To cite this article: Fenger-Eriksen C, Jensen TM, Kristensen BS, Jensen KM, Tønnesen E, Ingerslev J, Sørensen B. Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebocontrolled clinical trial. J Thromb Haemost 2009; 7: 795-802.Summary. Background: Infusion of artificial colloids such as hydroxyethyl starch (HES) induces coagulopathy to a greater extent than simple dilution. Several studies have suggested that the coagulopathy could be corrected by substitution with a fibrinogen concentrate. Objectives: The aims of the present prospective, randomized, placebo-controlled trial were to investigate the hemostatic effect of a fibrinogen concentrate after coagulopathy induced by hydroxyethyl starch in patients experiencing sudden excessive bleeding during elective cystectomy. Methods: Twenty patients were included. Blood loss was substituted 1:1 with HES 130/0.4. At a dilution level of 30%, patients were randomly selected for intra-operative administration of a fibrinogen concentrate or placebo. The primary endpoint was maximum clot firmness (MCF), as assessed by thromboelastometry. Secondary endpoints were blood loss and transfusion requirements, other thromboelastometry parameters, thrombin generation and platelet function. Results: Wholeblood MCF was significantly reduced after 30% dilution in vivo with HES. The placebo resulted in a further decline of the MCF, whereas randomized administration of fibrinogen significantly increased the MCF. Furthermore, only 2 out of 10 patients randomly chosen to receive fibrinogen substitution required postoperative red blood cell transfusions, compared with 8 out of 10 in the placebo group (P = 0.023). Platelet function and thrombin generation were reduced after 30% hemodilution in vivo, and fibrinogen administration caused no significant changes. Conclusions: During cystectomy, fluid resuscitation with HES 130/0.4 during sudden excessive bleeding induces coagulopathy that shows reduced whole-blood maximum clot firmness. Randomized administration of fibrinogen concentrate significantly improved maximum clot firmness and reduced the requirement for postoperative transfusion.

Background The extent of cardiac dysfunction post‐COVID‐19 varies, and there is a lack of data on arrhythmic burden. Methods and Results This was a combined multicenter prospective cohort study and cross‐sectional case‐control study. Cardiac function assessed by echocardiography in patients with COVID‐19 3 to 4 months after hospital discharge was compared with matched controls. The 24‐hour ECGs were recorded in patients with COVID‐19. A total of 204 patients with COVID‐19 consented to participate (mean age, 58.5 years; 44% women), and 204 controls were included (mean age, 58.4 years; 44% women). Patients with COVID‐19 had worse right ventricle free wall longitudinal strain (adjusted estimated mean difference, 1.5 percentage points; 95% CI, −2.6 to −0.5; P =0.005) and lower tricuspid annular plane systolic excursion (−0.10 cm; 95% CI, −0.14 to −0.05; P <0.001) and cardiac index (−0.26 L/min per m 2 ; 95% CI, −0.40 to −0.12; P <0.001), but slightly better left ventricle global strain (−0.8 percentage points; 95% CI, 0.2–1.3; P =0.008) compared with controls. Reduced diastolic function was twice as common compared with controls (60 [30%] versus 29 [15%], respectively; odds ratio, 2.4; P =0.001). Having dyspnea or fatigue were not associated with cardiac function. Right ventricle free wall longitudinal strain was worse after intensive care treatment. Arrhythmias were found in 27% of the patients, mainly premature ventricular contractions and nonsustained ventricular tachycardia (18% and 5%, respectively). Conclusions At 3 months after hospital discharge with COVID‐19, right ventricular function was mildly impaired, and diastolic dysfunction was twice as common compared with controls. There was little evidence for an association between cardiac function and intensive care treatment, dyspnea, or fatigue. Ventricular arrhythmias were common, but the clinical importance is unknown. Registration URL: http://clinicaltrials.gov . Unique Identifier: NCT04535154.

Fibrinogen in plasma includes three main fractions; high-molecular-weight (HMW)-fibrinogen, low-molecular-weight (LMW)-fibrinogen, and very-low-molecular-weight (LMW')-fibrinogen. During acute-phase conditions, plasma fibrinogen levels and the HMW-/LMW-fibrinogen ratio increase rapidly due to increased synthesis of HMW-fibrinogen. The consequences of elevated plasma fibrinogen levels and local deposition of fibrin in inflammatory tissues observed during acute-phase conditions are not clear. We wanted to investigate proinflammatory effects of fibrinogen and fibrin on peripheral blood mononuclear cells (PBMC) as reflected by altered mRNA expression and synthesis of the proinflammatory cytokines IL-6, TNF-alpha and IL-1 beta, and to explore the significance of altered HMW-/LMW-fibrinogen ratio. PBMC were isolated from whole blood using Lymphoprep. HMW-fibrinogen was separated from unfractioned fibrinogen by ammonium sulphate precipitation. Cells were incubated with unfractioned fibrinogen, HMW-fibrinogen or fibrin. Cytokine levels in cell lysates were determined using ELISA assays. Real-time PCR was used for mRNA quantification. We found that fibrinogen significantly increased mRNA levels, and induced synthesis of the proinflammatory cytokines IL-6 and TNF-alpha in PBMC in a dose dependent manner. Median (25, 75 percentile) IL-6 and TNF-alpha concentrations were 12 (5, 40) pg/ml and 16 (0,61) pg/ml, respectively. Median mRNA quantity was increased 12.3- (6.6, 48.6) and 1.7- (1.5, 6.5) fold for IL-6 and TNF-alpha compared to controls. The stimulatory effect of unfractioned fibrinogen was not significantly different from HMW-fibrinogen. Fibrinogen and fibrin were equally effective in promoting cytokine synthesis from PBMC. The results support that fibrin and fibrinogen may actively modulate the inflammatory process by inducing synthesis of proinflammatory cytokines from PBMC.

BackgroundTo determine whether the use of an electronic, sensor based stethoscope affects the cardiac auscultation skills of undergraduate medical students.MethodsForty eight third year medical students were randomized to use either an electronic stethoscope, or a conventional acoustic stethoscope during clinical auscultation training. After a training period of four months, cardiac auscultation skills were evaluated using four patients with different cardiac murmurs. Two experienced cardiologists determined correct answers. The students completed a questionnaire for each patient. The thirteen questions were weighted according to their relative importance, and a correct answer was credited from one to six points.ResultsNo difference in mean score was found between the two groups (p = 0.65). Grading and characterisation of murmurs and, if present, report of non existing murmurs were also rated. None of these yielded any significant differences between the groups.ConclusionWhether an electronic or a conventional stethoscope was used during training and testing did not affect the students' performance on a cardiac auscultation test.

BackgroundThe present study compares the value of additional use of computer simulated heart sounds, to conventional bedside auscultation training, on the cardiac auscultation skills of 3rd year medical students at Oslo University Medical School.MethodsIn addition to their usual curriculum courses, groups of seven students each were randomized to receive four hours of additional auscultation training either employing a computer simulator system or adding on more conventional bedside training. Cardiac auscultation skills were afterwards tested using live patients. Each student gave a written description of the auscultation findings in four selected patients, and was rewarded from 0-10 points for each patient. Differences between the two study groups were evaluated using student's t-test.ResultsAt the auscultation test no significant difference in mean score was found between the students who had used additional computer based sound simulation compared to additional bedside training.ConclusionsStudents at an early stage of their cardiology training demonstrated equal performance of cardiac auscultation whether they had received an additional short auscultation course based on computer simulated training, or had had additional bedside training.