Prabath W.B. Nanayakkara

The impact of the use of the Early Warning Score (EWS) on patient outcomes: A systematic review

BACKGROUND Acute deterioration in critical ill patients is often preceded by changes in physiological parameters, such as pulse, blood pressure, temperature and respiratory rate. If these changes in the patients vital parameters are recognized early, excess mortality and serious adverse events (SAEs) such as cardiac arrest may be prevented. The Early Warning Score (EWS) is a scoring system which assists with the detection of physiological changes and may help identify patients at risk of further deterioration. OBJECTIVES The aim of this systematic review is to evaluate the impact of the use of the Early Warning Score (EWS) on particular patient outcomes, such as in-hospital mortality, patterns of intensive care unit admission and usage, length of hospital stay, cardiac arrests and other serious adverse events of adult patients on general wards and in medical admission units. DESIGN AND SETTING Systematic review of studies identified from the bibliographic databases of PubMed, EMBASE.com and The Cochrane Library. SELECTION CRITERIA All controlled studies which measured in-hospital mortality, ICU mortality, serious adverse events (SAEs), cardiopulmonary arrest, length of stay and documentation of physiological parameters which used a EWS on the ward or the emergency department to identify patients at risk were included in the review. DATA COLLECTION AND ANALYSIS Three reviewers (NA, AT and EH) independently screened all potentially relevant titles and abstracts for eligibility, by using a standardized data-worksheet. Meta-analysis was not possible due to heterogeneity. MAIN RESULTS Seven studies met the inclusion criteria. The results of our included studies were mixed, with a positive trend towards better clinical outcomes following the introduction of the EWS chart, sometimes coupled with an outreach service. Six of the seven included studies used mortality as an endpoint: two of these studies reported no significant difference in in-hospital mortality rate; two found a significant reduction of in-hospital mortality; two other studies described a trend towards improved survival. Although, both ICU mortality and serious adverse events were not significantly improved, there was a trend towards reduction of these endpoints after introduction of the EWS. However only two studies looked respectively at each endpoint. There were conflicting results concerning cardiopulmonary arrests. One study found a reduction in the incidence of cardiac arrest calls as well as in the mortality of patients who underwent CPR, while another one found an increased incidence of cardio-pulmonary arrests. Neither study met all methodological quality criteria. CONCLUSION The EWS itself is a simple and easy to use tool at the bedside, which may be of help in recognizing patients with potential for acute deterioration. Coupled with an outreach service, it may be used to timely initiate adequate treatment upon recognition, which may influence the clinical outcomes positively. However, the use of adapted forms of the EWS together with different thresholds, poor or inadequate methodology makes it difficult in drawing comparisons. A general conclusion can thus not be generated from the lack of use of a single standardized score and the use of different populations. In future large multi-centre trials using one standardized score are needed also in order to facilitate comparison.

How to save costs by reducing unnecessary testing: Lean thinking in clinical practice

BACKGROUND The burden of health care expenditure on national budgets has increased dramatically over the past decade. A pilot study in our hospital demonstrated that many unnecessary diagnostic tests were performed routinely. The aim of this study was to reduce the costs of unnecessary diagnostic tests. METHODS All diagnostic costs between 2006 and 2008 of the internal medicine department of the VU University Centre were evaluated. A target was set to reduce diagnostic expenditure by 7.5% in 2009 compared to 2008. A few interventions were introduced including introducing posters and pocket cards detailing the costs of diagnostic tests, six weekly feedback on diagnostics costs, mentorship of junior doctors, unbundling panel tests and increasing protocol adherence. Main outcome measures were the reduction in the total diagnostic costs and the total number of laboratory tests performed in the internal medicine department in 2009. RESULTS In 2009, we achieved a 13% reduction in the total diagnostic costs compared to 2008. The department of internal medicine spent 2.80 million euro and 2.45 million euro on the diagnostic tests in 2008 and 2009 respectively and thereby saved 350.000 euro in 2009. The largest reduction was achieved by reducing the number of laboratory tests performed. CONCLUSION Introduction of a few simple measures to improve awareness among the physicians led to a significant reduction in the diagnostic costs in the department of internal medicine. Extending these measures to the entire hospital and even entire country will in our opinion lead to significant reduction in the health care costs.

