COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Extra-corporeal blood purification for critically ill patients with septic acute kidney injury

Septic acute kidney injury (AKI) is a leading cause of renal impairment in the critical care setting and is independently associated with increased mortality and morbidities. As the knowledge on pathophysiological mechanisms of AKI increases, its clinical management is evolving. The published literature on critically ill septic AKI patients has predominantly come from Caucasian patients. There is little data on the clinical features, management and outcome of critically ill septic AKI in Chinese patients. Results from my single-centred cross-sectional survey (n=3687) showed that septic AKI affected 27% of critically ill Chinese patients. Among those with documented sepsis upon ICU admission or during ICU stay, 71.6% developed AKI. Compared with non-septic AKI patients, septic AKI patients were older, had higher disease severity scores and required more intensive/invasive organ support. Renal replacement therapy (RRT) was used more often in septic AKI (23.3% vs. 12.6% for non-septic AKI, p<0.001), but full or partial renal recovery was also more common (97.5% vs. 93.6%, p<0.001) compared with non-septic AKI. However, the optimal timing for starting RRT among critically ill septic AKI patients remained controversial. My study (n=120) found no significant difference in organ function, defined as Sequential Organ Failure Assessment (SOFA) score changes within 48 hours after the initiation of RRT (improvement by 1.5 points for “early” vs. 2 points for “late”, p=0.523), and mortality (at 28-day 48.4% for “early” vs. 48.3% for “late”, p=0.994) when the initiation of RRT was classified using renal function-based criteria. APACHE score was the only independent predictor for organ function improvement. The application of global assessment tools as RRT initiation criteria warrant further investigation. Blood purification has emerged as an adjunctive therapy in critically ill septic AKI patients as they are effective in clearing endotoxin or inflammatory mediators. Four different techniques were assessed. Firstly, among those septic AKI patients due to gram-negative sepsis (n=30), SOFA score was improved by 37% at 48 hours post initiation of endotoxin/ cytokine adsorptive continuous venovenous haemofiltration (CVVH) compared to a deterioration of 3% among the control group (p=0.013). The treatment was well tolerated. Secondly, among those septic AKI patients with shock due to intra-abdominal sepsis (n=15), Alteco endotoxin haemoadsorption offered no extra benefit over the control group in terms of SOFA score changes at 48 and 72 hours. Thirdly, polymethylmethacrylate (PMMA) based CVVH (n=11) may delay organ function recovery, as assessed by SOFA score, when compared with septic AKI patients with shock who received polysulfone (PS) based CVVH (n=14). The 28-day mortality (55% vs. 21%, p=0.115) showed a trend in favour of the PS-CVVH groups. Finally, among septic AKI patients with shock (n=7), high cut-off CVVH achieved good cytokine modulation. Clinical improvement, in terms of SOFA changes and vasopressor usage, was noted after 24-36 hours of treatment. Albumin loss was limited. Since multiple factors including co-morbidities, causal microorganisms, and life-support measures impact on the outcome of septic AKI patients, whether the addition of blood purification procedures could benefit (or harm) these patients can only be determined through large-scale prospective randomised controlled studies.published_or_final_versionMedicineMasterDoctor of Medicin

A Retrospective Review of the Use of Regional Citrate Anticoagulation in Continuous Venovenous Hemofiltration for Critically Ill Patients

Background. The emergence of a commercially prepared citrate solution has revolutionized the use of RCA in the intensive care unit (ICU). The aim of this study was to evaluate the safety profile of a commercially prepared citrate solution. Method. Predilution continuous venovenous hemofiltration (CVVH) was performed using Prismocitrate 10/2 at 2500 mL/h and a blood flow rate of 150 mL/min. Calcium chloride solution was infused to maintain ionized calcium within 1.0–1.2 mmol/L. An 8.4% sodium bicarbonate solution was infused separately. Treatment was stopped when the predefined clinical target was reached or the filter clotted. Result. 58 sessions of citrate RCA were analyzed. The median circuit lifetime was 26.0 h (interquartile range IQR 21.2–44.3). The percentage of circuits lasting more than 12 h, 24 h, and 48 h was 94.6%, 58.9%, and 16.1%, respectively. There was no incidence of hypernatremia and median pH was 2.5, only four patients had evidence of citrate accumulation. Conclusion. The commercially prepared citrate solution could be used safely in critically ill patients who required CVVH with no major adverse events

