Seizing child recieving IN treatmentTherapeutic Intranasal Drug Delivery

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SEDATION: Intranasal sedatives

Table of contents:

Introduction to IN medications for sedation (click here)

Literature review and discussion

Dental procedural sedation (click here)

Emergency department procedural sedation (click here)

Pre-operative sedation (click here)

Radiologic procedural sedation (click here)

Agitated adults - sedation with intranasal haloperidol, midazolam or lorazepam (click here)

Intranasal flumazenil and intranasal naloxone as a reversal agents (click here)

Personal insights from experienced clinicians (click here)

Treatment protocol (click here)

Bibliography (click here)

Introduction

Interactions with medical providers are stressful experiences for children. Because of this stress and the anxiety it provokes, minor procedures often require mild to moderate sedation. Oral or rectal medications may be adequate for this sedation, however these delivery routes requires a considerable amount of time to take effect leading to delays in care and interrupted patient flow. Furthermore, since sedatives have wide inter-individual variations to response, it is difficult to find a single weight-based dose that is adequate to routinely sedate a patient but not so high as to cause prolonged sedation. This is not a problem if the medication can be titrated, but oral and rectal medications are not really reasonable methods for titration.  Intramuscular injections suffer similar problems in terms of delay in effect (not as much as oral) and difficulty in titrating to adequate but not excessive sedation. A further major problem with IM injections is that they are painful and frightening to the patient.  Intravenous therapy is the gold-standard for sedation – allowing rapid onset with titratable effect. It is ideal for any major procedure, but establishing an IV in a child is time and resource consuming for minor procedures. It also leads to an increased risk of respiratory depression due to the very high levels of medication that are achieved with bolus injection therapy. Finally, starting an IV is painful and frightening for many patients.

Wermerling data showing plasma concentrations of lorazepam following intravenous, intranasal and intramuscular administration

Intranasal and oral transmucosal (buccal, sublingual) delivery of sedative medications offers an alternative that provides some advantages over the above methods in properly selected minor procedure: they are faster than oral or rectal forms and less painful than injectable forms.  Situations where investigators have found them to be useful include dental procedures, minor pediatric laceration repairs, anxiolysis prior to radiologic procedures such as MRI, pediatric preoperative sedation to assist with separation anxiety as well as sedation before other minor procedures including IV starts, biopsies, esophagogastroduodenoscopy (EGD) and ophthalmologic procedures.

The appropriate method and medication chosen for sedation will depend on the clinical situation. If time is not an issue, oral forms are adequate. If deep sedation and rapid titration are needed, IV forms are probably indicated.  If mild to moderate sedation in a timely fashion is needed nasal medications may be ideal.  The three most commonly studied medications for intranasal sedation are midazolam, sufentanil and ketamine.  The following discussion will provide some insight into the literature on this topic.

Literature overview and discussion

Dental procedural sedation:

The dental literature contains the largest collection of data regarding intranasal medication use for sedation. In one of the original articles on the topic, Abrams et al compared the effects of single therapy with intranasal ketamine (3 mg/kg), midazolam (0.4 mg/kg) or sufentanil (1.0 and 1.5 mcg/kg) in children getting brief dental procedures.[1]Bjorkman 1997 data showing peak serum concentrations and time of onset for intranasal and intravenous midazolam They felt either midazolam or ketamine worked quite well (4/5 sedation score), as did the lower dose of sufentanil. However, sufentanil at 1.5 mcg/kg led to oversedation and oxygen desaturation.  Ten years later Roelofse et al compared combination therapy with intranasal sufentanil plus midazolam (1 mcg/kg plus 0.3 mg/kg) versus intranasal ketamine plus midazolam (5 mg/kg plus 0.3 mg/kg) 20 minutes prior to induction in a dental surgery center.[2] They found both methods easy, effective, safe and rapid in onset.  A smooth mask induction occurred in the majority of patients. They concluded that intranasal medication is a promising method of sedating preschool dental patients.

