Prompting With Checklist for Early Recognition and Treatment of Acute Illness On The Prevention of Acute Kidney Injury in Patients With Septic Shock

Background: Early identication of septic patients at high risk for acute kidney injury (AKI), followed by timely and appropriate interventions, is crucial for improving patients’ outcomes. Checklist for Early Recognition and Treatment of Acute Illness (CERTAIN) is a tool for evaluating and treating acute illness promptly based on best practices. We hypothesized that the use of CERTAIN would prevent the occurrence of AKI after septic shock. Methods: This was a before-and-after study. CERTAIN, included the care bundles recommended in the Sepsis 3.0 and Kidney Disease: Improving Global Outcomes (KDIGO) 2012 guidelines, used in daily practice to manage patients with septic shock. The primary outcome was the incidence of AKI within 72 hours in patients with septic shock. Secondary outcomes were mortality and major adverse kidney events (MAKEs) at 90 days after exposure to AKI. Results: 124 patients had been treated with CERTAIN, and 112 patients were in the Pre-CERTAIN group. AKI reduced signicantly in the Post-CERTAIN group compared to the Pre-CERTAIN group within 72h after enrollment (55.7% vs 68.8%, P=0.045). CERTAIN prolonged ventilator-free days and vasoactive agents free days at 28 days (22 vs 17, P<0.001; 23 vs 19, P=0.044; respectively). The mortality and MAKEs at 90 days were reduced in the Post-CERTAIN group compared to the Pre-CERTAIN group (17.7% vs 29.5%, P=0.045; 41.9% vs 56.3%, P=0.039; respectively). Conclusions: Implementation of CERTAIN reduced the AKI frequency, mortality at 90 days, and the rate of MAKEs at 90 days in septic shock patients. Trial registration: NCT01973829. Date of registration: 1st November 2013.


Background
Acute kidney injury (AKI) is common in critically ill patients and is associated with progression to chronic kidney disease (CKD) and higher in-hospital mortality and cost of care 1 . Sepsis is a major etiology of AKI in the intensive care unit (ICU). Sepsis-associated acute kidney injury (SA-AKI) contributes to extremely high mortality of critically ill patients. 2 While patients who survived SA-AKI had relatively high rates of recovery and survival 1 year after sepsis. 3,4 The current core problems were delayed diagnosis, inadequate diagnostic methods, and insu cient numbers of medical professionals capable of providing optimal management have contributed to adverse outcomes. 5 Critically ill patients have complex conditions, and the staff in ICU are faced with time constraints, large amounts of clinical data, and a heavy workload. Failure to treat patients within the optimal therapeutic window, misjudgment, and miscommunication can result in adverse events and even death of the patients. 6 In the era of evidence-based medicine and management based on clinical practice guidelines, Checklists are validated tools that can be used to standardize care models. Their application reduces certain types of adverse events in surgical departments. [7][8][9] However, delays in the updating of information, the incomplete usage of checklists, and the use of checklists only for monitoring purposes have indicated that checklists have not led to clinical improvements. 10 Building upon these experiences and advances in modern technology, a novel electronic tool, the Checklist for Early Recognition and Treatment of Acute Illness and Injury (CERTAIN), is being developed to support the evaluation and treatment of critically ill patients following optimized clinical practices. 11 Due to the strong performance, we used CERTAIN based on sepsis 3.0 and the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines to screen sepsis patients and initial the sepsis and KDIGO care bundles.
KDIGO guidelines were developed to promote the detection and prevention of AKI, thereby improving patient outcomes. 1 KDIGO care bundles focusing on optimization of uid management and haemodynamic monitoring, avoidance of nephrotoxins, adjustment of medication doses according to renal clearance, tight glucose control, administration of renal replacement therapy if necessary. 12 Despite these bundles were nonspeci c, the application of the KDIGO bundles in patients with nephrotoxic AKI or cardiac surgery-associated AKI had been shown a reduction in the occurrence of AKI progression. 13,14 Whether KDIGO care bundles will decrease the incidence of AKI in patients with sepsis is still unknown.
This study aimed to use CERTAIN to select septic shock patients, who were then treated based on the KDIGO care bundles. We hypothesized that the use of the implementation of CERTAIN would reduce the incidence and severity of SA-AKI.

