Originally published in Volume 35 Issue 6 of Artificial Organs, 14 June 2011
The term “Pioneer” indicates substantial experience (“vintage”) and presumes enhanced perspective. In thinking about how I might contribute to this series, I came to the conclusion that one logical action would be to write about a significant and unremitting medical problem that has been present for the duration of my career and has been a subject of interest for me for decades. That is what follows.
Early dialysis at the Peter Bent Brigham hospital, under the guidance of John P. Merrill, MD and his chief nurse Audrey Clemmens, RN, was conducted using a modified version of the Kolff rotating drum artificial kidney. During my presence (1960–1963) there was a gradual migration away from the rotating drum to the Travenol twin-coil dialyzer. This was driven by the comparative technical simplicity of the twin coil. Acute renal failure with surgical vascular access was the target population, and treatment times were 6 h every other day or more depending on the degree of uremia. With this migration of technology came the capacity to hydrostatically drive ultrafiltration (clamping the blood outflow line) as contrasted with the osmotic driving force (bath glucose) used by the drum. For the first time this permitted the dialysis clinician to remove vascular volume faster than it could be restored from the interstitial space, causing the occurrence of symptomatic intradialytic hypotension (SIH). However, the population treated and the duration of the dialysis made the occurrence of SIH an infrequent complication, unlike what we see today in the treatment of end-stage renal disease (ESRD) patients.
In 1977, a US registry reported a 24% incidence of SIH for thrice weekly 5-h twin-coil dialysis. More recent reports from the USA and UK indicate a comparable incidence that ranges from 20 to 60% depending on whom you read 1–4. It is distressing that the incidence of SIH, the most common complication of dialysis, has not changed over the past 30 years and continues to be a daily presence in dialysis units across the country. This rough comparability exists in spite of the many technical changes that were supposed to prevent this unpleasant event, for example, adding pressure transducers to the arterial blood path, switching to low compliance hollow fibers from tube membrane, switching from acetate to bicarbonate as the alkalinizing agent in the dialysate, etc. There is no lack of concern about this problem amongst nephrologists. A literature search on dialysis hypotension offers literally hundreds of references over the last 10 years that address SIH. This work has not yielded a clear nor comprehensive picture of the underlying pathophysiology. Noteworthy in the intrinsic cause of SIH is the failure of the patient to secrete pressor hormones in a normal fashion in the face of vascular volume depletion that results from ultrafiltration 5. Why this occurs has not yet been clearly identified over the 15-year interval since its description 6. It is not my purpose to review this material, but rather to describe and emphasize the serious nature of this complication and to discuss recent publications that underscore the mortal implications of SIH and the clinical quandary that results from its occurrence.
While there are minor differences in how this syndrome is defined, there are three primary requirements for “garden variety” SIH: (i) an abrupt fall in blood pressure (BP); (ii) symptoms such as leg cramps, nausea, vomiting headache, etc. and (iii) the need for an intervention, for example, placing the patient in the Trendelenburg position, administering intravenous (IV) saline, reducing the ultrafiltration rate, etc. Note that I use the term “garden variety” SIH to distinguish it from hypotension that occurs from autonomic nervous system neuropathy.
There are numerous reasons for the continued high incidence of SIH. Treatment times for a thrice weekly regimen have been uniformly reduced from 5–6 h to 3–4 h, resulting in an increase in the tempo of ultrafiltration required to remove the interdialytic build-up of sodium and water. Patients are older (65+ years) and the incidence of diabetes mellitus greater (50+%) than in 1977, invoking increased vascular “stiffness” as a common denominator 7.
Further, some of the technical “fixes” for preventing the occurrence of SIH have not proven to be helpful. For example, sodium profiling may reduce the frequency of SIH, but can subsequently result in a net positive sodium balance that drives thirst and increases both interdialytic weight gain (IDWG) and hypertension. This resulted in the KDOQI guideline’s recommendation not to use sodium profiling 8. Other technologies are available but not widely adopted in the clinic, for example, continuously monitoring changes in blood volume during dialysis. This technique presumably provides a good reflection of the balance between loss of plasma volume to ultrafiltration and the refilling rate from the interstitial space. Technology for making this measurement has been available for at least 15 years 9, but its widespread use has not occurred. This may be due to variation in the patterns displayed by the monitor for a given individual in sequential dialyses or because variability of the hematocrit-based measurement, when compared with the gold standard of radioisotope dilution, is on the order of ±1 L (nearly a third of the vascular volume for a 70-kg patient). A significant interventional study of this technique was conducted in 2007, the CLIMB trial. Interestingly, the study showed that monitoring hematocrit to control ultrafiltration rates resulted in an 8.7% mortality rate in 227 patients followed for 6 months, as contrasted with a 3.3% mortality rate in 216 patients using conventional dialysis treatment without this monitoring 10. This study is at odds with several others 11–13, but its rigor casts uncertainty on the efficacy of the technique and has likely contributed to its lack of adoption.
