What is the evidence to support intranasal midazolam use for malacia spells? How does it compare to other medications?

What is the evidence to support intranasal midazolam use for malacial spells?

Comment by InpharmD Researcher

While data is limited, they suggest that intranasal midazolam is effective and safe as a premedication sedation in pediatric patients that present with similar symptoms like Tetralogy of Fallot and Hypercyanotic Spells. However, one study that compared intranasal ketamine with midazolam suggests that ketamine was more effective at achieving sedation levels while another study comparing midazolam with dexmedetomidine reported similar results. Overall, variability in outcomes indicates that additional data is required to validate these results.

Background

A 2022 meta-analysis evaluated the efficacy and safety of intranasal midazolam versus intranasal ketamine as sedative premedications in pediatric patients. This meta-analysis included data from 16 randomized controlled trials with a total population of 1,066 children aged 24 weeks to 14 years undergoing various surgical or diagnostic procedures. The dose of intranasal midazolam was commonly reported as 0.2 mg/kg in most studies, with one study documenting a higher dose of 0.4 mg/kg. The findings suggested that intranasal midazolam was associated with a more satisfactory sedation level (61.76% vs. 40.74%, risk ratio [RR] 1.53, 95% confidence interval [CI] 1.28 to 1.83) and demonstrated faster onset of sedation (standardized mean difference [SMD] -0.59, 95% CI -0.90 to -0.28) and recovery (SMD -1.06, 95% CI -1.83 to -0.28) compared to intranasal ketamine. The analysis focused on outcomes such as hemodynamic parameters, which appear to be key factors in addressing malacial or cyanotic spells associated with Tetralogy of Fallot. Intranasal ketamine was associated with significantly higher mean blood pressure (MBP; SMD -0.53, 95% CI -0.93 to -0.13, p = 0.009, I² = 0%) and oxygen saturation (SMD -0.57, 95% CI -1.13 to -0.02, p = 0.04, I² = 57%). It also showed a potential association with increased heart rate (SMD -1.39, 95% CI -2.84 to 0.06, p = 0.06, I² = 96%). Adverse effects, including agitation, oxygen saturation below 90%, nausea, and vomiting, showed no significant differences between the two groups. The authors underscored the need for higher-quality and larger-sample studies to confirm these findings given the moderate-to-low evidence quality in some outcomes. [1]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What is the evidence to support intranasal midazolam use for malacial spells?

Level of evidence

A - Multiple high-quality studies with consistent results Read more→

Please see Tables 1-4 for your response.

Evaluation of Efficacy of Intranasal Midazolam, Ketamine and Their Mixture as Premedication and its Relation with Bispectral Index in Children with Tetralogy of Fallot Undergoing Intracardiac Repair
Design	Prospective, randomized study N= 60
Objective	To compare the efficacy of intranasal midazolam, ketamine and their mixture for premedication in children with tetralogy of Fallot (TOF), to find a correlation between the BIS values and adequacy of premedication using the clinical endpoint of separation from parent
Study Groups	Ketamine (n= 20) Midazolam (n= 20) Ketamine and midazolam (n= 20)
Inclusion Criteria	Children aged 1-10 years with Tetralogy of Fallot, weighing between 5-20 Kgs, scheduled for elective corrective surgical procedure
Exclusion Criteria	Emergency surgery, preoperative coil embolization of collaterals, Down’s syndrome, nasal atresia, recent nasal bleeding/nasal discharge
Methods	Participants were randomly assigned to one of three groups: Group A: 20 participants received intranasal ketamine (10 mg/Kg). Group B: 20 participants received intranasal midazolam (0.2 mg/Kg). Group C: 20 participants received a mixture of ketamine (7.5 mg/Kg) and midazolam (0.1 mg/Kg). Intranasal administration of drugs was performed in the presence of parents. BIS values, sedation, and separation scores were recorded at intervals. A 4-point scale was used for evaluation.
Duration	30 minutes post-premedication for evaluation.
Outcome Measures	Sedation score, Separation score, BIS values, Acceptance of intravenous cannulation
Baseline Characteristics		Ketamine (n= 20)	Midazolam (n= 20)	Ketamine and midazolam (n= 20)
	Age, years	43.8	47.42	36.3
	Female	7	8	9
	Weight, kg	11.0	11.4	10.8
Results	Endpoint	Ketamine (n= 20)	Midazolam (n= 20)	Ketamine and midazolam (n= 20)	p-value K vs M	p-value M vs K/M	p-value K vs K/M
	BIS Score at 30 min	96.7 ± 0.7	87.3 ± 1.1	90.0 ± 1.7	< 0.05	< 0.05	> 0.05
	Sedation Score, Mean ± SD	3.75 ± 0.44	3.25 ± 0.44	3.80 ± 0.41	< 0.05	< 0.05	> 0.05
	Separation Score, Mean ± SD	3.90 ± 0.28	2.9 ± 0.31	3.83 ± 0.35	< 0.05	< 0.05	> 0.05
	Sedation Score at Cannulation, Mean ± SD	3.90 ± 0.31	2.85 ± 0.37	3.85 ± 0.37	< 0.05	< 0.05	> 0.05
Adverse Events	No side effects of ketamine were observed in any of the children who received it alone or in the mixture form.
Study Author Conclusions	Intranasal ketamine is better than intranasal midazolam. The combination of ketamine and midazolam is better than midazolam alone but provides no additional benefit compared to ketamine alone.
InpharmD Researcher Critique	The study is well-designed with clear objectives and a randomized approach. However, the sample size is relatively small, and the study is limited to a specific patient population (children with Tetralogy of Fallot), which may limit the generalizability of the findings. The study effectively uses BIS as an objective measure of sedation, which is a strength.

