만성신부전증 환자의 투석효율성을
높이기 위한 연구계획서
박현우
Hypotension is a big problem!
• Hypotension during dialysis treatment is an unresolved
issue.
• Delivery of an adequate do...
IDH (Intradialytic Hypotension)
• Definition
: A fall in SBP by at least 20mmHg or SBP < 100mmHG

•
:
:
:
:
:
:
:
:
:
:
:
...
Intradialytic Hypotension (IDH)
mechanism?
Patient factors

 Cardiac disease
- Systolic dysfunction
- Diastolic dysfuncti...
IDH ---> Hypertension
• Mechanism of therapy for intradialytic hypotension are
of great interest (van der Zee. S et al.)
•...
Solution?
Routine management
of IDH

 Target dry weight
 Diet fluid counseling
 Medication adjustment
 Correct anemia
...
How to increase BP?
Farese S. et al. Am J Kidney Dis. 2008.
•

TEMS : Transcutaneous muscle simulation , PCMs : Passive cy...
Patient Characteristics
TEMS & PCMs during dialysis show
significant results in raising BP
Increased Cardiac Output!
• Heart rate was unchanged during both treatment (TEMS &
PCM) modalities.
• Therefore, the obser...
Efficiency? Urea & Phosphate!

• Longer observation periods with more patients are needed to
assess potential benefits of ...
Several Studies about Passive Training
• Passive movement of the lower leg has been found to result in an
approximate thre...
Capillarization and presence of proliferating endothelial cells in
skeletal muscle before and after passive training of th...
Relationship with CVD ?
• Farese et al. (Am J Kidney Dis)
: Blood flow in the Femoral Artery increased up to 40% with TEMS...
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Intradialytic hypotension [투석 중 저혈압]

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본국에서 진행될 새로운 연구계획서

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  • I am gonna talk about Intradialytic Hypotension and How Passive Cycling movement prevent IDH.The end of today’s my presentation, I will show future direction. If you guys have some good comments, please feel free to give me any feedback, I will decide to develop this idea or not. If it is not well match disertation topic, anyone use this idea for small project or involve current FES project. It has several option. Through the little time that we have, I’d like to express a new way I and JinHee found during my FES experiment to prevent intradialytic hypotension during passive training. Please ask any questions during the presentation and please feel free to give me any feedback as well. Any input will be greatly appreciated.I am going to talk about Passive Cycling Effect.
  • Low blood pressure during dialysis is a big problem. As I know, everyone is very familiar with this background without Alana and Mason, so I will explain little bit detaily. In order to achieve an effective result from 3 or more hours of dialysis, there must be a constant amount of pressure during the process. Therefore, intradialytic hypotension reduces the efficacy of dialysis, which is shown by the value of Kt/V.This is the reason why we see a lot of elder female patients just lying down during dialysis in order to minimize the chance of hypotension. Anyway, hypotension is a serious issue, as it decreases the effect of dialysis, which in turn deteriorates patients’ abilities to perform daily functions and increases the risk of developing CVD and naturally death. This is a problem much bigger than we think. From a researcher’s point of view, it might be hard to expect positive results, bu from a humanitarian perspective, I don’t think we should give up on patients who cannot exercise. 투석 중 저혈압은 환자들에게 큰 문제가 된다. 투석의 효율성, Kt/V를 떨어트리고;을 크게 낮춘다. 3시간이 넘는 투석중, 효율성을 유지하려면 어느정도의 혈압을 유지해야한다. 특히 나이가 많은 여성환자들에게 자주 볼 수 있는 현상이다. 클리닉에서 혈압이 떨어져 기운이 없어 옆으로 누워 자고 있는 할머니들을 쉽게 발견할 수 있다. 결국 투석의 효율성이 떨어져 일상생활에서 큰 문제로 연결된다.
