Investigation and Clinical Experience With Subcutaneous Dexmedetomidine: An Educational Focused Review With a Focus on Pediatric-Aged Patients

Abstract

Dexmedetomidine is a centrally acting selective α₂-adrenergic agonist that initially received US Food and Drug Administration approval in 1999 for the sedation of intubated and mechanically ventilated adult patients for up to 24 hours. Since then, it has seen widespread use in clinical practice in various clinical scenarios including sedation during mechanical ventilation, provision of adjunctive analgesia, procedural sedation, treatment of withdrawal, and sedation during end-of-life care. Although traditionally administered intravenously, animal investigations and anecdotal clinical experience has reported efficacy with subcutaneous (SC) administration. Clinical applications of SC dexmedetomidine have included procedural sedation; outpatient and home care where IV administration may not be feasible or interfere with patient comfort; the management or prevention of drug withdrawal symptoms; and during end-of-life care. This educational review outlines the basic physiology of dexmedetomidine, and details reports of its SC administration in laboratory animals as well as various clinical scenarios with a specific focus on its applications in pediatric-aged patients. Techniques for SC administration and dosing schemes are presented.

Introduction

Dexmedetomidine, a centrally active, selective α₂-adrenergic agonist, that is widely used across various medical specialties for its sedative, analgesic, and anxiolytic effects.¹ It initially received US Food and Drug Administration approval in 1999 for the sedation of intubated and mechanically ventilated adult patients for up to 24 hours and subsequently for the perioperative sedation of non-intubated patients (monitored anesthesia care). Since its initial introduction, its off-label use has continued to increase in both adult and pediatric-aged patients.^2–5 Applications have included ICU sedation during mechanical ventilation, provision of procedural sedation, treatment of withdrawal, and sedation during end-of-life care.^2–7

Traditionally dexmedetomidine is administered intravenously (IV); however, non-traditional alternative routes including oral, transmucosal (intranasal, sublingual, and buccal) as well as subcutaneous (SC) administration have emerged as potential alternative routes. These non-IV routes may offer potential benefits in various clinical scenarios where IV administration may not be feasible or becomes problematic. Clinical applications of SC dexmedetomidine have included procedural sedation for minor surgical and diagnostic procedures, outpatient and home care where IV administration may interfere with accessibility and comfort, management or prevention of drug withdrawal symptoms, and for home care during end of life sedation and analgesia.^8,9 This educational review outlines the cellular mechanisms and end-organ effects of dexmedetomidine and details reports of its SC administration in laboratory animals as well as various clinical scenarios. We also discuss techniques for SC administration and dosing schemes.

Literature Review

A systematic search of PubMed, Scopus, and Google Scholar was conducted using the terms: dexmedetomidine, dexmedetomidine dosing, subcutaneous administration, subcutaneous dexmedetomidine administration in animals, pharmacokinetic profile of subcutaneous dexmedetomidine, subcutaneous dexmedetomidine, palliative sedation, and end-of-life care. The search terms were individually and in various combinations to identify the published works. The abstracts from the publications were reviewed and those pertaining to the subcutaneous administration of dexmedetomidine were identified. Additionally, the reference lists of these publications were reviewed to ensure that all the applicable manuscripts had been identified.

Preliminary and Initial Investigations

Animal Studies (Table 1). Three studies were identified that evaluated the PK and safety profile of IM or SC dexmedetomidine in horses. A 2021 study compared the pharmacokinetic profile of intramuscular (IM) and IV dexmedetomidine in horses.¹⁰ The clearance and half-life of dexmedetomidine were found to be increased with intermittent IM administration compared with continuous IV administration. These findings may be an artifact of continued and slow absorption from the IM depot which then blunts the decay curve. The authors also reported that IM administration had a limited effect on gastrointestinal function as the incidence of decreased gastrointestinal motility was significantly higher with IV dexmedetomidine. The potential mechanisms behind this finding was not specifically identified. This preliminary study regarding the pharmacokinetics and dosing parameters of IM administration was used as the basis for subsequent animal studies that evaluated SC dexmedetomidine.

Table 1.

