This prospective multicentre study showed that a ≥40% increase in oxygen extraction during HD, measured using ΔOER%, identified patients with an increased risk of mortality during an average follow-up of 11.6 months.

This study enrolled 101 patients (average age, 72.9 years) with CVCs undergoing chronic HD treatment for 9.6 ± 16.6 years (Table 1) and evaluated the pre- and post-HD OER to obtain the intradialytic ΔOER. OER is obtained from the ratio of the central venous saturation to the arterial oxygen saturation, which measures the O2 parenchymal extraction better than the ScvO2 alone. In fact, the ScvO2 might change even in the case of arterial hypoxia, and in this case, its change does not represent a measure of parenchymal O2 extraction, especially in clinical conditions where SaO2 might change, as occurs during HD sessions [12]. For these reasons, OER is a more reliable parameter for monitoring parenchymal oxygen needs and use in HD patients [10]. In our population, the pre-HD OER was 30.8 ± 8.1%, which was within the normal range (20–30%). However, the OER increased during HD sessions, with a post-HD OER of 42.3 ± 13.8% and a ΔOER of 42.3 ± 34.8% (Table 1). This result confirms that during HD sessions, there is an increase in the extraction of parenchymal O2, characterised by a stability of the arterial oxygen saturation and a reduction of the ScvO2 (Table 1). This result is consistent with the evidence in the literature showing that hypoxic parenchymal stress develops during HD sessions [13,14]. This hypoxic parenchymal stress requires an increased oxygen extraction, which can be monitored using the OER [8]. Importantly, all OER sessions in the patients were in the absence of symptoms and evident changes in the blood pressure and heart rate (Table 1). It is important to note that OER and ΔOER values were stable over time (Figure 1) in our population, as already evidenced in previous studies [11]. This stability is crucial for rendering OER a clinically useful monitoring parameter. During the follow-up of 11.6 months, we recorded 44 deaths in the population, with an annual mortality of 20%. Of the deaths, 45%, 27%, and 27% were from cardiovascular, infectious, and neoplastic causes, respectively (Figure 4). This result is consistent with what is known in the literature on CVC HD patients, both in terms of the absolute mortality and the incidence of different causes of death [15]. Thus, our study population is representative of the general CVC HD patients in terms of mortality and causes of death. The main purpose of our study was to assess whether a high intradialytic ΔOER (40% threshold) is a risk factor for mortality in HD patients. This hypothesis is derived from the evidence that the hypoxic tissue stress that develops during an HD session causes alterations of organ functions, resulting in chronic organ damage and increased mortality [8]. In agreement with Chan et al., patients at greater clinical risk were identified as those with a greater ScvO2 reduction [16]. Furthermore, a pilot study of 20 patients identified the intradialytic ΔOER as a possible risk factor for mortality [11]. To verify the above hypothesis, we divided our population of 101 patients into two groups based on the first ΔOER value measured after enrolment in the study. The limit of the ΔOER used to identify the two groups was decided by the protocol to be 40% based on the data in the literature [11]. We dichotomised our population into two groups: ΔOER ≥ 40 and ΔOER Table 1, the two groups were clinically similar (same age, dialytic history, comorbidity, and dialytic efficiency), but the group with a ΔOER of ≥40% had a mortality of 60%, compared with 30% in the group with a ΔOER of p = 0.005, Table 1). This was confirmed by the survival curve (Figure 3), which showed that patients with a ΔOER of ≥40% had increased mortality (log-rank test: p = 0.001), and multivariate analysis, which highlighted a ΔOER of ≥40% as an independent risk factor in the studied population (Table 2). These results agree with other evidence confirming that patients who need to significantly increase oxygen extraction by the parenchyma during HD have a higher mortality risk, probably secondary to the increased chronic hypoxic parenchymal damage linked to the haemodialytic stress [17]. The change in oxygen extraction in our patients was not caused by a change in SaO2, which remained unchanged (Table 1), but by an increase in the parenchymal extraction, which resulted in a reduction of the ScvO2 and therefore an increase in the OER (Figure 2). An interesting fact that confirms what has already been highlighted in the literature [11] is that the ΔOER ≥ 40% group had a lower pre-HD OER (Table 1, Figure 2). These data may suggest that these patients have a lower adaptation to the uraemic condition. In fact, patients with ESRD have a chronic impairment of the ability to use and distribute O2 secondary to a reduction of the capillary bed and mitochondrial dysfunction [8,18,19]. According to various studies, the basal ScvO2 of patients undergoing HD is lower than expected because of the increased need for basal oxygen extraction in this population [17]. The presence of normal O2 extraction in a uraemic population can indicate a maladjustment to the condition, resulting in a large increase in the O2 extraction during the HD session. Patients who developed lower hypoxic stress (ΔOER Figure 2). Interestingly, the causes of death in the two groups studied (ΔOER ≥ 40% and Figure 4). In particular, the group with a ΔOER of ≥40% had an increased risk of mortality due to neoplastic causes (Figure 4, p = 0.04). These data are in agreement with the experimental evidence showing that intermittent hypoxia, such as that present in our patients, increases the risk of cancer [20,21]. This explains, at least in part, the increased presence of cancer in the group with increased intradialytic parenchymal hypoxia (Figure 4).Retrospectively assessing the differences between the non-survival (n = 44) and survival (n = 57) populations showed that non-survivors had a shorter dialysis history, lower albuminemia, and a higher average ΔOER and heart rate (Table 3). These data confirm some well-known risk factors in HD patients, such as low albuminemia and a high heart rate [22,23]. In particular, one of the parameters that changes in the case of tissue hypoxaemia is the heart rate, and our data showed that patients at greater risk of mortality had a higher heart rate and higher oxygen extraction during the HD treatment. According to our data, we identified two types of patients: those adapted to the uraemic state and those that were not adapted or maladjusted. The characteristics of this last typology of patients, with an increased risk of mortality, are an intradialytic ΔOER ≥ 40%, a lower pre-HD OER, a higher basal heart rate, and a shorter HD history. A major limitation of the OER measurement technique is that it can be exclusively applied to patients with CVC and without a fistula. However, recent evidence showed that CVC use in HD is nonetheless necessary in 50–60% of patients with poor vascular systems who are also fragile and have higher mortality rates (9). In these patients, the ΔOER could be an easily measurable parameter applicable in clinical practice to highlight the most fragile patients. This would allow us to act on these patients with targeted therapies. Another limitation of the study was that, due to the observational nature of the protocol, it was not possible to verify if the intradialytic ΔOER could be reduced by therapeutic interventions (e.g., modulation of intradialytic ultrafiltration, pre-HD physical activity, pharmacological heart rate modulation). This is a very interesting and important point and future interventional studies are needed to assess whether the ΔOER can be reduced with therapeutic actions.

In conclusion, our data showed that patients who develop greater parenchymal hypoxic damage during HD treatment have an increased mortality risk and that the measurement of the OER and intradialytic ΔOER can highlight the development of this critical hypoxic damage.