Optimising prednisolone or prednisone replacement in adrenal insufficiency.

Context: Patients with adrenal insufficiency (AI) have a higher mortality than the general population, possibly because of excess glucocorticoid exposure at inappropriate times. The cortisol circadian rhythm is difficult to mimic with twice- or thrice-daily hydrocortisone. Prednisolone is a once-daily alternative which may improve patient compliance through its convenience. Objectives: Prednisolone day curves can be used to accurately downtitrate patients to the minimum effective dose. This study aimed to review prednisolone day curves and determine therapeutic ranges at different time points after administration. Methods: Between August 2013 and May 2021, 108 prednisolone day curves from 76 individuals receiving prednisolone replacement were analysed. Prednisolone concentrations were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry. Spearman's correlation coefficient was used to determine the relationship between 2-, 4-, and 6-h prednisolone levels compared to the previously validated standard 8-h prednisolone level (15-25 µg/L). Results: The median dose was 4 mg of prednisolone once daily. There was a strong correlation between the 4- and 8-h (R = 0.8829, P ≤ 0.0001) and 6- and 8-h prednisolone levels (R = 0.9530, P ≤ 0.0001). Target ranges for prednisolone were 37-62 µg/L at 4 h, 24-39 µg/L at 6 h, and 15-25 µg/L at 8 h. Prednisolone doses were successfully reduced in 21 individuals, and of these, 3 were reduced to 2 mg once daily. All patients were well upon follow-up. Conclusion: This is the largest evaluation of oral prednisolone pharmacokinetics in humans. Low-dose prednisolone of 2-4 mg is safe and effective in most patients with AI. Doses can be titrated with either 4-, 6-, or 8-h single time point drug levels.

Cardiac Autonomic Neuropathy is Associated with Improved Diabetic Foot Ulcer Healing: A Single Centre Prospective Cohort Study.

AIMS: People with diabetes and peripheral neuropathy (DPN) are at high risk of diabetic foot ulceration (DFU). The prevalence of cardiac autonomic neuropathy (CAN) in people with DFU is unknown and if CAN influences DFU healing is unclear. METHODS: We investigated, in a prospective observational single-centre cohort study, if CAN predicts DFU healing in 47 (77% male) people with a DFU and DPN attending a university hospital foot clinic. CAN was diagnosed by 2 or more abnormal Ewing's tests. Baseline DFU severity was evaluated using the site, ischaemia, neuropathy, bacterial infection, area and depth (SINBAD) score. The primary outcome was defined as evidence of DFU healing on clinical examination. Median (interquartile) length of follow-up was 1150 (624-1331) days. RESULTS: The prevalence of CAN was 43%. Of the cohort, 70% had complete healing of their DFU. Participants with CAN had a shorter median (interquartile) duration time to heal compared to those without CAN [91 (44-164) days compared to 302 (135-413) (p=0.047)]. Minor/major amputation and mortality was similar in both groups. The presence of CAN increased DFU healing by two-fold [HR=2.05, 95% CI 1.01-4.16, p=0.046] in multivariable competing risk analyses. CONCLUSIONS: We demonstrate a high prevalence of CAN in a DFU cohort and that CAN is associated with improved DFU healing. The results of this study establish the scientific rationale for further studies to better understand the mechanisms between CAN and DFU outcomes.

Real World Patterns of Antimicrobial Use and Microbiology Investigations in Patients with Sepsis outside the Critical Care Unit: Secondary Analysis of Three Nation-Wide Point Prevalence Studies.

Recent description of the microbiology of sepsis on the wards or information on the real-life antibiotic choices used in sepsis is lacking. There is growing concern of the indiscriminate use of antibiotics and omission of microbiological investigations in the management of septic patients. We performed a secondary analysis of three annual 24-h point-prevalence studies on the general wards across all Welsh acute hospitals in years 2016-2018. Data were collected on patient demographics, as well as radiological, laboratory and microbiological data within 48-h of the study. We screened 19,453 patients over the three 24 h study periods and recruited 1252 patients who fulfilled the entry criteria. 775 (64.9%) patients were treated with intravenous antibiotics. Only in 33.65% (421/1252) of all recruited patients did healthcare providers obtain blood cultures; in 25.64% (321/1252) urine cultures; in 8.63% (108/1252) sputum cultures; in 6.79% (85/1252) wound cultures; in 15.25% (191/1252) other cultures. Out of the recruited patients, 59.1% (740/1252) fulfilled SEPSIS-3 criteria. Patients with SEPSIS-3 criteria were significantly more likely to receive antibiotics than the non-septic cohort (p < 0.0001). In a multivariable regression analysis increase in SOFA score, increased number of SIRS criteria and the use of the official sepsis screening tool were associated with antibiotic administration, however obtaining microbiology cultures was not. Our study shows that antibiotics prescription practice is not accompanied by microbiological investigations. A significant proportion of sepsis patients are still at risk of not receiving appropriate antibiotics treatment and microbiological investigations; this may be improved by a more thorough implementation of sepsis screening tools.

Clinical features and burden of new onset diabetic foot ulcers post simultaneous pancreas kidney transplantation and kidney only transplantation.

