Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial.

BACKGROUND: 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. METHODS: 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(activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups.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). FINDINGS: 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). INTERPRETATION: 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. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

The AMG model coupled with Rock-Eval® analysis accurately predicts cropland soil organic carbon dynamics in the Tuojiang River Basin, Southwest China.

Accurate soil organic carbon models are key to understand the mechanisms governing carbon sequestration in soil and to help develop targeted management strategies to carbon budget. The accuracy and reliability of soil organic carbon (SOC) models remains strongly limited by incorrect initialization of the conceptual kinetic pools and lack of stringent model evaluation using time-series datasets. Notably, due to legacy effects of management and land use change, the traditional spin-up approach for initial allocation of SOC among kinetic pools can bring substantial uncertainties in predicting the evolution of SOC stocks. The AMG model can fulfill these conditions as it is a parsimonious yet accurate SOC model using widely-available input data. In this study, we first evaluated the performance of AMGv2 before and after optimizing the potential mineralization rate (k0) of SOC stock following a leave-one-site-out cross-validation based on 24 long-term field experiments (LTEs) in the Southwest of China. Then, we used Rock-Eval® thermal analysis results as input variables in the PARTYSOC machine learning model to estimate the initial stable SOC fraction (CS/C0) for the 14 LTEs where soil samples were available. The results showed that initializing the CS/C0 ratio using PARTYSOC combined with the optimized k0 further improved the accuracy of model simulations (R2 = 0.87, RMSE = 0.25, d = 0.90). Combining average measured CS/C0 and k0 optimization across all 24 LTEs also improved the model predictive capability by 25% compared to using default parameterization, thus suggesting promising avenue for upscaling model applications at the regional level where only a few measurement data on SOC stability can be available. In conclusion, the new version of the AMG model developed in the Tuojiang River Basin context exhibits excellent performance. This result paves the way for further calibration and validation of the AMG model in a wider set of contexts, with the potential to significantly improve confidence in SOC predictions in croplands over regional scales.

Polycyclic aromatic hydrocarbon dynamics in soils along proglacial chronosequences in the Alps.

Polycyclic aromatic hydrocarbons (PAHs) were studied in the soils of three proglacial areas in France (Noir and Chardon Glaciers) and Italy (Miage Glacier). PAH contents, PAH stocks and PAH contents normalized to the total organic carbon contents (PAHs/TOC ratio) were investigated along proglacial soil chronosequences to infer their evolutions with soil age (from 3 to 4200 years), where the PAH contamination was only related to long-range atmospheric transport. Evolutions of PAH and TOC contents, PAHs/TOC ratio and PAH stock were fitted with exponential and logarithmic relations. For the three proglacial areas, PAH contents increased rapidly during the first 150 years of soil development, ranged from 4 to 152 ng·g-1, and showed a strong relationship with total organic carbon (TOC) contents (r = 0.83, p < 0.05). The joint increase of PAH and TOC contents suggested that PAH accumulation in soils were not only driven by PAH inputs but also by the capacity of soils to store these contaminants. PAH contents in the oldest soils (from 1200 BCE and 2200 BCE) were similar than for soils from 1850 CE. The period 1850-2019 CE corresponded to a decrease in the PAHs/TOC ratio suggesting both a faster accumulation of TOC than PAHs and a dilution effect of PAHs already present in soils. For the oldest soils, the PAHs/TOC ratio appeared similar to those for soils from 1850 CE, with values ranging from 0.48 to 2.06 ng·mg-1, suggesting an equilibrium between both parameters for soils older than 170 years. Finally, PAH stocks ranged from 0.41 mg·m-2 to 6.80 mg·m-2 in the youngest and oldest soils, respectively. These results do not allow us to identify the same period of greatest emission as other studies (estimated ~1960), but they revealed changes in the capacity of soils to store these pollutants.

Bioenergetic control of soil carbon dynamics across depth.

Soil carbon dynamics is strongly controlled by depth globally, with increasingly slow dynamics found at depth. The mechanistic basis remains however controversial, limiting our ability to predict carbon cycle-climate feedbacks. Here we combine radiocarbon and thermal analyses with long-term incubations in absence/presence of continuously 13C/14C-labelled plants to show that bioenergetic constraints of decomposers consistently drive the depth-dependency of soil carbon dynamics over a range of mineral reactivity contexts. The slow dynamics of subsoil carbon is tightly related to both its low energy density and high activation energy of decomposition, leading to an unfavourable 'return-on-energy-investment' for decomposers. We also observe strong acceleration of millennia-old subsoil carbon decomposition induced by roots ('rhizosphere priming'), showing that sufficient supply of energy by roots is able to alleviate the strong energy limitation of decomposition. These findings demonstrate that subsoil carbon persistence results from its poor energy quality together with the lack of energy supply by roots due to their low density at depth.

