Renal replacement therapy initiation strategies in comatose patients with severe acute kidney injury: a secondary analysis of a multicenter randomized controlled trial.

PURPOSE: The effect of renal replacement therapy (RRT) in comatose patients with acute kidney injury (AKI) remains unclear. We compared two RRT initiation strategies on the probability of awakening in comatose patients with severe AKI. METHODS: We conducted a post hoc analysis of a trial comparing two delayed RRT initiation strategies in patients with severe AKI. Patients were monitored until they had oliguria for more than 72 h and/or blood urea nitrogen higher than 112 mg/dL and then randomized to a delayed strategy (RRT initiated after randomization) or a more-delayed one (RRT initiated if complication occurred or when blood urea nitrogen exceeded 140 mg/dL). We included only comatose patients (Richmond Agitation-Sedation scale [RASS] < - 3), irrespective of sedation, at randomization. A multi-state model was built, defining five mutually exclusive states: death, coma (RASS < - 3), incomplete awakening (RASS [- 3; - 2]), awakening (RASS [- 1; + 1] two consecutive days), and agitation (RASS > + 1). Primary outcome was the transition from coma to awakening during 28 days after randomization. RESULTS: A total of 168 comatose patients (90 delayed and 78 more-delayed) underwent randomization. The transition intensity from coma to awakening was lower in the more-delayed group (hazard ratio [HR] = 0.36 [0.17-0.78]; p = 0.010). Time spent awake was 10.11 days [8.11-12.15] and 7.63 days [5.57-9.64] in the delayed and the more-delayed groups, respectively. Two sensitivity analyses were performed based on sedation status and sedation practices across centers, yielding comparable results. CONCLUSION: In comatose patients with severe AKI, a more-delayed RRT initiation strategy resulted in a lower chance of transitioning from coma to awakening.

Long-term outcomes after severe acute kidney injury in critically ill patients: the SALTO study.

BACKGROUND: The extent of the consequences of an episode of severe acute kidney injury (AKI) on long-term outcome of critically ill patients remain debated. We conducted a prospective follow-up of patients included in a large multicenter clinical trial of renal replacement therapy (RRT) initiation strategy during severe AKI (the Artificial Kidney Initiation in Kidney Injury, AKIKI) to investigate long-term survival, renal outcome and health related quality of life (HRQOL). We also assessed the influence of RRT initiation strategy on these outcomes. RESULTS: Follow-up of patients extended from 60 days to a median of 3.35 years [interquartile range (IQR), 1.89 to 4.09] after the end of initial study. Of the 619 patients included in the AKIKI trial, 316 survived after 60 days. The overall survival rate at 3 years from inclusion was 39.4% (95% CI 35.4 to 43.4). A total of 46 patients (on the 175 with available data on long-term kidney function) experienced worsening of renal function (WRF) at the time of follow-up [overall incidence of 26%, cumulative incidence at 4 years: 20.6% (CI 95% 13.0 to 28.3)]. Fifteen patients required chronic dialysis (5% of patients who survived after day 90). Among the 226 long-term survivors, 80 (35%) answered the EQ-5D questionnaire. The median index value reported was 0.67 (IQR 0.40 to 1.00) indicating a noticeable alteration of quality of life. Initiation strategy for RRT had no effect on any long-term outcome. CONCLUSION: Severe AKI in critically ill patients was associated with a high proportion of death within the first 2 months but less so during long-term follow-up. A quarter of long-term survivors experienced a WRF and suffered from a noticeable impairment of quality of life. Renal replacement therapy initiation strategy was not associated with mortality outcome.

Impact of renal replacement therapy strategy on beta-lactam plasma concentrations: the BETAKIKI study-an ancillary study of a randomized controlled trial.

BACKGROUND: Sepsis prognosis correlates with antibiotic adequacy at the early phase. This adequacy is dependent on antibacterial spectrum, bacterial resistance profile and antibiotic dosage. Optimal efficacy of beta-lactams mandates concentrations above the minimal inhibitory concentration (MIC) of the targeted bacteria for the longest time possible over the day. Septic acute kidney injury (AKI) is the most common AKI syndrome in ICU and often mandates renal replacement therapy (RRT) initiation. Both severe AKI and RRT may increase outside target antibiotic concentrations and ultimately alter patient's prognosis. PATIENTS AND METHODS: This is a secondary analysis of a randomized controlled trial that compared an early RRT initiation strategy with a delayed one in 620 critically ill patients undergoing severe AKI (defined by KDIGO 3). We compared beta-lactam trough concentrations between the two RRT initiation strategies. The primary outcome was the proportion of patients with sufficient trough plasma concentration of beta-lactams defined by trough concentration above 4 times the MIC. We hypothesized that early initiation of RRT could be associated with an insufficient antibiotic plasma trough concentration compared to patients allocated to the delayed strategy. RESULTS: One hundred and twelve patients were included: 53 in the early group and 59 in the delayed group. Eighty-three patients (74%) had septic shock on inclusion. Trough beta-lactam plasma concentration was above 4 times the MIC breakpoint in 80.4% (n = 90) of patients of the whole population, without differences between the early and the delayed groups (79.2% vs. 81.4%, respectively, p = 0.78). On multivariate analysis, the presence of septic shock and a higher mean arterial pressure were significantly associated with a greater probability of adequate antibiotic trough concentration [OR 3.95 (1.14;13.64), p = 0.029 and OR 1.05 (1.01;1.10), p = 0.013, respectively). Evolution of procalcitonin level and catecholamine-free days as well as mortality did not differ whether beta-lactam trough concentration was above 4 times the MIC or not. CONCLUSIONS: In this secondary analysis of a randomized controlled trial, renal replacement therapy initiation strategy did not significantly influence plasma trough concentrations of beta-lactams in ICU patients with severe AKI. Presence of septic shock on inclusion was the main variable associated with a sufficient beta-lactam concentration. TRIAL REGISTRATION: The AKIKI trial was registered on ClinicalTrials.gov (Identifier: NCT01932190) before the inclusion of the first patient.

