Intravenous versus intramuscular route of administration of natural adrenocorticotropic hormone in infantile epileptic spasm syndrome
Juan Wu1,2, Xiao-Lu Chen1,2, Qiu-Ji Tao1,2, Jing Chen1,2
Contributions: (I) Conception and design: J Chen; (II) Administrative support: J Chen; (III) Provision of study materials or patients: J Wu; (IV) Collection and assembly of data: XL Chen, QJ Tao; (V) Data analysis and interpretation: J Chen, XL Chen, QJ Tao; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.
Background: Infantile epileptic spasm syndrome (ISS) is an age-dependent epileptic condition typically emerging within the first year of life, and adrenocorticotropic hormone (ACTH) has been established as a first-line therapeutic drug for the ISS since 1958. However, there is a notable variation in ACTH dosage practices worldwide, with intramuscular injection being common in some countries and intravenous drip preferred in others, including China. This study aimed to identify a preferable administration modality for ACTH-based utilization in treating ISS.
Methods: A retrospective analysis was conducted on 221 ISS patients treated with ACTH via the two administration routes from January 2021 to December 2022. Clinical efficacy and adverse effects were assessed. Health economics were evaluated using a cost-effectiveness ratio, incorporating direct costs and a comprehensive effectiveness indicator.
Results: Intramuscular injection demonstrated a higher effective rate (97.20%) compared to intravenous infusion (80.50%). Adverse effects such as upper respiratory tract infections and diarrhea were significantly less in the intramuscular group. The unit effectiveness cost was significantly lower for intramuscular injection (¥19.53) than for intravenous infusion (¥32.86).
Conclusions: Although both routes of administration were successful in controlling spasms in patients, intramuscular injection of ACTH was deemed economically preferable due to its superior clinical efficacy, less adverse effects, and higher safety profile.
Keywords: Adrenocorticotropic hormone (ACTH); clinical efficacy; health economics; infantile epileptic spasm syndrome (ISS); intramuscular injection
Submitted Oct 10, 2024. Accepted for publication Dec 04, 2024. Published online Dec 27, 2024.
doi: 10.21037/tp-24-390
Highlight box
Key findings
• Intramuscular administration of adrenocorticotropic hormone (ACTH) offers superior efficacy, reduced adverse effects, improved patient compliance, and lower costs over intravenous injection for the treatment of infantile epileptic spasm syndrome.
What is known and what is new?
• Infantile epileptic spasm syndrome is an age-dependent epileptic condition typically emerging within the first year of life, with ACTH as a first-line therapeutic drug, yet there is considerable disparity in ACTH dosage and administration protocols both China and abroad.
• In our retrospective analysis of patient outcomes, including efficacy, side effects, and treatment costs, we found that intramuscular injection was more cost-effective and yielded better patient compliance compared to intravenous infusion.
What is the implication, and what should change now?
• Monitor for adverse reactions and intervene promptly to prevent escalation.
• Promote intramuscular injection of ACTH to enhance patient compliance, simplify the procedure for healthcare providers, and reduce treatment costs to alleviate the financial burden on patient families.
Introduction
Infantile epileptic spasm syndrome (ISS) represents an age-related epilepsy syndrome typically occurring within the first year of life, with a peak onset at 4 to 6 months of age (1,2). ISS is refractory to control and has a poor prognosis, with 70% to 90% of patients exhibiting severe cognitive impairments, imposing a significant burden on families and society (3). Since the first report in 1958 that the adrenocorticotropic hormone (ACTH) could control spasms, it has been used as a first-line treatment for ISS, with an efficiency of 40% to 94% (4,5).
ACTH can be administered both intravenously and intramuscularly, with dosing and administration practices varied worldwide, and even differing between the southern and northern regions of China (6-8). Traditionally, intravenous administration has been the preferred choice in China due to its rapid therapeutic onset, high bioavailability, and the precision it affords doctors in dose management (9). Nonetheless, given the short half-life of natural ACTH, the risks of infection and vascular damage in pediatric populations are considerably heightened by frequent venipuncture and extended catheterization. Consequently, there has been a shift in recent years towards intramuscular injection as a viable alternative for drug delivery. Following intramuscular injection, the drug is absorbed by the capillaries in the interstitial tissue and exerts its therapeutic effects gradually, mirroring the efficacy of intravenous administration (10).
