Early-phase cumulative hypotension duration and severe-stage progression in oliguric acute kidney injury with and without sepsis: an observational study

Acute kidney injury (AKI) is an extremely common burden in intensive care units (ICUs) [1]. When critical illness is complicated by AKI, there is a well-known association with increased mortality [1, 2], but preventive measures have not yet been established. Maintenance of normal or even increased mean arterial pressure (MAP) could provide a benefit because autoregulation of blood flow is known to be lost during certain forms of AKI, especially in patients with sepsis [3]. Recent studies [4, 5] suggest that maintaining MAP ≥70 mm Hg could better protect patients with sepsis and AKI compared to maintaining MAP ≥65 mm Hg as recommended in the worldwide guidelines for sepsis [6, 7]. Other studies indicate that the time elapsed with blood pressure below threshold might be the key indicator of developing postoperative AKI [8, 9]. On the other hand, the optimal blood pressure threshold is still a matter of debate. Some studies have failed to indicate the effectiveness of maintaining high MAP in AKI management [10, 11].

Blood pressure management strategies to prevent progression of AKI to severe stages need to be established. Some reports exhibit the association between the time spent with blood pressure below threshold MAP and progression of AKI in patients with sepsis [12, 13]. However, whether intensivists should also manage blood pressure in patients with AKI without sepsis remains a point of contention [4, 5, 12‐14]. Moreover, it is uncertain whether managing hypotension duration in early-phase AKI is important in preventing progression to severe-stage AKI.

This study focused on oliguria, an easy-to-find marker for early-stage AKI in the ICU. In the early phase of oliguric AKI (6 h after the diagnosis of oliguric AKI), we investigated the association between cumulative hypotension duration below threshold MAP and progression of AKI among critically ill patients with and without sepsis.

The selection process for the study patients is presented in Fig. 1. We extracted 807 patients who stayed in the ICU for ≥24 h after oliguric AKI diagnosis. After excluding 269 patients who met the aforementioned exclusion criteria, we enrolled 538 patients with stage-1 oliguric AKI for our analyses. Progression to stage 3 was observed in 27 (19.6%) of 138 patients with sepsis and 27 (6.8%) of 400 patients without sepsis at ICU admission.

Patient characteristics, vasoactive use and fluid balance are presented in Table 2. Among the patients, 51.7% (278/538) were admitted to the ICU after surgery; 25.7% (138/538) had sepsis at ICU admission. The median APACHE II score was 17 (IQR 13–22). Patients with stage-3 progression had significantly higher serum creatinine levels at ICU admission (1.54 mg/dL vs. 0.86 mg/dL, p < 0.001), shorter time to oliguric AKI (10.7 h vs. 19.0 h, p = 0.001), higher SOFA scores (11 vs. 7, p < 0.001), and higher APACHE II scores (22 vs. 17, p < 0.001). During the 6-h period after oliguric AKI diagnosis, patients with stage-3 progression had more frequently received norepinephrine (66.7% (36/54) vs. 42.4% (205/48), p = 0.001) and vasopressin (11.1% (6/54) vs. 2.9% (14/484), p = 0.010) than patients without progression. During the first measurable 8-h period after the start of oliguria, patients with stage-3 progression had more fluid input (949 mL vs. 758 mL, p = 0.004), less fluid output (272 mL vs. 326 mL, p = 0.028) and more positive fluid balance (723 mL vs. 432 mL, p < 0.001) than in patients without progression. In patients with sepsis, however, the fluid parameters were similar between groups of patients with stage-3 progression and those with no progression (input: 848 mL vs. 840 mL, p = 0.265; output: 281 mL vs. 262 mL, p = 0.979; balance: 514 mL vs. 470 mL, p = 0.551). Of all patients, 6.7% (36/538) and 15.6% (84/538) died in the ICU and in hospital, respectively.

Blood pressure parameters in patients with stage-3 progression and those with no progression are presented in Table 3. Among all patients, patients with stage-3 progression exhibited significantly lower time-averaged MAP (71 mm Hg vs. 75 mm Hg, p = 0.003), lower lowest MAP (61 mm Hg vs. 65 mm Hg, p < 0.001), larger area under any threshold MAP (65 mm Hg: 2.0 h × mm Hg vs. 0.0 h × mm Hg, p = 0.001; 70 mm Hg: 10.0 h × mm Hg vs. 3.3 h × mm Hg, p = 0.001; 75 mm Hg: 27.8 h × mm Hg vs. 14.4 h × mm Hg, p = 0.001), and longer time below any threshold MAP (65 mm Hg: 0.5 h vs. 0.0 h, p = 0.002; 70 mm Hg: 2.4 h vs. 1.0 h, p = 0.002; 75 mm Hg: 4.6 h vs. 2.8 h, p = 0.002) than patients without progression. The AUROC of time-averaged MAP and lowest MAP was 0.62 (95% CI 0.54–0.71) and 0.63 (95% CI 0.55–0.71), respectively, for all patients. The AUROC of area under threshold MAP was 0.63 (95% CI 0.55–0.71) in 65 mm Hg, 0.63 (95% CI 0.55–0.71) in 70 mm Hg and 0.64 (95% CI 0.56–0.71) in 75 mm Hg. For the AUROC of time below threshold MAP, the AUROC was 0.62 (95% CI 0.54–0.70) in 65 mm Hg, 0.63 (95% CI: 0.55–0.70) in 70 mm Hg and 0.63 (95% CI: 0.55–0.71) in 75 mm Hg.

The longer the time below any threshold MAP continued, the more frequently stage-3 progression occurred (Fig. 2 and Table 4). Primary multivariable logistic regression models revealed that a hypotension duration of 3–6 h was significantly associated with stage-3 progression when threshold MAP was 65 mm Hg (adjusted OR 3.73, 95% CI 1.53–9.09, p = 0.004); however, such an association was attenuated when the threshold was 70 mm Hg (adjusted OR 2.35, 95% CI 0.96–5.78, p = 0.063) and 75 mm Hg (adjusted OR 1.92, 95% CI 0.72–5.15, p = 0.200) (Table 4). When the patients were stratified into patients with or without sepsis, the hypotension time of 3–6 h below MAP 65 and 70 mm Hg was significantly associated with stage-3 progression in patients without sepsis (65 mm Hg: adjusted OR 4.53, 95% CI 1.35–15.30, p = 0.015; 70 mm Hg: adjusted OR 4.42, 95% CI 1.03–19.00, p = 0.046), but was weak and not significant in patients with sepsis (Table 4). The results were similar when we performed sensitivity analyses by focusing on RRT initiation (Table 5).

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.

In conclusion, early-phase cumulative hypotension time below a particular threshold MAP was significantly associated with progression to the severe stage among critically ill patients with early oliguric AKI, especially in patients without sepsis. This association was weak in patients with sepsis. More attention should be paid to the length of time spent in hypotension in ICU care.