The Mystery of the Dry Weight: Plasma Refill, Ultrafiltration Rates and Hematocrit Sensor

1. The Mystery of the Dry Weight: Plasma Refill, Ultrafiltration Rates and Hematocrit Sensor John Wigneswaran MD Chief Medical Officer CHF Solutions Inc. Edward Rychlick Co-Inventor/Engineer CHF Solutions Inc.

2. Challenges • No practical means of determining or defining euvolemia (or “dry weight”) • Challenges with current standard of care with regards to appropriate dosing and adverse effects • The Tortoise or the Hare?

3. S Y M P T O M S Abnormal lung function Respiratory muscle dysfunction Other factors  RV + RA pressure •  Hydrostatic pressure •  Oncotic pressure •  Permeability • Lymphatic drainage capacity • Alveolar-capillary membrane integrity Increase PA pressure Increased PCWP (congestion )  LA and LV diastolic pressure LVDP + Impaired volume regulation MitralRegurgitation Abnormal LV function (Sys and/or Dia) Symptoms: The Tip of the Congestion Iceberg in Heart Failure Systemic congestion(JVD, edema) Dyspnea Alveolar edema Redistribution in pulmonary vascular bed+ Interstitial edema

4. Euvolemia1 or “Dry Weight” Cardiac: • Defined as the weight at which dyspnea is relieved Renal: • OR Dry Weight is currently defined as the lowest weight a patient can tolerate without the development of symptoms, hypotension or renal failure 1. Metha et.al J Am Soc Nephrol 10:392-403, 1999

5. Assessing Volume Status1 • The capacity of body compartments (e.g., extracellular fluid [ECF] and intracellular fluid [ICF] • The amount of water in each compartment • The solute content (e.g., sodium), which may affect fluid shifts between compartments, interdialytic weight gain, and have an effect on the success of fluid removal during HD. Tools • Neuromarkers: ANP, cGMP • Echocardiogram (Vena Cava Diameter) • Bioimpedence tenchiques • Blood Volume Monitoring 1. Metha et.al J Am Soc Nephrol 10:392-403, 1999

6. Fluid Removal by Ultrafiltration Interstitial Space (edema) • Ultrafiltration can remove fluid from the blood at the same rate that fluid can be naturally recruited from the tissue • The transient removal of blood illicits compensatory mechanisms, termed plasma or intravascular refill (PR), aimed at minimizing this reduction1,2 Na P H2O Na K UF K PR P Vascular Space Na Vascular Space Na 1. Lauer et al. Arch Intern Med. 1983;99:455-460. 2. Marenzi et al. J Am Coll Cardiol. 2001;38:4.

7. Plasma Refill Mechanism • Fluid withdrawn from vascular compartment • Transient reduction in blood volume1,2 • Plasma Refill serves to mitigate this reduction from over-hydrated interstitium a. Hydrostatic and Oncotic forces between vascular/interstitial compartments 4. Other compensatory mechanisms include RAAS and SNS (impaired in ADHF/CKD) • J Am Coll Cardiol 2001;38:963-8 • Ann Int Med 1983;99:455-60 • Am Heart J 1979;98:567-71

8. Neurohormonal Activation by Modality Ultrafiltration: • Fluid mobilization from the vascular to interstitial compartment 12-14 cc/min1 Diuretics • Loop diuretics inhibit the Na/KCl pump in the loop of henle, including the macula densa, and thus ALWAYS stimulate the RAAS2 Neurohormonal Activation has been associated with poor outcomes3,4 • Fauchold P. Contrib Nephrol 1989;74:170-5; 2. Schrier J Am Coll Cardiol 2006;47:1-8; 3. Smilde Am Heart J 2004;148:165-72; 4. McCurley J Am Coll Card 2004;44:1301-7

9. + 170 – + 80 – + 40 – % 0 – - 40 - Effects of Ultrafiltration vs IV Furosemide Neurohormones NE PRA ALD • + 80 – • + 40 – • % 0 – • 140 – • + 80 – • + 40 – • % 0 – • 140 – d 0 1d 2d 3d 4d 3m d 0 1d 2d 3d 4d 3m d 0 1d 2d 3d 4d 3m Triangles = Ultrafiltration Squares = Furosemide Agostoni et al. Am J Med. 1994;96:191-199.