Reports of Subcutaneous or Intramuscular Dexmedetomidine Administration–Animal Studies

Author and Reference	Demographic Data and Clinical Scenario	Subcutaneous Dexmedetomidine Dosing and Outcomes
Shane10	8 adult horses	Clearance and half-life of dexmedetomidine were increased with intermittent IM administration compared with continuous IV administration. Incidence of decreased GI motility was significantly higher with IV dexmedetomidine. This preliminary study regarding the pharmacokinetics and dosing parameters of IM dexmedetomidine was used as the basis for subsequent animal studies that evaluated SC dexmedetomidine.
Rabbogliatti11	30 horses of various breeds	Comparison of anesthetic effects of IV vs SC dexmedetomidine. SC dosing included 2 μg/kg every 60 min until the end of the procedure. IV administration included an infusion of 1 μg/kg/hr for 106 ± 22 min. Dexmedetomidine maximum concentration was 0.50–2.27 ng/mL in the SC group and 0.39–1.18 ng/mL in the IV group. No significant differences between groups in heart rate and systolic arterial pressure with a higher mean and diastolic arterial pressure in the SC group. Lower dobutamine requirements to maintain the MAP ≥ 70 mm Hg and higher urinary output with SC administration. There was a significantly higher recovery score in the SC group (4.7 ± 0.5 vs 4.2 ± 1.0, p = 0.01). The recovery score as reported in this study encompassed the time to spontaneous ventilation, time to extubation, the time in between spontaneous ventilation and extubation, time to sternal recumbency, attempts to sternal recumbency, time to standing, and attempts to stand.
Di Cesare12	20 horses of various breeds	Comparison of the pharmacokinetic profile of IV and SC dosing. SC dosing included 2 μg/kg every 60 min until the end of the procedure. IV administration (10 horses) included an infusion at 1 μg/kg/hr for an average infusion time of 106 ± 22 min. IV administration demonstrated a half-life of 18.0 ± 10.0 min, a volume of distribution of 390.09 ± 204.21 mL/kg, a clearance of 16.26 ± 8.07 mL/min/kg, and a mean residence time (average time the molecules of dexmedetomidine spent in the body) of 11.7 ± 6.2 min. These results remained consistent with prior literature on the pharmacokinetic properties of IV dexmedetomidine. SC administration resulted in a half-life of 94.8 ± 69.8 min and mean residence time of 55.8 ± 19.7 min. These results were higher than the IV group thought to be due to a slower absorption than clearance rate. Maximum concentration and last concentration did not differ significantly between the 2 groups. SC max concentration was 1.14 ± 0.71 ng/mL reached a time of 105.5 ± 29.9 min; IV max concentration was 0.83 ± 0.27 ng/mL reached at a time of 57.0 ± 13.4 min.

GI, gastrointestinal; IM, intramuscular; IV, intravenous; MAP, mean arterial pressure; SC, subcutaneous

A subsequent study, also performed in horses, compared the clinical effects of IV and SC dexmedetomidine.¹¹ There were no significant differences between the 2 groups (IV and SC) when evaluating heart rate and systolic arterial pressure. However, significantly higher mean and diastolic blood pressures (BPs) were noted with SC administration. These findings are in distinction to the commonly seen hemodynamic effect of IV dexmedetomidine which include a central sympatholytic effect with lowering of heart rate and BP. There was also a decrease in infusion rates of dobutamine required to support BP and significantly higher urine output (8.8 ± 2.8 vs 6.7 ± 2.5 mL/kg/hr, p = 0.02) with SC vs IV dexmedetomidine. This was attributed to higher BP and the occurrence of hyperglycemia in the SC group. The recovery score was used to gauge the rapidity of recovery from anesthesia. It assesses various clinical features including time to spontaneous ventilation and attempts to stand to create an overall composite score of recovery; with a higher score demonstrating a faster recovery. The recovery score was higher with SC compared with IV administration.

A final study in horses reported that the pharmacokinetic profile of SC and IV dexmedetomidine were comparable.¹² In the cohort of 20 horses, the maximum plasma concentration of dexmedetomidine did not differ significantly between groups, but the time to reach maximum plasma concentration was significantly longer with SC administration. The mean residence time (average time dexmedetomidine molecules spent in the body using the last measurable concentration) and half-life elimination of SC administration were found to be longer than with IV administration. These differences were attributed to the rate of absorption being slower than the clearance rate in the SC group. There were no reported adverse effects in either group or notably, no injection site reactions in the SC group. The study suggests and supports that repeated SC administration of 2 μg/kg of dexmedetomidine every 60 minutes showed a comparable pharmacokinetic profile to a continuous IV infusion of dexmedetomidine at 1 μg/kg/hr, albeit with a longer onset of action.

