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Intranasal Lorazepam for Treatment of Severe Agitation in a Pediatric Behavioral Health Patient in the Emergency Department

      The treatment of severe agitation, aggression, and violent behavior in behavioral health patients who present to the emergency department (ED) often requires the intramuscular administration of a sedative. However, administering an intramuscular sedative to an uncooperative patient is associated with the risk of needlestick injuries to both patients and health care providers, and times to onset of sedation range from 15 to 45 minutes. Intranasal absorption is more rapid than intramuscular, with sedatives such as lorazepam reaching peak serum concentrations up to 6 times faster when administered intranasally. We present the first report of using intranasal lorazepam as a needle-free method of providing rapid and effective sedation to treat severe agitation in a pediatric behavioral health patient presenting to the ED.

      Introduction

      Agitation, aggression, and violent behavior in patients presenting to an emergency department (ED) for psychiatric care can be upsetting and dangerous to family members, health care providers, and patients, and often results in physical restraints, chemical restraints, or both. Because behavioral health patients typically do not have intravenous access and may be uncooperative with oral medications, they are often sedated in an emergency by the intramuscular route, which can be painful and is associated with the risk of needlestick injuries to both hospital personnel and patients.
      • Gerson R.
      • Malas N.
      • Feuer V.
      • et al.
      Best Practices for Evaluation and Treatment of Agitated Children and Adolescents (BETA) in the emergency department: consensus statement of the American Association for Emergency Psychiatry.
      • Prüss-Üstün A.
      • Rapiti E.
      • Hutin Y.
      Sharps injuries: Global burden of disease from sharps injuries to health-care workers.
      • Gerson R.
      • Malas N.
      • Mroczkowski M.M.
      Crisis in the emergency department: the evaluation and management of acute agitation in children and adolescents.
      The intranasal administration of a sedative is needle-free and eliminates the risk of needlestick injuries while providing both rapid and effective chemical restraint. In addition, intranasal absorption is more rapid than intramuscular, producing sedation within 5 minutes, whereas intramuscular sedatives can take as long as 15 to 30 minutes to take effect.
      • Tsze D.S.
      • Ieni M.
      • Fenster D.B.
      • et al.
      Optimal volume of administration of intranasal midazolam in children: a randomized clinical trial.
      Sedatives such as lorazepam can reach peak serum concentrations up to 6 times faster when administered intranasally compared with intramuscularly.
      • Wermeling D.P.
      • Miller J.L.
      • Archer S.M.
      • et al.
      Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration.
      We present the first report of using intranasal lorazepam to successfully treat severe agitation in a pediatric behavioral health patient presenting to the ED.

      Case Report

      A 7-year-old boy with a long-standing history of anxiety and oppositional defiant disorder presented to the ED with aggression and violent behavior at home. The patient had a history of one ED visit to an outside hospital, which necessitated intramuscular chlorpromazine for sedation, and had begun receiving sertraline 3 weeks before presentation. On arrival by emergency medical services, the patient was kicking the door of the room, throwing chairs at the walls, spitting at hospital personnel, punching his parents, and refusing to follow directions, including donning a hospital gown. His anger erupted without provocation, and he threatened the medical staff with death if they continued to hold him imprisoned in the room. Attempts by ED personnel to verbally de-escalate the situation were unsuccessful; the patient refused to cooperate with oral sedatives, and physical and chemical restraints were required. The patient’s parents expressed concern in regard to intramuscular sedative administration because they thought the patient had been “traumatized” by the intramuscular sedative he had received at his previous ED visit. We administered intranasal lorazepam (2 mg/mL) at a dose of 1.5 mg (0.05 mg/kg), using a mucosal atomization device, with the total volume divided in half and administered into both nares. Health care providers and hospital personnel donned masks with eye shields to protect themselves from exposure to bodily fluids, and security guards provided physical restraint and stabilization of the head during administration of the intranasal medication.
      At 5 minutes after intranasal lorazepam administration, the patient was calm and sitting on the stretcher without physical restraints. He was cooperative and interactive with his parents and health care providers, was no longer physically or verbally aggressive, and voluntarily changed into a hospital gown. The patient was reevaluated approximately every 10 minutes for the first hour after sedative administration and remained calm and cooperative throughout this period. Approximately 90 minutes after receiving intranasal lorazepam, the patient began kicking and biting the security guards. Verbal de-escalation was unsuccessful, the patient refused oral sedatives, and physical and chemical restraints were required again. Intramuscular haloperidol and diphenhydramine were administered at that time; the patient calmed down and subsequently slept through the night.
      The following evening while the patient remained in the ED awaiting inpatient admission, he had a repeat episode of agitation, aggression, and violent behavior, including an attempt to forcibly elope from the ED. As before, verbal de-escalation was unsuccessful and the patient refused oral sedatives. Physical and chemical restraints were required, and the parents requested that intranasal sedation be given. Intranasal lorazepam was administered again (approximately 16 hours after the previous dose), except at a higher dose of 3 mg (0.1 mg/kg). When checked at 5 minutes after intranasal lorazepam administration, the patient had calmed down and was sitting on the stretcher without physical restraints. Twenty-five minutes after receiving intranasal lorazepam, the patient fell asleep for 3 hours. When he awoke, he remained calm for the remaining 24 hours of his ED stay.
      The patient’s baseline vital signs included blood pressure 93/52 mm Hg, pulse rate 94 beats/min, respiratory rate 20 breaths/min, and oxygen saturation of 100% on room air. After the administration of each dose of intranasal lorazepam, his pulse rate and respiratory rate were checked every 10 minutes for an hour, during which time they remained at baseline. A full set of vital signs was checked at 1 hour after intranasal lorazepam administration and the check was repeated every 4 hours for the remainder of his ED stay, during which time the vital signs remained stable. There were no episodes of nausea, vomiting, respiratory depression, apnea, or paradoxical reaction. The patient did not complain of nasal burning associated with intranasal administration but did complain about the taste. When asked independently of one another, all but one member of the patient care team involved in this case, including security and nursing, thought that intranasal administration was easier and safer than intramuscular administration. The single outlier thought there was no difference in ease of administration or safety between the 2 routes. No one thought that intranasal administration was more difficult or less safe compared with intramuscular administration.