Another interesting finding is that compliance with nasal sedation is easier to achieve that with oral sedation in young children. Primosch et al found intranasal midazolam a useful alternative to oral midazolam in their dental clinic since a significant number of children (45%) refused to swallow the oral formulation.[5]

More recently Manley et al describe their experience using intranasal midazolam to sedate adults with learning disabilities.[54] Due to dose-volume issues they concentrated the midazolam to 40 mg/ml (see photo below). They also added lidocaine to the medication to reduce burning during administration.  They delivered 10 mg (0.25 ml) intranasally using a mucosal atomization device to enhance mucosal coverage. In a study of 222 adult sedations they found 93% success at sedation with no respiratory complications, allowing them to avoid the need for general anesthesia in the majority of cases. (Click here for article)

Manley 2008 - label for their concentrated midazolam:

Label for concentrated intranasal midazolam plus lidocaine for adult sedation

Many other authors have used IN midazolam for pediatric and mentally disabled adult sedation and anxiolysis prior to procedures with generally good results and little if any safety concerns in doses ranging from 0.2 to 0.4 mg/kg. [6-13]

The sum of this dental literature suggests that intranasal medications, specifically midazolam, are easy to use and effective mild sedatives prior to dental procedures.  They can be used in non-compliant patients such as small children and mentally disabled adults and they have few significant safety issues reported with the exception of oversedation when higher doses of sufentanil (1.5 mg/kg or more) are used.

 

Emergency department procedural sedation:

A number of studies exist investigating intranasal medication delivery for minor procedural sedation in the emergency department. Acworth compared intranasal midazolam (0.4 mg/kg) to IV ketamine (1 mg/kg) plus IV midazolam (0.1 mg/kg) for minor procedural sedation in the emergency department.[14] Not surprisingly the IV therapy was more effective and easier to titrate – 100%. However, intranasal midazolam provided adequate sedation in 92% of patients and resulted in discharge 19 minutes earlier than the IV therapy group. The authors conclude that IV therapy is superior but that IN therapy may still be adequate in many minor procedures.

Bates 1994 data demonstrating that intranasal sufentanil and midazolam provide similar depth of sedation as intramuscular meperidine, promethazine and chlorpromazine

Bates et al investigated the combination of intranasal sufentanil (0.75 mcg/kg) plus intranasal midazolam (0.2 mg/kg) to an intramuscular injection of meperidine, promethazine and chlorpromazine (IM-MPC) for sedation prior to laceration repair.[15]  The investigators chose these lower intranasal doses based on safety concerns with combined therapy. Based on past experience, they felt that these low doses of intranasal sufentanil or midazolam were not reliably effective if given as single drugs.  Never the less, their results indicate that the combination of IN sufentanil and midazolam in low doses was as effective as intramuscular MPC in sedating children for laceration repair. Furthermore, since the children tolerated the IN medication better than the IM medication and they had both shorter recovery times and times to discharge it might be a preferred sedation method for minor laceration repairs.

Yealy et al report their experience with IN midazolam dosing in 40 children undergoing laceration repair.[16] They found that IN doses of 0.2 to 0.29 mg/kg were inadequate (27% adequate sedation), 0.3 to 0.39 mg/kg was better (80% adequate sedation) but 0.4 to 0.5 mg was best (100% adequate sedation). Onset of sedation averaged 12 ± 4 minutes, recovery 41± 9 minutes and discharge 56 ± 11 minutes. They do not report problems with desaturation or respiratory depression even at the higher dose.  Theroux et al found similar efficacy of IN midazolam in doses of 0.4 mg/kg with marked improvement in patient cooperation compared to placebo.[17]

One common symptom associated with IN midazolam is nasal burning for the first 30-60 seconds.[18] Bates did not find this to be the case with combined IN sufentanil and midazolam, whereas other investigators such as Everitt have found burning to be an issue when midazolam is used alone.[15, 18]  Parents should likely be informed of this initial side effect so they are not surprised if their child cries even with a nasal medication. What has not been reported is any significant respiratory depression or desaturation when IN midazolam has been used.  This is likely due to the fact that intranasal midazolam delivery leads to drug absorption over a few minutes rather than an instant bolus that is seen with IV therapy. This slower onset of action probably prevents serum levels from crossing the respiratory depression threshold. Never the less, it is probably prudent to monitor oxygen saturation levels any time a patient is sedated with benzodiazepines. Powerful opiates such as sufentanil have definitely demonstrated respiratory depression and desaturation in higher intranasal dosing regimens.

