Wolfgang Korte

Decreased Factor XIII Availability for Thrombin and Early Loss of Clot Firmness in Patients with Unexplained Intraoperative Bleeding

To explore relevant changes in unexplained intraoperative bleeding, we evaluated elements of the final steps of the coagulation cascade in 226 consecutive patients undergoing elective surgery. Patients were stratified for the occurrence of unexplained intraoperative bleeding according to predefined criteria. Twenty patients (8.8%) developed unexplained bleeding. The median intraoperative blood loss was 1350 mL (bleeders) and 400 mL (nonbleeders) (P < 0.001). Fibrinogen and Factor XIII (F. XIII) were more rapidly consumed in bleeders (P < 0.001). Soluble fibrin formation (fibrin monomer) was increased in bleeders throughout surgery (P ≤ 0.014). However, F. XIII availability per unit thrombin generated was significantly decreased in bleeders before, during, and after surgery (P ≤ 0.051). Computerized thrombelastography showed a parallel, significant reduction in clot firmness. We suggest that mild preexisting coagulopathy is not rare in surgical patients and probably can result in clinically relevant intraoperative bleeding. This hemostatic disorder shows impaired clot firmness, probably secondary to decreased cross-linking (due to a loss of F. XIII, both in absolute measures and per unit thrombin generated). We suggest that the application of F. XIII might be worthwhile to test in a prospective clinical trial to increase clot firmness in patients at risk for this intraoperative coagulopathy.

Day-to-day titration to initiate transdermal fentanyl in patients with cancer pain: Short- and long-term experiences in a prospective study of 39 patients

Initial dose finding in patients with cancer pain who are started on TTS fentanyl (Duragesic, TTS-F) is often unsatisfactory with currently recommended doses and intervals. Acknowledging that studies reveal a psuedo steady state 15 to 20 hr after application of TTS-F, we prospectively investigated an increased initial dose and day-to-day titration of TTS-F in 39 (evaluable) patients with uncontrolled cancer pain. Significant pain reduction (P = 0.001) was seen after 24 hr, and satisfactory analgesia was achieved within 48 h and maintained for the rest of the study. Significant increases in TTS-F were necessary during weeks 1 through 4 to maintain pain control. Forty-nine percent of the patients needed one or more early dose increases. Only one patient had side effects partially due to the specific properties of the TTS. Other side effects seemed to be less common compared with usual morphine treatment. TTS-F can be titrated effectively and safely on a day-to-day basis with an increased initial dose and adequate patient monitoring, thus avoiding more complicated approaches. TTS-F seemed to induce less constipation than might be expected.

Elevated cardiac troponin I in sepsis and septic shock: no evidence for thrombus associated myocardial necrosis.

Background Elevated cardiac troponin I (cTnI) is frequently observed in patients with severe sepsis and septic shock. However, the mechanisms underlying cTnI release in these patients are still unknown. To date no data regarding coagulation disturbances as a possible mechanism for cTnI release during sepsis are available. Methodology/Principal Findings Consecutive patients with systemic inflammatory response syndrome (SIRS), sepsis or septic shock without evidence of an acute coronary syndrome were analyzed. Coagulation parameters (clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF), α-angle) were assessed in native whole blood samples, and using specific activators to evaluate the extrinsic and intrinsic as well as the fibrin component of the coagulation pathway with the use of rotational thrombelastometry (ROTEM). Thirty-eight patients were included and 22 (58%) were cTnI-positive. Baseline characteristics between TnI-positive and -negative patients were similar. The CT, CFT, MCF and the α-angle were similar between the groups with trends towards shorter CT in the extrinsic and fibrin activation. Conclusions/Significance We found no differences in coagulation parameters analyzed with rotational thrombelastometry between cTnI-positive and -negative patients with SIRS, severe sepsis, and septic shock. These findings suggest that pathophysiological mechanisms other than thrombus-associated myocardial damage might play a major role, including reversible myocardial membrane leakage and/or cytokine mediated apoptosis in these patients.