      Discussion

      We present the first report to our knowledge of intranasal lorazepam to successfully treat severe agitation in a pediatric behavioral health patient in the ED. The standard of care for treating severe agitation in the ED typically involves the intramuscular administration of medications such as lorazepam, haloperidol, diphenhydramine, and chlorpromazine.
      • Gerson R.
      • Malas N.
      • Feuer V.
      • et al.
      Best Practices for Evaluation and Treatment of Agitated Children and Adolescents (BETA) in the emergency department: consensus statement of the American Association for Emergency Psychiatry.
      • Gerson R.
      • Malas N.
      • Mroczkowski M.M.
      Crisis in the emergency department: the evaluation and management of acute agitation in children and adolescents.
      This may often require multiple injections, depending on the number and compatibility of medications prescribed, the dose (and volume) of each medication, and the availability of useable injection sites. Using intranasal sedatives for agitated and uncooperative patients may be preferable to using intramuscular ones because the intranasal route is a rapid and needle-free means of administering a sedative.
      Emergent situations involving an agitated and uncooperative patient, multiple hospital personnel, and an intramuscular injection are high risk and put all involved at risk for harm. Giving a sedative by the intranasal route can be safer than using the intramuscular route by eliminating use of a needle and need to inject an uncooperative and potentially combative patient. Any endeavor to decrease needlestick injuries is of paramount importance because ED health care workers have an enhanced risk of exposure to occupationally acquired bloodborne illnesses (eg, hepatitis B, hepatitis C, HIV) because of the nature of their frequent exposure to sharps.
      • Prüss-Üstün A.
      • Rapiti E.
      • Hutin Y.
      Sharps injuries: Global burden of disease from sharps injuries to health-care workers.
      In addition, foregoing a needle may make the experience less painful and distressing to the patient, and less likely to exacerbate an already volatile situation. According to our experience with this patient, it appears that intranasal administration was well received by both parents and hospital personnel because of the ability to eliminate pain and distress related to needles and ease and safety of administration.
      We observed a rapid onset of sedation associated with intranasal lorazepam during both episodes, with onset of minimal sedation within 5 minutes of administration. This onset of action corresponds to previous reports of intranasal administration of sedatives and analgesics in children, in which onset of sedation and clinically significant decreases in pain were observed within 5 minutes.
      • Tsze D.S.
      • Ieni M.
      • Fenster D.B.
      • et al.
      Optimal volume of administration of intranasal midazolam in children: a randomized clinical trial.
      • Tsze D.S.
      • Pan S.S.
      • DePeter K.C.
      • et al.
      Intranasal hydromorphone for treatment of acute pain in children: a pilot study.
      Intranasal administration of lorazepam in particular has been shown to achieve peak serum concentrations 6 times faster than when administered intramuscularly.
      • Wermeling D.P.
      • Miller J.L.
      • Archer S.M.
      • et al.
      Bioavailability and pharmacokinetics of lorazepam after intranasal, intravenous, and intramuscular administration.
      Rapid onset of action and systemic absorption are facilitated by both the highly vascularized nasal mucosa and involvement of the nose-brain pathway that transports medications through the olfactory and trigeminal nerves directly from the nasal cavity to the brain.
      • Pires A.
      • Fortuna A.
      • Alves G.
      • et al.
      Intranasal drug delivery: how, why and what for?.
      As a result, the intranasal administration of sedatives may be able to produce sedation faster than intramuscular sedatives such as lorazepam, haloperidol, and chlorpromazine, which typically take between 15 and 45 minutes.
      • Gerson R.
      • Malas N.
      • Mroczkowski M.M.