Heat loss dialysis, another technology, was first described in 1982. While it was effective in lowering the frequency of SIH, it could at times result in an unpleasant chilling of the patient, which may explain why it is not currently in wide use 14.
Carnitine supplementation to reduce SIH and/or muscle cramps was reimbursed by CMS, but failed on meta-analysis to affect either 15.
Bioimpedance analysis (BIA) is a relatively new technology for use in patients on hemodialysis. At present, the only Food and Drug Administration (FDA)-approved device for hemodialysis was developed primarily for use in intensive care units for assessing thoracic congestion in patients with heart failure. So far, there have been no studies of this single frequency device to identify the state of hydration in ESRD patients. Further, single-frequency BIA measures total body water and offers little insight into the compartmentalization of the fluid that is critical to judgments of euvolemia. Multiple-frequency techniques address compartmentalization and offer potential, but are new enough not to have been approved by the FDA nor studied specifically for reduction of SIH. A noteworthy study in Germany by Wizeman et al. 16 used a multifrequency BIA device to study 269 hemodialysis patients drawn from three centers for a study period of 3.5 years. He noted a near doubling of gross annual all-cause mortality (8.5 to 14.7%) in those subjects judged to have an excess of extracellular water above 15% (or about 2.5 L of fluid excess). This was second only to the presence of diabetes as an independent predictor of mortality. The correlation with SIH was not performed but, as treatment times were not a variable, one assumes that the higher IDWG would translate into an increased tempo of ultrafiltration. A study of 72 stable ESRD patients in the UK failed to show a correlation between multifrequency bioimpendence measurements with pre-, post-, or intradialytic blood pressure, that is, SIH, but there was correlation with hematocrit, plasma albumin, and extracellular fluid volume 17.
There has been recent strong appreciation of the impact of SIH, not only on the quality but also on the quantity of life in ESRD subjects. The correlation between SIH and mortality has been reported in a large observational study from Japan 18. Interestingly, this study in 1244 patients over a 2-year interval failed to show a correlation between mortality and either pre- or postdialysis systolic or diastolic blood pressure, but did show a significant correlation between mortality and SIH (adjusted odds ratio of 0.79 with a 95% confidence interval 0.64–0.98). This observation bears directly on the resolution of the clinical quandary to be described and will be commented on subsequently.
A second recent observational study from the USA looked at IDWG between two sequential mid-week dialyses (Monday, Wednesday or Tuesday, Thursday) in 34,107 study subjects over a 2-year period. It showed for the first time a clear correlation between IDWG and mortality 19. Broken out by 0.5-kg increments there is a near linear increase in both cardiovascular and all-cause mortality over the range from 1.0–1.49 kg to >4.0 kg of fluid weight gain. Data from this study was corrected for nutritional covariates that have, in the past, confounded the correlation between fluid weight gain and mortality. However, it did not specifically address blood pressure or SIH as potential causes for the correlation of IDWG and death. Most recently, the examination of data from the HEMO study by Flythe et al. 20 correlates higher ultrafiltration rates with increased risk of cardiovascular mortality. In1846 patients followed over a 7-year time frame, they used a baseline rate of ≤10 mL/h/kg body weight (approximately 2.8 L removed over a 4-h dialysis in a 70-kg patient) and compared this with values of 10–13 mL/h/kg (approximately 3.5 L) and greater than 13 mL/h/kg. Cardiovascular mortality adjusted hazards ratios were 1.59 and 1.71, respectively, that is, a huge increase in risk of cardiac death from higher ultrafiltration rates. The Flythe study, albeit observational, carries the weight of prospective and rigorous data collection with “diligent adjudication of death and hospitalization events” over the 7-year time frame.
