Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

Needleless treatment options for medical problems

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Featured new articles related to intranasal drug delivery

January-December 2017:

Adelgais, K. M., A. Brent, et al. (2017). "Intranasal Fentanyl and Quality of Pediatric Acute Care." J Emerg Med.

Abstract:

BACKGROUND: Changes in the manner in which medications can be delivered can have significant effects on the quality of care in the acute care setting. OBJECTIVE: The objective of this study was to evaluate the change in three Institute of Medicine quality indicators (timeliness, safety, and effectiveness) in the pediatric emergency department (ED) after the introduction of the Mucosal Atomizer Device Nasal (MADn) for opioid analgesia. METHODS: This was a retrospective review of patients receiving opioid analgesia for certain conditions over a 5-year period. We compared patients receiving intravenous opioid (IVO) to those receiving intranasal fentanyl (INF). Timeliness outcomes include time from medication order to administration, time from dose to discharge, overall time to analgesia, and ED length of stay. Effectiveness outcomes include change in pain score and frequency of repeat dosing. Safety outcomes were the frequency of reversal agent administration or a documented oxygen desaturation of < 90%. Sensitivity analyses were performed to evaluate the effect of moderate sedation on all three outcomes. RESULTS: During the study period, 1702 patients received opioid analgesia, 744 before and 958 after MADn introduction, of whom, 233 (24%) received INF. After MADn introduction, patients receiving INF had a shorter time to discharge from dose (109 vs. 203 min; p < 0.05) and shorter ED length of stay (168 vs. 267 min; p < 0.05). There was no difference in pain score reduction; however, repeat dosing was less frequent for patients receiving INF (16% vs. 27%). There was no use of reversal medication and no difference in the frequency of oxygen desaturations. When patients undergoing moderate sedation were removed from the analysis, there was no difference in the direction of findings for all three outcomes. CONCLUSIONS: INF is associated with improved timeliness and equivalent effectiveness and safety when compared to IVO in the setting of the pediatric ED.

Web site Editorial comments:

Here is another article showing that IN fentanyl is just as good as IV opiates at controlling severe pain in a pediatric emergency department but does not require nursing staff to establish any IV access. This study is unique in that IN fentanyl  was used not just for orthopedic cases but was used for any patient that needed opiates. Furthermore it results in faster delivery of pain medications, faster onset of analgesia (39 vs 68 minutes) and far shorter lengths of stay (168 vs 267 minutes) – freeing up beds, saving resources and allowing for more efficient management of beds and staff time.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/28967529

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Farnia, M. R., A. Jalali, et al. (2017). "Comparison of intranasal ketamine versus IV morphine in reducing pain in patients with renal colic." Am J Emerg Med 35(3): 434-437.

Abstract:

                BACKGROUND: Various drugs have been used to relieve abdominal pain in patients with renal colic. Ketamine is a popular choice as an analgesic. OBJECTIVE: To compare the effectiveness of intranasal (IN) ketamine versus intravenous (IV) morphine in reducing pain in patients with renal colic. METHODS: A randomized double-blind controlled trial was performed in 53 patients with renal colic recruited from the emergency department (ED) in 2015. Finally, 40 patients were enrolled in this study. Patients in the ketamine group received IN ketamine 1 mg/kg and IV placebo while patients in the control group received IV morphine 0.1mg/kg and IN placebo. Our goal was to assess visual analogue scale (VAS) changes between the 2 groups. Patients' VAS scores were reported before and 5, 15, 30min after drug injection. RESULTS: Before drug administration, the mean+/-SD VAS score was 7.40+/-1.18 in the morphine group (group A) and 8.35+/-1.30 in the ketamine group (group B) (P-value=0.021). After adjustment by the appropriate analysis, the mean+/-SD VAS score in group (A) and (B) at 5min were (6.07+/-0.47 vs 6.87+/-0.47; mean difference -0.79, 95% confidence interval (CI) -1.48 to -1.04) (P-value=0.025), at 15 and 30min, the mean+/-SD VAS score in group (A) and (B) were (5.24+/-0.49 vs 5.60+/-0.49; mean difference -0.36, 95% CI -1.08 to 0.34) and (4.02+/-0.59 vs 4.17+/-0.59; mean difference -0.15, 95% CI -1.02 to 0.71) (P-value=0.304 and 0.719) respectively. CONCLUSIONS: IN ketamine may be effective in decreasing pain in renal colic.

