Introduction

In addition to the impact of chronic kidney disease on lifestyle and patient well-being, haemodialysis treatments themselves may additionally cause symptoms [1,2,3,4,5]. Previous studies have reported a reduction of intra-dialytic symptoms by altering the standard dialysis schedule, with several studies reporting that more frequent and lower efficiency dialysis reduce intra-dialytic symptoms, although other studies have failed to confirm these findings [6,7,8]. On the other hand, there has been no substantive evidence to support that dialyzer selection, dialysis modality or choice of dialysate composition significantly impact on reducing patient self-reported intra-dialytic symptoms [1].

During dialysis, there are relatively rapid fluid and electrolyte shifts and changes in plasma osmolality which may result in hypotension, which is the commonest complication of outpatient haemodialysis [9]. Although only a minority of patients suffer with symptomatic intra-dialytic hypotension, there is growing concern about asymptomatic intra-dialytic hypotension [10], which may lead to longer term adverse health consequences. As such, we wished to determine whether changes in blood pressure during a haemodiafiltration session increased the frequency of patient self-reported intra-dialytic symptoms and increased postdialysis recovery times.

Patients and methods

In keeping with UK National Health Service (NHS) guidelines to obtain patient feedback on treatment, we asked all patients attending for outpatient dialysis treatment under the care of the Royal Free Hospital, London, to self-report the frequency of dialysis associated symptoms, including fatigue, feeling cold, cramps, dizziness, headache, nausea, abdominal pain, back ache, pruritus, short of breath and palpitations and time to recovery using a previously reported visual analogue scale [4, 11], when they attended for a routine out-patient mid-week dialysis session in four outlying satellite dialysis centres under the care of a university hospital in sequence in May, June and November 2017, respectively. Psychological distress was determined using the distress thermometer score, a visual scoring system initially introduced in the management of patients with cancer [12]. Hospital computerised medical records were reviewed to obtain their Stoke-Davies comorbidity grades, a comorbidity score developed in the UK and used by the UK national renal registry [13], and frailty using the Canadian geriatric frailty score, which assess functional ability, in terms of activities of daily living [14].

Pre-midweek blood samples were taken on the day of the questionnaire for standard biochemical measurement of urea, creatinine, albumin, C reactive protein (CRP) and N terminal pro-brain natriuretic peptide (NT-proBNP) (Roche Integra, Roche Diagnostics, Lewes, UK) [15] and haemoglobin along with the corresponding post-dialysis urea.

The dialysis prescription and dialysis session details were reviewed retrospectively from hospital computerised records. Patients dialysed using either a Fresenius 4000H, or 5008 dialysis machines (Fresenius MC, Bad Homburg, Germany) or BBraun DialogueR+ (BBraun, Melsungen, Germany) with a polysulphone dialyzer (Fresenius MC, Bad Homburg, Germany) [16] and anticoagulated with a bolus of tinzaparin low molecular weight heparin (Leo Laboratories, Princes Risborough, UK) [17]. All dialysates used a common concentration of bicarbonate 32 mmol/L, acetate 3.0 mmol/L, magnesium 0.5 mmol/L and glucose 5.5 mmol/L. Median dialysate sodium concentration was 136 (136–138) mmol/L and temperature 35oC (35–35.5). Conductivity modules were regularly calibrated and checked [18]. We used constant ultrafiltration profiles, and ultrafiltration rates (UFR) were calculated as the difference in pre- and post-dialysis weights divided by sessional time and adjusted for patient weight. When comparing UFR, we excluded sessions where the UFR had been altered in response to patient symptoms. We calculated the serum to dialysate sodium gradient by subtracting dialysate sodium from pre-dialysis serum sodium. All patients were treated with haemodiafiltration median convective volume exchange 19.1 (16.0–23.0) L.

Blood pressure was measured in the sitting position immediately prior to the start of the dialysis treatment using integrated automatic oscillometric devices. There have been various definitions of intra-dialytic hypotension ranging from the European Dialysis and Transplant clinical guidelines of a fall in systolic blood pressure of > 20 mmHg and patient symptoms [19], to others simply based on changes in blood pressure [20, 21]. Our computerised dialysis records code symptomatic hypotension; as 0 no symptomatic hypotension; 1 a reduction in ultrafiltration rate; 2 administration of intravenous fluids. We divided patients into those who had symptomatic hypotension (score 1 or 2), and also into three groups based on whether their post-dialysis systolic blood pressure, or intra-dialytic systolic blood pressure had fallen by > 20 mmHg (group 1), fell by less than 20 mmHg or increased by less than 10 mmHg (group 2), or increased by > 10 mmHg (post-dialysis hypertension) (group 3) [20]. In addition, we also used nadir cutoff systolic blood pressures of 90 and 100 mmHg or lower [21].