Changes of the Coagulation and Fibrinolysis System in Malignancy: Their possible Impact on Future Diagnostic and Therapeutic Procedures

Abstract The interaction between malignant cell growth and the coagulation and fibrinolysis system has been a well known phenomenon for decades. During recent years, this area of research has received new attention. Experimental data suggest a role for the coagulation and fibrinolysis system in tumor development, progression and metastasis. Also, clinical research suggests that targeting the coagulation system or fibrinolysis system might influence the course of malignant disease beneficially. This paper reviews data on various hemostatic and fibrinolytic parameters in malignancy; the possible use of such parameters as risk markers in oncology patients; and possible targets of anti-neoplastic therapies using anticoagulant and/or antifibrinolytic strategies. Current evidence suggests that the tissue factor/factor VIIa pathway mediates the most abundant procoagulant stimulus in malignancy via the increase in thrombin generation. Tissue factor has been suggested to mediate pro-metastatic properties via coagulation-dependent and coagulation-independent pathways; tissue factor has also been implicated in tumor neo-angiogenesis. However, so far no model has been validated that would allow the use of tissue factor in its soluble or insoluble form as a marker for risk stratification in tumor patients. On the other hand, there is now good evidence that parts of the fibrinolytic system, such as urokinase-type plasminogen activator and its receptor (“uPAR”), can be used as strong predictors of outcome in several types of cancer, specifically breast cancer. Observation of various treatment options in patients with thomboembolic disease and cancer as well as attempts to use anticoagulants and/or therapies modulating the fibrinolytic system as anti-neoplastic treatment strategies have yielded exciting results. These data indicate that anticoagulant therapy, and specifically low molecular weight heparin therapy, is likely to have anti-neoplastic effects; and that their use in addition to chemotherapy will probably improve outcome of tumor treatment in certain types of cancer. However, the body of clinical data is still relatively small and the question whether or not we should routinely consider the coagulation and/or fibrinolysis system as therapeutic targets in cancer patients is yet to be answered.

Multicentre evaluation of a new point-of-care test for the quantitative determination of D-dimer

Imprecision studies, interference testing and multicentre method comparisons using patient samples were carried out with of a new point-of-care test for D-dimer (CARDIAC D-Dimer). The CV of the within-series and the day-to-day imprecision with blood samples and control materials were between 7% and 13%. Compared with Tina-quant D-Dimer, CARDIAC D-Dimer showed a good correlation and accuracy (n=353; r=0.91; y=1.06x-0.03), compared with STA LIATEST D-Dimer some poorer accuracy (n=304; r=0.91; y=1.12x-0.03). No interference was detected for different hematocrit values (16% to 51%) and in investigations with hemoglobin (up to 0.13 mmol/l), biotin (up to 30 microg/l), bilirubin (up to 340 micromol/l), intralipid (up to 31.1 mmol/l) and rheumatic factor (up to 79 IU/ml). Overdosing or underdosing by 10 microl did not affect the test result. The diagnostic sensitivity of CARDIAC D-Dimer for the detection of acute venous thromboembolic diseases was 100% in our study. With CARDIAC D-Dimer reliable quantitative D-dimer results can be easily obtained. Because of the good analytical and clinical agreement with Tina-quant D-Dimer, it should be suitable for ruling out venous thromboembolic diseases.

Effects of long-term continuous positive airway pressure on body composition and IGF1

OBJECTIVEnTo investigate the long-term effects of nasal continuous positive airway pressure (CPAP) ventilation in patients with obstructive sleep apnea syndrome (OSAS) on body composition (BC) and IGF1.nnnDESIGNnObservational study.nnnSUBJECTSnSeventy-eight (11 females and 67 males) OSAS patients who were compliant with CPAP (age 51+/-1.1 years) participated in the study. We assessed body mass index (BMI), total body mass (TBM), total body fat (TBF; kg) and lean body mass (LBM; kg), abdominal subcutaneous (SC) and visceral (V) fat (cm(2)), and waist circumference (WC; cm) by magnetic resonance imaging, and IGF1 (ng/ml) before and after 7.8+/-1.3 months of CPAP use of an average of 5.9+/-1.2 h.nnnRESULTSnWomen had a higher BMI, WC; TBM, TBF, and more SC fat. Men had a higher LBM and more V fat. CPAP increased WC (+2.8+/-9.6 cm, P=0.02) and LBM (2.2+/-0.5 kg, P=0.006), but not IGF1. In men, CPAP increased BMI (0.5+/-0.2 kg/m(2), P=0.02), WC (1.7+/-6.9 cm, P=0.002), TBM (1.7+/-0.4 kg, P=0.0001), LBM (1.5+/-0.4 kg, P=0.0003), SC fat (12.9+/-5.1 cm(2), P=0.02), and IGF1 (13.6+/-4.2 ng/ml, P=0.002). Compliance with CPAP increased LBM in men aged <60 years, but not in those aged >60 years, and IGF1 increased in men aged 40-60 years only.nnnCONCLUSIONSnLong-term CPAP increased LBM in both sexes and IGF1 in men, while fat mass remained unchanged, suggesting a sexually dimorphic response of IGF1 to CPAP. The role of the GH axis activity and age to this response is unclear. The metabolic consequences of changes in LBM are still to be determined. Future studies on the effects of CPAP on BC should include LBM as an outcome.