Pediatric Studies (Table 2). We identified only 2 studies reporting the administration of SC dexmedetomidine in pediatric-aged patients.^8,13 The first report of continuous subcutaneous infusion (CSCI) dexmedetomidine in pediatric-aged patients was published in 2008 and included a retrospective review of 7 pediatric patients, ranging in age from 6 months to 3.75 years, who had required prolonged use of sedative and analgesic agents during mechanical ventilation in a pediatric intensive care unit (PICU) setting.⁸ Four of the patients had received dexmedetomidine and an opioid while the other patients had received an opioid and/or a benzodiazepine. In all 7 patients, the dexmedetomidine CSCI infusion was used to prevent withdrawal from prolonged administration of sedative and analgesic agents after liberation from mechanical ventilation and tracheal extubation. Dexmedetomidine was administered IV initially at rates varying from 0.8 to 1.4 μg/kg/h before switching to SC administration. The CSCI dexmedetomidine infusion was then decreased by 0.1 μg/kg/hr every 12 hours to avoid withdrawal. CSCI dexmedetomidine was administered for a total of 4 to 7 days. Effective control and prevention of withdrawal was noted as documented by clinical withdrawal scores (modified Finnegan score). The authors concluded that CSCI dexmedetomidine could be used to treat or prevent drug withdrawal following the prolonged administration of sedative and analgesic agents in a PICU setting. The authors also concluded that the technique may be an option in cases where peripheral venous access becomes problematic or where the removal of central venous catheters would be beneficial in patients recovering from critical illnesses.

Table 2.

Reports of Subcutaneous Dexmedetomidine Administration–Pediatric Studies

Author and Reference	Demographic Data and Clinical Scenario	Subcutaneous Dexmedetomidine Dosing and Outcomes
Tobias8	Retrospective study of 7 pediatric patients, ranging in age from 6 mo to 3.75 yr	SC dexmedetomidine to treat or prevent withdrawal following prolonged sedation in the PICU. Dexmedetomidine was administered IV at rates varying from 0.8–1.4 μg/kg/hr before switching to SC administration. Four of the patients received dexmedetomidine along with an opioid as part of a sedation regimen during mechanical ventilation. For the other patients, IV dexmedetomidine infusion was used to treat withdrawal following the prolonged use of an opioid and/or a benzodiazepine. An equivalent dose was administered when the switch was made from IV to SC administration. The SC infusion rate was decreased by 0.1 μg/kg/hr every 12 hr. SC dexmedetomidine was administered for 4–7 days. Effective control of withdrawal was noted by use of clinical withdrawal scores.
Álvarez-Betancourt13	Prospective study of 52 pediatric aged patients, ranging in age from 3 to 15 yr	Evaluation of SC dexmedetomidine in the perioperative setting. Following anesthetic induction, dexmedetomidine was administered via the SC route in the deltoid region: group 1 - placebo 0.9% saline solution; group 2 - SC 1 μg/kg; group 3 - SC 1.5 μg/kg; group 4 – SC 2 μg/kg. There was no difference in hemodynamic profile (BP, HR, O2 saturation). There was no difference noted in comfort or delirium scales. However, SC dexmedetomidine resulted in increased sedation, indicated by a higher Ramsay scale and less pain, indicated by a lower Wong-Baker faces score.

BP, blood pressure; HR, heart rate; IV, intravenous; PICU, pediatric intensive care unit; SC, subcutaneous

In a subsequent study published in 2022, which to date, remains the largest cohort of pediatric patients receiving SC dexmedetomidine, Álvarez-Betancourt et al¹³ evaluated the efficacy and safety of SC dexmedetomidine during the perioperative period. In their cohort of 52 patients, ranging in age from 3 to 15 years, SC dexmedetomidine was administered intraoperatively and its clinical effects noted during the perioperative period on hemodynamic and respiratory function as well as its utility in providing sedation and analgesia. Following the induction of anesthesia, dexmedetomidine was administered via the SC route in the deltoid region (placebo or 1 of 3 doses: 1, 1.5, or 2 μg/kg). The authors concluded that SC dexmedetomidine preserved hemodynamic and respiratory function while providing sedation as well as improving analgesia for up to 24 hours after surgery. They also reported less agitation and delirium in the postoperative period resulting in greater patient comfort.

