Dynamic prediction of mortality in COVID-19 patients in the intensive care unit: A retrospective multi-center cohort study.

Background: The COVID-19 pandemic continues to overwhelm intensive care units (ICUs) worldwide, and improved prediction of mortality among COVID-19 patients could assist decision making in the ICU setting. In this work, we report on the development and validation of a dynamic mortality model specifically for critically ill COVID-19 patients and discuss its potential utility in the ICU. Methods: We collected electronic medical record (EMR) data from 3222 ICU admissions with a COVID-19 infection from 25 different ICUs in the Netherlands. We extracted daily observations of each patient and fitted both a linear (logistic regression) and non-linear (random forest) model to predict mortality within 24 h from the moment of prediction. Isotonic regression was used to re-calibrate the predictions of the fitted models. We evaluated the models in a leave-one-ICU-out (LOIO) cross-validation procedure. Results: The logistic regression and random forest model yielded an area under the receiver operating characteristic curve of 0.87 [0.85; 0.88] and 0.86 [0.84; 0.88], respectively. The recalibrated model predictions showed a calibration intercept of -0.04 [-0.12; 0.04] and slope of 0.90 [0.85; 0.95] for logistic regression model and a calibration intercept of -0.19 [-0.27; -0.10] and slope of 0.89 [0.84; 0.94] for the random forest model. Discussion: We presented a model for dynamic mortality prediction, specifically for critically ill COVID-19 patients, which predicts near-term mortality rather than in-ICU mortality. The potential clinical utility of dynamic mortality models such as benchmarking, improving resource allocation and informing family members, as well as the development of models with more causal structure, should be topics for future research.

[Less ventilator-associated pneumonia after oral decontamination with chlorhexidine; a randomised trial]. / Minder beademingspneumonieën door orale decontaminatie met chloorhexidine; gerandomiseerde trial.

OBJECTIVE: To determine the effect of oral decontamination with either chlorhexidine (CHX, 2%) or the combination chlorhexidine-colistin (CHX-COL, 2%-2%) on the frequency and the time to onset of ventilator-associated pneumonia in Intensive Care patients. DESIGN: Double blind, placebo-controlled, multicentre, randomised trial. METHODS: Consecutive ICU patients needing at least 48 h of mechanical ventilation were enrolled in a randomized trial with 3 arms: CHX, CHX-COL, and placebo (PLAC). The trial medication was administered in the oral cavity every 6 h. Oropharyngeal swabs were obtained daily and analysed quantitatively for Gram-positive and Gram-negative microorganisms. Endotracheal colonisation was monitored twice weekly. Ventilator-associated pneumonia was diagnosed on the basis of a combination of clinical, radiological and microbiological criteria. RESULTS: Of 385 patients included, 130 received PLAC, 127 CHX and 128 CHX-COL. Baseline characteristics in the three groups were comparable. The daily risk of ventilator-associated pneumonia was reduced in both treatment groups compared to PLAC: 65% (HR= 0.352; 95% CI: 0.160-0.791; p = 0.012) for CHX and 55% (HR= 0.454; 95%/ CI: 0.224-0.925; p = 0.030) for CHX-COL. CHX-COL provided a significant reduction in oropharyngeal colonisation with both Gram-negative and Gram-positive microorganisms, whereas CHX significantly affected only colonisation with Gram-positive microorganisms. There were no differences in the duration of mechanical ventilation, ICU-stay or ICU-survival. CONCLUSION: Oral decontamination of the oropharyngeal cavity with chlorhexidine or the combination chlorhexidine-colistin reduced the incidence and the time to onset ofventilator-associated pneumonia.

Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion.