A 6.5% (P < 0.002) increase in death rate on Monday or Tuesday, depending on the dialysis schedule, has been clearly identified in a large US observational study drawn from the United States Renal Data System (USRDS) 21. A further observational study drawn from the Fresenius databases also found Monday as the day of highest cardiac arrest 22. A similar report from the DOPPS study in a large European patient base 23 found that skipping dialysis treatments increased the mortality risk by 30% (P < 0.01). Other correlates in DOPPS, that is, use of vascular access catheters or low potassium baths, were also identified. However, for all three of these studies, the restoration of dry weight after the “weekend” fluid overload and the correlations of ultrafiltration rate, SIH, and mortality are inescapable to this reader.
Further, landmark studies by McIntyre et al. using positron emission tomography demonstrate that the cardiac “stunning” that occurs acutely with SIH causes subsequent myocardial fibrosis and systolic dysfunction 24–26. Myocardial reperfusion injury as described by Yellon and Hausenloy 27 occurs when ischemic myocytes are suddenly reperfused during the course of myocardial surgery. Sniderman et al. astutely postulate that this injury occurs as a result of SIH for the ESRD population 28 and may well be the primary cause of the myocardial fibrosis and systolic dysfunction identified by McIntyre et al. These studies offer persuasive evidence that SIH causes significant acute myocardial injury and contributes significantly to the 50+% overall cardiovascular mortality of the ESRD patient.
The incidence of hypertension in the ESRD population is high. Using the “normal” value suggested by the JNC VII of >150/90 as the defining observation, it ranges from 50 to 60% 29. In children, the incidence is even higher at 70–75% 30. The departure from the common wisdom derived from hypertension studies in patients free of renal disease, for example, the Framingham study, may in part account for this high incidence. Specifically, the “U”-shaped curve of mortality plotted against blood pressure raises concern about whether “normotension” should be the clinical goal for patients with ESRD and what the appropriate defining numbers should be 31. The KDOQI guidelines for blood pressure control call out a predialysis pressure of <140/90 mm Hg as a “reasonable goal,” but the evidence for this conclusion was deemed “weak”29. The guideline was based on the MDRD trial and the observational experience of the reviewing nephrologists. The weakness is derived from the lack of randomized interventional trials to draw from and, as noted above, the conclusion of some studies that treatment of hypertension does not confer a mortality benefit 18, 32, 33. Inrig et al. have even identified that in a group of 16,959 study subjects, a systolic blood pressure >160 versus 140–149 mm Hg was associated with a lower mortality rate 34. If lower blood pressure in an ESRD patient is reflective of a damaged myocardium that cannot respond to the sodium/volume overload common to these patients, then the presence of modest hypertension, that is, greater than 140/90, would be appropriate. The therapeutic response then should be to remove the sodium/volume excess and not to add antihypertensive medications. Further, the identification that the use of antihypertensive medications in conjunction with the three times weekly acute reduction in total body water/sodium results in an increased incidence of SIH, supports the less aggressive use of such medications 35.
It is difficult to accept the equivalence of hypertension in ESRD patients with that of a normal population because of the multiple comorbidities of those with ESRD. In particular, the near universal sodium/volume overload that occurs three times weekly and in most patients persists even at the close of a dialysis session. The high incidence of diabetes, the inflammatory damage to heart and vessels inherent in the cardiorenal syndrome, the older age and higher incidence of heart failure, all blunt the comparability of these two populations. Unfortunately, there are no Framingham-style studies of a population with comparable comorbidities with the ESRD population to help us understand the relative rate of vascular deterioration between these two groups in response to hypertension. If one accepts that hypertension in ESRD patients has a comparable pathophysiologic tempo to those without kidney disease, then one must ask is there sufficient longevity in the ESRD subject to permit the pathophysiologic abnormalities to become manifest? This is clearly not the case. Note that the 2010 USRDS reports that only one patient in three survives for 5 years. Please note that mortality for the ESRD subject is driven predominantly by myocardial infarct and stroke (50%) with infection coming in a distant third.
A primary cause of hypertension in the ESRD patient is their inability to excrete the daily intake of sodium and fluid, that is, they are above “dry weight.” One commonly used definition of “dry weight” is “the lowest weight a patient can tolerate without the development of symptoms and/or hypotension”36. The concept of achieving “dry weight” with hemodialysis is most commonly understood to mean serial challenges to the amount of fluid removed during dialysis until there is a return to “normal” of total body water and sodium and their distribution throughout the body. Classically this means ultrafiltering off slightly more weight than the IDWG recorded since the last dialysis. This is commonly referred to as “probing” for dry weight. In a prospective, randomized, interventional study of 150 patients over an 8-week time frame, such probing was accompanied by an increase in the proportion of patients showing hypotension (12.6), dizziness (8.4), cramps (10.1), the need to stop ultrafiltration (8.4), and the need for a bolus of IV saline (8.4). All results had a significance of 0. 001 < P < 0.01 37. A significant reduction in BP was achieved at both week 4 and 8. Further use of antihypertensive medication in this study in conjunction with probing clearly imposed a higher incidence of these complications 38.