BACKGROUND: Patients with diabetes and kidney disease are at risk of diabetes-related foot ulcers (DFU). Whether this risk is modified post simultaneous pancreas-kidney (SPK) or kidney only (KO) transplant is unknown. METHODS: We evaluated the incidence of new onset DFU post SPK and KO transplant in 235 patients with diabetic kidney disease and diabetic neuropathy. In total 90 (51% male) SPK patients and 145 KO (66% male, 26% Type 1 DM) were evaluated in a single centre retrospective study. Median (range) follow up was 6 (3 to 13) years for both cohorts. RESULTS: We observed that 16 (17%) of SPK and 22 (15%) KO patients respectively developed a DFU during follow up. In both cohorts a history of peripheral arterial disease [37.5% vs. 4%] and pre-transplant history of DFU were associated with post transplant DFU (p ≪ 0.05). In KO cohort, patients who developed a DFU were more likely to have T1DM than T2DM (29% vs. 10%), p ≪ 0.05. There was no impact of DFU on SPK transplant failure. In contrast patients with DFU post KO transplant had more than five fold increased hazard ratio (HR) of transplant failure as compared to those without DFU independent of other risk factors [HR 5.19 95% CI (2.05 to 13.18) p = 0.001]. CONCLUSION: Nearly 1 in 7 patients develop a new onset DFU post KO or SPK transplantation and DFU also significantly increases risk of failure of the transplanted kidney. Our results highlight the need for greater awareness of regular foot examination, DFU prevention and risk evaluation in post-transplant patients. RESEARCH IN CONTEXT: Evidence before this study Patients with diabetes and kidney disease are at enhanced risk of diabetic foot ulcers (DFU). Whether this risk is modified post successful kidney only (KO) or simultaneous pancreas and kidney (SPK) transplantation is unknown. Small case series and studies with short term follow up report varied rates of incidence and are from historical cohorts before the use of modern anti-transplant medications and treatments. Short term studies also suggest that post SPK the resultant normoglycaemia may reverse some features and risk markers of DFU. There are no long term studies on the incidence and impact of diabetic foot ulcers in patients with diabetic kidney disease post SPK or KO transplantation. Added value of this study We report the long term follow up results on DFU incidence, clinical features and related impact on transplant viability in 235 patients with diabetic kidney disease and neuropathy post successful SPK and KO transplant at a single centre. We observed that nearly 1 in 7 patients developed a DFU during follow up and that in patients who received KO transplant onset of DFU was associated with more than 5 fold increase of transplant failure. Implications of all the available evidence Our results highlight the need for greater awareness of regular foot examination, DFU prevention and risk evaluation in post-transplant patients. Despite normoglycaemia post SPK there is a residual burden and risk of DFU. Our work establishes a clinical rationale for further research to explore putative mechanisms that could explain the association between DFU and renal transplant dysfunction.

Red-flag sepsis and SOFA identifies different patient population at risk of sepsis-related deaths on the general ward.

Controversy exists regarding the best diagnostic and screening tool for sepsis outside the intensive care unit (ICU). Sequential organ failure assessment (SOFA) score has been shown to be superior to systemic inflammatory response syndrome (SIRS) criteria, however, the performance of "Red Flag sepsis criteria" has not been tested formally.The aim of the study was to investigate the ability of Red Flag sepsis criteria to identify the patients at high risk of sepsis-related death in comparison to SOFA based sepsis criteria. We also investigated the comparison of Red Flag sepsis to quick SOFA (qSOFA), SIRS, and national early warning score (NEWS) scores and factors influencing patient mortality.Patients were recruited into a 24-hour point-prevalence study on the general wards and emergency departments across all Welsh acute hospitals. Inclusion criteria were: clinical suspicion of infection and NEWS 3 or above in-line with established escalation criteria in Wales. Data on Red Flag sepsis and SOFA criteria was collected together with qSOFA and SIRS scores and 90-day mortality.459 patients were recruited over a 24-hour period. 246 were positive for Red Flag sepsis, mortality 33.7% (83/246); 241 for SOFA based sepsis criteria, mortality 39.4% (95/241); 54 for qSOFA, mortality 57.4% (31/54), and 268 for SIRS, mortality 33.6% (90/268). 55 patients were not picked up by any criteria. We found that older age was associated with death with OR (95% CI) of 1.03 (1.02-1.04); higher frailty score 1.24 (1.11-1.40); DNA-CPR order 1.74 (1.14-2.65); ceiling of care 1.55 (1.02-2.33); and SOFA score of 2 and above 1.69 (1.16-2.47).The different clinical tools captured different subsets of the at-risk population, with similar sensitivity. SOFA score 2 or above was independently associated with increased risk of death at 90 days. The sequalae of infection-related organ dysfunction cannot be reliably captured based on routine clinical and physiological parameters alone.

Sepsis-related deaths in the at-risk population on the wards: attributable fraction of mortality in a large point-prevalence study.

OBJECTIVE: Sepsis mortality is reported to be high worldwide, however recently the attributable fraction of mortality due to sepsis (AFsepsis) has been questioned. If improvements in treatment options are to be evaluated, it is important to know what proportion of deaths are potentially preventable or modifiable after a sepsis episode. The aim of the study was to establish the fraction of deaths directly related to the sepsis episode on the general wards and emergency departments. RESULTS: 839 patients were recruited over the two 24-h periods in 2016 and 2017. 521 patients fulfilled SEPSIS-3 criteria. 166 patients (32.4%) with sepsis and 56 patients (17.6%) without sepsis died within 90 days. Out of the 166 sepsis deaths 12 (7.2%) could have been directly related to sepsis, 28 (16.9%) possibly related and 96 (57.8%) were not related to sepsis. Overall AFsepsis was 24.1%. Upon analysis of the 40 deaths likely to be attributable to sepsis, we found that 31 patients (77.5%) had the Clinical Frailty Score ≥ 6, 28 (70%) had existing DNA-CPR order and 17 had limitations of care orders (42.5%).

Situational judgement tests: important clarifications regarding the methodology.

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