A single-centre, placebo-controlled, double-blind randomised cross-over study of nebulised iloprost in patients with Eisenmenger syndrome: A pilot study.

BACKGROUND: Pulmonary arterial hypertension (PAH), is a rare and progressive disease with a high morbidity and mortality. Prostanoid pulmonary vasodilators are the most effective treatment for idiopathic and connective tissue associated PAH. Nonetheless, data examining their safety and efficacy in patients with Eisenmenger syndrome the most severe form of PAH, that is, related to cyanotic congenital heart disease (CHD-PAH) remains limited. AIM: To evaluate safety and the clinical efficacy of nebulised iloprost in patients with Eisenmenger syndrome who are on maximum background oral PAH therapy. METHODS: This pilot study was a randomised, double-blind, placebo-controlled, cross-over study. Patients were randomised to receive nebulised placebo or iloprost for 12 weeks and were then crossed over, with a 7-14-day washout. The primary endpoint was a change in 6-minute walk distance (6MWD). RESULTS: Sixteen patients (11 females, aged 47.3 ±â€¯9.8 year) were recruited, twelve completed the study. All were in WHO-FC III, with a resting oxygen saturation of 84 [81-87] % and a median 6MWD of 290 [260-300] m. There was no significant difference in the primary endpoint between nebulised iloprost (0[-4-9]m) and placebo (10 [-15-51]m), p = 0.58. There were no safety concerns with nebulised iloprost. CONCLUSIONS: Our pilot study provides preliminary evidence that the addition of nebulised iloprost to maximum oral PAH therapy did not improve the primary endpoint of 6MWD. Nebulised iloprost was well tolerated with no significant safety concerns in CHD-PAH.

Evaluating glycemic control algorithms by computer simulations.

BACKGROUND: Numerous guidelines and algorithms exist to achieve glycemic control. Their strengths and weaknesses are difficult to assess without head-to-head comparison in time-consuming clinical trials. We hypothesized that computer simulations may be useful. METHODS: Two open-label randomized clinical trials were replicated using computer simulations. One study compared performance of the enhanced model predictive control (eMPC) algorithm at two intensive care units in the United Kingdom and Belgium. The other study compared three glucose control algorithms-eMPC, Matias (the absolute glucose protocol), and Bath (the relative glucose change protocol)-in a single intensive care unit. Computer simulations utilized a virtual population of 56 critically ill subjects derived from routine data collected at four European surgical and medical intensive care units. RESULTS: In agreement with the first clinical study, computer simulations reproduced the main finding and discriminated between the two intensive care units in terms of the sampling interval (1.3 h vs. 1.8 h, United Kingdom vs. Belgium; P < 0.01). Other glucose control metrics were comparable between simulations and clinical results. The principal outcome of the second study was also reproduced. The eMPC demonstrated better performance compared with the Matias and Bath algorithms as assessed by the time when plasma glucose was in the target range between 4.4 and 6.1 mmol/L (65% vs. 43% vs. 42% [P < 0.001], eMPC vs. Matias vs. Bath) without increasing the risk of severe hypoglycemia. CONCLUSIONS: Computer simulations may provide resource-efficient means for preclinical evaluation of algorithms for glycemic control in the critically ill.

Intensive insulin therapy: enhanced Model Predictive Control algorithm versus standard care.

OBJECTIVE: To investigate the effectiveness of an enhanced software Model Predictive Control (eMPC) algorithm for intravenous insulin infusion, targeted at tight glucose control in critically ill patients, over 72 h, in two intensive care units with different management protocols. DESIGN: Comparison with standard care in a two center open randomized clinical trial. SETTING: Two adult intensive care units in University Hospitals. PATIENTS AND PARTICIPANTS: Thirty-four critically ill patients with hyperglycaemia (glucose >120 mg/dL) or already receiving insulin infusion. INTERVENTIONS: Patients were randomized, within each ICU, to intravenous insulin infusion advised by eMPC algorithm or the ICU's standard insulin infusion administration regimen. MEASUREMENTS AND RESULTS: Arterial glucose concentration was measured at study entry and when advised by eMPC or measured as part of standard care. Time-weighted average glucose concentrations in patients receiving eMPC advised insulin infusions were similar [104 mg/dL (5.8 mmol/L)] in both ICUs. eMPC advised glucose measurement interval was significantly different between ICUs (1.1 vs. 1.8 h, P < 0.01). The standard care insulin algorithms resulted in significantly different time-weighted average glucose concentrations between ICUs [128 vs. 99 mg/dL (7.1 vs. 5.5 mmol/L), P < 0.01]. CONCLUSIONS: In this feasibility study the eMPC algorithm provided similar, effective and safe tight glucose control over 72 h in critically ill patients in two different ICUs. Further development is required to reduce glucose sampling interval while maintaining a low risk of hypoglycaemia.