A second less common definition of dry weight has been offered by Charra et al. drawn from observational studies in Tassin, France. A requirement of their definition is a return to normal blood pressure along with the usual elimination of signs of edema. In this study, dry weight was achieved by engaging in a dialysis schedule of 8 h three times per week 39. The slower tempo of fluid removal in the 8-h time frame permitted the removal of excess sodium/volume without the occurrence of SIH. As an observational study, it is not possible to determine whether the return to normal blood pressure relates to simple restoration of sodium/volume to normal or a realignment of uremic toxicity from the considerably enhanced clearance spectrum that such a regimen provides. The remarkably good survival of their patients likely relates to all three variables, that is, absent SIH, normotension, and improved control of uremia.
A recent 12-month interventional study by the FHN trial group compared a control group using a conventional dialysis schedule of three times weekly (n = 120) for a 2.5 to 4.0 h duration per dialysis to the experimental group (n = 125) employing a six times per week schedule for a 1.5 to 2.75 h duration per session. This work resulted in a distinct benefit for both of their primary end points, namely, death or increase in left ventricular mass and improved score on the RAND SF 36-item health survey 40. In addition they achieved a secondary end point of improved blood pressure control. Again, all three variables are at play here, albeit blunting of the peak and valley disturbance of sodium/volume status was clearly an important element of this six times weekly schedule. This study confirmed in a more rigorous manner an earlier interventional study of six times weekly nocturnal dialysis performed in Canada 41. The FHN trial also supports the numerous less rigorous observational studies regarding improved blood pressure control in conjunction with more dialysis time per week. Unfortunately, longer dialysis times have the drawback of increased cost that is unlikely to be borne by the healthcare system in the USA 42.
Addressing the concern about how best to control hypertension in the ESRD population begets our clinical quandary.
To probe or not to probe is the nephrologists’ quandary. The nub of this quandary is found in the comparative impact of hypertension versus serial episodes of SIH on patient mortality. Specifically, is the timeframe for death from the cardiovascular complications of hypertension shorter or longer than that from repeated episodes of SIH that result from probing for dry weight? Unfortunately, for the reasons cited earlier, we do not have a clear answer from the literature about hypertension in the ESRD patient. If we assume that either the tempo of hypertension damage to the cardiovascular system is too slow to impact the short-lived ESRD patient or that SIH coupled with hypertension will accelerate myocardial fibrosis and dysfunction and enhance the death rate then we must conclude that a partial answer to our quandary is Do Not Probe. If we do not probe then the remaining component of our quandary is how do we treat the hypertension?
There is variable expression of “garden variety” SIH not only within the ESRD population but within a given individual over time. Further, there is a variable correlation between death and the presence of hypertension depending on age, race, and the presence of diabetes as noted by Myers in a sophisticated analysis of 16,283 ESRD patients 43. The likely patient-specific implications for hypertension in ESRD where we do not probe make it clear that there is the need for a case by case, dialysis by dialysis, physician judgment regarding whether to use antihypertensive agents. This judgment would require utilizing conventional clinical wisdom regarding the history of the patient with regard to vascular stability during dialysis, the magnitude of the interdialytic weight gain, age, race, comorbid status, body mass, and the proposed duration of the dialysis with its tempo of ultrafiltration. The key variable here should be the length of the dialysis planned for that day. I recognize that this flexibility may disrupt the routine conduct of serial dialysis shifts. That should not lead to the inherent mortality associated with a “one size fits all” judgment. This flexibility should encompass the possibility of adding an additional dialysis during the week, that is, four times weekly dialysis. Only then should a judgment be rendered as to the need for antihypertensive agents. Once again the ability to reimburse for this flexibility is in question but the need is there.
Finally, as a wish for evolution in dialysis technology, it is my hope and expectation that equipment to permit safe, user-friendly, and affordable overnight hemodialysis or hemofiltration will be available in the near future. Providing the needed flexibility in dialysis prescription will enhance biochemical normality and provide an upgrade in both the quality and quantity of life for patients with ESRD.