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Chloral hydrate: Is it still being used? Are there safer alternatives?
November 3, 2016

In early 2017, ISMP plans to update its list of high-alert medications to correspond with the release of a new ISMP Medication Safety Self Assessment® for High-Alert Medications. The new assessment tool, funded by the US Food and Drug Administration (FDA), will allow hospitals and outpatient facilities to evaluate their level of implementation of error-prevention strategies for 11 high-alert medications or categories. One of the high-alert medication categories included in the new self assessment is minimal and moderate sedation agents, including agents used to sedate pediatric patients for diagnostic tests or procedures in various settings, such as radiology, electrocardiography, neurologic testing labs, dentistry, the emergency department (ED), and the operating room. Sedation of pediatric patients for even painless diagnostic procedures is common because its use has been linked to higher quality studies and reduced diagnostic errors.1

The pediatric oral sedation agent provided as an example on our current ISMP List of High-Alert Medications in Acute Care Settings (www.ismp.org/sc?id=2820) is oral chloral hydrate, a sedative-hypnotic used for more than 100 years.2 Chloral hydrate liquid for pediatric sedation is also a specific medication on the ISMP List of High-Alert Medications in Community/Ambulatory Healthcare (www.ismp.org/sc?id=2821).  

Older chloral hydrate adverse events

Between 1996 and 2009, ISMP published dozens of errors about chloral hydrate used for sedation involving mostly dosing errors, oversedation, and administration of the oral liquid by the IV route. The events we published included 8 that resulted in death. In two of the cases, technical support personnel who were unauthorized to administer the drug failed to recognize they were administering an overdose. In a third fatality, a dentist ordered a weight-based dose of 6,000 mg for a 13-year-old child that led to respiratory arrest. In three more cases, the drug was administered to the child by a parent at home prior to a procedure. In two of these cases, the drug was prescribed by volume alone, and a higher concentration of the commercial product than intended by the prescriber was dispensed by the pharmacy (500 mg/5 mL instead of 250 mg/5 mL), leading to overdoses. In the other case, the pharmacy dispensed a 10-fold overdose. The seventh case involved a 4-year-old boy who was given chloral hydrate before a procedure and strapped onto a papoose board without proper positioning of his head to protect his airway. The final fatality was caused by repeated “5 mL prn” doses that led to respiratory arrest.

Compounded chloral hydrate

Since 2010, ISMP has not received additional reports of errors involving pediatric sedation with chloral hydrate, which we assumed was due in large part to the 2012 discontinuation of the only remaining commercially available chloral hydrate products (oral solution by Pharmaceutical Associates, oral capsules by Breckenridge) in the US, for business reasons.3 However, some ambulatory and hospital pharmacies are still compounding an oral suspension of chloral hydrate from crystals or powder for pediatric sedation in both inpatient and outpatient settings.4,5 The raw ingredient is available from pharmaceutical supply companies. A study5 comparing the previously available commercial formulation of chloral hydrate to the compounded formulation used for pediatric sedation during echocardiographic examination showed that the compounded drug resulted in a shorter duration of sedation, more frequent need for the use of a secondary sedation agent (increasing the risk of an adverse event4,6), and more frequent sedation failure.

There are no FDA-approved drug products that contain chloral hydrate. As mentioned above, the firms commercially manufacturing and distributing drug products containing chloral hydrate without FDA-approval voluntarily removed their products from the market in 2012. We were thinking about removing chloral hydrate from our lists of high-alert medications but have not done so given the unknown frequency of prescribing and compounding the drug. There have also been worrisome, more recent adverse events associated with the drug as reported in the news media and professional literature. Chloral hydrate has a US Pharmacopeial Convention (USP) monograph so pharmacists can compound it under section 503A (individual prescription) of the Federal Food, Drug, and Cosmetic (FD&C Act), but it can’t be compounded under 503B (outsourcing facilities) because it is NOT on FDA’s list of bulk drug substances (www.ismp.org/sc?id=2831).  

More recent chloral hydrate adverse events

In June 2014, Nordt et al. published three cases of pediatric chloral hydrate overdoses, one a fatality, that occurred in the outpatient setting following procedural sedation.2 These patients were all seen in the ED within a 4-month period, alerting the authors to a potential public safety issue.

The first case involved a 4-year-old girl for whom a dentist had prescribed 900 mg (70 mg/kg) of chloral hydrate prior to a dental extraction. The child was sedated upon arrival at the office, and the procedure was completed without further sedation. After an hour, the patient remained somnolent but arousable and was discharged. The child’s mother called 6 hours later to report ongoing somnolence and was reassured that the effects of sedation would decrease over time. Several minutes later, the child suffered a respiratory arrest and the mother called emergency medical services. Resuscitation efforts prehospital and in the ED were extensive, with an initial return of spontaneous circulation. But the child arrested again and died.

