Stéphane Gaudry

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.).

Use of High-Flow Nasal Cannula Oxygen Therapy to Prevent Desaturation During Tracheal Intubation of Intensive Care Patients With Mild-to-Moderate Hypoxemia*

Objectives:Tracheal intubation of ICU patients is frequently associated with severe hypoxemia. Although noninvasive ventilation reduces desaturation during intubation of severely hypoxemic patients, it does not allow for per-procedure oxygenation and has not been evaluated in mild-to-moderate hypoxemic patients for whom high-flow nasal cannula oxygen may be an alternative. We sought to compare pre- and per-procedure oxygenation with either a nonrebreathing bag reservoir facemask or a high-flow nasal cannula oxygen during tracheal intubation of ICU patients. Design:Prospective quasi-experimental before-after study (ClinicalTrials.gov: NCT01699880). Setting:University hospital medico-surgical ICU. Patients:All adult patients requiring tracheal intubation in the ICU were eligible. Interventions:In the control (before) period, preoxygenation was performed with a nonrebreathing bag reservoir facemask and in the change of practice (after) period, with high-flow nasal cannula oxygen. Measurements and Main Results:Primary outcome was median lowest SpO2 during intubation, and secondary outcomes were SpO2 after preoxygenation and number of patients with saturation less than 80%. One hundred one patients were included. Median lowest SpO2 during intubation were 94% (83–98.5) with the nonrebreathing bag reservoir facemask versus 100% (95–100) with high-flow nasal cannula oxygen (p < 0.0001). SpO2 values at the end of preoxygenation were higher with high-flow nasal cannula oxygen than with nonrebreathing bag reservoir facemask and were correlated with the lowest SpO2 reached during the intubation procedure (r = 0.38, p < 0.0001). Patients in the nonrebreathing bag reservoir facemask group experienced more episodes of severe hypoxemia (2% vs 14%, p = 0.03). In the multivariate analysis, preoxygenation with high-flow nasal cannula oxygen was an independent protective factor of the occurrence of severe hypoxemia (odds ratio, 0.146; 95% CI, 0.01–0.90; p = 0.037). Conclusions:High-flow nasal cannula oxygen significantly improved preoxygenation and reduced prevalence of severe hypoxemia compared with nonrebreathing bag reservoir facemask. Its use could improve patient safety during intubation.

Use of High-Flow Nasal Cannula Oxygen Therapy in Subjects With ARDS: A 1-Year Observational Study

BACKGROUND: Beneficial effects of high-flow nasal cannula (HFNC) oxygen on oxygenation and respiratory parameters have been reported in a small number of subjects with acute respiratory failure (ARF). We aimed to evaluate its effect in subjects with ARDS. METHODS: This was an observational single-center study. Prospectively obtained data were retrospectively analyzed. All patients admitted over 1 y to a university hospital medicosurgical ICU were included. Classification was according to the highest ventilatory support required. HFNC indications were reviewed, and demographics, clinical characteristics, and course of subjects with ARDS according to intubation need were compared. RESULTS: Of 607 subjects admitted, 560 required ventilatory or oxygen support, among whom 180 received noninvasive ventilatory support. HFNC was used in 87 subjects and as first-line treatment in 51 subjects (29% of first-line noninvasively treated subjects), 45 of which had ARDS (PaO2/FIO2 of 137 mm Hg; 22 men, 57.9 y of age). Pneumonia accounted for 82% of ARDS causes. The intubation rate in these subjects was 40%. Higher Simplified Acute Physiology Score II (SAPS II; 46 vs 29, P = .001), occurrence of additional organ failure (76% vs 26%, P = .002), mainly hemodynamic (50% vs 7%, P = .001) or neurological (22% vs 0, P = .01), and trends toward lower PaO2/FIO2 and higher breathing frequency after HFNC initiation were evidenced in subjects who failed HFNC. Higher SAPS II scores were associated with HFNC failure in multivariate analysis. CONCLUSIONS: In daily care, over one fourth of subjects requiring noninvasive ventilatory support were treated via HFNC, with a high success rate in subjects with severe ARDS. We conclude that HFNC may be considered as first-line therapy in ARF, including patients with ARDS.