  • Okay, I would like to start by looking at IDH. What is the IDH?There are lots of cause to IDH, AND main cause is Decline Cardiac Function and Systemic Vascular Resistance during removed solute. As time goes by, Patients Vascular Resistance is getting worse.AND Focus on cause which related with cardiac dysfunction in dialysis patients; LV Hypertrophy makes both of systolic and diastolic dysfunction.So Cardiac preload has declined during the dialysis, it is going to Intradialytic Hypotension.
  • So, I divided by two main category, One category is Patient Factors and another one is Dialysis Procedure factors. First Let’s look at the Patient factors about IDH. If patients have cardiac disease such as Systolic dysfunction and Diastolic dysfunction, these things will be a main factors to IDH. And another category is Dialysis procedure factors. There are High Ultrafiltration and solute removal and Low sodium and Calcium. If using low calcium concentration dialysate or low sodium concentration dialysate, specific below 138mEq/L, it is going to be IDH.Let’s suppose this is a cell and there is water inside cell, for patient, have maintain a normal amount of plasma volume we need high sodium concentration dialysate over 138!High sodium concentration dialysate, not too much higher, can transport water from inside cell to outside. Water goes out in the Cell.
  • And, this slide, I want to focus on how to connect IDH to Hypertension. All these factors can lead to Chronic Hypertension.In patients with end-stage renal disease (ESRD) treated with hemodialysis, removal of excess extracellular fluid during the relatively short period of a typical dialysis session frequently leads to symptomatic decreases in arterial pressure. In addition to its directly deleterious effects, intradialytic hypotension and/or attempts to prevent it hinder normalization of the extracellular fluid, leaving many patients chronically volume-expanded. In turn, volume expansion is a major cause of hypertension in patients on hemodialysis. As in the general population, hypertension in patients with ESRD on hemodialysis is associated with high rates of cardiovascular diseases and reduced lifespan. Thus, the mechanisms of and therapy for intradialytic hypotension are of great interest.Intradialytic hypotension is a most frequent complication of hemodialysis and may contribute to cardiovascular events and high mortality. There is a hypothesis that an increase inadenosine generation during hemodialysis may cause vasodilation and a decrease in cardiac output, which results in systemic hypotension.
  • So, I divided by two main category, One category is Patient Factors and another one is Dialysis Procedure factors. First Let’s look at the Patient factors about IDH. If patients have cardiac disease such as Systolic dysfunction and Diastolic dysfunction, these things will be a main factors to IDH. And another category is Dialysis procedure factors. There are High Ultrafiltration and solute removal and Low sodium and Calcium. If using low calcium concentration dialysate or low sodium concentration dialysate, specific below 138mEq/L, it is going to be IDH.
  • Oneday I investigated that how many patients were struggling with Hypotension during the dialysis.So, imagine the CU clinic. It is so easy to find patients who obviously need this type of intervention of passive exercise and electrical stimulus. Guess what kind of people these are. They are the old female patients who can only lie down because the drop of BP during dialysis makes them able to do nothing. In addition, we didn’t even have the time to recruit them. Why? Because they’re always sleeping. Why? Because that’s the only thing they can do.
  • Patients were studied for 9 consecutive hemodialysis sessions. They were randomly assigned to 1 of 3 groups, starting the study on Monday of the first week with either no intervention (NI), PCMs, or TEMS during the hemodialysis session. Patinets were studied for 9 consecutive hemodialysis sessions. They were randomly assigned to 1 of 3 groups, starting the study on Monday of the first week with either no intervention(NI), PCMs, or TEMS during the hemodialysis session.They want to randomization by using this processing.Consecutive interventions were applied to the 3 groups according to the scheme shown in Fig 2.
