puncture, two or more of the aforementioned procedures, MRI, radiotherapy, ophthalmologic examination, wound dressing and suturing, ultrasonography, and needle aspiration (Table 3).

Multivariable regression showed that the following factors were associated with an increased risk of overall complications during chloral hydrate sedation: general ward inpatient status, congenital syndrome, congenital heart disease, preterm birth, oxygen dependency, and a history of complications or sedation failure with chloral hydrate for the same procedure (Table 4).

Rescue sedation was administered to 93% (1,351/1,457) of the patients with failed procedural sedation. The first and overall rescue sedation success rates were 89.8% (1,213/1,351) and 91.0% (1,229/1,351), respectively (Fig. 1).

This retrospective, single-center, observational study revealed a significant incidence of procedural sedation failure with oral chloral hydrate. Risk factors for chloral hydrate sedation failure and complications associated with chloral hydrate sedation were also identified. Patients with sedation failure had higher overall complication rates than those with successful sedation at the initial dose.

Chloral hydrate has been prescribed for over a century for sedation because it is relatively safe and effective. It has been widely used for pediatric sedation due to its low cost and familiarity with the drug among healthcare professionals [19,20]. However, oral administration of chloral hydrate is challenging due to its bitter taste, often leading to nausea and vomiting that may potentially delay the onset of sedation [21]. Therefore, efficacy varies among individuals. At doses of 25–100 mg/kg for sedation induction, chloral hydrate exhibits a broad range of onset (15–45 min), duration (20–280 min), and success rate (37.4%–100%) [1]. After initial administration, the patient is usually observed for approximately 30–40 min to assess the success of sedation. Based on the present study, factors associated with successful chloral hydrate sedation include outpatient status and procedures less than 30 min. Echocardiography (88.9%) and hearing tests (93.2%) demonstrated similarly high success rates that were comparable to those of electroencephalography (85.6%, reference test). The three tests share the following characteristics: they are painless, do not take a long time, and can be successfully performed despite slight patient movement. If these conditions are met, oral chloral hydrate can be used as an initial sedative with a high success rate.

Previously, Cui et al. [21] reported risk factors associated with chloral hydrate sedation failure, including reduced dosage, increased body weight, history of previous sedation or sedation failure, and performance of multiple procedures or MRI scans. Our study further showed that sedation failure was associated with factors such as weight, general ward or intensive care unit stay, congenital syndrome, oxygen dependency, history of previous sedation failure or complications for the same procedure with chloral hydrate, procedure duration more than 60 min, and painful procedures (angiography, lumbar puncture, wound dressing, and needle aspiration) or procedures involving intense stimulus (ophthalmologic examination).

In 2012, all manufacturers in the United States voluntarily withdrew chloral hydrate from the market due to efficacy and safety concerns [22]. Animal studies have shown that high doses of chloral hydrate have genotoxic and carcinogenic effects, although the impact on humans remains uncertain [23]. Nonetheless, pediatric sedation in South Korea remains largely dependent on oral chloral hydrate [2,7]. According to a 2016 survey conducted by the Korean Society of Pediatric Anesthesiologists as part of the Korean guidelines for pediatric procedural sedation, 71.4% (10/14) of tertiary university hospitals reported using oral chloral hydrates as their primary sedative regardless of procedure type [24]. In addition to the variability in the effects of oral chloral hydrates, the limited availability of alternative options for non-IV sedation is a major concern. Our results showed that chloral hydrate continued to be used in patients who had previously experienced sedation failure or adverse effects with this medication. In these patients, the sedation failure rates were as high as 57.6% and 44.9%, respectively.

Another important factor contributing to the widespread use of chloral hydrate as a first-line drug for procedural sedation is the lack of specialized or dedicated pediatric sedation providers in many hospitals. For inpatients or those with IV access in place of other procedures (e.g., contrast injection for computed tomography or MRI), IV midazolam and ketamine can be used with rapid onset and short duration. However, owing to the associated risk of respiratory depression, these drugs are typically reserved for rescue sedation after failed chloral hydrate sedation. Chloral hydrate is often preferred as the first agent because it is considered safer for non-anesthesiologists who may have less experience and skills with pediatric sedation, particularly pediatric airway management. In the present study, if sedation failed after the first administration of chloral hydrate, a second dose of chloral hydrate (25 mg/kg) or IV midazolam (0.1–0.2 mg/kg) or ketamine (1–2 mg/kg) were used according to the institution’s pediatric sedation protocol. However, it is important to note that when sedatives are used in conjunction with other sedatives or repeated without proper assessment, there is an increased risk of respiratory depression or hemodynamic instability. Anesthesiologists, who are proficient in the use of a variety of sedative agents, are usually involved in specific procedures such as MRI, cardiac catheterization or intervention, and gastrointestinal endoscopy that constitute only a fraction of the cases of pediatric procedural sedation. The existence of a well-structured pediatric sedation team specializing in pediatric sedation and the management of a substantial number of patients has proven to be safe and effective [25–27], In a recent meta-analysis of non-IV sedation for MRI, the authors highlighted that the presence of well-organized teams appeared to be more important than the use of a specific sedative or anesthetic regimen [1]. However, the role of a sedation team extends beyond administering sedatives and monitoring patients. The sedation team should have a good understanding of the patient’s underlying disease, sedation history, and the nature of the procedure in order to select the safest and most effective sedation regimen. To prevent sedation failure and complications, it is essential to consider multiple sedation options rather than relying solely on a single type of medication, chloral hydrate, for all pediatric procedural sedation. Additionally, the sedation team should undergo regular education programs focused on delivering up-to-date evidence-based knowledge on sedative drugs and monitoring guidelines for pediatric procedural sedation.

