In this study, we demonstrated that early-phase cumulative hypotension time spent below a particular threshold MAP was associated with progression to stage-3 oliguric AKI (progression to oligoanuria and use of RRT) among critically ill patients with early oliguric AKI, especially in patients without sepsis. This is the first report examining the level and duration of hypotension, and the septic state in patients with early oliguric AKI, and may provide information to guide the management of early-stage AKI in the ICU.
Which blood pressure parameter is the best – time-averaged MAP, the area under threshold MAP, or time below threshold MAP? From the calculated AUROC, the prediction of stage-3 progression was similar. Previous researchers have reported the optimal threshold of blood pressure to prevent AKI by examining time-averaged MAP [4, 5]. However, in our study, although the difference in time-averaged MAP in patients with and without stage-3 progression was statistically significant, we should consider whether the difference was clinically meaningful (71 mm Hg vs. 75 mm Hg) (Table 3). In addition, the method using time-averaged MAP does not consider variation in blood pressure. Is the method appropriate to investigate the optimal threshold of blood pressure? On the other hand, in patients who underwent non-cardiac surgery, the time spent below intraoperative MAP of 55–60 mm Hg has been strongly associated with increased risk of postoperative AKI [8, 9]. The primary outcome in these studies was not progression to severe-stage AKI, and not all patients were admitted to the ICU. Although the outcome and patient profile of these studies are different from those of our study, they indicate the importance of cumulative hypotension time in AKI research. Accordingly, in our study, we examined both area under threshold MAP and time below threshold MAP, considering the importance of hypotension time, and time below threshold MAP seemed comparable with and easier to apply in clinical practice than area under threshold MAP (Table 3).
In this study, hypotension below a particular threshold MAP was associated with stage-3 progression. Surviving Sepsis Campaign Guidelines recommend maintaining MAP ?65 mm Hg in patients with sepsis [6, 7], while some earlier reports indicate that maintenance of MAP ?70 mm Hg would prevent AKI and progression to severe-stage AKI. Badin and colleagues reported that time-averaged MAP of 72–82 mm Hg might be necessary for septic shock patients with AKI defined by serum creatinine, to prevent progression of AKI [4]. On the other hand, a recent large randomized controlled trial comparing mortality, AKI incidence, and RRT initiation between the target MAP of 65–70 mm Hg (low-target group) and 80–85 mm Hg (high-target group) in patients with septic shock (the SEPSISPAM study) did not support the maintenance of blood pressure much higher than 65 mm Hg [21]. However, it should be noted that MAP in most patients in the low-target group in this trial was actually maintained at higher than 70 mm Hg [21]. In addition, the target MAP of 80–85 mm Hg in the high-target group might have been much higher than necessary. Therefore, some caution would be needed to interpret the trial results.
Another important result of our study was the association between early-phase cumulative hypotension time and stage-3 progression among oliguric patients with AKI without sepsis, and the association was weak among patients with sepsis in any threshold MAP. In this study, more than 60% of patients without sepsis were postoperative. The mechanism of progression to severe AKI might be different between patients with sepsis and postoperative patients with AKI. Postoperative AKI might be more sensitive to the continuation of hypotension than septic AKI. Factors other than hypotension might affect the stage progression in septic AKI.
Is there a “golden time” to treat early-phase AKI, as in acute myocardial infarction and acute ischemic stroke? We identified an association between cumulative hypotension time and severe oliguric AKI, even in a short time-frame such as 6 h after oliguric AKI diagnosis. A recent study revealed that urine output responsiveness after a furosemide stress test is superior to any recent biomarker in the prediction of severe-stage progression [22]. Another study indicated that oliguric AKI is associated with poor prognosis, even when the serum creatinine level is not increased [23]. These findings, including ours, suggest that urine output might be efficient as a continuous monitor. Early diagnosis of oliguric AKI through continuous urine output monitoring would enable us to initiate earlier treatment of AKI. Effective treatments have still not been established for AKI, but future studies might provide effective procedures including optimal blood pressure levels in patients with early oliguric AKI. If there is a “golden-time” to treat AKI, early diagnosis by urine output and early treatment with blood pressure management would be clinically important.
This study has several limitations. First, the control of confounding factors may be insufficient because of the observational study design. It was difficult to obtain data on diabetes mellitus, chronic hypertension, the presence of hypotension before ICU admission, and the exposure to radiocontrast or nephrotoxic agents. Positive fluid balance has recently been a well-known risk factor for patients’ prognoses [24–26]. In our study, only fluid balance during the first measurable 8-h period after start of oliguria was available. In addition, more than 50% of the included patients were postoperative, but it was difficult to assess retrospectively whether oliguria was due to hypovolemia. Therefore, the results of this study do not directly imply that increasing blood pressure itself has an impact on AKI incidence and progression.
Second, we used only urine output to define AKI and the AKI stages. Therefore, our definition of AKI did not strictly follow the definition in the KDIGO criteria. However, it is well-known that preadmission baseline creatinine data are often unavailable in clinical practice [27]. As shown in our previous paper [19], baseline serum creatinine levels were not known among more than 50% of the patients in the ICU despite an effort to obtain the data. In many AKI studies, the serum creatinine back-estimation method has frequently been used for complementing missing data on baseline serum creatinine [28–30]. However, Bernardi and colleagues have pointed out that this frequently used method, assuming a “true” glomerular filtration rate of 75 mL/min/1.73 m2, is not accurate and that it might have caused misclassification [31]. Therefore, although our current study fundamentally targeted only urine output as a continuous monitor, it could be acceptable that we did not use baseline serum creatinine data.
Third, baseline blood pressure measurements could not be obtained in this study. Even in the SEPSISPAM study, which showed no difference in outcomes between the high-target MAP group and the low-target MAP group, the proportion of AKI and RRT among patients with chronic hypertension was lower in the high-target group than in the low-target group [21]. Consequently, baseline blood pressure might be an important co-morbid factor in AKI-related studies.
Last, this study was conducted in a single center, and the number of patients was small. Although sepsis has been reported as the leading cause of AKI in the ICU [1], most patients included in this study were patients without sepsis rather than patients with sepsis, who accounted for only 25.7% of the study sample. Therefore, the generalizability of the study might be limited.