In summary, the majority of emergency department sedation articles involve sedation prior to minor laceration repair in children.  Drug doses required for successful sedation for laceration repair (midazolam at 0.4 to 0.5 mg/kg) need to be slightly higher than that described in the dental literature where inhaled nitric oxides is often used in combination. Combined nasal sufentanil plus midazolam was successful using lower doses.  Intravenous therapy is superior to intranasal therapy but requires an IV to be established – a painful and resource consuming procedure. 

Pre-operative sedation:

            Separation anxiety and acceptance of the mask during induction of general anesthesia are issues that lead many clinicians to prefer sedating children in the pre-operative phase before they take them from their parents into the operating theatre.  Oral medications are commonly used but have considerable delays in onset, whereas IV and IM medications are painful and frightening. This has led several investigators to consider intranasal medications as an alternate method of achieving smoother separation and mask acceptance.

Malinovsky 1993 data demonstrating peak levels of midazoalm when given via the intravenous, intranasal and rectal routes

Malinovsky et al compared the time of sedation onset and peak serum midazolam levels in children randomized to intranasal (0.2 mg/kg), oral (0.5 mg/kg) or rectal (0.3 mg/kg) medication for pre-operative sedation.[19] They found the mean onset of sedation was fastest and peak levels highest for nasal midazolam (7.7 minutes, 146 ng/ml peak at 11.5 minutes) compared to oral (12.5 minutes, 104 ng/ml peak at 21 minutes) and rectal dosing (16.3 minutes, 93 ng/ml peak at 23 minutes). The authors conclude that intranasal midazolam is an excellent alternative for rapid premedication of pediatric surgical patients.

Bayrak et al investigated oral midazolam (0.5 mg/kg), oral tramadol (0.3 mg/kg) and intranasal sufentanil (2 mcg/kg) for pre-operative sedation.[20] They found oral midazolam and intranasal sufentanil very effective for sedation and mask acceptance. However, IN sufentanil at this high dose led to significant decreases in oxygen saturation and respiratory rate – an effect they accepted since they placed the patients under general anesthesia shortly thereafter.  Karl et al conducted a similar study comparing low dose IN midazolam (0.2 mg/kg) to high dose intranasal sufentanil (2 mcg/kg).[21]  Both drugs markedly reduced separation anxiety, however they also found this dose of sufentanil led to oxygen desaturation as well minor chest wall stiffness. Zedie also compared intranasal midazolam (0.2 mg/kg) to intranasal sufentanil (2 mcg/kg) and found both equally effective at sedation.[22] They noted more nasal irritation and crying with the midazolam (71% versus 20%), but more nausea and vomiting and perhaps slightly reduced respiratory compliance with the sufentanil (34% versus 6%).  Both drugs resulted in easy separation of the children from their parents.

Weber et al found that adding intranasal ketamine to midazolam further enhances onset of action with slight improvement in sedation.[23, 24] Weksler et al studied intranasal ketamine alone (6 mg/kg) and found it superior to intramuscular meperidine and promethazine for sedating children.[25] Many additional authors have similar experiences with easy separation and acceptance of mask ventilation following pretreatment of pediatric patients with intranasal midazolam.[26-30] Other investigators confirm the efficacy of intranasal sedatives, though nasal burning with midazolam was commonly described.[31-33]

McCormick et al conducted a study with a bit of a twist - they investigate4d the efficacy of intranasal midazolam versus nebulized midazolam.[55] The nasal route resulted in far higher plasma levels, more sedation of faster onset. This is not surprising since many studies show that most nebulized drug ends up in the environment and not in  the lung.

McCormick 2008: Plasma levels of midazolam following intranasal versus nebulized delivery:

Plasma levels of midazolam following intranasal versus nebulized delivery

 
Intranasal Dexmedetomidine and clonidine for sedation:

Recent interest has emerged in the anesthesia literature regarding α2 adrenergic agonists for sedation. The two medications investigated are clonidine and dexmedetomidine. These drug act on the CNS in the area of the locus ceruleus and induce EEG activity that resembles natural sleep. Patients who are treated with intranasal alpha-2 agonists are easily aroused - perhaps due to the sleep like state they are in - but they are also not as "silly" as those given midazolam, nor do they obtain amnesia to the events.  The potential advantages of these drugs over nasal midazolam appear to be due to the fact that no transient nasal burning occurs, reduced confusional state is present after the procedure and there is no respiratory depression risk from the medication.

