The Use of Dexmedetomidine in Pediatric Palliative Care: A Preliminary Study

Abstract

Objective:

To evaluate the effect of dexmedetomidine infusions in patients with advanced malignancies, advanced heart disease, or after stem cell transplantation (SCT), who during end-of-life care had pain and/or agitation unresponsive to conventional therapies.

Background:

Pediatric patients with intractable advanced malignancies, end-stage congenital heart diseases, or after SCT can suffer a great deal during end of life. Pain, drowsiness, fatigue, irritability, and worrying are experienced frequently, considered distressing, and are strongly associated with reductions in health-related quality-of-life scores. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use can be ineffective and can be associated with increasing pain during end of life. Dexmedetomidine, a α₂-adrenoreceptor agonist with sedative and analgesic properties but without respiratory depressant effects, has been shown to reduce opioid requirement and to facilitate opioid weaning.

Methods:

Observational cohort study of consecutive patients treated with dexmedetomidine during end of life in a pediatric hospital. Primary outcomes included pain scores and morphine-equivalent intake.

Results:

We identified nine patients [median age 8 (interquartile range; IQR 0.55–17 years)] who during end of life had received dexmedetomidine infusions. In these patients, dexmedetomidine infusions had a median duration of two days (IQR 1.5–12 days) and were associated with significant (p < 0.001) reductions in pain scores and a trend toward decreasing morphine-equivalent intake. There were no hemodynamic changes requiring vasoactive or anticholinergic agents.

Conclusions:

These preliminary findings of beneficial effects of dexmedetomidine support the hypothesis that dexmedetomidine has a role in palliative care of children and adolescents during end of life.

Introduction

Studies using patient reported outcomes demonstrate that pain, drowsiness, and fatigue are the most reported symptoms during the last weeks of life in patients with advanced cancer.^1,2 In addition, these symptoms are distressing and strongly associated with reductions in health-related quality-of-life scores during end of life.² Thus, it is clear that children with advanced cancer experience distressing symptoms, and intensive management of those symptoms is likely to improve well-being of patients and their parents during end of life.^1–4

Significant efforts have aimed at integrating palliative care into treatment of patients with life-threatening diseases.⁵ As a result, researchers have shown that compared with earlier cohorts,⁶ there has been decreases in the proportion of children with cancer who suffer “a great deal” or “a lot” during end of life.^3,7 However, despite decreases in overall suffering, ∼80% of children have pain and over 40% suffer “a great deal” or “a lot” during end of life.⁷ Currently, opioids are the mainstay for pain management during end of life⁸ and in a large pediatric series, researchers showed that over the last weeks of life, there are increases in pain and escalation in opioid intake.⁹ However, the use of opioid significantly varies across hospitals and among hospitalized pediatric oncology patients, only 56% receive opioids daily during their last weeks of life.¹⁰ Therefore, despite significant advancements in end-of-life care, improvements in symptom management are needed.

Some have proposed that the α2-adrenoreceptor agonist dexmedetomidine, which is currently, used as a sedative in intensive care units (ICUs) for children and adults and as an opioid-sparing agent during the perioperative period,^11–14 might have a role in palliative medicine.¹⁵ In fact, in settings where high-opioid requirement is associated with undesirable side effects, tolerance and/or opioid-induced hyperalgesia, dexmedetomidine decreases opioid intake and facilitates opioid weaning.^16,17 Dexmedetomidine is a α2-adrenoreceptor agonist that binds to the A, B, and C receptor subtypes¹⁸ and has been shown to have antinociceptive and sedative effects, which, unlike opioids, are not associated with respiratory depression.¹¹ In our institution, we have used dexmedetomidine for palliative care purposes, and in this study, we examined its effects on pain and opioid intake in children receiving palliative care during end of life.

Methods

Our Institutional Review Board approved the study and waived the need for informed consent, as the data had been collected and was de-identified for the purpose of this study. We reviewed patients who received an order for dexmedetomidine during hospital admissions between January 2010 and April 2016 and included patients who received dexmedetomidine as part of palliative care during end of life. Patients who received dexmedetomidine for reasons other than treatment of symptoms during end of life were excluded. We collected demographic data (sex, age, and race), diagnosis, reasons for initiating dexmedetomidine, patient location when dexmedetomidine was initiated, infusion duration, pain scores, and opioid intake before and after dexmedetomidine. We also noted providers' or families' comments on the patients' overall comfort level, which had been recorded in the medical record. Pain scores were measured using the Face, Legs, Activity, Cry, and Consolability scale.

