A system to monitor segmental intracellular, interstitial, and intravascular volume and circulatory changes during acute hemodialysis

The Z-Spec-2, (UFI Inc., Morro Bay, CA) combines two bioimpedance instruments into a single device. It combines a fixed frequency impedance plethysmograph (IPG) and a multi-frequency electrical bioimpedance spectrograph into one unit. The IPG mode is used to quantify segmental blood flow and total segmental conductive volume. The BIS mode is used to monitor segmental intracellular and extracellular compartment volumes as is done by other BIS devices. However, our proprietary software also allows the Z-Spec-2 to divide the extracellular compartment volume into its intravascular and interstitial components.

The current Z-Spec-2 design, shown in Figure 3, is a unique bioimpedance measurement device that supplies subject tissue impedance while "sweeping" across 40 discrete excitation frequencies over a wide frequency range when functioning as a BIS for compartment volume measurements. The Z-Spec-2 can be paused at 50 kHz to function as a fixed frequency IPG for blood flow measurements.

Figure 3

The Z-Spec-2 provides a “scheduler” capability that can be used to operate the instrument continuously as either an IPG or an BIS or any desired time sequenced combination of the two modes.

The Z-Spec-2 includes a Lead I electrocardiographic (ECG) and a photoelectric plethysmographic (PPG) analog channel (via external transducers) which provide measures that are used to quantify segmental blood flow.

A built-in 16 bit microcontroller is responsible for management of all Z-Spec-2 functions.

Figure 4 shows the basic functional block diagram of our Z-Spec-2 EIS/IPG instrumentation.

Figure 4

The Z-Spec-2 final design has the following features:

The application and capability of the BIS when operated in the IPG mode to quantify segmental blood flow and hemodynamics is described elsewhere (4,6). Details of the analytical algorithm used to derive individual fluid compartment volumes from the impedance spectroscopic recordings are given in previous articles [30, 31, 32].

We hypothesize that this new instrument will be able to quantify changes in the three fluid compartments as fluid volume is removed during hemodialysis. We therefore, aimed to evaluate the changes in the three volume compartments (intravascular, interstitial, and intracellular), and hemodynamic patterns associated with fluid volume removal during dialysis.

Hemodialysis treatment sessions provide ideal opportunities to monitor exogenously induced inter-compartmental fluid shifts with minimal additional procedures. If the BIS net volume changes we compute do indeed provide a way to track three compartment fluid shifts, then such BIS-recorded fluid shifts should correlate with those of an independent physiologic measure of fluid volume changes.

The hemodialysis (HD) patient’s hematocrit (HCT), expressed as %, rises (due to hemoconcentration) as excess fluids are removed by ultra-filtration (UF) – and falls or rises more slowly (due to hemodilution) as extravascular fluid moves into the vascular system as a result of compensatory osmotic and hydrodynamic pressure changes. Both changes in HCT and changes in the rate of vascular “refill” can be measured noninvasively during routine HD therapy sessions. Changes in HCT can be measured by a CritLine® optical monitor (HemaMetrics, Kaysville, UT). The rate of “refill” can be calculated from the BIS volume data.

A CritLine® optical monitor served as the “gold standard” for validation and was used simultaneously to detect on-line changes in hematocrit. The CritLine® measures the optical absorption and scattering properties of red blood cells as they pass through the HD circuit. Since red blood cell mass and hemoglobin do not usually change during treatment, the relative changes in hematocrit should parallel the changes in blood fluid content. The CritLine® instrument is well validated [33,34], FDA-approved [35,36], and routinely used for patient management.

Validation was previously performed in 60 End Stage Renal Disease patients during chronic treatment session by analyzing the time profiles of fluid redistribution, obtained from the BIS data during hemodialysis, to mathematically derive post hoc hematocrit profiles. These profiles were then compared to the simultaneously measured hematocrit values recorded independently using the CritLine^® monitor. Regression and Bland Altman analyses were used to compare the BIS data and CritLine^® hematocrits at sequential times during the 60 chronic HD sessions with the patients in a horizontal position. The statistical and graphical evidence obtained [31] confirmed that the BIS system reliably monitors the continuous and real time rates of change of the fluid volumes of the three compartments in the chronic treatment setting.

However, it has been shown that the fluid responses in the intracellular, interstitial and intravascular compartments may differ during the acute and chronic HD sessions [37].43

It was therefore necessary to replicate the earlier validation procedures using the bioimpedance data from the 22 end stage kidney disease (ESKD) patients that took part in this study.

