Simon Finfer’s research while affiliated with Imperial College London and other places

International clinical practice guidelines addressing corticosteroid treatment for patients hospitalised with non-viral community-acquired pneumonia (CAP) are inconsistent. We conducted a systematic review of randomized controlled trials (RCTs) evaluating the use of corticosteroids in hospitalised adult patients with suspected or probable CAP. We performed random effects pairwise, Bayesian, and dose–response meta-analyses using the restricted maximum likelihood (REML) heterogeneity estimator. We assessed certainty of evidence using GRADE methodology. We identified 30 eligible RCTs, including a total of 7519 patients. The prednisone-equivalent doses ranged between 29 mg/day and 100 mg/day. Corticosteroids probably reduced short-term (28–30 days) mortality (RR 0.82 [95% CI 0.74–0.91]; moderate certainty) while the reduction in longer term (60–90 day) mortality is less certain (RR 0.89 [95% CI 0.76–1.03]; low certainty). Corticosteroids reduced the need for invasive mechanical ventilation (IMV) (RR 0.63 [95% CI 0.48–0.82]; high certainty) and may reduce duration of ICU stay (MD 1.53 days fewer [95% CI 0.31–2.75 days fewer]; low certainty), and hospital stay (MD 2.30 days fewer [95% CI 0.81–3.81 days fewer]; low certainty). Corticosteroids probably increased hyperglycaemia requiring intervention (RR 1.32 [95% CI 1.12–1.56]; moderate certainty) but probably have no effect on secondary infections (RR 0.97 [95% CI 0.85–1.11]; moderate certainty). Corticosteroids probably reduced short-term mortality and reduce the need for invasive mechanical ventilation in hospitalised patients with CAP. CRD42024521536.

Background: This study assessed the accuracy of three International Classification of Diseases (ICD) codes methods derived from Global Burden of Disease (GBD) sepsis study (modified GBD method) in identifying sepsis, compared to the Angus method. Sources of errors in these methods were also reported. Methods: Prospective multicentre, observational, study. Emergency Department patients aged > 16 years with high sepsis risk from nine hospitals in NSW, Australia were screened for clinical sepsis using Sepsis 3 criteria and coded as having sepsis or not using the modified GBD and Angus methods. The three modified GBD methods were: Explicit – sepsis-specific ICD code recorded; Implicit – sepsis-specific code or infection as primary ICD code plus organ dysfunction code; Implicit plus – as for Implicit but infection as primary or secondary ICD code. Agreement between clinical sepsis and ICD coding methods was assessed using Cronbach alpha (α). For false positive cases (ICD-coded sepsis but not clinically diagnosed), the ICD codes leading to those errors were documented. For false negatives (clinically diagnosed sepsis but ICD-coded), uncoded sources of infection and organ dysfunction were documented. Results: Of 6869 screened patients, 450 (median age 72.4 years, 48.9% females) met inclusion criteria. Clinical sepsis was diagnosed in 215/450 (47.8%). The explicit, implicit, implicit plus and Angus methods identified sepsis in 108/450 (24.0%),175/450 (38.9%), 222/450 (49.3%) and 170/450 (37.8%), respectively. Sensitivity was 41.4%, 58.1%, 67.4% and 55.8%, and specificity 91.9%, 78.7%, 67.2% and 79.1%, respectively. Agreement between clinical sepsis and all ICD coding methods was low (α = 0.52-0.56). False positives were 19, 50, and 77, while false negatives were 126, 90, and 70 for the explicit, implicit, and implicit plus methods, respectively. For false positive cases, unspecified urinary tract infection, hypotension and acute kidney failure were commonly assigned infection and organ dysfunction codes. About half (44.3%-55.6%) of the false negative cases didn’t have a pathogen documented. Conclusion: The modified GBD method demonstrated low accuracy in identifying sepsis; with the implicit plus method being the most accurate. Errors in identifying sepsis using ICD codes arise mostly from coding for unspecified urinary infections and associated organ dysfunction. Trial Registration: The study was registered at the ANZCTR (ACTRN12621000333819) on 24 March 2021.