Molecular epidemiology and clinical impact of Klebsiella spp. causing bloodstream infections in Hong KongResearch in context

Summary: Background: The epidemiological features of the Klebsiella pneumoniae causing bloodstream infections in Hong Kong and their potential threats to human health remained unknown. Methods: K. pneumoniae strains collected from four hospitals in Hong Kong during the period of 2009–2018 were subjected to molecular typing, string test, antimicrobial susceptibility testing, whole genome sequencing and analysis. Clinical data of patients from whom these strains were isolated were analyzed retrospectively using univariate and multivariate logistic regression approaches. Findings: The 240 Klebsiella spp. strains belonged to 123 different STs and 63 different capsule loci (KLs), with KL1 and KL2 being the major type. 86 out of 212 BSI-KP (40.6%) carried at least one of the virulence genes iuc, iro, rmpA or rmpA2. Virulence plasmid correlated well with the string test positive result, yet 8 strains without rmp genes were also hypermucoviscous, which was due to wzc mutation. The mortality rate of bloodstream infection patients was 43.0%. Univariant analysis showed that factors including renal replacement therapy (FDR adjusted p = 0.0007), mechanical ventilation (FDR adjusted p < 0.0001) and respiratory sepsis (FDR adjusted p < 0.0001) were found to pose the highest risk of death upon infection by Klebsiella spp. Interpretation: This study revealed the high mortality rate and risk factors associated with bloodstream infections caused by K. pneumoniae in Hong Kong, which warrants immediate action to develop effective solution to tackle this problem. Funding: Theme Based Research Scheme (T11-104/22-R), Research Impact Fund (R5011-18 F) and Postdoctoral Fellowship (PDFS2223-1S09)

Integrative Approach to Facilitate Fracture Healing: Topical Chinese Herbal Paste with Oral Strontium Ranelate

Strontium ranelate (SrR) is one of the pharmaceutical agents reported to be effective on the promotion of fracture healing. This study aimed to evaluate the integrative effect of the oral SrR with a topical Chinese herbal paste, namely, CDR, on facilitation of bone healing. The in vivo efficacy was evaluated using rats with tibial fracture. They were treated with either CDR topically, or SrR orally, or their combined treatments. The in vivo results illustrated a significant additive effect of CDR on SrR in increasing the yield load of the fractured tibia. The in vitro results showed that neither SrR nor CDR exhibited a cytotoxic effect on UMR106 and bone-marrow stem cell (BMSC), but both of them increased the proliferation of BMSC at low concentrations. The combination of CDR at 200 μg/mL with SrR at 200 or 400 μg/ml also showed an additive effect on increasing the ALP activity of BMSC. Both SrR and CDR alone reduced osteoclast formation, and the effective concentration of SrR to inhibit osteoclastogenesis was reduced in the presence of CDR. This integrative approach by combining oral SrR and topical CDR is effective in promoting fracture healing properly due to their additive effects on proosteogenic and antiosteoclastogenic properties

Essential Emergency and Critical Care: a consensus among global clinical experts

BackgroundGlobally, critical illness results in millions of deaths every year. Although many of these deaths are potentially preventable, the basic, life-saving care of critically ill patients are often overlooked in health systems. Essential Emergency and Critical Care (EECC) has been devised as the care that should be provided to all critically ill patients in all hospitals in the world. EECC includes the effective care of low cost and low complexity for the identification and treatment of critically ill patients across all medical specialties. This study aimed to specify the content of EECC and additionally, given the surge of critical illness in the ongoing pandemic, the essential diagnosis-specific care for critically ill patients with COVID-19.MethodsIn a Delphi process, consensus (&gt;90% agreement) was sought from a diverse panel of global clinical experts. The panel iteratively rated proposed treatments and actions based on previous guidelines and the WHO/ICRC's Basic Emergency Care. The output from the Delphi was adapted iteratively with specialist reviewers into a coherent and feasible package of clinical processes plus a list of hospital readiness requirements.ResultsThe 269 experts in the Delphi panel had clinical experience in different acute medical specialties from 59 countries and from all resource settings. The agreed EECC package contains 40 clinical processes and 67 requirements, plus additions specific for COVID-19.ConclusionThe study has specified the content of care that should be provided to all critically ill patients. Implementing EECC could be an effective strategy for policy makers to reduce preventable deaths worldwide

