Therapeutic Intranasal Drug Delivery

Abstract: To investigate connections between patient demographics, health care utilization, prescription use, and refills for patients using intranasal midazolam, per rectum diazepam, or both. A retrospective cohort contained patients with epilepsy prescribed intranasal midazolam, per rectum diazepam, or both. We analyzed number of emergency department visits, ambulance services, urgent care visits, and unplanned hospitalizations. A total of 5458 patients were identified. Patients on intranasal midazolam had on average 1.53 fewer emergency department visits (95% confidence interval 1.16-1.89, P < .0001), 0.29 fewer uses of ambulance services (95% confidence interval 0.17-0.41, P < .0001), and 0.60 fewer urgent care visits (95% confidence interval 0.36-0.83, P < .0001) compared to patients in the per rectum diazepam group. Patients with commercial insurance were more likely to have intranasal midazolam prescription (odds ratio = 1.73, 95% confidence interval 1.42-2.11, P < .0001). The results substantiate the cost-effective benefits of prescribing intranasal midazolam compared to per rectum diazepam because several aspects of health care utilization were decreased in those using intranasal midazolam.

Ostendorf, A. P., K. Merison, et al. (2018). "Decreasing Seizure Treatment Time Through Quality Improvement Reduces Critical Care Utilization." Pediatr Neurol 85: 58-66.

Abstract: BACKGROUND: Rapid, effective treatment for status epilepticus reduces associated morbidity and mortality, yet medication delivery remains slow in many hospitalized patients. We utilized quality improvement (QI) methodology to improve treatment times for hospitalized children with status epilepticus. We hypothesized rapid initial seizure treatment would decrease seizure morbidity. METHODS: We utilized QI and statistical process control analysis in a nonintensive care setting within a tertiary care pediatric hospital. We performed Plan-Do-Study-Act cycles including (1) revising the nursing process for responding to seizures, (2) emphasizing intranasal midazolam over intravenous lorazepam, (3) relocating medications and supplies, (4) developing documentation tools and reinforcing correct processes, (5) developing and disseminating an online education module for residents and nurse practitioners, and (6) completing standardization to intranasal midazolam. RESULTS: Seventeen months after starting the project, 66 seizures had been treated with a benzodiazepine in a median (p25-p75) time of 7.5 minutes (5 to 10), decreased from a baseline of 14 minutes (8-30) (P = 0.01). The proportion of patients receiving a benzodiazepine in 10 minutes or less improved from 39% to 79%. The proportion of patients transferred to intensive care decreased from a baseline of 39% to 9% (P < 0.005), resulting in an estimated $2.1 million in mitigated hospital charges. Significant harm did not occur during the implementation of these interventions. CONCLUSIONS: Children with status epilepticus were treated with benzodiazepines more rapidly and effectively following implementation of QI methodology. These interventions reduced utilization of critical care and mitigated hospital charges.

Web site Editorial comments:

I featured these two articles because they both show reductions in health care utilization with intranasal midazolam when compared to either home use of rectal diazepam or hospital use of IV lorazepam to treat acute seizures. If you treat epileptic patients and have not considered IN midazolam as first line therapy for acute prolonged seizures, I suggest you review the information on the topic on this website.  Intranasal midazolam is fairly compelling as first line treatment of prolonged seizures for many reasons, not just because it results in significant cost savings. It can be delivered more rapidly, it is as effective if not more effective than other options, it is non-invasive, it is preferred by patients and their families, it is affordable and portable, it reduces EMS ambulance calls freeing up families to travel, etc, etc. Read about it, you owe it to your patients.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/29233042

Abstract: OBJECTIVE: To compare the effectiveness of sedation by intranasal administration of midazolam (nMDZ) or ketamine (nKTM) for neonatal intubation. DESIGN: A multicentre, prospective, randomised, double-blind study. SETTING: Delivery rooms at four tertiary perinatal centres in France. PATIENTS: Preterm neonates with respiratory distress requiring non-emergent endotracheal intubation for surfactant instillation. INTERVENTIONS: Treatment was randomly allocated, with each neonate receiving a bolus of 0.1 mL/kg in each nostril, corresponding to 0.2 mg/kg for nMDZ and 2 mg/kg for nKTM. The drug was repeated once 7 min later at the same dose if adequate sedation was not obtained. MAIN OUTCOME MEASURES: Success was defined by adequate sedation before intubation and adequate comfort during the procedure. Intubation features, respiratory and cardiovascular events were recorded. RESULTS: Sixty newborns, with mean (SD) gestational age and birth weight of 28 (3) weeks and 1100 (350) g, were included within the first 20 min of life. nMDZ was associated with a higher success rate (89% vs 58%; RR: 1.54, 95% CI 1.12 to 2.12, p<0.01) and shorter delays between the first dose and intubation (10 (6) vs 16 (8) min, p<0.01).Number of attempts, time to intubation, mean arterial blood pressure measures over the first 12 hours after birth and length of invasive ventilation were not different. CONCLUSIONS: nMDZ was more efficient than nKTM to adequately sedate neonates requiring intubation in the delivery room. The haemodynamic and respiratory effects of both drugs were comparable. CLINICAL TRIAL: This clinical trial was recorded on the National Library of Medicine registry (NCT01517828).

Web site Editorial comments:

This is interesting data primarily given the patient population treated with nasal sedatives prior to intubation: Newborns with mean age of 28 weeks gestation and mean weights of 1100 grams. The results are not particularly surprising – IN ketamine at doses of 2 mg/kg (or even 4 mg/kg if re-dosed) are simply too low to achieve a sedative effect based on all other studies on the topic. However, low dose midazolam (0.2 mg/kg) did lead to fairly adequate sedation. The point of featuring this article is to emphasize that this treatment modality, intranasal medication delivery, works in all ages and all weights assuming you choose an adequate weight based dose.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/28818854

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Olgun, G. and M. H. Ali (2018). "Use of Intranasal Dexmedetomidine as a Solo Sedative for MRI of Infants." Hosp Pediatr.

Abstract: BACKGROUND: Dexmedetomidine, a selective alpha-2 receptor agonist, can be delivered via the intranasal (IN) route and be used for procedural sedation. The drug's favorable hemodynamic profile and relative ease of application make it a promising agent for sedation during radiologic procedures, although there are few studies on its efficacy for MRI studies. METHODS: A retrospective chart review was performed between June 2014 and December 2016. Outpatients between 1 and 12 months of age who received 4 mug/kg of IN dexmedetomidine for MRI were included in the analysis. Our aim with this study was to determine the rate of successful completion of the sedation procedure without the need for a rescue drug (other than repeat IN dexmedetomidine). RESULTS: A total of 52 subjects were included in our study. Median (interquartile range) patient age was 7 (5-8) months. Median (interquartile range) procedure length was 40 (35-50) minutes. Overall success rate (including first dose and any rescue dose IN) of dexmedetomidine was 96.2%. None of the patients had significant adverse effects related to dexmedetomidine. CONCLUSIONS: IN dexmedetomidine is an effective solo sedative agent for MRI in infants.

Web site Editorial comments:

Here is an important article showing 96% successful sedation of children less than one year of age with a single dose of IN dexmedetomidine. This drug has a very nice safety profile, leads to fairly prolonged sedation adequate for MRI studies or longer procedures, and does not carry the respiratory risks or CNS toxicity issues sometimes related to other sedatives like propofol. Read the accompanying editorial by Reynolds for more insight (Free Access PDF link below).