Despite recent diagnostic advances, a fever of unknown origin (FUO) remains a clinical challenge.
This study reports the clinical courses and outcomes of 103 cases of FUO and evaluates the places of ...18F-Fluorodeoxyglucose positrons emission tomography (18FDG-PET) and molecular biology in the diagnostic approach.
This retrospective study was carried out from 2002 to 2012 in two departments of internal medicine. The diagnosis of FUO was based on the updated criteria of Durack and Street. It included 54 men and 49 women (mean age: 57 years) in 52 of whom the final diagnosis could not be established. Among the 51 patients with final diagnosis, non-infectious inflammatory disorders were the most prevalent (61%). The other diagnoses were infectious diseases (23.5%), miscellaneous causes (10%) and malignancies (6%). 18FDG-PET was performed in 48 patients and was contributory in 10. Molecular biology techniques were performed in 28 patients and were contributory in only one case: detection of a cytomegalovirus infection by polymerase-chain-reaction assay. At study closure, eleven patients had died, of whom five died from the disease that caused the FUO. Only two deaths among the 52 patients without diagnosis could be attributed to the feverish illness.
As observed in the most recent case series, the rate of undiagnosed patients is increasing. The prognosis was good for undiagnosed FUO. Here, the yield of 18FDG-PET was 21% but that of molecular biology negligible. The recourse to molecular biology seems useless unless directed by a high degree of clinical suspicion.
Malgré les progrès diagnostiques récents, une fièvre d’origine inexpliquée (FOI) demeure un défi pour le clinicien.
Cette étude porte sur l’analyse de 103 cas et évalue l’apport de la tomographie par émission de positons au 18F-Fluorodésoxyglucose (18FDG-PET) et de la biologie moléculaire dans la démarche diagnostique.
Cette étude rétrospective a été menée de 2002 à 2012 dans deux départements de médecine interne. Le diagnostic de FOI a été basé sur les critères actualisés de Durack et Street. Elle comprenait 54 hommes et 49 femmes (âge moyen : 57ans) dont 52 chez qui le diagnostic final n’a pas pu être établi. Parmi les 51 patients avec diagnostic final, les maladies inflammatoires non infectieuses étaient les plus répandues (61 %). Les autres diagnostics étaient les maladies infectieuses (23,5 %), des causes diverses (10 %) et les tumeurs malignes (6 %). Une 18FDG-PET a été réalisée chez 48 patients et a été contributive chez 10 d’entre eux. Les techniques de biologie moléculaire ont été réalisées chez 28 patients et ont été contributives dans un seul cas : la détection d’une infection à cytomégalovirus par PCR. Sur la durée de l’étude, onze patients sont décédés, dont cinq de la maladie responsable de la FUO. Seuls deux décès parmi les 52 patients sans diagnostic pouvaient être attribués à la « maladie fébrile ».
Comme cela a été observé dans les études les plus récentes, le taux de patients non diagnostiqués est en augmentation. Le pronostic est bon pour les FOI sans diagnostic. Ici, le rendement de18FDG-PET était de 21 %, mais celui de la biologie moléculaire négligeable. Le recours à la biologie moléculaire semble donc inutile sauf si orienté par un haut degré de suspicion clinique.Learning points
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").
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.
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.
ClinicalTrials.gov, ID: NCT03396757. Registered on 11 January 2018.
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.
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.
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.
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.
Programme Hospitalier de Recherche Clinique.
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.
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.
Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled ...Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock.
APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 μg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209).
Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio OR 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction).
In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup.
Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.
IntroductionCorticosteroids affect variably survival in sepsis trials, suggesting heterogeneity in patients’ response to corticosteroids. The RECORDS (Rapid rEcognition of COrticosteRoiD resistant or ...sensitive Sepsis) trial aimed at defining endotypes associated with adults with sepsis responsiveness to corticosteroids.Methods and analysisRECORDS, a multicentre, placebo-controlled, biomarker-guided, adaptive Bayesian design basket trial, will randomly assign to a biomarker stratum 1800 adults with community-acquired pneumonia, vasopressor-dependent sepsis, septic shock or acute respiratory distress syndrome. In each stratum, patients will be randomly assigned to receive a 7-day course of hydrocortisone and fludrocortisone or their placebos. Patients with COVID-19 will be treated with a 10-day standard course of dexamethasone and randomised to fludrocortisone or its placebo. Primary outcome will be 90-day death or persistent organ dysfunction. Large simulation study will be performed across a range of plausible scenarios to foresee power to detect a 5%–10% absolute difference with corticosteroids. We will assess subset-by-treatment interaction by estimating in a Bayesian framework two quantities: (1) measure of influence, relying on the value of the estimation of corticosteroids’ effect in each subset, and (2) measure of interaction.Ethics and disseminationThe protocol was approved by the Ethics Committee (Comité de Protection des Personnes, Dijon, France), on 6 April 2020. Trial results will be disseminated at scientific conferences and results will be published in peer-reviewed journals.Trial registration numberClinicalTrials.gov Registry (NCT04280497).
Following publication of the original article 1, we have been notified that only the 11 members of the writing committee are listed as the collaborators of the SRLF Trial group
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