Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, Aguilar G, Alba F, González-Higueras E, Conesa LA, Martín-Rodríguez C, Díaz-Domínguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Añón JM, Fernández RL, González-Martín JM; dexamethasone in ARDS network. Lancet Respir Med. 2020 Mar;8(3):267-276.
There are no proven effective, specific pharmacological therapies for ARDS based on RCTs. Different regimens of corticosteroids have been tested in ARDS with inconclusive results, and professional societies conditionally recommend glucocorticoids. The authors studied dexamethasone with its potent, long-lasting anti-inflammatory effect as a treatment during the early phase of moderate-to-severe ARDS.
Using an investigator-initiated, multicenter RCT design of 17 ICUs in teaching hospitals across Spain, the investigators randomized patients who had PaO2/FiO2 ≤200mmHg on PEEP≥10cmH2O and FiO2≥0.5 at 24-hours after ARDS onset. The intervention group received IV dexamethasone 20mg once daily from day 1 to day 5 and 10mg once daily from day 6 to day 10. Treatment with dexamethasone was maintained for a maximum of 10 days after randomization or until extubation. Primary outcome measure was number of ventilator-free days at 28 days. Secondary outcome was death from any cause at 60 days.
Between March 28, 2013, to December 31, 2018, the authors enrolled 277 (139 dexamethasone, 138 standard care control) patients in ITT analysis. The trial was stopped due to low enrolment numbers at 88% enrolment of planned sample size. Patients in the dexamethasone group had a greater mean number of ventilator-free days (12.9±9.9 vs 7.5±9.0; between-groups difference 4.8 [95% CI 2.57-7.03]; p<0.0001) and lower rate of death (29 [21%] vs. 50 [36%]; one death avoided for every seven patients treated; p=0.0047). In addition, use of prone position was less frequent; SOFA scores lower as early as day 3; PaO2/FiO2 higher at day 6; and actual duration of mechanical ventilation in ICU survivors shorter, all in the dexamethasone group. The main adverse events of hyperglycemia and new infections were similar between the groups.
The observed treatment effect of dexamethasone for moderate-to-severe ARDS was larger than expected, and the difference of ventilator-free days was similar to results of a meta-analysis of nine previous RCTs. The authors suggest that glucocorticoid therapy may benefit alveolar-capillary membrane permeability and mediate inflammation and tissue repair, resulting in down-regulation of pulmonary and systemic inflammation and restoring homeostasis in ARDS. This large, multicenter study builds on previous smaller studies which may not have analyzed patients in the context of lung-protective ventilation strategies or did not demonstrate a reduction in hospital mortality. The study has limited generalizability given strict inclusion and exclusion criteria, enrolling 27% of eligible patients and excluding patients with major pre-existing comorbidities. Analyses of risks of various biases revealed generally low risk. The authors conclude that early administration of dexamethasone could reduce duration of mechanical ventilation and overall mortality in patients with moderate-to-severe ARDS.
Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury. STARRT-AKI Investigators; Canadian Critical Care Trials Group, the Australian and New Zealand Intensive Care Society Clinical Trials Group, the United Kingdom Critical Care Research Group, the Canadian Nephrology Trials Network, and the Irish Critical Care Trials Group, Bagshaw SM, Wald R, Adhikari NKJ, Bellomo R, da Costa BR, Dreyfuss D, Du B, Gallagher MP, Gaudry S, Hoste EA, Lamontagne F, Joannidis M, Landoni G, Liu KD, McAuley DF, McGuinness SP, Neyra JA, Nichol AD, Ostermann M, Palevsky PM, Pettilä V, Quenot JP, Qiu H, Rochwerg B, Schneider AG, Smith OM, Thomé F, Thorpe KE, Vaara S, Weir M, Wang AY, Young P, Zarbock A. N Engl J Med. 2020 Jul 16;383(3):240-251.
Acute kidney injury (AKI) is a common complication in patients admitted to an ICU and is associated with a high risk of death, major complications and resource utilization. The appropriate timing renal replacement therapy (RRT) initiation is unclear especially when AKI is not already complicated by major metabolic disorders and fluid disturbances. Previous studies of early RRT initiation in critically ill patients with AKI have shown discrepant findings. The authors hypothesized that an accelerated strategy for RRT initiation would result in a lower risk of death.
168 hospitals in 15 countries participated in this randomized, open-label, controlled trial. Adult patients ≥18yo admitted to an ICU with kidney dysfunction and severe AKI categorized as KDIGO stage 2 or 3 were included. Emergency indications, prior RRT, advanced chronic kidney disease, and uncommon causes of AKI were the foci of exclusion criteria. Full eligibility for the study required patients’ attending physicians to affirm clinical equipoise by noting the absence of any circumstances that would mandate either immediate initiation of RRT or a deferral of such therapy because of clinical judgement regarding the likelihood of imminent recovery of kidney function.