Treatments for intracranial hypertension in acute brain-injured patients: grading, timing, and association with outcome. Data from the SYNAPSE-ICU study

Purpose: Uncertainties remain about the safety and efficacy of therapies for managing intracranial hypertension in acute brain injured (ABI) patients. This study aims to describe the therapeutical approaches used in ABI, with/without intracranial pressure (ICP) monitoring, among different pathologies and across different countries, and their association with six&nbsp;months mortality and neurological outcome. Methods: A preplanned subanalysis of the SYNAPSE-ICU study, a multicentre, prospective, international, observational cohort study, describing the ICP treatment, graded according to Therapy Intensity Level (TIL) scale, in patients with ABI during the first week of intensive care unit (ICU) admission. Results: 2320 patients were included in the analysis. The median age was 55 (I-III quartiles = 39-69) years, and 800 (34.5%) were female. During the first week from ICU admission, no-basic TIL was used in 382 (16.5%) patients, mild-moderate in 1643 (70.8%), and extreme in 295 cases (eTIL, 12.7%). Patients who received eTIL were younger (median age 49 (I-III quartiles = 35-62) vs 56 (40-69) years, p &lt; 0.001), with less cardiovascular pre-injury comorbidities (859 (44%) vs 90 (31.4%), p &lt; 0.001), with more episodes of neuroworsening (160 (56.1%) vs 653 (33.3%), p &lt; 0.001), and were more frequently monitored with an ICP device (221 (74.9%) vs 1037 (51.2%), p &lt; 0.001). Considerable variability in the frequency of use and type of eTIL adopted was observed between centres and countries. At six&nbsp;months, patients who received no-basic TIL had an increased risk of mortality (Hazard ratio, HR = 1.612, 95% Confidence Interval, CI = 1.243-2.091, p &lt; 0.001) compared to patients who received eTIL. No difference was observed when comparing mild-moderate TIL with eTIL (HR = 1.017, 95% CI = 0.823-1.257, p = 0.873). No significant association between the use of TIL and neurological outcome was observed. Conclusions: During the first week of ICU admission, therapies to control high ICP are frequently used, especially mild-moderate TIL. In selected patients, the use of aggressive strategies can have a beneficial effect on six&nbsp;months mortality but not on neurological outcome

Association of Country Income Level With the Characteristics and Outcomes of Critically Ill Patients Hospitalized With Acute Kidney Injury and COVID-19

Introduction: Acute kidney injury (AKI) has been identified as one of the most common and significant problems in hospitalized patients with COVID-19. However, studies examining the relationship between COVID-19 and AKI in low- and low-middle income countries (LLMIC) are lacking. Given that AKI is known to carry a higher mortality rate in these countries, it is important to understand differences in this population. Methods: This prospective, observational study examines the AKI incidence and characteristics of 32,210 patients with COVID-19 from 49 countries across all income levels who were admitted to an intensive care unit during their hospital stay. Results: Among patients with COVID-19 admitted to the intensive care unit, AKI incidence was highest in patients in LLMIC, followed by patients in upper-middle income countries (UMIC) and high-income countries (HIC) (53%, 38%, and 30%, respectively), whereas dialysis rates were lowest among patients with AKI from LLMIC and highest among those from HIC (27% vs. 45%). Patients with AKI in LLMIC had the largest proportion of community-acquired AKI (CA-AKI) and highest rate of in-hospital death (79% vs. 54% in HIC and 66% in UMIC). The association between AKI, being from LLMIC and in-hospital death persisted even after adjusting for disease severity. Conclusions: AKI is a particularly devastating complication of COVID-19 among patients from poorer nations where the gaps in accessibility and quality of healthcare delivery have a major impact on patient outcomes