Statistical analysis was performed using MedCalc Ver. 10.0.0.0. A Student’s t test was used to compare paired observations. Pearson’s correlation (38) and Bland-Altman (39) analyses were used to compare the BIS hematocrit (BISHCT) and the CritLine® hematocrit (CLHCT) results at each time point. Results are reported as mean ± SD.

The institutional review board approved protocol allowed BIS measurement in consented adult ESKD patients receiving dialysis in an acute dialysis unit. Patients with the following conditions were excluded from the study: irregular heartbeat, unstable angina, active gastrointestinal bleeding, pregnancy, poor peripheral circulation, skin conditions such as psoriasis, damaged nerves in the arms or legs, liver failure, cancer, collagen vascular disease such as lupus, chronic swelling of the arms or legs due to obstruction of the lymph or blood vessels, implanted pacemaker, or other implanted electrical device, overactive thyroid disease, or chronic substance abuse. Studies were performed in patients who were resting in the supine position for at least 2 hours before obtaining measurements.

All patients were treated with Cobe Century hemodialysis machine and Polyflux 170H dialyzer. Dialysis fluid sodium concentration (140 mEq/L) and ultrafiltration rate (UFR) were kept constant throughout the treatment. Blood flow rate, dialysis fluid flow rate, treatment time, and total volume removed were ordered by the Attending physician according to the patient’s requirement.

Blood Pressure (BP) and heart rate (HR) were measured and recorded by a technician immediately before dialysis, every 15 minutes throughout the treatment, and at the end of treatment. Signs and symptoms related to hypotension and dialysis complications were recorded. All patients were treated in the supine position.

Hematocrit (HCT), an indirect measure of blood volume (BV), was continuously monitored on-line using CritLine®-TQA (Hema-Metrics, Kaysville, UT). Percent change in BV (%BV) during HD was determined from the % variation of HCT.

A bioelectric impedance spectroscopic system (LDM, San Jose, CA and UFI, Inc., Morro Bay, CA) was used to obtain periodic, noninvasive relative measurements of intracellular (V_c), interstitial (V_i), and intravascular (V_b) volumes, segmental blood flow and hemodynamic properties during dialysis. Compartment volume results were displayed in real time, while blood flow and hemodynamic properties were computed in post-session analyses. Changes in interstitial and intravascular volumes from the BIS recordings were used to calculate the HCT-time profile for each patient..

The BIS instrument was attached to the subject’s dominant lower leg. The source electrodes were placed just above the knee, and just above the malleolus, laterally. The sampling electrodes were placed just below the knee and above the ankle, medially. Figure 5 shows electrode placement on the calf.

Figure 5

All dialysis sessions included in this analysis lasted at least 120 minutes. Shortly after 120 minutes some of the dialysis sessions were terminated for different reasons; patients experiencing syncope, cramps, completion of the required dialysis, etc. Mean calculated BIS and observed CritLine® hematocrit (± SD) values are presented in Table 1 for elapsed dialysis times of 30, 60, 90, 120, and END. The END values that are given in Table 1 were taken from the last minute before cessation of dialysis. The average ( ± SD) time for the END data is 171.2 ± 21.7 min. from the start of dialysis. The CritLine® hematocrit values measured by the optical sensor in Table 1 and the following tables and figures are designated CLHCT. The values calculated from the BIS measurements are designated by BISHCT. No significant differences were found between the BISHCT and the CLHCT values at any of the elapsed times listed in Table 1.

Results of the regression and Bland Altman analyses, at each of the elapsed times, are listed in Table 1. Graphical results of the regression and Bland Altman analyses at the specified elapsed times are given in Figures 6A and 6B, respectively.

Figure 6A

Figure 6B

The regression equation and R² value for BISHCT vs. CLHCT are given in Figure 6A. The solid trace in Figure 6A represents the corresponding regression equation. The BISHCT/CLHCT points included in the Bland Altman analysis for each time period are represented as: 30 min. are open circles, 60 min. are solid squares, 90 min. are solid circles, 120 min. are open triangles, and the END values are open squares.

Table 2 lists the corresponding Bland Altman results.

These regression and Bland Altman analyses confirm that the BIS algorithm can be used to reliably derive the continuous and real time rates of change of the intra-cellular, interstitial, and intravascular compartmental fluid volumes in both acute and chronic ESKD patients.

Regression results yielded a R² > 0.99 between the two measures of hematocrit at different times during dialysis. The slopes of the regression equations at the different times were nearly identical, demonstrating an almost one to one correspondence between the calculated BIS and the measured CritLine® hematocrits.