The primary outcome was pain scores before and after dexmedetomidine (daily average). We also examined daily morphine-equivalent intake before and after dexmedetomidine. As previously described, we calculated daily oral morphine-equivalent (per body weight) intake using the opioid conversion tool available at website www.globalrph.com/narcoticonv.htm¹⁹

Dexmedetomidine administration

Before 2011 in our institution, the administration of dexmedetomidine had been restricted to perioperative and ICUs. In instances when our pain medicine consultants determined that a patient would benefit from receiving dexmedetomidine for symptom management during end of life, he/she would have to be transferred to the ICU. In the ICUs, hemodynamic monitoring is conducted as prescribed by the primary ICU team.

In 2011, we requested guidance and approval from the District of Columbia Board of Nursing to develop a program allowing administration of dexmedetomidine for symptom management during end of life on the regular inpatient care units when certain conditions were met rather than in the ICU. The request to allow dexmedetomidine administration during end-of-life care in regular inpatient care units was approved by the District of Columbia Board of Nursing in 2011. We then developed an order set for administration of dexmedetomidine for symptom management during end of life. The use of the order set for dexmedetomidine administration in palliative care during end-of-life care is restricted to pain medicine and ICU physicians and can be used both in the ICUs or regular inpatient floors. When patients receive dexmedetomidine on the hospital's regular inpatient care units or ICUs, a visible high-alert labeling is placed on the tubing and a locked medical infusion pump is used. Members of the nursing staff (both from the ICU and regular inpatient units) administering dexmedetomidine undergo an extensive educational program about the drug and its use. To receive dexmedetomidine for symptom management during end of life, patients must have a resuscitation status order either for limited resuscitation, which is restricted to airway suction, supplemental oxygen, and administration of fluids and blood products or to allow natural death. On the regular inpatient floor, cardiopulmonary monitoring and recording of vital signs is not required. Pain assessments are conducted every four hours or more as indicated. The Care Delivery Model used, Patient–Family-Centered Care²⁰ provided shared decision-making, and at any time patient/family can request a change in level of care and monitoring.

When used for symptom management during end of life both in the ICU and on the regular inpatient floor, the suggested dexmedetomidine regimen is a bolus dose of 1 mcg/kg administered over 10 minutes followed by a continuous infusion at 0.1–3 mcg/kg/hour. Bolus doses of 0.1 mcg/kg can be administered up to every 30 minutes if pain scores are equal to or greater than five.

Statistical analysis

We used descriptive statistics to present variables. Pain scores and morphine-equivalent intake were analyzed using repeated measures one-way ANOVA and using time (days) as a factor. All analyses were conducted using SigmaPlot 13 (Systat Software, Inc., San Jose, CA).

Results

We identified nine patients who died in the hospital and had received dexmedetomidine infusions during end of life. Table 1 lists patients' demographics, diagnoses, resuscitation orders, and reasons for and duration of dexmedetomidine infusions. The median age was eight and interquartile range (IQR) 6.6 months to 17 years. Table 2 lists other pharmacologic agents in use at the start of dexmedetomidine. Dexmedetomidine was ordered by the Pain Medicine team for the following reasons: (1) escalating opioid requirements and development of untoward side effects (respiratory depression, agitation, anxiety, nausea/vomiting, rash, chest rigidity); (2) inadequate pain management despite escalating opioids, and (3) the impression that opioid-induced hyperalgesia was contributing to the patient's pain and or/agitation. Dexmedetomidine was started in the ICUs in eight patients. Four patients were on mechanical ventilation (patients 4, 5, 7, and 8) and one on extracorporeal membrane oxygenation (patient 7) when dexmedetomidine was initiated. Two patients received dexmedetomidine on the regular inpatient care unit. In one of those patients, dexmedetomidine had been initiated in the ICU and was then continued on the regular inpatient floor (Patient 1). Dexmedetomidine infusions lasted a median of two days (IQR, 1.5–12 days; Table 1). Two of nine patients received dexmedetomidine for over two weeks (patients 4 and 5). In patient 5, the infusion of dexmedetomidine was maintained for 111 days and it was initiated because the patient developed severe rash and pruritus with morphine and ketamine administration. As there were significant improvements in pain and agitation in response to dexmedetomidine, the drug was continued as the main therapeutic agent for pain management and sedation.

Table 1.

