Background

Septic shock remains a significant cause of death in critically ill patients. During septic shock, some patients will retain microcirculatory disorders despite optimal hemodynamic support (i.e., fluid resuscitation, vasopressors, inotropes). Alterations in the microcirculation are a key pathophysiological factor of organ dysfunction and death in septic shock patients. Ilomedin is a prostacyclin analog with vasodilatory effect and anti-thrombotic properties (i.e., inhibition of platelet aggregation) preferentially at the microcirculatory level. We hypothesize that early utilization of intravenous Ilomedin in septic shock patients with clinical persistence of microperfusion disorders would improve the recovery of organ dysfunction.

Methods

The I-MICRO trial is a multicenter, prospective, randomized, double-blinded, placebo-controlled study. We plan to recruit 236 adult patients with septic shock and persistent microcirculatory disorders (i.e., skin mottling or increased capillary refill time) despite hemodynamic support. Participants will be randomized to receive a 48-h intravenous infusion of either Ilomedin or placebo starting at the earliest 6 h and later 24 h after septic shock. The primary outcome will be the change (delta) of sequential organ failure assessment (SOFA) score between randomization and day 7. Secondary outcomes will include mean SOFA score during the first 7 days after randomization, mortality at day 28 post-randomization, number of ventilation-free survival days in the 28 days post-randomization, number of renal replacement therapy-free survival days in the 28 days post-randomization, number of vasopressor-free survival days in the 28 days post-randomization, and mottling score at day 1 after randomization.

Discussion

The trial aims to provide evidence on the efficacy and safety of Ilomedin in patients with septic shock and persistent microcirculatory disorders.

Trial registration

NCT NCT03788837 . Registered on 28 December 2018.

Background

Beyond the question of short-term survival, days spent at home could be considered a patient-centered outcome in critical care trials.

Research question

What are the days spent at home and health care trajectories during the year after surviving critical illness?

Study design and methods

Data were extracted on adult survivors spending at least 2 nights in a French ICU during 2018 who were treated with invasive mechanical ventilation or vasopressors or inotropes. Trauma, burn, organ transplant, stroke, and neurosurgical patients were excluded. Stays at home, death, and hospitalizations were reported before and after ICU stay, using state sequence analysis. An unsupervised clustering method was performed to identify cohorts based on post-ICU trajectories.

Results

Of 77,132 ICU survivors, 89% returned home. In the year after discharge, these patients spent a median of 330 (interquartile range [IQR], 283-349) days at home. At 1 year, 77% of patients were still at home and 17% had died. Fifty-one percent had been re-hospitalized, and 10% required a further ICU admission. Forty-eight percent used rehabilitation facilities, and 5.7%, hospital at home. Three clusters of patients with distinct post-ICU trajectories were identified. Patients in cluster 1 (68% of total) survived and spent most of the year at home (338 [323-354] days). Patients in cluster 2 (18%) had more complex trajectories, but most could return home (91%), spending 242 (174-277) days at home. Patients in cluster 3 (14%) died, with only 37% returning home for 45 (15-90) days.

Interpretation

Many patients had complex health care trajectories after surviving critical illness. Wide variations in the ability to return home after ICU discharge were observed between clusters, which represents an important patient-centered outcome.

Background

Chronic treatment of hypertension or heart failure very often includes an angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) as renin-angiotensin system inhibitors (RASi) treatments. To stop or not to stop these medications before major surgery remains an unresolved issue. The lack of evidence leads to conflicting guidelines with respect to RASi management before major surgery. The purpose of this study is to evaluate the impact of a strategy of RASi continuation or discontinuation on perioperative complications in patients undergoing major non-cardiac surgery.

Methods

This is a multicenter, open-labeled randomized controlled trial in > 30 French centers. In the experimental group, RASi will be continued while the treatment will be stopped 48 h before the surgery in the control arm. The primary endpoint is a composite endpoint of major complications after surgery. An endpoint adjudication committee will review clinical data and adjudicate efficacy endpoints while blinded to the assigned study drug group. Main analysis will be by intention-to-treat comparing the composite outcome measure at 28 days in the two groups. A total of 2222 patients are planned to detect an absolute complications difference of 5%.

Discussion

The results of the trial should provide robust evidence to anesthesiologists and surgeons regarding management of RASi before major non-cardiac surgery.

Trial registration

ClinicalTrials.gov, NCT03374449 . Registered on 11 December 2017.

Background

Oliguria is one of the leading triggers of fluid loading in patients in the intensive care unit (ICU). The purpose of this study was to assess the predictive value of urine Na(+) (uNa(+)) and other routine urine biomarkers for cardiac fluid responsiveness in oliguric ICU patients.

Methods

We conducted a prospective multicenter observational study in five university ICUs. Patients with urine output (UO) <0.5 ml/kg/h for 3 consecutive hours with a mean arterial pressure >65 mmHg received a fluid challenge. Cardiac fluid responsiveness was defined by an increase in stroke volume >15 % after fluid challenge. Urine and plasma biochemistry samples were examined before fluid challenge. We examined renal fluid responsiveness (defined as UO > 0.5 ml/kg/h for 3 consecutive hours) after fluid challenge as a secondary endpoint.