Ethics

This audit of clinical service complied with the UK National Health Service (NHS) guidelines for clinical audit and service development, and met with approval from the Health Research Authority (HRA). In keeping with UK guidelines, all patient data was anonymised prior to analysis (https://www.hra.nhs.uk).

Statistical analysis

Data is presented as mean ± standard deviation, median (interquartile range) or as percentage. Standard statistical tests were used to analyse data; D’Agostino and Pearson normality test, t test, Wilcoxon rank sum tests, ANOVA, Kruskal Wallis, or chi square test) with appropriate corrections made for multiple testing, by Tukey or Gannet-Howell post-hoc testing. Spearman correlation analysis was used for univariate analysis. To develop a multi-variable model for dialysis symptoms, we took all variables associated with the total symptom score p < 0.1, and variables thought to be clinically relevant (weight loss, ultrafiltration rate, dialyzer surface area, dialysate to serum sodium gradient, dialysate temperature, months of dialysis treatment, serum albumin, haemoglobin, glucose and N terminal brain natriuretic peptide). A step backward logistic regression model with above and below the median total symptom score as the dependent variable was generated, removing variables which were not significant, or 95% confidence limits crossed the line of unity, unless they added to the model strength. Statistical analysis used Prism 8.2 (Graph Pad, San Diego, USA) and Social and Political Sciences Statistical Package (SPSS 24.0, IBM, Armonk, USA). Statistical significance was taken as p < 0.05.

Results

A total of 633 patients were scheduled to dialyse on the day of the prospective audit in their dialysis centre, and 603 (95.4%) completed the self-reported questionnaires. Thirty patients were unable to complete the questionnaires; 8 due to their inability to understand English, 5 due to dementia or other cognitive disorders, and 17 declined to participate. The questionnaire was read out to those patients unable to read the questionnaire. Twenty-nine patients suffered symptomatic intra-dialytic hypotension during the dialysis session (4.7%). These patients more frequently reported muscle cramps, dizziness, palpitations and feeling cold (Fig. 1). Patients suffering from symptomatic intra-dialytic hypotension were more likely to be female, of lower body weight, with greater frailty scores and with more comorbidity, and started dialysis with a lower blood pressure and serum albumin (Table 1). There were no differences between groups in terms of previous coronary artery bypass surgery (CABG) (6.8 vs 13.8%), coronary artery stenting (9.6 vs 10.3%), peripheral vascular disease (PVD) (15.2 vs 10.3%), prescription of blood pressure medications(62.2 vs 65.5%); calcium channel blockers (CCB) (24.9 vs 13.8%), angiotensin converting enzyme inhibitors (ACEI) (10.3 vs 10.3%), angiotensin receptor blocker (ARB) (9.1 vs 13.8%) or βblocker prescription (40.4 vs 55.2%) (all p > 0.05).

Fig. 1
figure 1

Dialysis symptom frequency scores using a visual analogue scale of 0 to 10. Patients divided into those who suffered symptomatic intra-dialytic hypotension requiring nursing intervention and those who had dialysis sessions without any intervention.

Results expressed as median, interquartile and 95% limits. *p < 0.05, **p < 0.01, ***p < 0.001 vs those with no interventions

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Table 1 Comparison of patient demographics, dialysis session and pre-dialysis blood tests of the 29 dialysis patients who suffered symptomatic hypotension requiring a nursing intervention vs all other patients who had no nursing interventions (574)
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As less than 5% of patients had suffered symptomatic intra-dialytic hypotension, we then divided patients into three groups based on whether their post-dialysis or intra-dialytic systolic blood pressure had fallen by > 20 mmHg (intra-dialytic hypotension), post-dialysis systolic blood pressure fallen by less than 20 mmHg or increased by less than 10 mmHg, or post-dialysis systolic blood pressure increased by > 10 mmHg (intradialytic hypertension) [20]. The demographics and comorbidity of these three groups are set out in Table 2. Compared with those with intra-dialytic hypertension, patients in the intra-dialytic hypotensive group who experienced the greater fall in systolic blood pressure reported more intra-dialytic cramps, headache, dizziness, shortness of breath and backache (Fig. 2. and Table 3), but time to recover post-dialysis was not different (X2 6.4, p = 0.6). There were no differences in specific comorbidities, or drug prescriptions between the three study groups in terms of previous CABG (7.5 vs 7.3 vs 3.5%), coronary artery stenting (8 vs 10 vs 9.6%), PVD (17.5 vs 11.6 vs 14.8%), prescription of blood pressure medications (60.4 vs 57.4 vs 67.8%); CCBs, (19.3 vs 23.9 vs 31.3%), ACEIs (10.2 vs 8.3 vs 13%), ARBs (10.7 vs 8 vs 9.6%) or βblocker prescription (40.6 vs 38.2 vs 44.3%) (all p > 0.05).