Study design and participants
This was a single-center before-and-after study performed in a comprehensive ICU in a tertiary public hospital in Tianjin. This study was carried out from April 1st, 2016, to June 1st, 2017. The study protocol was approved by the Ethics Committee of the Hospital of Tianjin First Center Hospital (approval No 2015KZ019). All patients provided informed consent. This trial was a subgroup analysis of a clinical trial registered at ClinicalTrials.gov (NCT01973829). Participants were recruited from the patients admitted to the ICU with septic shock. Those 18 years or older were eligible to participate in this study. Patients enrolled in the study had to meet the criteria for Sepsis 3.0 with persistent hypotension requiring vasopressors to maintain MAP ≥ 65mmHg and having a serum lactate level > 2mmol/L despite adequate volume resuscitation 15 . The exclusion criteria were preexisting AKI (≥ stage 1), advanced chronic kidney disease (CKD stage 4 and stage 5), hospitalization duration less than 72 hours, previous renal replacement therapy (RRT), renal transplantation, pregnancy, non-infectious causes of AKI (obstructive diseases of the urinary system, medications of nephrotoxic drugs and contrast-induced nephropathy), and participation in another interventional trial within the last 3 months.

Protocol Description
The protocol had 4 distinct phases. The rst phase was the Pre CERTAIN stage. Patients with sepsis were treated before the usage of CERTAIN (April 1st, 2016 to August 31st, 2016). The treatment of the patients was made by their attending physician. The second phase, which we called the training phase, involved 1 month of training for the entire clinical team. The training was the implementation of CERTAIN. The topics were based on the Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock (2016). 15 and the KDIGO care bundles. 16 Moreover, the monitoring and therapeutic recommendations and treatment targets for resuscitation, antimicrobial therapy, vasoactive medications, RRT, uid responsiveness assessments were addressed. 15,16 (see Table 1). In addition, the identi cation of electronic warnings. The third phase was the Post CERTAIN stage (September 1st, 2016 to February 28th, 2017). In this phase, the medical staff used CERTAIN daily to select patients with septic shock and applied KDIGO care bundles to evaluate and treat patients with septic shock. The last phase was the follow-up phase (March 1st, 2017 to June 1st, 2017). All enrolled patients were tracked for 3 months after hospital discharge to monitor their prognosis and acute and chronic adverse events.

Outcomes
The primary outcome was the incidence and severity of AKI according to the KDIGO 2012 guidelines (see Table 2) within 72h after enrollment. The secondary outcomes included the number of days free of RRT; the numbers of ventilator-free and vasoactive-free days; 17 90-day all-cause mortality; the length of hospitalization and time of hospitalization-free days at 90 days after discharge; the proportion of patients with major adverse kidney events (MAKEs), which was de ned as death, dependence on renal replacement therapy (RRT), or a sustained reduction in kidney function at 90 days after discharge (i.e., an estimated glomerular ltration rate [eGFR] of < 75% of the baseline value). 18 Table 1 Recommendations of sepsis and KDIGO care bundles 15,16 Items Initial resuscitation 30mL/kg of crystalloid uid is given within the rst 3 hours for hypotension or lactate ≥ 4mmol/L Antibiotics Use broad-spectrum antibiotics within 3 hours and obtain blood culture; daily assessment for de-escalation of antimicrobial therapy Two-sided P values less than 0.05 were considered statistically signi cant in the nal analyses.   Table 3. There were no signi cant differences in age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, comorbidities, site of infection (P > 0.05).

Measures during the evaluation period for Pre versus Post CERTAIN application
In the Post-CERTAIN group, both the ratio of uid response evaluation before uid resuscitation and 30mL/kg of crystalloid uid was given within the rst 3 hours for early resuscitation was higher than that in the Pre-CERTAIN group (100% vs 48.2% P < 0.001, 100% vs 60.7% P < 0.001, respectively). The daily uid balance for day 1 was higher in the Post-CERTAIN group (3180 mL vs 1715 mL, P < 0.001). However, uid balance on day 2 was lower in the Post-CERTAIN group (777.5 mL vs 1275mL, P = 0.002). Furthermore, the use of noradrenaline was signi cantly higher in the Post-CERTAIN group, but signi cantly patients in Pre-CERTAIN group received dopamine (P < 0.001). Compared to the Pre-CERTAIN group, the mean arterial pressure (MAP) of the patients in Post-CERTAIN group signi cantly increased during the rst 6 hours after enrollment (Table 4). In contrast, the level of lactate during the rst 12 hours was signi cantly decreased in the Post-CERTAIN group (Table 4). In addition, the use of the nephrotoxic drug was signi cantly reduced in the Post-CERTAIN group (P < 0.001).