Talon et al conducted a randomized, controlled trial on 100 children comparing intranasal dexmedetomidine (2 ug/kg) to oral cherry flavored midazolam syrup (0.5 mg/kg).[51]  He found dexmedetomidine to be more effective at inducing sleep and equivalent to oral midazolam in terms of conditions at induction (45 min later) and emergence. They also felt nasal medication was easier to administer because the child could not resister or spit it out.  They concluded that intranasal dexmedetomidine was rapidly effective, reliable, safe and relatively less traumatic than oral midazolam syrup for pre-operative sedation.

Intranasal dexmedetomidine versus oral midazolam

Talon et al - Level of sedation following intranasal dexmedetomidine versus oral midazolam

Yuen et al compared two different doses of intranasal dexmedetomidine (0.5 or 1.0 mcg/kg) to oral  midazolam (5 mg/kg) in a preoperative sedation study of 96 children.[43]  These authors found both doses of dexmedetomidine to be superior to oral midazolam for sedation and more adequate sedation at induction was present in patients receiving the 1.0 mcg/kg dose. Stella and colleagues reported 3 cases of intranasal clonidine (1.5 to 2.0 mcg/kg) sedation in children.[44] In one case it was used to rescue a child who was having paradoxical agitation due to oral midazolam, another was a child who had many experiences with oral and nasal midazolam and refused any more - but was willing to try clonidine and did well with it. The third was a 3 month old agitated, hypertensive child with renal disease who obtained both sedation and blood pressure control with nasal clonidine.  In all cases onset was within 5 minutes. Both groups of authors found these medications useful for selected patient populations and suggest further research be conducted.

In summary, generic midazolam, sufentanil, ketamine, clonidine and dexmedetomidine (which is not generic) all appear effective in sedating children, reducing separation anxiety and improving mask acceptance in the pre-operative pediatric setting.  Midazolam can lead to nasal burning and crying while sufentanil at high doses (2 mcg/kg) can cause excessive respiratory depression and mild chest wall stiffness. The α2 adrenergic agonists appear to cause more of a sleep like state - easing separation, but also easily aroused.  The option of intranasal preoperative sedation might be most useful in situations where the prior case ends quickly and the next patients has not had sufficient time for their oral medication to take effect (or has not even received it). In this case, nasal sedatives are rapidly effective (5-10 minutes), reliable and possibly titratable.

 

Radiologic procedural sedation (relief of claustrophobia)

Sedation for radiologic procedures is commonly administered to prevent excessive patient motion and for problems with claustrophobia.  Agents with rapid onset of action, short duration of effect and ease of administration are preferred for these relatively brief, painless procedures. Since intranasal medication delivery with midazolam fulfills all of these criteria it has been used in multiple studies with excellent results.

Low doses of intranasal medication (midazolam) appears to be especially effective for cross-sectional imaging such as MRI and CT. Hollenhorst randomized adult patients scheduled for MRI to a single dose of 4 mg IN midazolam versus placebo.[34] They found they achieved better quality exams with no cancellations in the study arm, whereas the quality decreased and 15% could not complete the MRI in the placebo group.  Tschirch et al randomized adult patients to nasal (1-2 mg) versus oral midazolam (7.5 mg). Patients treated with nasal midazolam had a 97% success rate in obtaining a quality MRI while half of the orally treated patients could not finish the exam.[35] These authors view low dose IN midazolam as an effective and patient friendly solution to overcoming anxiety and claustrophobia in patients undergoing MRI.  In a similar study Moss et al found they could reduce the need for IV sedatives from 67% to 17% by using IN midazolam prior to MRI imaging. Louon and Reddy also noted effective sedation and improved computed tomographic image quality when using a combination of nasal ketamine and midazolam in pediatric patients.[36] Weber compared IN midazolam to rectal chloral hydrate prior to brain imaging.  Midazolam was effective in 82% of cases with mean time to test completion being 55 minutes.  Chloral hydrate often required re-dosing to complete the study (70% completed) and required 42 minutes additional time to successfully obtain images. There was a clear preference of the nursing staff for intranasal midazolam over rectal chloral hydrate. Harcke and Grissom found 0.2 mg/kg of IN midazolam adequate to calm their pediatric patients for imaging studies and recommend its routine use with pulse oximetry as a safe and effective minor sedative.[37]

