Prone ventilation in intubated COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: The efficacy and safety profiles of prone ventilation among intubated Coronavirus Disease 2019 (COVID-19) patients remain unclear. The primary objective was to examine the effect of prone ventilation on the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) in intubated COVID-19 patients. METHODS: Databases of MEDLINE, EMBASE and CENTRAL were systematically searched from inception until March 2021. Case reports and case series were excluded. RESULTS: Eleven studies (n = 606 patients) were eligible. Prone ventilation significantly improved PaO2/FiO2 ratio (studies: 8, n = 579, mean difference 46.75, 95% CI 33.35‒60.15, p < 0.00001; evidence: very low) and peripheral oxygen saturation (SpO2) (studies: 3, n = 432, mean difference 1.67, 95% CI 1.08‒2.26, p < 0.00001; evidence: ow), but not the arterial partial pressure of carbon dioxide (PaCO2) (studies: 5, n = 396, mean difference 2.45, 95% CI 2.39‒7.30, p = 0.32; evidence: very low), mortality rate (studies: 1, n = 215, Odds Ratio 0.66, 95% CI 0.32‒1.33, p = 0.24; evidence: very low), or number of patients discharged alive (studies: 1, n = 43, Odds Ratio 1.49, 95% CI 0.72‒3.08, p = 0.28; evidence: very low). CONCLUSION: Prone ventilation improved PaO2/FiO2 ratio and SpO2 in intubated COVID-19 patients. Given the substantial heterogeneity and low level of evidence, more randomized- controlled trials are warranted to improve the certainty of evidence, and to examine the adverse events of prone ventilation.

High-Dose versus Low-Dose Corticosteroids in COVID-19 Patients: a Systematic Review and Meta-analysis.

OBJECTIVES: The clinical efficacy of corticosteroids remains unclear. The primary aim of this systematic review and meta-analysis was to evaluate the use of high-dose versus low- dose corticosteroids on the mortality rate of COVID-19 patients. DESIGN: Systematic review and meta-analysis. SETTING: Electronic search for randomized controlled trials and observational studies (MEDLINE, EMBASE, CENTRAL). PARTICIPANTS: Hospitalized adults ≥ 18 years old who were SARS-CoV-2 PCR positive. INTERVENTIONS: High-dose and low-dose corticosteroids. MEASUREMENTS AND MAIN RESULTS: A total of twelve studies (n=2759 patients) were included in this review. The pooled analysis demonstrated no significant difference in mortality rate between the high-dose and low-dose corticosteroids groups (n=2632; OR: 1.07 [95%CI 0.67, 1.72], p=0.77, I2=76%, trial sequential analysis=inconclusive). No significant differences were observed in the incidence of intensive care unit (ICU) admission rate (n=1544; OR: 0.77[95%CI 0.43, 1.37], p=0.37, I2= 72%), duration of hospital stay (n=1615; MD: 0.53[95%CI -1.36, 2.41], p=0.58, I2=87%), respiratory support (n=1694; OR: 1.51[95%CI 0.77, 2.96], p=0.23, I2=84%), duration of mechanical ventilation (n=419; MD: -1.44[95%CI -4.27, 1.40], p=0.32, I2=93%), incidence of hyperglycemia (n=516, OR: 0.91[95%CI 0.58, 1.43], p=0.68, I2=0%) and infection rate (n=1485, OR: 0.86[95%CI 0.64, 1.16], p=0.33, I2=29%). CONCLUSION: The meta-analysis demonstrated high-dose corticosteroids did not reduce mortality rate. However, high-dose corticosteroids did not pose higher risk of hyperglycemia and infection rate for COVID-19 patients. Due to the inconclusive trial sequential analysis, substantial heterogeneity and low level of evidence, future large-scale randomized clinical trials are warranted to improve the certainty of evidence for the use of high-dose compared to low-dose corticosteroids in COVID-19 patients.

Clinical characteristics and outcomes of critically ill coronavirus disease 2019 patients in Malaysia during the first wave: A multi-center observational study (COVIDICU-MY).