Continuous renal replacement therapy versus intermittent hemodialysis as first modality for renal replacement therapy in severe acute kidney injury: a secondary analysis of AKIKI and IDEAL-ICU studies.

BACKGROUND: Intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) are the two main RRT modalities in patients with severe acute kidney injury (AKI). Meta-analyses conducted more than 10 years ago did not show survival difference between these two modalities. As the quality of RRT delivery has improved since then, we aimed to reassess whether the choice of IHD or CRRT as first modality affects survival of patients with severe AKI. METHODS: This is a secondary analysis of two multicenter randomized controlled trials (AKIKI and IDEAL-ICU) that compared an early RRT initiation strategy with a delayed one. We included patients allocated to the early strategy in order to emulate a trial where patients would have been randomized to receive either IHD or CRRT within twelve hours after the documentation of severe AKI. We determined each patient's modality group as the first RRT modality they received. The primary outcome was 60-day overall survival. We used two propensity score methods to balance the differences in baseline characteristics between groups and the primary analysis relied on inverse probability of treatment weighting. RESULTS: A total of 543 patients were included. Continuous RRT was the first modality in 269 patients and IHD in 274. Patients receiving CRRT had higher cardiovascular and total-SOFA scores. Inverse probability weighting allowed to adequately balance groups on all predefined confounders. The weighted Kaplan-Meier death rate at day 60 was 54·4% in the CRRT group and 46·5% in the IHD group (weighted HR 1·26, 95% CI 1·01-1·60). In a complementary analysis of less severely ill patients (SOFA score: 3-10), receiving IHD was associated with better day 60 survival compared to CRRT (weighted HR 1.82, 95% CI 1·01-3·28; p < 0.01). We found no evidence of a survival difference between the two RRT modalities in more severe patients. CONCLUSION: Compared to IHD, CRRT as first modality seemed to convey no benefit in terms of survival or of kidney recovery and might even have been associated with less favorable outcome in patients with lesser severity of disease. A prospective randomized non-inferiority trial should be implemented to solve the persistent conundrum of the optimal RRT technique.

Impact of targeted hypothermia in expanded-criteria organ donors on recipient kidney-graft function: study protocol for a multicentre randomised controlled trial (HYPOREME).

INTRODUCTION: Expanded-criteria donors (ECDs) are used to reduce the shortage of kidneys for transplantation. However, kidneys from ECDs are associated with an increased risk of delayed graft function (DGF), a risk factor for allograft loss and mortality. HYPOREME will be a multicentre randomised controlled trial (RCT) comparing targeted hypothermia to normothermia in ECDs, in a country where the use of machine perfusion for organ storage is the standard of care. We hypothesise that hypothermia will decrease the incidence of DGF. METHODS AND ANALYSIS: HYPOREME is a multicentre RCT comparing the effect on kidney function in recipients of targeted hypothermia (34°C-35°C) and normothermia (36.5°C-37.5°C) in the ECDs. The temperature intervention starts from randomisation and is maintained until aortic clamping in the operating room. We aim to enrol 289 ECDs in order to analyse the kidney function of 516 recipients in the 53 participating centres. The primary outcome is the occurrence of DGF in kidney recipients, defined as a requirement for renal replacement therapy within 7 days after transplantation (not counting a single session for hyperkalemia during the first 24 hours). Secondary outcomes include the proportion of patients with individual organs transplanted in each group; the number of organs transplanted from each ECD and the vital status and kidney function of the recipients 7 days, 28 days, 3 months and 1 year after transplantation. An interim analysis is planned after the enrolment of 258 kidney recipients. ETHICS AND DISSEMINATION: The trial was approved by the ethics committee of the French Intensive Care Society (CE-SRLF-16-07) on 26 April 2016 and by the competent French authorities on 20 April 2016 (Comité de Protection des Personnes-TOURS-Région Centre-Ouest 1, registration #2016-S3). Findings will be published in peer-reviewed journals and presented during national and international scientific meetings. TRIAL REGISTRATION NUMBER: NCT03098706.