In the accelerated-strategy group, clinicians started RRT as soon as possible within 12 hours. In the standard-strategy group, clinicians were discouraged from initiating RRT until: serum potassium ≥6mmol/L, pH ≤7.20, bicarbonate ≤12mmol/L, PaO2/FiO2≤200 plus clinical volume overload, or persistent AKI for ≥72 hours. The primary outcome was death from any cause at 90 days. Secondary outcomes included RRT dependence; a composite of death or RRT dependence; major adverse kidney event; and LOS.
From October 2015 through September 2019, 2927 (1465 accelerated-strategy and 1462 standard-strategy) patients were included in the modified ITT analysis. Baseline characteristics were well-balanced in the two groups. RRT was initiated at a median (IQR) of 6.1 (3.9-8.8) hours in the accelerated-strategy group and 31.1 (19.0-71.8) hours in the standard-strategy group. At time of RRT initiation, SOFA score, serum creatinine, blood urea nitrogen, and positive fluid balance were higher among patients in the standard-strategy group. Death at 90 days was similar (43.9% vs 43.7%, p=0.92) with relative risk 1.00, absolute risk difference 0.2%, and adjusted odds ratio 1.05. Among patients who were alive at 90 days, RRT dependence was 10.4% in the accelerated-strategy group and 6.0% in the standard-strategy group (relative risk, 1.74 [95% CI, 1.24 to 2.43]). There was no meaningful between-group difference in the composite of death or RRT dependence, major adverse kidney events, death in ICU or LOS. Adverse events (primarily hypotension and hypophosphatemia) were more common in the accelerated-strategy group (23.0% vs. 16.5%, p<0.0001).
Unlike prior similar studies, the authors aimed to enrich their patient population by incorporating clinical equipoise to guide eligibility. Without yielding benefits to the primary or secondary outcomes, the accelerated-strategy for RRT initiation resulted in a greater percentage of survivors who were RRT dependent and who had adverse events, suggesting that greater exposure to RRT may compromise kidney repair and the return of endogenous kidney function.
Impact of protocolized diuresis for de-resuscitation in the intensive care unit. Bissell BD, Laine ME, Thompson Bastin ML, Flannery AH, Kelly A, Riser J, Neyra JA, Potter J, Morris PE. Crit Care. 2020 Feb 28;24(1):70.
Early IV fluid resuscitation is a necessary tool to improve hemodynamic stability and organ perfusion and possibly decrease mortality in critically ill patients. However, benefit of continued fluid administration after resuscitation is unclear, and positive fluid balance has been associated with diverse and persistent organ system dysfunction. Once hemodynamic stability is achieved, de-resuscitation with diuretics or renal replacement therapy (RRT) may benefit patient outcomes and requires further study.
The authors performed a pilot study of a diuresis protocol for patients requiring mechanical ventilation with net-positive or –even cumulative fluid or clinical signs of fluid overload determined via CXR or physical examination between April 1, 2018, and April 1, 2019. The intervention group was matched to three patient visits from a historical time period (January 2016-December 2017) who received a non-protocolized, provider-determined diuresis practice with furosemide. Intervention included diuresis to -1000mL to -3000mL in 24 hours assessed at 8-hour intervals. In addition to furosemide, metolazone or chlorothiazide were allowed as combination diuresis, and compliance was ensured by use of conditional order sets. The primary outcome was net cumulative fluid balance 72 hours following shock resolution. Secondary outcomes included mortality, ICU & hospital LOSs, ventilator-free days, RRT dependence at discharge, and incidence of severe metabolic disturbance.
364 (91 intervention, 273 matched controls) patients were analyzed. Matching procedures resulted in balanced groups without major, meaningful differences in baseline clinical criteria. The diuresis protocol group received higher doses of furosemide and more frequently received other diuretics. The standard therapy group had more adjunctive albumin use. At 72 hours, the intervention group had more negative median (IQR) fluid balance (-2257mL [-5676-920] vs 265mL [-2283-3025], p<0.0001) and also a statistically significant increase in rate of electrolyte disturbances driven by hypernatremia and hypokalemia. The intervention group had a lower in-hospital mortality rate (5.5% vs. 16.1%, p=0.008); 2 more ICU-free days (p=0.030); less RRT receipt in ICU (0 vs 17 [6.2%], p<0.0001) and lower RRT dependence at discharge (0 vs 14 [5.1%], p= 0.025).
The authors demonstrated a significant decrease in 72-hour cumulative fluid volume with addition of a diuresis protocol and associated improved outcomes in the critically ill. The key limitation to this study is lack of randomization and blinding, and additional questions of compliance to the protocol are raised. Although potentially confounded, the study supports the implementation of a diuresis protocol in the ICU and the implementation of larger randomized controlled trials of de-resuscitation.