10. D PV (%) 10 – 5 – 0 – –5 – –10 – Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF PRR (mL/min) 20 – 15 – 10 – 5 – 0 – Before UF 1 liter 2 liter 3 liter 4 liter After UF 24h after UF Changes in Plasma Volume and Refilling Rate During Ultrafiltration • Ultrafiltration can be done safely without significant changes in plasma volume • Plasma refill rates may decrease as volume removal continues Marenzi et al. J Am Coll Cardiol. 2001;38:963-968.

11. Ultrafiltration Rates • Disease State • ADHF (200-250 cc/hr) • Right Sided Heart Failure (50-100cc/hr) • Cirrhosis/Hepatorenal syndrome • Hypoalbuminemic States • Cardiogenic Shock • Severe Renal Failure(>3 mg/dl) • Acuity • Impending intubation • Outpatient

12. Strategies for Success • Choose Appropriate Rate • Choose Appropriate Goal • Realize the Clinical Rules of Fluid Removal are the same • Create a favorable environment • Hold non-essential blood pressure medications • Decide early (avoid diuretic toxicity) • Consider holding Ace-inhibitors/ARBS

13. Setting the Fluid Removal Rate F • Users must set the fluid removal rate from 0 to 500 mL/hour in increments of 10 mL/hour. Default is 0 mL/hour. The average is 250 mL/hour*. • Press the UF RATE key • Press Arrow UP or DOWN keys (▼▲) • Press ACCEPT. • With this feature, our users can set and adjust the fluid removal rate that is best for the patient. • * Patients in volume sensitive states (e.g. right heart failure, pulmonary distress, hepatic disease, cardiogenic shock) usually require rates lower than the average (e.g. 50-150 ml/hour). Monitor patient for clinical signs of hypovolemia and hypotension as appropriate.

14. Appropriate Removal Rate Extravascular Setting the fluid removal rate to not exceed the plasma refill rate (PRR) will minimize risk of hypovolemia, hypotension, etc. Periodic monitoring of the systolic blood pressure or enabling the Hematocrit Monitoring feature and setting specific limits that would warrant a reduction in the fluid removal rate (UFR) prevents this from occurring. Plasma Refill Rate Intravascular Vascular Space UFR UFR ≤ PRR For details, refer to your Aquapheresis Standing Orders.

15. Appropriate Removal Rate • NET Fluid removal at a rate of _____ mL/hr (10-500 mL/hr) for ____ hours OR until _____ liters of fluid removed. • The average removal rate is approximately 250 ml/hour. • Monitor patient for clinical signs of hypovolemia and hypotension as appropriate. • Vital signs Q 15 minutes x 4, then q1 hour for duration of treatment Intravascular Vascular Space

16. Proven technology and results • Used for years in extracorporeal therapies, such as: • hemodialysis, apheresis, and cardiopulmonary bypass • “Base technology” – used in over 200,000 treatments/year • Automated, Simplified, and integrated into the next generation of the Aquapheresis console • By monitoring Hct during Aquapheresis, • changes in blood volume can be estimated • volume depletion can be detected earlier • drops in blood pressure or creatinine rises can be prevented Hematocrit Monitoring

17. AUTOMATICALLY limits the fluid removal rate to help prevent volume depletion due to high ultrafiltration rates and extended treatment times. Hematocrit Monitoring (Hct) • “Never too fast, never too much” • Analogy: Thermostat in your Home