Web site Editorial comments:

I included this article in the featured section because we need alternatives to opiates for many painful conditions in the ED given the ongoing opiate epidemic and the known addictive potential of these medications. Maybe IN ketamine is a good alternative? Or maybe it could lead to addiction as well.  Of further interest is the ability to reduce resources if we were to treat many of our renal colic cases with IN ketamine and either IN or buccal nausea medications.  Most of these patients need little other care – just control of their symptoms, confirmation they have not renal infectious process and at times renal function testing – none of which require and IV. It is a thought for future studies: Randomize patients  to transmucosal therapy and no IV versus standard therapy and look at cost of care, length of stay and efficacy of treatment.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/27931762

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Mellion, S. A., D. Bourne, et al. (2017). "Evaluating Clinical Effectiveness and Pharmacokinetic Profile of Atomized Intranasal Midazolam in Children Undergoing Laceration Repair." J Emerg Med 53(3): 397-404.

Abstract:

BACKGROUND: Atomized intranasal midazolam is a common adjunct in pediatrics for procedural anxiolysis. There are no previous studies of validated anxiety scores with pharmacokinetic data to support optimal procedure timing. OBJECTIVES: We describe the clinical and pharmacokinetic profile of atomized intranasal midazolam in children presenting for laceration repair. METHODS: Children 11 months to 7 years of age and weighing <26 kg received 0.4 mg/kg of atomized intranasal midazolam for simple laceration repair. Blood samples were obtained at 3 time points in each patient, and the data were fit with a 1-compartment model. Patient anxiety was rated with the Observational Scale of Behavioral Distress. Secondary outcomes included use of adjunctive medications, successful completion of procedure, and adverse events. RESULTS: Sixty-two subjects were enrolled, with a mean age of 3.3 years. The median time to peak midazolam concentration was 10.1 min (interquartile range 9.7-10.8 min), and the median time to the procedure was 26 min (interquartile range 21-34 min). There was a trend in higher Observational Scale of Behavioral Distress scores during the procedure. We observed a total of 2 adverse events, 1 episode of vomiting (1.6%) and 1 paradoxical reaction (1.6%). Procedural completion was successful in 97% of patients. CONCLUSIONS: Atomized intranasal midazolam is a safe and effective anxiolytic to facilitate laceration repair. The plasma concentration was >90% of the maximum from 5 to 17 min, suggesting this as an ideal procedural timeframe after intranasal midazolam administration.

Mellion et al IN midazolam blood concetrations

Mellion Figure 1: Midazolam blood concentration

This graph demonstrates the rapid absorption of 5 mg/ml generic midazolam when administered by a syringe driven atomizer. The peak is in 10 minutes and the 90% of peak time range is 5 to 17 minutes at which point it begins to drop off (this  is a logarithmic scale so the slope is not as steep looking as a normal scale). This timing of the peak suggests the ideal time to do the procedure (start work as soon as they are goofy which is about 5 minutes, go fast as it wears o ff relatively quickly).

Web site Editorial comments:

This study confirms in a research study what this website has recommended all along: You have limited time and must utilize it all very efficiently to successfully use nasal midazolam for laceration repair. The peak is at 10 minutes, the 90% peak time frame is 5-17 minutes and the half life is 33 minutes so it comes on quickly but goes away quickly. Here is the synopsis of their recommendations: Give the kid a nasal dose of lidocaine first then get all your tools out and ready (our recommendation); administer a weight based dose of nasal midazolam  in the 0.4 to 0.5 mg/kg range (higher is better); as soon as they are goofy (about 5 minutes) position them, anesthetize and begin cleansing the wound (this requires some restraint as they are not unconscious); sew it. Do all this in 20-30 minutes if possible. If you will need longer sedation time for a complex wound consider alternate sedative like IM ketamine.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/28992870

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Reynolds, S. L., K. K. Bryant, et al. (2017). "Randomized Controlled Feasibility Trial of Intranasal Ketamine Compared to Intranasal Fentanyl for Analgesia in Children with Suspected Extremity Fractures." Acad Emerg Med.