Critical pathways for controlled donation after circulatory death in France.

INTRODUCTION: In 2015, France authorised controlled donation after circulatory death (cDCD) according to a nationally approved protocol. The aim of this study is to provide an overview from the perspective of critical care specialists of cDCD. The primary objective is to assess how the organ donation procedure affects the withdrawal of life-sustaining therapies (WLST) process. The secondary objective is to assess the impact of cDCD donors' diagnoses on the whole process. MATERIAL AND METHODS: This 2015-2019 prospective observational multicentre study evaluated the WLST process in all potential cDCD donors identified nationwide, comparing 2 different sets of subgroups: 1- those whose WLST began after organ donation was ruled out vs. while it was still under consideration; 2- those with a main diagnosis of post-anoxic brain injury (PABI) vs. primary brain injury (PBI) at the time of the WLST decision. RESULTS: The study analysed 908 potential cDCD donors. Organ donation remained under consideration at WLST initiation for 54.5% of them with longer intervals between their WLST decision and its initiation (2 [1-4] vs. 1 [1-2] days, P < 0.01). Overall, 60% had post-anoxic brain injury. Time from ICU admission to WLST decision was longer for primary brain injury donors (10 [4-21] vs. 6 [4-9] days, P < 0.01). Median time to death (agonal phase) was 15 [15-20] min. CONCLUSIONS: French cDCD donors are mostly related to post-anoxic brain injury. The organ donation process does not accelerate WLST decision but increases the interval between the WLST decision and its initiation.

Vascular access for renal replacement therapy among 459 critically ill patients: a pragmatic analysis of the randomized AKIKI trial.

BACKGROUND: Vascular access for renal replacement therapy (RRT) is routine question in the intensive care unit. Randomized trials comparing jugular and femoral sites have shown similar rate of nosocomial events and catheter dysfunction. However, recent prospective observational data on RRT catheters use are scarce. We aimed to assess the site of RRT catheter, the reasons for catheter replacement, and the complications according to site in a large population of critically ill patients with acute kidney injury. PATIENTS AND METHODS: We performed an ancillary study of the AKIKI study, a pragmatic randomized controlled trial, in which patients with severe acute kidney injury (KDIGO 3 classification) with invasive mechanical ventilation, catecholamine infusion or both were randomly assigned to either an early or a delayed RRT initiation strategy. The present study involved all patients who underwent at least one RRT session. Number of RRT catheters, insertion sites, factors potentially associated with the choice of insertion site, duration of catheter use, reason for catheter replacement, and complications were prospectively collected. RESULTS: Among the 619 patients included in AKIKI, 462 received RRT and 459 were finally included, with 598 RRT catheters. Femoral site was chosen preferentially (n = 319, 53%), followed by jugular (n = 256, 43%) and subclavian (n = 23, 4%). In multivariate analysis, continuous RRT modality was significantly associated with femoral site (OR = 2.33 (95% CI (1.34-4.07), p = 0.003) and higher weight with jugular site [88.9 vs 83.2 kg, OR = 0.99 (95% CI 0.98-1.00), p = 0.03]. Investigator site was also significantly associated with the choice of insertion site (p = 0.03). Cumulative incidence of catheter replacement did not differ between jugular and femoral site [sHR 0.90 (95% CI 0.64-1.25), p = 0.67]. Catheter dysfunction was the main reason for replacement (n = 47), followed by suspected infection (n = 29) which was actually seldom proven (n = 4). No mechanical complication (pneumothorax or hemothorax) occurred. CONCLUSION: Femoral site was preferentially used in this prospective study of RRT catheters in 31 French intensive care units. The choice of insertion site depended on investigating center habits, weight, RRT modality. A high incidence of catheter infection suspicion led to undue replacement.

Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): a multicentre, open-label, randomised, controlled trial.

