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October - 2018

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Timing of Renal-Replacement Therapy in Patients with Acute Kidney Injury and Sepsis

S Barbar, R Clere-Jehl, A Bourredjem, et al for the IDEAL-ICU Trial andCRICS TRIGGERSEP Network New Eng J Med, 2018, 379:1431-1442

Comment

In this weeks NEJM we have the IDEAL-ICU Trial, examining the effect of timing of renal-replacement therapy for patients with severe sepsis and severe acute kidney injury. 

The initiation of RRT is accepted if there are life-threatening complications of AKI (eg hyperkalaemia, acidosis), however timing in the absence of these is less clear. In 2016 we had 2 RCTs that shed light on this;

  1. Zarboci et al JAMA 2016 https://www.crit-iq.com/index.php/Library/Review/1222/Early-Delayed-Initiation-Renal-Replacement-Therapy-Mortality-Criticall-illness-Acute%20Kidney-Injury-RRT 
  • Single centre, 231 patients 
  • Adult patients needed all of
    • stage 2 AKI (KDIGO - 2x increase creatinine, UO<0.5 ml/kg/hr for >12hrs)
    • NGAL  >150ng/ml
    • severe sepsis or vasopressors or catecholamines or fluid overload or SOFA >=2
  • Early CRRT was within 8 hrs vs delayed which was initiated within 12 hrs of stage 3 AKI
  • In practice the timing of CRRT post enrolment was 6.0 hrs (early) vs 25.5 hrs (delayed)
  • 100% early vs 91% delayed received CRRT
  • Primary outcome, mortality at 90 days was 39.3% early vs 54.7% delayed (HR 0.66, 95% CI 045,0.97, p=0.03)
  • The early group recovered renal function more quickly (9 vs 25 days), had shorter hospital stay 51 days vs 82 days, but no difference in requirement for RRT after day 90.  

 

  1. AKIKI Trial NEJM 2016 https://www.crit-iq.com/index.php/Library/Review/1220/Early-delayed-inititation-Renal-Replacement-Therapy-Intensive-care-ihd-crrt-mortality 
  • Prospective multicentre RCT with 620 ventilated, catecholamine requiring patients with severe AKI, and no life-threatening renal failure indication, to immediate RRT vs delayed RRT
  • Early group RRT was commenced median of 4.3hrs after stage 3 AKI, commenced at a median of 57 hours in the delayed group, and 49% of the delayed group didnt need RRT. A lot of IHD
  • Primary outcome, day 60 survival, was not different (48.5% early vs 49.7% delayed, p=0.79)
  • CLABSI was higher in the early group, diuresis occurred earlier in delayed group, no. of days free of RRT increased in delayed group, and blood loss from non-digestive tract causes was higher delayed group.No difference VFD, ICU and hospital LOS, RRT dependence

So very different outcomes from the two studies. The two studies had fairly similar entry criteria, and mortality rates (different time points 90 vs 60 days), the time to delayed RRT was different (25.5 hrs vs 57 hrs), the  modes were different (CRRT vs predominantly IHD), and the proportion that didn’t receive RRT in the delayed group were different (9% vs 50%). Did the first study show a treatment benefit because they used CRRT, i.e. avoiding the cardiovascular effects of intermittent ? Because they gave “delayed” treatment 30-hrs earlier, or because >90% of delayed received the therapy? Is it simply the single centre limitation?

Bring on the IDEAL-ICU Trial;

  • Prospective, multicenter, randomized, controlled trial
  • Patients with early-stage septic shock, severe acute kidney injury at the failure stage of RIFLE classification system, without life-threatening complications related to acute kidney injury
  • renal-replacement therapy either within 12 hours (early strategy) vs delay of 48 hours if renal recovery had not occurred (delayed strategy). 
  • Trial was stopped early for futility after the second planned interim analysis. 
  • A total of 488 patients underwent randomization; no significant between-group differences in the characteristics at baseline. 
  • Primary outcome was death at 90 days:  58% early-strategy vs 54% delayed-strategy group, P=0.38
  • In the delayed-strategy group, 38% did not receive RRT (29% due to recovery of renal function, 8% died, 1% other reason)
  • Median time to RRT was 7.6 hrs vs 51.5 hrs
  • In terms of secondary outcomes delayed strategy was associated with increase in renal replacement therapy free days 16 vs 12, p=0.006. No difference in fluid balance.

So, overall, in a homogeneous population of patients with severe AKI in the early phase of septic shock, the initiation of early RRT was not associated with improved 90-d mortality or secondary outcomes compared to delayed RRT. Delayed RRT did result in 38% of patients not receiving RRT. 

The authors provide a good last word “risk of death is not increased if renal replacement therapy is postponed for at least 48 hours, as long as care id taken to identify patients in whom criteria for emergency renal replacement therapy are likely to be met”


 

Abstract

BACKGROUND

Acute kidney injury is the most frequent complication in patients with septic shock and is an independent risk factor for death. Although renal-replacement therapy is the standard of care for severe acute kidney injury, the ideal time for initiation remains controversial.

METHODS

In a multicenter, randomized, controlled trial, we assigned patients with early-stage septic shock who had severe acute kidney injury at the failure stage of the risk, injury, failure, loss, and end-stage kidney disease (RIFLE) classification system but without life-threatening complications related to acute kidney injury to receive renal-replacement therapy either within 12 hours after documentation of failure-stage acute kidney injury (early strategy) or after a delay of 48 hours if renal recovery had not occurred (delayed strategy). The failure stage of the RIFLE classification system is characterized by a serum creatinine level 3 times the baseline level (or ≥4 mg per deciliter with a rapid increase of ≥0.5 mg per deciliter), urine output less than 0.3 ml per kilogram of body weight per hour for 24 hours or longer, or anuria for at least 12 hours. The primary outcome was death at 90 days.

RESULTS

The trial was stopped early for futility after the second planned interim analysis. A total of 488 patients underwent randomization; there were no significant between-group differences in the characteristics at baseline. Among the 477 patients for whom follow-up data at 90 days were available, 58% of the patients in the early-strategy group (138 of 239 patients) and 54% in the delayed-strategy group (128 of 238 patients) had died (P=0.38). In the delayed-strategy group, 38% (93 patients) did not receive renal-replacement therapy. Criteria for emergency renal-replacement therapy were met in 17% of the patients in the delayed-strategy group (41 patients).

CONCLUSIONS

Among patients with septic shock who had severe acute kidney injury, there was no significant difference in overall mortality at 90 days between patients who were assigned to an early strategy for the initiation of renal-replacement therapy and those who were assigned to a delayed strategy.

October


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