Abstract:

OBJECTIVE: We compared the tolerability and efficacy of intranasal sub-dissociative ketamine to intranasal fentanyl for analgesia of children with acute traumatic pain and investigated the feasibility of a larger non-inferiority trial that could investigate the potential opioid sparing effects of intranasal ketamine. METHODS: This randomized controlled trial compared intranasal ketamine 1 mg/kg to intranasal fentanyl 1.5 mug/kg in children 4-17 years old with acute pain from suspected, isolated extremity fractures presenting to an urban level II pediatric trauma center from December 2015 to November 2016. Patients, parents, treating physicians, and outcome assessors were blinded to group allocation. The primary outcome, a tolerability measure, was the frequency of cumulative side effects and adverse events within 60 minutes of drug administration. The secondary outcomes included the difference in mean pain score reduction at 20 minutes, the proportion of patients achieving a clinically significant reduction in pain in 20 minutes, total dose of opioid pain medication in morphine equivalents/kg/hour (excluding study drug) required during the emergency department (ED) stay, and the feasibility of enrolling children presenting to the ED in acute pain into a randomized trial conducted under US regulations. All patients were monitored until 6 hours after their last dose of study drug, or until admission to the hospital ward or operating room. RESULTS: Of 629 patients screened, 87 received the study drug and 82 had complete data for the primary outcome (41 patients in each group). The median age (interquartile range) was 8 (3) years and 62% were male. Baseline pain scores were similar among patients randomized to receive ketamine (73 +/- 26) and fentanyl (69 +/- 26) [mean difference (95% CI): 4 (-7 to 15)]. The cumulative number of side effects was 2.2 times higher in the ketamine group, but there were no serious adverse events and no patients in either group required intervention. The most common side effects of ketamine were bad taste in the mouth (37; 90.2%), dizziness (30; 73.2%), and sleepiness (19; 46.3%). The most common side effects of fentanyl were sleepiness (15; 36.6%), bad taste in the mouth (9; 22%), and itchy nose (9; 22%). No patients experienced respiratory side effects. At 20 minutes, the mean pain scale score reduction was 44 +/- 36 for ketamine and 35 +/- 29 for fentanyl [mean difference: 9 (95% CI: -4 to 23)]. Procedural sedation with ketamine occurred in 28 ketamine patients (65%) and 25 fentanyl patients (57%) prior to completing the study. CONCLUSIONS: Intranasal ketamine was associated with more minor side effects than intranasal fentanyl. Pain relief at 20 minutes was similar between groups. Our data support the feasibility of a larger, non-inferiority trial to more rigorously evaluate the safety, efficacy, and potential opioid sparing benefits of intranasal ketamine analgesia for children with acute pain. This article is protected by copyright. All rights reserved.

Web site Editorial comments:

This article is included here due to results that show we may be able to reduce opiate use safely and effectively simply by using IN ketamine for acute pain control. As in other studies they did find more side effects using ketamine, all were minor and relatively non-concerning given the issues that now surround opiates.  I have been resistant to using ketamine for acute pain in the ED as I have extensive experience with IN fentanyl at 2 mcg/kg in kids and IN sufentanil at 0.5 to 0.7 mcg/kg in adults and find them almost 100% effective (titration to effect is rarely needed but easily done so you can almost always achieve very adequate pain control). However, given the opiate epidemic we are now suffering I can see it may be time to consider a change and look for other alternatives. It looks like IN ketamine may offer such an alternative and it is a single drug with a single weight based dosing regimen for both kids and adults so I am interested in possibly changing my recommendations. I might push my doses a bit higher than theirs as there is plenty of other literature demonstrating the safety of a higher ketamine dose and some enhanced efficacy.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/28926159

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Milesi, C., J. Baleine, et al. (2017). "Nasal midazolam vs ketamine for neonatal intubation in the delivery room: a randomised trial." Arch Dis Child Fetal Neonatal Ed.

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:

The results of this study should not surprise our readers as the data is very clear that nasal ketamine is very effective for pain control in this dose range, but a MUCH higher dose is needed for sedation. The authors found low dose ketamine at 2 mg/kg only 58% effective at sedating neonates while low dose midazolam (0.2 mg/kg) was 89% effective.  We would expect ketamine at 2 mg/kg to have almost no sedative effects and in older children 0.2 mg/kg midazolam will stop seizures but give minimal sedation.  However, this study is important for another reason – it is one of our few studies noting both safety and efficacy of nasal drugs in neonates who often do not have IV access readily available.

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

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Schrier, L., R. Zuiker, et al. (2017). "Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation." Br J Clin Pharmacol 83(4): 721-731.

