Search

Supplemental Digital Content is available in the text., OBJECTIVES: Lung- and diaphragm-protective ventilation is a novel concept that aims to limit the detrimental effects of mechanical ventilation on the diaphragm while remaining within limits of lung-protective ventilation. The premise is that low breathing effort under mechanical ventilation causes diaphragm atrophy, whereas excessive breathing effort induces diaphragm and lung injury. In a proof-of-concept study, we aimed to assess whether titration of inspiratory support based on diaphragm effort increases the time that patients have effort in a predefined “diaphragm-protective” range, without compromising lung-protective ventilation. DESIGN: Randomized clinical trial. SETTING: Mixed medical-surgical ICU in a tertiary academic hospital in the Netherlands. PATIENTS: Patients (n = 40) with respiratory failure ventilated in a partially-supported mode. INTERVENTIONS: In the intervention group, inspiratory support was titrated hourly to obtain transdiaphragmatic pressure swings in the predefined “diaphragm-protective” range (3–12 cm H2O). The control group received standard-of-care. MEASUREMENTS AND MAIN RESULTS: Transdiaphragmatic pressure, transpulmonary pressure, and tidal volume were monitored continuously for 24 hours in both groups. In the intervention group, more breaths were within “diaphragm-protective” range compared with the control group (median 81%; interquartile range [64–86%] vs 35% [16–60%], respectively; p < 0.001). Dynamic transpulmonary pressures (20.5 ± 7.1 vs 18.5 ± 7.0 cm H2O; p = 0.321) and tidal volumes (7.56 ± 1.47 vs 7.54 ± 1.22 mL/kg; p = 0.961) were not different in the intervention and control group, respectively. CONCLUSIONS: Titration of inspiratory support based on patient breathing effort greatly increased the time that patients had diaphragm effort in the predefined “diaphragm-protective” range without compromising tidal volumes and transpulmonary pressures. This study provides a strong rationale for further studies powered on patient-centered outcomes.

Background Lung ultrasound has established itself as an accurate diagnostic tool in different clinical settings. However, its effects on clinical-decision making are insufficiently described. This systematic review aims to investigate the impact of lung ultrasound, exclusively or as part of an integrated thoracic ultrasound examination, on clinical-decision making in different departments, especially the emergency department (ED), intensive care unit (ICU), and general ward (GW). Methods This systematic review was registered at PROSPERO (CRD42021242977). PubMed, EMBASE, and Web of Science were searched for original studies reporting changes in clinical-decision making (e.g. diagnosis, management, or therapy) after using lung ultrasound. Inclusion criteria were a recorded change of management (in percentage of cases) and with a clinical presentation to the ED, ICU, or GW. Studies were excluded if examinations were beyond the scope of thoracic ultrasound or to guide procedures. Mean changes with range (%) in clinical-decision making were reported. Methodological data on lung ultrasound were also collected. Study quality was scored using the Newcastle–Ottawa scale. Results A total of 13 studies were included: five studies on the ED (546 patients), five studies on the ICU (504 patients), two studies on the GW (1150 patients), and one study across all three wards (41 patients). Lung ultrasound changed the diagnosis in mean 33% (15–44%) and 44% (34–58%) of patients in the ED and ICU, respectively. Lung ultrasound changed the management in mean 48% (20–80%), 42% (30–68%) and 48% (48–48%) of patients in the ED, in the ICU and in the GW, respectively. Changes in management were non-invasive in 92% and 51% of patients in the ED and ICU, respectively. Lung ultrasound methodology was heterogeneous across studies. Risk of bias was moderate to high in all studies. Conclusions Lung ultrasound, exclusively or as a part of thoracic ultrasound, has substantial impact on clinical-decision making by changing diagnosis and management in the EDs, ICUs, and GWs. The current evidence level and methodological heterogeneity underline the necessity for well-designed trials and standardization of methodology.

