What is the role of droxydopa for vasopressor weaning in critically ill patients?

Comment by InpharmD Researcher

Limited data from retrospective studies and case reports suggest droxidopa may be safe and effective for hypotension in critical care patients. 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. Treatments in this study would differ based on the providers' discretion, and critically ill patients may have presented with confounding factors that were not controlled.

Background

A 2024 poster 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]

References:

[1] Webb A, Lauren Casal G, Culshaw J, et al. 940: safety and effectiveness of droxidopa administration for persistent hypotension via gastric tube. Critical Care Medicine. 2024;52(1):S442. doi: 10.1097/01.ccm.0001001924.44320.37

Literature Review

A search of the published medical literature revealed 7 studies investigating the researchable question:

What is the role of droxydopa for vasopressor weaning in critically ill patients?

Level of evidence

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



Please see Tables 1-7 for your response.


 

Droxidopa for Vasopressor Weaning in Critically Ill Patients with Persistent Hypotension: A Multicenter, Retrospective, Single-Arm Observational Study

Design

Multicenter, retrospective, single-arm, observational study

N= 30

Objective

To describe the use of droxidopa for vasopressor weaning in critically ill patients with prolonged hypotension

Study Groups

Patients administered droxidopa (N= 30)

Inclusion Criteria

Age ≥ 18 years, received intravenous vasopressors, received droxidopa for vasopressor weaning

Exclusion Criteria

Prescribed droxidopa prior to admission or received droxidopa for an indication other than assistance with vasopressor weaning

Methods

Patient data were extracted from electronic medical records of two tertiary academic medical center intensive care units (ICU) in Boston, MA. The most common starting dose of droxidopa was 100 mg q8h. 

Duration

Treated between June 2016 to July 2023

Outcome Measures

Primary: time to vasopressor discontinuation (when vasopressors were stopped and remained off for at least 24 h)

Secondary: rates of tachycardia and hypotension post-initiation, norepinephrine equivalents pre- and post-initiation, concomitant oral agent use, dosing

Baseline Characteristics

 

All patients (N= 30)

Age, years (IQR)

62 (54 to 68)

Female

40% 

Race

White

Black

Asian

 

77%

10%

3.3%

Weight, kg

73

Height, m

1.68

Length of stay, days

Hospital

ICU

 

63

44

SOFA score

At admission

At droxidopa initiation

 

4.5

7.0

In hospital mortality

47%

Duration of vasopressors prior to droxidopa, days

16

Vasopressor use during ICU admission

Norepinephrine

Phenylephrine

Vasopressin

Epinephrine

Methylene Blue

Hydroxocobalamin

Dopamine

 

97%

33%

100%

87%

20%

27%

3.3%

IQR, interquartile range; SOFA, sequential organ failure assessment

Results

Endpoint

All patients (N= 30)

Time to vasopressor discontinuation, hours

70 (23 to 192)

Droxidopa dose

At time of vasopressor discontinuation, mg/day (IQR)

Maximum daily dose, mg/day

 

600 (300 to 1125)

2,400

Heart rate, bpm

Pre-initiation

Post-initiation

p-value

 

84

86

0.37

Mean arterial pressure, mmHg

Pre-initiation

Post-initiation

p-value

 

66.5

68.8 

0.008

Norepinephrine equivalents, mcg/kg/min

24 hours pre-initiation

24 hours post-initiation

p-value

 

0.08

0.02

< 0.001

Incidence of tachycardia

Pre-initiation

Post-initiation

p-value

 

17%

22%

0.43

Incidence of hypotension

Pre-initiation

Post-initiation

p-value

 

29%

19%

0.14

 

Adverse Events

See Results

Study Author Conclusions

Droxidopa added as an adjunct vasoactive agent for vasopressor weaning was associated with successful vasopressor discontinuation within a week of initiation in 70.3% of patients with a median time to discontinuation of 70 h. In patients without adequate response to midodrine or other common adjunctive agents, droxidopa could be considered to assist in vasopressor weaning. Further prospective, randomized studies should evaluate the role of droxidopa in vasopressor weaning in critically ill patients against usual care.

InpharmD Researcher Critique

Several confounding variables may have been unaccounted for due to the retrospective nature of the study and the ICU setting. No comparison group was included, hindering the ability to associate outcomes with the use of droxidopa. 



