Wireless non-invasive continuous respiratory monitoring with FMCW radar: a clinical validation study.

Altered respiratory rate is one of the first symptoms of medical conditions that require timely intervention, e.g., sepsis or opioid-induced respiratory depression. To facilitate continuous respiratory rate monitoring on general hospital wards a contactless, non-invasive, prototype monitor was developed using frequency modulated continuous wave radar. We aimed to study whether radar can reliably measure respiratory rate in postoperative patients. In a diagnostic cross-sectional study patients were monitored with the radar and the reference monitor (pneumotachograph during mechanical ventilation and capnography during spontaneous breathing). Eight patients were included; yielding 796 min of observation time during mechanical ventilation and 521 min during spontaneous breathing. After elimination of movement artifacts the bias and 95 % limits of agreement for mechanical ventilation and spontaneous breathing were -0.12 (-1.76 to 1.51) and -0.59 (-5.82 to 4.63) breaths per minute respectively. The radar was able to accurately measure respiratory rate in mechanically ventilated patients, but the accuracy decreased during spontaneous breathing.

Haemodynamics in a patient with Fontan physiology undergoing laparoscopic cholecystectomy.

Laparoscopic surgery in patients with Fontan circulation is a haemodynamic challenge; venous return may be compromised by insufflation of carbon dioxide into the abdomen (increasing intra-abdominal pressure), the use of reverse Trendelenburg position and positive pressure ventilation. Combined with an increase in pulmonary vascular resistance due to hypercarbia, cardiac output may be reduced. However, for non-haemodynamic reasons, laparoscopic surgery has advantages over open surgery: less postoperative pain, shorter hospital stay, a reduction in postoperative wound infections and a reduction of respiratory complications. In this case report, we present a patient with Fontan circulation who underwent uneventful laparoscopic cholecystectomy.

Venous thromboembolism in overt hyperthyroidism - a direct association with clinical implications?

Hyperthyroidism is associated with procoagulant changes in the haemostatic system. At present, it is uncertain whether this leads to an increased risk of venous and/or arterial thrombosis. Only a few small studies have investigated this association but due to methodological limitations it is not possible to draw any definitive conclusions at this stage. Here we report two patients with severe venous thromboembolism (VTE) and concomitant hyperthyroidism without any risk factors for VTE. Hereby, we emphasise a possible association as supported by a number of previous studies. In a planned prospective multicentre cohort study we will examine the association between hyperthyroidism and VTE and determine its clinical relevance.

High levels of procoagulant factors mediate the association between free thyroxine and the risk of venous thrombosis: the MEGA study.

BACKGROUND: Thyroid hormone affects the coagulation system, but its effect on clinical disease is not clear. We determined the associations of levels of free thyroxine (FT4), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase antibodies (antiTPO) with levels of coagulation factors and the risk of venous thrombosis. METHODS: In a large population based case-control study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study) on the etiology of venous thrombosis, we determined the levels of FT4, TSH, antiTPO, factor FII, FVII, FVIII, FIX, FX, von Willebrand factor (VWF), antithrombin, protein C, protein S and fibrinogen in 2177 cases and 2826 controls. RESULTS: High levels of FT4 were associated with increased concentrations of procoagulant factors, and not with levels of anticoagulant factors. High levels of FT4 were also associated with the risk of venous thrombosis, up to an odds ratio (OR) of 2.2 (95% confidence interval [CI] 1.0-4.6) for levels above 24.4 pm relative to FT4 levels between 15.5 and 18.9 pm. In 11 cases and one control, clinical hyperthyroidism had been diagnosed within a year of the thrombotic event, leading to an OR of 17.0 (95% CI 2.2-133.0) for thrombosis. The ORs approached unity after adjustment for FVIII and VWF, which suggests that the effect was mediated by these factors. Low TSH levels were also, but less evidently, associated with thrombosis, whereas there was no association between antiTPO and venous thrombosis risk. CONCLUSIONS: High levels of FT4 increase the concentrations of the procoagulant proteins FVIII, FIX, fibrinogen, and VWF, and by this mechanism increase the risk of venous thrombosis.

The effect of levothyroxine on expression of inflammation-related genes in healthy subjects: a controlled randomized crossover study.