BACKGROUND: Delaying renal replacement therapy (RRT) for some time in critically ill patients with severe acute kidney injury and no severe complication is safe and allows optimisation of the use of medical devices. Major uncertainty remains concerning the duration for which RRT can be postponed without risk. Our aim was to test the hypothesis that a more-delayed initiation strategy would result in more RRT-free days, compared with a delayed strategy. METHODS: This was an unmasked, multicentre, prospective, open-label, randomised, controlled trial done in 39 intensive care units in France. We monitored critically ill patients with severe acute kidney injury (defined as Kidney Disease: Improving Global Outcomes stage 3) until they had oliguria for more than 72 h or a blood urea nitrogen concentration higher than 112 mg/dL. Patients were then randomly assigned (1:1) to either a strategy (delayed strategy) in which RRT was started just after randomisation or to a more-delayed strategy. With the more-delayed strategy, RRT initiation was postponed until mandatory indication (noticeable hyperkalaemia or metabolic acidosis or pulmonary oedema) or until blood urea nitrogen concentration reached 140 mg/dL. The primary outcome was the number of days alive and free of RRT between randomisation and day 28 and was done in the intention-to-treat population. The study is registered with ClinicalTrial.gov, NCT03396757 and is completed. FINDINGS: Between May 7, 2018, and Oct 11, 2019, of 5336 patients assessed, 278 patients underwent randomisation; 137 were assigned to the delayed strategy and 141 to the more-delayed strategy. The number of complications potentially related to acute kidney injury or to RRT were similar between groups. The median number of RRT-free days was 12 days (IQR 0-25) in the delayed strategy and 10 days (IQR 0-24) in the more-delayed strategy (p=0·93). In a multivariable analysis, the hazard ratio for death at 60 days was 1·65 (95% CI 1·09-2·50, p=0·018) with the more-delayed versus the delayed strategy. The number of complications potentially related to acute kidney injury or renal replacement therapy did not differ between groups. INTERPRETATION: In severe acute kidney injury patients with oliguria for more than 72 h or blood urea nitrogen concentration higher than 112 mg/dL and no severe complication that would mandate immediate RRT, longer postponing of RRT initiation did not confer additional benefit and was associated with potential harm. FUNDING: Programme Hospitalier de Recherche Clinique.

Determinants of hospital and one-year mortality among older patients admitted to intensive care units: results from the multicentric SENIOREA cohort.

BACKGROUND: Improving outcomes of older patients admitted into intensive care units (ICU) is a raising concern. This study aimed at determining which geriatric and ICU parameters were associated with in-hospital and long-term mortality in this population. METHODS: We conducted a prospective multicentric observational cohort study, including patients aged 75 years and older requiring mechanical ventilation, admitted between September 2012 and December 2013 into ICU of 13 French hospitals. Comprehensive geriatric assessment at ICU admission and ICU usual parameters were registered in a standardized manner. Survival was recorded and comprehensive geriatric assessment was updated after 1 year during a dedicated home visit. RESULTS: 501 patients were analyzed. 108 patients (21.6%) died during the hospital stay. One-year survival rate was 53.8% (IC 95% [49.2%; 58.2%]). Factors associated with increased in-hospital mortality were higher acute illness severity score, resuscitated cardiac arrest as primary ICU diagnosis, perception of anxiety and low quality of life by the proxy, and living in a chronic care facility before ICU admission. Among patients alive at hospital discharge, factors associated with increased 1-year mortality in multivariate analysis were longer duration of mechanical ventilation, all primary ICU diagnoses other than septic shock, a Katz-activities of daily living (ADL) score below 5 and living in a chronic care facility before ICU admission. Among the 163 survivors at 1 year who received a second comprehensive geriatric assessment, the ADL score (functional abilities) showed a significant but moderate decline over time, whereas the Mini-Zarit score (family burden) improved. No significant change in patients' place of life was observed after 1 year, and quality of life was reported as happy-to-very-happy in 88% of survivors. CONCLUSIONS: The mortality rate remains high among older ICU patients requiring mechanical ventilation. Factors associated with short- and long-term mortality combined geriatric and ICU criteria, which should be jointly evaluated in routine care. Clinical trial registration NCT01679171.

Nutrition During Targeted Temperature Management After Cardiac Arrest: Observational Study of Neurological Outcomes and Nutrition Tolerance.

BACKGROUND: Whether providing nutrition support is beneficial or deleterious during targeted temperature management (TTM) after cardiac arrest is unclear. We therefore performed a retrospective observational study to determine whether early nutrition was beneficial or deleterious during TTM. METHODS: We retrospectively studied patients admitted to our intensive care unit (ICU) between 2008 and 2014 after successfully resuscitated cardiac arrest. We compared the group given nutrition within 48 hours after ICU admission (E+ group) to the group given nutrition later on or not at all (E- group). RESULTS: Of the 203 included patients, 143 were in the E+ group and 60 in the E- group. The E+ group had a significantly higher proportion of patients with a good 3-month neurological outcome (42.7% vs 16.7%, P < 0.001). The difference remained significant after adjustment on a propensity score (odds ratio, 3.47; 95% confidence interval, 1.48-8.14; P = 0.004). The cumulative energy deficit for an energy goal of 20 kcal/kg/d from admission to day 7 was significantly lower in the E+ group (3304 ± 2863 kcal vs 5017 ± 2655 kcal, P < 0.001). Within the E+ group, the subgroups with nutrition initiation when body temperature was <36°C vs ≥36°C were not significantly different regarding the frequencies of early-onset pneumonia, ventilator-associated pneumonia, vomiting, and prokinetic drug use (all P-values > 0.05). CONCLUSIONS: Early nutrition after cardiac arrest during TTM appears safe and may be associated with better neurological outcomes. These findings warrant a randomized controlled trial to resolve the remaining issues.

The Artificial Kidney Initiation in Kidney Injury 2 (AKIKI2): study protocol for a randomized controlled trial.

