Midodrine for Prevention of Intradialytic Hypotension in High Risk Patients at a Tertiary Referral Hospital: A Retrospective Study

Background: Intradialytic hypotension (IDH) is the most common complication during hemodialysis procedure. Midodrine, an oral α-1 adrenergic agonist, is commonly used to prevent IDH. However, limited data is available to demonstrate midodrine effectiveness in prevention of IDH in high-risk hemodialysis patients. Objective: To describe the clinical outcomes of using midodrine in patients receiving hemodialysis concerning the incidence of IDH. Also, we aimed to explore the appropriate dose for midodrine use to prevent IDH. Methodology A retrospective cohort of adult with end-stage-renal failure. Exposure: Midodrine. Outcomes measure: IDH was defined as a decline in systolic blood pressure (SBP) by ≥20 mmHg or a decline in main arterial pressure (MAP) by ≥10 mmHg during hemodialysis session. Recurrent IDH was defined as three or more episodes of IDH throughout a year of starting midodrine. Analysis: A descriptive analysis of the frequency of IDH and recurrent IDH. We also, compared the risk of recurrent IDH across various doses of midodrine use. Result: From a total of 68-screened patients’ charts, 45 patients were included in the final analysis. 41.8% (n=28) of the study population had an IDH that required additional interventions to restore the SBP and MAP. IDH occurred in 68% (n=19, P=0.03) of patients with hypoalbuminemia. Recurrent IDH occurred in 36% (n=16) of the patients over their hemodialysis procedure. Incidence of treatment failure (57%, p= 0.02) and recurrent IDH (36%, p=0.04) were statistically significant in patients who received midodrine three time per week (57%) in comparison to those who received more than three days per week Conclusion: This exploratory study shows that a considerable proportion of patients receiving midodrine did not develop IDH or recurrent IDH. A long-term follow-up

appropriate dose for midodrine use to prevent IDH. Methodology A retrospective cohort of adult with end-stage-renal failure. Exposure: Midodrine. Outcomes measure: IDH was defined as a decline in systolic blood pressure (SBP) by ≥20 mmHg or a decline in main arterial pressure (MAP) by ≥10 mmHg during hemodialysis session. Recurrent IDH was defined as three or more episodes of IDH throughout a year of starting midodrine. Analysis: A descriptive analysis of the frequency of IDH and recurrent IDH. We also, compared the risk of recurrent IDH across various doses of midodrine use. Result: From a total of 68-screened patients' charts, 45 patients were included in the final analysis. 41.8% (n=28) of the study population had an IDH that required additional interventions to restore the SBP and MAP. IDH occurred in 68% (n=19, P=0.03) of patients with hypoalbuminemia.
Recurrent IDH occurred in 36% (n=16) of the patients over their hemodialysis procedure. Incidence of treatment failure (57%, p= 0.02) and recurrent IDH (36%, p=0.04) were statistically significant in patients who received midodrine three time per week (57%) in comparison to those who received more than three days per week Conclusion: This exploratory study shows that a considerable proportion of patients receiving midodrine did not develop IDH or recurrent IDH. A long-term follow-up 3 study with larger number of patients in comparison to the control group would be useful to evaluate the magnitude of efficacy of midodrine in hemodialysis patients with high risk for IDH. Moreover, a future prospective trial that focus on an important clinical outcomes such as cardiovascular events and mortality with midodrin is warranted.

Background
Intradialytic hypotension (IDH) is the most common complication that is well recognized during hemodialysis, it occurs in around 15% to 50% of hemodialysis patients (1) . IDH is associated with a negative impact on health-related quality of life: because it requires an early termination of the hemodialysis session causing insufficient fluid removal, then increasing the cardiovascular morbidity and mortality (2) . The pathogenesis mechanism of IDH is very complex, but mainly results from an excessive rate of fluid removal than that required for achieving a rate for intravascular filling, which ends in causing an intravascular volume depletion (3) . There is no consensus definition of IDH, however, according to the Kidney Disease Outcomes Quality Initiative and European Best Practice Guidelines, IDH is defined as a decline in systolic blood pressure ≥20 mmHg or a decrease in a mean arterial pressure by 10 mmHg and associated with clinical events like abdominal pain, nausea, vomiting, muscle cramps, dizziness, fatigue, and restlessness (4), (5) . Major factors that contribute to IDH are older age ≥ 65 years, female gender, predialysis systolic blood pressure < 100 mmHg , presence of diabetes mellitus, cardiovascular disease, using a peripheral vasodilator or shortacting antihypertensive medication(s), anemia, uremia, autonomic or neuropathy 4 dysfunction, hypoalbuminemia or poor nutritional status, higher dialysate temperature, or higher ultrafiltration volume (5), (6) . There are numerous therapeutic strategies that have been used to manage IDH with varied degrees of success, including placing the patient in the trendelenburg position, decreasing ultrafiltration rate, elevating dialysate calcium level, using bicarbonatebased dialysate, and giving boluses of intravenous fluids like isotonic saline and colloid solutions (4),(5), (7) . The third-line approach to manage and prevent IDH is using a pharmacological intervention including: Midodrine, Carnitine, or Sertraline (4), (5), (8) . Midodrine is an oral α-1 adrenergic agonist pro-drug with an active metabolite desglymidodrine that increases arteriolar and venous tone which causes a rise in standing, sitting, and supine systolic and diastolic blood pressure (9) . It is effectively cleared by the hemodialysis with reducing in half-life to 1.4 hour in hemodialysis patient (10) . The best data are from a systematic review of 10 literatures revealing that using 2.5 to 10 mg of midodrine given 15-30 minutes before the dialysis elevated the post-dialysis systolic and diastolic blood pressures by 12.4 mmHg and 7.3 mmHg above the values in controls, respectively, and that the nadir systolic and diastolic blood pressure was higher by 13.3 mmHg and 5.9 mmHg compared with the control group, respectively (11) . Midodrine (5 mg twice daily) showed a significant increase in mean arterial pressure among hemodialysis patients with chronic hypotension secondary to autonomic dysfunction as well (12) .
In most circumstances, the usual management of patients with a high risk of IDH requires a various of modalities to prevent IDH. However, more clinical studies are needed to validate the efficacy of one approach over any other . (5) . The objective of this study is to evaluate the efficacy of Midodrine for prevention of IDH in high-risk 5 hemodialysis patients.