An excess of thyroid hormone leads to a prothrombotic state; however, the underlying pathophysiological mechanisms remain unknown. As evidence points towards an extensive "cross-talk" between the inflammatory and coagulation cascade, inflammation has been claimed as a possible mechanism through which different risk factors trigger venous thrombus formation. We aimed to study changes in expression of inflammation-related genes of the leukocyte RNA expression profile in healthy subjects in response to supraphysiological doses of levothyroxine. In a randomized single-blinded crossover design, 12 healthy volunteers (aged 18-40 years) received levothyroxine and no medication, both for 14 days with a wash-out period of at least 28 days between the periods. Blood was sampled at baseline and day 14 of each study period. MRNA was isolated from whole blood and used for multiplex ligation-dependent probe amplification to study the expression of inflammation-related genes. Compared to the control situation no significant changes were found in the expression of proinflammatory cytokines and mediators after the intake of levothyroxine. The results of this study show that high thyroid hormone levels do not lead to an altered inflammatory profile. This provides evidence against a major role of the inflammatory system as mediator in the effect of thyroid hormone on the coagulation system. The mechanisms by which thyroid hormone may influence coagulation proteins remain to be elucidated.

Acquired von Willebrand syndrome in patients with overt hypothyroidism: a prospective cohort study.

Numerous case reports have been published on acquired von Willebrand syndrome (aVWS) in patients with hypothyroidism, but no prospective studies have been published. The aim of this study was to investigate laboratory and clinical characteristics of aVWS in patients with newly diagnosed overt hypothyroidism. An observational cohort study was performed between May 2007 and February 2012. Consecutive hypothyroid patients before or within the first 48 h of replacement therapy were enrolled. At inclusion, blood was sampled for coagulation tests and bleeding history was documented by means of a standardized bleeding questionnaire. Repeat samples were obtained after restoration of euthyroidism. The prevalence of aVWS, defined as von Willebrand factor antigen (VWF:Ag) ≤50% and/or VWF ristocetin activity (VWF:RCo) ≤50%, was calculated. Patients with aVWS were subsequently divided into severe (VWF:Ag and/or VWF:RCo ≤10%), moderate (VWF:Ag and/or VWF:RCo between 10 and 30%) or mild (VWF:Ag and/or VWF:RCo between 30 and 50%). A total of 90 patients were included among whom a prevalence of aVWS of 33% was found. There were no patients with severe aVWS. Eight patients (9%) had moderate aVWS and 21 (23%) had mild aVWS. Bleeding score was negatively correlated with both VWF:Ag (ß -0.32, P = 0.03) and VWF:RCo (ß -0.32, P = 0.02). After restoration of euthyroidism, VWF:Ag had significantly increased by 44%, VWF:RCo by 36%, factor VIII by 39%, and endogenous thrombin potential by 10%. aVWS has a high prevalence in hypothyroid patients. Highest bleeding scores in patients with lower VWF levels suggest clinical relevance.

Thyroid dysfunction and fibrin network structure: a mechanism for increased thrombotic risk in hyperthyroid individuals.

CONTEXT: Hyperthyroidism is associated with increased thrombosis risk, and fibrin clot structure determines susceptibility to vascular thrombotic events. OBJECTIVE: Our objective was to investigate clot formation and lysis in hyperthyroidism using observational and interventional studies. DESIGN: Ex vivo fibrin clot structure/fibrinolysis and plasma levels of thrombotic/inflammatory markers were investigated in hyperthyroid individuals (n = 24) and matched controls (n = 19), using turbidimetric assays, ELISA, and confocal and electron microscopy. The effects of normalizing thyroid function were analyzed (n = 19) and the role of short-term exogenous hyperthyroidism in healthy volunteers studied (n = 16). RESULTS: Hyperthyroid subjects displayed higher clot maximum absorbance compared with controls (0.41 ± 0.03 and 0.27 ± 0.01 arbitrary units, respectively; P < 0.01), and longer clot lysis time (518 ± 23 and 461 ± 18 sec, respectively; P < 0.05), which correlated with free T(4) levels. Plasma levels of fibrinogen and plasminogen activator inhibitor-1 were significantly higher in patients compared with controls. Normalizing thyroid function in 19 subjects was associated with lower maximum absorbance and shorter lysis time, accompanied by reduction in fibrinogen, plasminogen activator inhibitor-1, and D-dimer levels. Complement C3, but not C-reactive protein, levels were higher in hyperthyroid subjects compared with controls (0.92 ± 0.05 and 0.64 ± 0.03 g/liter, respectively; P < 0.01), correlated with clot structure parameters, and decreased after intervention. Confocal and electron microscopy confirmed more compact clots and impaired fibrinolysis during hyperthyroidism. Exogenous hyperthyroidism in healthy volunteers had no effect on any of the clot structure parameters. CONCLUSIONS: Endogenous hyperthyroidism is associated with more compact clots and resistance to fibrinolysis ex vivo, related to the degree of hyperthyroidism and C3 plasma levels, and these changes are modulated by achieving euthyroidism. Altered clot structure/lysis may be one mechanism for increased thrombotic risk in hyperthyroidism.

