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Electrolyte imbalances as poor prognostic markers in COVID-19: a systemic review and meta-analysis.
Song, HJJMD, Chia, AZQ, Tan, BKJ, Teo, CB, Lim, V, Chua, HR, Samuel, M, Kee, A
Journal of endocrinological investigation. 2023;46(2):235-259
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Salt imbalances in individuals with Covid-19 are highly prevalent, however it is not fully understood if they determine whether a patient has a good or bad prognosis. This systematic review and meta-analysis of 28 observational studies aimed to determine the associations and prognostic value of different salt imbalances in individuals with Covid-19. The results showed that out of several salt imbalances analysed, high and low sodium levels and low calcium levels could predict poor outcomes in those with Covid-19. High sodium levels were particularly indicative, but this was not due to the relationship between high sodium and inflammation in the body and causal reasons remained undiscovered. It was concluded that sodium imbalances and low calcium levels were associated with poor clinical outcomes in individuals with Covid-19. This study could be used by healthcare professionals to understand that correcting these imbalances may be of benefit to individuals with Covid-19.
Abstract
PURPOSE Serum electrolyte imbalances are highly prevalent in COVID-19 patients. However, their associations with COVID-19 outcomes are inconsistent, and of unknown prognostic value. We aim to systematically clarify the associations and prognostic accuracy of electrolyte imbalances (sodium, calcium, potassium, magnesium, chloride and phosphate) in predicting poor COVID-19 clinical outcome. METHODS PubMed, Embase and Cochrane Library were searched. Odds of poor clinical outcome (a composite of mortality, intensive-care unit (ICU) admission, need for respiratory support and acute respiratory distress syndrome) were pooled using mixed-effects models. The associated prognostic sensitivity, positive and negative likelihood ratios (LR + , LR-) and predictive values (PPV, NPV; assuming 25% pre-test probability), and area under the curve (AUC) were computed. RESULTS We included 28 observational studies from 953 records with low to moderate risk-of-bias. Hyponatremia (OR = 2.08, 95% CI = 1.48-2.94, I2 = 93%, N = 8), hypernatremia (OR = 4.32, 95% CI = 3.17-5.88, I2 = 45%, N = 7) and hypocalcemia (OR = 3.31, 95% CI = 2.24-4.88, I2 = 25%, N = 6) were associated with poor COVID-19 outcome. These associations remained significant on adjustment for covariates such as demographics and comorbidities. Hypernatremia was 97% specific in predicting poor outcome (LR + 4.0, PPV = 55%, AUC = 0.80) despite no differences in CRP and IL-6 levels between hypernatremic and normonatremic patients. Hypocalcemia was 76% sensitive in predicting poor outcome (LR- 0.44, NPV = 87%, AUC = 0.71). Overall quality of evidence ranged from very low to moderate. CONCLUSION Hyponatremia, hypernatremia and hypocalcemia are associated with poor COVID-19 clinical outcome. Hypernatremia is 97% specific for a poor outcome, and the association is independent of inflammatory marker levels. Further studies should evaluate if correcting these imbalances help improve clinical outcome.
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Randomized Controlled Clinical Trial of the Effect of Treatment with Vitamin K2 on Vascular Calcification in Hemodialysis Patients (Trevasc-HDK).