Discussion
In this before-and-after study, we examined whether CERTAIN based on sepsis and KDIGO care bundles targeted at prevention of AKI on patients with septic shock. This study showed that the use of CERTAIN as a screening and treating tool reduced the ratio of AKI in patients with septic shock, especially the rate of moderate to severe AKI in the Post-CERTAIN group. Moreover, the patients who were managed with CERTAIN had a lower proportion of mortality and rate of MAKEs within 90 days.
Whether KDIGO care bundles improve the short or long outcomes of critically ill patients is inconsistent due to the heterogeneity of AKI. Previously, Koeze et al. discovered that care bundles focusing on KDIGO 2012 had no bene cial effect on critically ill patients when evaluated the ICU mortality, RRT dependency, and AKI progression. 19 However, our data indicated that implementation of CERTAIN focusing on sepsis 3.0 and KDIGO bundles can reduce the occurrence of AKI, mortality, and incidence of MAKEs within 90 days of patients with septic shock. These results are consistent with the studies that evaluated KDIGO care bundles in patients after cardiac surgery and major surgery. 14,20,21 It is noteworthy that the implementation of the Surviving Sepsis Campaign and KDIGO care bundles improved the short-and long-term outcomes of sepsis and AKI, respectively. 22,23 However, in clinical practice, these interventions have been shown to have poor performance. Bundle fatigue was one of the main issues affecting their implementation. 24 Moreover, in the absence of su cient support for decision making and the inappropriate selection of medical interventions, medical errors are the leading cause of death in hospitals. 25,26 In this study, CERTAIN was associated with improvement of eight of 10 practices of the KDIGO care bundles. The compliance of the crucial practices may in uence the prognosis of the patients, as the higher adherence to active measures has been shown great bene ts of care bundles. 27 Recently, a multicentre international study showed that CERTAIN improved daily care processes in ICU, especially in low-and middle-income countries. 28 Care bundles in the form of a list combined with an electronic warning could improve the compliance of medical staff to evidence-based guidelines, minimize medical errors and improve outcomes in ICU. 29 The high adherence of care bundles after CERTAIN training was associated with improvement in the treatment of patients with septic shock.
Fluid resuscitation and vasoactive agents are cornerstones in the treatment of both septic shock and AKI. 15,16 Fluid challenge should be evaluated between the balance of increasing in oxygen delivery to tissues and inhibiting of edema formation. 30 In contrast to the Pre-CERTAIN group, all the patients in the Post-CERTAIN group were evaluated for uid responsiveness, then monitored CVP during the following uid management. CVP is not an accurate indicator to predict uid responsiveness, but CVP is the most frequently used and most easily obtained variable to guide uid resuscitation in ICU. 31 Single CVP value cannot differentiate responder from nonresponder. However, the changing of CVP during uid bolus may predict responsiveness. Thus, patients in the Post-CERTAIN group were given 200-500mL crystalloid uid within 10-15 minutes. If CO and SV detected by transthoracic Doppler increased by 10%-15% with a rise in CVP < 5mmHg indicates good tolerance to uids, whereas an increase in CVP ≥ 5mmHg indicates poor tolerance to uids. 31 To inhibit delayed resuscitation and uid overload, this study used changes in CVP during uid challenge together with changes in CO to predict uid responsiveness. 31 In addition, CVP maintained to 8-12mmHg as the following target as the majority of patients respond to uids. 32 The increased use of noradrenaline and de-escalation uid resuscitation in the Post-CERTAIN group maintained a better haemodynamic stabilization and tissue perfusion.
The pathophysiology of SA-AKI is complicated. Surviving Sepsis Campaign care bundles showed no reduction in the incidence of AKI within the rst week after the development of sepsis. 33 We implemented a bundle of supportive measures which are recommended by sepsis and KDIGO guidelines. The multifactorial measures may reduce the occurrence of AKI after septic shock. SA-AKI is associated with increased morbidity and mortality. Our ndings were in line with goal-directed therapy in a reduction of mortality and MAKEs. 34 However, the PreAKI study showed that the implementation of the KDIGO guidelines had no impact on mortality and MAKEs at day 90. That might be due to the different eligible patients. We assumed that the positive effect of the CERTAIN checklist on reducing the incidence and severity of AKI, decrease in mortality, and MAKEs at day 90 was caused by optimal uid resuscitation with de-escalation uid management and kidney protection.
Our study has several limitations. First, it was a single-center study of patients with septic shock may limit the generalizability of its results. Second, this study was not blinded, which resulted in measurement bias. Third, the Hawthorne effect was the confounding factor in before-after studies. Further trials with a larger multicenter cohort of patients with septic shock are warranted.

Conclusions
To our knowledge, this is the rst report of the use of CERTAIN based on sepsis 3. Availability of data and materials: The datasets generated and/or analyzed during the current study are not publicly available due to limitations of ethical approval involving the patient data and anonymity but are available from the corresponding author on reasonable request.
Competing interests: All the authors declare that they have no competing interests.  Study ow diagram