Several investigators have reported that interferon-gamma (IFN gamma) can alter tumor necrosis factor alpha induced effects in vitro. We assessed in vivo effects of recombinant interferon-gamma (rIFN gamma) on recombinant tumor necrosis factor-alpha (rTNF alpha) induced activation of systemic blood coagulation in a non-randomized study in 20 consecutive cancer patients. Eight patients were treated with rIFN gamma prior to and during hyperthermic isolated limb perfusion with rTNF alpha and melphalan (IFN gamma group). They were compared with twelve patients who did not additionally receive rIFN gamma (non-IFN gamma group). Before start of perfusion, higher levels of TNF alpha, F-1+2 and TAT levels were found in the IFN gamma group. Fibrinogen and ATIII levels tended to,be lower in this group. High TNF alpha levels, due to leakage during perfusion, were associated with activation of coagulation in all patients, that became obvious after the end of perfusion, when heparin treatment had been antagonized. Activation, measured by increased F-1+2 and TAT levels, was significantly stronger in the IFN gamma group. Monocytic TF remained low, possibly due to shedding of TF positive vesicles and/or sequestration of TF positive activated monocytes against the vessel wall. In both groups F-1+2 and TAT levels declined 24 h after the perfusion, whereas monocytic TF increased to levels that were higher in the IFN gamma group. In conclusion, our data confirm a strong activation of coagulation induced by rTNF alpha in cancer patients. They suggest that rIFN gamma may lead to a slight activation of coagulation and augments TNF alpha induced procoagulant activity. These effects may be due to rIFN gamma induced sustained monocytic TF activity.

Dopamine is administered frequently in the operating theatre and intensive care unit patients undergoing mechanical ventilation with the aim of specifically enhancing renal uncontrolled, open study, sequentially different doses of dopamine (0, 2, 4, 8 and 0 mu g kg(-1) min(-1)) during a 1-h period each. Systemic haemodynamic and renal haemodynamic variables were measured simultaneously using a pulmonary artery catheter and radiopharmaceuticals, respectively. We studied seven haemodynamically stable patients (mean age 66 yr), with a serum creatinine concentration

Objectives: To analyze the mechanism of vasodilation and circulatory shock occurring in patients who are treated with isolated limb perfusion with melphalan and recombinant tumor necrosis factor (TNF)-alpha for locally advanced malignant tumors, To determine the role of nitric oxide, if any, by measuring plasma nitrite and nitrate concentrations. Design: Observational survey. Setting: A 12-bed surgical intensive care unit in a university referral hospital. Patients: Eight patients treated with hyperthermic isolated limb perfusion. Interventions: Ninety minutes of hyperthermic isolated limb perfusion with recombinant TNF-alpha (3 or 4 mg) and melphalan (10 to 13 mg/L limb volume). Measurements and Main Results: All patients developed sepsis syndrome due to leakage of recombinant TNF-alpha from the perfusion circuit to the systemic circulation, Despite the presence of very high systemic TNF-alpha concentrations during and immediately after perfusion, and despite definite signs of hyperdynamic circulatory shock (increased heart rate, increased cardiac index, decreased systemic vascular resistance), nitrite acid nitrate concentrations, as measured in plasma at several time points, were not increased. Conclusions: The hypothesis that in humans, TNF-alpha induces vasodilation and shock through activation of inducible nitric-oxide synthase and subsequent formation of excessive quantities of nitric oxide is not substantiated by our results, Normal nitric oxide metabolite concentrations were found in the presence of high TNF-alpha concentrations and shock, Other mechanisms that do not involve the nitric oxide pathway are likely to play a role in the generation of hypotension and septic shock in this setting.