Incidence of venous thromboembolism in patients with Cushing's syndrome: a multicenter cohort study.

CONTEXT: Venous thrombosis has frequently been reported in patients with endogenous Cushing's syndrome (CS). OBJECTIVE: The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. DESIGN AND SETTING: We conducted a multicenter cohort study at all university medical centers in The Netherlands. PATIENTS: Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. MAIN OUTCOME MEASURES: We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. RESULTS: A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). CONCLUSIONS: Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.

Alterations in coagulation and fibrinolysis after levothyroxine exposure in healthy volunteers: a controlled randomized crossover study.

BACKGROUND: Several hemostatic abnormalities have been reported in hyperthyroidism, but the overall effect of thyroid hormone excess on coagulation and fibrinolysis is unclear. OBJECTIVE: Our aim was to assess whether the use of supraphysiological doses of levothyroxine leads to coagulation activation and inhibition of fibrinolysis. PATIENTS AND METHODS: Healthy volunteers were randomized to receive levothyroxine or no medication for 14 days with a washout period of at least 28 days in a crossover design. To study the effects of different degrees of thyroid hormone excess, 16 participants received levothyroxine in a dose of 0.3 mg per day, and 12 received levothyroxine 0.45 or 0.6 mg per day depending on body weight. Several variables of coagulation and fibrinolysis were measured. RESULTS: Levels of von Willebrand factor activity (VWF:RiCo) and antigen (VWF:Ag), factor (F) VIII, plasminogen activator inhibitor-1 (PAI-1) and clot-lysis time were slightly higher after levothyroxine 0.3 mg per day than after the control situation, but only levels of VWF showed a significant increase from baseline. After levothyroxine 0.45 or 0.6 mg per day, levels of fibrinogen increased by 17%, VWF activity by 24%, VWF antigen by 26%, FVIII by 19%, FIX by 14%, FX by 7%, PAI-1 by 116% and clot-lysis time by 14%, and activated partial thromboplastin time decreased by 3%; all were significant changes compared with the control situation. We did not observe clear evidence of coagulation activation. CONCLUSIONS: Our data suggest that thyroid hormone excess increases coagulation factor levels and inhibits fibrinolysis in a dose-dependent fashion. This implies an increased risk of venous thrombosis during hyperthyroidism.

Prolactin is involved in the systemic inflammatory response in myocardial infarction.

Prolactin may contribute to an atherogenic phenotype. Furthermore, previous studies have shown that prolactin levels increase in situations of acute stress and inflammation. We therefore aimed to investigate the relationship between prolactin, acute stress and inflammation in patients with myocardial infarction. We performed a case-control study in 40 patients with myocardial infarction and 39 controls, aged 41-84 years. Blood for assessment of prolactin and high sensitive C-reactive protein (hsCRP) was drawn at inclusion, that is, during the acute phase of the event, and 2-3 weeks later. Unexpectedly, prolactin levels at inclusion did not differ between cases and controls (7.0 ng/ml and 6.0 ng/ml, respectively, p=0.28). 2-3 weeks later prolactin levels in cases had not decreased. However, univariate regression analysis indicated that hsCRP is associated with prolactin levels (regression coefficient ß 0.11; [95% CI 0.01; 0.21]; p=0.03) in cases during the acute phase of myocardial infarction. Our findings may suggest that prolactin is involved in the systemic inflammatory response, which takes place during myocardial infarction; however, this association may not be strong enough to induce higher prolactin levels in patients with myocardial infarction.

Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors.