Common side effects of chloral hydrate are nausea and vomiting (28%–37%), motor imbalance (31%–66%), restlessness (14%–29%), agitation (0.5%–29%), prolonged sedation (0.18%–30%), and drowsiness the next day (27%–35%) [4,5]. Serious complications including respiratory depression (0.2%–3.6%) [21], respiratory arrest (0.06%), and cardiac arrest (0.3%) [4] can occur, particularly when repeated doses are administered to achieve the required sedation level. The present study identified the following as risk factors for complications of chloral hydrate sedation: general ward inpatient status, congenital syndrome or congenital heart disease, preterm birth, oxygen dependency, and a history of complications or sedation failure with chloral hydrate for the same procedure. The most common complication of chloral hydrate was desaturation, occurring in both patients with successful procedural sedation (3.9%) and patients with failed procedural sedation (11.6%). Oral administration of chloral hydrate is challenging in patients receiving oxygen supplementation, as adequate oxygenation through a face mask is compromised because of the frequent occurrence of nausea and vomiting, and of patient refusal because of the bitter taste of chloral hydrate. Delayed oral administration of chloral hydrate may lead to desaturation and hypoxemia in high-risk patients. For example, irritability and crying during oral administration can potentially trigger a right-to-left shunt in patients with uncorrected cyanotic heart disease, resulting in severe hypoxemia [28]. Additionally, due to the variability in the duration of action of oral chloral hydrate, repeated administration may result in oversedation and complications. Therefore, for procedural sedation involving these risk factors, alternative methods should be considered to increase the success rate and decrease sedation-related complications.

Dexmedetomidine, a highly selective alpha-2 adrenoceptor agonist, exhibits sedative and analgesic properties in the pediatric population without inducing respiratory depression or neurotoxic effects. It can be administered either intranasally or intramuscularly. Therefore, dexmedetomidine is increasingly used for non-IV pediatric sedation, either as the primary sedative [1,2,10,11,13–16], as rescue sedation [12,29], or in combination with other agents such as oral chloral hydrate, intranasal midazolam [1], and intranasal ketamine [17,18]. Intranasal dexmedetomidine, administered at doses of 1–4 μg/kg, has been shown to be safe and effective in pediatric procedural sedation, without causing nasal irritation or burning pain. Intranasal administration delivers high bioavailability at 83.8%, and the low end of sedative efficacy (mean arterial plasma concentration of 100 pg/ml) can be achieved within 10 (for 2 μg/kg) to 20 min (for 1 μg/kg) [30]. Peak plasma concentrations are reached at approximately 40 min, and the sedative effects last approximately 70–80 min. Although bradycardia can occur (10%), clinically significant hypotension is rare, making dexmedetomidine a safe choice even for patients with congenital heart disease [18]. Other sedatives such as ketamine and midazolam can also be administered intranasally or intramuscularly.

Some limitations of this study should be noted. First, the data were retrospectively collected from a single tertiary pediatric center in Seoul, Korea. Therefore, institutional variations in sedative use, sedation providers, and monitoring systems were not evaluated. Second, most data were collected by the pediatric sedation nurses working in outpatient settings and general ward or intensive care unit during the daytime. Procedural sedation in the emergency room setting and overnight were provided by on-duty physicians. Sedation records in these cases were not available for the present study. Finally, detailed patient information including the American Society of Anesthesiologists’ physical status classification and the severity of the underlying disease that are crucial for the assessment of sedation success and associated complications were unavailable and not included in the statistical analysis. The diagnosis and sedation records allowed verification of the presence of congenital syndrome, congenital heart disease, and oxygen dependence or preterm birth history. Despite these limitations, our study utilized comprehensive data on pediatric procedural sedation with chloral hydrate, collected at a tertiary children’s hospital in South Korea.

In conclusion, oral chloral hydrate (50 mg/kg) resulted in a significant incidence of sedation failure in pediatric patients, and patients with failed sedation experienced a higher overall complication rate than those with successful sedation at the initial dose. Effective and safe sedation with oral chloral hydrate requires careful consideration of the patient’s sedation history, risk factors, and procedure type and duration.