Abstract:

            AIM: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. METHODS: In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and alpha-hydroxy-midazolam were characterized and related to outcome variables for sedation (saccadic peak velocity, the Bond and Lader visual analogue scale for sedation, the simple reaction time task and the observer's assessment of alertness/sedation). Nasal tolerance was evaluated through subject reporting, and ear, nose and throat examination. RESULTS: Nazolam bioavailability was 75%. Maximal plasma concentrations of 31 ng ml-1 (CV, 42.3%) were reached after 11 min (2.5 mg Nazolam), and of 66 ng ml-1 (coefficient of variability, 31.5%) after 14 min (5.0 mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1 +/- 0.7 min after administration of 2.5 mg intravenous midazolam, 7 +/- 4.4 min after 2.5 mg Nazolam, and 4 +/- 1.8 min after 5 mg Nazolam. Sedation duration was 118 +/- 95.6 min for 2.5 mg intravenous midazolam, 76 +/- 80.4 min for 2.5 mg Nazolam, and 145 +/- 104.9 min for 5.0 mg Nazolam. Nazolam did not lead to nasal mucosa damage. CONCLUSIONS: This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation.

Web site Editorial comments:

This study reports pharmacokinetic data related to a new highly concentrated from of Midazolam designed for IN delivery called Nazolam. It has 75% bioavailability, fairly rapid onset and good duration of action and does not damage mucosa. We can expect this to be on the market soon. It is a very well designed product that will be prepackaged as single dose applicators making them very convenient to administer and highly predictable in their effects. If priced and marketed correctly these products should replace our current techniques of using generic drugs. The question of course will be affordability when compared to the less concentrated inexpensive generic concentrations. Hopefully the manufacturers will find a middle ground price structure where they make a fair profit and the price is affordable so that widespread use occurs.

Schrier IN Midazolam plasma concentrations

Schrier - Graph of midazolam concentration versus time profiles: This graph demonstrates two important findings: First the high immediate peak for IV midazolam but the lack of an immediate high peak concentration for nasal midazolam – meaning the risk of respiratory depression is minimal using the nasal drug. Second, nearly equivalent plasma levels of nasal and IV drugs once the high risk high peak levels abate – meaning similar sedative and anti-seizure effects regardless of which route of delivery is chosen.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/27780297

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Smith, D., H. Cheek, et al. (2017). "Lidocaine Pretreatment Reduces the Discomfort of Intranasal Midazolam Administration: A Randomized, Double-blind, Placebo-controlled Trial." Acad Emerg Med 24(2): 161-167.

Abstract:

OBJECTIVE: Intranasal (IN) midazolam is a commonly prescribed medication for pediatric sedation and anxiolysis. One of its most frequently encountered adverse effects is discomfort with administration. While it has been proposed that premedicating with lidocaine reduces this undesirable consequence, this combination has not been thoroughly researched. The objective of our study was to assess whether topical lidocaine lessens the discomfort associated with IN midazolam administration. METHODS: This was a double-blind, randomized, placebo-controlled trial performed in an urban, academic pediatric emergency department. Children 6-12 years of age who were receiving IN midazolam for procedural sedation received either 4% lidocaine or 0.9% saline (placebo) via mucosal atomizer. Subjects were subsequently given IN midazolam in a similar fashion and then rated their discomfort using the Wong-Baker FACES Pain Rating Scale (WBS). The primary endpoint of WBS score was analyzed with a two-tailed Mann-Whitney U-test, with p < 0.05 considered statistically significant. RESULTS: Seventy-seven patients were enrolled over a consecutive 8-month period. One child was excluded from analysis due to a discrepancy in recording the drug identification number. Study groups were similar in regard to demographic information and indication for sedation. Subjects who received IN lidocaine reported less discomfort with IN midazolam administration (median WBS = 3, interquartile range [IQR] = 0-6) than those who received placebo (median WBS = 8, IQR = 2-9; p = 0.006). CONCLUSIONS: Premedication with topical lidocaine reduces the discomfort associated with administration of IN midazolam (ClinicalTrials.gov, NCT02396537).

Web site Editorial comments:

Here is another study in a list of similar studies that show pre-administration of lidocaine will significantly decrease the pain children experience when they are administered IN midazolam. This study is the most rigorous yet and shows and impressive difference in discomfort between those treated with lidocaine and those given placebo 5 minutes prior to midazolam administration. This pretreatment should be added to all sedation protocols using nasal midazolam administration.

Smith et al Pain scores with lidocaine prior to midazolam

Smith et al: Graph contrasting pain scores of patients who received lidocaine (WBS = 3) versus placebo (WBS = 8) 5 minutes prior to IN midazolam administration.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/27739142

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Sanchez Fernandez, I., M. Gainza-Lein, et al. (2017). "Nonintravenous rescue medications for pediatric status epilepticus: A cost-effectiveness analysis." Epilepsia 58(8): 1349-1359.