References:

Webb AJ, Casal GL, Newman KA, et al. Droxidopa for Vasopressor Weaning in Critically Ill Patients with Persistent Hypotension: A Multicenter, Retrospective, Single-Arm Observational Study. J Intensive Care Med. Published online August 7, 2024. doi:10.1177/08850666241270089

 

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 from patients who were treated with droxidopa for autonomic impairment. Patients included for analysis met criteria for OH, including a documented systolic decrease of ≥20 mmHg or diastolic decrease of ≥10 mmHg after standing for 1-3 minutes.

Duration

Data collection: October 1, 2014 to May 31, 2017

Outcome Measures

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 blood pressure augmentation after acute spinal cord injury: case reports

Design

 Case series

Case presentation 1

A 64-year-old male suffered a C3–4 fracture-dislocation injury after a fall, resulting in paralysis of his lower extremities,  upper right extremity, and minimal function of his left upper extremity. After urgent C3–4 laminectomies and posterior C3–6 fusion, the patient failed to respond to aggressive fluid resuscitation to meet a target mean arterial pressure (MAP) goal >85 mm Hg. After a tertiary trauma survey revealed hemodynamic instability from hypovolemia was from no other aggravating injury, intravenous (IV) norepinephrine was started to maintain target MAP for 5 to 7 days and treat neurogenic shock. Nasogastric midodrine 10 mg three times daily (TID) failed to facilitate maintenance of MAP while weaning norepinephrine for 4 days, where the patient experienced several episodes of significant bradycardia before midodrine discontinuation.

On post-injury day 5, droxidopa 100 mg TID was initiated, where the patient experienced clinical improvement with improved activation of the proximal upper extremity muscles, and the MAP goal was liberalized to >65 mm Hg. IV norepinephrine was successfully discontinued within 24 hours of droxidopa initiation. Droxidopa was continued for 8 days, where MAP averaged 70 mm Hg without dropping below 65 mm Hg. Additionally, during this time, the patient underwent tracheostomy and percutaneous endoscopic gastrostomy tube placement, secondary to his high cervical injury. The patient was transitioned to a lower level of care within 72 hours of droxidopa initiation. At discharge, droxidopa was discontinued, and his neurological exam was unchanged from presentation. 

Case presentation 2

A 73-year-old male with existing severe cervical spinal stenosis suffered a bicycle crash with hyperflexion injury causing paraplegia secondary to herniated C3–4 and C4–5 disc fragments. Vital signs were notable for sinus bradycardia (40 beats per minute) and relative hypotension (MAP of 65 mm Hg) that did not improve with fluid resuscitation. After a cardiology consult, norepinephrine was initiated to facilitate blood pressure augmentation for neurogenic shock. The patient underwent urgent decompressive laminectomies at C3–5 with posterior fusion, and postoperative norepinephrine was continued and successfully maintained a goal MAP >85 mm Hg for 7 days. Norepinephrine was later transitioned to phenylephrine, and the patient was extubated and was able to tolerate per os intake after a swallow evaluation.

However, after 7 days, the phenylephrine could not be weaned off without MAP dropping < 65 mm Hg. On post-injury day 12, midodrine was started and up-titrated to a total daily dose of 70 mg, resulting in several bradycardic episodes. On post-injury day 18, droxidopa was started at 100 mg twice daily and up-titrated over several days to 300 mg TID. A pacemaker was considered but deferred to first determine the patient's response to droxidopa. Pseudoephedrine was briefly initiated but failed to improve the MAP. Nearly 3 weeks after the initial injury, midodrine was restarted at 20 mg TID in addition to droxidopa 600 mg TID. Norepinephrine was weaned off by post-injury day 27. By post-injury day 32, midodrine and droxidopa were down-titrated to 5 mg TID and 400 mg TID, respectively. The patient was discharged to rehabilitation on this regimen with an improved neurological exam of antigravity strength in elbow flexion and extension bilaterally, as well as antigravity strength in the right lower extremity. At the last follow-up, 4 months after presentation, he remained on droxidopa therapy to maintain normotension (MAP >60 mm Hg).

Study Author Conclusions

Droxidopa may be considered as an enteral agent to augment MAP in patients with autonomic dysfunction from acute traumatic spinal cord injury (SCI) and facilitate the weaning of IV vasopressors. It may be a more optimal option than midodrine for SCI-related hemodynamic pathology due to less risk of bradycardia and, hypothetically, may be particularly suited to patients with pre-existing cardiac co-morbidities. This strategy may avoid pacemaker placement and liberalize stable patients but require continued admission in the intensive care unit for IV vasopressors, which can be costly and human-resource depleting. Further case studies are necessary to define the parameters and dosages for which droxidopa administration may be indicated in patients experiencing hemodynamic instability from autonomic dysfunction after SCI.

