- Mr. Tarantula, a 30-year-old man, was admitted to the ICU 6 hours ago with respiratory failure and septic shock. His kidney function is severely impaired with a creatinine of 250 mmol/L. - The document discusses whether to start renal replacement therapy (RRT) now or delay treatment for Mr. Tarantula given his condition. - It also summarizes the ELAIN randomized clinical trial which found that initiating RRT earlier in critically ill patients with acute kidney injury (within 8 hours of meeting criteria) reduced 90-day mortality compared to delayed initiation (within 12 hours of meeting worse criteria).

2. …while I was preparing for the Journal Club!

3. The Story of Mr. Tarantula!
30 YOM, Mr. Tarantula, was admitted
to ITU 6 hours ago with some form of
Respiratory Failure and septic shock. I
& V. On Inotrope support for
hemodynamic instability.
His bloods are as deranged as we can
predict. His UEs were -
Serum Creatinine : 250mmol/L
Urea : 25 mg/dL
Potassium : 5.9 mmols/L
Sodium : 130 mmols/L
Trailing UO
SOFA Score -> 6
No huge list of co-morbid conditions.
Fit and active otherwise.
To Dialyze now or to wait ?

4. Journal Club Topic
The ELAIN Randomized Clinical Trial
Effect of Early vs Delayed Initiation of Renal
Replacement Therapy on Mortality in Critically Ill
Patients With Acute Kidney Injury
Authors :- Alexander Zarbock, MD; John A. Kellum, MD; Christoph Schmidt, MD; Hugo Van Aken, MD;
Carola Wempe, PhD; Hermann Pavenstädt, MD; Andreea Boanta, MD; Joachim Gerß, PhD;
Melanie Meersch, MD
Affiliations: - Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, University
Hospital Münster, Germany. Center for Critical Care Nephrology, Department of Critical Care
Medicine, University of Pittsburgh, Pennsylvania. Department of Internal Medicine D, University
Hospital Münster, Germany. Institute of Biostatistics and Clinical Research, University of Münster,
Münster, Germany.
Date of publication :- May 2016 in JAMA. (Impact Factor :-35)

5. Clinical Question
“In critically unwell patients with acute kidney injury,
does early initiation of renal replacement therapy
(RRT) compared to delayed initiation reduce all cause
mortality at 90 days?”

6. Design of the trial
Randomized, single centre, 2 group, parallel-group trial.
1:1 randomization between treatment arms.
Block randomization in each stratum with block size of
10.
Group sequential adaptive design with single interim
analysis, performed after half the total number of death
across both groups.
230 patients in total required to generate 80% power to
detect treatment effect of 18% reduction in 90-day
mortality from a baseline of 55% (based on previous
literature).

7. Population characteristics
 Setting
 University Hospital Munster, Germany
 August 2013 to December 2015 (28 months)
 Population
 Inclusion: must have met all five of the following
 Acute kidney Injury- KDIGO stage 2:
 2-fold increase in serum creatinine from baseline, or urine output <0.5ml/kg/hr for ≥12 hrs despite optimal resuscitation (PCWP>12, CI
>2.6, MAP>65, IAP<15)
 NGAL >150ng/dl
 At least one of the following conditions:
 Severe sepsis
 Catecholamines (noradrenaline/adrenaline) >0.1mcg/kg/min
 Refractory fluid overload (worsening pulmonary oedeoma, P/F <300mgHg, fluid balance >10% body weight)
 Development or progression of non-renal organ dysfunction (SOFA organ system score ≥2)
 Age between 18 and 90
 Intention to provide full intensive care treatment for at least 3 days
 Exclusion:
 Patients with pre-existing kidney disease not requiring RRT
 Patients who had received any previous RRT
 AKI caused by permanent occlusion/surgical lesions of the renal artery
 Obstructive AKI
 HUS/TTP
 Prior Kidney transplant
 Hepatorenal syndrome
 AIDS with CD4 count <0/05 X109/L
 604 screened, 231 randomised and included in primary analysis

