Malignant hyperthermia incidence in the kids inpatient database after the release of Sugammadex





Abstract


Aims


To determine if the incidence of Malignant Hyperthermia (MH) has changed in a large sample of pediatric patients since the US Food and Drug Administration’s approval of sugammadex.


Methods


Deidentified data was obtained from the US Department of Health and Human Services Agency for Healthcare Research and Quality’s 2019 Kid’s Inpatient Database (KID). Patients with the diagnosis of MH were identified by the International Classification of Diseases, 10th edition code T88.3XXA. Comparisons were made using Chi square or Fisher’s exact and Student’s T-test or Mann Whitney U-Test as appropriate. Historical MH rates from previous studies from KID samples were compared to the rates identified in the 2019 KID sample to assess for a change overtime.


Results


There were 30 cases of MH identified by the ICD10 code in the 2019 KID. (Table 1) The overall rate was low (0.001%). Two children diagnosed with MH died during hospitalization (6.7% of MH cases). The mean age of patients diagnosed with MH was 9.6 years. Of the 30 cases, 17 occurred in patients who did not undergo an operative procedure. In 12 of these 17 patients, there was a diagnosis of acute respiratory failure. There were 13 cases among patients undergoing operative procedures. The rate was higher among patients undergoing operative procedures (0.005% vs.0.00007%, P < 0.001).


Conclusion


The incidence of MH remains low and seems lower than previous reports. We speculate the approval of sugammadex has reduced the use of succinylcholine which resulted in a decreased rate of MH. There is potentially room for a further reduction in MH incidence rate among nonoperative patients requiring tracheal intubation.


Malignant hyperthermia (MH) is a rare genetic linked disorder. It has been estimated to occur in between 1 and 2 in every 100,000 of all patients discharged from a hospital in the US and up to 3 per 100,000 patients discharged whose hospitalization involved a surgical procedure. Succinylcholine has been identified as a potential trigger for MH. Succinylcholine is a neuromuscular blocking agent (NMB) with a rapid onset and the shortest clinical duration of currently available NMBs. These characteristics make it useful in specific situations. High doses of rocuronium can approach the onset time of succinylcholine but the duration is far longer, which can be disadvantageous in some circumstance. Sugammadex is a NMB reversal agent which can rapidly bind and quickly counter the effect of steroidal NMBs such as rocuronium. This rapid reversal could make rocuronium a viable alternative to succinylcholine and reduce succinylcholine’s utilization and possibly led to a reduction in MH rates.


The US Food and Drug Administration (FDA) approved the use of sugammadex for the reversal of rocuronium or vecuronium in adult patients in 2015. , In June 2021 the FDA approved its use in pediatric patients over the age of 2 years. A search of PUBMED yielded 87 articles using the search term “pediatric sugammadex” published before the FDA’s approval for pediatric patients. Of these 87 articles, 25 were trials or systematic reviews of use in pediatric patients. We theorized that the 2015 FDA approval of the use of sugammadex may have led to a reduction in the incidence of MH in children.


The FDA may have previously caused a reduction in succinylcholine administration that possibly was the cause of a reduction in another rare event. In 1993 the FDA added a black box warning to the succinylcholine package insert stating its use could lead to cardiac arrest in young males due to undiagnosed muscular dystrophies. After this warning was added, there was a reduction in cardiac arrests in children undergoing anesthesia which was postulated to be the result of decreased succinylcholine administration. The FDA’s approval of the use of sugammadex may have similarly led to a further reduction in succinylcholine usage and a concomitant reduction in MH incidence.


Two reports of the incidence of MH in children have been published in the recent past prior to the FDA’s approval of Sugammadex. In 2011 Li, et al. reported rates of MH in the Kid’s Inpatient Database (KID) of 3.8 per 100,000 (0.0038%) among surgical patients and 2.5 per 100,000 (0.0025%) among non-surgical patients. In a 2014 report, Salazar, et al. reported the incidence of MH in the among pediatric surgical patients in the KIDS database was 10.4/100,000 (0.0104%) while the rate among non-surgical patients was 1.1/1000,000 (0.0011%). The approval of sugammadex subsequent to these two reports may have reduced the use of succinylcholine and as a result, the incidence of MH.


Data from the 2019 KID was used to assess the incidence of MH since the approval of sugammadex. The KID is a representative sample of pediatric admissions which includes data from 48 states and the District of Columbia. The KID was first collected in 1997 and has been repeated and reported every three years. The 2019 KID is the most recent available and represents approximately 80% of all non-newborn discharges of pediatric patients. The large sample size enables analysis of rare diseases, such as MH. We compared results from the 2019 KID to previous reports to determine if there was a change in incidence of MH after the FDA’s approval of sugammadex.