Haroon, S, Davenport, A, Ling, LH, Tai, BC, Teo, LL, Schurgers, L, Chen, Z, Shroff, R, Fischer, DC, Khatri, P, et al
Kidney international reports. 2023;(9):1741-1751
Abstract
INTRODUCTION Vitamin K deficiency among patients on hemodialysis (HD) affects the function of matrix GLA protein (MGP), a potent vitamin K-dependent inhibitor of vascular calcification (VC). METHODS We conducted a single-center randomized controlled trial (RCT) on maintenance HD patients to examine if vitamin K2 supplementation can reduce progression of coronary artery calcification (CAC) over an 18-month study period. Patients were randomized to vitamin K2 group receiving menaquinone-7360 μg 3 times/wk or control group. The primary outcome was CAC scores at the end of the study period. The secondary outcomes were aortic valve calcification (AVC), carotid-femoral pulse wave velocity (cfPWV), aortic augmentation index (AIx), dephosphorylated undercarboxylated MGP (dp-ucMGP) levels, major adverse cardiac events (MACE), and vascular access events. RESULTS Of the 178 patients randomized, follow-up was completed for 138 patients. The CAC scores between the 2 groups were not statistically different at the end of 18 months (relative mean difference [RMD] 0.85, 95% CI 0.55-1.31). The secondary outcomes did not differ significantly in AVC (RMD 0.82, 95% CI 0.34-1.98), cfPWV (absolute mean difference [AMD] 0.55, 95% CI -0.50 to 1.60), and AIx (AMD 0.13, 95% CI -3.55 to 3.80). Supplementation with vitamin K2 did reduce dp-ucMGP levels (AMD -86, 95% CI -854 to -117). The composite outcome of MACE and mortality was not statistically different between the 2 groups (Hazard ratio = 0.98, 95% CI 0.50-1.94). CONCLUSION Our study did not demonstrate a beneficial effect of vitamin K2 in reducing progression of VC in this population at the studied dose and duration.
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Treatment to reduce vascular calcification in hemodialysis patients using vitamin K (Trevasc-HDK): A study protocol for a randomized controlled trial.
Haroon, SW, Tai, BC, Ling, LH, Teo, L, Davenport, A, Schurgers, L, Teo, BW, Khatri, P, Ong, CC, Low, S, et al
Medicine. 2020;(36):e21906
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Abstract
INTRODUCTION End stage renal failure patients on hemodialysis have significant vascular calcification This is postulated to be related to sub-clinical vitamin K deficiency, which is prevalent in hemodialysis patients. Vitamin K deficiency result in the failure of the matrix GLA protein (MGP) to undergo carboxylation. MGP is a natural local inhibitor of vascular calcification and the lack of functional carboxylated MGP may contribute to increase vascular calcification. Vitamin K supplement should therefore correct this anomaly and decrease the rate or severity of vascular calcification in this population of patients on long-term maintenance hemodialysis. Our study seeks to evaluate the prevalence and the progression of vascular calcification in a cohort of maintenance hemodialysis patients. It will also evaluate the efficacy of vitamin K supplementation in reducing the progression of vascular calcification in this group of patients. METHODS This will be a single-center randomized, prospective and open-label interventional clinical trial of end stage renal failure patients on hemodialysis. We aim to recruit 200 patients. Eligible patients will be randomized to either the standard care arm or active treatment arm. Active treatment arm patients will receive standard care plus supplementation with oral vitamin K2 isoform 360 mcg 3 times weekly for a total duration of 18 months. Primary outcome measured will be absolute difference in coronary artery calcification score at 18-month between control and intervention arms. Secondary outcomes will be to compare absolute difference in aortic valve calcification, percentage of patients with regression of coronary artery calcification of at least 10%, absolute difference in aortic and systemic arterial stiffness, mortality from any cause and major adverse cardiovascular over the same period. DISCUSSION Evidence of successful regression or retardation of vascular calcification will support the conduct of larger and longer-term trials aimed at reducing cardiovascular disease mortality and major adverse cardiovascular events in this high-risk population using a safe and inexpensive strategy TRIAL REGISTRATION ClinicalTrials.gov NCT02870829. Registered on 17 August 2016 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02870829National University Hospital's Institutional Review Board (2015/01000).
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Hyperlactatemia Predicts Citrate Intolerance With Regional Citrate Anticoagulation During Continuous Renal Replacement Therapy.
