Predicting Volume Responsiveness Among Sepsis Patients Using Clinical Data and Continuous Physiological Waveforms.

The efficacy of early fluid treatment in patients with sepsis is unclear and may contribute to serious adverse events due to fluid non-responsiveness. The current method of deciding if patients are responsive to fluid administration is often subjective and requires manual intervention. This study utilizes MIMIC III and associated matched waveform datasets across the entire ICU stay duration of each patient to develop prediction models for assessing fluid responsiveness in sepsis patients. We developed a pipeline to extract high frequency continuous waveform data and included waveform features in the prediction models. Comparing across five machine learning models, random forest performed the best when no waveform information is added (AUC = 0.84), with mean arterial blood pressure and age identified as key factors. After incorporation of features from physiologic waveforms, logistic regression with L1 penalty provided consistent performance and high interpretability, achieving an accuracy of 0.89 and F1 score of 0.90.

Optimizing and Interpreting Insular Functional Connectivity Maps Obtained During Acute Experimental Pain: The Effects of Global Signal and Task Paradigm Regression.

The insula is uniquely located between the temporal and parietal cortices, making it anatomically well-positioned to act as an integrating center between the sensory and affective domains for the processing of painful stimulation. This can be studied through resting-state functional connectivity (fcMRI) imaging; however, the lack of a clear methodology for the analysis of fcMRI complicates the interpretation of these data during acute pain. Detected connectivity changes may reflect actual alterations in low-frequency synchronous neuronal activity related to pain, may be due to changes in global cerebral blood flow or the superimposed task-induced neuronal activity. The primary goal of this study was to investigate the effects of global signal regression (GSR) and task paradigm regression (TPR) on the changes in functional connectivity of the left (contralateral) insula in healthy subjects at rest and during acute painful electric nerve stimulation of the right hand. The use of GSR reduced the size and statistical significance of connectivity clusters and created negative correlation coefficients for some connectivity clusters. TPR with cyclic stimulation gave task versus rest connectivity differences similar to those with a constant task, suggesting that analysis which includes TPR is more accurately reflective of low-frequency neuronal activity. Both GSR and TPR have been inconsistently applied to fcMRI analysis. Based on these results, investigators need to consider the impact GSR and TPR have on connectivity during task performance when attempting to synthesize the literature.

The Quality of Randomized Controlled Trials in Pediatric Orthopaedics: Are We Improving?

PURPOSE: The quality of randomized controlled trials (RCTs) in orthopaedics is a topic of considerable importance, as RCTs play a major role in guiding clinical practice. The quality of RCTs published between 1995 and 2005 has previously been documented. The purpose of the current study was to assess and describe the quality of pediatric orthopaedic RCTs published from 2005 to 2012, by identifying study characteristics associated with higher quality and outlining areas for improvement. METHODS: A standardized literature search was used to identify pediatric orthopaedic RCTs published in 7 well-recognized journals between September 2005 and July 2012 inclusive. The Detsky Quality Assessment Scale and the CONSORT checklist for Non-Pharmacologic Trials were used to assess the quality of the RCTs. Scores for the Detsky and CONSORT were calculated by 2 independent blinded orthopaedic surgeon reviewers with epidemiologic training. RESULTS: Forty RCTs were included in this analysis. The mean percentage score on the Detsky quality scale was 67%. Sixteen (40%) of the articles satisfied the threshold for a satisfactory level of methodological quality (Detsky >75%). Twenty-five (63%) of these studies were negative studies, concluding no difference between treatment arms. In 52% of the negative studies, an a priori sample size analysis was absent, and 28% were self-described as underpowered. In multiple variable regression analysis, only working with a statistician was significantly associated with higher Detsky percentage scores (P=0.01). CONCLUSIONS: There is a trend for improving quality in pediatric orthopaedic RCTs. Compared with past reports, the mean Detsky score improved from 53% to 67%, and the proportion meeting an acceptable level of quality improved from 19% to 40%. One of the most concerning findings of this study was the lack of attention to sample size and power analysis, and the potential for underpowered studies. Ongoing efforts are necessary to improve the conduct and reporting of clinical trials in pediatric orthopaedics. SIGNIFICANCE: Pediatric orthopaedic surgeons, JPO, and POSNA are working toward improving levels of quality in pediatric orthopaedic research. This paper highlights progress that has been made, and addresses some high-yield areas for future improvement.

Changes in right heart haemodynamics and echocardiographic function in an advanced phenotype of pulmonary hypertension and right heart dysfunction associated with pulmonary fibrosis.