Randomized Intubation with Polyurethane or Conical Cuffs to Prevent Pneumonia in Ventilated Patients

RATIONALE The occurrence of ventilator-associated pneumonia (VAP) is linked to the aspiration of contaminated pharyngeal secretions around the endotracheal tube. Tubes with cuffs made of polyurethane rather than polyvinyl chloride or with a conical rather than a cylindrical shape increase tracheal sealing. OBJECTIVES To test whether using polyurethane and/or conical cuffs reduces tracheal colonization and VAP in patients with acute respiratory failure. METHODS We conducted a multicenter, prospective, open-label, randomized study in four parallel groups in four intensive care units between 2010 and 2012. A cohort of 621 patients with expected ventilation longer than 2 days was included at intubation with a cuff composed of cylindrical polyvinyl chloride (n = 148), cylindrical polyurethane (n = 143), conical polyvinyl chloride (n = 150), or conical polyurethane (n = 162). We used Kaplan-Meier estimates and log-rank tests to compare times to events. MEASUREMENTS AND MAIN RESULTS After excluding 17 patients who secondarily refused participation or had met an exclusion criterion, 604 were included in the intention-to-treat analysis. Cumulative tracheal colonization greater than 10(3) cfu/ml at Day 2 was as follows (median [interquartile range]): cylindrical polyvinyl chloride, 0.66 (0.58-0.74); cylindrical polyurethane, 0.61 (0.53-0.70); conical polyvinyl chloride, 0.67 (0.60-0.76); and conical polyurethane, 0.62 (0.55-0.70) (P = 0.55). VAP developed in 77 patients (14.4%), and postextubational stridor developed in 28 patients (6.4%) (P = 0.20 and 0.28 between groups, respectively). CONCLUSIONS Among patients requiring mechanical ventilation, polyurethane and/or conically shaped cuffs were not superior to conventional cuffs in preventing tracheal colonization and VAP. Clinical trial registered with clinicaltrials.gov (NCT01114022).

Brainstem responses can predict death and delirium in sedated patients in intensive care unit.

Objectives:In critically ill patients, the assessment of neurologic function can be difficult because of the use of sedative agents. It is not known whether neurologic signs observed under sedation can predict short-term outcomes. The objective of this study was to assess whether abnormal brainstem responses within the first 24 hrs of sedation are associated with mortality and altered mental status postsedation. Design:Observational prospective study including an initial single-center and a subsequent multicenter study to develop and then validate the prognostic models. Setting:Three mixed and two medical intensive care units. Patients:Mechanically ventilated intensive care unit patients sedated with midazolam (± sufentanyl). Interventions:Neurologic examination including the Glasgow Coma Scale, the Assessment to Intensive Care Environment score, cranial nerve examination, response to noxious stimuli, and the cough reflex was performed. Measurements and Main Results:Seventy-two patients were included in the initial group and 72 in a subsequent validation study. Neurologic responses were independent of sedative dose. Twenty-two patients in the development cohort and 21 (29%) in the validation group died within 28 days of inclusion. Adjusted for Simplified Acute Physiology Score II score, absent cough reflex was independently associated with 28-day mortality in the development (adjusted odds ratio [OR], 7.80; 95% confidence interval [CI], 2.00–30.4; p = .003) and validation groups (adjusted OR, 5.44; 95% CI, 1.35–22.0; p = .017). Absent oculocephalic response, adjusted for Simplified Acute Physiology Score II score, was independently associated with altered mental status after the withdrawal of sedation in the development (adjusted OR, 4.54; 95% CI, 1.34–15.4; p = .015) and validation groups (adjusted OR, 6.10; 95% CI, 1.18–25.5; p = .012). Conclusions:Assessment of brainstem responses is feasible in sedated critically ill patients and loss of selected responses is predictive of mortality and altered mental status.

Clinical Features and Outcomes in Patients With Disseminated Toxoplasmosis Admitted to Intensive Care: A Multicenter Study