References:

Gharde P, Chauhan S, Kiran U. Evaluation of efficacy of intranasal midazolam, ketamine and their mixture as premedication and its relation with bispectral index in children with tetralogy of fallot undergoing intracardiac repair. Ann Card Anaesth. 2006;9(1):25-30.

Effects of intranasal dexmedetomidine versus intranasal midazolam as premedication in children with tetralogy of Fallot undergoing corrective cardiac surgery: A randomized trial
Design	Prospective, randomized, double-blind trial N= 40
Objective	To compare intranasal dexmedetomidine and intranasal midazolam as premedication for sedation and ease of child-parent separation in pediatric patients of tetralogy of Fallot (TOF) undergoing corrective cardiac surgery
Study Groups	Intranasal dexmedetomidine (n= 20) Intranasal midazolam (n= 20)
Inclusion Criteria	TOF patients aged 1–10 years, belonging to the American Society of Anesthesiologists (ASA) physical Status II or III and New York Heart Association (NYHA) Class 1 and 2
Exclusion Criteria	Undergoing emergency or redo surgeries, had renal or hepatic derangement, known drug allergy, nasal deformity, or mental retardation
Methods	Patients were randomized to treatment with either intranasal midazolam (0.2 mg/kg) or intranasal dexmedetomidine (1 µg/kg) 30 minutes prior to transition to operating room (OR). Drugs were administered in the supine position, with both nostrils pinched lightly to prevent discomfort and facilitate spread of drugs over the nasal mucosal surface.
Duration	April 2022 to March 2023
Outcome Measures	Primary: Sedation (per Ramsay Sedation Score), child-parent separation score Secondary: Hemodynamic parameters
Baseline Characteristics		Intranasal dexmedetomidine (n= 20)	Intranasal midazolam (n= 20)
	Age, years	5.0 ± 3.06	3.25 ± 2.57
	Female	4 (20%)	6 (30%)
	Body weight, kg	16.56 ± 8.34	12.51 ± 5.00
Results	Endpoint	Intranasal dexmedetomidine (n= 20)	Intranasal midazolam (n= 20)	p-Value
	Sedation score at: 0 min 30 min OR Induction	1.5 ± 0.51 2.95 ± 0.88 3.55 ± 0.82 3.4 ± 0.75	1.25 ± 0.44 2.60 ± 0.82 2.8 ± 0.83 2.7 ± 0.86	0.1077 0.2031 0.0069 0.0096
	Child-parent separation score	1.2 ± 0.41	1.45 ± 0.60	0.13
	Hemodynamic parameters, including heart rate, blood pressure, SpO2, respiratory rate, were comparable between groups, with no significant differences (data presented as graphs). Similarly, no significant differences were noted for premedication to induction time between groups (p= 0.33). Sedation score determined via 6-point Ramsay Sedation Score scale; child-parent separation score determined via 3-point score Child-parent separation score determined while shifting inside the OR.
Adverse Events	No adverse effects were observed.
Study Author Conclusions	We conclude that intranasal dexmedetomidine and intranasal midazolam provide an adequate level of sedation and ease of child–parent separation in children with TOF undergoing corrective cardiac surgery. Dexmedetomidine provided better levels of sedation as compared to midazolam at the time of shifting the patient to the OR and at the time of induction of anesthesia. The groups had similar parameters such as heart rate, blood pressure, respiratory rate, and SpO2 levels. A study on a larger population will help establish the safety and superiority of dexmedetomidine and further its regular use as an intranasal premedication.
InpharmD Researcher Critique	Although this study is not specific to malacial spells/cyanotic spells, TOF patients are prone to hypercyanotic spells at times of stress such as parental separation, induction of anesthesia, IV cannulation, and other painful procedures due to increased sympathetic stimulation resulting in infundibular spasm of the right ventricular outflow tract. Some outcomes were subjective, such as sedation scale scores and child-parent separation scores. While the sample size in this study is larger than other similar studies, the overall number of patients is still low.