Background: Coronavirus disease 2019 (COVID-19) emerged with a wide range of clinical presentations; Malaysia was not spared from its impact. This study describes the clinical characteristics of COVID-19 patients admitted to intensive care unit, their clinical course, management, and hospital outcomes. Methods: COVIDICU-MY is a retrospective analysis of COVID-19 patients from 19 intensive care units (ICU) across Malaysia from 1 March 2020 to 31 May 2020. We collected epidemiological history, demographics, clinical comorbidities, laboratory investigations, respiratory and hemodynamic values, management, length of stay and survival status. We compared these variables between survival and non-survival groups. Results: A total of 170 critically ill patients were included, with 77% above 50 years of age [median age 60, IQR (51-66)] and 75.3% male. Hypertension, diabetes mellitus, hyperlipidemia, chronic cardiac disease, and chronic kidney disease were most common among patients. A high Simplified Acute Physiology Score (SAPS) II score [median 45, IQR (34-49)] and Sequential Organ Failure Assessment (SOFA) score [median 8, IQR (6-11)] were associated with mortality. Patients were profoundly hypoxic with a median lowest PaO2/FiO2 ratio of 150 (IQR 99-220) at admission. 91 patients (53.5%) required intubation on their first day of admission, out of which 38 died (73.1% of the hospital non-survivors). Our sample had more patients with moderate Acute Respiratory Distress Syndrome (ARDS), 58 patients (43.9%), compared to severe ARDS, 33 patients (25%); with both ARDS classification groups contributing to 25 patients (54.4%) and 11 patients (23.9%) of the non-survival group, respectively. Cumulative fluid balance over 24 h was higher in the non-survival group with significant differences on Day 3 (1,953 vs. 622 ml, p < 0.05) and Day 7 of ICU (3,485 vs. 830 ml, p < 0.05). Patients with high serum creatinine, urea, lactate dehydrogenase, aspartate aminotransferase and d-dimer, and low lymphocyte count throughout the stay also had a higher risk of mortality. The hospital mortality rate was 30.6% in our sample. Conclusion: We report high mortality amongst critically ill patients in intensive care units in Malaysia, at 30.6%, during the March to May 2020 period. High admission SAPS II and SOFA, and severe hypoxemia and high cumulative fluid balance were associated with mortality. Higher creatinine, urea, lactate dehydrogenase, aspartate aminotransferase and d-dimer, and lymphopenia were observed in the non-survival group.

Contribution of Viral Respiratory Infections to Dengue-Like Illness Presentation at a Community Clinic in Southern Malaysia.

This study explored the contribution of viral respiratory infections (VRIs) in dengue-like illness (DLI) patients and their distinguishing clinicolaboratory parameters. Two hundred DLI patients were prospectively recruited (July 1- October 1, 2019) from a community clinic in Southern Malaysia. Patients ≥ 18 years with acute fever and fulfilling the WHO criteria of probable dengue were recruited. They underwent blood testing: blood counts, rapid dengue tests (nonstructural antigen-1/IgM) and polymerase chain reaction (PCR) for dengue, Zika, chikungunya, and Leptospira. Nasopharyngeal swabs (NPSs) were collected for FilmArray®RP2plus testing. From the 200 NPSs, 58 respiratory viruses (RVs) were detected in 54 patients. Of the 96 dengue-confirmed cases, 86 had dengue mono-infection, and 10 were coinfected with RVs. Of the 104 nondengue, 44 were RV positive and 4 Leptospira positive. Zika and chikungunya virus were not detected. Overall, the etiological diagnosis was confirmed for 72% of patients. Clinicolaboratory parameters were compared between dengue mono-infection and VRI mono-infection. Patients with coinfections were excluded. Multiple logistic regression showed that recent household/neighborhood history of dengue (adjusted odds ratio [aOR]: 5.9, 95% CI = 1.7-20.7), leukopenia (aOR: 12.5, 95% CI = 2.6-61.4) and thrombocytopenia (aOR: 5.5, 95% CI = 1.3-23.0) predicted dengue. Inversely, rhinorrhoea (aOR: 0.1, 95% CI = 0.01-0.3) and cough (aOR: 0.3, 95% CI = 0.1-0.9) favored VRI. Thus, VRIs comprise many infections diagnosed initially as DLIs. Early clinicolaboratory parameters can guide physicians screen patients for further testing.