Results

Fifty-four patients (age 51 ± 37 years, Simplified Acute Physiology Score II score 40 ± 20) were included. Most patients (72 %) were not cardiac responders (CRs), and 50 % were renal responders (RRs) to fluid challenge. Patient characteristics were similar between CRs and cardiac nonresponders. uNa(+) (37 ± 38 mmol/L vs 25 ± 75 mmol/L, p = 0.44) and fractional excretion of sodium (FENa(+)) (2.27 ± 2.5 % vs 2.15 ± 5.0 %, p = 0.94) were not statistically different between those who did and those who did not respond to the fluid challenge. Areas under the receiver operating characteristic (AUROC) curves were 0.51 (95 % CI 0.35-0.68) and 0.56 (95 % CI 0.39-0.73) for uNa(+) and FENa(+), respectively. Fractional excretion of urea had an AUROC curve of 0.70 (95 % CI 0.54-0.86, p = 0.03) for CRs. Baseline UO was higher in RRs than in renal nonresponders (1.07 ± 0.78 ml/kg/3 h vs 0.65 ± 0.53 ml/kg/3 h, p = 0.01). The AUROC curve for RRs was 0.65 (95 % CI 0.53-0.78) for uNa(+).

Conclusions

In the present study, most oliguric patients were not CRs and half were not renal responders to fluid challenge. Routine urinary biomarkers were not predictive of fluid responsiveness in oliguric normotensive ICU patients.

Background

Intensive care unit (ICU) survivors have reduced long-term survival compared to the general population. Identifying parameters at ICU discharge that are associated with poor long-term outcomes may prove useful in targeting an at-risk population. The main objective of the study was to identify clinical and biological determinants of death in the year following ICU discharge.

Methods

FROG-ICU was a prospective, observational, multicenter cohort study of ICU survivors followed 1 year after discharge, including 21 medical, surgical or mixed ICUs in France and Belgium. All consecutive patients admitted to intensive care with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 h following ICU admission and discharged from ICU were included. The main outcome measure was all-cause mortality at 1 year after ICU discharge. Clinical and biological parameters on ICU discharge were measured, including the circulating cardiovascular biomarkers N-terminal pro-B type natriuretic peptide, high-sensitive troponin I, bioactive-adrenomedullin and soluble-ST2. Socioeconomic status was assessed using a validated deprivation index (FDep).

Results

Of 1570 patients discharged alive from the ICU, 333 (21%) died over the following year. Multivariable analysis identified age, comorbidity, red blood cell transfusion, ICU length of stay and abnormalities in common clinical factors at the time of ICU discharge (low systolic blood pressure, temperature, total protein, platelet and white cell count) as independent factors associated with 1-year mortality. Elevated biomarkers of cardiac and vascular failure independently associated with 1-year death when they are added to multivariable model, with an almost 3-fold increase in the risk of death when combined (adjusted odds ratio 2.84 (95% confidence interval 1.73-4.65), p < 0.001).

Conclusions

The FROG-ICU study identified, at the time of ICU discharge, potentially actionable clinical and biological factors associated with poor long-term outcome after ICU discharge. Those factors may guide discharge planning and directed interventions.

Trial registration

ClinicalTrials.gov NCT01367093 . Registered on 6 June 2011.

Importance

Before surgery, the best strategy for managing patients who are taking renin-angiotensin system inhibitors (RASIs) (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) is unknown. The lack of evidence leads to conflicting guidelines.

Objective

To evaluate whether a continuation strategy vs a discontinuation strategy of RASIs before major noncardiac surgery results in decreased complications at 28 days after surgery.

Design, setting, and participants

Randomized clinical trial that included patients who were being treated with a RASI for at least 3 months and were scheduled to undergo a major noncardiac surgery between January 2018 and April 2023 at 40 hospitals in France.

Intervention

Patients were randomized to continue use of RASIs (n = 1107) until the day of surgery or to discontinue use of RASIs 48 hours prior to surgery (ie, they would take the last dose 3 days before surgery) (n = 1115).

Main outcomes and measures

The primary outcome was a composite of all-cause mortality and major postoperative complications within 28 days after surgery. The key secondary outcomes were episodes of hypotension during surgery, acute kidney injury, postoperative organ failure, and length of stay in the hospital and intensive care unit during the 28 days after surgery.

Results

Of the 2222 patients (mean age, 67 years [SD, 10 years]; 65% were male), 46% were being treated with angiotensin-converting enzyme inhibitors at baseline and 54% were being treated with angiotensin receptor blockers. The rate of all-cause mortality and major postoperative complications was 22% (245 of 1115 patients) in the RASI discontinuation group and 22% (247 of 1107 patients) in the RASI continuation group (risk ratio, 1.02 [95% CI, 0.87-1.19]; P = .85). Episodes of hypotension during surgery occurred in 41% of the patients in the RASI discontinuation group and in 54% of the patients in the RASI continuation group (risk ratio, 1.31 [95% CI, 1.19-1.44]). There were no other differences in the trial outcomes.

Conclusions and relevance

Among patients who underwent major noncardiac surgery, a continuation strategy of RASIs before surgery was not associated with a higher rate of postoperative complications than a discontinuation strategy.

Trial registration

ClinicalTrials.gov Identifier: NCT03374449.