Second dose "titration" of intranasal midazolam

Lazol et al describe their experience using intranasal midazolam for minor sedation prior to pediatric echocardiography.[52] These authors review their results on 100 patients, using 0.2 to 0.3 mg/kg IN midazolam for the initial dose, and following up in 10-15 minutes with a second identical dose if inadequate sedation was present. They achieved 24% adequate sedation with the initial low dose, and 80% adequate sedation following the second dose.  They report no adverse effects with either dose. This study points out a key component to sedation and pain control that most clinician are already aware of - the concept of titration to effect. Like IV medications, nasal sedatives and pain medications demonstrate inter-individual variation in patients, requiring additional dosing to achieve adequate effect. Fortunately, titration is possible and if one dose is not adequate, simply give another dose.  A second observation can be made from this study - that of using an adequate initial intranasal dose in the first place. Many clinicians fail to use adequate IN drug doses, have inadequate effect and assume the drug is not useful when given via the nose - because they are u sing IV doses rather than the needed higher nasal doses. Based on extensive publication data and personal insights from years of use, the authors of this web site suggest an initial dose on 0.4 to 0.5 mg/kg of intranasal midazolam since lower doses are well known to be inadequate most of the time (the exception being if you simply wish the patient to be calm for a CT scan, but do not intend to do any procedure- in which case a lower dose such as in this study would be adequate).

In summary, nasal midazolam is very effective both in adults and children for sedation prior to CT and MRI imaging as well as for echocardiography. The use of this method speeds up patient care, reduces the rate of incomplete exams and improves the image quality. Fairly low doses (0.2 mg/kg in children, 1-4 mg total in adults) are effective and safe for CT and MRI, while higher doses appear to be warranted, and titration to effect is needed in invasive procedures such as echocardiography. 

Miscellaneous sedation (ophthalmology, endoscopy, biopsy)

Numerous additional indications have been described for intranasal sedation including upper GI endoscopy, ophthalmologic examinations in the anxious patient and minor biopsy procedures. Two studies have found IN midazolam to provide acceptable amnesia and mild sedation for EGD, though IV therapy was superior.[38, 39] Two additional studies note rapidly effective sedation to enhance ophthalmologic exam in children and one study describes relief of anxiety surrounding minor procedures such as venous blood sampling, IV catheter placement or subcutaneous IV port access.[40-42]

Sedation Literature Summary:

Summing up the literature, several general impressions can be stated. First, the three most commonly used intranasal sedation agents (midazolam, sufentanil, ketamine) all seem to have an effect in 5-10 minutes, peak in 12-20 minutes and become less effective after about 30-40 minutes though perhaps longer for higher doses of sufentanil. With the limited available evidence, it appears that a combination of midazolam plus sufentanil or midazolam plus ketamine achieves slightly more effective and deeper sedation than any alone. On the other hand, for simple induction of drowsiness for non-painful procedures such as MRI, a single agent such as midazolam at a low dose (0.2 mg/kg) is very effective. In terms of safety, it is very rare to see any desaturations with midazolam or ketamine. However, sufentanil in higher doses (> 1.5 mcg/kg) appears to have an increased incidence of nausea, vomiting, reduced respiratory rate and oxygen desaturation with occasional chest wall tightening described at dose ³ 2 mcg/kg - emphasizing the importance of careful monitoring with sufentanil therapy. Midazolam appears quite safe via the nasal route and it is an effective sedative and amnestic for minor procedures. It is also an effective alternative to oral formulations when patients refuse to swallow the oral dose. However it causes brief nasal mucosal burning following application. This burning may lead to crying immediately following application in children and parents must be forewarned to expect this initial response.

 

