Chiefs’ Inquiry Corner- 8/16/2021

 The overall evidence favors delaying initiation of renal replacement therapy (RRT) until indications (e.g., severe hyperkalemia or refractory fluid overload) develop. How long RRT can be safely delayed isn’t known. Studies generally demonstrate no benefit in starting RRT in asymptomatic patients or at a specific eGFR cutoff compared with watchful waiting and initiating RRT for symptoms or metabolic abnormalities that are refractory to medical treatment. However, a recently published study suggests there may be a limit after which postponing was associated with potential risk. In the AKIKI 2 trial, 278 critically ill patients with severe AKI, no urgent indications for RRT, and either oliguria for 72 hours or a blood urea nitrogen (BUN) between 112 and 140 mg/dL were randomly assigned to initiate RRT immediately or to defer RRT until either an urgent indication developed or BUN exceeded 140 mg/dL. RRT was ultimately initiated in 79% of those assigned to defer RRT. At 28 and 60 days, mortality was higher in the deferred RRT group (45% vs 38% and 55% vs 44%, respectively), although these differences were not statistically significant. These findings may suggest that while early initiation of RRT is not preferred, there may be limits beyond which delaying RRT is no longer beneficial.

References: AKIKI 2 Trial

  Elevated lactate in septic shock was traditionally thought to be due to anaerobic metabolism resulting from inadequate tissue perfusion and oxygen deliver. This theory, however, has fallen out of favor as the primary etiology of lactate production. More recent theories posit that in sepsis, increased beta-2 adrenergic stimulation leads to increase in glycolysis and pyruvate production and when the TCA cycle is overwhelmed, lactate concentration rises. Long term beta-blocker therapy, therefore, may decrease lactate in patients presenting with sepsis. Contenti et al. assessed blood lactate production in 260 patients with severe sepsis or septic shock, and found that the lactate concentration was significantly lower in patients previously treated with beta- blockers (3.9 ± 2.3 mmol/L vs 5.6 ± 3.6 mmol/L; p < 0.001).

References: Long-Term Beta-Blocker Therapy Decreases Blood Lactate Concentrations in Severely Septic Patients

  Use of direct oral anticoagulants (DOACs) is associated with an approximately 3% annual risk for major bleeding on average (exact rate is dependent on other factors, such as age, other comorbidities, and concurrent medications). A recent meta-analysis of 60 studies (N=4735 patients) examined the effect of the reversal agents 4-factor prothrombin complex concentrate (4PCC), idarucizumab, and andexanet  on clinical outcomes in severe DOAC-associated bleeding. The mortality rate from severe DOAC-associated bleeding with use of reversal agents was approximately 18%.  Thromboembolic events occurred in 4.6%, with the pooled rate of venous thromboembolism 1.8% and arterial thromboembolism 2.2%. Effective hemostasis was achieved in 78.5%. The results of this meta-analysis revealed that even with the utilization of reversal agents, mortality from DOAC-associated severe bleeding remains high, and approximately 20% of people did not achieve effective hemostasis with these agents. Thus, it remains of the utmost importance to prevent bleeding and minimize risks when able, as the advent of reversal agents for DOAC-associated severe bleeding has not completely mitigated the sequelae of severe bleeding.

References: Meta-Analysis of Reversal Agents for Severe Bleeding Associated with Direct Oral Anticoagulants