Timing of Renal Replacement Therapy in the Critically Ill Patients
Timing of Renal Replacement Therapy in the Critically Ill Patients
Background: Severe acute kidney injury (AKI) among critically ill patients is sometimes
 treated with renal replacement therapy (RRT), and in Sweden continuous RRT (CRRT) is the
 dominant modality used in this population.

 -  The optimal timing of renal replacement therapy (RRT) initiation in critically ill
 patients with acute kidney injury (AKI) is unknown

 -  No consensus to guide clinical practice on this issue

 -  Lack of consistency regarding outcome measurements; should we look at morbidity or
 mortality?

 -  Wide variability in the timing of RRT initiation in the intensive care unit (ICU)
 population

 Hypothesis: This is an important knowledge gap in the support of critically ill patients with
 AKI and we hypothesize that early initiation of RRT is beneficial.

 Methods: The present study aims to test this hypothesis by using a large scale high
 resolution intensive care database, the Clinisoft repository. In this database, we have
 information on >60 000 patients from three different hospitals and five ICUs, during the
 years 2005 up until today. The repository will be crossmatched, using the unique Swedish
 national ID number, with hospital records; to gather information on preexisting illnesses,
 chronic medication and post-ICU outcomes. It is likely that over 5%, more than 3000 patients,
 have been treated with RRT. We will categorize these patients into "early" and "late" groups
 using both biomarker data and clinical data. Importantly, early and late RRT can be
 categorized using biomarkers, like urea and creatinine; using degree of fluid accumulation,
 by level of pH in blood and just by using hours-days after ICU admission. All possible
 definitions of early/late RRT initiation can be tested in this study.

 Outcomes: Our primary outcome is 90 day mortality. Secondary outcomes include: mortality at
 30, 60, 180 and 365 days. Two- and three year mortality.

 Morbidity, measured as end-stage renal disease (ESRD) for 90-day survivors. ICU length of
 stay, hospital length of stay.
Background

 -  Optimal timing of renal replacement therapy (RRT) initiation in critically ill patients
 with acute kidney injury (AKI) is unknown

 -  No consensus guides clinical practice on this issue

 -  Conflicting results from randomized controlled trials

 -  Lack of consistency regarding outcome; should we look at morbidity or mortality?

 -  Wide variability in the timing of RRT initiation in this population

 -  This is an important knowledge gap in the support of critically ill patients with AKI

 Most previous studies have pointed to benefits of early RRT:

 1. The SOAP study (Payen 2008) enrolled> 3100 patients and 278 patients required RRT - in
 these patients, "early RRT" was defined as RRT initiation within two days of ICU
 admission while "late RRT" was defined as RRT initiation occurring thereafter. The early
 RRT group was significantly sicker, including higher SAPS II/SOFA scores, greater need
 for mechanical ventilation, and lower urine output compared to the late RRT group.
 Despite this (and without adjustment for these clinical differences at baseline), both
 ICU and hospital mortality along with ICU length of stay were significantly lower in the
 early RRT group.

 2. A secondary analysis of the FINNAKI (Vaara 2014) studied 239 critically ill patients
 with acute kidney injury treated with renal replacement therapy. The exposure was timing
 relative to evidence of developing ≥ 1 "conventional" indications, and three groups were
 defined. A) "Pre-emptive" - no conventional indication. B) "Classic - urgent" - renal
 replacement therapy started < 12 hr of indication. C) "Classic - delayed" - renal
 replacement therapy started ≥ 12 hr after indication. The analysis was stratified by
 group + propensity-matched analysis of "pre-emptive" to non-renal replacement therapy
 treated. 90-Day Mortality results were quite striking.

 Pre-emptive renal replacement therapy vs. Classic renal replacement therapy 30% vs. 49%;
 OR 2.05; 95%, CI 1.0-4.1 Classic Urgent vs. Classic Delayed 39% vs. 68%; OR 3.85; 95%
 CI, 1.5-10.2 Pre-emptive vs. no renal replacement therapy (67% matched) 27% vs. 49%
 (diff 22.4%; 95% CI, 7.5-35.9)

 3. Karvellas (2011) performed a meta-analysis comparing early vs late initiation of renal
 replacement therapy. 15 unique studies (2 randomised, 4 prospective cohort, 9
 retrospective cohort) out of 1,494 citations. The overall methodological quality was
 low. Early, compared with late therapy, was associated with a significant improvement in
 28-day mortality (odds ratio (OR) 0.45; 95% confidence interval (CI), 0.28 to 0.72).

 4. Leite (2013) performed a study of 150 patients with AKIN stage 3. Mortality was lower in
 the early renal replacement therapy group (51.5 vs. 77.9%, P = 0.001). After achieving
 balance between the groups using a propensity score, there was a significant 30.5 (95%
 confidence interval [CI] 14.4 to 45.2%, P = 0.002) relative decrease of mortality in the
 early renal replacement therapy group. Moreover, patients on the early renal replacement
 therapy group had lower duration of mechanical ventilation, time on renal replacement
 therapy and a trend to lower intensive care unit (ICU) length of stay.