Rapid testing requires clinical evaluation for accurate diagnosis of dengue disease: A passive surveillance study in Southern Malaysia.

BACKGROUND: Dengue fever is the most common mosquito-borne infection worldwide where an expanding surveillance and characterization of this infection are needed to better inform the healthcare system. In this surveillance-based study, we explored the prevalence and distinguishing features of dengue fever amongst febrile patients in a large community-based health facility in southern peninsular Malaysia. METHODS: Over six months in 2018, we recruited 368 adults who met the WHO 2009 criteria for probable dengue infection. They underwent the following blood tests: full blood count, dengue virus (DENV) rapid diagnostic test (RDT), ELISA (dengue IgM and IgG), nested RT-PCR for dengue, multiplex qRT-PCR for Zika, Chikungunya and dengue as well as PCR tests for Leptopspira spp., Japanese encephalitis and West Nile virus. RESULTS: Laboratory-confirmed dengue infections (defined by positive tests in NS1, IgM, high-titre IgG or nested RT-PCR) were found in 167 (45.4%) patients. Of these 167 dengue patients, only 104 (62.3%) were positive on rapid diagnostic testing. Dengue infection was significantly associated with the following features: family or neighbours with dengue in the past week (AOR: 3.59, 95% CI:2.14-6.00, p<0.001), cutaneous rash (AOR: 3.58, 95% CI:1.77-7.23, p<0.001), increased temperature (AOR: 1.33, 95% CI:1.04-1.70, p = 0.021), leucopenia (white cell count < 4,000/µL) (AOR: 3.44, 95% CI:1.72-6.89, p<0.001) and thrombocytopenia (platelet count <150,000/µL)(AOR: 4.63, 95% CI:2.33-9.21, p<0.001). Dengue infection was negatively associated with runny nose (AOR: 0.47, 95% CI:0.29-0.78, p = 0.003) and arthralgia (AOR: 0.42, 95% CI:0.24-0.75, p = 0.004). Serotyping by nested RT-PCR revealed mostly mono-infections with DENV-2 (n = 64), DENV-1 (n = 32) and DENV-3 (n = 17); 14 co-infections occurred with DENV-1/DENV-2 (n = 13) and DENV-1/DENV-4 (n = 1). Besides dengue, none of the pathogens above were found in patients' serum. CONCLUSIONS: Acute undifferentiated febrile infections are a diagnostic challenge for community-based clinicians. Rapid diagnostic tests are increasingly used to diagnose dengue infection but negative tests should be interpreted with caution as they fail to detect a considerable proportion of dengue infection. Certain clinical features and haematological parameters are important in the clinical diagnosis of dengue infection.

A cross-sectional study on the rate of non-adherence to anti-seizure medications and factors associated with non-adherence among patients with epilepsy.

BACKGROUND: Non-adherence to anti-seizure medication (ASM) therapy is an important contributing factor to the higher mortality rate and treatment failure of epilepsy. This study aimed to determine the rate and factors associated with non-adherence to ASM therapy through the WHO five dimensions of medication adherence framework. METHODS: We conducted a cross-sectional study at an outpatient Neurology Clinic of a tertiary government hospital in Malaysia. Between March and July 2019, we identified 217 patients with a confirmed diagnosis of epilepsy, receiving oral ASM therapy and able to administer their medications. We performed a semi-structured interview to gather information on sociodemographic background, clinical and medication history, and perceptions on healthcare services. Adherence to ASM therapy was evaluated using the Medication Compliance Questionnaire (MCQ). Patient's illness perception was assessed by the Brief Illness Perception Questionnaire (B-IPQ). RESULTS: 208 patients participated in this study. The median age of the study participants was 35 years (IQR 26-44). 58.2% were females and majority, 55.8%, were from the Malay ethnic group. Based on the MCQ scoring, 89 patients (42.8%) were non-adherent. Multiple logistic regression demonstrated that being employed or students (adjusted odds ratio [aOR] 2.26, 95%CI: 1.19-4.29 p = 0.012) and having an average or below average perceived access to pharmacy services (aOR 2.94, 95%CI: 1.38-6.24, p = 0.005) were significant contributors to non-adherence. CONCLUSION: Being employed or students and having an average or below average perceived access to pharmacy services were associated with ASM non-adherence Efforts to improve ASM adherence should adopt a comprehensive approach considering the success of adherence is contingent on the interrelationship of multiple dimensions.