18. What clinical literature supports Hct Monitoring? • Data supporting the use of inline, continuous hematocrit monitoring is extensive. A brief sampling follows: • Dasselaar JJ, Huisman RM, DE Jong PE, Franssen CF. Relative blood volume measurements during hemodialysis: Comparisons between three noninvasive devices. Hemodial Int. 2007;11(4):448-455. • De Vries JPPM, Kouw PM, van der Meer NJM, Olthof CG, Oe LP, Donker AJM, de Vries PMJM. Non-invasive monitoring of blood volume during hemodialysis: Its relation with postdialytic dry weight. 1993 Kidney Int 44:851-854. • De Vries JP, Donker AJ, De Vries PM. Prevention of hypovolemia-induced hypotension during hemodialysis by means of an optical reflection method. Int J Artif Organs. 1994 Apr;17(4):209-14. • Kim KE, Neff M, Cohen B, Somerstein M, Chinitz J, Onesti G, Swartz C: Blood volume changes and hypotension during hemodialysis. Trans Amer Soc Artif Int Organs 197016:508-514. • Lopot F. Clinical use of continuous blood volume monitoring. EDTNA ERCA J. 1996;22(4):7-11. • Marenzi G, Lauri G, Grazi M, Assanelli E, Campodonico J, Agostoni P: Circulatory response to fluid overload removal by extracorporeal ultrafiltration in refractory congestive heart failure. J Am Coll Cardiol. 2001 Oct;38(4):963-8. • Prakash S, Reddan D, Heidenheim AP, Kianfar C, Lindsay RM. Central, peripheral, and other blood volume changes during hemodialysis. ASAIO J. 2002;48(4):379-82. • Ronco C, Bellomo R, Ricci Z. Hemodynamic Response to Fluid Withdrawal in Overhydrated Patients Treated with Intermittent Ultrafiltration and Slow Continuous Ultrafiltration: Role of Blood Volume Monitoring. Cardiology 2001;96:196–201 • Schroeder KL, Sallustio JE, Ross EA. Continuous haematocrit monitoring during intradialytic hypotension: Precipitous decline in plasma refill rates. Nephrol Dial Transplant. 2004;19(3):652-656. • Shulman T, Heidenheim AP, Kianfar C, Shulman SM, Lindsay RM. Preserving central blood volume: changes in body fluid compartments during hemodialysis. ASAIO J. 2001 Nov-Dec;47(6):615-8. • Steuer RR, Harris DH, Conis JM. A new optical technique for monitoring hematocrit and circulating blood volume: Its application in renal dialysis. Dialysis Transplant. 1993;22(5):260-264. • Steuer RR, Bell DA, Barrett LL. Optical measurement of hematocrit and other biological constituents in renal therapy. Adv Ren Replace Ther. 1999;6(3):217-224. • Steuer RR, Leypoldt JK, Cheung AK, et al. Hematocrit as an indicator of blood volume and a predictor of intradialytic morbid events. ASAIO J. 1994;40(3):M691-M695. • Steuer RR, Leypoldt JK, Cheung AK, et al. Reducing symptoms during hemodialysis by continuously monitoring the hematocrit. Am J Kidney Dis. 1996;17(4):525-532. • Yashiro M, Hamada Y, Matsushima H, Muso E. Estimation of Filtration Coefficients and Circulating Plasma Volume by Continuously Monitoring Hematocrit during Hemodialysis. ASAIO J. 2002 Jul-Aug;48(4):379-82. Questions/Comments

19. How and when is Hct an indicator of volume depletion? Currently with standard diuretic care, symptoms such as a rise in serum creatinine or a drop in blood pressure are used to titrate therapy. Many consider these methods as late indications of volume depletion. Renal malperfusion and other detrimental effects have already occurred by then. Hct Monitoring has been shown in multiple studies to provide an earlier indication of volume depletion and allow a proactive method to avoid the detrimental renal impact. “Blood volume measurement is a useful tool to prevent major complications during extracorporeal ultrafiltration… a reduction in the circulating blood volume may further decrease cardiac output, leading to a further impairment of organ perfusion. This can be avoided if the circulating volume is maintained and the ultrafiltration rate is driven by the refilling capacity of the cardiovascular system of the patient.” Ronco C et al Cardiology 2001;96:196–201. Questions/Comments

20. Conclusions • Euvolemia should be the ultimate goal of volume removal (ACC/AHA) • Ultrafiltration rates/goals can be disease state specific • Assessment of plasma volume may be helpful in guiding therapeutic strategies • Clinical “rules” of fluid removal with a device are similar