References:

Srivastava S, Das S, Makhija N, Chauhan S. Effects of intranasal dexmedetomidine versus intranasal midazolam as premedication in children with tetralogy of Fallot undergoing corrective cardiac surgery: A randomized trial. Ann Pediatr Cardiol. 2024;17(2):109-115. doi:10.4103/apc.apc_10_24

Efficacy of Intranasal Midazolam in Cessation of Hypercyanotic Spells in Children with Tetralogy of Fallot
Design	Semi-experimental observational study N= 10
Objective	To evaluate the effect of intranasal midazolam on the control of spells in children with hypercyanotic tetralogy of fallot (TOF)
Study Groups	Patients treated with intranasal midazolam (N= 10)
Inclusion Criteria	Age < 6 years, had TOF
Exclusion Criteria	Runny nose, upper respiratory tract infection, required emergency surgery
Methods	Children included in the study were admitted to the pediatric emergency department of Golestan Hospital in Iran. The children were administered intranasal midazolam 0.2 mg into the nasal cavity. The selection process for patients was not described in detail.
Duration	Children admitted between November 2017 to October 2018
Outcome Measures	Clinical findings, including heart rate, respiratory rate, and arterial blood oxygen following intervention
Baseline Characteristics		All patients (N= 10)
	Age, years (range)	1.66 ± 0.98 (6 months to 3.5 years)
	Female	4 (40%)
	Patient emotive state Recovery Crying Fearful	6 (60%) 2 (20%) 2 (20%)
	Sedation level Calm Agitated	8 (80%) 2 (20%)
	Duration of masking, min	9.6 ± 2.87
	Duration of recovery, min	45.5 ± 9.55
Results	Endpoint	All patients (N= 10)	p-Value, before vs. after
	Heart rate, per min Before intervention After intervention	137 ± 18.28 110.5 ± 17.39	< 0.001
	Respiratory rate, per min Before intervention After intervention	68.5 ± 8.51 48.5 ± 11.55	< 0.001
	Arterial blood oxygen, % Before intervention After intervention	45 ± 8.16 61.5 ± 9.73	< 0.001
Adverse Events	No adverse effects were observed.
Study Author Conclusions	According to the results of this study, administration of intranasal midazolam to children with TOF spells resulted in significant relaxation, reduction in heart rate, improvement in arterial blood oxygenation, and increased acceptance of the mask by the children. It was also not associated with side effects. Therefore, intranasal midazolam can be considered an effective and safe drug for controlling spells in patients with TOF.
InpharmD Researcher Critique	Sample size of this study was limited, with no comparator group. Additionally, the study was conducted in Iran, where standard of care may vary compared to the United States.

References:

Riahi K, Najibi B, Razmara M. Efficacy of Intranasal Midazolam in Cessation of Hypercyanotic Spells in Children with Tetralogy of Fallot. Caspian J Pediatrs. 2023;9(16).

Intranasal Midazolam for the Emergency Management of Hypercyanotic Spells in Tetralogy of Fallot
Design	Case report
Case presentation	A 2-month-old boy with prenatally diagnosed Tetralogy of Fallot (TOF) was brought to the emergency department for cyanosis and distress when crying. Despite being on propranolol, he presented tachycardic, tachypneic, and profoundly cyanotic. After unsuccessful attempts to calm him with oxygen and position, intranasal midazolam at 0.2 mg/kg was administered, rapidly sedating and stabilizing the patient, allowing for IV access and fluid resuscitation. The patient was then admitted to the PICU and underwent corrective surgery 3 days later, with no adverse events reported from the use of intranasal midazolam.
Study Author Conclusions	The administration of nasal Midazolam provided a good sedation and immediately increased systemic arterial saturation, probably by decreasing sympathetic tone, augmenting pulmonary blood flow. There were no adverse effects.

References:

Montero JV, Nieto EM, Vallejo IR, Montero SV. Intranasal midazolam for the emergency management of hypercyanotic spells in tetralogy of Fallot. Pediatr Emerg Care. 2015;31(4):269-271. doi:10.1097/PEC.0000000000000403