 5. Shiao (2012) looked at 648 postoperative renal replacement therapy cases. Definitions
 were: early (EG, ≦1 day), intermediate (IG, 2-3 days), and late (LG, ≧4 days) groups.
 The in-hospital mortality rate censored at 180 day was defined as the endpoint. A
 U-shaped curve was found, indicating that intermediate start of renal replacement
 therapy was beneficial in this cohort.

 6. The two RCTs; the AKIKI and ELAIN-studies (2016) from NEJM and JAMA report conflicting
 results. AKIKI showed no benefit with early initiation of renal replacement therapy but
 ELAIN did. Complicating matters were the fact that AKIKI dosing was unknown, and IHD was
 used in around 50% of those patients.

 There are ongoing randomized controlled trials, but STARRT-AKI (see #2) have released
 feasibility data.

 1. I.D.E.A.L.-I.C.U. (NCT01682590) (start Mar 2012): - RCT of "early" (within 12 hrs of
 RIFLE-F) vs. "deferred" (48-60 hr) on 90-day mortality in septic AKI (planned
 recruitment ~ 824) - PI: J.P. Quenot (Dijon) - completion March 2015.

 2. STARRT-AKI (NCT01557361) (May 2012-October 2013). "Accelerated" (n=48) vs "Standard"
 (n=52). 90-day mortality was similar, 38 and 37%. Surviving patients requiring renal
 replacement therapy at Day 90 were only found in the standard arm, where 3.8% were
 dialysis dependent. Median ICU length of stay and number of renal replacement therapy
 sessions were insignificantly lower in the accelerated group.

 It is clear that more knowledge regarding outcome concerning mortality, morbidity (end-stage
 renal disease) as well as ICU- and hospital care consumption would be beneficial. The
 investigators have highly detailed data from three hospitals based on a cohort of over 50 000
 ICU patients from Stockholm. The investigators believe that the sheer number of patients
 combined with the subjective nature* of renal replacement therapy initiation allow for useful
 information, potentially adding to the knowledge that the RCTs hopefully will bring.

 *Initiation of renal replacement therapy (= CRRT) is based on a spectrum of clinical
 information and provider bias. Clinicians always initiate renal replacement therapy when
 confronted with life-threatening complications (like hyperkalemia or pulmonary edema).
 However, wide variations in the minimum severity of indications prompting renal replacement
 therapy initiation exist. Factors influencing decisions include: age, comorbidity,
 responsiveness to diuretic challenge; illness severity (predicted mortality); prescribing
 service and time of day.

 The fact that renal replacement therapy is so "unregulated" is beneficial for a cohort study,
 as it is likely to create a wide variety of patients in early and late groups. It creates a
 "natural experiment". If it is good for the patients is another matter.

 Hypothesis: early renal replacement therapy is beneficial compared to late renal replacement
 therapy.

 Methods: this is an observational cohort study of critically ill patients treated in three
 hospitals (Karolinska Solna, Karolinska Huddinge and Södersjukhuset) and in five different
 ICUs in Stockholm, Sweden, between 2007 and 2017 using the Clinisoft database.

 Registry: The Clinisoft database (Centricity Clinisoft, General Electric) is based on a
 patient database management system (PDMS), implemented 2005 and initially only recorded data
 from Karolinska University Hospital Solna (Central medicosurgical ICU and
 neurosurgical/neurological ICU, NIVA) and Karolinska University Hospital Huddinge
 (medicosurgical ICU, IVA). From 2006 to 2008 the other ICUs (Cardiothoracic ICU, Karolinska
 Solna and Södersjukhusets two ICUs, one medical and one surgical) started using Clinisoft.
 Essentially, the investigators will have complete data coverage from 2007/2008-2017. The
 neurosurgical/neurological ICU will not participate in this study; their patients with need
 of CRRT are treated in other ICUs.

 The investigators will collect demographic data, age, sex and comorbidities. Moreover, The
 investigators will collect ICU specific data; illness severity, mechanical ventilation, need
 for vasoactive therapy, reason for ICU admission, data on initiation of renal replacement
 therapy. Post-ICU mortality and mortality data at different time points (30, 60, 90, 180, 365
 and when applicable 2 and 3 year mortality) will be reported. Lastly, The investigators will
 investigate post-ICU morbidity, including new onset CKD diagnosis and ESRD for 90 day
 survivors.