This study retrospectively analyzed the efficacy and safety of intravenous and intramuscular ACTH administration for treating ISS, and comparing the health economic aspects of the two methods. This study aimed to provide a scientific foundation for optimized hospital resources, decreased costs, and improved patient satisfaction, thus guiding clinical medication choices. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-390/rc).
Methods
Ethics statement
The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics committee of the West China Second University Hospital of Sichuan University [No. 2023(29)] and individual consent for this retrospective analysis was waived. Data were anonymously analyzed and reported.
Participants
A retrospective chart review of all ISS patients, who were admitted to the Division of Pediatric Neurology from January 2021 to December 2022, was conducted. Diagnosis and inclusion criteria met the classification criteria of epilepsy and epileptic syndrome proposed by the International League Against Epilepsy 2017 (ILAE 2017) (11).
Inclusion criteria were as follows: (I) initial onset occurred before 2 years of age; (II) children with epileptic spasms or accompanied by focal seizures; (III) patients with developmental retardation or regression; (IV) EEGs with hypsarrhythmia during the interictal periods; (V) children with newly diagnosed ISS and children who previously received other treatments but without control of epileptic spasms; (VI) children who were nonresponsive to a 3-day high dose of vitamin B6. Exclusion criteria were as follows: (I) patients who received both intravenous and intramuscular administration of ACTH during one treatment course; (II) patients whose clinical information before ACTH treatment was unavailable; (III) patients who did not complete the treatments or treatment duration >14 days.
Data were collected and analyzed anonymously based on patient medical files using a predesigned proforma. Patient information was obtained from medical records or from parents/guardians, including gender, treatments since seizure onset, physical examination, biochemical tests, EEG, brain imaging, liver and renal functions, and chest computed tomography (CT), ruling out serious infections, tuberculosis, and heart failure.
Treatment protocol
Adrenocorticotropime for Injection (Shanghai No. 1 Biochemical and Pharmaceutical Co., Ltd., 25 U/vial) administered in this study was a natural biologic short-acting ACTH. Patients who were intravenously given 25 U ACTH (dissolved in 250 mL 5% glucose solution) were referred as Group A, and the infusion was completed in 6–8 hours; patients who were given an intramuscular injection of ACTH 25U (dissolved in 2 mL sterilized water) were referred as Group B. Patients in both groups were treated once daily for straight 14 days.
Evaluation of efficacy and adverse effects
Clinical efficacy was evaluated at the end of treatment (14 days). Patients were categorized into three groups based on their response to ACTH treatment: (I) notable response (NR): the disappearance of full-day seizure episodes at 14-day treatment; (II) moderate response (MR): a decrease of more than 50% in the number of full-day seizure episodes; (III) ineffective (IE): a decrease of less than 50% or even an increase in the number of full-day seizure episodes (9,12).
Adverse effects were abstracted from the medical files, mainly described as upper respiratory tract infections, and diarrhea incidence.
Health economics evaluation
Treatment costs were gathered from our hospital database for further analysis, and health economics evaluation of the two dosing methods was performed using cost-effectiveness analysis. The cost-effectiveness ratio (CER) was calculated as C/E, with C representing direct treatment costs and E representing overall effectiveness. Direct treatment costs covered ACTH, other medication, material, physical examination, nursing, and bed charges. Effectiveness was the conversion of the individual effect indicators into a comprehensive effect indicator that serves as a representative value for the total efficacy of the scheme. The analytic hierarchy process (AHP) was employed to determine weights, with greater importance assigned to factors associated with larger numerical values (13). Seven experts were asked to rate the relative importance of the four factors: total operating time, patient satisfaction, operator satisfaction, and clinic efficacy. The mean value was calculated after removing the maximum and minimum values, and the weights of the factors were further obtained (Table S1).
Statistical analysis
The data were analyzed using the SPSS version 26.0. Measurement data were presented as mean ± standard deviation. An independent samples t-test was used for group comparisons. The Chi-squared test and the rank-sum test were employed to examine the count and categorical data, respectively. The significance levels were defined as P<0.05.