Association between global leukocyte DNA methylation, renal function, carotid intima-media thickness and plasma homocysteine in patients with stage 2–4 chronic kidney disease

BACKGROUND Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease (CVD). Preliminary evidence suggests a role for global DNA hypomethylation in the pathogenesis of atherosclerotic complications in CKD. The aims of this study in patients with stage 2-4 CKD were (1) to assess the association between renal function and DNA methylation, (2) to assess the association between DNA methylation and two markers of atherosclerosis [common carotid intima-media thickness (CCA-IMT)] and brachial artery endothelium-dependent, flow-mediated dilatation (BA-FMD) and (3) to examine the effect of a multi-step treatment strategy on DNA methylation. METHODS In the Anti-Oxidant Therapy In Chronic Renal Insufficiency study (ATIC-study), 93 patients with stage 2-4 CKD were included. In a randomized, double-blind, placebo-controlled design, the treatment group received pravastatin to which vitamin E was added after 6 months and homocysteine-lowering B-vitamin therapy after another 6 months. DNA methylation was assessed using tandem mass spectrometry. CCA-IMT and BA-FMD were assessed using B-mode ultrasonography. RESULTS At baseline, global DNA methylation was not associated with the estimated glomerular filtration rate (P = 0.32) or with CCA-IMT (P = 0.62) or BA-FMD (P = 0.51). No effect of the treatment strategy including B-vitamin on global DNA methylation was found either in the total study group or within separate strata of homocysteine concentration and renal function. CONCLUSION In patients with stage 2-4 CKD, global DNA methylation is not associated with renal function or with CCA-IMT or BA-FMD. A treatment strategy that includes B-vitamins did not alter global DNA methylation in these patients. These data do not support the role of DNA hypomethylation in CKD-associated vascular disease in patients with stage 2-4 CKD.

Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vitamin D–deficient non-Western immigrants in the Netherlands: a randomized placebo-controlled trial

BACKGROUND Low serum 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with insulin resistance, the metabolic syndrome, and type 2 diabetes. Because many non-Western immigrants in the Netherlands are vitamin D deficient, obese, and at high risk of diabetes, vitamin D supplementation may contribute to prevent diabetes and insulin resistance. OBJECTIVE We examined the effect of vitamin D supplementation on insulin sensitivity and β cell function in overweight, vitamin D-deficient, non-Western immigrants at high risk of diabetes. DESIGN The study was a 16-wk, randomized, placebo-controlled trial. A total of 130 non-Western immigrants with prediabetes (fasting glucose concentration >5.5 mmol/L or random glucose concentration from 7.8 to 11.1 mmol/L) and vitamin D deficiency (serum 25[OH]D concentration <50 nmol/L) were randomly assigned after stratification by sex to receive either cholecalciferol (1200 IU/d) or a placebo for 16 wk. All participants received 500 mg Ca/d as calcium carbonate. The primary outcome was the difference in the area under the curve of insulin and glucose after a 75-g oral-glucose-tolerance test after 4 mo of treatment. Secondary outcomes were insulin-sensitivity variables, β cell-function variables, and metabolic syndrome. RESULTS Mean serum 25(OH)D concentrations increased significantly in the vitamin D compared with placebo groups. After 4 mo of therapy, the mean between-group difference was 38 nmol/L (95% CI: 32.1, 43.9 nmol/L; P < 0.001). There was no significant effect on insulin sensitivity and β cell function. In a post hoc analysis, when patients with diabetes at baseline were excluded, a significant increase in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L (P = 0.040). CONCLUSIONS Vitamin D supplementation in non-Western vitamin D-deficient immigrants with prediabetes did not improve insulin sensitivity or β cell function or change the incidence of metabolic syndrome. However, after the exclusion of diabetic subjects, an improvement in the insulinogenic index was observed in participants who obtained a 25(OH)D concentration ≥60 nmol/L. This trial was registered at trialregister.nl as NTR1827.

Randomized Placebo-Controlled Trial Assessing a Treatment Strategy Consisting of Pravastatin, Vitamin E, and Homocysteine Lowering on Plasma Asymmetric Dimethylarginine Concentration in Mild to Moderate CKD

BACKGROUND Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). The Anti-oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study showed that a multistep treatment strategy improved carotid intima-media thickness, endothelial function, and microalbuminuria in patients with stages 2 to 4 CKD. Increased plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been linked to greater CVD risk in patients with CKD. The aim of this study is to assess effects of the multistep intervention on plasma ADMA concentrations in the ATIC Study. STUDY DESIGN Secondary analysis of a randomized double-blind placebo-controlled trial. SETTING & PARTICIPANTS 93 patients with creatinine clearance of 15 to 70 mL/min/1.73 m(2) (according to the Cockcroft-Gault equation) from 7 outpatient clinics in Amsterdam, The Netherlands. INTERVENTION The treatment group received sequential treatment consisting of pravastatin, 40 mg/d. After 6 months, vitamin E, 300 mg/d, was added, and after another 6 months, homocysteine-lowering therapy (folic acid, 5 mg/d; pyridoxine, 100 mg/d; and vitamin B(12), 1 mg/d, all in 1 tablet) were added and continued for another year. The control group received matching placebos. OUTCOME & MEASURES Plasma ADMA levels. RESULTS 36 participants (77%) in the treatment group and 38 (83%) in the placebo group completed the study. Mean ADMA and symmetric dimethylarginine concentrations in the total study population were 0.53 +/- 0.07 (SD) and 1.14 +/- 0.46 mumol/L, respectively. After 24 months, there was no overall effect of the treatment strategy on ADMA concentrations (beta = -0.006; P = 0.27). Analysis of separate treatment effects suggested that vitamin E significantly decreased ADMA levels by 4% in the treatment group compared with the placebo group (multiple adjusted P = 0.02). LIMITATIONS The study was a secondary analysis, power calculation was based on the primary end point of carotid intima-media thickness, mean plasma ADMA levels were relatively low. CONCLUSION Overall, a multistep treatment strategy consisting of pravastatin, vitamin E, and B vitamins had no effect on plasma ADMA levels in a stage 2 to 4 CKD population. This suggests that the beneficial effects of the intervention were not mediated by changes in ADMA levels. Possible ADMA-lowering effects of vitamin E deserve further attention.