      Crisis in the emergency department: the evaluation and management of acute agitation in children and adolescents.
      • Pires A.
      • Fortuna A.
      • Alves G.
      • et al.
      Intranasal drug delivery: how, why and what for?.
      • Marzullo R.
      Pharmacologic management of the agitated child.
      • Klein L.R.
      • Driver B.E.
      • Miner J.R.
      • et al.
      Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation in the emergency department.
      • Nobay B.C.
      • Simon M.A.
      • Levitt M.A.
      • et al.
      A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients.
      • Huf G.
      • Coutinho E.S.
      • Adams C.E.
      Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine.
      Other intranasal benzodiazepines such as midazolam have been shown to produce similarly rapid onset of sedation and time to peak serum concentrations.
      • Tsze D.S.
      • Ieni M.
      • Fenster D.B.
      • et al.
      Optimal volume of administration of intranasal midazolam in children: a randomized clinical trial.
      • Mellion S.A.
      • Bourne D.
      • Brou L.
      • et al.
      Evaluating clinical effectiveness and pharmacokinetic profile of atomized intranasal midazolam in children undergoing laceration repair.
      However, we chose to administer lorazepam instead of midazolam to treat our patient’s severe agitation because of lorazepam’s longer duration of action.
      There appeared to be a dose-response relationship when 2 different doses of intranasal lorazepam were administered to the same patient on separate occasions. The lower dose of 0.05 mg/kg produced a state of minimal sedation that lasted approximately 90 minutes, after which additional sedatives were required. The higher dose of 0.1 mg/kg also rapidly achieved minimal sedation, which then progressed to sleep in approximately 25 minutes, lasting up to 3 hours and followed by a prolonged period of calm and cooperation after the patient woke. The dose of 0.1 mg/kg (with a maximum total dose of 4 mg) corresponds to the dose previously reported for treating seizures in children, and may also be the preferable dose in the context of treating agitation.
      • Arya R.
      • Gulati S.
      • Kabra M.
      • et al.
      Intranasal lorazepam for control of acute seizures in children: a randomized open-label study.
      Although our patient was successfully treated with intranasal lorazepam, we do not know whether these results are generalizable to the agitated patient experiencing acute psychosis. It is unclear whether antipsychotic medication with or without a benzodiazepine is more effective for treating severe agitation in a patient experiencing acute psychosis.
      • Zaman H.
      • Sampson S.J.
      • Beck A.L.S.
      • et al.
      Benzodiazepines for psychosis-induced aggression or agitation.
      However, the administration of benzodiazepines alone has been shown to be effective in treating undifferentiated agitation in adults.
      • Klein L.R.
      • Driver B.E.
      • Miner J.R.
      • et al.
      Intramuscular midazolam, olanzapine, ziprasidone, or haloperidol for treating acute agitation in the emergency department.
      • Nobay B.C.
      • Simon M.A.
      • Levitt M.A.
      • et al.
      A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients.
      Another consideration when using intranasal lorazepam to treat severe agitation is the possibility of a paradoxical reaction, which is associated with the administration of benzodiazepines. However, these reactions are uncommon and occur in less than 1% of patients.
      • Mancusco C.E.
      • Tanzi M.G.
      • Gabay M.
      Paradoxical reactions to benzodiazepines: literature review and treatment options.
      Intranasal lorazepam appears to be an effective sedative for treating severe agitation in a pediatric behavioral health patient in the ED, with potential advantages of intranasal over intramuscular administration. Further studies are warranted to determine the ideal dose of intranasal lorazepam for this indication, to better delineate the adverse event profile, and to determine the drug’s efficacy in providing sedation for the agitated patient compared with common intramuscular regimens.

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