BACKGROUND: Whether glucocorticoid use contributes to a hypercoagulable state, and thereby enhances the thrombotic risk, is controversial. OBJECTIVE: We aimed to examine the effects of glucocorticoid use on coagulation and fibrinolysis. METHODS: MEDLINE and EMBASE databases were searched to identify published studies comparing glucocorticoid treatment with a glucocorticoid-free control situation. Subjects could be either patients or healthy volunteers. Two investigators independently performed study selection and data extraction. Results were expressed as standardized mean difference, if possible; data were pooled with a random-effects model. RESULTS: Of the 1967 identified publications, 36 papers were included. In healthy volunteers, a clear rise in factor (F)VII, VIII and XI activity was observed after glucocorticoid treatment, but these data alone provided insufficient evidence to support hypercoagulability. However, during active inflammation, glucocorticoids significantly increased levels of plasminogen activator inhibitor-1 (PAI-1), whereas levels of von Willebrand factor (VWF) and fibrinogen decreased. Peri-operative use of glucocorticoids inhibited the increase in tissue-type plasminogen activator induced by surgery. CONCLUSIONS: The present study showed differential effects of glucocorticoids depending on the clinical situation in which it is given, most likely as a result of their disease modifying properties. Clinical outcome studies are needed to adequately assess the risk-benefit of glucocorticoid use per population when thrombotic complication is the focus.

Diagnostic accuracy of modified transoesophageal echocardiography for pre-incision assessment of aortic atherosclerosis in cardiac surgery patients.

BACKGROUND: Epiaortic ultrasound scanning (EUS) is regarded as the reference standard for detecting atherosclerosis in the ascending aorta (AA). Combined with appropriate surgical modifications, EUS use can significantly reduce the incidence of postoperative stroke when detecting severe AA atherosclerosis. A recently introduced modification of conventional transoesophageal echocardiography (TOE), known as the A-View method, has proven capable of inspecting the distal AA. The objective of this study was to quantify the diagnostic accuracy of modified TOE in assessing atherosclerosis of the distal AA. METHODS: After approval by the institutional medical ethical committee and after obtaining written informed consent, 465 consecutive patients above 65 yr old, undergoing elective cardiac surgery with a median sternotomy, were included. The study followed a cross-sectional diagnostic design. All consecutive patients underwent modified TOE followed by EUS (reference standard) to assess the severity of distal AA atherosclerosis. We constructed contingency tables to compare the presence (and severity) of atherosclerosis, detected by the two techniques. RESULTS: The positive predictive value of modified TOE for the detection of clinically significant atherosclerosis was 67%, and the negative predictive value was 97%. The sensitivity was 95% and the specificity was 79%. One patient suffered a pulmonary haemorrhage, although he recovered without further sequelae. We did not observe any clinical significant haemodynamic or ventilatory effects. CONCLUSIONS: The high negative predictive value and sensitivity show that modified TOE yields adequate diagnostic accuracy for excluding clinically relevant aorta atherosclerosis without significant cardiopulmonary side-effects, provided that the A-View catheter is introduced carefully.

Meta-analysis of the diagnostic accuracy of transesophageal echocardiography for assessment of atherosclerosis in the ascending aorta in patients undergoing cardiac surgery.

BACKGROUND: Stroke after cardiac surgery may be caused by emboli emerging from an atherosclerotic ascending aorta (AA). Epiaortic ultrasound scanning (EUS), the current 'gold' standard for detecting AA atherosclerosis, has not gained widespread use because there is a lack of optimized ultrasound devices, it lengthens the procedure, it endangers sterility, and there is a false belief by many surgeons that palpation is as sensitive as EUS. Furthermore there is no clear evidence proving that the use of epiaortic scanning changes outcome in cardiac surgery. Various researchers investigated the ability of transesophageal echocardiography (TEE) to discriminate between the presence and absence of AA atherosclerosis. It is acknowledged that TEE has limited value in this, but it has never been supported by a meta-analysis estimating the true diagnostic accuracy of TEE based on all quantitative evidence. We aimed to do this using state-of-the-art methodology of diagnostic meta-analyses. METHODS: We searched multiple databases for studies comparing TEE vs. EUS for detection of atherosclerosis. A random-effects bivariate meta-regression model was used to obtain summary estimates of sensitivity and specificity, incorporating the correlation between sensitivity and specificity as well as covariates to explore heterogeneity across studies. RESULTS: We extracted six studies with a total of 346 patients, of whom 419 aortic segments were analyzed, including 100 segments with atherosclerosis [median prevalence 25% (range 17-62%)]. Summary estimates of sensitivity and specificity were 21% (95% CI 13-32%) and 99% (96-99%), respectively. CONCLUSIONS: Because of the low sensitivity of TEE for the detection of AA atherosclerosis, a negative test result requires verification by additional testing using epiaortic scanning. In case of a positive test result, AA atherosclerosis can be considered as present, and less manipulative strategies might be indicated.