Exploring the performance of the National Early Warning Score (NEWS) in a European emergency department.

BACKGROUND Several triage systems have been developed for use in the emergency department (ED), however they are not designed to detect deterioration in patients. Deteriorating patients may be at risk of going undetected during their ED stay and are therefore vulnerable to develop serious adverse events (SAEs). The national early warning score (NEWS) has a good ability to discriminate ward patients at risk of SAEs. The utility of NEWS had not yet been studied in an ED. OBJECTIVE To explore the performance of the NEWS in an ED with regard to predicting adverse outcomes. DESIGN A prospective observational study. Patients Eligible patients were those presenting to the ED during the 6 week study period with an Emergency Severity Index (ESI) of 2 and 3 not triaged to the resuscitation room. INTERVENTION NEWS was documented at three time points: on arrival (T0), hour after arrival (T1) and at transfer to the general ward/ICU (T2). The outcomes of interest were: hospital admission, ICU admission, length of stay and 30 day mortality. RESULTS A total of 300 patients were assessed for eligibility. Complete data was able to be collected for 274 patients on arrival at the ED. NEWS was significantly correlated with patient outcomes, including 30 day mortality, hospital admission, and length of stay at all-time points. CONCLUSION The NEWS measured at different time points was a good predictor of patient outcomes and can be of additional value in the ED to longitudinally monitor patients throughout their stay in the ED and in the hospital.

Hyperfibrinolysis in out of hospital cardiac arrest is associated with markers of hypoperfusion

AIM OF THE STUDY This study investigated the incidence of hyperfibrinolysis upon emergency department (ED) admission in patients with out of hospital cardiac arrest (OHCA), and the association of the degree of hyperfibrinolysis with markers of hypoperfusion. METHODS From 30 OHCA patients, cardiopulmonary resuscitation (CPR) time, pH, base excess (BE), and serum lactate were measured upon ED admission. A 20% decrease of rotational thromboelastometry maximum clot firmness (MCF) was defined as hyperfibrinolysis. Lysis parameters included maximum lysis (ML), lysis onset time (LOT) and lysis index at 30 and 45 min (LI30/LI45). The study was approved by the Human Subjects Committee. RESULTS Hyperfibrinolysis was present in 53% of patients. Patients with hyperfibrinolysis had longer median CPR times (36 (15-55) vs. 10 (7-18)min; P=0.001), a prolonged activated partial thromboplastin time (54 ± 16 vs. 38 ± 10s; P=0.006) and elevated D-dimers (6.1 ± 2.1 vs. 2.3 ± 2.0 μg/ml; P=0.02) when compared to patients without hyperfibrinolysis. Hypoperfusion markers, including pH (6.96 ± 0.11 vs. 7.17 ± 0.15; P<0.001), base excess (-20.01 ± 3.53 vs. -11.91 ± 6.44; P<0.001) and lactate (13.1 ± 3.7 vs. 8.0 ± 3.7 mmol/l) were more disturbed in patients with hyperfibrinolysis than in non-hyperfibrinolytic subjects, respectively. The LOT showed a good association with CPR time (r=-0.76; P=0.003) and lactate (r=-0.68; P=0.01), and was longer in survivors (3222 ± 34s) than in non-survivors (1,356 ± 833; P=0.044). CONCLUSION A substantial part of OHCA patients develop hyperfibrinolysis in association with markers for hypoperfusion. Our data further suggest that the time to the onset of clot lysis may be an important marker for the severity of hyperfibrinolysis and patient outcome.

