Authors: Swetha Reddy, Bo Hu, Kianoush Kashani
Categories: Original Article, Acute kidney injury, fluid, rate, resuscitation, septic shock
Source: International Journal of Critical Illness and Injury Science
Septic shock is the leading cause of acute kidney injury (AKI) in critically ill patients. The foundation of early septic shock management includes early fluid resuscitation, but the association between fluid resuscitation rates and kidney outcomes remains unclear. This investigation examines the association between fluid resuscitation rate and AKI recovery.
In the medical intensive care unit of Mayo Clinic Rochester, adult patients with AKI and septic shock were retrospectively studied from January 1, 2006 to May 31, 2018. The surviving sepsis campaign recommends an initial fluid bolus of 30 ml/kg for sepsis resuscitation. The cohort of patients was divided into three groups based on the average fluid resuscitation time (<1 h, 1.1–3 h, >3 h) and the corresponding fluid rate ≥0.5, 0.17–0.49, and <0.17 ml/kg/min, respectively. The primary outcome was the recovery of AKI on day 7. To account for potential confounders, multivariable regression analyses were conducted.
After meeting the eligibility, 597 patients were included in the analysis. The AKI recovery was considerably different among the groups (P = 0.006). Patients in group 1 who received fluid resuscitation faster had a higher rate of AKI recovery (53%) compared to group 2 and group 3 (50% and 37.8%).
In septic shock patients with AKI, a higher fluid resuscitation rate of 30 ml/kg IV fluids within the 1^st^-h sepsis diagnosis (i.e., >0.50 ml/kg/min) lead to higher AKI recovery compared with slower infusion rates.
Keywords: Acute kidney injury, fluid, rate, resuscitation, septic shock
Sepsis pathophysiology includes dysregulation in the host response to infection, which can lead to life-threatening organ dysfunction. Septic shock is a subset of sepsis and is associated with a higher mortality risk than sepsis alone due to its effects on profound circulatory, metabolic, and cellular abnormalities.[1] Conservative estimates indicate that sepsis is a leading cause of mortality and critical illness worldwide, although the incidence remains unknown.[2] Sepsis was a major public health concern, accounting for more than $20 billion (5.2%) of the US hospital costs in 2011.[3]
The estimated incidence of acute kidney injury (AKI) in intensive care units (ICU) is more than 50% and the most common complication from sepsis and septic shock.[4] Sepsis-associated AKI (SA-AKI) is correlated with high mortality and morbidity.[4,5,6] SA-AKI pathophysiology is often due to multiple factors, including sepsis-mediated hypoperfusion and systemic inflammatory response. Evidence shows that inflammation, microvascular dysfunction, and metabolic reprogramming are the cardinal mechanisms that likely contribute to the development of SA-AKI. In addition, exposure to nephrotoxic antibiotics could increase the AKI intensity.[7]
Various studies have reported the clinical presentation and patient characteristics of SA-AKI. These studies have shown notably unfavorable outcomes with SA-AKI versus non-septic AKI.[6,8,9] Scarce information about any targeted therapy for AKI recovery in sepsis is known.
Before the onset of irreversible tissue damage, fluid resuscitation for septic shock restores sepsis-induced hypovolemia, modulates early inflammation, and prevents cardiovascular collapse and death.[10] Hence, fluid resuscitation within the first 3 h of the shock state is strongly recommended by the surviving sepsis campaign (SSC) guidelines as the key foundation of septic shock treatment.[11,12] In addition, Hu et al. showed an association between the completion of SSC bundle components within 3 h, resulting in earlier shock reversal and lower mortality. In septic shock patients, a higher fluid resuscitation rate, when given within the initial 2 h, correlated with early shock reversal and lower mortality.[13]
But so far, with early goal-directed therapy, no improvement in kidney outcomes has been discovered.[14,15,16,17] No advantage of protocol-based management on mortality or need for kidney replacement therapy (KRT) has been demonstrated in the three leading clinical trials in patients with septic shock (Protocolized Care for Early Septic Shock, Australasian Resuscitation in Sepsis Evaluation, and Protocolized Management in Sepsis).[15,16,17]
While the association between fluid resuscitation rate and septic shock reversal has been analyzed recently, very little is known about kidney outcomes based on the rate of fluid resuscitation. Based on the above data, we hypothesize that the fluid replacement rates <0.17 ml/kg/min during sepsis resuscitation are associated with a lower recovery rate of kidney function following AKI development in septic shock patients.
