Netherlands Journal of Critical Care

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

Midodrine for ICU patients suffering from refractory hypotension

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 , an oral α1-receptor agonist, in two patients suffering from refractory hypotension.

Keywords - midodrine, hypotension, intensive care, inotropic therapy

Introduction tient developed severe renal insufficiency that required the start Persistent hypotension is a common problem in intensive care unit of intermittent haemodialysis which was complicated by severe (ICU) treatment. Hypotension is caused either by a low systemic hypotension. The patient was transferred to the ICU and treat- vascular resistance (sepsis, spinal shock, vasodilatory medica- ment with and continuous venovenous haemo- tion), low stroke volume (hypovolaemia, adrenal insufficiency, filtration (CVVH) was started. After 3 weeks a peritoneal dialysis tachyarrhythmia, tamponade, high PEEP, pulmonary embolism, (PD) catheter was implanted and PD was started. Despite the right and left sided heart failure, valvular dysfunction) or low heart discontinuation of CVVH the patient remained dependent on in- rate. Chronic hypotension and inotropic dependency is less com- travenous vasopressor therapy. Oral ibopamine was added to mon. Treatment can be challenging when blood pressure remains the medication but the patient developed ventricular tachycardia low due to continuous or intermittent haemodialysis. within 24 hours. Following this the patient was started on oral This report covers two hypotensive patients who are both suf- , which was soon discontinued due to side effects. Fi- fering from renal insufficiency with concurrent heart disease. In nally, we decided to introduce oral midodrine which was started addition, the introduction of midodrine therapy is discussed. 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 Case A from the ICU using midodrine 10 mg tid. A 60-year-old man was referred to the department of internal medicine because of a six-month history of fatigue and recurrent Case B infections. His medical history was positive for chronic obstruc- A 76-year-old man was admitted to the ICU following aortic valve tive pulmonary disease and he was not taking any medication. replacement. He had a medical history of coronary surgery (1978), After bone marrow examination, the diagnosis of multiple my- redo-coronary surgery (1991), severe aortic valve calcification eloma, stage Ia according to the Durie-Salmon staging system, and stenosis, reduced left ventricular function, and renal failure was made. During induction chemotherapy and autologous stem due to familial polycystic kidney disease. Intermittent haemodi- cell transplantation the patient gained weight and developed alysis was started in May 2008. One day post-surgery CVVH was shortness of breath. Transthoracic echocardiography (E/A < 1; initiated. However, profound hypotension associated with CVVH Deceleration time > 220 msec; E’ 6.4 cm/sec; E/E’ 13.8) and therapy forced us to start intravenous norepinephrine which was cardiac MRI (Figure 1 and http://www.nvic.nl/njcc.php) demon- later replaced by as the patient experienced severe strated severe hypertrophy of the left and right ventricles as well peripheral vasoconstriction. After 2 weeks the dopamine treat- as a hypertrophic interatrial septum, causing diastolic dysfunc- ment was tapered. However, the patient’s systolic blood pres- tion with delayed relaxation. The late enhancement pattern was sure dropped below 55-60 mm Hg. Intravenous inotropic treat- highly suggestive of cardiac amyloidosis. Furthermore, the pa- ment was reintroduced. Three days later, midodrine 2.5 mg tid was initiated and the patient was weaned from inotropic support. Correspondence CVVH therapy was terminated and after 33 days in the ICU the patient was discharged. The final invasive blood pressure before RMA van de Wal discharge was 124/69 mm Hg. E-mail: [email protected]

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Discussion be prolonged three times. Importantly, haemodialysis effectively Common causes of hypotension in patients in the ICU are sep- removes both the prodrug and active metabolite [5]. In patients sis, the use of vasodilatory medication, and adrenal insufficiency. with a normal renal function the usual starting dose is 2.5 mg tid. Both patients in this report did not use antihypertensive or va- The dose can be gradually increased up to 10 mg tid. In a previ- sodilatory medication. Furthermore, infection was ruled out as a ous report, the pharmacokinetic characteristics of the prodrug possible cause of hypotension and the blood pressure of both and its active metabolite in a dialysis patient approximated those patients did not react to treatment with hydrocortisone. reported for patients with normal renal function [6]. This seems to 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 Figure 1. Steady-state free precession (SSFP) image during a) autonomic nervous system. In case report A, we present a patient diastole and b) systole showing severe thickened left ventricular suspected of cardiac amyloidosis who simultaneously suffered walls with preserved systolic function (kissing walls in systole). from end stage renal failure, initially leading to CVVH and later There is also hypertrophy of the right ventricle and interatrial to PD. Both amyloidosis and haemodialysis have been associ- septum and pleural effusion. 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 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 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]. A Theoretically, the calcium sensitizer 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 , such as . Peak levels of the active metabolite in serum are achieved in 1 hour and its half-life is approximately 3 B hours. In patients with end stage renal disease, the half-life will

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suggest that similar dosing schedules could be used for patients investigation, midodrine has also been studied in the treatment on dialysis. In patients with end stage renal disease who are not of dialysis induced hypotension [9,10]. Unfortunately, these stud- on dialysis, the dose is not yet clear and great care should be ies were small and not always randomized. While there are no taken when midodrine is administered in these patients. Several known studies in patients on peritoneal dialysis, trials in patients side effects have been reported, such as scalp paraesthesias, on haemodialysis have shown that midodrine is safe and can be heartburn, flushing, headache, urinary retention, supine - hyper useful in the treatment of symptomatic dialysis-related hypoten- tension, neck soreness and weakness. However, please note that sion [11]. To our knowledge no studies have been published that none of our patients experienced any of these side effects. describe the use of midodrine as a replacement therapy for intra- Midodrine is known to increase glomerular pressure and has venous inotropic or vasopressive agents. been used therapeutically to reverse endogenous vasodilators that result in low glomerular pressure in hepatorenal syndrome Conclusion [7]. Furthermore, midodrine has been prescribed for the treat- In these case reports, we have described the successful intro- ment of neurogenic orthostatic hypotension in patients with duction of midodrine as an oral alternative for low-dose intrave- spinal cord injury, for patients with neurocardiogenic syncope, nous inotropic or vasopressive therapy in patients in the intensive for the treatment of hypotension associated with carotid artery care unit. stenting, and for several other indications [8]. Although still under

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