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Afshari A.,Rigshospitalet
Cochrane database of systematic reviews (Online) | Year: 2010

BACKGROUND: Acute hypoxaemic respiratory failure (AHRF), defined as acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), are critical conditions. AHRF results from a number of systemic conditions and is associated with high mortality and morbidity in all ages. Inhaled nitric oxide (INO) has been used to improve oxygenation but its role remains controversial. OBJECTIVES: To systematically assess the benefits and harms of INO in critically ill patients with AHRF. SEARCH STRATEGY: Randomized clinical trials (RCTs) were identified from electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 1); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to 31st January 2010). We contacted trial authors, authors of previous reviews, and manufacturers in the field. SELECTION CRITERIA: We included all RCTs, irrespective of blinding or language, that compared INO with no intervention or placebo in children or adults with AHRF. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as relative risks (RR) with 95% confidence intervals (CI). Our primary outcome measure was all cause mortality. We performed subgroup and sensitivity analyses to assess the effect of INO in adults and children and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis. MAIN RESULTS: We included 14 RCTs with a total of 1303 participants; 10 of these trials had a high risk of bias. INO showed no statistically significant effect on overall mortality (40.2% versus 38.6%) (RR 1.06, 95% CI 0.93 to 1.22; I(2) = 0) and in several subgroup and sensitivity analyses, indicating robust results. Limited data demonstrated a statistically insignificant effect of INO on duration of ventilation, ventilator-free days, and length of stay in the intensive care unit and hospital. We found a statistically significant but transient improvement in oxygenation in the first 24 hours, expressed as the ratio of partial pressure of oxygen to fraction of inspired oxygen and the oxygenation index (MD 15.91, 95% CI 8.25 to 23.56; I(2) = 25%). However, INO appears to increase the risk of renal impairment among adults (RR 1.59, 95% CI 1.17 to 2.16; I(2) = 0) but not the risk of bleeding or methaemoglobin or nitrogen dioxide formation. AUTHORS' CONCLUSIONS: INO cannot be recommended for patients with AHRF. INO results in a transient improvement in oxygenation but does not reduce mortality and may be harmful.


Afshari A.,Rigshospitalet
Cochrane database of systematic reviews (Online) | Year: 2011

Severe bleeding and coagulopathy as a result of massive transfusion are serious clinical conditions that are associated with high mortality. Thromboelastography (TEG) and thromboelastometry (ROTEM) are increasingly used to guide transfusion strategy but their roles remain disputed. To systematically assess the benefits and harms of a TEG or ROTEM guided transfusion strategy in randomized trials involving patients with severe bleeding. Randomized clinical trials (RCTs) were identified from electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 9); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (up to 31st October 2010). We contacted trial authors, authors of previous reviews, and manufacturers in the field. We included all RCTs, irrespective of blinding or language, that compared transfusion guided by TEG or ROTEM to transfusion guided by clinical judgement and standard laboratory tests, or both. Two authors independently abstracted data; they resolved any disagreements by discussion. We presented pooled estimates of the intervention effects on dichotomous outcomes as relative risks (RR) and on continuous outcomes as mean differences, with 95% confidence intervals (CI). Our primary outcome measure was all cause mortality. We performed subgroup and sensitivity analyses to assess the effect of TEG or ROTEM in adults and children on various clinical and physiological outcomes. We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis. We included nine RCTs with a total of 776 participants; only one trial had a low risk of bias. We found two ongoing trials but were unable to retrieve any data from them. Compared with standard treatment, TEG or ROTEM showed no statistically significant effect on overall mortality (3.78% versus 5.11%, RR 0.77, 95% CI 0.35 to 1.72; I(2) = 0%) but only five trials provided data on mortality. Our analyses demonstrated a statistically significant effect of TEG or ROTEM on the amount of bleeding (MD -85.05 ml, 95% CI -140.68 to -29.42; I(2) = 26%) but failed to show any statistically significant effect on other predefined outcomes. There is an absence of evidence that TEG or ROTEM improves morbidity or mortality in patients with severe bleeding. Application of a TEG or ROTEM guided transfusion strategy seems to reduce the amount of bleeding but whether this has implications for the clinical condition of patients is still uncertain. More research is needed.