PRactice of VENTilation in Middle-Income Countries (PRoVENT-iMIC): rationale and protocol for a prospective international multicentre observational study in intensive care units in Asia.

INTRODUCTION: Current evidence on epidemiology and outcomes of invasively mechanically ventilated intensive care unit (ICU) patients is predominantly gathered in resource-rich settings. Patient casemix and patterns of critical illnesses, and probably also ventilation practices are likely to be different in resource-limited settings. We aim to investigate the epidemiological characteristics, ventilation practices and clinical outcomes of patients receiving mechanical ventilation in ICUs in Asia. METHODS AND ANALYSIS: PRoVENT-iMIC (study of PRactice of VENTilation in Middle-Income Countries) is an international multicentre observational study to be undertaken in approximately 60 ICUs in 11 Asian countries. Consecutive patients aged 18 years or older who are receiving invasive ventilation in participating ICUs during a predefined 28-day period are to be enrolled, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cm H2O) during the first 3 days of mechanical ventilation-compared between patients at no risk for acute respiratory distress syndrome (ARDS), patients at risk for ARDS and in patients with ARDS (in case the diagnosis of ARDS can be made on admission). Secondary outcomes include occurrence of pulmonary complications and all-cause ICU mortality. ETHICS AND DISSEMINATION: PRoVENT-iMIC will be the first international study that prospectively assesses ventilation practices, outcomes and epidemiology of invasively ventilated patients in ICUs in Asia. The results of this large study, to be disseminated through conference presentations and publications in international peer-reviewed journals, are of ultimate importance when designing trials of invasive ventilation in resource-limited ICUs. Access to source data will be made available through national or international anonymised datasets on request and after agreement of the PRoVENT-iMIC steering committee. TRIAL REGISTRATION NUMBER: NCT03188770; Pre-results.

Renal effects of an emergency department chloride-restrictive intravenous fluid strategy in patients admitted to hospital for more than 48 hours.

OBJECTIVE: Patients commonly receive i.v. fluids in the ED. It is still unclear whether the choice of i.v. fluids in this setting influences renal or patient outcomes. We aimed to assess the effects of restricting i.v. chloride administration in the ED on the incidence of acute kidney injury (AKI). METHODS: We conducted a before-and-after trial with 5008 consecutive ED-treated hospital admissions in the control period and 5146 consecutive admissions in the intervention period. During the control period (18 February 2008 to 17 August 2008), patients received standard i.v. fluids. During the intervention period (18 February 2009 to 17 August 2009), we restricted all chloride-rich fluids. We used the Kidney Disease: Improving Global Outcomes (KDIGO) staging to define AKI. RESULTS: Stage 3 of KDIGO-defined AKI decreased from 54 (1.1%; 95% confidence interval [CI] 0.8-1.4) to 30 (0.6%; 95% CI 0.4-0.8) (P = 0.006). The rate of renal replacement therapy did not change, from 13 (0.3%; 95% CI 0.2-0.4) to 8 (0.2%; 95% CI 0.1-0.3) (P = 0.25). After adjustment for relevant covariates, liberal chloride therapy remained associated with a greater risk of KDIGO stage 3 (hazard ratio 1.82; 95% CI 1.13-2.95; P = 0.01). On sensitivity assessment after removing repeat admissions, KDIGO stage 3 remained significantly lower in the intervention period compared with the control period (P = 0.01). CONCLUSION: In a before-and-after trial, a chloride-restrictive strategy in an ED was associated with a significant decrease in the incidence of stage 3 of KDIGO-defined AKI.