Homocysteine and asymmetric dimethylarginine (ADMA): biochemically linked but differently related to vascular disease in chronic kidney disease

Abstract Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is formed by methylation of arginine residues in proteins and released after proteolysis. In this reaction, S-adenosylmethionine is methyldonor and S-adenosylhomocysteine the demethylated product. ADMA and homocysteine are thus biochemically linked. Both plasma homocysteine and ADMA concentrations are increased in patients with renal dysfunction, probably as a result of an impairment in their metabolic, but not urinary, clearance. Hyperhomocysteinemia has been associated with an increased risk of cardiovascular disease in end-stage renal disease, especially in patients without malnutrition and inflammation. Also, plasma ADMA levels have been associated with cardiovascular disease in renal failure patients. Both homocysteine and ADMA are thought to mediate their adverse vascular effects by impairing endothelial, nitric oxide-dependent function resulting in decreased vasodilatation, increased smooth muscle cell proliferation, platelet dysfunction and increased monocyte adhesion. At the same time, it has been shown that the correlation between plasma ADMA and homocysteine is weak and that, in renal patients, the association of plasma ADMA carotid intima-media thickness, cardiovascular events and overall mortality is independent of homocysteine. This indicates that the negative vascular effects of ADMA and homocysteine have a different etiology. Treatment with folic acid substantially lowers homocysteine, but not ADMA concentration. So far, homocysteine-lowering therapy has not been very successful in decreasing cardiovascular disease. In patients with renal failure, ADMA reduction may be an interesting new goal in the prevention of cardiovascular disease. Clin Chem Lab Med 2007;45:1683–7.

Plasma adiponectin concentration has an inverse and a non linear association with estimated glomerular filtration rate in patients with K/DOQI 3 ― 5 chronic kidney disease

BACKGROUND Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). A few studies have demonstrated elevated plasma adiponectin and leptin levels in CKD. The aims of this study were to assess whether 1) estimated glomerular filtration rate (eGFR) is associated with plasma leptin and adiponectin; and 2) adiponectin and leptin (partly) explain associations of CKD with endothelial dysfunction, insulin resistance, and low-grade inflammation in patients with K/DOQI Stage 3 - 5 CKD. METHODS Baseline data from 91 patients with Stage 3 - 4 CKD in the anti-oxidant therapy in chronic renal insufficiency study, a randomized, double-blind, placebo-controlled trial, in which the effects of oxidative stress-lowering treatment on vascular function and structure were studied, and from 50 dialysis naïve patients, who took part in an open-label, randomized study that compared two peritoneal dialysis regimens, used in the analysis. All subjects for both the studies were recruited in the same centres. RESULTS The association between eGFR and adiponectin was non-linear. In multivariate analysis, log-eGFR (unstandardized beta = 8.303 microg/ml, p < 0.0001) was the strongest determinant of adiponectin, and body mass index the strongest determinant of leptin (beta = 2.477 ng/ml, p < 0.0001). Plasma adiponectin and leptin did not modify the associations between eGFR and plasma von Willebrand factor or soluble vascular adhesion molecule-1. Plasma leptin had the strongest association with the homeostatic model assessment (HOMA-IR) index. Plasma C-reactive protein had no association with adiponectin or leptin. CONCLUSIONS In patients with K/DOQI Stage 3 - 5 CKD, renal function had a significant non-linear inverse association with and was the strongest predictor of adiponectin. BMI was the strongest predictor of plasma leptin. Plasma adiponectin and leptin did not explain, and thus presumably are not involved in, the association between eGFR and some markers of endothelial dysfunction.

Efficacy and safety of haloperidol for in-hospital delirium prevention and treatment: A systematic review of current evidence

OBJECTIVE Haloperidol is generally considered the drug of choice for in-hospital delirium management. We conducted a systematic review to evaluate the evidence for the efficacy and safety of haloperidol for the prevention and treatment of delirium in hospitalized patients. METHODS PubMed, Embase, Cumulative Index to Nursing and Allied Health (CINAHL), PsycINFO, and the Cochrane Library were systematically searched up to April 21, 2015. We included English full-text randomized controlled trials using haloperidol for the prevention or treatment of delirium in adult hospitalized patients reporting on delirium incidence, duration, or severity as primary outcome. Quality of evidence was graded. Meta-analysis was not conducted because of between-study heterogeneity. RESULTS Twelve studies met our inclusion criteria, four prevention and eight treatment trials. Methodological limitations decreased the graded quality of included studies. Results from placebo-controlled prevention studies suggest a haloperidol-induced protective effect for delirium in older patients scheduled for surgery: two studies reported a significant reduction in ICU delirium incidence and one study found a significant reduction in delirium severity and duration. Although placebo-controlled trials are missing, pharmacological treatment of established delirium reduced symptom severity. Haloperidol administration was not associated with treatment-limiting side-effects, but few studies used a systematic approach to identify adverse events. CONCLUSION Although results on haloperidol for delirium management seem promising, current prevention trials lack external validity and treatment trials did not include a placebo arm on top of standard nonpharmacological care. We therefore conclude that the current use of haloperidol for in-hospital delirium is not based on robust and generalizable evidence.