BACKGROUND: The Artificial Kidney Initiation in Kidney Injury (AKIKI) trial showed that a delayed renal replacement therapy (RRT) strategy for severe acute kidney injury (AKI) in critically ill patients was safe and associated with major reduction in RRT initiation compared with an early strategy. The five criteria which mandated RRT initiation in the delayed arm were: severe hyperkalemia, severe acidosis, acute pulmonary edema due to fluid overload resulting in severe hypoxemia, serum urea concentration > 40 mmol/l and oliguria/anuria > 72 h. However, duration of anuria/oliguria and level of blood urea are still criteria open to debate. The objective of the study is to compare the delayed strategy used in AKIKI (now termed "standard") with another in which RRT is further delayed for a longer period (termed "delayed strategy"). METHODS/DESIGN: This is a prospective, multicenter, open-label, two-arm randomized trial. The study is composed of two stages (observational and randomization stages). At any time, the occurrence of a potentially severe condition (severe hyperkalemia, severe metabolic or mixed acidosis, acute pulmonary edema due to fluid overload resulting in severe hypoxemia) suggests immediate RRT initiation. Patients receiving (or who have received) intravenously administered catecholamines and/or invasive mechanical ventilation and presenting with AKI stage 3 of the KDIGO classification and with no potentially severe condition are included in the observational stage. Patients presenting a serum urea concentration > 40 mmol/l and/or an oliguria/anuria for more than 72 h are randomly allocated to a standard (RRT is initiated within 12 h) or a delayed RRT strategy (RRT is initiated only if an above-mentioned potentially severe condition occurs or if the serum urea concentration reaches 50 mmol/l). The primary outcome will be the number of RRT-free days at day 28. One interim analysis is planned. It is expected to include 810 patients in the observational stage and to randomize 270 subjects. DISCUSSION: The AKIKI2 study should improve the knowledge of RRT initiation criteria in critically ill patients. The potential reduction in RRT use allowed by a delayed RRT strategy might be associated with less invasive care and decreased costs. Enrollment is ongoing. Inclusions are expected to be completed by November 2019. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03396757. Registered on 11 January 2018.

Nephrotoxic drug burden among 1001 critically ill patients: impact on acute kidney injury.

BACKGROUND: Nephrotoxic drug prescription may contribute to acute kidney injury (AKI) occurrence and worsening among critically ill patients and thus to associated morbidity and mortality. The objectives of this study were to describe nephrotoxic drug prescription in a large intensive-care unit cohort and, through a case-control study nested in the prospective cohort, to evaluate the link of nephrotoxic prescription burden with AKI. RESULTS: Six hundred and seventeen patients (62%) received at least one nephrotoxic drug, among which 303 (30%) received two or more. AKI was observed in 609 patients (61%). A total of 351 patients were considered as cases developing or worsening AKI a given index day during the first week in the intensive-care unit. Three hundred and twenty-seven pairs of cases and controls (patients not developing or worsening AKI during the first week in the intensive-care unit, alive the case index day) matched on age, chronic kidney disease, and simplified acute physiology score 2 were analyzed. The nephrotoxic burden prior to the index day was measured in drug.days: each drug and each day of therapy increasing the burden by 1 drug.day. This represents a semi-quantitative evaluation of drug exposure, potentially easy to implement by clinicians. Nephrotoxic burden was significantly higher among cases than controls: odds ratio 1.20 and 95% confidence interval 1.04-1.38. Sensitivity analysis showed that this association between nephrotoxic drug prescription in the intensive-care unit and AKI was predominant among the patients with lower severity of disease (simplified acute physiology score 2 below 48). CONCLUSIONS: The frequently observed prescription of nephrotoxic drugs to critically ill patients may be evaluated semi-quantitatively through computing drug.day nephrotoxic burden, an index significantly associated with subsequent AKI occurrence, and worsening among patients with lower severity of disease.

Being Convinced and Taking Responsibility: A Qualitative Study of Family Members' Experience of Organ Donation Decision and Bereavement After Brain Death.

OBJECTIVES: Family members of brain dead patients experience an unprecedented situation in which not only they are told that their loved one is dead but are also asked to consider organ donation. The objective of this qualitative study was to determine 1) what it means for family members to make the decision and to take responsibility, 2) how they interact with the deceased patient in the ICU, 3) how family members describe the impact of the process and of the decision on their bereavement process. DESIGN: Qualitative study using interviews with bereaved family members who were approached for organ donation after the death of their relative in the ICU (brain death). SETTING: Family members from 13 ICUs in France. SUBJECTS: Bereaved family members who were approached for organ donation after the death of their relative in the ICU (brain death). INTERVENTION: None. MEASUREMENTS AND RESULTS: Twenty-four interviews were conducted with 16 relatives of organ donor patients and with eight relatives of nonorgan donor patients. Three themes emerged: 1) taking responsibility-relatives explain how they endorse decisional responsibility but do not experience it as a burden, on the contrary; 2) ambiguous perceptions of death-two groups of relatives emerge: those for whom ambiguity hinders their acceptance of the patient's death; those for whom ambiguity is an opportunity to accept the death and say goodbye; and 3) donation as a comfort during bereavement. CONCLUSIONS: In spite of caregivers' efforts to focus organ donation discussions and decision on the patient, family members feel a strong decisional responsibility that is not experienced as a burden but a proof of their strong connection to the patient. Brain death however creates ambivalent experiences that some family members endure whereas others use as an opportunity to perform separation rituals. Last, organ donation can be experienced as a form of comfort during bereavement provided family members remain convinced their decision was right.