Results
Clinical efficacy
Of all the ISS patients admitted in our institution from January 2021 to December 2022, a total of 221 participants were enrolled in our study based on previously defined inclusion criteria. They were categorized by the administration route into the intravenous group (Group A, 113 cases) and the intramuscular group (Group B, 108 cases). The severity of the disease was classified based on the frequency and duration of spasm episodes as severe (more than 10 episodes per day), moderate (5 to 10 episodes per day), and mild (fewer than 5 episodes per day). The differences in gender, age, time of ISS diagnosis, and severity of disease were not statistically significant between the two groups (P=0.77, see Table 1).
Table 1
| Group | Gender (male/female) | Mean age (months) | Age of diagnosis (months) | Outcome measure (cases) | Total effectiveness (%) | ||
|---|---|---|---|---|---|---|---|
| NR | MR | IE | |||||
| Intravenous drip (A) | 113 (53/60) | 9.7 | 7.3 | 60 | 31 | 22 | 80.50 |
| Intramuscular injection (B) | 108 (52/56) | 8.8 | 6.7 | 64 | 41 | 3 | 97.20 |
| t/χ2 value | 0.491 | 15.85 | |||||
| P value | 0.77 | <0.01 | |||||
NR, notable response; MR, moderate response; IE, ineffective.
One hundred and thirteen patients received intravenous infusion, of which 60 had their complete cessation of epileptic spasms, 31 responded effectively, and the effective ratio of intravenous therapy was 80.53% (91/113). By comparison, 108 patients were treated with intramuscular injections, of which 64 had complete cessation of epileptic spasms, 41 responded moderately, and the effective ratio of intramuscular therapy was 97.22% (105/108). The Chi-squared test showed a significant difference in effectiveness between the two groups (P=0.01), with the intramuscular group being more effective than the intravenous group (Table S2).
Adverse effects
Fifty-seven out of 113 patients in Group A developed upper respiratory tract infections and 69 had diarrhea. Of the 108 patients in Group B, 30 developed upper respiratory tract infections, and 24 had diarrhea (Figure 1). Most of the adverse reactions in both groups were mild to moderate and were alleviated through symptomatic therapy or slowing down the infusion rate. The incidence of diarrhea was higher in Group A than in Group B, and the chi-square test revealed a significant difference between the two administration routes (P<0.001) (see Table S3). Similarly, the incidence of upper respiratory infection was higher in the intravenous group, probably because of sluggish immune functions, and the chi-square test showed a significant difference between the two groups (P<0.001) (see Table S4).
The majority of the increased leukocytes and platelets had no clinical symptoms, and patients with co-infectious disorders were treated with anti-infective medication to recover. Statistical analysis of the data revealed that intramuscular injection of ACTH was more efficient than intravenous drip in decreasing the deleterious effects of ACTH. This study focused mostly on upper respiratory tract infections and diarrhea, but the findings were sufficient to demonstrate that intramuscular injection is safer than intravenous infusion. ACTH entered the bloodstream directly when delivered intravenously, resulting in high plasma concentrations and hence significant adverse reactions.
Health economics evaluation
Table 2 shows that the average direct treatment cost of Group A was higher than that of Group B. Materials such as syringes and infusion sets required for the treatment in both groups would not be charged according to the regulations of the Price Bureau, and secondary medical attendance was required in both groups. Patients in Group B incurred reduced bed costs compared to Group A, attributable to the absence of intravenous treatment, leading to their treatment being conducted on an outpatient basis without necessitating hospital admission. A comparison of additional prescription expenses, treatment costs, nursing costs, and examination fees between the two groups revealed no statistically significant differences. The C/E value in Group A was ¥32.86 and that in Group B was ¥19.53. The treatment cost spent to obtain the same effectiveness in Group B was less than in Group A, suggesting that intramuscular ACTH treatment was economically preferential.
Table 2
| Cost item | Intravenous group (¥) | Intramuscular group (¥) |
|---|---|---|
| ACTH | 4,102 | 4,102 |
| Other medication | 1,270 | 956 |
| Materials | 1,450 | 674 |
| Physical and biochemical examinations | 1,175 | 1,026 |
| Medical attendance | 458 | 342 |
| Bed | 840 | 570 |
| Total | 9,295 | 7,670 |
ACTH, adrenocorticotropic hormone.