BACKGROUND Characteristics and outcomes of adult patients with disseminated toxoplasmosis admitted to the intensive care unit (ICU) have rarely been described. METHODS We performed a retrospective study on consecutive adult patients with disseminated toxoplasmosis who were admitted from January 2002 through December 2012 to the ICUs of 14 university-affiliated hospitals in France. Disseminated toxoplasmosis was defined as microbiological or histological evidence of disease affecting >1 organ in immunosuppressed patients. Isolated cases of cerebral toxoplasmosis were excluded. Clinical data on admission and risk factors for 60-day mortality were collected. RESULTS Thirty-eight patients were identified during the study period. Twenty-two (58%) had received an allogeneic hematopoietic stem cell transplant (median, 61 [interquartile range {IQR}, 43-175] days before ICU admission), 4 (10%) were solid organ transplant recipients, and 10 (27%) were infected with human immunodeficiency virus (median CD4 cell count, 14 [IQR, 6-33] cells/µL). The main indications for ICU admission were acute respiratory failure (89%) and shock (53%). The 60-day mortality rate was 82%. Allogeneic hematopoietic stem cell transplant (hazard ratio [HR] = 2.28; 95% confidence interval [CI], 1.05-5.35; P = .04) and systolic cardiac dysfunction (HR = 3.54; 95% CI, 1.60-8.10; P < .01) within 48 hours of ICU admission were associated with mortality. CONCLUSIONS Severe disseminated toxoplasmosis leading to ICU admission has a poor prognosis. Recipients of allogeneic hematopoietic stem cell transplant appear to have the highest risk of mortality. We identified systolic cardiac dysfunction as a major determinant of outcome. Strategies aimed at preventing this fatal opportunistic infection may improve outcomes.

Airway Fungal Colonization Compromises the Immune System Allowing Bacterial Pneumonia to Prevail

Objective:To study the correlation between fungal colonization and bacterial pneumonia and to test the effect of antifungal treatments on the development of bacterial pneumonia in colonized rats. Design:Experimental animal investigation. Setting:University research laboratory. Subjects:Pathogen-free male Wistar rats weighing 250–275 g. Interventions:Rats were colonized by intratracheal instillation of Candida albicans. Fungal clearance from the lungs and immune response were measured. Both colonized and noncolonized animals were secondarily instilled with different bacterial species (Pseudomonas aeruginosa, Escherichia coli, or Staphylococcus aureus). Bacterial phagocytosis by alveolar macrophages was evaluated in the presence of interferon-gamma, the main cytokine produced during fungal colonization. The effect of antifungal treatments on fungal colonization and its immune response were assessed. The prevalence of P. aeruginosa pneumonia was compared in antifungal treated and control colonized rats. Measurements and Main Results:C. albicans was slowly cleared and induced a Th1-Th17 immune response with very high interferon-gamma concentrations. Airway fungal colonization favored the development of bacterial pneumonia. Interferon-gamma was able to inhibit the phagocytosis of unopsonized bacteria by alveolar macrophages. Antifungal treatment decreased airway fungal colonization, lung interferon-gamma levels and, consequently, the prevalence of subsequent bacterial pneumonia. Conclusions:C. albicans airway colonization elicited a Th1-Th17 immune response that favored the development of bacterial pneumonia via the inhibition of bacterial phagocytosis by alveolar macrophages. Antifungal treatment decreased the risk of bacterial pneumonia in colonized rats.

Functional outcome of prolonged refractory status epilepticus.

IntroductionTo characterize etiology, clinical course and outcomes of patients in prolonged refractory status epilepticus (PRSE) and looking for prognostic factors.MethodsRetrospective study conducted in patients hospitalized from January 1, 2001 to December 31, 2011 in 19 polyvalent intensive care units in French university and general hospitals. Patients were adults with a generalized convulsive refractory status epilepticus that lasted more than seven days, despite treatment including an anesthetic drug and mechanical ventilation. Patients with anoxic encephalopathy were excluded. Follow-up phone call was used to determine functional outcome using modified Rankin Scale (mRS) with mRS 0–3 defining good and mRS 4–6 poor outcome.Results78 patients (35 female) were included. Median age was 57 years. Causes of status epilepticus were various, mainly including prior epilepsy (14.1%), CNS infection (12.8%), and stroke (12.8%). No etiology was found in 27 (34.6%) patients. PRSE was considered controlled in only 53 (67.9%) patients after a median duration of 17 (IQR 12–26) days. The median length of ICU stay was 28 (19–48) days. Forty-one (52.5%) patients died in the ICU, 26 from multiple organ failure, 8 from care withdrawal, 2 from sudden cardiac arrest, 1 from brain death and 4 from unknown causes. PRSE was previously resolved in 20 patients who died in the ICU. At one-year follow-up, there were 12 patients with good outcome and 58 with poor outcome and 8 lost of follow-up. On multivariate analysis, only vasopressor use was a predictor of poor outcome (OR 6.54; 95%CI 1.09-39.29; p = 0.04).ConclusionPoor outcome was observed in about 80% of this population of PRSE. Most patients died from systemic complications linked to their ICU stay. Some patients can recover satisfactorily over time though we did not identify any robust factor of good outcome.