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha (r-TNF-alpha) and melphalan, with or without pretreatment with recombinant IFN-gamma (r-IFN-gamma). Twenty patients were treated with r-TNF-alpha and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF-alpha and melphalan, eight received r-IFN-gamma for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF-alpha from the perfusion circuit to the systemic circulation was observed in all r-TNF-alpha-treated patients (mean maximum TNF-alpha, 87,227 ng/liter versus 31 ng/liter in controls; P

Objectives: To describe the postoperative course of patients who underwent hyperthermic isolated limb perfusion with recombinant tumor necrosis factor (TNF)-alpha and melphalan after pretreat ment with recombinant interferon-gamma as treatment for recurrent melanoma, primary nonresectable soft-tissue tumors, planocellular carcinoma, or metastatic carcinoma. To measure systemic TNF-alpha concentrations and relate these values with indices of disease severity. Setting: A 12-bed surgical intensive care unit (ICU) in a university referral hospital. Design: Prospective, descriptive study. Patients: Consecutive patients (n = 25) treated with hyperthermic isolated limb perfusion. Interventions: Blood samples were taken at regular intervals to determine TNF-alpha concentrations during and after hyperthermic isolated limb perfusion with recombinant TNF-alpha. Hemodynamic variables were obtained with a Swan-Ganz pulmonary artery catheter. Measurements and Main Results: All patients developed features of sepsis syndrome and required intensive care treatment. Most patients recovered quickly, with a median ICU stay of 2 days (range 1 to 25). Maximum systemic TNF-alpha concentrations ranged from 2284 to 83,000 ng/L (median 25,409) and returned to baseline values within 8 hrs. Despite these high concentrations of TNF-alpha, no patient died in the ICU, although the patient with the highest TNF-alpha concentration developed multiple organ failure and required continuous venovenous hemofiltration for 16 days. Linear regression analysis showed positive correlations between maximum TNF-alpha concentrations and systemic vascular resistance (p

There is increasing evidence that both neurohumoral and hemodynamic factors play a role in disease progression in chronic heart failure (CHF). To examine the influence of the oral dopamine agonist ibopamine on these factors, we studied 20 rats with chronic myocardial infarction and CHF, and compared them with 20 normal rats. After 6 weeks, rats were randomly divided between control treatment (50%) or ibopamine (50%) for 3 weeks. At the end of the study, plasma and tissue neurohumoral parameters, as well as hemodynamics, were determined. In infarcted rats, the elevated plasma norepinephrine (PNE) levels were reduced by ibopamine (251 +/- 19 vs. 138 +/- 32 pg/ml; p

Dopamine, a naturally occurring catecholamine, has been extensively used in intensive care for many years. Dopamine stimulates different types of adrenergic receptors: alpha-1 and -2, beta-1 and -2, and dopamine-1 and -2. The renal effects of dopamine are the result of dopamine-1 receptor (DA1) stimulation: renal vasodilation and natriuresis. DA2-receptor stimulation lowers plasma aldosterone and norepinephrine levels. Recently, several new dopamine agonists have been developed. Fenoldopam, a selective DA1-agonist, induces renal and systemic vasodilation with an increase in renal blood flow. This is accompanied by an increase in natriuresis and diuresis. Dopexamine, a DA1- and beta-2 agonist, is administered intravenously. It is used, like dopamine, in the treatment of congestive heart failure. However, the use of dopamine (and dopexamine) is limited by its unique intravenous availability. Ibopamine is an aselective dopamine agonist for oral use. Several clinical studies have demonstrated the efficacy of ibopamine in the treatment of patients with congestive heart failure and its mild renal effects.