Table 2 Patient demographics of 603 dialysis patients, divided into three groups depending on whether systolic blood pressure (SBP) fell by 20 mmHg or greater (group 1), fell by less than 20 mmHg or increased by less than 10 mmHg (group 2), or increased by more than 10 mmHg (group 3)
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Fig. 2
figure 2

Dialysis symptom frequency scores using a visual analogue scale of 0 to 10. Patients divided into three groups based on whether their post-dialysis systolic blood pressure (SBP) had fallen by > 20 mmHg, fell by less than 20 mmHg or increased by less than 10 mmHg, or increased by > 10 mmHg. Results expressed as median, interquartile and 95% limits. *p < 0.05, vs those with an increase in SBP of > 10 mmHg

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Table 3 Percentage of patients reporting no symptoms during dialysis, divided into three groups depending on whether systolic blood pressure (SBP) fell by 20 mmHg or greater (group 1), fell by less than 20 mmHg or increased by less than 10 mmHg (group 2), or increased by more than 10 mmHg (group 3)
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Patients who had an asymptomatic 20 mmHg fall in systolic blood pressure or greater were heavier and had both greater absolute weight loss, and also when adjusted for pre-dialysis weight, and had higher pre-dialysis blood pressures (Table 2). However, there were no differences in comorbidity grading, frailty or self-reported distress thermometer scores, and haematocrit was highest in the group with the greatest fall in blood pressure with dialysis.

Systolic blood pressure fell to 90 mmHg in 12 patients (< 2%) and less than 100 mmHg in 42 patients (7%). In both cases lower nadir blood pressure was more common in female patients (X2 10, p = 0.002; X2 9.7, p = 0.02, respectively), and although individual symptom scores did not differ, total symptom scores were greater for those with a nadir systolic blood pressure of than 90 mmHg or lower (42.5 (21.5–61.5) vs 23 (19–38), p = 0.03) and with a nadir of 100 mmHg or less (22 (12–36) vs 13 (5–21) , p = 0.003). Time to recover reported was also longer for those patients with a nadir systolic blood pressure of than 90 mmHg or 100 mmHg compared with those with higher systolic blood pressures (Fig. 3).

Fig. 3
figure 3

Percentage of patients reporting time to recover after their haemodialysis session between less than an hour to more than 12 h. Patients divided into four groups based on whether their nadir systolic blood pressure (SBP) had fallen to 90 or 100 mmHg or less. Patients with a SBP of ≤ 90 mmHg reported longer recovery times compared with those with SBP > 90 mmHg (adjusted X2 15.7, p = 0.004); as did those with SBP of ≤ 100 mmHg compared to those with SBP > 100 mmHg (adjusted X2 = 12.1, p = 0.017)

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On univariate analysis, the change in systolic blood pressure, the absolute difference between the pre-dialysis and post-dialysis systolic pressures, so a greater fall in systolic blood pressure was associated with greater self-reported total symptom scores (r = 0.102, p = 0.013), backache (r = 0.13, p = 0.002), symptoms of low blood pressure (r = 0.098, p = 0.016), dizziness (r = 0.096, p = 0.019), headache (r = 0.09, p = 0.027), but not tiredness (r = 0.070, p = 0.088) or cramps (r = 0.070, p = 0.096). There was no statistically significant correlation between dialysis symptoms scores and psychological distress as assessed by self-reported distress thermometer scores, or dialysate temperature and patients reporting feeling cold during dialysis sessions, both p > 0.05.

We calculated the total symptom score for each patient and performed univariate analysis (Table 3). Taking the composite score, then there was a significant association with psychological distress, post-dialysis recovery time, and also the fall in systolic blood pressure and for patients with a systolic blood pressure < 100 mmHg (Table 4). A step-backward logistic regression model showed that a higher distress thermometer score, female gender, younger patients and those with a systolic blood pressure of < 100 mmHg were independently associated with a higher total symptom score (Table 5).

Table 4 Spearman univariate association with self-reported total dialysis symptom score
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Table 5 Step backward logistic multivariable model of high self-reported total dialysis symptom score compared to low total dialysis scores
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Discussion

Although haemodialysis treatments have been transformed over the last 50 years with many patients now attending for their dialysis treatment in free-standing dialysis centres without medical supervision, dialysis is not without complications. As intra-dialytic hypotension remains the most commonly reported complication of dialysis session [19,20,21], we wished to determine whether changes in blood pressure led to increased symptom reporting, as previous studies have reported that higher ultra-filtration rates result in longer post-dialysis recovery times [22].