The next event involved a 3-year-old boy for whom a dentist had prescribed 500 mg (50 mg/kg) of chloral hydrate to be administered at home prior to arrival in the office for a dental procedure. (Only healthcare professionals should administer sedatives to children prior to a procedure after they have arrived at the facility to ensure proper supervision, monitoring, and access to resuscitation equipment and other medications if needed.) The dentist had anticipated repeat visits and prescribed 60 mL of chloral hydrate (100 mg/mL). The child’s mother could speak Spanish and English, but could read only Spanish, so she asked a family member to read the label. That person misdirected her to give the child the entire 60 mL (6,000 mg) bottle. The child became somnolent within 10 minutes and unresponsive once in the dental office. The mother alerted the office staff, who called emergency medical services. The child vomited on the way to the ED, where he was intubated and treated with an esmolol infusion for life-threatening cardiac dysrhythmias. He was admitted to a pediatric intensive care unit and discharged 24 hours later without sequelae.

The third event involved a 15-month-old child with a history of severe neurodevelopmental deficits who was given 1,200 mg of chloral hydrate (100 mg/kg) at an outpatient ophthalmology clinic prior to evaluation. Within 25 minutes of receiving the drug, the child vomited, became obtunded, and developed stridor, periods of apnea, and cyanosis. The child improved after an oral airway was established and oxygen was administered. She was transferred to the ED, monitored for 12 hours, and then discharged. 

Other issues with chloral hydrate

In addition to the risk of respiratory depression associated with most sedatives used for pediatric sedation, chloral hydrate carries several other risks worthy of mention:

Resedation after discharge. Chloral hydrate can result in prolonged sedation or resedation with effects persisting beyond 24 hours in children of all ages, including those who have demonstrated resolution of sedation prior to discharge.2,4,7 This appears to have played a role in the fatality of the 4-year-old girl described previously. Chloral hydrate is rapidly converted to an active metabolite (trichloroethanol) responsible for its sedative properties, which has a half-life at therapeutic doses of up to 66 hours in neonates, 28-40 hours in infants, 8-12 hours in children, and much longer following an overdose.2,7 

No reversal agent. If respiratory depression occurs or the patient becomes obtunded, no specific agent is available to reverse the effects of chloral hydrate.2

Narrow therapeutic index. Chloral hydrate has a relatively narrow therapeutic index, which can increase the risk of adverse effects when higher therapeutic doses or overdoses are administered.2

Cardiac toxicity and hypotension. Ventricular dysrhythmias and severe hypotension leading to some fatalities from chloral hydrate toxicity have been reported. This has been seen mostly after large doses or overdoses since this effect is dose dependent.2,8

Irritating gastric effects. Nordt et al. notes that chloral hydrate is more rapidly absorbed with food; fasting before a procedure where chloral hydrate is used for sedation is not recommended since it can delay the drug’s onset, leading to sedation failures.2 However, gastric irritation has led to vomiting, which can result in aspiration of the stomach contents.

Large volume per dose. Chloral hydrate is very bitter tasting and requires a large volume per dose. Poor palatability has necessitated administration via a nasogastric tube at times.9 In addition, compounded chloral hydrate is difficult to concentrate, leading to even larger volumes per dose than the previously available commercial formulation.5 This can lead to vomiting or spitting out of unquantifiable amounts of the dose. 

Comparison to other pediatric sedation agents

Chloral hydrate has been a drug of choice for pediatric sedation in some facilities due to its low cost.5 However, in regards to efficacy, there are conflicting studies regarding which sedation agent is best. Numerous studies suggest there are many other effective sedative agents with more predictable pharmacokinetic profiles than chloral hydrate, including oral or intranasal midazolam.6,7,10-12 Other studies have shown that chloral hydrate resulted in more effective sedation of pediatric patients than other agents,9,13-15 and recommendations for its continued use for certain procedures exist in the literature, particularly for painless diagnostic procedures such as neurologic imaging,13,16 echocardiography,5 and auditory brainstem response testing.17

Nevertheless, numerous studies have also shown that other sedation agents, such as midazolam, produce less severe adverse effects. For example, Costa et al. studied pediatric patients who received a high dose of either oral chloral hydrate (70-100 mg/kg) or oral midazolam (1-1.5 mg/kg) during outpatient dental treatment. They found that the chance of an adverse event, including post-discharge, was significantly lower among children who received midazolam than those who received chloral hydrate.7 Cote et al. found that, among 118 cases of serious (neurologic injury) or fatal outcomes reported to FDA, most (65%) of the children had been sedated with chloral hydrate.6

Seeking your input

The risks of adverse events and the potential for compounding errors associated with chloral hydrate are concerning. Thus, the literature is replete with recommendations to use a safer alternative agent instead of chloral hydrate when sedating pediatric patients.2,4,6,7,10-12,18-19 However, the evidence regarding efficacy of chloral hydrate and alternative sedatives is conflicting. Before ISMP takes a position on the issue in our ISMP Medication Safety Self Assessment® for High-Alert Medications, we would appreciate your participation in a short survey on the topic, which should take less than 15 minutes to complete, even less if you do not use chloral hydrate for pediatric sedation. Either way, we need your input on this important issue and would sincerely appreciate your encouragement of participation by healthcare providers working in both inpatient and outpatient settings! Please include radiology, dentistry, or other areas that may use chloral hydrate and complete the survey, which appears on page 5, by December 16, 2016, by entering your responses at: www.ismp.org/sc?id=2829.   