Agitated adults - sedation with intranasal haloperidol, midazolam or lorazepam

Acutely agitated patients present a dangerous situation to both themselves and to health care providers. For this reason, they are often physically restrained and provided pharmacologic sedation as soon as possible.  Traditionally  sedative is administered via an intramuscular shot because IV’s are notoriously difficult to establish and maintain, while oral therapy is usually refused by the patient.  However, intramuscular administration of medications in these patients carries a substantial risk of needle stick injury to the health care provider - alternate routes of drug delivery would be useful.  Too date, very little literature exists on this topic – perhaps due to the nearly impossible requirement of obtaining informed consent to conduct such a trial. Never the less there is some limited data to suggest that intranasal delivery of medications such as midazolam, lorazepam and haloperidol are effective.  In 2004 Neff et al reported a small case series of adult ambulance patients (5 total) who were treated with intranasal midazolam (10 mg in 2 ml dose was their protocol) for acute agitation.[45] Despite failing to provide the entire dose as directed in 3/5 patients, they were still able to obtain resolution of the agitation 60% of the time. Manley et al showed adequate pre procedural sedation in > 90% of mentally disabled adults using a concentrated form of midazolam (40 mg/ml) and administering 10 mg to an adult - avoiding the need for general anesthesia in these situations (click here for article).[55]Lorazepam may also be effective in this situation. Wermeling et al reports lorazepam bioavailability at 78% when given intranasally,[46] and one of the web authors has used intranasal lorazepam in multiple acutely agitated patients (2 mg IN in adults) with about 70% effectiveness and fairly prolonged sedation (several hours). Finally, intranasal haloperidol may offer another option for intranasal sedation of acutely agitated adults. Miller et al report maximal serum levels of Haldol occurring in 15 minutes following intranasal delivery with rapid onset of sedation.[47] They conclude that intranasal haloperidol or other similar antipsychotic medications could play a role in treating psychiatric emergencies.  Clearly all of this data is preliminary and would ideally undergo more rigorous research, but it does suggest an option (why not try first rather than risk a needle stick?) for EMS and ER providers to try before they move onto more invasive and dangerous treatment options. 

Intranasal flumazenil and intranasal naloxone as a reversal agents in sedated patients without an IV line

A concern that often comes up regarding administration of sedatives and opiates to patients who are given these powerful drugs via the intranasal route is how they can be reversed should too much sedation develop (since they presumably do not have an intravenous line). The first point that needs to be considered is whether significant respiratory depression requiring intervention beyond oxygen therapy will even occur from intranasal drug delivery. To date it has not been reported for midazolam and it does not even seem to occur with very high doses of the extremely powerful drug sufentanil.  This is probably because the medications absorb via the nasal mucosa are spread out over 10-15 minutes and never achieve peak levels seen with intravenous boluses (see detailed discussion on therapeutic threshold and side effect threshold concept in the overview section and the pain medication section - click here).  Never the less, antidotes to opiates - i.e. naloxone - work very well  intranasally as well as via subcutaneous and intramuscular routes (see separate section on this topic - click here).  In terms of intranasal flumazenil - the benzodiazepine antagonist - there is limited data but that which exists also suggests that it is effective when administered via the nasal route.  Two animal studies found transmucosal flumazenil delivered via the sublingual route resulted in rapidly measurable serum drug levels that achieved the therapeutic threshold and approached 100% bioavailability.[48,49] One of these studies actually demonstrated reversal of benzodiazepine induced sedation about 4 minutes after drug delivery.[48] Two human studies exist in children using flumazenil intranasally Scheepers found maximal concentrations in the serum were achieved very quickly (2 minutes), again at therapeutic blood levels and concluded that this may offer an alternate delivery route for benzodiazepine antagonist reversal agents.[50]  Heard presents a case where and child undergoing a dental procedure was oversedated using intranasal midazolam combined with intranasal sufentanil. [53] the authors responded to this problem by administering 0.4 on intranasal naloxone and 200 mcg of intranasal flumazenil.  Three minutes following antidote administration the pati9ent was fully awake and did not become re-sedated during the next  2.5 hours of observation.

Personal insights from experienced clinicians

Doug Nelson, MD, Medical Director, Emergency Department, Primary Children's Medical Center, Salt Lake City, UT

We have been using the intranasal route for many years in our pediatric emergency department. Administering IN midazolam at a dose of 0.4 mg/kg results in effective sedation in >90% of children. More importantly we have never had a single adverse outcome in the literally thousands of children treated using this method.

Roni Lane, MD, Assistant Professor, Emergency Department, Primary Children's Medical Center, Salt Lake City, UT

I am one of 19 pediatric emergency medicine physicians practicing in a busy Level 1 Trauma center in a free standing children's hospital.  We perform multiple sedations daily for a variety of procedures including closed fracture reduction, laceration repair, lumbar puncture, radiologic imaging and hernia reduction.  Prior to the development of atomization devices, drip instillation of benzodiazepines frequently resulted in ineffective sedation with much of the medication lost to the oral cavity.  For a number of years now, children undergoing minor procedures requiring sedation in our ED are given midazolam via a mucosal atomizer device resulting in successful sedation (anxiolysis) in 70-80% of patients.  In addition, we use the mucosal atomizer device to deliver midazolam to patients who are seizing as well as fentanyl for some patients who are suffering from pain due to fractures.  After thousands of sedations, we have noted no significant adverse events associated with midazolam administered in this fashion.  With the exception of some nasal burning that occurs with administration, it is well tolerated.  We are fortunate to have a method of providing effective light sedation in a fairly non-invasive fashion. 

