Non-invasive hemodynamic profiling of patients undergoing hemodialysis - a multicenter observational cohort study

Hemodialysis (HD) induces significant hemodynamic imbalances due to rapid intravascular volume reduction, fluid and electrolyte shift, often occur simultaneously. This imposes significant stress on the heart and peripheral vasculature and leads to activation of various compensatory mechanisms necessary for the preservation of tissue perfusion. Since a large proportion of HD patients have coexisting cardiovascular comorbidities, their ability to compensate for these changes may be hampered by reduced cardiac output (CO) at baseline, autonomic neuropathy, or the concomitant use of drugs. While some patients are able to compensate adequately for blood pressure reductions, a substantial fraction of treatments will be accompanied by intradialytic hypotension (IDH), which is associated with poor long term outcomes [1].

At present, blood pressure (BP) measurement is the pivotal objective intradialytic monitoring parameter.. Pre-dialysis BP together with patient weights and clinical examination are used to guide dry weight goals and ultrafiltration rate. However, pre-dialytic low BP and/or the rapid development of IDH will require changes in dialysis plan or a modification of the patient’s chronic drug prescriptions. Currently, these modifications are largely based on clinical judgment in the absence of objective hemodynamic data.

BP is determined and affected three components- heart rate (HR), stroke volume (SV) and systemic vascular resistance. Scarce data exists regarding the hemodynamic changes induced by dialysis. This is probably due to the need for invasive methods (e.g. pulmonary artery catheter) to asses these parameters. Conflicting reports exist regarding the physiological responses to HD with most data coming from small scale studies and obsolete HD protocols [2‐7]. More recently, continuous hemodynamic assessment has become feasible with the emergence of non-invasive monitoring systems. The objective of this study was to explore and describe the various hemodynamic changes that occur during chronic HD utilizing such a device.

The results of this multicenter study demonstrate distinct variability in the hemodynamic response to HD. (1) While a significant proportion of patients demonstrates normal hemodynamics prior to initiation of HD, the procedure induces significant alterations in the hemodynamic status in most patients. (2) These responses can be grouped into 4 separate hemodynamic responses with observed differences in outcome. (3) At the end of dialysis, patients tend to return towards normal hemodynamic status.

Despite many years of experience with HD, the actual hemodynamic changes occurring during this treatment are poorly described despite the dire outcome of patients sustaining IDH [16]. Most data regarding the hemodynamic responses to HD date back to the ‘70s and ‘80s of the twentieth century. These data do not reflect the current practice of shorter, high ultrafiltration rate dialysis [4, 5, 17]. For example, Rouby et al. in 1980 described the hemodynamic response of ten patients undergoing HD and sequential ultrafiltration using an invasive pulmonary artery catheter technique. Similarly to other studies, they recorded decreases in CI and MAP with preserved TPRI. It should be noted that this study excluded patients prescribed with antihypertensive or cardiovascular drugs and those with cardiomyopathies. [5] Beyond being a small scale study, the included population did not reflect a “real-world” HD population in which many patients have multiple co-morbidities [18, 19] and are prescribed with multiple drugs- all of which might potentially impact the hemodynamic response to HD. These gaps in knowledge motivated the initiation of the current study which included all-comers, “real-world” population of HD patients treated with current HD protocols.