Grief Symptoms in Relatives Who Experienced Organ Donation Requests in the ICU.

RATIONALE: Studies show that the quality of end-of-life communication and care have a significant impact on the living long after the death of a relative and have been implicated in the burden of psychological symptoms after the ICU experience. In the case of organ donation, the patient's relatives are centrally involved in the decision-making process; yet, few studies have examined the impact of the quality of communication on the burden of psychological symptoms after death. OBJECTIVES: To assess the experience of the organ donation process and grief symptoms in relatives of brain-dead patients who discussed organ donation in the ICU. METHODS: We conducted a multicenter longitudinal study in 28 ICUs in France. Participants were the relatives of brain-dead patients who were approached to discuss organ donation. Relatives were followed-up by phone at three time points: at 1 month, to complete a questionnaire describing their experience of the organ donation process; at 3 months, to complete the Hospital Anxiety and Depression Scale and the Impact of Event Scale-Revised; and at 9 months, to complete the Impact of Event Scale-Revised and the Inventory of Complicated Grief. MEASUREMENTS AND MAIN RESULTS: In total, 202 relatives of 202 patients were included, of whom 158 consented to and 44 refused organ donation. Interviews were conducted at 1, 3, and 9 months with 78%, 68%, and 58% of relatives, respectively. The overall experience of the organ donation process was significantly more burdensome for relatives of nondonors. They were more dissatisfied with communication (27% vs. 10%; P = 0.021), more often shocked by the request (65% vs. 19%; P < 0.0001), and more often found the decision difficult (53% vs. 27%; P = 0.017). However, there were no significant differences in grief symptoms measured at 3 and 9 months between the two groups. Understanding of brain death was associated with grief symptoms; our results show a higher prevalence of complicated grief symptoms among relatives who did not understand the brain death process than among those who did (75% vs. 46.1%; P = 0.026). CONCLUSIONS: Experience of the organ donation process varied between relatives of donor versus nondonor patients, with relatives of nondonors experiencing lower-quality communication, but the decision was not associated with subsequent grief symptoms. Importantly, understanding of brain death is a key element of the organ donation process for relatives.

Timing of Renal Support and Outcome of Septic Shock and Acute Respiratory Distress Syndrome. A Post Hoc Analysis of the AKIKI Randomized Clinical Trial.

RATIONALE: The optimal strategy for initiation of renal replacement therapy (RRT) in patients with severe acute kidney injury in the context of septic shock and acute respiratory distress syndrome (ARDS) is unknown. OBJECTIVES: To examine the effect of an early compared with a delayed RRT initiation strategy on 60-day mortality according to baseline sepsis status, ARDS status, and severity. METHODS: Post hoc analysis of the AKIKI (Artificial Kidney Initiation in Kidney Injury) trial. MEASUREMENTS AND MAIN RESULTS: Subgroups were defined according to baseline characteristics: sepsis status (Sepsis-3 definition), ARDS status (Berlin definition), Simplified Acute Physiology Score 3 (SAPS 3), and Sepsis-related Organ Failure Assessment (SOFA). Of 619 patients, 348 (56%) had septic shock and 207 (33%) had ARDS. We found no significant influence of the baseline sepsis status (P = 0.28), baseline ARDS status (P = 0.94), and baseline severity scores (P = 0.77 and P = 0.46 for SAPS 3 and SOFA, respectively) on the comparison of 60-day mortality according to RRT initiation strategy. A delayed RRT initiation strategy allowed 45% of patients with septic shock and 46% of patients with ARDS to escape RRT. Urine output was higher in the delayed group. Renal function recovery occurred earlier with the delayed RRT strategy in patients with septic shock or ARDS (P < 0.001 and P = 0.003, respectively). Time to successful extubation in patients with ARDS was not affected by RRT strategy (P = 0.43). CONCLUSIONS: Early RRT initiation strategy was not associated with any improvement of 60-day mortality in patients with severe acute kidney injury and septic shock or ARDS. Unnecessary and potentially risky procedures might often be avoided in these fragile populations. Clinical trial registered with www.clinicaltrials.gov (NCT 01932190).

Clinicians' Perception and Experience of Organ Donation From Brain-Dead Patients.

