Over the past few decades, the incidence of acute kidney injury (AKI) has increased, and it is a common complication in patients admitted to intensive care units (ICUs), and is closely associated with adverse outcomes such as prolonged ICU and hospital stay, development of chronic kidney disease (CKD), and increased risk of short-and long-term mortality (1–3). In ICUs, the probability of AKI leading to death is up to 50% (4).

AKI is not a single disease, but a syndrome consisting of multiple clinical conditions. The prognosis of AKI depends on the underlying disease, the severity and duration of renal impairment, the patient’s renal baseline condition, and the treatment status (5). Fluids are one of the most commonly used therapies for critically ill patients and represent the cornerstone of hemodynamic management in ICUs. The use of fluids to optimize hemodynamics during the perioperative and early stages of sepsis has been shown to improve patient outcomes (6). On the other hand, liberal administration of fluids may lead to a positive fluid balance, and recent observational studies have demonstrated an association between positive fluid balance, renal non-recovery, and mortality in children and adults with AKI (7).

Acidosis is the most common acid–base disturbance seen in AKI, and recent studies have shown that AKI with metabolic acidosis potentially indicates a more severe course and worse outcome, including high mortality and increased length of stay in the hospital and ICU (8). On the one hand, AKI can cause metabolic acidosis; on the other hand, accumulating evidence identifies metabolic acidosis not only as a consequence of, but also as a contributor to the progression of kidney dysfunction (9). Anion gap (AG), an indicator that reflects the unmeasured anion concentration, is applied to detect and evaluate the presence and severity of metabolic acidosis. While AKI has been investigated widely for hospital mortality, AKI in association with metabolic acidosis has been less well studied.

Sodium bicarbonate (SB) infusion is mostly administered to treat severe metabolic acidosis. However, it is controversial whether SB should be used and which dosage should be used in clinical practice (10, 11). A retrospective observational study revealed that SB infusion may reduce ICU mortality in septic patients who presented with AKI stage 2 or 3 (12). Therefore, we hypothesized that early sodium bicarbonate infusion may be able to correct acidosis and halt its progression, thereby mitigating the risk of additional renal damage and resulting in lower mortality in patients with AKI.

We identified AKI adult patients according to the KDIGO criteria, and after including only adult patients’ first ICU admissions, 1853 AKI patients with metabolic acidosis 48 h after ICU admission from the MIMIC-IV database were included in our study. Among the study cohort, 614 patients received SB treatment, and 1,239 patients did not receive SB treatment in the first 48 h after entering the ICU department (Figure 1).

The baseline characteristics of the SB treatment group and non-SB treatment group before and after PSA matching are shown in Table 1. The SB treatment group had a more serious situation than the non-SB group. The SB treatment group had significantly higher severity scores on admission [SOFA 9.0 (7.0, 11.0) vs. 7.0 (5.0, 9.0)]. A larger proportion of the SB patients received vasopressors (36.5% vs. 17.1%) during the first 24 h of their ICU stay, but there were few differences in mechanical ventilation. In the first 24 h of admission, PH [7.19 (0.11) vs. 7.26 (0.07)], BC [12.36 (4.26) vs. 15.96 (3.25) mmol/L] and urine output [684.00 (264.25, 1399.25) vs. 1000.00 (561.00, 1667.00) mL] were significantly lower in the SB group. On the first day, fluid input [3825.00 (2081.25, 6257.50) vs. 2300.00 (1100.50, 3922.50) mL] and anion gap [24.23 (7.79) vs. 19.89 (5.82)] was significantly higher in the SB treatment group. Renal function, including creatinine [2.60 (1.60, 4.10) vs. 1.60 (1.10, 2.70) mg/dL] and BUN [42.00 (26.00, 67.00) vs. 32.00 (20.00, 51.50) mmol/L], was more serious in the SB treatment group.

After propensity score analysis, we matched 390 pairs of SB treatment and non-SB treatment patients in subsequent studies. The imbalance of variables was reduced, and all variables had an SMD value <0.1. In our study, SB infusion was not associated with improved mortality in all AKI patients after PSA matching (p = 0.056). However, SB infusion is associated with beneficial mortality in AKI patients with high AG metabolic acidosis (p = 0.012), as shown in Table 2. Our further study found that the use of SB was an important factor correlating with the mortality outcome in AKI patients with high AG acidosis (p = 0.021), as shown in Table 3.