In this historical cohort study, we conducted in Mayo Clinic, Rochester, Minnesota, of adult patients admitted to the medical intensive care unit (MICU) from January 1, 2006 to May 31, 2018. Screening patients for eligibility was conducted using electronic health records (EPIC®, Verona, WI, United States). Inclusion criteria included adult patients who were >18 years of age and who developed AKI following septic shock. They underwent resuscitation with IV fluids >30 ml/kg within the first 24 h of admission. Patients with all other types of shock (cardiogenic shock, obstructive shock, and hypovolemic shock according to the International Classification of Diseases-10 [ICD-10] code of discharge diagnosis) were excluded. Other exclusion criteria included patients without Minnesota research authorization, prisoners, vulnerable adults, known pregnancy at the time of index admission, and patients who stayed in the MICU for <48 h. The Institutional Review Board (# 21-011762) reviewed and approved the study. Due to the minimal risk nature of the study, informed consent was waived for patients.
AKI on admission was defined using KDIGO criteria where an increase in serum creatinine of ≥0.3 mg/dL within 48 h or ≥50% within 7 days and further defined into stage 1 with an increase in serum creatinine of ≥0.3 mg/dL or 1.5–1.9 times baseline, stage 2 with an increase in serum creatinine to 2.0–2.9 times baseline and stage 3 with an increase in serum creatinine to ≥3.0 times baseline or increase in serum creatinine of ≥0.3 mg/dL to ≥4.0 mg/dL or the initiation of KRT.[18] Kidney function recovery was defined as per the ADQI definition,[19] that is, the return to within 50% above baseline serum creatine and liberation from KRT. Based on clinical judgment, the decision to start KRT was made by the combined decisions between the nephrology and critical care teams. The modality of dialysis was at the discretion of the nephrologist. Sepsis was defined as an increase in the Sequential (Sepsis-related) Organ Failure Assessment (SOFA) score of 2 points or more, which was caused by presumed or confirmed infection (Sepsis-3).[20] The criteria for the diagnosis of septic shock included the diagnosis of septic shock based on ICD-10 code of discharge diagnosis, mean arterial pressure (MAP) <65 mmHg with vasopressor use and serum lactate level >2 mmol/L along with an antibiotic prescription, or criteria of sepsis described by Sepsis-3. Patients whose first recorded MAP of <65 mmHg occurred in MICU were the only patients included minimizing the bias of pre-hospital fluid resuscitation. There was no record of vasopressor utilization before MICU admission.
A volume of 30 ml/kg of crystalloid on admission divided by time was determined as the initial fluid resuscitation rate (ml/kg/min) as a cutoff for the inclusion of patients in our study based on the surviving sepsis guideline recommendations. Patients were categorized into groups 1–3, based on the resuscitation ≤1 h, 1.1–3 h, and >3 h, respectively. The corresponding fluid rates for the groups described above were ≥0.5, 0.17–0.49, and <0.17 ml/kg/min, respectively.
Acute Physiology And Chronic Health Evaluation (APACHE) III and SOFA scores and Charlson comorbidity index (CCI) were determined at hospital admission and calculated automatically.
The Multidisciplinary Epidemiology and Translational Research in Intensive Care Data Mart was used to collect baseline variables, including patient demographics, hospital admission weight, hemodynamic variables, SOFA, APACHE III scores, and CCI.[21] Resolution of AKI on day 7 was the primary outcome, including the recovery of stage 3 AKI and day 28 AKI. Along with the liberation of hemodialysis on MICU and hospital discharge.
Multiple secondary outcomes were evaluated, including weight-adjusted fluid balance in the first 3 h of resuscitation and throughout MICU stay, lactate clearance and MAP within the first 3 h of resuscitation, need and length of mechanical ventilation, SOFA score changes between day 1 and day 2, and the mortality at MICU, hospital discharge and on day-28.
The data were summarized using frequencies and percentages for categorical variables and medians and interquartile ranges for continuous variables. Associations between AKI recovery and outcomes were analyzed using the univariable and multivariable models to adjust for age, sex, race, weight, fluid balance, and SOFA scores. Data distributions were compared between the three groups using Chi-square and Kruskal–Wallis tests for categorical and continuous data, respectively. We used a logistic regression model for the analysis. A two-sided P < 0.05 was determined to be statistically significant. All analyses were performed using Bluesky statistics (Version 7.40, Chicago, IL, United States).