Background The optimal choice of fluid therapy for patients with diabetic ketoacidosis (DKA) is uncertain, though preliminary data suggest that buffered crystalloid solutions (Plasma-Lyte® 148) may offer some advantages over 0.9% saline. Objective To describe the study protocol for the ‘Balanced Electrolyte Solution versus Saline Trial for Diabetic Ketoacidosis’ (BEST-DKA) trial. Design, setting and participants BEST-DKA is a Phase 3 cluster-crossover, blinded, pragmatic, randomised, controlled trial comparing the effects of saline or buffered crystalloid solution in patients with moderate to severe DKA treated in the emergency department and/or intensive care unit at twenty hospitals in Australia. Each hospital will be randomised to use either saline or buffered crystalloid solution for a period of 12 months before crossing over to the alternate fluid for the next 12 months. The blinded study fluid will be used for all resuscitation and maintenance purposes for included patients. Main outcome measures This cluster-randomised, crossover randomised controlled trial (RCT) has been designed with the aim of enrolling a minimum of 400 patients, which will provide >91.4% power to detect a 2-day increase in the primary outcome, days alive and out of hospital to day 28, chosen with consumer representation. Secondary outcomes include quality of life and fatigue scores at day 28, intensive care unit and hospital lengths of stay, acute kidney injury, and time to resolution of DKA. All analyses will be conducted on an intention-to-treat basis. A prespecified statistical analysis plan will be developed prior to interim analysis. Results and conclusion The BEST-DKA trial commenced enrolment in March 2024 and should generate results that will determine whether treatment with Plasma-Lyte® 148, compared with saline, results in increased days alive, and out of hospital to day 28 for patients with moderate or severe DKA.

To determine whether there is an interaction between baseline serum chloride concentration and pH and treatment effects in Intensive Care Unit (ICU) patients receiving intravenous fluid therapy with balanced solution versus 0.9% sodium chloride (saline). A secondary analysis of a randomized controlled trial in which patients were divided into cohorts according to quartiles of baseline serum chloride concentration and pH. The primary outcome was day-90 mortality. From 4846 patients with outcome data available, 4823 with relevant baseline data were included in this analysis, with 1347, 1333, 993 and 1150 patients in the chloride quartiles of < 102, 102–106, 107–109 and > 109 mmol/L, respectively. Data were also analysed in pH quartiles of ≤ 7.27, 7.27–7.34, 7.34–7.39 and > 7.39. The risk-adjusted odds ratio (95% confidence interval [CI]) for day-90 mortality for patients assigned balanced solution compared to saline was 1.23 (0.95–1.58), 0.95 (0.73–1.25), 0.88 (0.64–1.21), and 0.76 (0.57–1.01) for lowest to highest chloride subgroups, respectively (P value for interaction = 0.10), and 0.89 (95% CI 0.69–1.15), 0.94 (0.70–1.27), 0.96 (0.67–1.38) and 1.15 (0.82–1.60) for pH quartiles from lowest to highest, respectively (P value for interaction = 0.63). There were no significant differences in the treatment effect of balanced solutions compared to saline according to baseline serum chloride concentration or pH.

To generate consensus and provide expert clinical practice statements for the management of adult sepsis in resource-limited settings. An international multidisciplinary Steering Committee with expertise in sepsis management and including a Delphi methodologist was convened by the Asia Pacific Sepsis Alliance (APSA). The committee selected an international panel of clinicians and researchers with expertise in sepsis management. A Delphi process based on an iterative approach was used to obtain the final consensus statements. A stable consensus was achieved for 30 (94%) of the statements by 41 experts after four survey rounds. These include consensus on managing patients with sepsis outside a designated critical care area, triggers for escalating clinical management and criteria for safe transfer to another facility. The experts agreed on the following: in the absence of serum lactate, clinical parameters such as altered mental status, capillary refill time and urine output may be used to guide resuscitation; special considerations regarding the volume of fluid used for resuscitation, especially in tropical infections, including the use of simple tests to assess fluid responsiveness when facilities for advanced hemodynamic monitoring are limited; use of Ringer’s lactate or Hartmann’s solution as balanced salt solutions; epinephrine when norepinephrine or vasopressin are unavailable; and the administration of vasopressors via a peripheral vein if central venous access is unavailable or not feasible. Similarly, where facilities for investigation are unavailable, there was consensus for empirical antimicrobial administration without delay when sepsis was strongly suspected, as was the empirical use of antiparasitic agents in patients with suspicion of parasitic infections. Using a Delphi method, international experts reached consensus to generate expert clinical practice statements providing guidance to clinicians worldwide on the management of sepsis in resource-limited settings. These statements complement existing guidelines where evidence is lacking and add relevant aspects of sepsis management that are not addressed by current international guidelines. Future studies are needed to assess the effects of these practice statements and address remaining uncertainties.