Bland Altman analyses show that the BIS algorithm can be used interchangeably with the CritLine® monitor for the measurement of hematocrit. In addition, it also shows that the calculated volume changes can then be used to derive other variables that can provide valuable insight into the various fluid responses that take place during fluid management therapy.

The intracellular, interstitial and intravascular volume changes that were calculated from the series of HD sessions used in the above validation study are given in Figures 7A, B and C, respectively below. Figure 7 shows that the three component volumes of the acute patients undergoing HD varied widely among the individual patients. This finding may, in part, be attributed to the differences in the progression of ESKD and other accompanying diseases of the various patients. The patients monitored during these acute HD sessions were in the hospital for treatment of a number of disease states and/or complications of their kidneys. As such, they may have been given HD for the first time in our facility without knowledge as to their responses during previous HD treatments.

Figure 7A

Figure 7B

Figure 7C

Due to the observed variance of the individual patients, each patient had to be considered as a specific case for HD treatment. Use of the BIS system, described herein, would greatly facilitate administration of HD in the acute patients or in those patients being treated during their initial fluid management therapy.

To demonstrate the capability of the ZSpec-2 to provide information regarding fluid compartment volume and circulatory changes for individual patients during HD we provide the results of two very different patients below. The results of BIS and CritLine® along with simultaneous BP and hemodynamic (blood flow) measurements were obtained in the two ESKD patients:

Prior to dialysis, both patients had no overt signs of congestive heart failure or fluid overload and showed comparable pre-dialysis BP. As shown in Figures 8A and 8B the ultrafiltration (UF) rates were similar, e.g. 1.0-1.3 L/hr and the total amount of fluid removed during dialysis was the same for both patients.

Figure 8A

Figure 8B

Figures 9A and 9B illustrate the change in the CritLine® HCT and the corresponding HCT calculated from the BIS data for the Type A and B patients, respectively. The HCT for the Type A patient increased from 24% to approximately 27% during dialysis. That of Type B increased from ~37.5% to 39%. The extent of agreement between the CritLine® measured HCT and that of the calculated values for both patients show that the algorithms used to derive the three fluid compartment volumes may be used for both chronic and acute patients during dialysis.

Figure 9A

Figure 9B

Figures 10A and 10B depict the volume changes of the intracellular, interstitial and intravascular fluid compartments of the Type A & B patients, respectively. HD in the Type A patient with minimal BV change was accompanied by removal of a large volume of fluid from the interstitial space and an increase in cellular volume. HD in the Type B patient with marked decrease in BV was accompanied by minimal net changes in both the interstitial and cellular volumes.

Figure 10A

Figure 10B

The fluid removed from the Type A patient appears to be primarily from the extravascular (Vb and Vi) space. Whereas, fluid removed from the Type B patient was mainly from the vascular space, leading to symptoms of low blood pressure and dizziness.

Subject A’s BP remained stable throughout the entire HD session with practically the same UF rate of about 1 L/hr. Hence, there was no intradialytic hypotension (IDH) However, the decline in vascular volume during HD was temporally accompanied by a proportionate decrease in interstitial volume. This suggests that a proportionate amount of vascular refilling occurred, which may have prevented the development of IDH (Figure 10A).

Figure 10B shows that Patient B had a progressive decline in vascular volume, which reached its climax toward the end (130-180 min) of the HD session, while both interstitial and cellular volumes remained relatively stable. In Patient B an IDH episode was noted near the end of dialysis session when the same UF rate of about 1 L/hr was applied. This hypotensive response is consistent with his impaired autonomic function.

The individual compartment volumes are then used to provide a measure of outflow or “refill” from the extravascular (XV) space into the vascular system during dialysis. In patient Type A, XV fluid moved to refill the intravascular space, Figure 11A. Whereas in patient Type B, not much fluid was transferred from the XV space into the vascular system resulting in hypotension and symptoms of dizziness, Figure 11B.

Figure 11A

Figure 11B

The following results were obtained from the hand recorded blood pressures and the output of the bioimpedance instrument when it was operated in its fixed frequency mode with a constant input current of 50 kHz and the pulsatile waveforms recorded for a period of 60 seconds. The parameter values provided below were calculated using the Rheosys computer program [16] and are mainly dependent upon the morphology and shape of the recorded pulsatile waveforms.

Figure 12A shows that the systolic BP of the Type A patient remains relatively stable, dropping about 15 mmHg during dialysis.

