Is there any literature supporting use of droxidopa in critical care for hypotension? similar to midodrine for pressor sparing?

Is there any literature supporting use of droxidopa in critical care for hypotension? similar to midodrine for pressor sparing?

Comment by InpharmD Researcher

Limited data from retrospective studies and a case report suggests that droxidopa may be safe and effective for hypotension in patients requiring emergency care and did not respond to midodrine treatment. However, there is a lack of direct comparisons except for one study that did not find a difference between using atomoxetine, droxidopa, or both agents (Table 1). Treatments in this study would differ based on provider’s discretion and critically ill patients may have presented with confounding factors that were not controlled.

Background

A 2024 presentation abstract describes a study that evaluated the safety and effectiveness of droxidopa administered through gastric tubes in adult intensive care patients. A total of 21 patients met the criteria to be included in the analysis. The median age was 62 years old, with 33% being female. Most patients (80.5%) were admitted to a cardiac ICU. The most common reason for admission was heart transplantation, which accounted for 19% of cases. The most common starting dose of droxidopa was 100 mg administered every 8 hours. The maximum dose used was 600 mg every 8 hours. Prior to starting droxidopa, all patients had tried at least one adjunct agent to help wean off vasopressors, including midodrine (100%), pseudoephedrine (52%), fludrocortisone (48%), and pyridostigmine (9.5%). A total of 954 doses of droxidopa were administered via gastric tubes during the study period. The most frequent type of gastric tube used was nasogastric tubes, making up 57% of administrations. The primary outcomes showed the median time to discontinuation of all vasopressors after starting droxidopa was 87 hours. Episodes of tachycardia occurred at similar rates before (3.5%) and after (1.1%) initiation of droxidopa. However, episodes of hypotension were less frequent after starting droxidopa, occurring in 48% of patients before compared to 37% after. Mean norepinephrine equivalent requirements were also lower following droxidopa initiation, at 0.08 mcg/kg/min compared to 0.05 mcg/kg/min in the 24 hours prior. [1]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is there any literature supporting use of droxidopa in critical care for hypotension? similar to midodrine for pressor sparing?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Droxidopa or Atomoxetine for Refractory Hypotension in Critically Ill Cardiothoracic Surgery Patients
Design	Single-center, retrospective, cohort study N= 45
Objective	To evaluate the effects of droxidopa or atomoxetine on intravenous (IV) vasoactive agent discontinuation in cardiothoracic intensive care unit (ICU) patients with hypotension refractory to midodrine
Study Groups	Atomoxetine (n= 18) Droxidopa (n= 17) Both (n= 10)
Inclusion Criteria	Age 18 years or older, experienced hypotension refractory to midodrine therapy during the index encounter, continued to receive midodrine with the study medication, received at least 4 consecutive doses of the initially administered study medication
Exclusion Criteria	Patients experiencing clinical deterioration after study medication initiation requiring vasoactive agent addition or IV vasoactive agent dosage escalation for at least 12 hours
Methods	Patient data were collected from a single cardiothoracic intensive care unit (CTICU). The starting dose for droxidopa was 300 mg daily dose, and the median maximum daily dose was 1200 mg (interquartile range [IQR] 600, 1800 mg). Hypotension was defined as inadequate blood pressure or mean arterial pressure requiring the addition of any vasoactive agent.
Duration	Data collection: January 2017 to August 2022
Outcome Measures	Primary: Time from study medication initiation to discontinuation of IV vasoactive agents
Baseline Characteristics		Atomoxetine (n= 18)	Droxidopa (n= 17)	Both (n= 10)
	Age, years	66	64	65
	Male	55.6%	70.6%	60%
	Midodrine total daily dose, mg	45	60	15
	Index surgery CABG and valve replacement/repair Heart transplant Thoracic surgery, general Isolated valve replacement/repair Lung transplant Other Isolated CABG LVAD Thoracic aortic surgery None	16.7% 16.7% 16.7% 11.1% 11.1% 11.1% 5.6% 5.6% 5.6% 0	11.8% 17.6% 11.8% 0 35.3% 5.9% 0 11.8% 0 5.9%	30% 30% 0 0 10% 0 0 20% 10% 0
	Other vasoactive agents Corticosteroids Fludrocortisone	55.6% 11.1%	58.8% 47.1%	50% 40%
	Starting study dose, total daily dose, mg (IQR)	10 (10, 20)	300 (300, 300)	10 (10, 20) atomoxetine 300 (300, 300) droxidopa
	Maximum study dose, total daily dose, mg (IQR)	20 (10, 22.5)	1200 (600, 1800)	40 (20, 40) atomoxetine 300 (300, 1,800) droxidopa
	Study medication duration, days	12	17	24.5 atomoxetine 15 droxidopa
Results	Endpoint	Atomoxetine (n= 18)	Droxidopa (n= 17)	Both (n= 10)	p-Value
	Time to IV vasopressor cessation, days	21.9	8	13.9	0.259
	ICU length of stay, days	30 (14.8, 58.8)	18 (8.5, 50.5)	35 (24.3, 48.8)	0.466
	Hospital length of stay, days	64.5 (37, 120.3)	57 (42, 119.5)	64.5 (52, 87.3)	0.893
	ICU readmission	0	0	0	N/A
	Discharged from hospital on midodrine	1 (5.6%)	6 (35.3%)	4 (40%)	0.053
	Discharged from hospital on study medication	2 (11.1%)	2 (11.8%)	2 (20%) atomoxetine	0.780
	Alive at hospital discharge	8 (44.4%)	13 (76.5%)	9 (90%)	0.028
Adverse Events	No stroke or heart attack events occurred in any treatment groups. The most common adverse event was new cardiac arrhythmias, which occurred in 3 patients receiving atomoxetine, 2 patients receiving droxidopa, and 1 patient receiving both, but these differences were not statistically significant.
Study Author Conclusions	Droxidopa and atomoxetine are oral vasoactive agents with potential mechanisms to facilitate IV vasopressor weaning for patients in the ICU with hypotension refractory to midodrine, but further prospective research is needed.
InpharmD Researcher Critique	This study had several limitations as it was a single-center retrospective study with a small population size, and critically ill patients have many confounding factors that could influence clinical outcomes. Additionally, treatment decisions were based on provider discretion and the study population involved cardiothoracic surgery patients, so findings may not be generalizable to non-surgical ICU patients.