Adult Studies (Table 3). We identified 3 studies reporting the use of SC dexmedetomidine in the adult population, published in the timeframe of 2018 to 2022.^9,14,15 The first report of SC dexmedetomidine administration in the adult population included a cross-over study in 8 healthy adult volunteers, who received dexmedetomidine (1 μg/kg) via the IV or SC routes.⁹ Peak concentrations of dexmedetomidine occurred at an average of 15 minutes after SC administration with a mean bioavailability of 81%. The authors reported that SC dexmedetomidine was rapidly and efficiently absorbed, resulted in an attenuated cardiovascular effect (decreased impact on heart rate and BP) when compared with IV administration, and may be a feasible alternative in palliative sedation.

Table 3.

Reports of Subcutaneous Dexmedetomidine Administration–Adult Studies

Author and Reference	Demographic Data and Clinical Scenario	Subcutaneous Dexmedetomidine Dosing and Outcomes
Uusalo9	Cross-over study of 10 healthy adult volunteers (only 8 completed the study)	Comparison of the hemodynamic profile and pharmacokinetics of IV vs SC dexmedetomidine. Dexmedetomidine (1 μg/kg) was administered via the IV and SC routes. Peak concentrations of dexmedetomidine occurred 15 min after SC administration (range 15–240 minutes) and 10.2 min after IV administration (range 4.8–10.2 min). After 3 hr, similar plasma concentrations were measured with both routes of administration. The mean bioavailability of SC dexmedetomidine was 81% (range 49%–97%). The mean peak concentration of SC dexmedetomidine was 0.3 ng/mL and plasma concentrations associated with sedation (>0.2 ng/mL) were maintained for 4 hr after SC dosing. Plasma noradrenaline concentrations were significantly lower after IV compared with SC administration. Subjective scores for vigilance and performance were significantly lower for up to 60 min after IV than SC dosing. The metrics of vigilance and performance were determined by the subjects completing a VAS. Cardiovascular, sympatholytic, and sedative effects of dexmedetomidine were less with SC than IV administration.
Srinivas14	Prospective study of 90 adult patients scheduled for elective surgery, divided into 3 groups	Group P received 1 mL of normal saline SC, group D received 0.5 µg/kg of SC dexmedetomidine SC, and group C received 1 µg/kg of SC. The dose was administered after subarachnoid block was performed. Mean duration of postoperative analgesia was prolonged in the SC group (838.10 ± 348.22 min) compared with the normal saline group (332.10 ± 110.91 min). Total paracetamol consumption was less in the SC dexmedetomidine group (1400.00 ± 770.13 mg) when compared with the normal saline group (1900.00 ± 758.86 mg).
Ashraf15	Retrospective study of 10 patients (8 in the IV phase) healthy adult aged patients	Follow-up study of the pharmacokinetic data from reference 9. To achieve a therapeutic plasma concentration of dexmedetomidine as determined by prior studies, the final pharmacokinetic model indicated that either IV or SC administration in doses of 0.5–1 µg/kg are required. Time to achieve steady-state plasma concentrations with a constant SC infusion was 15–20 hr, compared with 3 hr with IV dosing. SC dexmedetomidine had a milder inhibition of NE release, which translated into an attenuation of the hemodynamic effect. SC dosing did not evoke notable hypertensive effect. Clearance with SC dosing varied from 41 to 57 L/min which was consistent with previous studies reporting elimination clearance estimates. The net bioavailability of dexmedetomidine via SC administration was 89%.

IV, intravenous; NE, norepinephrine; SC, subcutaneous; VAS, visual analogue score

A subsequent and to date, the largest clinical trial of SC dexmedetomidine in adults, evaluated the use of SC dexmedetomidine as an adjunct to patients receiving spinal anesthesia for elective infra-umbilical surgery (wound debridement, ureteroscopic stenting, transurethral resection of the prostate, abdominal tubectomy, and split skin grafting).¹⁴ Ninety patients, 20 to 70 years of age, were randomly assigned into 1 of 3 groups; group P received 1 mL of SC normal saline, group D received 0.5 µg/kg of SC dexmedetomidine, and group C received 1 µg/kg of clonidine SC.¹⁴ When compared with SC saline (group P or placebo), SC dexmedetomidine and clonidine prolonged the duration of postoperative analgesia and reduced overall analgesic requirements, while maintaining hemodynamic stability comparable without significant bradycardia or hypotension, requiring pharmacologic treatment. The authors also reported that SC dexmedetomidine provided a longer duration of analgesia and intraoperative sedation than the SC clonidine.