Although only a small minority of patients had symptomatic hypotension requiring nursing interventions, when directly questioned the majority of patients reported some symptoms with their dialysis session. Both patients who had nursing interventions for intra-dialytic hypotension, and also those with an absolute fall in systolic blood pressure of more than 20 mmHg or a fall in systolic blood pressure to 100 mmHg or less, reported more symptoms,. Symptomatic patients were generally frailer, more likely to be female with lower pre-dialysis weight, which is in keeping with previous studies reporting that women are more likely to be at risk of intra-dialytic hypotension [23]. There has been a debate as to whether dialysis prescription factors or patient psychological factors are more important in determining patient reports of symptoms associated with dialysis [24, 25]. We found that patients reporting psychological distress, as assessed by self-reported distress thermometer scores [12], reported more symptoms with dialysis

As the number of patients who developed symptomatic hypotension requiring a nursing intervention, or those with a nadir systolic blood pressure of 90 mmHg or lower was relatively small, we reviewed the symptom scores from those patients with asymptomatic hypotension [18, 19]. These patients had a greater percentage weight loss, which would be in keeping with reports of higher ultrafiltration rates leading to more post-dialysis fatigue [26]. However, the ultrafiltration rates used in our patient cohort were much lower than those previously reported, and as such in our study, there was no statistically significant association [27]. Even so, a reduction in blood pressure during dialysis has been shown to lead to a reduction in the blood supply to vital internal organs. In addition to reports demonstrating reduced perfusion to the heart and brain, recent reports have also highlighted an association with mesenteric ischaemia [28, 29], which may reflect the increase in reports of backache with dialysis, in addition to the increased frequency of self-reported dizziness, headache, cramps and breathlessness comparing patients who had asymptomatic hypotension to those with intra-dialytic hypertension. Those patients with the lowest systolic blood pressures recorded during dialysis reported taking longer to recover post-dialysis.

Our study demonstrates that patients with both symptomatic and asymptomatic intra-dialytic hypotension report more symptoms with dialysis sessions. This would suggest that interventions to alter the dialysis session prescription could potentially reduce patient symptoms. As previous studies reporting on dialysis symptoms have observed an association between symptom reporting and higher ultrafiltration rates [26], required as a consequence of greater inter-dialytic weight gains, then designing interventions ranging from patient education initiatives to reduce inter-dialytic weight gains [30], altering dialysate sodium to achieve greater sodium losses without causing adverse effects [31, 32] could potentially ameliorate patient symptoms, although we could not demonstrate any effect of dialysate sodium or serum to dialysate sodium gradient on symptom reporting. We dialysed patients against cooled dialysates, and interestingly, there was no association between dialysate temperature and patients reporting feeling cold. Previous studies reporting on using lower dialysate temperatures have reported fewer intra-dialytic symptoms [33]. We found no effect of dialysate temperature on symptom reporting.

When we analysed patient total symptom scores, we found that patients with higher dialysis symptom scores also reported longer post-dialysis recovery times. Patients with higher symptom scores had higher distress thermometer scores [34], in keeping with an earlier report from a multi-centre study [24]. Previous studies have reported that younger dialysis patients report greater psychological distress [35], and this may account for our findings of greater dialysis symptom scores in younger patients. In addition, there was an association between patent symptom scores with low systolic blood pressure and female gender. Previous studies have reported that female dialysis patients are at greater risk of intra-dialytic hypotension [23]. On multivariable logistic regression, then psychological distress, female gender, younger age and a systolic blood pressure of < 100 mmHg remained independently associated with higher total dialysis symptom scores.

Although only a minority of our patients had nadir systolic blood pressure of 90 and 100 mmHg or lower, again these patients reported greater total symptom scores. Despite these patients having dialysis sessions which required no nursing interventions, they reported more intra-dialytic symptoms, and patients with a fall in systolic blood pressure also reported longer post-dialysis recovery times. It is therefore important to try and reduce hypotensive episodes during dialysis. Our study showed that a major difference between patients who had a fall in systolic blood pressure and those with a more stable blood pressure, or an increase in blood pressure, was greater weight loss, and as these patients had a higher pre-dialysis systolic blood pressure, this would suggest that these patients potentially were more fluid overloaded. As such, greater emphasis on patient education to restrict sodium intake may help to reduce inter-dialytic weight gains [36] and so reduce the amount of fluid required to be removed during the dialysis session [22].

Our study suggests that although most patients do not request nursing help and so appear to tolerate a fall in systolic blood pressure during dialysis, the fall in blood pressure is not asymptomatic as these patients report more intra-dialytic symptoms when directly questioned, and repetitive episodes of what has been thought to be asymptomatic temporary episodes of hypotension may result in permanent organ damage in the longer term, and increased risk of mortality [21, 37]. As such, more attention is required to minimise changes in blood pressure during dialysis sessions, and dialysis staff should also take more note of what are currently considered as asymptomatic changes in blood pressure.