Characteristics of Nine Patients Who Received Dexmedetomidine Infusions for Palliative Care during End of Life

Patient	Age	Sex	Race	Primary diagnosis	Treatment location	Code status	ETT	Dex infusion duration (days)	Reason for dexmedetomidine
1	17 Years	F	White	Chronic myelogenous leukemia	ICU, floor	Limited resuscitation^a	N	2	Inadequate pain control, agitation
2	14 Years	F	White	B-cell lymphoma	Floor	Limited resuscitation	N	1	Inadequate pain control, agitation
3	8 Years	F	Other	Hepatoblastoma	ICU	Limited resuscitation	N	2	OIH
4	1.4 Years	M	Black	Shwachman–Diamond syndrome (SCT)	ICU	Limited resuscitation	Y	19	Inadequate pain control
5	17 Years	F	Black	Sickle cell anemia (SCT)	ICU	Limited resuscitation	Y	111	Inadequate pain control^b
6	7 Months	M	White	Complex congenital heart disease	ICU	Limited resuscitation	N	2	Inadequate pain control
7	3 Weeks	M	Other	Complex congenital heart disease	ICU	Limited resuscitation	Y	5	Inadequate pain control^c
8	6 Months	F	Black	Congenital diaphragmatic hernia	ICU	Limited resuscitation	Y	4	Inadequate pain control
9	17 Years	F	Black	Renal medullary carcinoma	ICU	DNR/AND	N	1	Inadequate pain control, agitation

Limited resuscitation indicate that resuscitation measures were restricted to airway suction, supplemental oxygen, and administration of fluids and blood products.

Patient 5 had a history of allergies to morphine and ketamine.

Patient 7 developed chest rigidity after administration of fentanyl.

AND, allow natural death; DNR, do not resuscitate; ETT, endotracheal tube; F, female; ICU, intensive care unit (cardiac or medical-surgical); M, male; OIH, opioid-induced hyperalgesia; SCT, stem cell transplant.

Table 2.

Drugs Used for Symptom Management before Initiation of Dexmedetomidine

Patient	Opioid	Anti-inflammatories ^a	Ketamine	Benzodiazepine	Methadone	Pregabalin
1	Y	Y	N	Y	Y	N
2	Y	Y	N	N	Y	N
3	Y	N	Y	Y	Y	N
4	Y	Y	N	Y	Y	N
5	Y	Y	Y	N	N	Y
6	Y	N	N	Y	Y	N
7	Y	N	N	Y	N	N
8	Y	N	N	Y	N	N
9	Y	N	N	Y	Y	N

Anti-inflammatory drugs include steroids and nonsteroid anti-inflammatory drugs.

Figure 1 shows pain scores on the day before and up to six days of dexmedetomidine infusion in nine patients treated with dexmedetomidine during end of life. For patients who received dexmedetomidine for over six days (patients 4 and 5), pain scores after day six were comparable with those shown in the figure during dexmedetomidine infusions. While we did not correct for underlying primary diagnosis, overall, dexmedetomidine was associated with significant decreases in pain scores (p < 0.001; Fig. 1A). In addition, we observed a trend toward decreases in morphine-equivalent intake (p = 0.088; Fig. 1B). We note that as patients were receiving end-of-life care, there was little effort to decrease opioid intake. In addition to reductions in pain scores, we found documentation in nurses and physicians notes indicating subjective improvement in overall patient comfort level in six of the nine patients. One family (patient 3) indicated that their child's pain was very well controlled on dexmedetomidine, and with reduction of opioid, their child was more alert and more engaged.

FIG. 1.

Pain scores and morphine-equivalent intake before and after dexmedetomidine infusion. The down arrow in (A) and (B) indicates the start of dexmedetomidine infusion. (A) The points indicate pain scores immediately before (0) and after (daily average) dexmedetomidine infusions. Overall, over days, dexmedetomidine infusions were associated with significant decreases in pain scores (p < 0.001). (B) The points indicate daily oral morphine-equivalent intake before (0) and after dexmedetomidine infusion. Overall, over days, dexmedetomidine infusions were associated with a trend toward decreases in daily morphine-equivalent intake (p = 0.088).

There were no records of administration of anticholinergics or vasoactive drugs to treat bradycardia or changes in blood pressure associated with dexmedetomidine.

Discussion

In this study, we reported the use of dexmedetomidine as an adjuvant therapy to treat pain and agitation in nine children and adolescents with advanced life-threatening illnesses during end of life. To our knowledge, this is the first report of dexmedetomidine in a series of children and adolescents during end of life. In our patients, we noted a significant decrease in pain scores after initiation of dexmedetomidine as well as a trend toward decreases in opioid intake. In addition, dexmedetomidine was associated with overall subjective improvement in comfort level according to clinicians and family members. These findings suggests that (1) using dexmedetomidine as an adjuvant for pain therapy in pediatric patients during end of life is feasible and can be done in regular inpatient care units; (2) dexmedetomidine holds great promise as an adjuvant to analgesic and sedation strategies to alleviate suffering during end of life.