Hypothyroidism and acquired von Willebrand's syndrome: a systematic review.

Acquired von Willebrand's syndrome type I is the supposed main underlying cause of bleeding tendency in hypothyroid patients. The purpose of this systematic review was to summarize the published evidence on the association between hypothyroidism and acquired von Willebrand's syndrome. All published clinical epidemiological and interventional studies, case reports and in vitro studies that investigated the association between hypothyroidism and acquired von Willebrand's syndrome were identified by a computer-assisted search of the MEDLINE and EMBASE electronic databases. A quality assessment was performed for clinical epidemiological studies. A total of 41 papers were included. A total of 22 epidemiological in vivo studies, two in vitro studies and 47 case reports were finally analyzed. No high quality in vivo study was identified. Almost all bleeding episodes described in the case reports were mucocutaneous. von Willebrand factor (VWF) antigen value was available for 23 patients: median value 28 U/dL (range: 4-45); VWF activity was available for 24 patients: median value 28.5 U/dL (range: <3-55); factor VIII activity was available for 16 patients: median value 47 U/dL (range: 9-74). Acquired von Willebrand's syndrome may be the main factor responsible for bleeding diathesis in overt hypothyroid patients. Even if bleeding episodes are mainly mild and mucocutaneous, blood transfusion, drug administration or surgical procedure may be required.

QUOTAC: QUestionnaire On day and night Time respiratory symptoms in Asthmatic Children -- a validity study.

The aim of this study was to validate the QUOTAC, a questionnaire on day and night time respiratory symptoms in asthmatic children. Validity was examined by measuring agreement between the QUOTAC and a self-report diary in children aged 6 to 16 years, divided in an asthma group and a control group. As an extra interest in our study a sum score was computed as a measure of the severity of asthma. This study shows that the QUOTAC is discriminative between asthmatic and healthy children and is a reliable and sensitive scale for measuring the severity of asthma. However, cut-off scores for mild, moderate, or severe asthma should be investigated in further research.

Resolving the blind spot of transoesophageal echocardiography: a new diagnostic device for visualizing the ascending aorta in cardiac surgery.

BACKGROUND: Atherosclerosis of the ascending aorta (AA) and stroke after cardiac surgery are related. Knowledge of the location of AA-atherosclerosis pre-sternotomy allows changes in surgical strategy to avoid manipulation of the AA. The gold-standard for assessment of AA-atherosclerosis is intraoperative epiaortic ultrasound scanning (EUS). Transoesophageal echocardiography (TOE) is unable to detect atherosclerosis in the distal AA due to the 'blind spot'. A new method [A-View (Aortic-view) method] using a fluid-filled catheter may enhance the assessment of distal AA-atherosclerosis. The aim of this study was to evaluate whether the A-View method indeed visualizes the distal AA and to assess the safety of this technology. METHODS: In a cross-sectional diagnostic study, 41 patients undergoing cardiac surgery including sternotomy underwent the same work-up including TOE, the A-View method, EUS, and routine operative monitoring. RESULTS: With the A-View method, the distal AA was visible in all (100%) patients. There were no clinical important side-effects associated with the use of the A-View catheter; however, in one patient the endotracheal tube was accidentally dislocated leading to a decrease in Sa(O2). Severity of atherosclerosis visualized with the A-View method compared with EUS results showed good agreement between the two methods [Kappa of 0.69 (0.50-0.88)]. The Bland-Altman analysis showed poor agreement in plaque-size measurements (bias 0.05 cm2, limits of agreement - 0.63 to 0.74 cm2). CONCLUSIONS: The A-View method offers a minimally invasive and safe approach to preoperatively resolving the blind spot of TOE. Compared with EUS, the A-View method yielded satisfactory results in the detection of AA-atherosclerosis. The A-View method seems a promising tool for patients undergoing cardiac surgery to direct surgical management.