  • Each group has nine sessions, that means each group have nine average dataes.This pilot study investigated the effect of 2 passive interventions applicable to virtually all dialysis patients independent of comorbid conditions on intradialytic blood pressure control and dialysis efficacy.Ten patients were randomly allocated to TEMS, PCMs, or no intervention (NI) for 9 consecutive dialysis sessions. Motor-powered cycle movements were performed with 36 rpm for 20 minutes/treatmenthour using a Therafit-plus ergometer (Medica GmbH, Hochdorf, Germany) fixed to the dialysis chair. TEMS was applied for 15 minutes/treatment hour using aCompex2 Stimulator (Compex SA, Ecublens, Switzerland).As you can see in this graph, electrical stimulation and passive training during dialysis show significant results in raising BP. And especially, as you can see on the bottom of the graph, those with systolic P below 100 are also showing positive results. This is a very meaningful result considering the fact that those below 100 cannot finish a 3-hour dialysis, or they could die. Heart rate was unchanged during both treatment modalities. Therefore, the observed increase in blood pressure can only be explained by an increase in either peripheral resistance or cardiac output. For TEMS and active exercise, decreased vascular resistance has been described. Thus, increased cardiac output is a more likely explanation for the increase in blood pressure, a contention supported because increased central blood and preload volume positively alter cardiac output, and there is evidence that electrical muscle stimulation increases venous backflow from the musculature.이 그래프에서 보듯이,전기자극과 수동적 운동이 투석중 환자들의 혈압을 올리고 있다. 특히 수축기 혈압이 100이 안되는 저혈압환자의 혈압마저도 올리고 있는 것을 볼 수 있다.
  • And How about Efficiency? Let’s focus on Urea &amp; Phosphate removed amount!But just iT! They figure out changes of only Urea &amp; Phosphate, not Kt/V and different kinds of removed amount of materials in dialysate. Let’s take a look at this graph. This graph shows that these two types of intervention techniques increase the efficiency of the patients getting rid of urea and phosphate. [p value &lt; .001] Although other factors may exist, it is hard to overlook that an increase in BP somehow related. We cannot exclude a prolonged effect of PCMs or TEMS on blood pressure beyond the intradialytic interval.No changes in predialysis and postdialysisserum urea and phosphate concentrations, URR, equilibrated Kt/V, or online-measured Kt/V were detected during PCMs or TEMS.Longer observation periods with more patients are needed to assess potential benefits of TEMS and PCMs on hypotensive episodes during dialysis sessions.Increasing Intervention time and collaborate two different effective intervention MIGHT be !!!혈압이 올라가면서 Urea와 Phosphate를 제거하는 효율성이 올라갔다. 다른 작은 이유들도 있지만 혈압의 변화로 생긴 결과물임을 간과하거나 무시할 수 없는 상황이다.
  • Now Let’s look at the our FES 002 subject’s blood pressure changes!!!Actually we have 36 day dataes but just only got 26 day 45 mins BP dataes because the beginning of 3 month intervention session we tried to make 45 mins steadily.
  • And I averaged these dataes at each time points.P &lt; .034Now these are the results from FES 002. In contrary to active exercise, we can see that passive exercise shows a trend of increasing BP. This certainly points to the fact that passive exercise during dialysis increases blood flow, thereby increasing BP, which in turn brings positive advantages for both safety and efficiency of dialysis. From this graph, I found the need to seriously reconsider what type of dialysis patients will need passive exercise.Active Exercise와 반대로 Passive Exercise의 경우 혈압이 올라가는 것을 볼 수 있다. 이것은 Passive Exercise가 환자의 Blood Flowing을 도와 투석하는 중에서도 그들의 혈압을 올리는 기현상을 보였고, 이것은 분명 Safety와 Efficiency 모두의 장점을 가져온다.
  • As we imagined, PWV is working but not B-stiffness.
  • Group 1 : FES control, passive Group 2 : FES intervention, active + electrical stimulationThis graph shows the BP change by 15 minute intervals of all individual training sessions throughout three months of FES 001, which is the intervention group. Contrary to the common situation, we can see that the BPs actually drop. Just in case of FES 001 :However, this could actually be the common situation for intradialysis exercise. This graph involves the combination of two factors, exercise and electrical stimulus. In other words, intradialytic electrical stimulus could decrease BP while intradialytic exercise could increase BP. As a result, the trend we see here could be a result of the two combined. FES 001의 지난 3달간Active 운동 중 변화했던 혈압을 15분 단위로 쪼개서 분석해보았다. 운동 중 혈압이 올라가는 보편적인 현상의 반대로 혈압이 떨어지는 상황이 벌어졌다.