Chloride-liberal vs. chloride-restrictive intravenous fluid administration and acute kidney injury: an extended analysis.

PURPOSE: In a previous study, restricting intravenous chloride administration in ICU patients decreased the incidence of acute kidney injury (AKI). To test the robustness of this finding, we extended our observation period to 12 months. METHODS: The study extension included a 1-year control period (18 August 2007 to 17 August 2008) and a 1-year intervention period (18 February 2009 to 17 February 2010). During the extended control period, patients received standard intravenous fluids. During the extended intervention period, we continued to restrict all chloride-rich fluids. We used the Kidney Disease: Improving Global Outcomes (KDIGO) staging to define AKI. RESULTS: We studied 1,476 control and 1,518 intervention patients. Stages 2 and 3 of KDIGO defined AKI decreased from 302 (20.5 %; 95 % CI, 18.5-22.6 %) to 238 (15.7 %; 95 % CI, 13.9-17.6 %) (P < 0.001) and the use of RRT from 144 (9.8 %; 95 % CI, 8.3-11.4 %) to 103 (6.8 %; 95 % CI, 5.6-8.2 %) (P = 0.003). After adjustment for relevant covariates, liberal chloride therapy remained associated with a greater risk of KDIGO stages 2 and 3 [hazard ratio 1.32 (95 % CI 1.11-1.58); P = 0.002] and use of RRT [hazard ratio 1.44 (95 % CI 1.10-1.88); P = 0.006]. However, on sensitivity assessment of each 6-month period, KDIGO stages 2 and 3 increased in the new extended intervention period compared with the original intervention period. CONCLUSIONS: On extended assessment, the overall impact of restricting chloride-rich fluids on AKI remained. However, sensitivity analysis suggested that other unidentified confounders may have also contributed to fluctuations in the incidence of AKI.

Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults.

CONTEXT: Administration of traditional chloride-liberal intravenous fluids may precipitate acute kidney injury (AKI). OBJECTIVE: To assess the association of a chloride-restrictive (vs chloride-liberal) intravenous fluid strategy with AKI in critically ill patients. DESIGN, SETTING, AND PATIENTS: Prospective, open-label, sequential period pilot study of 760 patients admitted consecutively to the intensive care unit (ICU) during the control period (February 18 to August 17, 2008) compared with 773 patients admitted consecutively during the intervention period (February 18 to August 17, 2009) at a university-affiliated hospital in Melbourne, Australia. INTERVENTIONS: During the control period, patients received standard intravenous fluids. After a 6-month phase-out period (August 18, 2008, to February 17, 2009), any use of chloride-rich intravenous fluids (0.9% saline, 4% succinylated gelatin solution, or 4% albumin solution) was restricted to attending specialist approval only during the intervention period; patients instead received a lactated solution (Hartmann solution), a balanced solution (Plasma-Lyte 148), and chloride-poor 20% albumin. MAIN OUTCOME MEASURES: The primary outcomes included increase from baseline to peak creatinine level in the ICU and incidence of AKI according to the risk, injury, failure, loss, end-stage (RIFLE) classification. Secondary post hoc analysis outcomes included the need for renal replacement therapy (RRT), length of stay in ICU and hospital, and survival. RESULTS Chloride administration decreased by 144 504 mmol (from 694 to 496 mmol/patient) from the control period to the intervention period. Comparing the control period with the intervention period, the mean serum creatinine level increase while in the ICU was 22.6 µmol/L (95% CI, 17.5-27.7 µmol/L) vs 14.8 µmol/L (95% CI, 9.8-19.9 µmol/L) (P = .03), the incidence of injury and failure class of RIFLE-defined AKI was 14% (95% CI, 11%-16%; n = 105) vs 8.4% (95% CI, 6.4%-10%; n = 65) (P <.001), and the use of RRT was 10% (95% CI, 8.1%-12%; n = 78) vs 6.3% (95% CI, 4.6%-8.1%; n = 49) (P = .005). After adjustment for covariates, this association remained for incidence of injury and failure class of RIFLE-defined AKI (odds ratio, 0.52 [95% CI, 0.37-0.75]; P <.001) and use of RRT (odds ratio, 0.52 [95% CI, 0.33-0.81]; P = .004). There were no differences in hospital mortality, hospital or ICU length of stay, or need for RRT after hospital discharge. CONCLUSION The implementation of a chloride-restrictive strategy in a tertiary ICU was associated with a significant decrease in the incidence of AKI and use of RRT. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00885404.

