To the best of our knowledge, the present study is the first report explored the CRRT initiation timing on patient mortality and risk factors of patient mortality in RM patients who underwent CRRT. We have the following findings in our present study. Firstly, RM patients who received CRRT had high short-term mortality. Secondly, relatively earlier CRRT initiation (before the peak CK) was association with lower risk of 90-day mortality. Moreover, the requirement of mechanical ventilation and the elevated serum cTnI concentration were identified as independent risk factors of 90-day mortality as well.
RM is a common severe clinical presentation with complicated etiologies. The causes of RM were different among various studies [4, 8, 20]. In our present cohort, the common causes were trauma, heat stroke, and vascular ischemia. Trauma and vascular ischemia had been widely reported as major causes of RM as well [21, 22]. Compared with previous studies, a higher proportion of heat stroke was found in our cohort. Due to the inclusion of RM patients who received CRRT, the incidence of AKI (82.84%) of our cohort was dramatically higher than previous reports. Half of the patients need aggressive therapies such as mechanical ventilation (45.52%), vasoactive drugs (37.31%), and blood transfusion (60.3%). Most likely, the disease severity of the included patients mainly contributed to relatively high 90-day mortality rate (38.1%), which in the upper range of the previous reports (20.5%-40%) [8, 22].
CRRT is increasingly used in critically ill patients as a part of organ support. There are still no clear criteria for when to initiate CRRT in clinical practice. Premature CRRT may expose patients to the risk of additional CRRT-related complications. Nevertheless, delayed initiation of CRRT might increase the risk of organ injury by fluid overload and acid-base and electrolyte disorder [23, 24].The timing of CRRT for AKI was evaluated by several high-quality RCT, but the conclusions were controversial. The ELAN trial, which included 93% of surgical patients, showed that the early CRRT group had a significantly lower mortality and 1-year renal function unrecovered rate than the delayed treatment group [25]. Similar findings were observed in the AKIKI2 trail, the timing of treatment in this trail was further delayed in the later CRRT group (treatment was initiated only after 72 hours of oliguria or a blood urea nitrogen concentration above 112 mg/dL and emergence of mandatory indications) [26]. However, the other studies didn’t observe increased patient survival in the earlier CRRT group [27-29]. The inclusion of patients with different baseline disease was considered to be one of the causes of these controversial results, which suggested that the timing of RRT initiation should be evaluated in specialized patient group [30].
Compared to AKI patients with other etiologies, the patients with RM induced AKI are more likely to be benefited from CRRT by the continuous clearance of serum myoglobin and other toxic substances released from the damaged myocytes. Up to now, there is no study evaluated the timing of CRRT initiation for RM patients. However, the risk factors for patients who may developed AKI and required RRT have been extensively reported. It is believed that the increased serum myoglobin is the causative factor of AKI in RM patients. However, the short half-life (2-6 hours) limited the predictive validity of myoglobin on AKI development [31]. CK rises within 12 hours after the onset of muscle injury and peaks within 24-72 hours [31]. CK does not directly cause kidney damage, but it is considered to be a sensitive marker of muscle injury. Saskya Byerly et al. found out that patients with higher serum peak CK had more severe muscle injuries, greater Injury severity score, and increased risk of fracture [32]. Meanwhile, the longer half-life of CK makes it a relatively good marker for predicting patient prognosis. In a large cohort of 3111 trauma patients, Anatole Harrois et al. reported that the peak CK value was higher in patients with AKI stage R, I, and F than patients without AKI (2800IU/L vs. 977IU/L, p < 0.001) [33]. Additionally, CK level was reported to be associated with the need of CRRT as well. In a retrospective study of 2371 RM patients, McMahon et al. developed a prediction model of RRT or mortality with eight clinical variables, which included CK value [8]. However, the use of CK value to predict death and RRT in patients with RM is controversial because of the large variation in CK cutoff values.[15].
Our study further explored the predictive role of CK and found that CRRT initiation before peak CK time were associated with lower 90-day mortality risk. The appearance of peak CK can be localized the phase of 24-72 hours after myocytes damage, the CRRT initiation before the CK peak time could be considered as earlier CRRT, compared with the CRRT initiation after the CK peak time. Additionally, CK is a large molecule with a molecular weight of 87 KD and can not be cleared by CRRT [34, 35]. The appearance of peak CK is theoretically independent of CRRT. Therefore, the classification of earlier and later CRRT according to the CK peak is reliable in RM patients with CRRT. Furthermore, in the earlier phase of RM, the systemic inflammatory response was activated [36]. The increase of CK and MB were accompanied by a gradual rise in various inflammatory cytokines, including TNF-α, IL-1β, and IL-6 , as well [37]. And, it is reported that CRRT could reduce serum inflammation cytokines and facilitates immunomodulation [38, 39]. Therefore, earlier CRRT most likely could benefit RM patients by the clearance of MB and the alleviation of inflammatory response.
Moreover, the requirement of mechanical ventilation and serum cTnI concentration were identified as independent risk factors of 90-day mortality in our present study. Previous studies showed that the need of mechanical ventilation in patients underwent RRT is an independent risk factor of patient mortality [40]. In our cohort, the requirement of mechanical ventilation, which indicated severe physical condition and additional organ involvement, was understandable to be identified as one of the independent risk factors of 90-day mortality as well.
CTnI is a sensitive biomarker of myocardial injury, while elevated cTnI has been observed in RM patients in previous studies [41, 42], which indicated cardiac involvement and are associated with poor prognosis [43]. In a cohort study of 178 RM patients, a high accuracy of hs-cTnI was reported on the prediction of in-hospital death or prolonged hospital stay (AUC 0.74;95%CI 0.68-0.80) [44].The causes of RM, including sepsis, stroke, medications, and trauma, may lead to micro-injury to the myocardium, which is the major cause of elevated cTnI [45]. Moreover, massive release of cytokines, oxygen free radicals, and activation of systemic inflammatory response in RM patient could result in myocardial cell damage as well [42]. And in RM patients with CRRT, volume overload and ischemic-hypoxic injury to the myocardium could also be considered as the potential cause of elevated cTnI. These relationships most likely explain the identification of cTnI as one of the independent risk factor of 90-day mortality in our present study. The routinely monitoring of cardiac function would be helpful for RM patients with or without CRRT.
Our present study has several limitations. First, this is a single-center study. The disease spectrum might be different from other centers. Multi-center study should be performed to validate our findings. Second, although we reported a large cohort of RM patients with CRRT, the overall sample size is relatively small. The second type of error needs to be alerted on understanding our results. Third, the peak of CK cannot be judged prospectively, which may limit the direct use of our findings in clinical practice. However, our findings suggested that earlier CRRT may benefit RM patient survival. Further studies evaluate the timing of CRRT on RM patients are warranted and could consider the use of CK as one of the criteria for CRRT initiation.