In our study, variables could be estimated using inverse probability weighting (IPW) to correct both for confounding and for forms of selection bias (Figure 2). PH, BC and lactate were the most important predicting variables of SB use; among them, pH ((for each 0.1) increase, p < 0.001), BC (for each 5 mmoL/L increase, p < 0.001) and lactate (for each 1 increase, p = 0.002), as time-varying variables, all have significance (Table 4). Our results revealed that SB treatment was not associated with improving hospital mortality in the overall cohort of patients (p = 0.179). MSCM showed that AKI stage 1 to 3 patients had a less significant relationship between SB use and mortality (AKI phase 1, p = 0.126; AKI phase 2, p = 0.131; AKI phase 3, p = 0.106). SB use still closely correlated with the improving outcome of the AKI patients with high AG metabolic acidosis (HR:0.88, p = 0.045) as shown in Table 5.

By considering 48 h SB volumes, the results showed that receiving 800–1,600 mL was associated with reduced risk of mortality as compared with the non-SB group (HR 0.56; 95% CI 0.31–0.99; p = 0.045). Beneficial effect was not observed in the small (dose <400 mL) and large volume (dose >1,600 mL) groups (Table 6).

The present study focused on the effect of SB infusion on hospital mortality in AKI patients with metabolic acidosis. In our study, SB infusion was verified to not benefit all-stage AKI patients. But the improving hospital mortality of the AKI patients with high AG metabolic acidosis was associated with SB infusion; Previous studies have confirmed that high AG is an important predictor of all-cause death (18, 19), and the rate of patients with elevated AG requiring admission to the ICU and the mortality rate were significantly higher (20). Another study suggested that the risk of death of AKI patients within 28 days during hospitalization in the ICU was increased when AG ≥14 mmol/L (21).

The metabolic acidoses are readily subdivided into those with a large AG (HAGMA) and those with a normal AG (by definition the hyperchloremic metabolic acidoses). When HAGMA exists, the reciprocal relationship between the amount of increase of [AG] and decrease in [HCO3−] (designated as the Δ [AG]/Δ[HCO3−] can be a very helpful indicator of certain forms of mixed acid–base disorders (22)).

When HAGMA occurs, the ratio of Δ[AG] to Δ[HCO3-] is disrupted and the acid–base balance of the body is impaired. Infusion of SB provided a weak base and was able to correct the acidosis by adding bicarbonate base. The results of this study further confirm that SB infusion improves hospital mortality in AKI patients with high AG metabolic acidosis.

This study used PSM and MSCM and considered the effect of baseline and time-varying confounders. PH, PaCO2, lactate and BC were examined as time-varying factors. SB infusion and pH, PaCO2, lactate and BC are an interacting and dynamically changing relationship throughout the course of medical care, and the use of MSCM, can effectively minimize the effects of these confounding factors. Previous studies have confirmed that the MSCM model can be used for the observation and analysis of time variables and outcomes (23, 24).

In our study, SB infusion was verified to not benefit all-stage AKI patients. But the improving hospital mortality of the AKI patients with high AG metabolic acidosis was associated with SB infusion. This study also has some limitations, as an observational single-center study that retrospectively reviewed electronic health record (EHR) data, the potential for residual confounding by uncaptured variables in the EHR and the generalizability of the findings to other institutions require further investigation. Second, we used PSM and MSCM to balance important confounders, but residual confounders could not be completely excluded. Finally, we hope to explore this in some prospective trials and conduct further randomized controlled trials to confirm the results of this study.

In conclusion, we found that the use of SB infusion in AKI patients complicated with metabolic acidosis has little association on hospital mortality. At the same time, we also found that timely use of SB for AKI patients with high AG acidosis significantly correlated with improving hospital mortality. Further larger randomized controlled trials are needed to confirm these results.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Massachusetts Institute of Technology (Cambridge, MA) and Beth Israel Deaconess Medical Center (Boston, MA). The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants' legal guardians/next of kin in accordance with the national legislation and institutional requirements.

YW: Data curation, Methodology, Writing – original draft, Writing – review & editing. LC: Data curation, Writing – review & editing. GG: Data curation, Writing – review & editing. YG: Methodology, Writing – review & editing. HG: Supervision, Writing – review & editing.