Methods
A descriptive retrospective cohort study was approved by the Institutional Review Board in January 2018. It was conducted at a tertiary care center in Riyadh. The medical and pharmacy data used in this study was retrieved from electronic health records for adult patients with end-stage renal disease on hemodialysis who were placed on midodrine. IDH was defined as a decline in SBP by ≥20 mmHg or a decline in MAP by ≥10 mmHg (5) . Recurrent IDH was defined as three or more episodes of IDH throughout a year of starting midodrine. (6) . The risk factors that contributed to IDH were identified through the following variables: patient's age, gender, body mass index (13) , presence of diabetes mellitus, cardiovascular disease, iron deficiency anemia (14) , hypoalbuminemia (8) , neuropathy dysfunction, and uremia (15) . Dose and frequency of midodrine were recorded for each hemodialysis session.

Statistical analyses:
Statistical analyses was performed by using SPSS 19.0 software (IBM, NY, USA).
Categorical data was expressed as percentage and analyzed with chi-square test.
Continuous data was expressed as mean ± SD and compared by the Student's ttest. All statistical assessments was 2-tailed and the level of significance was set to be at p = 0.05. Multiple logistic regression was applied to find the association between using Midodrine with the multiple independent variables such as systolic and diastolic blood pressure, treatment failure, and IDH recurrence.   For the statistical purpose and due to the small number of sample size, midoddrine doses were classified into three groups, 19 patients were received 2.5mg to <5mg, 37 patients were received 5mg, and 38 patients were received >5mg of midodrine.
For the midodrine frequency, it was classified into two groups. (See Figure 1A, 1B). The death event was reported in 23 patients (51.1%), however, the cause of death most likely related to the patient's condition like septic shock (n=9), respiratory distress syndrome (n=1), cardiac arrest (n=2), septic shock with hypotension (n=9), distress syndrome with cardiac arrest (n=1), and septic shock with heart failure (n=1).

Discussion
IDH is the most frequently adverse event that reported during the hemodialysis procedure. Midodrine seems to be gaining favor as a strategy to aid in management and prevention of IDH. (9,10) Midodrine and cool dialysate therapies are the most approaches that have been used. (16,17,18,19) It is worth noting the beneficial effects of midodrine in the treatment of IDH and prevention of recurrent IDH with the adjusting the dialysate composition and reducing the ultrafiltration rate continuously throughout the procedure to assist the vascular refilling. Beside to the correction of the modifiable risk factors like an anemia, hypoalbuminemia, and holding the antihypertensive mediations prior to the hemodialysis session. (20, 21,22.23,24) Interestingly, in 2010 the U.S. Food and Drug Administration proposed to withdraw approval of midodrine due to lacking of post marketing studies to predict the clinical outcome of midodrine rather than just improved the hemodynamic parameters. The proposed withdrawal attained disagreement from the American Society of Nephrology, then FDA came to an agreement to remain FDA-approved on 9 the market in the meantime until pharmaceutical company would conduct two clinical trials to verify a clinical benefit of midodrine. (25,26) The strength of our study that had a larger sample sizes in comparison to the previous studies were they ranged from 6 to 21 patients. And we gave a rough estimation about the rate of death in among hemodialysis patients who received midodrin. The limitation of our study is that we don't have a comparison group.

Conclusion
Our results suggest that receiving of midodrine is significantly increased the intradialytic blood pressure and decreased the intradialytic hypotensive episodes. A future prospective trial that focus on an important clinical outcomes such as cardiovascular events and mortality with midodrin is warranted.
Abbreviations IDH: Intradialytic hypotension; SBP: systolic blood pressure; MAP: main arterial pressure; BID: Twice a day; TID: Three times a day.

Declarations
The authors declare that they have no competing interests Ethics approval and consent to participate: The study protocol was approved by the King Abdullah International Medical Research Center.