Treatment of hypocalcemia in septic patients remains a controversial issue. The international guidelines developed by the Surviving Sepsis Campaign have no recommendation for calcium administration as a therapeutic measure. However, we still lack evidence-based guidance since no randomized controlled trial has investigated whether calcium supplementation should be given to septic patients. Unlike previous studies, our investigation assessed the prognosis of septic patients with or without calcium supplementation by stratified analysis of the iCa and SOFA scores. We found that calcium supplementation prolonged the time of hospitalization and had a double effect on mortality depending on the severity of the disease.
The morality curve in non-calcium supplement patients stratified by iCa intervals showed a U-shape, implying that abnormal iCa poses a risk to septic patients. Because hypocalcemia is more prevalent among septic patients than hypercalcemia is (in our case, 70.12% vs 3.30%) and patients with severe hypocalcemia require critical care for a longer period, thus, hypocalcemia would be another prognostic marker of sepsis. Nevertheless, we found that the minimum point of this mortality curve was located at the mild hypocalcemia interval but not at the normal iCa range, suggesting that patients maintained under mild hypocalcemia may gain a benefit in outcome. Our recently experiment using septic model also showed that the mouse pre-treated with EDTA-2Na before the cecal ligation and punctuation (CLP)-operation, had 20 ~ 50% lower mortality compared with the non-EDTA-2Na treatment group (unpublished data). Despite these finding, whether the iCa change in blood is a protective mechanism or simply a consequence of metabolic dysregulation when the body undergoes a critical illness remains to be established. If the former is true, calcium supplementation may increase the burden of the body, which would attempt to downregulate the iCa and therefore worsen the outcome. Overall, the LOS in the ICU and hospital in septic patients with calcium supplementation was higher than that in the non-calcium supplement group. To examine whether the LOS may vary under different subranges of iCa and severity of disease, we stratified the LOS according to the iCa and SOFA scores. Nevertheless, the LOS tended to be higher in nearly all subranges of the calcium treatment group, suggesting that patients with calcium supplementation, longer stays in the hospital are caused by calcium treatment instead of the difference in iCa and severity of cases. In addition to septic patients, critically ill patients with calcium supplementation tend to stay longer in the hospital. One retrospective analysis of the effect of calcium treatment on critically ill patients showed that their LOS in both the ICU and hospital was longer than that of the non-calcium supplement group (3.25 (1.89 ~ 7.04) vs 1.79 (0.96 ~ 3.19), p < 0.001; 10 (6 ~ 17) vs 6 (4 ~ 12), p < 0.001, respectively), although a lower mortality was observed in the calcium supplement group.
Unlike hospitalization, there were crosses between the two mortality curves, suggesting that calcium supplementation has the opposite effect from case by case. It would be valuable for clinical decision making to determine which situation is suitable for calcium supplementation. Therefore, the intersection of the mortality curves was calculated, and we found that patients with calcium supplementation tended to have a higher hospital mortality when their iCa on first ICU admission was approximately 0.94 ~ 1.16 mmol/L, suggesting that attempted blood calcium correction at this interval would be harmful. Because the majority of septic patients’ iCa on the first ICU admission was located at this iCa interval, this may explain why some studies revealed that calcium supplementation has an adverse effect on the prognosis of septic patients[16, 20] and septic model[21, 22]. However, on the contrary, there is a trend showing that calcium supplementation decreased mortality when iCa on the first ICU admission was lower than 0.9 mmol/L and higher than 1.20 mmol/L, although we would not confirm this finding in the survival analysis, probably due to the small number of patients in those subgroups.
The double effect of calcium supplementation was significant when the patients were stratified according to the SOFA score. From this perspective, taking the SOFA score as a reference index for clinical decision making would be valuable. Although the SOFA score is not a routine clinical reference index for calcium administration. However, the incidence of severe hypocalcemia tends to be more pervasive in severe septic cases, as a negative correlation between iCa concentration and mortality was observed in our and previously studies[9, 10]. Moritoki et al. reported that iCa concentration has no independent association with mortality and only extreme abnormalities of iCa are independent predictors of mortality. In keeping with these results, it might be more convincing to say that calcium supplementation would benefit the outcome when the SOFA score is > 8 as well as when patient under severe hypocalcemia.
The underlying mechanism of the double effect of calcium supplementation in septic patients is not well illustrated. On the one hand, calcium supplementation administered to patients with severe hypocalcemia may avoid life-threatening complications such as cardiac arrest or seizures, which may explain why patients with iCa levels lower than 0.90 mmol/L have the highest mortality compared with patients with other iCa ranges. In addition, iCa also plays an important role in maintaining hemodynamics, and a direct relationship between iCa and arterial pressure has been found in critically ill patients. It has also been reported that calcium supplementation may improve hemodynamics by increasing the mean arterial pressure (MAP), left ventricular stroke work index, and CO in critically ill patients[26, 27] and may improve heart function. On the other hand, calcium supplementation can be deleterious at the cellular level because iCa may shifts into cells[29–31], giving additional parenteral calcium could therefore potentially aggregate the accumulation of cytosolic iCa concentrations, which would over activate pathways and generate reactive oxygen species that finally trigger cell death. Studies using calcium blockers as a treatment for sepsis showed an improvement in the outcome[33–35], supporting this notion.
Therefore, the advantages and disadvantages should be weighed before calcium supplementation to the patient. Interestingly, our study showed that given calcium supplementation to patients with iCa on first ICU admission, more than 1.20 mmol/L tended to result in less mortality, as too high of an iCa level is also an increased risk factor for mortality in sepsis. However, it is important to note that although hypocalcemia is very common in septic patients, there are still a certain number of patients who do not present with hypocalcemia even though their SOFA scores are relatively high. Is it possible that these patients do not have an iCa influx problem? If so, it would be valuable to examine the contribution of calcium supplementation to hemodynamics in those individuals.
There are several limitations in this study. First, it was retrospective and purely observational. In particular, some patients who may have received calcium supplementation prior to admission to the ICU were not included in the analysis. Second, the dynamic of iCa could be fast-changing, both hypo- and hypercalcemia may present at one patient during the ICU stay, our study only focus on the iCa on the first ICU admission may be inadequate, despite we found it correlated with mortality in septic patients. In addition, the sample size of patients with iCa < 0.90 or > 1.20 mmol/L was small, also rendering the study underpowered to produce convincing conclusions in this subgroup. Third, our approach did not investigate the interactions with other factors associated with prognosis in sepsis. Finally, our study only presented a rough reference range of iCa and SOFA scores for calcium supplementation; greater amounts of data are required, and controlled intervention research should be performed to assess the accurate range to which this intervention should be applied for clinical decision making.