Programmed electrical stimulation was performed in 12 patients with moderate to severe congestive heart failure and ventricular tachycardia (VT) to study possible arrhythmogenic properties of ibopamine, a new orally active dopamine agonist. Ibopamine induced no significant changes in spontaneous cycle length, PR, QRS, QTc, AH or HV intervals, and also right ventricular effective refractory periods were unaffected (for paced cycle lengths of 600 and 430 ms, respectively, using 1 extrastimulus: 287 +/- 16 ms at baseline vs 283 +/- 27 ms after ibopamine and 270 +/- 23 ms during the control study vs 262 +/- 19 ms after ibopamine). In 6 of the 8 patients with coronary artery disease but in none of the 4 patients with dilated cardiomyopathy, sustained VT was induced before and after ibopamine. Proarrhythmia was present in 1 patient, who became inducible after ibopamine. However, 1 patient had sustained VT only at baseline but not after ibopamine. The number of extrastimuli required for VT induction was equal (2.7 +/- 0.2 vs 2.7 +/- 0.2). Holter monitoring showed no changes in ventricular premature complexes, ventricular couplets and runs of VT after 1 week of ibopamine therapy. The signal-averaged electrocardiogram was abnormal in 11 and showed late potentials in 5 patients, but no changes occurred after ibopamine. During hemodynamic evaluation, increases in cardiac (32%) and stroke volume (34%) indexes were seen after administration of 100 mg of ibopamine, accompanied by a decrease in vascular resistance and filling pressures. Plasma norepinephrine decreased significantly after ibopamine (p = 0.02) but plasma epinephrine was unaffected. In conclusion, ibopamine has no significant proarrhythmic effects in patients with congestive heart failure and VT, presumably because of its favorable influence on hemodynamics and plasma norepinephrine levels.

To evaluate the effects of the oral aselective dopamine congener ibopamine, heart rate, blood pressure, cardiac rhythm, electrocardiographic (ECG) parameters and plasma catecholamines were studied in ten healthy subjects on three occasions: without medication, after 100 mg oral ibopamine and after combined treatment of ibopamine and the dopamine antagonist metoclopramide. Ibopamine was well tolerated by all subjects. No significant changes in heart rate or blood pressure were seen during either ibopamine alone or during concomitant metoclopramide administration. In addition, there were no differences in PR-, QRS- and QTc- intervals on the ECG and plasma norepinephrine, epinephrine and dopamine levels were unchanged. None of the ten volunteers showed proarrhythmia from ibopamine. However, in one subject, episodes of accelerated idioventricular rhythm were observed after ibopamine, which were asymptomatic and did not exceed a rate of 51 beats/minute. During concomitant metoclopramide infusion, ibopamine did not induce accelerated idioventricular rhythm. In conclusion, in healthy subjects ibopamine appears to be a safe drug and causes neither proarrhythmia, nor changes in heart rate, blood pressure, ECG-parameters, or plasma catecholamines.

1 Ibopamine is a new orally active inodilator, which is developed for the treatment of congestive heart failure (CHF). We treated 13 patients with moderate to severe CHF already on maximal conventional medication with ibopamine and studied its effects on haemodynamic parameters, exercise capacity, plasma norepinephrine (NE) and ventricular arrhythmias on ambulatory EGG monitoring. 2 Both cardiac and stroke volume index increased significantly after ibopamine (33% and 35% resp.). These changes were accompanied by a fall in systemic vascular resistance without changes in heart rate or blood pressure. During cardiopulmonary exercise testing, both maximal oxygen consumption and exercise time increased. Plasma NE levels were not significantly changed after ibopamine. Using the Morganroth criteria for proarrhythmia on ambulatory EGG monitoring, two patients showed proarrhythmia from ibopamine, which was not clinically relevant, but four patients had a decrease in ventricular arrhythmias. 3 This study suggests that ibopamine elicits favourable effects on haemodynamics and exercise tolerance in patients with CHF. During ibopamine treatment, there appears to be no increase in ventricular arrhythmias.

Hyperthermic isolated limb perfusion (HILP) with recombinant tumor necrosis factor-alpha (r-TNF alpha) and melphalan has been shown to result in a sepsis-like syndrome due to leakage of r-TNF alpha from the perfusion system to the systemic circulation. We have studied renal function parameters in 11 cancer patients, who underwent 12 perfusions. Three patients, perfused with melphalan only, served as controls, All patients treated with r-TNF alpha developed a sepsis syndrome and needed volume replacement ansi inotropes to remain normotensive; controls had an uneventful postoperative course, Creatinine clearance decreased transiently on the day of perfusion in both groups (mean preperfusion clearance 118 ml/min, mean post-perfusion clearance 68 ml/min, p