The biochemical effects of restricting chloride-rich fluids in intensive care.

OBJECTIVE: To determine the biochemical effects of restricting the use of chloride-rich intravenous fluids in critically ill patients. DESIGN: Prospective, open-label, before-and-after study. SETTING: University-affiliated intensive care unit. PATIENTS: A cohort of 828 consecutive patients admitted over 6 months from February 2008 and cohort of 816 consecutive patients admitted over 6 months from February 2009. INTERVENTIONS: We collected biochemical and fluid use data during standard practice without clinician awareness. After a 6-month period of education and preparation, we restricted the use of chloride-rich fluids (0.9% saline [Baxter, Sydney, Australia], Gelofusine [BBraun, Melsungen, Germany], and Albumex 4 [CSL Bioplasma, Melbourne, Australia]) in the intensive care unit and made them available only on specific intensive care unit specialist prescription. MEASUREMENTS AND MAIN RESULTS: Saline prescription decreased from 2411 L in the control group to 52 L in the intervention group (p < .001), Gelofusine from 538 to 0 L (p < .001), and Albumex 4 from 269 to 80 L (p < .001). As expected, Hartmann's lactated solution prescription increased from 469 to 3205 L (p < .001), Plasma-Lyte from 65 to 160 L (p < .05), and chloride-poor Albumex 20 from 87 to 268 L (p < .001). After intervention, the incidence of severe metabolic acidosis (standard base excess <-5 mEq/L) decreased from 9.1% to 6.0% (p < .001) and severe acidemia (pH <7.3) from 6.0% to 4.9% (p < .001). However, the intervention also led to significantly greater incidence of severe metabolic alkalosis (standard base excess >5 mEq/L) and alkalemia (pH >7.5) with an increase from 25.4% to 32.8% and 10.5% to 14.7%, respectively (p < .001). The time-weighted mean chloride level decreased from 104.9 ± 4.9 to 102.5 ± 4.6 mmol/L (p < .001), whereas the time-weighted mean standard base excess increased from 0.5 ± 4.5 to 1.8 ± 4.7 mmol/L (p < .001), mean bicarbonate from 25.3 ± 4.0 to 26.4 ± 4.1 mmol/L (p < .001) and mean pH from 7.40 ± 0.06 to 7.42 ± 0.06 (p < .001). Overall fluid costs decreased from $15,077 (U.S.) to $3,915. CONCLUSIONS: In a tertiary intensive care unit in Australia, restricting the use of chloride-rich fluids significantly affected electrolyte and acid-base status. The choice of fluids significantly modulates acid-base status in critically ill patients.

Bench-to-bedside review: Chloride in critical illness.

Chloride is the principal anion in the extracellular fluid and is the second main contributor to plasma tonicity. Its concentration is frequently abnormal in intensive care unit patients, often as a consequence of fluid therapy. Yet chloride has received less attention than any other ion in the critical care literature. New insights into its physiological roles have emerged together with progress in understanding the structures and functions of chloride channels. In clinical practice, interest in a physicochemical approach to acid-base physiology has directed renewed attention to chloride as a major determinant of acid-base status. It has also indirectly helped to generate interest in other possible effects of disorders of chloraemia. The present review summarizes key aspects of chloride physiology, including its channels, as well as the clinical relevance of disorders of chloraemia. The paper also highlights current knowledge on the impact of different types of intravenous fluids on chloride concentration and the potential effects of such changes on organ physiology. Finally, the review examines the potential intensive care unit practice implications of a better understanding of chloride.