OBJECTIVES: The efficacy of high dose furosemide as a continuous infusion was compared with a bolus injection of equal dose in patients with severe heart failure. BACKGROUND: The delivery rate of furosemide into the nephron has been proved to be a determinant of diuretic efficacy in healthy volunteers. METHODS: In a randomized crossover study we compared the efficacy of a continuous infusion of high dose furosemide (mean daily dosage 690 mg, range 250 to 2,000) versus a single bolus injection of an equal dose in 20 patients with severe heart failure. The patients received an equal dosage, either as a single intravenous bolus injection or as an 8-h continuous infusion preceded by a loading dose (20% of total dosage). RESULTS: Mean (+/- SEM) daily urinary volume (infusion 2,860 +/- 240 ml, bolus 2,260 +/- 150 ml, p = 0.0005) and sodium excretion (infusion 210 +/- 40 mmol, bolus 150 +/- 20 mmol, p = 0.0045) were significantly higher after treatment with continuous infusion than with bolus injection, despite significantly lower urinary furosemide excretion (infusion 310 +/- 60 mg every 24 h, bolus 330 +/- 60 mg every 24 h, p = 0.0195). The maximal plasma furosemide concentration was significantly higher after bolus injection than during continuous infusion (infusion 24 +/- 5 micrograms/ml, bolus 95 +/- 20 micrograms/ml, p < 0.0001). Short-term, completely reversible hearing loss was reported only after bolus injection in 5 patients. CONCLUSIONS: We conclude that in patients with severe heart failure, high dose furosemide administered as a continuous infusion is more efficacious than bolus injection and causes less ototoxic side effects.

Vascular effects of loop diuretics.

Although it is generally believed that the beneficial effect of loop diuretics is the result of a rapid increase in diuresis, substantial evidence, from a large number of in vitro and in vivo experiments, has accumulated showing that administration of furosemide causes direct vascular effects, which probably contribute to its acute clinical effects. Several mechanisms are involved in the vascular response to loop diuretics. The role of the renin-angiotensin-adolsterone axis, prostaglandins and the direct vascular effects of loop diuretics on both the arterial and venous parts of the vasculature are discussed.

Evaluation of indium-111-polyclonal immunoglobulin G to quantitate atherosclerosis in Watanabe heritable hyperlipidemic rabbits with scintigraphy: effect of age and treatment with antioxidants or ethinylestradiol.

Scintigraphic detection of atherosclerotic lesions using 111In-polyclonal IgG was studied. In Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for hypercholesterolemia with spontaneous atherosclerosis, aged WHHL rabbits incorporated more 111In-IgG into atherosclerotic lesions than young WHHL or control NZW rabbits. This result is in agreement with histological analysis. However, due to the low ratio of lesion-incorporated radioactivity to circulating radioactivity, in vivo gamma imaging of atherosclerosis with 111In-IgG scintigraphy was unsuccessful. Interventional agents, Probucol or vitamin E, used for 28 days to reduce the amount of autoantibodies produced against biological modified low-density lipoproteins did not produce differences in 111In-IgG incorporation into the aorta ex vivo. Ethinylestradiol, used for 28 days, exhibited similar incorporation with decreased serum cholesterol by 45%. Although atherosclerosis histology and lesion surfaces of WHHL rabbits are similar to those in adult humans, it is obvious that noninvasive gamma imaging with polyclonal 111In scintigraphy is not reliable for serial evaluation of the extent of atherosclerosis. Our results emphasize the need to develop pharmaceuticals to image atherosclerosis.

Combination diuretic therapy in severe congestive heart failure.

Severe congestive heart failure (CHF) is often characterised by fluid retention. A (chronic) state of overhydration has a negative influence on both the quality of life and prognosis of these patients. Therefore, the use of diuretics remains a cornerstone in the treatment of heart failure. However, diuretic resistance, a failure to correct the hydration state adequately with the use of conventional dosages of loop diuretics, is a frequently occurring complication in the treatment of advanced stages of CHF. Several intra- and extrarenal mechanisms may be involved in the development of diuretic resistance. An important pathophysiological mechanism leading to diuretic resistance seen after chronic use of loop diuretics is the functional adaptation of the distal tubule. Studies in animals demonstrate that the sodium reabsorption capacity of this nephron segment increases significantly when the sodium delivery to this segment is augmented, as is the case during administration of loop diuretics. The use of combinations of diuretics acting on different segments of the nephron appears to be an effective option in the treatment of diuretic resistance. Several combinations have been used; however, the combination of a loop diuretic and a thiazide drug acting on the distal tubule appears to be the most effective. However, since the use of this combination may lead to serious adverse effects such as hypokalaemia, metabolic alkalosis and dehydration, careful monitoring of the patient of combination diuretic therapy is necessary.

Pulmonary lymphangioleiomyomatosis and cerebrotendinous xanthomatosis: is there a link?

A 41-year-old woman had progressive shortness of breath. Cerebrotendinous xanthomatosis was diagnosed 4 years before. An open-lung biopsy showed the simultaneous presence of cerebrotendinous xanthomatosis and pulmonary lymphangioleiomyomatosis. This is perhaps the first time the coincidental occurrence of these two diseases is described.

