We report the first analysis of the potential role of chloremia on the outcome of patients with septic shock. Our results show that hyperchloremia was frequent in patients with septic shock resuscitated with chloride rich crystalloids, however, significantly less frequent than hyperlactatemia. Independently of the presence of hyperlactatemia, hyperchloremia was associated with more frequent metabolic acidosis and more pronounced acidemia. Nevertheless, resuscitation using chloride rich fluids did not worsen shock-related metabolic acidosis nor impeded its correction, even in the presence of hyperchloremia. Hyperchloremia was not associated with an increased risk for AKI or death.
Strong associations between high chloride levels and worse outcome, AKI or death, have been reported; however, in various cohort studies discrepant results exist [12, 13, 20, 21]. Our findings are consistent with several negative retrospective cohorts assessing the role of hyperchloremia in ICU patients. In a single centre study enrolling 1045 patients with sepsis, 29% of them developing hyperchloremia, Yessayan et al. [22] did not show an association between hyperchloremia nor delta chloremia (as defined by increase > 5 mmol/L) and AKI. In a multicentre study including patients with severe acidemia, 54% of them with septic shock, the pH value and lactatemia were significantly associated with increased mortality, while chloremia was not [23]. Similarly, in a general population of ICU patients, Gunnerson et al. [24] found that lactate was a strong and independent predictor of mortality contrary to chloremia. A moderate increase in serum chloride of 5 mmol/L, even in patients with chloremia in normal range, has been shown to impair renal function and worsen survival in septic patients [12, 13]. We, therefore, tested different chloride parameters (i.e., hyperchloremia, chloremia as a time-dependent variable, maximal concentration, increase in concentration > 5 mmol/L); none of them was significantly associated with neither AKI or mortality. The negative results of our study deserve discussion of the underlying hypothesis. We assessed the role of chloremia in the most severe population reported so far. On the one hand, severe patients who receive large volumes of fluids are more exposed to the risk of hyperchloremia and its related adverse effects, on the other hand, stronger factors determining renal function and survival could hide the specific effect of chloremia. In patients with shock, the benefit of fluids on shock reversal could outweigh the risks of hyperchloremia. In our study, despite the occurrence of hyperchloremia, fluid resuscitation did not worsen acidemia, which is in contrast to data reported in surgical patients with normal pH at baseline [25]. Of note, in cohort studies reporting a negative impact of chloride load, the volume of fluid administered (i.e. around 5 litres within 24 or 48 h) was usually higher than in our study, despite a lower severity of patients studied [26,27,28].
We assessed the impact of hyperchloremia in the context of hypertonic fluid resuscitation. Occurrence of hyperchloremia was, therefore, driven by hypernatremia which per se might have a different impact on the outcome. However, the reduced difference between sodium and chloride concentrations indicating excessive chloride load was not associated with worse outcome. In trauma patients, hypertonic fluid resuscitation induced a huge, but transitory, increase in chloremia [29]. Compared to isotonic crystalloids, hypertonic solutions have never been identified as a significant risk for inducing AKI under these conditions [30].
The mechanism by which hyperchloremia would induce AKI remains highly speculative, particularly in the context of and the presence of markedly altered vasomotion. Comparing NaCl solutions of different chloride concentrations, animal studies have suggested that infusing a chloride-rich solution, directly into the renal artery, critically determined changes in renal blood flow due to intra-renal vasoconstriction [31, 32]. This finding was not confirmed in a more relevant animal model of sepsis resuscitated with large amounts of crystalloids [33]. Compared to a balanced solution, normal saline induced hyperchloremia and acidosis; however, no difference was found for renal hemodynamics and function [33]. Moreover, decreased renal blood flow velocity and cortical tissue perfusion have been reported in healthy volunteers after infusion of 2L of saline [34]. Finally, ICU patients in whom renal perfusion was assessed by renal Doppler, no relation was found between chloremia and resistive index [35].
Our study has several strengths: (i) the study design combines a number of features that reduce the risk of bias, (ii) metabolic parameters were prospectively recorded at precise time points with a concomitant record of serum lactate and chloride allowing precise adjustment, (iii) the choice of the fluids, the metabolic parameters to be recorded and the renal monitoring were imposed by the study design. Hence, in contrast to previous retrospective cohort studies based on administrative funding databases, biases related to fluid selection and metabolic dosage determined by patient characteristic and physician choices were ruled out. Such biases are present in the “SMART” trial in which the type of balanced solution, metabolic and renal function monitoring were left at the discretion of investigators [4].
Our study also has limitations that deserve attention. It is a post hoc analysis and the number of patients, hence, is quite limited. Nevertheless, it is noteworthy that no trend of worse evolution was observed among patient with hyperchloremia. Of note, we observed a trend toward higher risk of AKI in the sensitivity analysis when hyperchloremia was imputed to the early dying patient at H24 but not at H0 (Additional file 1: Table S3). Crystalloids used were only chloride rich with a high proportion of patient developing hyperchloremia. However, a sufficient number of patients remained free of hyperchloremia. The rules applied in the study for stopping hypertonic saline when hypernatremia occurred might have minimized the risk and the intensity of hyperchloremia. However, hyperchloremia over beyond 120 mmol/l was observed in 25% of the patients (Additional file 1: Table S2).
Our study did not assess the potential beneficial effect of using balanced crystalloid. The resolution of metabolic acidosis could have been more rapid using balanced solutions. The impact of the rapidity of acidemia correction on the patients’ evolution, however, remains unknown. Our results merely suggest that the potential beneficial effects of balanced solution in septic shock patients are might be unrelated to the serum chloride concentration. The definition of AKI was based on serum creatinine level at inclusion in the “HYPER2S” study. Using baseline serum creatinine before septic shock occurrence may have allowed detection and exclusion of patients with AKI occurrence before exposure and may have resulted in different finding. We used baseline creatinine at H0, i.e. just before exposure, because otherwise patients developing AKI before the start of sepsis start and exposure to chloride-rich solutions (H0) would have been wrongly classified as AKI-related to hyperchloremia. Considering the design of our study and the large confidence intervals of associations, our results do not rule out a negative association between chloride parameters and outcomes in patients with septic shock. Our results need to be confirmed by a larger study specifically designed to address this question in patients with septic shock of similar severity.
In conclusion, patients with septic shock resuscitated with chloride rich crystalloids are frequently exposed to hyperchloremia. However, the impact of hyperchloremia on outcomes might be negligible compared to the inherent risks from acute disease. Further studies are required to identify the specific role of chloride disturbances and use of balanced crystalloids on the outcome of septic shock patients.