In a follow-up study from the authors of the first report of SC dexmedetomidine in the adult population by Uusalo et al,⁹ a retrospective study further analyzed the pharmacokinetic and hemodynamic profile of SC dexmedetomidine administration.¹⁵ The authors reported that there was less inhibition of NE release (demonstrated by assays of plasma catecholamine concentrations from arterial blood) with SC dexmedetomidine administration, which led to the subtle differences in hemodynamic changes compared with IV administration. Clearance and pharmacokinetic parameters of SC dexmedetomidine remained consistent with prior studies (see Table 3). Impact on blood pressure, clearance rate, and other pharmacokinetic properties of SC dexmedetomidine remained consistent with prior studies.

Case Reports (Table 4). Two additional case studies reporting the use of SC dexmedetomidine in the adult population were identified.^16,17 The first patient is a 55-year-old female with end stage cervical cancer suffering from intractable neuropathic pain and delirium. Despite the use of multiple pain regimens and medications, adequate pain control was not achieved with methadone, gabapentin, ketamine, and hydromorphone administered by CSCI plus frequent breakthrough doses of hydromorphone and sufentanil. Dexmedetomidine was administered via a CSCI improving pain relief and delirium. Subcutaneous dexmedetomidine was started at 0.3 µg/kg/hr and gradually increased up to 1.14 µg/kg/hr. The patient was able to converse with family members and caregivers and peacefully expired 3 weeks after starting the administration of dexmedetomidine CSCI.

Table 4.

Reports of Subcutaneous Dexmedetomidine Administration–Adult Case Reports

Author and Reference	Demographic Data and Clinical Scenario	Subcutaneous Dexmedetomidine Dosing and Outcomes
Hilliard16	55-yr-old woman with locally advanced cervical cancer and uncontrolled pelvic pain	Despite the use of methadone 12 mg SC every 8 hr, hydromorphone CSCI at 12.5 mg/hr, ketamine CSCI at 21 mg/hr, gabapentin 400 mg PO TID, hydromorphone 15 mg SC (8 doses per 24 hr), and sufentanil 75 µg SL (11 doses per 24 hr), pain remained poorly controlled. Dexmedetomidine was administered via CSCI at 0.3 µg/kg/hr with no bolus dose. The methadone and ketamine infusions were both continued. The patient responded within hours with improvement in her confusion and pain. Five days later, her pain began to escalate and the dexmedetomidine CSCI was increased to 1.14 µg/kg/hr. The patient was adequately sedated, but responsive. Pain and delirium were improved. She was able to converse with family members and caregivers. The patient expired peacefully 3 wk after starting the dexmedetomidine CSCI. There was no bradycardia, hypotension, or local cutaneous concerns at the SC site.
LaRoche17	55-yr-old man with multiple comorbid conditions	Dexmedetomidine was administered via a CSCI to control baclofen withdrawal during end-of-life care. Dexmedetomidine was started at 20 µg/hr and titrated up by 10 µg/hr every 30 min to a maximum dose of 70 µg/hr. The baclofen withdrawal symptoms were controlled. No bradycardia, hypotension, or adverse effects were noted.

CSCI, continuous subcutaneous infusion; IV, intravenous; SC, subcutaneous; SL = sublingual; PO, by mouth

The second case report describes the use of SC dexmedetomidine to treat baclofen withdrawal in a 55-year-old man with multiple comorbid conditions during end-of-life care.¹⁷ Despite increasing doses of benzodiazepines, the symptoms of baclofen withdrawal were not controlled. A CSCI of dexmedetomidine was started at 20 µg/hr and titrated up by 10 µg/hr every 30 minutes to a maximum dose of 70 µg/hr. This resulted in resolution of symptoms of baclofen withdrawal.