Use of Desmopressin Acetate in Severe Hyponatremia in the Intensive Care Unit

BACKGROUND AND OBJECTIVES Excessive correction of chronic and profound hyponatremia may result in central pontine myelinolysis and cause permanent brain damage. In the case of foreseeable or established hyponatremia overcorrection, slowing down the correction rate of sodium plasma levels (PNa) or reinducing mild hyponatremia may prevent this neurologic complication. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This retrospective and observational study was performed with 20 consecutive patients admitted to two intensive care units for severe hyponatremia, defined by PNa <120 mmol/L and/or neurologic complications ascribable to hyponatremia and subsequently treated by desmopressin acetate (DDAVP) during correction of hyponatremia when the rate of correction was overtly or predictably excessive. The primary endpoint was the effectiveness of DDAVP on PNa control. RESULTS DDAVP dramatically decreased the rate of PNa correction (median 0.81 mmol/L per hour [interquartile range, 0.46, 1.48] versus -0.02 mmol/L per hour [-0.16, 0.22] before and after DDAVP, respectively; P<0.001) along with a concurrent decrease in urine output (650 ml/h [214, 1200] versus 93.5 ml/h [43, 143]; P=0.003), and a rise in urine osmolarity (86 mmol/L [66, 180] versus 209 mmol/L [149, 318]; P=0.002). The maximal magnitude of PNa variations was also markedly reduced after DDAVP administration (11.5 mmol/L [8.25, 14.5] versus 5 mmol/L [4, 6.75]; P<0.001). No patient developed seizures after DDAVP or after subsequent relowering of PNa that occurred in 11 patients. CONCLUSIONS Desmopressin acetate is effective in curbing the rise of PNa in patients admitted in the intensive care unit for severe hyponatremia, when the initial rate of correction is excessive.

Comparison of two strategies for initiating renal replacement therapy in the intensive care unit: study protocol for a randomized controlled trial (AKIKI).

BackgroundThere is currently no validated strategy for the timing of renal replacement therapy (RRT) for acute kidney injury (AKI) in the intensive care unit (ICU) when short-term life-threatening metabolic abnormalities are absent. No adequately powered prospective randomized study has addressed this issue to date. As a result, significant practice heterogeneity exists and may expose patients to either unnecessary hazardous procedures or undue delay in RRT.Methods/designThis is a multicenter, prospective, randomized, open-label parallel-group clinical trial that compares the effect of two RRT initiation strategies on overall survival of critically ill patients receiving intravenous catecholamines or invasive mechanical ventilation and presenting with AKI classification stage 3 (KDIGO 2012). In the ‘early’ strategy, RRT is initiated immediately. In the ‘delayed’ strategy, clinical and metabolic conditions are closely monitored and RRT is initiated only when one or more events (severity criteria) occur, including: oliguria or anuria for more than 72 hours after randomization, serum urea concentration >40 mmol/l, serum potassium concentration >6 mmol/l, serum potassium concentration >5.5 mmol/l persisting despite medical treatment, arterial blood pH <7.15 in a context of pure metabolic acidosis (PaCO2 < 35 mmHg) or in a context of mixed acidosis with a PaCO2 ≥ 50 mmHg without possibility of increasing alveolar ventilation, acute pulmonary edema due to fluid overload despite diuretic therapy leading to severe hypoxemia requiring oxygen flow rate >5 l/min to maintain SpO2 > 95% or FiO2 > 50% under invasive or noninvasive mechanical ventilation.The primary outcome measure is overall survival, measured from randomization (D0) until death, regardless of the cause. The minimum follow-up duration for each patient will be 60 days. Two interim analyses are planned, blinded to group allocation. It is expected that there will be 620 subjects in all.DiscussionThe AKIKI study will be one of the very few large randomized controlled trials evaluating mortality according to the timing of RRT in critically ill patients with AKI classification stage 3 (KDIGO 2012). Results should help clinicians decide when to initiate RRT.Trial registrationClinicalTrials.gov NCT01932190.