Fluid accumulation and ascites are nearly universal in patients with decompensated liver disease, and their development in a cirrhotic patient generally portrays poor prognosis.1,2 The current hypothesis on the pathophysiology of ascites is that profound vasodilatation and hyper-dynamic circulatory dysfunction induce reflex activation of the neurohormonal systems, nonosmotic release of antidiuretic hormone, and activation of the renin-angio-tensin-aldosterone system (RAAS) with subsequent renal retention of sodium and water. Large-volume paracentesis (LVP), which removes at least 5 L of ascitic fluid, is used in patients with cirrhosis and tense ascites. When this treatment is used alone, it induces systemic vasodilatation and a decrease in effective arterial blood volume, and it is associated with impaired renal function and increased activity of the RAAS in approximately 80% of cases.3 Previous studies suggest that administration of a vasocontrictor may be effective in preventing the hemodynamic alterations caused by paracentesis-induced circulatory dysfunction (PICD).4–6
Midodrine hydrochloride, an α1-agonist, increases effective circulating blood volume and renal perfusion by increasing systemic and splanchnic blood pressure.4 Midodrine is a prodrug that is absorbed from the gastrointestinal tract and metabolized by the liver into an active metabolite, desglymidodrine. Midodrine is an orally available, α-adrenergic agonist approved by the US Food and Drug Administration to treat symptomatic orthostatic hypotension. Investigations of midodrine alone or in combination have shown conflicting results for systemic and renal hemodynamics and renal function in patients with cirrhosis-related complications.7
Sourianarayanane and colleagues report the beneficial effect of midodrine in hypotensive cirrhotic patients with refractory ascites.8 One patient had been on hemodialysis for HIV-related nephropathy. The other patient had hepatorenal syndrome (HRS) requiring hemodialysis. In both cases, midodrine was apparently initiated to treat hypotension. In these 2 patients, the addition of midodrine was found to be beneficial, causing a decrease in both the frequency of LVP and the volume of ascitic fluid drained. However, the report is unclear about the starting dose for the first patient and how it was titrated upward. In addition, the report does not address why different doses were given to these 2 patients. Furthermore, we do not know if these patients experienced any side effects from midodrine.
Angeli and colleagues were the first to report the utility of midodrine to treat renal dysfunction in patients with cirrhosis.9 Their results suggest that oral administration of midodrine is associated with significantly improved systemic hemodynamics in nonazotemic cirrhotic patients with ascites.9 In patients with type 2 HRS, however, midodrine has modest effects on systemic hemodynamics and no effect on renal hemodynamics or renal function. A subsequent study showed that long-term administration of midodrine in combination with octreotide is safe and effective in individuals with type 1 HRS.10 In another study, a combination of midodrine, octreotide, and albumin was administered until the serum creatinine level was below 1.5 mg/dL for at least 3 days. This endpoint was achieved in 70% of patients with type 1 HRS.11
Administration of a vasoconstrictor may be a viable therapeutic approach for improving the systemic and splanchnic vasodilatation involved in PICD.3 Kalambokis and colleagues reported the effects of a 7-day treatment with midodrine in nonazotemic cirrhotic patients with and without ascites.5 Midodrine was administered at a dose of 10 mg TID for 7 days and was found to improve systemic hemodynamics and increase natriuresis in these patients. In patients with ascites, but not those without ascites, these effects were associated with a suppression of RAAS activity, suggesting that improvement in sodium excretion is related to improvement in effective arterial blood volume.
Two studies compared midodrine to intravenous albumin for preventing PICD in patients with cirrhosis and refractory ascites.6,12 In a study of 24 patients, 11 patients were randomized to receive midodrine administered at a dose of 12.5 mg every 8 hours for 2 days following 8 L of paracentesis.12 Compared to patients who received albumin (n=13), more patients in the midodrine group had PICD, suggesting that midodrine is not necessarily effective in preventing circulatory dysfunction following LVP. However, another study showed that midodrine is as effective as intravenous albumin if its dose is titrated to maintain adequate blood pressure.6 In this study, midodrine was administered at a dose of 5–10 mg every 8 hours to maintain a mean arterial pressure 10 mmHg above baseline for 72 hours.
Another study investigated the effect of a 1-month course of therapy with midodrine, octreotide-LAR, and albumin in patients with refractory ascites.4 The authors observed a significant reduction in plasma renin and aldosterone concentration and a trend toward a reduction in the volume of ascitic fluid removed by paracentesis without an effect on renal function. However, there was deterioration in Model for End-Stage Liver Disease scores during treatment due to a reversible increase in international normalized ratio and a trend toward an increase in bilirubin level.
Upon surveying the literature, it appears that midodrine has been explored for many indications in patients with cirrhosis; in large part, however, studies have yielded conflicting results, making it difficult to definitively conclude what role midodrine should play in this patient population (Table 1).4–6,9–14 In our practice, we consider midodrine therapy for cirrhotic patients with persistently low blood pressure (systolic pressure <90 mmHg) and patients with early type 1 HRS. When we administer midodrine for patients with type 1 HRS, we administer it in combination with octreotide and albumin. Based upon our anecdotal experience, as well as our interpretation of the published literature, midodrine is not useful to prevent PICD or to improve the natriuretic effect of loop diuretics. Rigorous studies are needed to investigate the precise role of this drug in the management of complications related to cirrhosis; unfortunately, funding agencies and the pharmaceutical industry traditionally have not invested in the management of end-stage liver disease.
Table 1.
Summary of Select Studies Using Midodrine for Various Indications in Patients with Liver Cirrhosis
| Indication | Reference | Concomitant drugs | Results |
|---|---|---|---|
| Type 1 HRS | Angeli P, et al10 | Octreotide, albumin | Effective |
| Wong F, et al11 | Octreotide, albumin | Reduction of serum creatinine level | |
| Type 2 HRS | Angeli P, et al9 | Modest effect on SH No effect on RF |
|
| Natriuretic effect | Kalambokis G, et al5 | Improved SH and sodium excretion | |
| Misra VL, et al13 | IV furosemide | No increase in natriuretic response to furosemide | |
| PICD | Singh V, et al6 | As effective as albumin | |
| Appenrodt B, et al12 | Not as effective as albumin | ||
| Refractory ascites | Tandon P, et al4 | Octreotide, albumin | Reduction in the volume of ascites removed No effect on RF Reversible deterioration in MELD score |
| Post-LT renal outcomes | Rice J P, et al14 | Octreotide, albumin | Pre-LT treatment did not have superior post-LT renal function |
- HRS
hepatorenal syndrome
- IV
intravenous
- LT
liver transplantation
- MELD
Model for End-Stage Liver Disease
- PICD
paracentesis-induced circulatory dysfunction
- RF
renal function
- SH
systemic hemodynamic.
Footnotes
This commentary was supported in part by a HAESF Senior Leaders & Scholar Fellowship to Dr. Werling.
References
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