Background The combination of intravenous hydrocortisone and enteral fludrocortisone may reduce mortality in patients with septic shock. The optimal dose and reliability of absorption of fludrocortisone in critically ill patients are unclear. Methods In a multi-centre, open label, phase II randomized clinical trial, intravenous hydrocortisone alone or in combination with one of three doses of enteral fludrocortisone (50 µg, 100 µg or 200 µg daily) for 7 days was compared in patients with septic shock. The primary outcome was time to shock resolution. We conducted pharmacokinetic studies to assess absorption. Results Out of 153 enrolled patients, 38 (25%) received hydrocortisone alone, 42 (27%) received additional 50 µg, 36 (24%) received 100 µg and 37 (24%) received 200 µg fludrocortisone. Plasma concentrations of fludrocortisone were detected in 97% of patients at 3 h-median (interquartile range [IQR]) 261 (156–334) ng/L. There was no significant difference in the time to shock resolution between groups with median (IQR) of 3 (2.5–4.5), 3 (2–4), 3 (2–6) and 3 (2–5.5) days in the hydrocortisone alone, 50 µg, 100 µg and 200 µg fludrocortisone groups, respectively. The corresponding 28-day mortality rates were 9/38 (24%), 7/42 (17%), 4/36 (11%) and 4/37 (11%), respectively. There were no significant differences between groups with respect to, recurrence of shock, indices of organ failure or other secondary outcomes. Conclusions Enteral fludrocortisone resulted in detectable plasma fludrocortisone concentrations in the majority of critically ill patients with septic shock, although they varied widely indicating differing absorption and bioavailability. Its addition to hydrocortisone was not associated with shorter time to shock resolution.

Purpose To generate consensus and provide expert clinical practice statements for the management of adult sepsis in resource-limited settings. Methods An international multidisciplinary Steering Committee with expertise in sepsis management and including a Delphi methodologist was convened by the Asia Pacific Sepsis Alliance (APSA). The committee selected an international panel of clinicians and researchers with expertise in sepsis management. A Delphi process based on an iterative approach was used to obtain the final consensus statements. Results A stable consensus was achieved for 30 (94%) of the statements by 41 experts after four survey rounds. These include consensus on managing patients with sepsis outside a designated critical care area, triggers for escalating clinical management and criteria for safe transfer to another facility. The experts agreed on the following: in the absence of serum lactate, clinical parameters such as altered mental status, capillary refill time and urine output may be used to guide resuscitation; special considerations regarding the volume of fluid used for resuscitation, especially in tropical infections, including the use of simple tests to assess fluid responsiveness when facilities for advanced hemodynamic monitoring are limited; use of Ringer's lactate or Hartmann's solution as balanced salt solutions; epinephrine when norepinephrine or vasopressin are unavailable; and the administration of vasopressors via a peripheral vein if central venous access is unavailable or not feasible. Similarly, where facilities for investigation are unavailable, there was consensus for empirical antimicrobial administration without delay when sepsis was strongly suspected, as was the empirical use of antiparasitic agents in patients with suspicion of parasitic infections. Conclusion Using a Delphi method, international experts reached consensus to generate expert clinical practice statements providing guidance to clinicians worldwide on the management of sepsis in resource-limited settings. These statements complement existing guidelines where evidence is lacking and add relevant aspects of sepsis management that are not addressed by current international guidelines. Future studies are needed to assess the effects of these practice statements and address remaining uncertainties.