 Early renal replacement therapy can be defined in many ways, based on:

 1. Blood urea nitrogen level

 2. Grade of RIFLE/AKIN/KDIGO stage

 3. Hours from ICU admission

 4. Degree of fluid overload

 5. Level of pH at initiation

 The Clinisoft registry, as mentioned, based on the Centricity Critical Care suite of programs
 is run by General Electric. This registry has data based on intensive care monitors and
 machines, ranging from medical pumps, respirators to invasive monitoring data. The registry
 also has laboratory variables automatically imported from the electronic medical records
 (EMR) system, Take Care. Moreover, illness severity scores, central lines, body weight,
 urinary output and medications are entered manually into the system on a regular basis. Data
 is regularly audited as part of the hospital standard operating procedure. There are data sum
 checks ensuring that predefined rules and ranges are followed. The investigators have source
 data verification, as some laboratory data from the electronic medical records (EMR) system
 Take Care is exported to the Clinisoft registry. Coding information and a data dictionary
 exists.

 Matching: The Standard Operating Procedures for patient recruitment, data collection, data
 management and data analysis is as follows. For each case of early CRRT, The investigators
 will create a sequentially propensity matched control patient that a) either will never
 receive CRRT or b) will go on to get late CRRT based on absolute indications.

 Absolute indications:

 1. hyperkalemia (serum potassium≥6 mEq/L),

 2. severe acidosis (pH≤7.15),

 3. plasma urea>36 mmol/L (equals BUN=100.8 mg/dl),

 4. oliguria or anuria (urine output<0.3 ml/kg per hour for ≥24 hours or anuria for ≥12
 hours), and

 5. fluid overload with pulmonary edema as defined by the presence of all the following
 factors: (a) >10% fluid accumulation (cumulative fluid balance/baseline weight>10%), (b)
 oliguria (urine output<0.5 ml/kg per hour for ≥12 hours), and (c) severely impaired
 oxygenation (PaO2/FiO2<200 indicated by respiratory Sequential Organ Failure Assessment
 [SOFA] score≥3) A patient where initiation of renal replacement therapy is started
 without the absolute indications ("early renal replacement therapy") will be matched
 based on age, sex, chronic kidney disease, admission diagnosis group, presence of severe
 sepsis and cumulative urine output. The investigators will try to find matched pairs
 going on to get "late renal replacement therapy" and never renal replacement therapy;
 i.e. two matched patients per early renal replacement therapy-patient.

 Sample size assessment: first off, out of the total number of patients - around 50 000
 patients collected during the years 2007-2017 - the investigators anticipate at least 5%
 treated with CRRT, i.e. 2500 patients.

 value for p1: 0.35 value for p2: 0.45 value for α: .05 value for power (default is .80): .80
 sample size (for each sample separately) is: 376

 This power analysis is based on regular alpha and power (0.5 and 0.8) and expects a 10% (a
 35% mortality and 45% for early vs late renal replacement therapy) difference in mortality at
 six months - significantly smaller difference than in the Vaara, Karvellas and Leite studies.

 This gives us a sample size of 375 patients in the two groups, 750 patients in total.

 The investigators are likely to greatly exceed the numbers needed to find a difference in
 mortality if such a mortality difference exists. It is unclear if the investigators will
 exceed the numbers needed to find a difference in ESRD-morbidity, since the field lacks
 adequate data to allow for a power analysis.

 Plan for missing data: our trial design seeks to limit the likelihood of missing data. If
 variables are missing, unavailable, non-reported or uninterpretable the investigators will
 use imputation by last observation. This is, admittedly, based on unscientific assumptions,
 therefore sensitivity analyses will be conducted to assess the robustness of findings when
 missing data has been an issue.

 Statistical analysis plan: The investigators will report continuous data as medians with
 interquartile ranges and categorical data as counts and percentages. The investigators will
 use the Mann-Whitney U test to compare continuous data and the Fisher's exact test to compare
 categorical data. All statistics is two-tailed and a P value of less than 0.05 will be
 considered significant.

 CRRT initiation will be categorised according to early and late start according to several
 different criteria i.e. time from ICU admission, biochemical data at initiation and
 percentage of body weight increase. The investigators will then perform separate univariate
 and multivariate analysis for each definition, using Cox and Poisson regression models for
 primary and secondary outcomes and adjust for clinically relevant confounders and independent
 factors with observed differences between patients with early and late renal replacement
 therapy initiation.

 A competing risks polynomial logistic regression will be performed to identify predictors of
 primary and secondary outcome at 6 months. This risks model will include four-level
 polytomous outcomes defined as death, ESRD, ESRD and death or no negative outcome. The area
 under the receiver operating characteristic curve (AUC) will be used to assess discrimination
 of each of our CRRT timing models.

 Analysis will be performed using Stata version 12 (StataCorp LP, College Station, Tx, USA).
Inclusion Criteria:

 *Critically ill patients admitted to intensive care units in Stockholm at: Karolinska
 University Hospital (Solna and Huddinge) and at Södersjukhuset.

 *Patients over 18 years of age

 Exclusion Criteria:

 -  Patients <18 years

 -  Patients with DNAR (do not attempt resuscitation)-orders

 -  Patients dying within 12 hours of commencing renal replacement therapy.