Abstract:

OBJECTIVE: To quantify the cost-effectiveness of rescue medications for pediatric status epilepticus: rectal diazepam, nasal midazolam, buccal midazolam, intramuscular midazolam, and nasal lorazepam. METHODS: Decision analysis model populated with effectiveness data from the literature and cost data from publicly available market prices. The primary outcome was cost per seizure stopped ($/SS). One-way sensitivity analyses and second-order Monte Carlo simulations evaluated the robustness of the results across wide variations of the input parameters. RESULTS: The most cost-effective rescue medication was buccal midazolam (incremental cost-effectiveness ratio ([ICER]: $13.16/SS) followed by nasal midazolam (ICER: $38.19/SS). Nasal lorazepam (ICER: -$3.8/SS), intramuscular midazolam (ICER: -$64/SS), and rectal diazepam (ICER: -$2,246.21/SS) are never more cost-effective than the other options at any willingness to pay. One-way sensitivity analysis showed the following: (1) at its current effectiveness, rectal diazepam would become the most cost-effective option only if its cost was $6 or less, and (2) at its current cost, rectal diazepam would become the most cost-effective option only if effectiveness was higher than 0.89 (and only with very high willingness to pay of $2,859/SS to $31,447/SS). Second-order Monte Carlo simulations showed the following: (1) nasal midazolam and intramuscular midazolam were the more effective options; (2) the more cost-effective option was buccal midazolam for a willingness to pay from $14/SS to $41/SS and nasal midazolam for a willingness to pay above $41/SS; (3) cost-effectiveness overlapped for buccal midazolam, nasal lorazepam, intramuscular midazolam, and nasal midazolam; and (4) rectal diazepam was not cost-effective at any willingness to pay, and this conclusion remained extremely robust to wide variations of the input parameters. SIGNIFICANCE: For pediatric status epilepticus, buccal midazolam and nasal midazolam are the most cost-effective nonintravenous rescue medications in the United States. Rectal diazepam is not a cost-effective alternative, and this conclusion remains extremely robust to wide variations of the input parameters.

Web site Editorial comments:

This article confirms what all of us in practice know – rectal diazepam is not as effective as nasal or buccal drugs and it costs an exorbitant amount of money ($326/dose versus $6 to $12/dose for buccal and nasal midazolam) for its poor performance so it is not worth using given all our better options. The only reason this author thinks it can possibly still be in active use is it has regulatory approval for treating increasingly frequent seizures, while nasal and buccal drugs are generic IV formulations without regulator approval for other modes of delivery. Interestingly, they point out that rectal diazepam does NOT have regulatory approval for treating ongoing seizures or status epilepticus so it is in effect being used off label as well. (It  is approved just for reducing frequency of seizures.)  It is unfortunate that today, despite the fairly compelling evidence of superior efficacy (and outcomes) we clinicians still prescribe this outdated rectal drug and force our patients to pay its ridiculous costs for worse results and a socially unacceptable delivery method.  These authors and I predict it will disappear as soon as nasal benzodiazepines cross the regulatory approval threshold. They point out that rectal diazepam NOT recommended for use in status epilepsy by the American epilepsy society – rather they recommend non-IV midazolam delivery methods.  I also predict that buccal and IM formulations will struggle to compete with the nasal drug once it gets regulatory approval as there is a fair amount of literature showing more rapid onset of seizure control and slightly higher efficacy using the nasal formulations.

Sanchez drug costs for epilepsy

Sanchez graph of cost vs efficacy for seizure meds

The table and graph above shows the parameters Sanchez Fernandez et al used to determine their results: Cost is the total cost of the drug plus applicator (nasal atomizer or syringe and needle etc). Effectiveness is the literature reported percentage of cases (from 24 studies reviewed) that the medication and delivery route will stop prolonged seizures. The graph plots the cost versus the effectiveness with the ideal drug being one that plots out at the lower right corner of the graph (low cost, highly effective). As is readily apparent rectal diazepam is an absolute outlier.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/28620949

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Bailey, A. M., R. A. Baum, et al. (2017). "Review of Intranasally Administered Medications for Use in the Emergency Department." J Emerg Med 53(1): 38-48

McBride, D. L. (2017). "Emergency Departments Increasingly Administering Medications through the Nose." J Pediatr Nurs.

