Netherlands Journal of Critical Care

NETH J CRIT CARE - VOLUME 14 - NO 1 - FEBRUARY 201036

Introduction

Persistent hypotension is a common problem in intensive care unit

(ICU) treatment. Hypotension is caused either by a low systemic

vascular resistance (sepsis, spinal shock, vasodilatory medica-

tion), low stroke volume (hypovolaemia, adrenal insufficiency,

tachyarrhythmia, tamponade, high PEEP, pulmonary embolism,

right and left sided heart failure, valvular dysfunction) or low heart

rate. Chronic hypotension and inotropic dependency is less com-

mon. Treatment can be challenging when blood pressure remains

low due to continuous or intermittent haemodialysis.

This report covers two hypotensive patients who are both suf-

fering from renal insufficiency with concurrent heart disease. In

addition, the introduction of midodrine therapy is discussed.

Case A

A 60-year-old man was referred to the department of internal

medicine because of a six-month history of fatigue and recurrent

infections. His medical history was positive for chronic obstruc-

tive pulmonary disease and he was not taking any medication.

After bone marrow examination, the diagnosis of multiple my-

eloma, stage Ia according to the Durie-Salmon staging system,

was made. During induction chemotherapy and autologous stem

cell transplantation the patient gained weight and developed

shortness of breath. Transthoracic echocardiography (E/A < 1;

Deceleration time > 220 msec; E’ 6.4 cm/sec; E/E’ 13.8) and

cardiac MRI (Figure 1 and http://www.nvic.nl/njcc.php) demon-

strated severe hypertrophy of the left and right ventricles as well

as a hypertrophic interatrial septum, causing diastolic dysfunc-

tion with delayed relaxation. The late enhancement pattern was

highly suggestive of cardiac amyloidosis. Furthermore, the pa-

tient developed severe renal insufficiency that required the start

of intermittent haemodialysis which was complicated by severe

hypotension. The patient was transferred to the ICU and treat-

ment with norepinephrine and continuous venovenous haemo-

filtration (CVVH) was started. After 3 weeks a peritoneal dialysis

(PD) catheter was implanted and PD was started. Despite the

discontinuation of CVVH the patient remained dependent on in-

travenous vasopressor therapy. Oral ibopamine was added to

the medication but the patient developed ventricular tachycardia

within 24 hours. Following this the patient was started on oral

caffeine, which was soon discontinued due to side effects. Fi-

nally, we decided to introduce oral midodrine which was started

at a low dose of 2.5 mg three times daily (tid). After more than 60

days, the patient was weaned off norepinephrine and discharged

from the ICU using midodrine 10 mg tid.

Case B

A 76-year-old man was admitted to the ICU following aortic valve

replacement. He had a medical history of coronary surgery (1978),

redo-coronary surgery (1991), severe aortic valve calcification

and stenosis, reduced left ventricular function, and renal failure

due to familial polycystic kidney disease. Intermittent haemodi-

alysis was started in May 2008. One day post-surgery CVVH was

initiated. However, profound hypotension associated with CVVH

therapy forced us to start intravenous norepinephrine which was

later replaced by dopamine as the patient experienced severe

peripheral vasoconstriction. After 2 weeks the dopamine treat-

ment was tapered. However, the patient’s systolic blood pres-

sure dropped below 55-60 mm Hg. Intravenous inotropic treat-

ment was reintroduced. Three days later, midodrine 2.5 mg tid

was initiated and the patient was weaned from inotropic support.

CVVH therapy was terminated and after 33 days in the ICU the

patient was discharged. The final invasive blood pressure before

discharge was 124/69 mm Hg.

RMA van de wal1, MJ Swaans1, VH Deneer2, H Biemond-Moeniralam3,4, AJ Meinders3,4

1 Department of Cardiology, St. Antonius Hospital, Nieuwegein, The Netherlands

2 Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands

3 Department of Anaesthesiology, Intensive Care and Pain Management, St. Antonius Hospital, Nieuwegein, The Netherlands

4 Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands

Abstract - Hypotension is a common clinical problem in the intensive care unit, and intravenous inotropic or vasopressor therapy is

often necessary. In dialysis-dependent patients the process of tapering the dose of intravenous inotropics can be complicated by refrac-

tory hypotension. The two cases described in this report outline the successful introduction of midodrine, an oral α1-receptor agonist,

in two patients suffering from refractory hypotension.

Keywords - midodrine, hypotension, intensive care, inotropic therapy

Copyright © 2010, Nederlandse Vereniging voor Intensive Care. All Rights Reserved. Received July 2009; accepted November 2009

Midodrine for ICU patients suffering from refractory hypotension

CASE REPORT

RMA van de Wal

E-mail: rumwal@hotmail.com

Correspondence

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NETH J CRIT CARE - VOLUME 14 - NO 1 - FEBRUARY 2010 37

Netherlands Journal of Critical Care

Midodrine for ICU patients suffering from refractory hypotension

Discussion

Common causes of hypotension in patients in the ICU are sep-

sis, the use of vasodilatory medication, and adrenal insufficiency.