OBJECTIVE: ICU clinicians are primarily involved in organ donation after brain death of ICU patients. Their perceptions of organ donation may affect outcomes. Our objective was to describe ICU clinician's perceptions and experience of organ donation. DESIGN AND SETTING: Cross-sectional study among physicians and nurses (90 ICUs in France). We used factorial correspondence analysis to describe categories of clinicians regarding their perceptions and experience of organ donation. Factors associated with a positive (motivating) or negative (stressful) experiences were studied using multivariate logistic regression. PARTICIPANTS: Physicians and nurses. MEASUREMENTS AND MAIN RESULTS: Three thousand three hundred twenty-five clinicians working in 77 ICUs returned questionnaires. Professionals who experienced organ donation as motivating were younger (odds ratio, 0.41; 95% CI, 0.32-0.53; p < 0.001), more often potential organ donors (odds ratio, 1.92; 95% CI, 1.56-2.35; p < 0.001), less likely to describe inconsistency (odds ratio, 0.43; 95% CI, 0.23-0.8) or complexity (odds ratio, 0.55; 95% CI, 0.45-0.67) of their feelings versus their professional activity, less likely to report that organ donation was not a priority in their ICU (odds ratio, 0.68; 95% CI, 0.55-0.84), and more likely to have participated in meetings of transplant coordinators with relatives (odds ratio, 1.71; 95% CI, 1.37-2.14; p < 0.001). Professionals who felt organ donation was stressful were older (odds ratio, 1.84; 95% CI, 1.34-2.54; p < 0.001), less often physicians (odds ratio, 0.58; 95% CI, 0.44-0.77; p < 0.001), more likely to describe shift from curative care to organ donation as emotionally complex (odds ratio, 1.83; 95% CI, 1.52-2.21; p < 0.001), care of relatives of brain-dead patients as complex (odds ratio, 1.59; 95% CI, 1.32-1.93; p < 0.001), and inconsistency and complexity of personal feelings about organ donation versus professional activity (odds ratio, 3.25; 95% CI, 1.92-5.53; p < 0.001), and more likely to have little experience with caring for potential organ donors (odds ratio, 1.49; 95% CI, 1.09-2.04). CONCLUSIONS: Significant differences exist among ICU clinician's perceptions of organ donation. Whether these differences affect family experience and consent rates deserves investigation.

Antibiotic Therapy in Comatose Mechanically Ventilated Patients Following Aspiration: Differentiating Pneumonia From Pneumonitis.

OBJECTIVES: To determine the proportion of patients with documented bacterial aspiration pneumonia among comatose ICU patients with symptoms suggesting either bacterial aspiration pneumonia or non-bacterial aspiration pneumonitis. DESIGN: Prospective observational study. SETTING: University-affiliated 30-bed ICU. PATIENTS: Prospective cohort of 250 patients admitted to the ICU with coma (Glasgow Coma Scale score ≤ 8) and treated with invasive mechanical ventilation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the proportion of patients with microbiologically documented bacterial aspiration pneumonia. Patients meeting predefined criteria for aspiration syndrome routinely underwent telescopic plugged catheter sampling during bronchoscopy before starting probabilistic antibiotic treatment. When cultures were negative, the antibiotic treatment was stopped. Of 250 included patients, 98 (39.2%) had aspiration syndrome, including 92 before mechanical ventilation discontinuation. Telescopic plugged catheter in these 92 patients showed bacterial aspiration pneumonia in 43 patients (46.7%). Among the remaining 49 patients, 16 continued to receive antibiotics, usually for infections other than pneumonia; of the 33 patients whose antibiotics were discontinued, only two subsequently showed signs of lung infection. In the six patients with aspiration syndrome after mechanical ventilation, and therefore without telescopic plugged catheter, antibiotic treatment was continued for 7 days. Mechanical ventilation duration, ICU length of stay, and mortality did not differ between the 43 patients with bacterial aspiration pneumonia and the 49 patients with non-bacterial aspiration pneumonitis. The 152 patients without aspiration syndrome did not receive antibiotics. CONCLUSIONS: Among comatose patients receiving mechanical ventilation, those without clinical, laboratory, or radiologic evidence of bacterial aspiration pneumonia did not require antibiotics. In those with suspected bacterial aspiration pneumonia, stopping empirical antibiotic therapy when routine telescopic plugged catheter sampling recovered no microorganisms was nearly always effective. This strategy may be a valid alternative to routine full-course antibiotic therapy. Only half the patients with suspected bacterial aspiration pneumonia had this diagnosis confirmed by telescopic plugged catheter sampling.

Modulation by Polymyxin-B Hemoperfusion of Inflammatory Response Related to Severe Peritonitis.