  • VEGF shows a close interaction with NO formed from NOS; NO regulate VEGF expression and VEGF has been shown to regulate NO formation. (Tsurumi et al. 1997)The present study used passive limb movement as an experimental model to study the effect of increased blood flow and passive stretch, without enhanced metabolic demand, in young healthy male subjects. The model used was 90 min of passive movement of the leg leading to a 2.8-fold increase (P &lt; 0.05) in blood flow without a significant enhancement in oxygen uptake. Muscle interstitial fluid was sampled with microdialysis technique and analyzed for vascular endothelial growth factor (VEGF) protein and for the effect on endothelial cell proliferation. Biopsies obtained from the musculusvastuslateralis were analyzed for mRNA content of VEGF, endothelial nitric oxide synthase (eNOS), and matrix metalloproteinase-2 (MMP-2). The passive leg movement caused an increase (P &lt; 0.05) in interstitial VEGF protein concentration above rest (73 +/- 21 vs. 344 +/- 83 pg/ml). Addition of muscle dialysate to cultured endothelial cells revealed that dialysate obtained during leg movement induced a 3.2-fold higher proliferation rate (P &lt; 0.05) than dialysate obtained at rest. Passive movement also enhanced (P &lt; 0.05) the eNOS mRNA level fourfold above resting levels. SubjectsSeven healthy male subjects with a mean age of 24.7 (range: 19 –31) yr and mean weight of 81.1 (67–98) kg participated in the study (experimental group). In another group of 11 healthy male subjects [age: 23.8 (21–26) yr, weight: 76.9 (67.9 – 87.3) kg], blood flow and oxygen uptake were measured during passive movement of the leg.
  • The subjects carried out 4 weeks of passive leg movement training with one leg. The training was performed 4 times per week with, in total, 17 (range 15–20) training sessions, each of 90 min duration. With the subject seated in an upright position, the knee was passively extended from an angle of 90 deg to 35 deg and back to 90 deg again at a rate of 80 cyclesmin−1 by a machine specifically built for this purpose. The other leg served as control. After two familiarization sessions, prior to the training and after the passive training period, the subjects performed an incremental exercise test to exhaustion with each leg on a one-leg knee-extensor ergometer. The test was initiated by a 10min warm-up at a power output of 10W at 60 cycles min−1 followed by 5min rest. Hereafter the work load was set at 30W and increased 5W every min until] exhaustion was achieved, when the subject was unable to maintain a kicking frequency of&gt;55 cycles min−1 for 10 s.VEGF protein measurementsDialysate VEGF levels were determined by enzyme-linked immunosorbent assay (ELISA) kit according to the manufacturer’s protocol (Quantikine Human VEGF; R&amp;D System, Minneapolis, MN, USA).Measurement of endothelial cell proliferationuse in the culture of endothelial cells (Cytotech MK-200-2 Medium 200 kit) were grown on 96-well plates for 24 h before the medium was replaced with 50 μl of microdialysate, perfusate, or supplemented medium 200.