A total of 217,696 patients were screened who were admitted to ICU from January 01, 2006 to May 31, 2018 [Figure 1]. Among them, 1,052 patients met the eligibility criteria for septic shock, and 597 individuals were found to have AKI and entered the final analysis. Of the 597 patients with SA-AKI, 204 (34%) patients had stage 1 AKI, 95 (16%) had stage 2 AKI, and 298 (50%) were in stage 3 AKI [Figure 2]. In addition, 240 (40%) patients required initiation of KRT during hospitalization. The 597 patients with SA-AKI were divided into three groups based on the rate of fluid resuscitation as described above, 142 (23.8%) were in group 1, 125 (20.9%) in group 2, and 330 (55.3%) in group 3. Baseline characteristics for each category are presented in Table 1. The three groups were similar in demographic characteristics, comorbid conditions, and severity of illness.
Figure 1 The consort flow diagram of patient enrolment. ICU: Intensive care units, SOFA: Sequential (Sepsis-related) Organ Failure Assessment, ICD: International Classification of Diseases, MAP: Mean arterial pressure, AKI: Acute kidney injury
Figure 2 Incidence and staging of AKI on admission in septic shock patients. AKI: Acute kidney injury
Among the groups, 53%, 50%, and 38% achieved AKI recovery on day 7 in groups 1–3, respectively (P = 0.006), as shown in Figure 3. Patients with stage 3 AKI had statistically significant improvement in the recovery of AKI on day 7, 18%, 17%, and 8% among groups 1–3, respectively (P ≤ 0.04). Corresponding to the fluid resuscitation rate, AKI recovery was also noted on day 1, day 3, day 5 of the ICU, and hospital discharge, as shown in Figure 4. Finally, on day 28, 87%, 80%, and 73% had complete AKI recovery based on serum creatinine in groups 1, 2, and 3, respectively (P ≤ 0.001). Liberation from hemodialysis was analyzed for the day of ICU discharge and hospital discharge among the three groups, which were 42%, 31%, 27%, 51%, 33%, and 16%, respectively.
Figure 3 AKI recovery on day 7 with different initial fluid resuscitation rates (mg/kg/min). AKI: Acute kidney injury
Figure 4 AKI recovery on days 1, 3, 5, 7, ICU and hospital discharge based on the three groups of fluid resuscitation rate (ml/kg/min)
The lactate clearance was evaluated from the time of admission at h zero and the repeat lactate at the 3^rd^ h. This determined the change in lactate before fluid resuscitation compared to after fluid resuscitation. The lactate clearance was significantly different among groups (P < 0.001); group 1 had more lactate reduction compared to group 3 (0.9 vs. 0.3 mg/dl; P < 0.001). The change in MAP was evaluated at 3 h, a median increase of 5 mmHg was noted in group 3 compared to group 1. A higher initial fluid resuscitation rate was associated with a higher mean fluid balance at 3 h (P < 0.001), but the fluid balance remained similar among the groups from 3 h to MICU discharge (P ≤ 0.001). The SOFA score between day 1 and day 2 declined in group 1 compared to group 3 (−3 vs. −2; P < 0.001). More patients in group 3 were required to be on mechanical ventilators, with the groups showing no statistically significant difference in ventilator duration. A significant difference in ICU and hospital mortality was noted among the three groups (P = 0.001). Day 28 mortality was 19.7%, 25.6%, and 36%, among groups 1 through 3, respectively (P ≤ 0.001). Mortality evaluated in MICU and at hospital discharge showed a statistically significant decrease in mortality in the group that received a higher rate of fluid resuscitation. Table 2 shows the associations between fluid resuscitation rates and secondary outcomes. Table 3 indicates the univariate and multivariate analysis of AKI recovery and outcomes at various points.
This is a retrospective study that we conducted in a single center of patients with septic shock who had AKI on admission to the MICU. Our study demonstrates that prompt fluid resuscitation is associated with a higher AKI recovery rate (even among stage 3 AKI) in septic shock patients. While the primary outcome of this study was to evaluate AKI recovery on day 7, we demonstrated that a higher rate of fluid resuscitation showed statistically significant recovery of AKI from day one through ICU and hospital discharge. On day 28, the recovery rate of AKI continued to be higher among group one patients as compared to group three significantly. In our study, the faster initial fluid resuscitation was also associated higher rate of recovery among stage 3 AKI patients and lower 28-day mortality. Our study looked at the recovery of AKI and other kidney-related outcomes. Our study is unique in that we could compare three cohorts of patients with different rates of fluid resuscitation and recovery of AKI. Recently, Hu et al. looked at fluid resuscitation rates and shock reversal.[13] This study cohort was larger to include patients with and without AKI. No kidney-related outcomes were analyzed in their study.