At present, HD hemodynamics are monitored by intermittent measurements of BP. In the present analysis, in only 6.9% of patients, hemodynamics was preserved during dialysis while in the remainder response was variable. This highlights the need for more relevant assessment tools which would enable a more accurate differentiation of causes for IDH and related clinical problems. IDH is known to be a significant clinical event during dialysis since it is associated with poor long term outcome [1, 20‐22]. These and other data clearly indicate that IDH results from two distinct hemodynamic responses- decrease in TPRI or decrease in CPI [15]. Low TPRI can be described as the relative inability of the peripheral vasculature to respond to stimuli for vasoconstriction to compensate for the hypovolemia induced by ultrafiltration. This may result from autonomic dysfunction, probably more common in diabetic patients [23], or overmedication with anti-hypertensive, vasodilator drugs. Low CPI, on the other hand, results mainly from an acute reduction in CO, stemming from either systolic or diastolic cardiac dysfunction. Left ventricular (LV) systolic dysfunction is significantly more prevalent in HD patients compared with the non-HD population [24] probably due to the high prevalence of hypertension and concomitant risk factors for coronary artery disease- the main etiologies for reduced LV function but also due to repetitive stunning induced by IDH as suggested by McIntyre et al [25, 26]. More importantly, diastolic dysfunction (DD), is probably a more common phenomenon than LV systolic dysfunction in HD patients [16]. DD is closely related with left-ventricular hypertrophy both caused by gradual myocardial fibrosis. From a physiological standpoint, HD patients with DD are preload dependent- i.e. their ability to fill the heart is limited and thus if preload is lowered (such as in the case of too rapid fluid removal by ultrafiltration), the CO and CPI will decrease. The ability to differentiate between two separate processes leading to IDH practically should be useful for therapeutic intervention. First, if CPI is reduced during HD, it is important to establish whether systolic or diastolic dysfunction (DD) is present by cardiac evaluation including echocardiography. If systolic dysfunction is diagnosed, certain CCBs should not be prescribed mainly due to their negative inotropic effect [27]. Of note, these drugs were prescribed to approximately 40% of the patients in the low CPI group in the present study. Patients with systolic dysfunction may also benefit from β receptor blockers and ACEi. The former can prolong diastole and the latter reduces afterload. On the other hand, if DD is diagnosed as the etiology for low CPI, assuming that these patients are preload dependent, the target weight goal could be increased and/or the ultrafiltration rate reduced. When low TPRI is diagnosed as the cause for BP decrease, dialysate cooling or use of an adrenergic stimulating agent (e.g. midodrine) may be useful. [28] These patients may also benefit from a decrease in the dose of afterload reducing antihypertensive drugs. The major implication of this ability to differentiate between the two major etiologies of IDH during HD is a paradigm shift toward a more personalized, specific approach to the diagnosis and management of individual episodes of IDH. Similar implications may be relevant for patients demonstrating hypertension during dialysis in which two distinct reactions were demonstrated- either high TPRI or high CPI. Those with high CPI may be hypervolemic and may benefit from a reduction in target dry weight while those with high TPRI, which result from elevated sympathetic over-activity [25, 26] may benefit from the use of pharmacologic afterload reduction (e.g. ACEi) or β-receptor blocker. The sequence of intradialytic analysis interpretation and potential implications is summarized in Fig. 4.

Several limitations to this work are acknowledged: First, this was a relatively small-scale study aimed at establishing the ability of this technique to add clinical knowledge of intradialytic hemodynamics which goes well beyond BP measurement. Thus, the interpretation of these data with regards to the association between certain hemodynamic profiles and mortality should be taken cautiously. Secondly, differences were noted between the baseline characteristics and hemodynamic indices of patients from different sites. Since this was an all-comers study aimed for description of hemodynamic patterns before, during and after dialysis, we believe that the fact that different patients treated in different centers and countries were included truly reflect the diversity of responses seen in dialysis which highlights the need for an online monitoring tool. Thirdly, the maximal change from baseline during dialysis was performed at 30–60 min intervals. It should be acknowledged that hemodynamic changes may have possibly occurred between these intervals, yet we believe that the probability of missing a significant hemodynamic event is relatively low. Finally, this was a proof-of-concept observational study and thus the efficacy of the recommendations given for each of the hemodynamic profile is yet to be determined in prospective interventional studies.

BP is a poor indicator of hemodynamic status in patients undergoing HD. A more thorough understanding of the different parameters impacting patients’ response to HD is a clear and relevant need. By utilizing a valid non-invasive whole-body impedance device, a relatively complete picture of the patient’s hemodynamic status can be visualized throughout the treatment and a personalized approach to these changes may be applied. This potentially may guide an appropriate response to the varied etiologies of repeated IDH episodes with the reasonable possibility of reversion or prevention of the deleterious outcomes of these episodes.