Discussion
To date, agreement on the adrenocorticotrophin hormone treatment for ISS in administration route, dosage, and duration has not been achieved (14). Slow intravenous drip infusion of natural ACTH for clinical ISS therapy is currently recommended in China due to rapid (6,9). ACTH has a half-life of approximately 15 min in plasma and acts rapidly after intravenous injection, starting within minutes, necessitating continuous intravenous infusion to maintain effective plasma concentration (15,16). Clinically, intravenous infusion of ACTH for ISS treatment is problematic due to various reasons, including poor compliance in young children, difficult venous access, and inexperienced use of peripheral intravenous catheters (17-19). Meanwhile, long-term needle procedures cause great inconvenience and psychological distress to afflict children and their families. In comparison, intramuscular administration with feasible access increases drug safety significantly by lowering administration time and local vascular damage.
In our study, 59.26% of patients (64/108) had complete cessation of spasms at 3 to 5 days of treatment, with the EEG background rhythm restoration and occasional spike discharges, 37.96% of patients (41/108) experienced significant alleviation of spasm episodes after 10 to 14 days of treatment; and the rest three children did not effectively respond after 2 weeks of ACTH treatment. The children’s mental condition, skin and lip color changes, cough, shortness of breath, abdominal distention, diarrhea, etc. were all evaluated during the treatment, which included symptomatic supportive treatment such as calcium and potassium supplementation. Thirty children developed upper respiratory tract infections and 24 children had diarrhea. Monitoring vital signs, blood glucose, and electrolytes, the 108 children had no significant abnormalities in blood pressure, blood sugar, and electrolyte. Among the 113 children with intravenous drip under the same treatment, 60 had complete cessation of spasms, 31 children effectively responded, and the rest 22 were non-responders to 2-week ACTH treatment. Fifty-seven out of the 113 patients developed upper respiratory tract infections and 69 had diarrhea. In addition, 35 children experienced severe agitation and crying during treatment. ACTH administration was suspended until the crying and distressful feelings were alleviated, and the patients had no obvious discomfort in the subsequent treatment. It’s suggested that intramuscular injection with fewer side effects and higher compliance, is more effective than intravenous drip in patients with ISS.
Health economics, as one of the key metrics for evaluating the rationality of clinical treatment procedures, provides substantial support for rational drug usage in clinics and optimizing pharmaceutical resource allocation (20,21). The cost-effectiveness analysis revealed that patients treated with intramuscular ACTH spent less on treatment and benefited from more straightforward procedures than those receiving intravenous ACTH, thus providing a superior economic benefit while maintaining equivalent therapeutic efficacy.
We conducted a retrospective study of 221 ISS patients, providing a comprehensive comparison of the two administration routes of ACTH from the perspectives of clinical efficacy, side effects, and economic considerations. However, this study is not without limitations. The retrospective design may limit the robustness and precision of the data collected, which in turn impacts the reliability of the outcomes. This was compounded by a single-center sample source, unaccounted confounding variables, such as genetic and lifestyle factors, as well as the absence of long-term follow-up and a comprehensive economic evaluation, further limiting the generalizability of the findings. Future research endeavors should consider employing prospective, multicenter, randomized controlled trials to substantiate these findings, manage potential confounding elements, and conduct long-term follow-up studies to assess the enduring efficacy of ACTH therapy and the quality of life in patients. Moreover, it would be beneficial to include an economic evaluation that incorporates indirect costs like accommodation and transportation expenses for patients’ families to gain a more holistic view of treatment efficacy and cost-effectiveness.
Conclusions
In summary, the research indicated that intramuscular injection emerges as a more favorable administration route for ACTH in the short term, revealing fewer adverse effects and a lower cost profile over intravenous administration, considering safety, efficacy, patient adherence, and economic factors. Despite its constraints, the study offered significant guidance for medical professionals in choosing the most appropriate method of ACTH administration. Future investigations should address the current limitations to better elucidate the best practices for ACTH in the management of ISS.
Acknowledgments
Funding: This study was supported by
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-390/rc
Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-390/dss
Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-390/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-390/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional ethics committee of the West China Second University Hospital of Sichuan University [No. 2023(29)] and individual consent for this retrospective analysis was waived.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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