1


Methods


The George Washington University School of Medicine and Health Science’s Institutional Review Board (GW IRB) reviewed the study prior to commencement and determined it was exempt from review. Deidentified data was obtained from the US Department of Health and Human Services Agency for Healthcare Research and Quality’s 2019 KID. Inclusion criteria was all patients in the 2019 KID excluding those born during that admission. Patients with the diagnosis of MH were identified by the International Classification of Diseases, 10th edition (ICD10) code T88.3XXA. For each patient identified with MH, the primary diagnosis was determined by a consensus of the investigators after reviewing the specific patient entry. The primary procedure, if applicable, was identified by the procedure performed on the earliest date during the admission. Comparisons were made using Chi square or Fisher’s exact and Student’s T-test or Mann Whitney U-Test, as appropriate. Historical MH rates from previous studies from the KID database were compared to the incidence rates identified from the 2019 KID sample to assess for a change over time. Analyses were performed using Statistical Package for Social Sciences, version 27, International Business Machines, Armonk, New York). The manuscript was prepared in accordance with strengthening the reporting of observational studies in epidemiology (STROBE) guidelines.


2


Results


There was a total of 3089,283 total patient entries in the 2019 KID. There were 30 cases of MH identified by the ICD 10 code in the sample. ( Table 1 ) Two children diagnosed with MH died during hospitalization (6.7% of MH cases). The mean age of patients diagnosed with MH was 9.6 years (standard deviation (SD) 6.7). Of the 30 cases, 22 patients were male. The median number of diagnoses was higher among the cohort diagnosed with MH compared to all other patients (13.3, SD 6.9 vs. 5.9, SD 4.7 among those without, P < 0.001). There was no difference in age distribution between genders of patients identified with MH (males average age 9.7 years, SD 6.3 vs. females 9.1, SD 8.1, P = 0.87). The two deaths occurred in males. Mortality rates were not different between genders (9.1% vs 0, P = 0.38).



Table 1

Malignant hyperthermia incidence rates.



























Category Subcategory Total number of discharges Number of cases of MH P
All discharges All patients 3089,283 30
Surgical discharges 370,880 13 <0.001
Non-surgical discharges 2718,373 17

Comparison made using Chi square. MH = malignant hyperthermia.


3


Operative vs. non-operative patients


There was a higher rate of MH among patients undergoing an operative procedure compared to those not (0.005% vs. 0.00007%, P < 0.01). ( Table 1 ) There were 13 cases of MH identified among 370,880 patients undergoing an operative procedure and 17 among the 2718,373 patients who did not undergo an operative procedure. The mean number of diagnoses was not different between the 13 operative patients with MH and the 17 non-operative patients with MH (13.1, SD 5.5 among operative patients vs. 13.4, SD 8.0, P = 0.83).


4


Elective vs. non-elective admissions


The majority of admissions in the 2019 KID were designated as non-elective admissions (2740,027 of 3089,283). Among the non-elective admissions, 220,266 underwent an operative procedure. Among these non-elective admission operative patients there were 3 cases of MH. The rate of MH among non-electively admitted patients was not significantly different between operative and non-operative patients (0.0014% among operative patients vs. 0.0007%, P = 0.46). ( Table 2 ) There were 349,256 patients whose admissions were designated as elective in the 2019 KID. There were zero cases of MH among electively admitted patients who did not undergo a procedure ( N = 199,454) while there were 10 cases of MH diagnosed among those who did undergo a procedure ( N = 149,802). The rate was significantly different between these groups (0% elective admission without a procedure vs. 0.0067%, P < 0.001).



Table 2

Malignant hyperthermia by admission type and procedural status.
























Underwent procedure during admission No procedure during admission P for collum-to-collum comparison within row
Elective admission 10/149,802 0/199,454 <0.001
Nonelective admission 3/220,266 17/2519,761 0.46
P for row-to-row comparison within collum 0.02 0.48

Data presented as number of cases of malignant hyperthermia/total number of patients in category. Comparisons made using Chi square.


5


Discussion


The rate of MH in the 2019 KIDS database appears to be lower than previous reports by both Li, et al. and Salazar, et al. The highest rate of MH in the 2019 sample occurred among patients who underwent an operative procedure. The majority of cases occurred among non-operative patients but the incidence rate was lower in this subset and only occurred among those non-electively admitted. The lower rate among non-operative patients is intuitive but it is challenging to identify the number of non-operative patients who may have been exposed to succinylcholine in order to make a true comparison to operative patients. The majority of cases occurred in males.


The overall rate of MH remained low. There was a lower overall rate of MH among patients in the 2019 KID database compared to the Salazar et al. report, which used the combined KID samples from 2000, 2003, 2006, and 2009 (0.001% vs. 0.002%, P = 0.02). ( Table 3 ) The 2019 KID sample also had a lower overall MH incidence than the Li, et al. report (0.001% vs. 0.003%, P < 0.001). Mortality remains low and does not appear to have changed significantly between epochs (2.9% from Salazar et al. vs 6.7% in 2019, P = 0.57), but the small sample size limits this conclusion. The lower overall incidence rate in 2019 may possibly have been mediated by the availability of sugammadex in 2019. The ability to rapidly reverse the effect of rocuronium without the adverse side effect profile of succinylcholine may have reduced the use of succinylcholine over time and led to a lower incidence of MH. Looking further at the cases of MH in the 2019 KID reveals detailed patterns which further support this theory.


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May 22, 2025 | Posted by in ANESTHESIA | Comments Off on Malignant hyperthermia incidence in the kids inpatient database after the release of Sugammadex

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