Mark Talon, MSN, CRNA, Department of Anesthesia, Shriners Hospital for Children, University of Texas Medical Branch - Galveston

The nasal atomizer has changed our pediatric practice significantly. We have
been using IN therapy in many different fashions over the last several years and have found dexmedetomidine to be a very valuable addition to our premedications. As a sole medication for procedural sedation dexmedetomidine is limited. Like clonidine the patient is easily arousable yet sedate in a fashion similar to normal sleep. Thus as a sole agent its effect is variable. Our practice for procedural sedation with dexmedetomidine is to combine 2ug/kg of IN dexmedetomidine with .5mg/kg of oral midazolam. This combination has proven to be far better then either the Precedex or midazolam as a sole agent and usually results in significant procedural sedation that allows us to remove burn wound dressings, pins and often do casting and molding without further intervention. We have used this method to sedate children for the MRI and CT scanners without problems. This is also our standard premedication for children less then 50kg going to surgery. The combined effects are relatively consistent with the majority of children and results in significant sedation in 30-40 minutes. Please realize that the majority of our children are very anxious as they have been through multiple surgeries and procedures for burn and reconstructive treatment, so they have been exposed to many pharmacological mixes. In normal children that have not been exposed to poly pharmacy the effects are much more consistent. The duration of action is approximately 1.5 hours at which point we see criteria that would meet discharge requirements. We have also used combinations of intranasal opiates for sedation and analgesia, but this is a much longer discussion.

Dan Tsze, MD; Assistant Professor, Hasbro Children's Hospital, Providence, RI

Our pediatric emergency department is currently conducting a trial that initially started by comparing three different doses of intranasal ketamine for procedural sedation for laceration repairs: 3, 6, and 9 mg/kg.  We decided to use the MAD to optimize nasal absorption and minimize the amount of solution that might be swallowed instead.  We are utilizing the 100 mg/mL concentration, which was the highest concentration we could obtain, to minimize the volume needed.  There is a 150 mg/mL concentration available from a pharmaceutical company (but they did not want to participate in our trial), as well as higher concentrations which were limited to veterinary medicine.

The study is double blinded, but we noticed that there was a large number of clinical failures, meaning patients who did not achieve adequate sedation within 30 minutes of drug administration.  Our safety committee reviewed the data while we remained blinded, and made the recommendation to drop the 2 lower doses and consider adding a higher dose(s) to the trial.  We revised the study and are now comparing 9 mg/kg and 12 mg/kg doses.  We are not concurrently giving any midazolam or glycopyrrolate/atropine, and the patients range from 1 to 7 years old.  We have limited the maximum dose to 300 mg (i.e. 3 mL), simply for pragmatic reasons related to total volume and discomfort related to intranasal administration.

As far as we can tell, while currently blinded, the time to onset of sedation has ranged anywhere from 6 minutes to just over 20 minutes. Patients who reached adequate sedation did not ever require "rescue" doses of additional ketamine to complete the laceration repairs, which were limited to simple lacerations less than 5 cm and did not require a consult service to perform the repair.  Recovery times have been comparable to patients who have received IV ketamine. Unfortunately, since we are still blinded at this time, we cannot make any further comments regarding a specific dose and its effect.

Pat Crocker, DO, Chief of Emergency Medicine, Dell Children's Medical Center, Austin TX

We have had great success with IN fentanyl for immediate pain control in children and it is much quicker than waiting for an iv to be established. Giving the fentanyl IN immediately and applying some topical anesthetic cream makes subsequent iv insertion less traumatic for the child as well.

The combination of IN fentanyl and Versed prior to minor procedures and administration of local anesthetic has been quite useful as well. No child has fallen asleep at the suggested doses but generally is quite a bit more tractable for the procedure reducing our need for full sedations some. We have also combined the above with nitrous oxide for children 5 yo and older and get nice results.

