Pretreatment with beta agonists in ENT surgery
Myron Yaster MD, James M. Peyton, MBChB, MRCP, FRCA, and Melissa Brooks Peterson MD
Today’s PAAD is a study on the effects of a tulobuterol patch in reducing respiratory adverse events in children undergoing tonsillectomy? Tulobuterol patch you ask? Never heard of it? Tulobuterol (INN) is a long-acting beta2-adrenergic receptor agonist, marketed in Japan as a transdermal patch under the name Hokunalin tape. Currently, it is only available in 8 countries: Japan, Germany, China, South Korea, Bangladesh, Pakistan, India, and Venezuela. So, if it’s not available in the U.S. why review it? We are going to review this article and its accompanying editorial to launch a discussion of the use of beta agonists preoperatively in ENT patients. But more importantly for those of you who work in teaching institutions this is a MUST read because of its accompanying editorial by Drs. Adam Adler and Britta von Ungern-Sternberg.
Many of our readers often wonder what makes an article, with an apology to Elaine in a Seinfeld episode, “PAAD worthy”? Today’s article(1) and editorial(2) are in our opinion perfect for discussion in a journal club (or a PBLD) and how one should read a research study. The editorial by Adler and von Ungern-Sternberg in particular is a road map into the pros and cons of the article by Kim et al. We will break down some of their key discussion points in today’s PAAD. Fortunately, I’ve asked Dr. Mel Brooks of the Children’s Hospital Colorado and Dr. James Peyton of the Boston Children’s Hospital and the PAADs airway and ENT gurus to assist. Myron Yaster MD
Original article
Eun-Hee Kim, Sang Hyun Lee, Jin Kyoung Kim, Yong-Hee Park, Pyoyoon Kang, Jung-Bin Park, Sang-Hwan Ji, Young-Eun Jang, Ji-Hyun Lee, Jin-Tae Kim, Hee-Soo Kim. Effect of Tulobuterol Patch Versus Placebo on the Occurrence of Respiratory Adverse Events in Children Undergoing Tonsillectomies: A Randomized Controlled Trial. Anesth Analg. 2023 Jun 1;136(6):1067-1074. PMID: 36727868
Editorial
Adler AC, von Ungern-Sternberg BS. Beta Agonists for Prevention of Respiratory Adverse Events in Children Undergoing Adenotonsillectomy: Long-Acting, Short Acting, or Not Acting. Anesth Analg. 2023 Jun 1;136(6):1064-1066. PMID: 37205802
Approximately 5 million American children undergo anesthesia each year and approximately 20-25% of them undergo ENT surgery. Because many of these children often have histories of recurrent URIs, sleep disordered breathing, and/or asthma, pediatric tonsillectomy patients are at an increased risk of perioperative respiratory adverse events (PRAEs). These include both minor (oxygen desaturation < 95%, and upper airway obstruction) and major (laryngospasm, bronchospasm, severe coughing lasting more than 10 s, and postoperative stridor) events compared with others.(1,2)
A recent prospective, randomized study by von Ungern-Sternberg et al.(3) demonstrated a marked reduction of PRAEs, particularly a reduction in major PRAEs (laryngospasm or bronchospasm) in patients who received inhaled albuterol shortly before tonsillectomy compared to those who received a placebo. Kim et al.(1) wondered if a beta agonist transdermal patch would similarly reduce the incidence of PRAEs in tonsillectomy patients. Why a transdermal patch? “When applied once daily, it reaches maximal plasma concentration 9 to 12 hours after application and induces sustained β-2 agonist effects for 24 hours in patients with asthma, acute bronchitis, and emphysema. The tulobuterol patch improves compliance in young children as a parent applies it on the body of the child, and user error decreases.”(4)
What did Kim et al. find? “The tulobuterol patch (1 mg), reduced the occurrence of PRAEs in preschool children undergoing tonsillectomy.”(1) Sounds great doesn’t it? Not so fast and this is why this article and the accompanying editorial are so terrific for discussion.