Rech, M. A., B. Barbas, et al. (2017). "When to Pick the Nose: Out-of-Hospital and Emergency Department Intranasal Administration of Medications." Ann Emerg Med 70(2): 203-211.

Abstracts:

            BACKGROUND: Intranasal (IN) medication delivery is a viable alternative to other routes of administration, including intravenous (IV) and intramuscular (IM) administration. The IN route bypasses the risk of needle-stick injuries and alleviates the emotional trauma that may arise from the insertion of an IV catheter. OBJECTIVE: This review aims to evaluate published literature on medications administered via the IN route that are applicable to practice in emergency medicine. DISCUSSION: The nasal mucosa is highly vascularized, and the olfactory tissues provide a direct conduit to the central nervous system, bypass first-pass metabolism, and lead to an onset of action similar to IV drug administration. This route of administration has also been shown to decrease delays in drug administration, which can have a profound impact in a variety of emergent scenarios, such as seizures, acutely agitated or combative patients, and trauma management. IN administration of midazolam, lorazepam, flumazenil, dexmedetomidine, ketamine, fentanyl, hydromorphone, butorphanol, naloxone, insulin, and haloperidol has been shown to be a safe, effective alternative to IM or IV administration. As the use of IN medications becomes a more common route of administration in the emergency department setting, and in prehospital and outpatient settings, it is increasingly important for providers to become more familiar with the nuances of this novel route of medication delivery. CONCLUSIONS: IN administration of the reviewed medications has been shown to be a safe and effective alternative to IM or IV administration. Use of IN is becoming more commonplace in the emergency department setting and in prehospital settings.

Administering medications through the nose as an alternative to intramuscular or intravenous injections is increasingly popular in emergency departments and out-of hospital settings because it is simple, fast, and can be used in situations where obtaining intravenous access is difficult or time intensive. This article examines the literature and indications for the out-of-hospital and emergency department administration of five commonly used intranasal medications: midazolam (used to sedate children and treat seizures), fentanyl (for pain relief), naloxone (for opioid overdoses), ketamine (to induce anesthesia) and dexmedetomidine (to sedate and relieve pain in children).

The intranasal route for medication administration is increasingly popular in the emergency department and out-of-hospital setting because such administration is simple and fast, and can be used for patients without intravenous access and in situations in which obtaining an intravenous line is difficult or time intensive (eg, for patients who are seizing or combative). Several small studies (mostly pediatric) have shown midazolam to be effective for procedural sedation, anxiolysis, and seizures. Intranasal fentanyl demonstrates both safety and efficacy for the management of acute pain. The intranasal route appears to be an effective alternative for naloxone in opioid overdose. The literature is less clear on roles for intranasal ketamine and dexmedetomidine.

Web site Editorial comments:

These three articles by authors Bailey, McBride and Rech  review the literature regarding the use of IN drugs in the emergency department. They don't really fit anywhere on this site as they are review articles that essentially confirm what is written here on this web site, citing some of the many articles within these pages. Their publication made me feel good as  it now appears that in 2017 the concept of IN drug delivery is finally going mainstream in US emergency medicine literature (it was adopted by many ED clinicians far earlier: 1- 2 decades ago). 

Pubmed links:

https://www.ncbi.nlm.nih.gov/pubmed/28259526

https://www.ncbi.nlm.nih.gov/pubmed/28551041

https://www.ncbi.nlm.nih.gov/pubmed/28366351

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Nemeth, M., N. Jacobsen, et al. (2017). "Intranasal Analgesia and Sedation in Pediatric Emergency Care-A Prospective Observational Study on the Implementation of an Institutional Protocol in a Tertiary Children's Hospital." Pediatr Emerg Care.

Abstract:

            OBJECTIVES: Children presenting with acute traumatic pain or in need of therapeutic or diagnostic procedures require rapid and effective analgesia and/or sedation. Intranasal administration (INA) promises to be a reliable, minimally invasive delivery route. However, INA is still underused in Germany. We hence developed a protocol for acute pain therapy (APT) and urgent analgesia and/or sedation (UAS). Our aim was to evaluate the effectiveness and safety of our protocol. METHODS: We performed a prospective observational study in a tertiary children's hospital in Germany. Pediatric patients aged 0 to 17 years requiring APT or UAS were included. Fentanyl, s-ketamine, midazolam, or combinations were delivered according to protocol. Primary outcome variables included quality of analgesia and/or sedation as measured on age-appropriate scales and time to onset of drug action. Secondary outcomes were adverse events and serious adverse events. RESULTS: One hundred pediatric patients aged 0.3 to 16 years were enrolled, 34 for APT and 66 for UAS. The median time onset of drug action was 5 minutes (ranging from 2 to 15 minutes). Fentanyl was most frequently used for APT (n = 19). Pain scores decreased by a median of 4 points (range, 0-10; P < 0.0001). For UAS, s-ketamine/midazolam was most frequently used (n = 25). Sedation score indicated minimal sedation in most cases. Overall success rate after the first attempt was 82%. Adverse events consisted of nasal burning (n = 2) and vomiting (n = 2). No serious adverse events were recorded. CONCLUSIONS: A fentanyl-, s-ketamine-, and midazolam-based INA protocol was effective and safe for APT and UAS. It should then be considered where intravenous access is impossible or inappropriate.