Chronic intermittent haemofiltration and haemodialysis in end stage chronic heart failure with oedema refractory to high dose frusemide.

OBJECTIVE: To assess the benefits and problems of chronic intermittent treatment with haemofiltration or haemodialysis or both in patients with severe chronic heart failure (New York Heart Association class III or IV) and oedema refractory to pharmacological treatment. DESIGN AND SETTING: A retrospective case-cohort study. A general hospital in The Netherlands. PATIENTS: The results of chronic intermittent treatment with haemofiltration (n = 10) or haemodialysis (n = 2) were analysed in patients with severe chronic heart failure, predominantly due to coronary heart disease, and oedema refractory to a pharmacological regimen including high dose frusemide. INTERVENTION: Patients had an average of 25 (SD 38) treatments. RESULTS: There was improvement of NYHA class IV to III in seven patients. However, this was not reflected in a decrease in hospital admission: only two patients could be managed as outpatients. The median survival after start of the treatment was 24 days (varying from 0 to 393 days). In four patients the treatment was discontinued after discussion with the patient and family. CONCLUSIONS: The use of chronic intermittent haemofiltration and haemodialysis is of limited value in end stage chronic heart failure with oedema, refractory to maximal conventional treatment.

Acute renal failure as first presentation of acute lymphoblastic leukaemia.

A 26-year-old man presented with acute renal failure, which appeared to be due to uric acid nephropathy occurring as a metabolic complication of acute lymphoblastic leukaemia with T-cell immunophenotype. At presentation there were neither other manifestations of leukaemic disease nor signs of a large leukaemic cell burden, which is very uncommon.

[Failing diuretics in severe chronic heart failure]. / Falende diuretica bij ernstig chronisch hartfalen.

Three patients with chronic heart failure, men aged 29, 78 and 69 years, developed severe dyspnoea and oedema in spite of reduced sodium and fluid intake and medication including furosemide. Heart failure may become 'resistant to diuretics' due to pharmacokinetic and pharmacodynamic causes. High-dose continuous intravenous administration of a loop diuretic may afford relief in such cases, if necessary in combination with a thiazide derivative, an ACE inhibitor, an inotropic agent or an extracorporal technique. Monitoring and correction of the state of hydration of a patient with chronic heart failure may improve the prognosis and the quality of life.

Combination of high-dose furosemide and hydrochlorothiazide in the treatment of refractory congestive heart failure.

OBJECTIVE: We studied the synergism between high-dose furosemide and hydrochlorothiazide in patients with severe congestive heart failure and impaired renal function showing diuretic resistance to a daily dose of furosemide of at least 250 mg. DESIGN AND SETTING: An open study. A general hospital in The Netherlands. METHODS: In 20 patients with severe congestive heart failure (stage III-IV according to the New York Heart Association) with an oedematous mass of more than 5 kg and a proven diuretic resistance to high-dose furosemide, hydrochlorothiazide (25-100 mg daily) was added to the medication for 3-12 days, leaving the other medication unchanged. After correction of the hydration state, hydrochlorothiazide was withdrawn. Variables included body weight, serum electrolytes, renal function and natriuresis. RESULTS: Addition of hydrochlorothiazide resulted in a mean (+/-standard deviation) body weight reduction of 6.7 +/- 3.3 kg per patient. Mean daily urine volume increased from 1899 +/- 958 ml to 3065 +/- 925 ml (P < 0.001). Fractional sodium excretion increased significantly from 3.5 +/- 3.2% to 11.5 +/- 9.0% (P < 0.001). The most important side effect of this combination therapy appeared to be hypokalaemia. Mean endogenous creatinine clearance decreased (not significantly) from 32.7 +/- 22.5 ml. min-1.1.73 m-2 to 27.6 +/- 22.5 ml. min-1.1.73 m-2. CONCLUSIONS: Addition of hydrochlorothiazide to high-dose furosemide is a powerful diuretic tool, even in patients with a significantly reduced renal function. Because of its potentially dangerous side effects (hypokalaemia), it should be used in a carefully controlled setting.

Single-spin density-gradient ultracentrifugation vs gradient gel electrophoresis: two methods for detecting low-density-lipoprotein heterogeneity compared.