  • Smart machine, we can combine Passive and Stimulation effects with vey smart FES machine. Future and larger studies with consecutive dialysis sessions using the same intervention repetitively are needed to show the clinical relevance of these single-session findings on the persistence of increased removal and a concomitant decrease in serum urea and/or phosphorus levels over time.As I said in the beginning, there are only a few studies on the effect of short passive exercise and electrical stimulus during dialysis, which are two of the most important factors in determining the safety of intradialytic exercise and efficiency of dialysis treatment. However, the important point is that there are no studies on the effect of giving both passive exercise and electrical stimulation, thereby observing the change of BP and furthermore Kt/V. AND, there is no study for longer training for passive exercise Another important point is that we are able to investigate this idea with our FES machine. Furthermore, this smart FES machine standardizes and presents the speed of passive exercise and the amount of electrical stimulus of each individual session, which enables me to statistically classify all of the data.So, imagine the CU clinic. It is so easy to find patients who obviously need this type of intervention of passive exercise and electrical stimulus. Guess what kind of people these are. They are the old female patients who can only lie down because the drop of BP during dialysis makes them able to do nothing. In addition, we didn’t even have the time to recruit them. Why? Because they’re always sleeping. Why? Because that’s the only thing they can do. I’m sure people are wondering how we are going to be able to make these sleeping people exercise during dialysis. Let’s think about the control group of FES 002 and 004. I was able to see them, numerous times, enjoying passive exercise while they were sleeping. Although we haven’t took a look at their Kt/V results yet, it is obvious that there has been a positive effect on their BP.
  • Farese et al. observed that blood flow in the femoral artery, measured by using Doppler ultrasound, increased up to 40% with TEMS and PCMs compared with baseline measurements in healthy volunteers or dialysis patients (S.F and D.E.U., unpublished data).Heart rate was unchanged during the both treatment modalities. Therefore, the observed increase in blood pressure can only be explained by an increase in either peripheral resistance or cardiac output. For TEMS and active exercise, decreased vascular resistance has been described. Thus, increased cardiac output is a more likely explanation for the increase in BP, a contention supported because increased blood and preload volume positively alter cardiac output, and there is evidence that electrical muscle stimulation increases venous backflow from the musculature. All of these studies focus on the effect of hypotension and Kt/V on CVD risk. Based on such references, I feel the need to study the effects of passive exercise and electrical stimulus on the CVD risk of the patient groups I just mentioned. To these patients, who are probably the closest to death than any of us, I think that this is the best way to increase their quality of life and extend their longevity. It might be a very difficult study, but through your constructive feedback, this project just might be possible. Although there are still many corners to polish, I deeply thank you for listening to my first lab meeting presentation.
  • Intradialytic hypotension [투석 중 저혈압]

    1. 1. 만성신부전증 환자의 투석효율성을 높이기 위한 연구계획서 박현우
    2. 2. Hypotension is a big problem! • Hypotension during dialysis treatment is an unresolved issue. • Delivery of an adequate dose of dialysis is essential to improve the prognosis of dialysis patients • Low blood pressure during the hemodialysis procedure is expected to occur more frequently in patients with comorbidities because it compels a limit to dialysis time and dialysis efficacy. - van der Zee S, Thompson A, Zimmerman R, et al: Vasopressin administration facilitates fluid removal during hemodialysis. - Davenport A: Intradialytic complications during hemodialysis. - Imai E, Fujii M, KohnoY, et al: Adenosine A1 receptor antagonist improves intradialytic hypotension.
    3. 3. IDH (Intradialytic Hypotension) • Definition : A fall in SBP by at least 20mmHg or SBP < 100mmHG • : : : : : : : : : : : : : : : Cause Decline Cardiac Function and Systemic Vascular Resistance (SVR) during removed solute A rapid reduction in Plasma osmolality High Interdialytic weight gain Anemia Autonomic neuropathy Decrease pressor response to Vasopressor agents LV Hypertrophy & Decrease cardiac preload Decrease cardiac reserve Increase arterial stiffness Impaired venous compliance Meal Use of low sodium/ Increase magnesium dialysate Anti-hypertension medication before HD Excessive release of vasodilators (Not Adrenomedullin and Adenosine) Imbalance in the synthesis of vasoconstrictors (Endothelin & Vasopressin)
    4. 4. Intradialytic Hypotension (IDH) mechanism? Patient factors  Cardiac disease - Systolic dysfunction - Diastolic dysfunction  Arrhythmias  Pericardial disease  Autonomic neuropathy  Dietary excess  Interdialytic weight gain  Food ingestion in dialysis  Antihypertensive agents  Anemia (< Hb 7.0g/dL) Dialysis procedure factors  Ultrafiltration, solute removal  Thermal amplication  Sympathetic failure - Increased adenosine - Increased nitric oxide  Dialysate composition  Low sodium (<138mEq/L)  Low calcium  High magnesium  Acetate
    5. 5. IDH ---> Hypertension • Mechanism of therapy for intradialytic hypotension are of great interest (van der Zee. S et al.) • Increase in adenosine generation during hemodialysis may cause vasodilation and decrease in cardiac output, which results in systemic hypotension (Imai. E et al.) • Removal of excess extracellular fluid -> symptomatic decreases in arterial pressure -> intradialytic hypotension -> chronically volume-expanded -> Chronic Hypertension (van der Zee. S et al.)