Topsoil organic matter build-up in glacier forelands around the world.

Since the last glacial maximum, soil formation related to ice-cover shrinkage has been one major sink of carbon accumulating as soil organic matter (SOM), a phenomenon accelerated by the ongoing global warming. In recently deglacierized forelands, processes of SOM accumulation, including those that control carbon and nitrogen sequestration rates and biogeochemical stability of newly sequestered carbon, remain poorly understood. Here, we investigate the build-up of SOM during the initial stages (up to 410 years) of topsoil development in 10 glacier forelands distributed on four continents. We test whether the net accumulation of SOM on glacier forelands (i) depends on the time since deglacierization and local climatic conditions (temperature and precipitation); (ii) is accompanied by a decrease in its stability and (iii) is mostly due to an increasing contribution of organic matter from plant origin. We measured total SOM concentration (carbon, nitrogen), its relative hydrogen/oxygen enrichment, stable isotopic (13 C, 15 N) and carbon functional groups (C-H, C=O, C=C) compositions, and its distribution in carbon pools of different thermal stability. We show that SOM content increases with time and is faster on forelands experiencing warmer climates. The build-up of SOM pools shows consistent trends across the studied soil chronosequences. During the first decades of soil development, the low amount of SOM is dominated by a thermally stable carbon pool with a small and highly thermolabile pool. The stability of SOM decreases with soil age at all sites, indicating that SOM storage is dominated by the accumulation of labile SOM during the first centuries of soil development, and suggesting plant carbon inputs to soil (SOM depleted in nitrogen, enriched in hydrogen and in aromatic carbon). Our findings highlight the potential vulnerability of SOM stocks from proglacial areas to decomposition and suggest that their durability largely depends on the relative contribution of carbon inputs from plants.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

Urgent Chemotherapy for Life-Threatening Complications Related to Solid Neoplasms.

OBJECTIVES: Solid neoplasms can be directly responsible for organ failures at the time of diagnosis or relapse. The management of such specific complications relies on urgent chemotherapy and eventual instrumental or surgical procedures, combined with advanced life support. We conducted a multicenter study to address the prognosis of this condition. DESIGN: A multicenter retrospective (2001-2015) chart review. SETTING: Medical and respiratory ICUs. PATIENTS: Adult patients who received urgent chemotherapy in the ICU for organ failure related to solid neoplasms were included. The modalities of chemotherapy, requirements of adjuvant instrumental or surgical procedures, and organ supports were collected. Endpoints were short- and long-term survival rates. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred thirty-six patients were included. Lung cancer was the most common malignancy distributed into small cell lung cancer (n = 57) and non-small cell lung cancer (n = 33). The main reason for ICU admission was acute respiratory failure in 111 patients (81.6%), of whom 89 required invasive mechanical ventilation. Compression and tissue infiltration by tumor cells were the leading mechanisms resulting in organ involvement in 78 (57.4%) and 47 (34.6%) patients. The overall in-ICU, in-hospital, 6-month, and 1-year mortality rates were 37%, 58%, 74%, and 88%, respectively. Small cell lung cancer was identified as an independent predictor of hospital survival. However, this gain in survival was not sustained since the 1-year survival rates of small cell lung cancer, non-small cell lung cancer, and non-lung cancer patients all dropped below 20%. CONCLUSIONS: Urgent chemotherapy along with aggressive management of organ failures in the ICU can be lifesaving in very selected cancer patients, most especially with small cell lung cancer, although the long-term survival is hardly sustainable.

Severe hypernatremia after hypertonic saline irrigation of hydatid cysts.

IMPLICATIONS: Patients with iatrogenic hypernatremia and serum sodium levels >170 mmol/L either die or sustain severe central nervous system damage. We report the first case of an adult patient who survived an extreme iatrogenic acute hypernatremia (200 mmol/L) resulting from a hypertonic saline irrigation of multiple intraabdominal hydatid cysts. It is a unique report of an intraoperatively developed serum sodium increase without subsequent neurological damage.