Dosing Technique and Strategies

Administration of SC dexmedetomidine and dosing strategies varied among the studies reviewed. In 2 of the horse studies, dexmedetomidine was administered as repeated SC injections (2 μg/kg) every 60 minutes until the end of the study protocol. In the pediatric population dexmedetomidine was administered as a CSCI or by individual bolus SC injection. Dosing regimens for SC administration have paralleled those used intravenously although the onset times of SC vs IV administration are longer. Bolus SC dosing has generally included intermittent doses of 1 to 2 µg/kg in pediatric patients and 0.5 to 1 µg/kg in adults. For the first pediatric report of SC dexmedetomidine reported by Tobias,⁸ the medication was initially administered IV and then switched using the same dose to the SC route. In general, no local tissue reactions were observed with the SC administration of dexmedetomidine, either by intermittent injection of CSCI.

Several areas are suitable for subcutaneous administration including the subclavicular region, abdomen, deltoid, or anterior aspect of the thigh. For intermittent or continuous infusions CSCI, a standard intravenous cannula (20 or 22 gauge) can be used and placed subcutaneously with the needle removed after placement as would be done for intravascular placement.^8,18 Other SC techniques have reported the use of metal butterfly needles (23 or 25 gauge). Prior to placement, the tubing and needle are flushed with the dexmedetomidine solution to clear the dead space. The insertion site and needle are then covered with a transparent, bio-occlusive dressing. The site is changed every 7 days or sooner if erythema develops. Infusions can be delivered via a standard infusion pump or a syringe pump. The pressure limit may need to be adjusted to allow for SC administration. Based on personal clinical experience, a concentrated solution of dexmedetomidine, prepared and diluted if needed from the commercially available vial (100 µg/mL), is recommended so that the infusion rate doses not exceed 3 mL/hr.

Conclusion

To date, laboratory investigation (animal studies) and clinical experience with the use SC dexmedetomidine has been somewhat limited. Outside of single anecdotal reports, there have been 3 animal studies (2 with SC and 1 with IM administration), 2 pediatric trials, and 3 adult studies contributing to the limited experience of SC dexmedetomidine in these distinct populations. These initial studies have suggested that, although the time to peak concentration is longer, SC dexmedetomidine can reach the same therapeutic plasma concentrations as IV administration with comparable clinical effects. In addition, the hemodynamic effects of SC dexmedetomidine are blunted when compared with IV administration with better maintenance of hemodynamic status. The limited clinical studies have had no reports of bradycardia, hypotension, or respiratory depression following SC administration. Although different factors have been proposed to account for the blunted hemodynamic impact of SC administration, SC dexmedetomidine has less of an impact on NE levels when compared with IV administration.^9,14,15

During palliative and end-of-life care, the use of SC dexmedetomidine is increasing due to its ability to manage symptoms such as discomfort, anxiety and agitation while allowing for ongoing home administration without the need for hospital admission. SC dexmedetomidine is rapidly and efficiently absorbed with an attenuated cardiovascular, sympatholytic, and sedative effect when compared with IV administration.⁶ Continuous SC infusions can provide steady and consistent plasma concentrations of dexmedetomidine with stable symptom control without the need for IV access in various clinical scenarios. The ease of application and administration has made SC dexmedetomidine a practical option for at home or less intensive care settings, making it practical for the palliative care patient.

In the pediatric population, SC dexmedetomidine offers promising alternatives especially in cases where the administration of dexmedetomidine via peripheral venous access becomes problematic or where SC dexmedetomidine may facilitate the removal of central venous catheters in patients recovering from critical illnesses. SC administration may also offer a viable route of administration in home settings when IV administration is not feasible. When compared with IV administration, the only drawback would be the rapidity of onset with a bolus dose, which can be expected to be slower with SC vs IV administration. However, the adult literature has demonstrated that the potential for adverse effects may be less with SC vs IV administration. Future research is needed to further evaluate and standardize the dosing schemes of SC dexmedetomidine and to evaluate its use in additional clinical scenarios. Comparative studies with other non-intravenous routes (transmucosal including nasal) may be indicated as we explore options for this valuable pharmacologic agent.

ABBREVIATIONS

CSCI

continuous subcutaneous infusion

IM

intramuscular

IV

intravenous

MAP

mean arterial pressure

PICU

pediatric intensive care unit

PO

by mouth

SC

subcutaneous

SL

sublingual

TID

three times a day