Conflicting results have been reported on the influence of Polymyxin-B hemoperfusion treatment on systemic inflammation markers. The aim of the study was to assess in a randomized control trial the influence on plasma cytokine concentrations of Polymyxin-B hemoperfusion in septic shock due to peritonitis. A panel of 10 pro- or anti-inflammatory cytokines was measured in 213 patients with peritonitis-induced septic shock enrolled in the randomized trial ABDOMIX testing the impact of 2 Polymyxin-B hemoperfusion sessions with standard treatment. Gram-negative bacteria were identified in 69% of patients. In the overall population, baseline plasma cytokine concentrations were not different between the two groups. Circulating tumor necrosis factor-α, interleukin (IL)-1ß, IL-10, IL-6, and IL-1RA decreased significantly over time in both groups (P <0.0001 for all in controls, and P = 0.0002, 0.003, and <0.0001 in patients treated with Polymyxin-B hemoperfusion). IL-17A decreased significantly in patients treated with Polymyxin B hemoperfusion (P = 0.045) but not in controls. At the end of the second Polymyxin-B hemoperfusion session or at corresponding time in controls, plasma levels of cytokines did not differ between the two groups. Similar results were found in the subgroup of patients with gram-negative peritonitis who completed two Polymyxin-B hemoperfusion sessions. These results do not support a significant influence of Polymyxin-B hemoperfusion on circulating cytokines assessed except for IL-17A which clinical significance remains to be elucidated.

Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit.

BACKGROUND: The timing of renal-replacement therapy in critically ill patients who have acute kidney injury but no potentially life-threatening complication directly related to renal failure is a subject of debate. METHODS: In this multicenter randomized trial, we assigned patients with severe acute kidney injury (Kidney Disease: Improving Global Outcomes [KDIGO] classification, stage 3 [stages range from 1 to 3, with higher stages indicating more severe kidney injury]) who required mechanical ventilation, catecholamine infusion, or both and did not have a potentially life-threatening complication directly related to renal failure to either an early or a delayed strategy of renal-replacement therapy. With the early strategy, renal-replacement therapy was started immediately after randomization. With the delayed strategy, renal-replacement therapy was initiated if at least one of the following criteria was met: severe hyperkalemia, metabolic acidosis, pulmonary edema, blood urea nitrogen level higher than 112 mg per deciliter, or oliguria for more than 72 hours after randomization. The primary outcome was overall survival at day 60. RESULTS: A total of 620 patients underwent randomization. The Kaplan-Meier estimates of mortality at day 60 did not differ significantly between the early and delayed strategies; 150 deaths occurred among 311 patients in the early-strategy group (48.5%; 95% confidence interval [CI], 42.6 to 53.8), and 153 deaths occurred among 308 patients in the delayed-strategy group (49.7%, 95% CI, 43.8 to 55.0; P=0.79). A total of 151 patients (49%) in the delayed-strategy group did not receive renal-replacement therapy. The rate of catheter-related bloodstream infections was higher in the early-strategy group than in the delayed-strategy group (10% vs. 5%, P=0.03). Diuresis, a marker of improved kidney function, occurred earlier in the delayed-strategy group (P<0.001). CONCLUSIONS: In a trial involving critically ill patients with severe acute kidney injury, we found no significant difference with regard to mortality between an early and a delayed strategy for the initiation of renal-replacement therapy. A delayed strategy averted the need for renal-replacement therapy in an appreciable number of patients. (Funded by the French Ministry of Health; ClinicalTrials.gov number, NCT01932190.).

Acute respiratory distress syndrome (ARDS)-associated acute cor pulmonale and patent foramen ovale: a multicenter noninvasive hemodynamic study.

INTRODUCTION: Acute cor pulmonale (ACP) and patent foramen ovale (PFO) remain common in patients under protective ventilation for acute respiratory distress syndrome (ARDS). We sought to describe the hemodynamic profile associated with either ACP or PFO, or both, during the early course of moderate-to-severe ARDS using echocardiography. METHODS: In this 32-month prospective multicenter study, 195 patients with moderate-to-severe ARDS were assessed using echocardiography during the first 48 h of admission (age: 56 (SD: 15) years; Simplified Acute Physiology Score: 46 (17); PaO2/FiO2: 115 (39); VT: 6.5 (1.7) mL/kg; PEEP: 11 (3) cmH2O; driving pressure: 15 (5) cmH2O). ACP was defined by the association of right ventricular (RV) dilatation and systolic paradoxical ventricular septal motion. PFO was detected during a contrast study using agitated saline in the transesophageal bicaval view. RESULTS: ACP was present in 36 patients, PFO in 21 patients, both PFO and ACP in 8 patients and the 130 remaining patients had neither PFO nor ACP. Patients with ACP exhibited a restricted left ventricle (LV) secondary to RV dilatation and had concomitant RV dysfunction, irrespective of associated PFO, but preserved LV systolic function. Despite elevated systolic pulmonary artery pressure (sPAP), patients with isolated PFO had a normal RV systolic function. sPAP and PaCO2 levels were significantly correlated. CONCLUSIONS: In patients under protective mechanical ventilation with moderate-to-severe ARDS, ACP was associated with LV restriction and RV failure, whether PFO was present or not. Despite elevated sPAP, PFO shunting was associated with preserved RV systolic function.