Tim Wolfe, MD, Associate Professor, Division of Emergency Medicine, University of Utah, Salt Lake City, Utah

In the early 1990’s IN midazolam made a brief splash in the ED literature and then seemed to disappear. I suspect this was due to two factors – variable effect due to inadequate dosing or inadequate delivery and nasal burning associated with nasal midazolam. I also had similar initial impressions. I began using IN midazolam in 1992 for pediatric sedation – primarily for sedation prior to laceration repair in children. Initially I found the effect quite variable. I attributed this variability to the method of delivery (dripping the medication into the nose with a syringe resulting in a lot of runoff into the mouth or blown back into the environment) and as I learned more I found that I administered an inadequate dose.  Following the introduction of atomized delivery, the variable effect was reduced but not eliminated: some children are rapidly and effectively sedated and hold still for the procedure while others are not well sedated.  I also increased my dosing. I initially started with doses in the 0.2 mg/kg range and found that this was inadequate for the majority of emergency room procedures. With better understanding of the pharmacokinetics (the lower peak and the slower absorption that occurs with intranasal therapy compared to intravenous therapy) I realized higher doses were safe and pushed the dose until it seemed to work the majority of the time. I now use doses of about 0.5 mg/kg as an atomized mist delivering half to each nostril. To take advantage of the sedation time window I now am sure all procedural tools are ready so that the child is quickly prepped once the drug takes effect (about 6-10 minutes) and my suturing or procedure is done before the drug starts to wear off (about 30 minutes). Some of my colleagues have combined midazolam with an opiate and report more consistent effect. This improved efficacy with dual therapy appears to be supported by the literature as well.  It would be nice if midazolam came in a more concentrated formula and if it had a pH closer to physiologic – this would allow smaller volumes with less drug runoff and likely less burning with application. This may be part of the reason sufentanil seems so effective – it is highly concentrated and small volumes of medication (volumes appropriate for a child or adult nose) will achieve adequate mucosal coverage with little or no run-off.  I think intranasal medication use for sedation and for pain control is a nice tool for the appropriately selected patient.  It is also an area ripe for investigative research – a lot is still unknown and good studies would easily be published in the emergency medicine literature. Pediatric sedation is a critical skill in emergency medicine and having a large variety of options available for different situations would enhance care and improve patient, parent and clinician satisfaction.

Tom Macfarlane, MD, Emergency Physician, Salt lake City UT

Intranasal delivery of midazolam is an important niche therapy in my practice.  I find it most useful in children who have a need for anxiolysis or light procedural sedation.  I use it frequently for sedation in laceration repairs and in splinting of fractures that do not require reduction.  Another common indication is light sedation for radiographic imaging. Onset is quite rapid and adverse events appear to be very rare.  In addition patients are safe for discharge quite quickly thereby enhancing emergency department throughput.  Overall I feel that this delivery route provides safe and effective light sedation in the emergency department.

Treatment protocol

General points:

Teaching materials:

Download a basic photographic display of how to draw up and administer intranasal midazolam for seizures or sedation (click here for MS word document 0.53 MB)

Sedation Billing CPT codes for clinicians

There is at least one billing CPT code for intranasal drug delivery: CPT 99142. You will need to review this with your professional biller to be sure this is up to date. It is related to sedation:

  • 99141: Sedation with or without analgesia; intravenous, intramuscular, or inhalation

  • 99142: Sedation with oral, rectal and/or intranasal

 

Peer Reviewed Articles -

Intranasal Midazolam for sedation

Al-Rakaf, Intra-nasal midazolam for conscious sedation of pediatric dental patients, Int J Ped Dentistry 2001 (click here) -  PDF 0.32 MB

Lane, Atomized intranasal midazolam  use for minor procedures in the pediatric emergency department, Pediatric Emergency Care 2008 (click here for web site link)

Manley, IN and IV midazolam for sedation in adults with learning disability, Br Dent Journal 2008

Morgans-Perri, MAD for IN midazolam pre-op, J Perianesthtic Nursing 2009 abstract

Intranasal ketamine for sedation

Kazemi, Intranasal ketamine versus intranasal midazolam for preoperative sedation in children, Pak J Med Sci 2005 (click here) - PDF 0.12 MB

Intranasal Dexmedetomidine for sedation and premedication before anesthesia

Intranasal clonidine for sedation and premedication before anesthesia

 

Bibliography (click here for abstracts)

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