Tan, JN, Haroon, SWP, Mukhopadhyay, A, Lau, T, Murali, TM, Phua, J, Tan, ZY, Lee, N, Chua, HR
Journal of intensive care medicine. 2019;(5):418-425
Abstract
PURPOSE We aim to determine whether hyperlactatemia, which suggests multi-organ dysfunction and impaired organic substrate metabolism, may predict intolerance to regional citrate anticoagulation (RCA) during continuous venovenous hemofiltration (CVVH). METHODS We performed a single-center, retrospective observational study in critically ill patients with acute kidney injury or end-stage renal disease and evaluated the association of peak serum lactate levels with citrate intolerance (CI) during the initial 72 hours of RCA-CVVH, defined by serum total-to-ionized calcium >2.5 plus systemic hypocalcemia. RESULTS Eighty-eight patients were studied (aged 59 ± 14 years, 66% males, Acute Physiology and Chronic Health Evaluation II: 31 ± 8). Citrate was dosed at median 2.1 mmol/L of blood flow, with citrate load of 30 mmol/h, and CVVH effluent of 43 mL/kg/h. Twenty patients developed CI. Comparing patients with CI versus none, peak lactate levels were 8 (5-11) versus 3 (2-6) mmol/L, calcium replacement was 13 (10-17) versus 11 (8-12) mmol/h, and standard base excess was -4 (-12 to 1) versus 2(-4 to 7) mmol/L, respectively ( P < .05). Citrate intolerance developed in 38%, 44%, and 55%, in patients with peak lactate >4, >6, >7 mmol/L, respectively, versus 7% in those with peak lactate ≤4 mmol/L ( P ≤ .001), despite comparable citrate load and effluent rates across all categories. On multivariate analysis, hyperlactatemia and hyperbilirubinemia predicted CI ( P ≤ .01), which was associated with increasing calcium infusion requirement. Higher peak lactate from >4 to >7 mmol/L predicted CI with graded increase in odds ratio and specificity from 59% to 87%, but the corresponding negative predictive value from 93% to 87%. Area under nonparametric receiver operating characteristic curve for peak lactate and CI was 0.78. CONCLUSION Hyperlactatemia predicts CI during RCA-CVVH with reasonable discriminatory performance in critically ill patients. Serum lactate surveillance may help preempt issues with citrate toxicity.
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Electronic health records accurately predict renal replacement therapy in acute kidney injury.
Low, S, Vathsala, A, Murali, TM, Pang, L, MacLaren, G, Ng, WY, Haroon, S, Mukhopadhyay, A, Lim, SL, Tan, BH, et al
BMC nephrology. 2019;(1):32
Abstract
BACKGROUND Electronic health records (EHR) detect the onset of acute kidney injury (AKI) in hospitalized patients, and may identify those at highest risk of mortality and renal replacement therapy (RRT), for earlier targeted intervention. METHODS Prospective observational study to derive prediction models for hospital mortality and RRT, in inpatients aged ≥18 years with AKI detected by EHR over 1 year in a tertiary institution, fulfilling modified KDIGO criterion based on serial serum creatinine (sCr) measures. RESULTS We studied 3333 patients with AKI, of 77,873 unique patient admissions, giving an AKI incidence of 4%. KDIGO AKI stages at detection were 1(74%), 2(15%), 3(10%); corresponding peak AKI staging in hospital were 61, 20, 19%. 392 patients (12%) died, and 174 (5%) received RRT. Multivariate logistic regression identified AKI onset in ICU, haematological malignancy, higher delta sCr (sCr rise from AKI detection till peak), higher serum potassium and baseline eGFR, as independent predictors of both mortality and RRT. Additionally, older age, higher serum urea, pneumonia and intraabdominal infections, acute cardiac diseases, solid organ malignancy, cerebrovascular disease, current need for RRT and admission under a medical specialty predicted mortality. The AUROC for RRT prediction was 0.94, averaging 0.93 after 10-fold cross-validation. Corresponding AUROC for mortality prediction was 0.9 and 0.9 after validation. Decision tree analysis for RRT prediction achieved a balanced accuracy of 70.4%, and identified delta-sCr ≥ 148 μmol/L as the key factor that predicted RRT. CONCLUSION Case fatality was high with significant renal deterioration following hospital-wide AKI. EHR clinical model was highly accurate for both RRT prediction and for mortality; allowing excellent risk-stratification with potential for real-time deployment.
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Phoxilium vs Hemosol-B0 for continuous renal replacement therapy in acute kidney injury.