 

References:

Hong CS, Effendi MK, Ammar AA, et al. Use of droxidopa for blood pressure augmentation after acute spinal cord injury: case reports. Acute Crit Care. Published online December 7, 2022. doi:10.4266/acc.2021.01662

 

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

 

904: Combination Of Droxidopa and Midodrine For Hemodynamic Augmentation in Acute Spinal Cord Injury

Design

Case report

Case presentation

A 2022 poster presentation abstract published in the Society of Critical Care Medicine presents a case of a 73-year-old male with existing severe cervical spinal stenosis who presented with paraplegia from a bicycle crash that fractured the spine. After posterior spine infusion, the patient was placed on intravenous vasopressor with norepinephrine (NE) to maintain mean arterial pressure (MAP) of > 85 mmHg. Attempts at weaning were unable to maintain MAP > 65 mmHg, attributed to autonomic dysfunction. On day 12 after the operation, midodrine 70 mg daily was administered to wean off NE, which resulted in bradycardia (20-30 beats per minute). On day 18, droxidopa 100 mg BID was started and titrated up to 300 mg TID. Midodrine 20 mg TID was restarted on day 21, along with up-titrating droxidopa to 600 mg TID which allowed for weaning off NE on day 27.

On day 32, the midodrine and droxidopa were tapered to 5 mg TID and 400 mg TID, respectively, and the patient was successfully discharged for rehabilitation.

Study Author Conclusions

Enteral droxidopa combination therapy with midodrine may be considered to augment MAP in patients with autonomic dysfunction post-acute spinal cord injury and facilitate weaning of vasopressors. This strategy may avoid pacemaker placement and liberalize stable patients that require continued admission in the intensive care unit for intravenous vasopressors, which can be cost-ineffective and human resource-depleting. 

 

References:

Ammar A, Hong C, Koo A, et al. 904: combination of droxidopa and midodrine for hemodynamic augmentation in acute spinal cord injury. Critical Care Medicine. 2022;50(1):448-448. doi:10.1097/01.ccm.0000809940.38528.14

 

Droxidopa for Hypotension of Different Etiologies: Two Case Reports

Design

Case report

Case presentation

A 75-year-old Caucasian female presented to the emergency department (ED) after being found on the floor for over 24 hours. Based on clinical and laboratory parameters, including blood pressure of 70/50 mmHg, she was suspected of having systemic inflammatory response syndrome and was treated with norepinephrine (NE) 30 mcg/min along with sodium bicarbonate, vancomycin, meropenem, packed red blood cells, along with fluid resuscitation. However, the patient developed respiratory failure and required intubation with CT scan revealing a T8 compression fracture. 

Her stay continued to be complicated, which included development of rhabdomyolysis and amputation of the right leg due to lost perfusion. To maintain BP, the patient was consistently on NE up to 30 mcg/min and vasopressin 2.4 units/hr. Her progress continued to decline with acute kidney failure and periodic hypotensive episodes requiring intermittent NE support. After day 24, she was initiated on midodrine 5 mg TID for BP support but failed to discontinue NE despite initial improvement. After 11 days of failed treatment with midodrine, the patient switched to droxidopa 100 mg TID but experienced more hypotension after the second dose. Eventually, droxidopa was titrated up to 300 mg TID to maintain BP response which was discontinued after receiving two doses. The patient restarted on midodrine 15 mg PO TID which led to eventual weaning of NE 11 days afterward. She was eventually discharged to a rehabilitation facility with BP of 120/55 mmHg and heart rate of 101 beats per minute.

Study Author Conclusions

Although the droxidopa trial was unsuccessful in this patient, she may have benefited from a decreased dose of midodrine (starting at the lowest dose of 2.5 mg TID) with concurrent droxidopa administration (starting at 100 mg TID). These two medications have different mechanisms of action and can have an additive effect.

 

References:

Oommen J, Chen J, Wang S, Caraccio T, Hanna A. Droxidopa for Hypotension of Different Etiologies: Two Case Reports. P T. 2019;44(3):125-144.