In septic shock patients, the concept for early goal-directed fluid therapy is to restore intravascular volume, oxygen delivery, and cardiac output.[22] However, by providing crystalloid fluids, we encounter increased fluid loss into the interstitium through leaky vascular endothelium. Hence, it has been hypothesized that a faster rate of fluid resuscitation will likely counter this loss[23] and restore euvolemia and systemic hemodynamics in septic patients.[24] Hu et al. showed an association between the completion of SSC bundle components within 3 h, resulting in earlier shock reversal and lower mortality. In septic shock patients, a higher fluid resuscitation rate, when given within the initial 2 h, correlated with early shock reversal and lower mortality.[13] However, there is minimal knowledge regarding AKI recovery in sepsis, and no focused therapy has been discovered. Specifically, fluid resuscitation in AKI is considered a preventive measure as restoration of circulating volume will improve kidney perfusion. The estimation of intravascular volume status and amount of fluid to be given often is difficult to determine in patients.
In critically ill patients with hypotension or on pressors and not already with established AKI or KRT, the 90-day survival was evaluated in The Balanced Solutions in Intensive Care Study.[25] This factorial trial compared a slower fluid bolus rate (333 mL/h) versus control rate (999 mL/h). Although the study determined that infusing at a slower rate than a faster rate did not reduce 90-day mortality, no difference in the incidence of AKI or need for KRT was noted. Therefore, these findings did not support using a slower infusion rate. On the other hand, our study evaluated patients with established AKI and found a significant difference in AKI recovery and mortality.
Studies have shown that nearly half of the septic shock patients had AKI,[5,26,27] and 15%–20% required KRT.[28,29] The incidence of AKI in our study is consistent with the previous data. Also, a higher proportion of our AKI patients had stage 3 AKI and required initiation of KRT. Among the septic shock patients with AKI who received the 30cc/kg fluid resuscitation as per the surviving sepsis guidelines, our results show that a fluid resuscitation rate >0.5 ml/kg/min was associated with a higher rate of AKI recovery as well as a higher rate of liberation from KRT at ICU and hospital discharge.
While fluid resuscitation remains essential to manage hypovolemia in patients at risk for AKI, Undue fluid loading and positive fluid balance appear harmful. Many observational studies have highlighted a negative impact of a positive fluid balance on outcomes in patients with AKI.[30] In our study, although the group with the higher fluid resuscitation that a larger positive balance at 3 h, ultimately, the fluid balance did not appear to be significantly different between the groups on MICU discharge. Based on the fluid resuscitation rate, our study evaluated the liberation from dialysis of stage 3 AKI patients in the sepsis setting. We found that the group that received a higher fluid resuscitation rate was associated with a higher chance of liberation from hemodialysis. Our study also evaluated other clinical outcomes, including lactate clearance, change in MAP, and SOFA score change that positively impacted the group with faster fluid resuscitation.
The limitations of our study are many. Prospective studies are required to verify our results as we cannot imply any causal relationship due to its retrospective design.[31] A change in creatinine determined AKI by KDIGO criteria alone and urine output was not considered. This could have led to a false interpretation of creatinine and AKI staging, especially during septic shock and volume resuscitation. While kidney recovery often occurs within the first 3 months of dialysis initiation, we evaluated the liberation from dialysis at hospital discharge.[32] Finally, the changes in the clinical practice could have led to bias in our results as the study period traversed over 12 years.
Our study demonstrates that a higher fluid resuscitation rate of 30 ml/kg IV fluids within the 1^st^-h of sepsis diagnosis (i.e., >0.50 ml/kg/min) leads to a higher rate of AKI recovery in patients with AKI and septic shock. Furthermore, prompt fluid resuscitation is associated with a higher AKI recovery rate from day 1 through ICU, hospital discharge, and 28-day follow-up. Our results lay a foundation for future trials to validate our hypothesis.
This study was approved by the Institutional Review Board/Ethics Committee at the Mayo Clinic (Approval #: 21-001762; Approval Sept 1, 2022). A waiver for consent was not applicable. The authors followed the applicable EQUATOR Network (http://www.equator-network.org/) guidelines, specifically the STROBE Guideline, during this research project.
Nil.
There are no conflicts of interest.