References

  1. Stern KW, Gauvreau K, Geva T, Benavidez OJ. The impact of procedural sedation on diagnostic errors in pediatric echocardiography. J Am Soc Echocardiogr. 2014;27(9):949-55.
  2. Nordt SP, Rangan C, Hardmaslani M, Clark RF, Wendler C, Valente M. Pediatric chloral hydrate poisonings and death following outpatient procedural sedation. J Med Toxicol. 2014;10(2):219-22.
  3. American Society of Health-System Pharmacists. Chloral hydrate oral solution and capsules. Drugs No Longer Available Bulletin. November 5, 2012. www.ismp.org/sc?id=2819.  
  4. Cote CJ, Wilson S; American Academy of Pediatrics; American Academy of Pediatric Dentistry. Guidelines for monitoring and management of pediatric patients before, during, and after sedation for diagnostic and therapeutic procedures: update 2016. Pediatrics. 2016;138(1).
  5. Hill GD, Walbergh DB, Frommelt PC. Efficacy of reconstituted oral chloral hydrate from crystals for echocardiography sedation. J Am Soc Echocardiogr. 2016;29(4):337-40.
  6. Cote CJ, Karl HW, Notterman DA, Weinberg JA, McCloskey C. Adverse sedation events in pediatrics: analysis of medications used for sedation. Pediatrics. 2000;106(4):633-44.
  7. Costa LR, Costa PS, Brasileiro SV, Bendo CB, Viegas CM, Paiva SM. Post-discharge adverse events following pediatric sedation with high doses of oral medication. J Pediatr. 2012;160(5):807-13.
  8. Bowyer K, Glasser SP. Chloral hydrate overdose and cardiac arrhythmias. Chest. 1980;77(2):232-5.
  9. Wheeler DS, Jensen RA, Poss WB. A randomized, blinded comparison of chloral hydrate and midazolam sedation in children undergoing echocardiography. Clin Pediatr (Phila). 2001;40(7):381–7.
  10. Layangool T, Sangtawesin C, Kirawittaya T, et al. A comparison of oral chloral hydrate and sublingual midazolam sedation for echocardiogram in children. J Med Assoc Thai. 2008;91(Suppl 3):S45–52.
  11. Dallman JA, Ignelzi MA Jr, Briskie DM. Comparing the safety, efficacy and recovery of intransal midazolam vs. oral chloral hydrate and promethazine. Pediatr Dent. 2001;23(5):424–30.
  12. Nicolson SC, Montenegro LM, Cohen MS, et al. A comparison of the efficacy and safety of chloral hydrate versus inhaled anesthesia for sedating infants and toddlers for transthoracic echocardiograms. J Am Soc Echocardiogr. 2010;23(1):38-42.
  13. D’Agostino J, Terndrup TE. Chloral hydrate versus midazolam for sedation of children for neuroimaging: a randomized clinical trial. Pediatr Emerg Care. 2000;16(1):1–4.
  14. Roach CL, Husain N, Zabinsky J, Welch E, Garg R. Moderate sedation for echocardiography of preschoolers. Pediatr Cardiol. 2010;31(4):469–73.
  15. Schmalfuss I. Oral sedation of pediatric patients for noninvasive radiological procedures: chloral hydrate versus midazolam. J Radiol Nurs. 2005;24(3):42–8.
  16. Hare M. Question 1. Chloral hydrate or midazolam: which is better for sedating children for painless diagnostic imaging? Arch Dis Child. 2012;97(8):750–2.
  17. Avlonitou E, Balatsouras DG, Margaritis E, Giannakopoulos P, Douniadakis D, Taskanikos M. Use of chloral hydrate as a sedative for auditory brainstem response testing in a pediatric population. Int J Pediatr Otorhinolaryngol. 2011;75(6):760-3.
  18. Koo SH, Lee DG, Shin H. Optimal initial dose of chloral hydrate in management of pediatric facial laceration. Arch Plast Surg. 2014;41(1):40–4.
  19. Miller MA, Levy P, Patel MM. Procedural sedation and analgesia in the emergency department: what are the risks? Emerg Med Clin North Am. 2005;23(2):551-72.
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