BACKGROUND: Pulmonary hypertension (PH)-targeted therapy in the setting of pulmonary fibrosis (PF) is controversial; the main clinical concern is worsening of systemic hypoxaemia. We sought to determine the effects of gentle initiation and chronic administration of parenteral treprostinil on right heart function in patients with PF associated with an advanced PH phenotype. METHODS: Open-label, prospective analysis of patients with PF-PH referred for lung transplantation (LT). Advanced PH was defined as mean pulmonary artery pressure (mPAP) ≥35 mm Hg. We compared haemodynamics, Doppler echocardiography (DE), oxygenation, dyspnoea and quality of life indices, and 6 min walk distance (6MWD) before and 12 weeks after parenteral treprostinil. RESULTS: 15 patients were recruited in the study. After therapy, there were significant improvements in right heart haemodynamics (right atrial pressure (9.5 ± 3.4 vs 6.0 ± 3.7); mPAP (47 ± 8 vs 38.9 ± 13.4); CI (2.3 ± 0.5 vs 2.7 ± 0.6); pulmonary vascular resistance (698 ± 278 vs 496 ± 229); transpulmonary gradient (34.7 ± 8.7 vs 28.5 ± 10.3); mvO2 (65 ± 7.2 vs 70.9 ± 7.4); and stroke volume index (29.2 ± 6.7 vs 33 ± 7.3)) and DE parameters reflecting right heart function (right ventricular (RV) end diastolic area (36.4 ± 5.2 vs 30.9 ± 8.2 cm(2)), left ventricular eccentricity index (1.7 ± 0.6 vs 1.3 ± 0.5), tricuspid annular planar systolic excursion (1.6 ± 0.5 vs 1.9 ± 0.2 cm)). These changes occurred without significant alteration in systemic oxygenation, heart rate, or mean systemic arterial pressure. In addition, improvements were seen in 6MWD (171 ± 93 vs 230 ± 114), 36-Item Short Form Health Survey Mental Component Summary aggregate (38 ± 11 vs 44.2 ± 10.7), University of California, San Diego Shortness of Breath Questionnaire (87 ± 17.1 vs 73.1 ± 21), and brain natriuretic peptide (558 ± 859 vs 228 ± 340). CONCLUSIONS: PH-targeted therapy may improve right heart haemodynamics and echocardiographic function without affecting systemic oxygen saturation in an advanced PH phenotype associated with RV dysfunction in the setting of PF.

Inflammation-induced shift in spinal GABA(A) signaling is associated with a tyrosine kinase-dependent increase in GABA(A) current density in nociceptive afferents.

To account for benzodiazepine-induced spinal analgesia observed in association with an inflammation-induced shift in the influence of the GABA(A) receptor antagonist gabazine on nociceptive threshold, the present study was designed to determine whether persistent inflammation is associated with the upregulation of high-affinity GABA(A) receptors in primary afferents. The cell bodies of afferents innervating the glabrous skin of the rat hind paw were retrogradely labeled, acutely dissociated, and studied before and after the induction of persistent inflammation. A time-dependent increase in GABA(A) current density was observed that was more than twofold by 72 h after the initiation of inflammation. This increase in current density included both high- and low-affinity currents and was restricted to neurons in which GABA increased intracellular Ca(2+). No increases in GABA(A) receptor subunit mRNA or protein were detected in whole ganglia. In contrast, the increased current density was completely reversed by 20-min preincubation with the tyrosine kinase inhibitor genistein and partially reversed with the Src kinase inhibitor PP2. Genistein reversal was partially blocked by the dynamin inhibitor peptide P4. Changes in nociceptive threshold following spinal administration of genistein and muscimol to inflamed rats indicated that the pronociceptive actions of muscimol observed in the presence of inflammation were reversed by genistein. These results suggest that persistent changes in relative levels of tyrosine kinase activity following inflammation provide not only a sensitive way to dynamically regulate spinal nociceptive signaling but a viable target for the development of novel therapeutic interventions for the treatment of inflammatory pain.

Brief report: effect of ambrisentan treatment on exercise-induced pulmonary hypertension in systemic sclerosis: a prospective single-center, open-label pilot study.

OBJECTIVE: Exercise-induced pulmonary hypertension (ePH) may represent an early, clinically relevant phase in the spectrum of pulmonary vascular disease. The purpose of this pilot study was to describe the changes in hemodynamics and exercise capacity in patients with systemic sclerosis (SSc) spectrum-associated ePH treated with open-label daily ambrisentan. METHODS: Patients were treated with ambrisentan, 5 mg or 10 mg once daily, for 24 weeks. At baseline and 24 weeks, patients with SSc spectrum disorders exercised in a supine position, on a lower extremity cycle ergometer. All patients had normal hemodynamics at rest. We defined baseline ePH as a mean pulmonary artery pressure of >30 mm Hg with maximum exercise and a transpulmonary gradient (TPG) of >15 mm Hg. The primary end point was change in pulmonary vascular resistance (PVR) with exercise. Secondary end points included an improvement from baseline in 6-minute walking distance, health-related quality of life assessments, and cardiopulmonary hemodynamics. RESULTS: Of the 12 enrolled patients, 11 completed the study. At 24 weeks there were improvements in mean exercise PVR (85.8 dynes × second/cm(5) ; P = 0.003) and mean distance covered during 6-minute walk (44.5 meters; P = 0.0007). Improvements were also observed in mean exercise cardiac output (1.4 liters/minute; P = 0.006), mean pulmonary artery pressure (-4.1 mm Hg; P = 0.02), and total pulmonary resistance (-93.0 dynes × seconds/cm(5) ; P = 0.0008). Three patients developed resting pulmonary arterial hypertension during the 24 weeks. CONCLUSION: Exercise hemodynamics and exercise capacity in patients with SSc spectrum-associated ePH improved over 24 weeks with exposure to ambrisentan. Placebo-controlled studies are needed to confirm whether this is a drug-related effect and to determine optimal therapeutic regimens for patients with ePH.