RESULTS: A decrease in tumour permeability after one series of chemotherapy was positively correlated with clinical response after three series of chemotherapy. Significant changes in permeability and tumour volume were apparent after three series of chemotherapy in both clinical and histological responders. A cut-off value of more than 25% reduction in tumour permeability yielded a sensitivity of 69% and a specificity of 58% for predicting clinical response.CONCLUSION: Early decrease in permeability is correlated with the likelihood of clinical response to pre-operative chemotherapy in GEJ and gastric cancer. As a single diagnostic test, CT Perfusion only has moderate sensitivity and specificity in response assessment of pre-operative chemotherapy making it insufficient for clinical decision purposes.OBJECTIVES: To evaluate whether early reductions in CT perfusion parameters predict response to pre-operative chemotherapy prior to surgery for gastroesophageal junction (GEJ) and gastric cancer.MATERIALS AND METHODS: Twenty-eight patients with adenocarcinoma of the gastro-esophageal junction (GEJ) and stomach were included. Patients received three series of chemotherapy before surgery, each consisting of a 3-week cycle of intravenous epirubicin, cisplatin or oxaliplatin, concomitant with capecitabine peroral. The patients were evaluated with a CT perfusion scan prior to, after the first series of, and after three series of chemotherapy. The CT perfusion scans were performed using a 320-detector row scanner. Tumour volume and perfusion parameters (arterial flow, blood volume and permeability) were computed on a dedicated workstation with a consensus between two radiologists. Response to chemotherapy was evaluated by two measures. Clinical response was defined as a tumour size reduction of more than 50%. Histological response was evaluated based on residual tumour cells in the surgical specimen using the standardized Mandard Score 1 to 5, in which values of 1 and 2 were classified as responders, and 3 to 5 were classified as nonresponders.


Every year in Europe about 25,000 infants are born extremely preterm. These infants have a 20% mortality rate, and 25% of survivors have severe long-term cerebral impairment. Preventative measures are key to reduce mortality and morbidity in an extremely preterm population. The primary objective of the SafeBoosC phase II trial is to examine if it is possible to stabilize the cerebral oxygenation of extremely preterm infants during the first 72 hours of life through the application of cerebral near-infrared spectroscopy (NIRS) oximetry and implementation of an clinical treatment guideline based on intervention thresholds of cerebral regional tissue saturation rStO2. SafeBoosC is a randomized, blinded, multinational, phase II clinical trial. The inclusion criteria are: neonates born more than 12 weeks preterm; decision to conduct full life support; parental informed consent; and possibility to place the cerebral NIRS oximeter within 3 hours after birth. The infants will be randomized into one of two groups. Both groups will have a cerebral oximeter monitoring device placed within three hours of birth. In the experimental group, the cerebral oxygenation reading will supplement the standard treatment using a predefined treatment guideline. In the control group, the cerebral oxygenation reading will not be visible and the infant will be treated according to the local standards. The primary outcome is the multiplication of the duration and magnitude of rStO2 values outside the target ranges of 55% to 85%, that is, the 'burden of hypoxia and hyperoxia' expressed in '%hours'. To detect a 50% difference between the experimental and control group in %hours, 166 infants in total must be randomized. Secondary outcomes are mortality at term date, cerebral ultrasound score, and interburst intervals on an amplitude-integrated electroencephalogram at 64 hours of life and explorative outcomes include neurodevelopmental outcome at 2 years corrected age, magnetic resonance imaging at term, blood biomarkers at 6 and 64 hours after birth, and adverse events. Cerebral oximetry guided interventions have the potential to improve neurodevelopmental outcome in extremely preterm infants. It is a logical first step to test if it is possible to reduce the burden of hypoxia and hyperoxia. ClinicalTrial.gov, NCT01590316.


Jeppesen P.B.,Rigshospitalet
Current Opinion in Endocrinology, Diabetes and Obesity | Year: 2015

Purpose of Review: The approval of teduglutide, a recombinant analog of human glucagon-like peptide (GLP) 2, by the US Food and Drug Administration (Gattex) and the European Medicines Agency (Revestive) has illustrated the potential of selected gut hormones as treatments in patients with short-bowel syndrome and intestinal failure. Gut hormones may improve the structural and functional intestinal adaptation following intestinal resection by decreasing a rapid gastric emptying and hypersecretion, by increasing the intestinal blood flow, and by promoting intestinal growth. This review summarizes the findings from phase 2 and 3 teduglutide studies, and pilot studies employing GLP-1 and agonists for this orphan condition. Recent Findings: In a 3-week, phase 2, metabolic balance study, teduglutide increased the intestinal wet weight absorption by approximately 700 g/day and reduced fecal energy losses by approximately 0.8 MJ/day (∼200 Kcal/day). In two subsequent 24-week, phase 3 studies, teduglutide reduced the need for parenteral support in the same magnitude. Adverse events were mainly of gastrointestinal origin and consistent with the known mechanism of action of teduglutide. Pilot studies suggest that GLP-1 may be less potent. Synergistic effects may be seen by co-treatment with GLP-2. Summary: Gut hormones promote intestinal adaptation and absorption, decreasing fecal losses, thereby decreasing or even eliminating the need for parenteral support. This will aid the intestinal rehabilitation in these severely disabled short-bowel syndrome patients. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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