Web site Editorial comments:

This study is one of the few nasal drug delivery papers coming out of Germany.  As these authors elude, German physicians have been a bit hesitant to adopt this treatment modality until they see more evidence from their own colleagues. Here is a very well done study using adequate doses of IN drugs and an atomizer to deliver the drugs – so the results should be reliable and believable. The authors provide good evidence that IN drug delivery is safe and effective for sedation and pain control when delivered by German clinicians to their patients using the protocols and doses they recommend.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/28121974

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Tsze, D. S., M. Ieni, et al. (2017). "Optimal Volume of Administration of Intranasal Midazolam in Children: A Randomized Clinical Trial." Ann Emerg Med 69(5): 600-609.

Abstract:

STUDY OBJECTIVE: The optimal intranasal volume of administration for achieving timely and effective sedation in children is unclear. We aimed to compare clinical outcomes relevant to procedural sedation associated with using escalating volumes of administration to administer intranasal midazolam. METHODS: We conducted a randomized, single-blinded, 3-arm, superiority clinical trial. Children aged 1 to 7 years and undergoing laceration repair requiring 0.5 mg/kg intranasal midazolam (5 mg/mL) were block-randomized to receive midazolam using 1 of 3 volumes of administration: 0.2, 0.5, or 1 mL. Procedures were videotaped, with outcome assessors blinded to volume of administration. Primary outcome was time to onset of minimal sedation (ie, score of 1 on the University of Michigan Sedation Scale). Secondary outcomes included procedural distress, time to procedure start, deepest level of sedation achieved, adverse events, and clinician and caregiver satisfaction. RESULTS: Ninety-nine children were enrolled; 96 were analyzed for the primary outcome and secondary outcomes, except for the outcome of procedural distress, for which only 90 were analyzed. Time to onset of minimal sedation for each escalating volume of administration was 4.7 minutes (95% confidence interval [CI] 3.8 to 5.4 minutes), 4.3 minutes (95% CI 3.9 to 4.9 minutes), and 5.2 minutes (95% CI 4.6 to 7.0 minutes), respectively. There were no differences in secondary outcomes except for clinician satisfaction with ease of administration: fewer clinicians were satisfied when using a volume of administration of 0.2 mL. CONCLUSION: There was a slightly shorter time to onset of minimal sedation when a volume of administration of 0.5 mL was used compared with 1 mL, but all 3 volumes of administration produced comparable clinical outcomes. Fewer clinicians were satisfied with ease of administration with a volume of administration of 0.2 mL.

Web site Editorial comments:

This is an important clinical article for those who are interested in a deeper understanding of intranasal medication delivery and the pharmaceutical/FDA approach to dosing and concentration versus the approach of clinicians who just want to help their patients. In order for a pharmaceutical company to get a nasal medication approved they need to achieve certain parameters set down by the FDA or other regulatory body. One of those parameters is often a bioavailability test of the nasal drug when compared to an already approved method of delivering the same medication such as via the intramuscular route. For example, the FDA required that  IN naloxone bioavailability needed to be the same as IM naloxone before they would approve the commercially available kit released in 2015. This bioavailability was determined to be 40% compared to the same dose give IV (which for all intents and purposes is 100% bioavailable). To achieve this bioavailability there can be NO waste of drug due to run-off (regardless of whether that waste allows more total drug to be absorbed by giving a higher mg dose). For this reason nasal drugs are highly concentrated and packaged into volumes of around 0.1 ml for delivery. While this small volume when delivered in a volunteer setting ensures no run-off and high bioavailability, it is not necessarily optimal for clinical use. Clinicians in the real world want the best clinical effect which is not the same as the best bioavailability. Tiny doses (0.1 ml) are hard to deliver and might accidentally be sprayed onto the nasal ala or septum with little resulting clinical efficacy. Volumes in the 0.3 to 0.5 range are clinically easier to deliver, cover a larger surface area and a little waste is fine as long as the clinical effect is adequate and no additional side effects occur. This study confirms this concept in the real world and finds that the 0.5 ml  or 1 ml volume  is easier to use and preferred by clinicians to 0.2ml volume. However, its findings are debatable because they did not give a single dose of 0.2, 0.5 or 1 ml with variable concentrations. Instead they  gave the same weight based volume of the drug to each child but varied the number of administrations using 0.2, 0.5 or 1.0 ml aliquots.  Perhaps a future study will be able to concentrate the IN medication into multiple concentrations (similar to how diamorphine is administered – starting with lyophylized powder and solubilizing it with three different volumes having identical drug doses, then testing that method.)