Two of our patients had undergone stem cell transplantation (SCT) for nonmalignant hematologic diseases. Researchers have shown that after SCT, patients are more likely to die in ICUs and to suffer significantly from their last therapy.²¹ The two patients who had undergone SCT received the longest dexmedetomidine infusions (over two weeks) and in both, dexmedetomidine yielded significant reduction in pain scores and increased comfort. We also had two children with complex congenital heart disease, who, in keeping with reports of significant suffering during end of life in children dying of advanced heart disease,²² had significant distress and/or pain unresponsive to high-dose opioids. Both patients tolerated dexmedetomidine and had improvement in pain scores. Therefore, in this small heterogeneous series of patients with intractable advanced diseases at end of life tolerated dexmedetomidine infusions and had significant symptom relief. These findings support the conduct of additional studies of dexmedetomidine for symptom management during end of life in pediatric patients.

While the issue of opioid intake escalation during end of life was beyond the scope of this work, our findings of a trend toward decrease in opioid intake are of relevance given that others have shown that during end of life, there is often significant escalation of opioid intake.⁹ Therefore, in settings where opioid escalation is associated with undesirable side effects and/or tolerance or opioid-induced hyperalgesia, dexmedetomidine could be used as an adjuvant for symptom management during end-of-life care. Furthermore, there are few reports of the use of dexmedetomidine during end of life in adults^23–26 and in one adolescent undergoing withdrawal of respiratory support.²⁷ Our findings are in keeping with those previous reports indicating that dexmedetomidine was tolerated, improved pain management, and increased comfort during end of life. In addition, we showed that the use of dexmedetomidine as an adjuvant to treat pain and/or agitation in regular inpatient units is feasible and holds promise to allow for end of life in hospital environments other than ICUs. Therefore, additional studies of the use of dexmedetomidine during end-of-life care to treat symptoms when standard strategies fail or are associated with adverse effects are warranted.

While pain scores decreased and there was a trend toward decreasing opioid requirement after dexmedetomidine, we cannot definitively determine its efficacy in the absence of a control group, which is a limitation of this study. In addition, given the small sample size and the heterogeneity of our patients, our ability to draw definitive conclusions is limited. Furthermore, while we showed the feasibility of administering dexmedetomidine while patients were admitted to regular inpatient care units, most of our patients received dexmedetomidine while in the ICUs. Future studies will determine which patients would be better served by receiving dexmedetomidine while admitted to regular inpatient units. Nevertheless, in our patients, dexmedetomidine was well tolerated and associated with significant reduction in pain scores. Furthermore, while we did not report on other distressing symptoms, the patients subjectively appeared more comfortable. Taken together, these results suggest that dexmedetomidine might have a role as an adjuvant for symptom management during end-of-life care.

Footnotes

Acknowledgments

The authors are grateful to Karen V. Scipio-Skinner, MSN, RN and Cheryl Reggio, BN-PC, RN, CPON for their guidance and efforts during the implementation of the program for the use of dexmedetomidine during end of life. We are also grateful to our patients and their families for allowing our participation in their care. This work was supported by a grant from the Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute.

Author Disclosure Statement

No competing financial interests exist

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Patient	Opioid	Anti-inflammatories ^a	Ketamine	Benzodiazepine	Methadone	Pregabalin
1	Y	Y	N	Y	Y	N
2	Y	Y	N	N	Y	N
3	Y	N	Y	Y	Y	N
4	Y	Y	N	Y	Y	N
5	Y	Y	Y	N	N	Y
6	Y	N	N	Y	Y	N
7	Y	N	N	Y	N	N
8	Y	N	N	Y	N	N
9	Y	N	N	Y	Y	N

Patient	Opioid	Anti-inflammatories ^a	Ketamine	Benzodiazepine	Methadone	Pregabalin
1	Y	Y	N	Y	Y	N
2	Y	Y	N	N	Y	N
3	Y	N	Y	Y	Y	N
4	Y	Y	N	Y	Y	N
5	Y	Y	Y	N	N	Y
6	Y	N	N	Y	Y	N
7	Y	N	N	Y	N	N
8	Y	N	N	Y	N	N
9	Y	N	N	Y	Y	N

Patient	Opioid	Anti-inflammatories ^a	Ketamine	Benzodiazepine	Methadone	Pregabalin
1	Y	Y	N	Y	Y	N
2	Y	Y	N	N	Y	N
3	Y	N	Y	Y	Y	N
4	Y	Y	N	Y	Y	N
5	Y	Y	Y	N	N	Y
6	Y	N	N	Y	Y	N
7	Y	N	N	Y	N	N
8	Y	N	N	Y	N	N
9	Y	N	N	Y	Y	N