Single-spin density-gradient ultracentrifugation (DUC) has proven to be a reproducible method for detection of low-density-lipoprotein (LDL) heterogeneity. Recently another method has been described for this: gradient gel electrophoresis (GGE) of serum, a method that might be more suitable for screening. To gain insight into the relationship of GGE to DUC and into their reproducibility, we determined LDL heterogeneity by DUC and GGE in 41 healthy individuals. In 90.2% (n = 37) of the subjects, the number of LDL subfractions found by both methods agreed. In addition, the density and the relative migration distance of the predominant LDL subfraction observed with the respective methods showed a strong correlation (Pearson correlation, r = 0.85, P less than 0.0001). Although it was not possible to compare for all aspects of LDL heterogeneity, these data suggest that GGE is a valid method of analysis for LDL heterogeneity. In screening programs, it may be necessary to store samples. Therefore, we studied in 24 sera the influence of storage at -80 degrees C for one, four, and 12 weeks on the LDL subfraction distribution detected by each method. LDL heterogeneity was maintained during storage under these conditions.

Continuous infusion of furosemide in the treatment of patients with congestive heart failure and diuretic resistance.

OBJECTIVES: To assess the value of treatment with continuous intravenous infusion of furosemide (F) in patients with refractory congestive heart failure. DESIGN: Open uncontrolled dose-response study. SUBJECTS: Patients with congestive heart failure (those with New York Heart Association (NYHA) classes III and IV with an assessed amount of oedema of more than 5 kg and diuretic resistance were included [n = 10]). Diuretic resistance was defined as: failure to lose weight and/or inappropriate urinary sodium excretion (50 mmol 24 h-1) despite bed rest for a period of 2-3 days, salt and water restriction, orally and intravenously administered furosemide in a dose of 250 mg day-1, digoxin, and when possible an ACE inhibitor. Included patients were treated with continuous F infusion at a delivery rate of 20 mg-1 over 24 h. The infusion rate was gradually heightened up to a maximum dose of 160 mg h-1. MAIN OUTCOME MEASURES: Daily physical examination, history of side-effects, determination of serum electrolytes and 24-h electrolyte excretion during treatment with furosemide. RESULTS: Weight loss (mean +/- SD; 12.5 +/- 5 kg) and relief of symptoms was achieved in all patients. Mean (+/- SD) 24-h sodium output rose from 19 +/- 16 mmol 24 h-1 (n = 10) on oral therapy with 250 mg F to 137 +/- 85 mmol 24 h-1 (n = 8) during 80 mg h-1 and to 268 +/- 124 mmol 24 h-1 (n = 3) on the maximal dose of 160 mg h-1. CONCLUSION: Continuous infusion of F under careful monitoring of the patient is a safe, controllable and efficient treatment in patients with severe congestive heart failure and diuretic resistance.

Direct vascular effects of furosemide in humans.

BACKGROUND: In humans, hemodynamic changes observed within minutes after systemic administration of furosemide are often referred to as direct vasoactivity. However, these immediate changes do not per se imply a direct vascular effect. We examined the genuine direct vascular effects of furosemide on the human forearm vascular bed and dorsal hand vein. METHODS AND RESULTS: Forearm blood flow in response to infusion of increasing dosages of furosemide into the brachial artery was recorded by venous occlusion plethysmography. Local plasma concentrations of furosemide reached a maximum of 234+/-40 microg/mL during the highest infused dose but did not significantly affect the ratio of flow in the infused/noninfused arms. Venous distensibility of a dorsal hand vein was measured with a linear variable differential transformer. During precontraction with norepinephrine, five increasing dosages of furosemide (1 to 100 microg/min) were administered locally. Additional experiments using local administration of indomethacin or N(G)-monomethyl-L-arginine (L-NMMA) were carried out to determine whether effects were dependent on local prostaglandin or nitric oxide synthesis, respectively. Also, the effects of systemic administration of furosemide were examined. Local administration of furosemide led to a dose-dependent venorelaxation of 18+/-6% at the first to 72+/-16% at the last dose. Indomethacin almost completely abolished furosemide-induced venorelaxation, whereas L-NMMA had no effect. Systemic administration of furosemide resulted in a time-dependent increase of hand vein distensibility, reaching 45+/-11% after 8 minutes. CONCLUSIONS: Furosemide does not exert any direct arterial vasoactivity in the human forearm, even at supratherapeutic concentrations. In contrast, at concentrations estimated to be in the therapeutic range, we observed a dose-dependent direct venodilator effect on the dorsal hand vein that appears to be mediated by local vascular prostaglandin synthesis.