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/27823876

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Weiner, S. G., P. M. Mitchell, et al. (2017). "Use of Intranasal Naloxone by Basic Life Support Providers." Prehosp Emerg Care 21(3): 322-326.

Abstract:

STUDY OBJECTIVES: Intranasal delivery of naloxone to reverse the effects of opioid overdose by Advanced Life Support (ALS) providers has been studied in several prehospital settings. In 2006, in response to the increase in opioid-related overdoses, a special waiver from the state allowed administration of intranasal naloxone by Basic Life Support (BLS) providers in our city. This study aimed to determine: 1) if patients who received a 2-mg dose of nasal naloxone administered by BLS required repeat dosing while in the emergency department (ED), and 2) the disposition of these patients. METHODS: This was a retrospective review of patients transported by an inner-city municipal ambulance service to one of three academic medical centers. We included patients aged 18 and older that were transported by ambulance between 1/1/2006 and 12/12/2012 and who received intranasal naloxone by BLS providers as per a state approved protocol. Site investigators matched EMS run data to patients from each hospital's EMR and performed a chart review to confirm that the patient was correctly identified and to record the outcomes of interest. Descriptive statistics were then generated. RESULTS: A total of 793 patients received nasal naloxone by BLS and were transported to three hospitals. ALS intervened and transported 116 (14.6%) patients, and 11 (1.4%) were intubated in the field. There were 724 (91.3%) patients successfully matched to an ED chart. Hospital A received 336 (46.4%) patients, Hospital B received 210 (29.0%) patients, and Hospital C received 178 (24.6%) patients. Mean age was 36.2 (SD 10.5) years and 522 (72.1%) were male; 702 (97.1%) were reported to have abused heroin while 21 (2.9%) used other opioids. Nasal naloxone had an effect per the prehospital record in 689 (95.2%) patients. An additional naloxone dose was given in the ED to 64 (8.8%) patients. ED dispositions were: 507 (70.0%) discharged, 105 (14.5%) admitted, and 112 (15.5%) other (e.g., left against medical advice, left without being seen, or transferred). CONCLUSIONS: Only a small percentage of patients receiving prehospital administration of nasal naloxone by BLS providers required additional doses of naloxone in the ED and the majority of patients were discharged.

Web site Editorial comments:

This is an important study. These patients were resuscitated by BLS administration of generic low concentration naloxone (not the new highly concentrated commercially available form). The success of resuscitation was 95%  - this shows that if left alone without ALS intervention, patients given generic nasal naloxone (which is probably a bit dilute) is effective in the same percentage of patients as the more expensive highly concentrated formulations or even IV naloxone. If you read some of the early studies such as the very first studies on this topic the efficacy was deemed to be around 85%, but if you dig into the methods of these early studies they were all ALS delivered drug and the ALS providers moved immediately on to further interventions including IV naloxone if they did not detect rapid effect of the IN formulation. Often,  the IN drug was only in the system a few minutes before IV naloxone was given and that patient would be deemed an IN failure. This study does not have that “flaw” – it looks at actual clinical response over a longer time period and finds that 19 of 20 opioid toxic patients will respond to nasal naloxone even in the dilute 1 mg/ml formulations. So be patient, assist ventilation, let the drug do its job and if your budget is limited generic naloxone therapy is more cost effective and just as clinically effective in the hands of BLS providers as the new potentially more expensive commercially available kit. If there is no price difference, the new kits make more sense, but if there is a substantial difference in cost, this study defends using the original generic formulations.

Pubmed link: https://www.ncbi.nlm.nih.gov/pubmed/28166446