Chua, HR, Schneider, AG, Baldwin, I, Collins, A, Ho, L, Bellomo, R
Journal of critical care. 2013;(5):884.e7-14
Abstract
PURPOSE This study aimed to compare the biochemical effects of Phoxilium (containing phosphate at 1.2 mmol/L; Gambro Lundia AB, Lund, Sweden) and Hemosol-B0 (Gambro Lundia AB) as dialysate and/or replacement fluid during continuous renal replacement therapy (CRRT). METHODS We examined serum biochemistry in critically ill patients for 42 hours of Phoxilium administration for the prevention of hypophosphatemia during CRRT and compared them with corresponding results in random historical controls who received Hemosol-B0. RESULTS We studied 15 patients in each arm (Phoxilium vs Hemosol-B0). Respective median ages were 57 (49-68) and 64 (57-67) years. Baseline patient illness severity scores, prescribed CRRT effluent rates, and cumulative phosphate intakes were comparable. After 36 to 42 hours of Phoxilium administration, serum phosphate levels increased from 0.95 (0.81-1.13) to 1.44 (1.23-1.78) mmol/L, in contrast to the decline from 1.71 (1.09-2.00) to 0.83 (0.55-1.59) mmol/L with Hemosol-B0 (P=.0001). Serum ionized calcium levels decreased from 1.27 (1.22-1.37) to 1.12 (1.06-1.21) mmol/L with Phoxilium, compared with an increase from 1.09 (0.90-1.19) to 1.20 (1.16-1.25) mmol/L with Hemosol-B0 (P<.0001). Serum bicarbonate, base excess levels, and effective strong ion difference decreased with Phoxilium and were lower than those with Hemosol-B0 at 36 to 42 hours (P<.05). CONCLUSION Phoxilium effectively prevented hypophosphatemia during CRRT but was associated with relative metabolic acidosis and hypocalcemia compared with Hemosol-B0 use.
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Amino acid balance with extended daily diafiltration in acute kidney injury.
Chua, HR, Baldwin, I, Fealy, N, Naka, T, Bellomo, R
Blood purification. 2012;(4):292-9
Abstract
BACKGROUND The impact of hybrid dialysis therapies on amino acid (AA) balance in critically ill patients with acute kidney injury is unknown. METHODS We examined prospectively the AA balance with extended daily diafiltration (EDDF). RESULTS We studied 7 patients. AA clearances with EDDF ranged from 21.6 ml/min (tryptophan) to 66.9 ml/min (taurine). AA loss was 4.2 (IQR 1.4-12.3) g/day and 4.5% of daily protein intake for patients on enteral nutrition (EN). Percentage AA loss per hour on EDDF was highest for glutamine (32.1%) and lowest for glutamic acid (0.8%). Blood AA levels correlated with corresponding EDDF losses. Median total nitrogen appearance was 25.0 (IQR 20.6-29.3) g/day for patients on EN. This resulted in a negative nitrogen balance of -10.7 (IQR -16.6 to -1.4) g/day, of which 6.5% was attributable to AA loss. CONCLUSIONS AA loss with EDDF was limited, but with much individual variability, and contributed to a strongly negative daily nitrogen balance.
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Bicarbonate in diabetic ketoacidosis - a systematic review.
Chua, HR, Schneider, A, Bellomo, R
Annals of intensive care. 2011;(1):23
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Abstract
OBJECTIVE This study was designed to examine the efficacy and risk of bicarbonate administration in the emergent treatment of severe acidemia in diabetic ketoacidosis (DKA). METHODS PUBMED database was used to identify potentially relevant articles in the pediatric and adult DKA populations. DKA intervention studies on bicarbonate administration versus no bicarbonate in the emergent therapy, acid-base studies, studies on risk association with cerebral edema, and related case reports, were selected for review. Two reviewers independently conducted data extraction and assessed the citation relevance for inclusion. RESULTS From 508 potentially relevant articles, 44 were included in the systematic review, including three adult randomized controlled trials (RCT) on bicarbonate administration versus no bicarbonate in DKA. We observed a marked heterogeneity in pH threshold, concentration, amount, and timing for bicarbonate administration in various studies. Two RCTs demonstrated transient improvement in metabolic acidosis with bicarbonate treatment within the initial 2 hours. There was no evidence of improved glycemic control or clinical efficacy. There was retrospective evidence of increased risk for cerebral edema and prolonged hospitalization in children who received bicarbonate, and weak evidence of transient paradoxical worsening of ketosis, and increased need for potassium supplementation. No studies involved patients with an initial pH < 6.85. CONCLUSIONS The evidence to date does not justify the administration of bicarbonate for the emergent treatment of DKA, especially in the pediatric population, in view of possible clinical harm and lack of sustained benefits.