Both patients in this report did not use antihypertensive or va-

sodilatory medication. Furthermore, infection was ruled out as a

possible cause of hypotension and the blood pressure of both

patients did not react to treatment with hydrocortisone.

Cardiac involvement is frequent in systemic amyloidosis, of-

ten leading to diastolic dysfunction and restrictive cardiomyopa-

thy [1]. In addition, amyloidosis may induce dysfunction of the

autonomic nervous system. In case report A, we present a patient

suspected of cardiac amyloidosis who simultaneously suffered

from end stage renal failure, initially leading to CVVH and later

to PD. Both amyloidosis and haemodialysis have been associ-

ated with hypotension. In this particular case, ultrafiltration in-

duced plasma depletion, probably causing inadequate filling of

a hypertrophic heart muscle, which when combined with an im-

paired compensatory increase in sympathetic tone led to severe

hypotension [2]. In order to induce appropriate vasoconstriction

norepinephrine was started. After unsuccessful oral treatment

with the dopamine agonist ibopamine and the adenosine recep-

tor antagonist caffeine, this patient (A) was treated with mido-

drine. Norephinephrine was successfully discontinued. In case B,

the pathophysiological mechanism underlying the patient’s low

blood pressure also involved diastolic dysfunction. However, in

this patient hypertrophy and impaired relaxation of the left ven-

tricle were caused by severe aortic stenosis. Furthermore, his left

ventricular systolic function was impaired.

Instead of using sympathicomimetic amines in the initial

stage of stabilization, treatment with the phosphodiesterase III

inhibitor enoximone could have been effective for this patient.

Given the underlying pathophysiological considerations, the

α-sympathicomimetic properties of norepinephrine were pre-

ferred over the vasodilatory effects of enoximone in patient A [3].

Theoretically, the calcium sensitizer levosimendan could become

an alternative therapy for similar patients in the future. It appears

to be more beneficial and it has also proved to be energetically

less disadvantageous for the myocardium than existing inotropic

agents [4]. Both enoximone and levosimendan could potentially

have been effective in the stabilization of patient B as his left

ventricular function was impaired. After stabilization, patient B

was treated with low-dose midodrine and he was able to resume

intermittent dialysis after a post-operative interval of CVVH.

Midodrine is a selective α1-receptor agonist and is a prod-

rug of 1-(2´5´-dimethoxyphenyl)-2-aminoethanol (DMAE) that

combines glycine by a peptide bond. After oral administration,

the bioavailability of midodrine is reported to be approximately

100%, whereas that of DMAE is approximately 50%. The me-

tabolite increases peripheral resistance by inducing constriction

of both arterial and venous capacitance vessels and it prevents

venous pooling of the blood thus increasing blood pressure. Its

action is identical to that of other α1-adrenoceptor stimulants,

such as phenylephrine. Peak levels of the active metabolite in

serum are achieved in 1 hour and its half-life is approximately 3

hours. In patients with end stage renal disease, the half-life will

be prolonged three times. Importantly, haemodialysis effectively

removes both the prodrug and active metabolite [5]. In patients

with a normal renal function the usual starting dose is 2.5 mg tid.

The dose can be gradually increased up to 10 mg tid. In a previ-

ous report, the pharmacokinetic characteristics of the prodrug

and its active metabolite in a dialysis patient approximated those

reported for patients with normal renal function [6]. This seems to

Figure 1. Steady-state free precession (SSFP) image during a)

diastole and b) systole showing severe thickened left ventricular

walls with preserved systolic function (kissing walls in systole).

There is also hypertrophy of the right ventricle and interatrial

septum and pleural effusion.

A

B

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NETH J CRIT CARE - VOLUME 14 - NO 1 - FEBRUARY 201038

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References

suggest that similar dosing schedules could be used for patients

on dialysis. In patients with end stage renal disease who are not

on dialysis, the dose is not yet clear and great care should be

taken when midodrine is administered in these patients. Several

side effects have been reported, such as scalp paraesthesias,

heartburn, flushing, headache, urinary retention, supine hyper-

tension, neck soreness and weakness. However, please note that

none of our patients experienced any of these side effects.

Midodrine is known to increase glomerular pressure and has

been used therapeutically to reverse endogenous vasodilators

that result in low glomerular pressure in hepatorenal syndrome

[7]. Furthermore, midodrine has been prescribed for the treat-

ment of neurogenic orthostatic hypotension in patients with

spinal cord injury, for patients with neurocardiogenic syncope,

for the treatment of hypotension associated with carotid artery

stenting, and for several other indications [8]. Although still under

investigation, midodrine has also been studied in the treatment

of dialysis induced hypotension [9,10]. Unfortunately, these stud-

ies were small and not always randomized. While there are no

known studies in patients on peritoneal dialysis, trials in patients

on haemodialysis have shown that midodrine is safe and can be

useful in the treatment of symptomatic dialysis-related hypoten-

sion [11]. To our knowledge no studies have been published that

describe the use of midodrine as a replacement therapy for intra-

venous inotropic or vasopressive agents.

Conclusion

In these case reports, we have described the successful intro-

duction of midodrine as an oral alternative for low-dose intrave-

nous inotropic or vasopressive therapy in patients in the intensive

care unit.

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