8. Two arms of the trial
 Intervention
 Initiation of RRT within 8 hours of confirmation of KDIGO stage 2
 Delivered to 100% of patients assigned to early group
 Median time to RRT was 6.0 hours.
 Control
 Initiation of RRT within 12 hours of either --
 KDIGO stage 3 criteria
 Creatinine rise >3 fold increase from baseline, or oliguria <0.3ml/kg/hr for ≥24 hours or serum creatinine
> 4mg/dl (353.6 μmol/l) with an acute increase of at least 0.5mg/dl (44.2μmol/l) within 24 hours
 Absolute indication for RRT
 Urea >100mg/dl
 Potassium >6mmol/l and or ECG abnormalities
 Magnesium >4mmol/l and/or anuria/absence of deep tendon reflexes
 Blood pH <7.15
 Urine production <200ml/12hr or anuria
 Organ oedema in the presence of AKI resistant to diuretic treatment (defined as one trial of furosemide)
 Delivered to 91% of patients assigned to delayed group
 Median time to RRT was 25.5 hours.

9. Outcome

10. Biochemical Analysis
Exploratory analysis:
 Inflammatory mediators (comparison of MIF, IL-6, IL8, IL-10, IL-18):
 No difference at randomization
 24 hours post randomization: significantly lower IL-6 and IL-8 in early group compared to
delayed group (100% of early group and 21.8% of late group had received RRT but this time
point)

11. Pros & Cons
 Strengths
 Very strict definitions of AKI used and followed. KDIGO Classification.
 No patients lost to follow up, and very little data lost.
 Clear separation achieved between groups.
 Exploratory analysis of inflammatory mediators provides a potential
mechanism by which early RRT may improve outcomes.
 Weaknesses
 Fragility Index 3: a shift of 3 patients would render it non-significant
(however, this is greater than the number lost-to-follow-up)
 Single center study: limits its external validation
 External validation further challenged by skewed patient population:
 216/231 (93.5%) were surgical of which 108 (46.75%) were cardiac surgery
patients
 203 (88%) were mechanically ventilated at time of randomization

13. How many of you want to dialyze Mr. Tarantula, now?

14. Critical Appraisal
 What was the theory/hypothesis ?
 The AKIKI authors  delayed RRT would confer an absolute survival benefit of at least 15%.
 The ELAIN authors  early RRT would confer an absolute survival benefit of 18%.
 Although the null hypotheses are the same, it does change how you should appraise the power calculations and subsequent
statistics.
 Who did they study?
 Surgical patients(ELAIN): possibly reduced renal blood flow related with stress response pathophysiology.
 Medical patients(AKIKI): possibly increased renal blood flow with significant immune complex / toxaemia.
 What did they study?
 Timing of RRT
 ELAIN was really early (KDIGO stage 2) and AKIKI was just early (KDIGO stage 3).
 The control groups were slightly different too: the ELAIN trial used KDIGO stage 3 (85% patients) or metabolic
derangement (15% patients) as the indication for RRT, but the AKIKI trial used metabolic derangement only. This
means that the control group in ELAIN was actually a very similar treatment to the AKIKI intervention group.
 So ELAIN was really early vs early and AKIKI was early vs conventional.
 Delivery of RRT
 AKIKI whatever mode of RRT, at whatever dosage. This was mixed intermittent and / or continuous RRT.
 ELAIN defined the RRT modality and dose: (CVVHDF) at 30 ml/kg/hr with 100% pre-dilution and 1:1 dialysate to
replacement fluid.

15. My take! (as if it matters…)
AKIKI (Artificial Kidney Initiation in Kidney
Failure): In sick patients that are medical or
surgical with sepsis, then I don’t know if early or
delayed RRT is the right therapy.
ELAIN (Early vs Late Initiation of Renal
Replacement Therapy in Critically Ill Patients
With Acute Kidney Injury): In really sick
patients on a surgical intensive care unit, then I
cautiously think very early CVVHDF is the right
therapy.

16. The End!

17. AKIKI Patient Profile

18. ELAIN Trial Outcome

19. ELAIN Trial patient characteristic