Figure 12A

The systolic blood pressure of the Type B patient dropped about 55 mmHg during the total dialysis treatment, which included a 45 mmHg during the last hour of dialysis. Note that the large decrease in Type B's systolic blood pressure started at approximately 125 min elapsed time. This time was the period in dialysis at which the maximum amount of fluid was removed from the intravascular compartment (Figure 11B).

Figure 12B shows that the diastolic BP of the two patients experience decrease at the same points in elapsed time. Type B's diastolic blood pressure decreased approximately 30 mmHg and that of Type A decreased ~10 mmHg.

Figure 12B

Figure 12C illustrates the mean arterial pressure = diastolic + 1/3(pulse pressure) that results from the blood pressure responses displayed above. MAP decreased from ~ 125 mmHg to ~85 mmHg for Type B and remained relatively constant for Type A, decreasing approximately 10 mmHg during the last period of dialysis.

Figure 12C

The following results compare the changes in heart rate (Figure 13A), maximum pulse amplitude (Figure 13B) and resulting calf blood flow (Figure 13C) for Patients A and B during dialysis.

Figure 13A

Figure 13B

Figure 13C

One potential contributing factor to Patient B's responses may be the observation that the various physiologic mechanisms that normally respond to minimize hypotension are inactive or become fatigued during dialysis of ESKD patients who exhibit serious complications or advanced kidney disease. Also, the various parameters that are displayed tend to become less effective after approximately 125 - 150 minutes elapsed time during which the compartment volumes experienced their maximum fluid removal.

These results were obtained even though both patients had the same relative UF rate and similar amounts of total fluid withdrawn. The Type B patient had several conditions that may have altered or influenced his autonomic/sympathetic responses to dialysis. The Type A patient did not have (at the time of study) any complications that might alter his natural responses to dialysis.

Heart rate (BPM - Figure 13A) was calculated from time between subsequent QRS peaks of the recorded ECG waveforms. The heart rate of both patients increased during dialysis. Patient A's heart rate increase from approximately 75 BPM to 90 BPM during dialysis while that of patient B only increased about 5 BPM.

The maximum pulse amplitude (Amp) for each patient (Figure 13B) was taken from the maximum height of the systolic portion of the bioimpedance waveform when converted to ohms resistance. Amp increased for the Type A patient and decreased slightly for the Type B patient.

The heart rate and pulse amplitude responses above yield an increase in calf blood flow (ml/100ml/min) for Type A and a decrease of ~ 50% for Type B between 25 and 100 min of dialysis as shown in Figure 13C.

Pulse Transit Time (PTT - sec, Figure 14A) is the time interval between the ECG QRS complex and the start of the bioimpedance pulse waveform. PTT remains constant for Type A and increases markedly for Type B starting about 125 min elapsed time. This PTT increase indicates that the systemic circulation of the Type B patient dilated extensively starting at approximately 125 min elapsed time.

Figure 14A

Peripheral resistance (PR, Figure 14B) is defined as MAP/%BF (where BF is in units of ML/100 ML/Min). PR remained constant during the Type A patient dialysis but increased dramatically twice during the Type B patient dialysis.

Figure 14B

In the Type A patient, PR remained relatively stable in association with no changes in BP. In the Type B patient, however, PR increased initially and became erratic subsequently but did not increase in association with the fall in BP near the end of dialysis session.

The average blood pulse inflow angle (LA - between 10 and 90% of pulse amplitude) (Figure 15) is a measure of the contractility of the heart. An increase in LA indicates an increase in the contractility of the heart. LA of the Type A patient increases slightly during most of the dialysis period. LA is more varied for the Type B patient and decreases at 150 min showing a reduction in contractility at that point in time.

Figure 15

Arteriolar tone is expressed as the Dicrotic Index (DCI - Figure 16A) and is defined as the ratio of the maximum amplitude of the post-dicrotic segment of the impedance pulse waveform to the maximum amplitude of the pulse (17). Venular tone is given as the Diastolic Index ( DSI - Figure 16B) and is defined as the pulse amplitude at the time of the dicrotic notch to the maximum amplitude of the pulse (18). DCI and DSI indicate the response of the local vascular bed in the calf segment during dialysis.

Figure 16A

Figure 16B

Figure 16A shows that there is a marked increase in arteriolar tone for Patient B while that of Patient A remains constant during dialysis.

The venular tone responses of the two patients (Figure 16B) are similar to the arteriolar tone responses; venular tone remained constant for patient A and increased for Patient B.