    6. 6. Solution? Routine management of IDH  Target dry weight  Diet fluid counseling  Medication adjustment  Correct anemia  High sodium dialysate  Sodium modeling Individualized therapy of IDH  High calcium dialysate  Low-magenesium dialysate  Carnitine  Sertraline  Cool dialysate  Midodrine (A vasopressor / antihypotensive agent)
    7. 7. How to increase BP? Farese S. et al. Am J Kidney Dis. 2008. • TEMS : Transcutaneous muscle simulation , PCMs : Passive cycling movement • For each patient, each procedure was performed only once weekly and never on the same weekday.
    8. 8. Patient Characteristics
    9. 9. TEMS & PCMs during dialysis show significant results in raising BP
    10. 10. Increased Cardiac Output! • Heart rate was unchanged during both treatment (TEMS & PCM) modalities. • Therefore, the observed increase in blood pressure can only be explained by an increase in either peripheral resistance or cardiac output. • For TEMS and active exercise, decreased vascular resistance has been described. Miller BF et al. Phys Ther 80:53-60, 2000 • Thus, increased cardiac output is a more likely explanation for the increase in blood pressure, a contention supported because increased central blood and preload volume positively alter cardiac output. Hanft LM et al. Cardiovasc Res 77:627-636, 2008 • There is an evidence that electrical muscle stimulation increases venous backflow from the musculature. Clarke Moloney M et al. Eur J Vasc Endovasc Surg 31:300-305, 2006
    11. 11. Efficiency? Urea & Phosphate! • Longer observation periods with more patients are needed to assess potential benefits of TEMS and PCMs on hypotensive episodes during dialysis sessions
    12. 12. Several Studies about Passive Training • Passive movement of the lower leg has been found to result in an approximate three-fold increase in muscle blood flow, and stretch of the muscle tissue without an alteration in either EMG activity or muscle oxygen uptake. (Krustrup et al. 2004) • Vascular endothelial growth factor (VEGF) is probably one of the most important factor for endothelial activation, proliferation and migration. • The passive movement model induced an enhanced level of muscle interstitial VEGF protein and an increased endothelial cell proliferative effect of muscle interstitial fluid from the muscle as well as a higher expression of endothelial nitric oxide synthase (eNOS) mRNA in the muscle. (Hellsten et al. 2008, Am J Physiol Regul Integr Comp Physiol)
    13. 13. Capillarization and presence of proliferating endothelial cells in skeletal muscle before and after passive training of the leg • B. Hoier et al. J Physiol 588.19 (2010) pp 3833–3845
    14. 14. Relationship with CVD ? • Farese et al. (Am J Kidney Dis) : Blood flow in the Femoral Artery increased up to 40% with TEMS and PCMs (unpublished) : Increased Cardiac Output by electrical muscle stimulation increases venous backflow from the musculature (Increased venous return) • Future direction : ABI (Ankle Brachial Index) : BP Function between Ankle and Brachial : FMD : specific to Femoral Arterial function : Heart Rate Variability : Autonomic dysfunction : Cardiac Function : Mitral Inflow Conventional Doppler, Mitral Annular Velocity Tissue Doppler
    15. 15. Thank you
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