Adler and von Ungern-Sternberg(2) point out that the patch is expensive compared to inhaled albuterol and must be applied at least 8-10 hours before the tonsillectomy compared to the inhalational route which can be administered minutes before the procedure, and is often used by some during procedures should bronchospasm occur. “However, perhaps the most significant issue with the design of the study by Kim et al.(1) is reflected in the definition of PRAEs and the potential for mitigation using a beta agonist. A transitory oxygen desaturation <95%, particularly in a cohort prone to obstructive sleep apnea and frequent nocturnal desaturation, is hardly considerable as a significant adverse event. Similarly, while not optimal, the classification of coughing following an airway surgery as a significant adverse event is debatable. The authors’ observation of PRAEs in 42.5% of the control group reinforces the inconsequential nature of the criteria being used to define the outcomes. In the study by Kim et al,1 and in previous studies investigating the preemptive use of beta agonists, the reduction in PRAEs was observed as a reduction in minor events of coughing and obstruction, while the most critically important adverse events of laryngospasm and bronchospasm were, in contrast to the inhaled route, not different between the treatment and placebo groups when using the patch.”(2) While this creates some eye-catching figures and enables what appear to be large differences in complications to be described it devalues the study and is a significant flaw in the trial design.
Next, Adler and von Ungern-Sternberg(2) point out that sample size is critical in designing prospective clinical trials. Because the incidence of larygospasm and bronchospasm are relatively infrequent and varies greatly by patient, surgical and anesthetic related factors, the sample size needed to identify a difference is quite large and larger than the study investigators used. This is one of the reasons that large scale databases, such as the Pediatric Difficult Intubation Registry, have had to be created in lieu of attempting RCTs or prospective observational trials due to the logistical and practical difficulties creating such trials pose. Finally, “or reasons unknown, the authors made the unusual choice to exclude patients with known reactive airway disease and patients with symptoms of upper respiratory tract infection for which preemptive treatment with a long-acting beta agonist would be more efficacious in reducing the incidence of PRAEs.”(3). This is the group of patients who may benefit most from their intervention, and commonly appear for this surgery. Instead of excluding them it would have made more sense to look at them as a subgroup of the study and compare their results with that of the non-reactive airway disease group.
There’s much more in the study and editorial to consider so we would urge all of you to read the paper and the editorial and discuss in a journal club or as a PBLD. Finally, we are wondering how many of you routinely administer albuterol preoperatively to ALL of your tonsillectomy patients? Or in patients at greatest risk of bronchospasm and laryngospasm? Send your comments to Myron who will post in the Friday Reader Response.
References
1. Kim EH, Lee SH, Kim JK, Park YH, Kang P, Park JB, Ji SH, Jang YE, Lee JH, Kim JT, Kim HS. Effect of Tulobuterol Patch Versus Placebo on the Occurrence of Respiratory Adverse Events in Children Undergoing Tonsillectomies: A Randomized Controlled Trial. Anesth Analg 2023;136:1067-74.
2. Adler AC, von Ungern-Sternberg BS. Beta Agonists for Prevention of Respiratory Adverse Events in Children Undergoing Adenotonsillectomy: Long-Acting, Short Acting, or Not Acting. Anesth Analg 2023;136:1064-6.
3. von Ungern-Sternberg BS, Sommerfield D, Slevin L, Drake-Brockman TFE, Zhang G, Hall GL. Effect of Albuterol Premedication vs Placebo on the Occurrence of Respiratory Adverse Events in Children Undergoing Tonsillectomies: The REACT Randomized Clinical Trial. JAMA pediatrics 2019;173:527-33.
4. Kim CK, Callaway Z, Choi J, Kim HB, Kwon EM, Chang YS, Rha YH, Hong SJ, Oh JW, Kim HH, Lim DH, Kim SW, Park KS, Cho YH, Chung HL, Park HJ, Jung SG, Kang IJ, Hyun MC, Oh MY, Jung JA, Kim MS, Shim JY, Kim JT, Koh YY. Multicenter Adherence Study of Asthma Medication for Children in Korea. Allergy Asthma Immunol Res 2019;11:222-30.