References:

Lessing JK, Kram SJ, Levy JH, Grecu LM, Katz JN. Droxidopa or Atomoxetine for Refractory Hypotension in Critically Ill Cardiothoracic Surgery Patients. J Cardiothorac Vasc Anesth. 2024;38(1):155-161. doi:10.1053/j.jvca.2023.09.023

Initiation of droxidopa during hospital admission for management of refractory neurogenic orthostatic hypotension in severely ill patients
Design	Cross-sectional, retrospective, cohort study N= 20
Objective	To determine the safety and effectiveness of droxidopa initiation in severely ill patients in the inpatient setting
Study Groups	Study patients (N= 20)
Inclusion Criteria	Age 18 years or older, neurogenic OH (nOH) refractory to midodrine and/or fludrocortisone, received at least one dose of droxidopa during hospitalization.
Exclusion Criteria	Droxidopa initiated in the outpatient setting, droxidopa initiation for an indication other than nOH
Methods	Data were collected and analyzed from electronic medical records of a university medical center.
Duration	Data collection: October 1, 2014 to May 31, 2017
Outcome Measures	Primary: Safety, change in physician global impression of illness severity from admission to discharge, persistence on medication after 180 day follow-up
Baseline Characteristics		Study patients (N= 20)
	Age, years	65
	Female	20%
	Race White Black Other	80% 15% 5%
	Cardiovascular conditions Congestive heart failure Hypertension Atrial fibrillation	35% 45% 15%
	Endocrine conditions Diabetes Fall fractures Thyroid disease	30% 10% 25%
	Neurological conditions Parkinson's disease Peripheral neuropathy Syncope	10% 40% 85%
	Other chronic conditions Cancer Kidney disease Transplant	30% 30% 10%
Results	Endpoint	Study patients (N= 20)
	Physician judgment of response Better and Improved Moderately Better Somewhat Better Hardly any Change No Change	30% 25% 25% 10% 10%
	Follow-up chart reviews were available for 18 of the initial patients. Of these, 13 (65% of the cohort) continued taking droxidopa for over 180 days after hospital discharge. On average, patients remained on droxidopa treatment for 140 ± 68 days. The 5 patients who discontinued droxidopa before 180 days did so for the following reasons: 3 stopped due to side effects, 1 no longer had nOH symptoms, and 1 died from progressive amyloidosis while still in inpatient care. Follow-up data was not available for the remaining 2 patients out of the original 20.
Adverse Events	Four patients developed supine hypertension requiring anti-hypertensive treatment, one had severe hypertension of 199/120, and one discontinued droxidopa due to hypertension. However, no cardiovascular events, arrhythmias, or other adverse effects were observed during rapid droxidopa titration or the subsequent two weeks, except for one death attributed to amyloidosis.
Study Author Conclusions	In a retrospective cohort of hospitalized, severely ill patients with refractory nOH, supervised rapid titration of droxidopa was safe and effective. Treatment persistence was high, suggesting that symptomatic benefit extended beyond acute intervention.
InpharmD Researcher Critique	As a retrospective chart review study with no control group, the results are observational in nature. Additionally, follow-up data was only available for 18 of the 20 patients included. However, despite the small sample, the study was still able to capture a diverse range of underlying autonomic diagnoses and high rates of comorbidities within this group, helping to reflect real-world clinical experience with different types of patients receiving droxidopa treatment.

References:

McDonell KE, Preheim BA, Diedrich A, et al. Initiation of droxidopa during hospital admission for management of refractory neurogenic orthostatic hypotension in severely ill patients. J Clin Hypertens (Greenwich). 2019;21(9):1308-1314. doi:10.1111/jch.13619

Use of Droxidopa for Hemodynamic Support and Vasopressor Weaning in the Intensive Care Unit
Design	Case report
Case presentation	A 57-year-old female with a history of liver transplant, chronic kidney disease, pulmonary hypertension, and scleroderma was admitted for fluid overload and worsening renal function requiring continuous renal replacement therapy and multiple vasopressors due to persistent hypotension. After failing other therapies, droxidopa was initiated and gradually titrated up to 500 mg TID, allowing for the discontinuation of norepinephrine by hospital day 34. With droxidopa, the patient was successfully transitioned to prolonged intermittent renal replacement therapy and later intermittent hemodialysis, before being discharged home on hospital day 53 continuing droxidopa for outpatient management of her hypotension.
Study Author Conclusions	The addition of enteral droxidopa may be considered as a potential strategy to facilitate vasopressor weaning in ICU patients with persistent hypotension. The use of this oral agent may allow for cost savings by reducing time to ICU discharge and facilitating the use of less resource-dependent dialysis modalities.

References:

Noble M, Sunjic K, Ferguson K. 774: use of droxidopa for hemodynamic support and vasopressor weaning in the intensive care unit. Critical Care Medicine. 2023;51(1):377. doi: 10.1097/01.ccm.0000908828.94115.82