Transdermal fentanyl in uncontrolled cancer pain: titration on a day-to-day basis as a procedure for safe and effective dose finding — a pilot study in 20 patients

All communications on the use of transdermal fentanyl as well as the recommendations of the manufacturer include the direction that patients should be titrated with a short-acting narcotic to control their cancer pain before they are converted to a fentanyl transdermal therapeutic system (TTS). We investigated the possibility of avoiding this titration phase by immediate fentanyl TTS therapy in patients with uncontrolled cancer pain. Dose finding was performed by direct titration of fentanyl TTS according to clinical necessity on a day-to-day basis. Morphine solution for rescue medication was available. Short-term follow-up was 28 days, and 20 patients (10 in- and 10 outpatients) were evaluable. On the average, sufficient pain control [visual analogue scale (VAS) <35 mm] was reached within 48 h of the start of fentanyl TTS. The mean VAS values before and during fentanyl TTS therapy were 53 mm (before), 27 mm (week 1), 21 mm (week 2), 18 mm (week 3) and 21 mm (week 4). There were statistically significant lower VAS values at all follow-up times compared to pretreatment values (e.g. pretreatment to day 1:P=0.019; pretreatment to day 28:P=0.002, Wilcoxon sign-rank test). The mean fentanyl TTS doses were 70 μg/h (week 1), 98 μg/h (week 2), 107 μg/h (week 3) and 116 μg/h (week 4). The differences of mean fentanyl TTS doses were significantly different between days 1 and 7 (P<0.001) and between days 8 and 14 (P=0.006), but not between days 15 and 21 and days 22 and 28. Mean morphine doses as rescue medication were steadily decreasing from 11 mg/day in week 1 to 3 mg/day in week 4 of treatment, but no statistically significant differences between these amounts could be found. Our results indicate that the titration phase with a short-acting narcotic prior to the conversion to fentanyl TTS is not necessary. Fentanyl TTS can be titrated safely and effectively on a day-to-day basis according to clinical necessity if the patients are well monitored, thus simplifying pain therapy with fentanyl TTS.

Continuous positive airway pressure improves exercise capacity and heart rate recovery in obstructive sleep apnea

BACKGROUNDnThere is a relationship between obstructive sleep apnea (OSA) and heart failure (HF). Peak oxygen consumption (peak VO(2)), heart rate recovery, and N-terminal-pro-BNP (NT-proBNP) are strong prognostic predictors in HF. The effects of nasal continuous positive airway pressure (nCPAP) on these parameters in OSA patients are not well defined.nnnMETHODSnForty patients with newly diagnosed OSA [apnea-hypopnea index (AHI) 37 (20-65) h(-1)] underwent cardiopulmonary exercise testing for assessment of peak VO(2) and heart rate recovery at one (HRR-1) and two (HRR-2) minutes after exercise termination as well as NT-proBNP measurement at baseline and after 7.9+/-1.4 months of effective nCPAP (nightly usage>3.5 h). The effects of nCPAP were compared in patients with mild-to-moderate (AHI<30 h(-1); n=16) vs. severe (AHI>or=30 h(-1); n=24) OSA.nnnRESULTSnIn the group as a whole, peak VO(2) (baseline: 31.9+/-9.3 vs. follow-up: 33.7+/-9.0 ml/kg/min; p=0.02) and HRR-2 [38 (32-43) vs. 42 (32-47) bpm; p=0.01] but not HRR-1 [22 (15-26) vs. 22 (16-27) bpm; p=0.16] improved from baseline to follow-up. The effect on peak VO(2) was mainly driven by a trend towards an increase in patients with mild-to-moderate OSA (31.8+/-10.7 vs. 33.9+/-10.2 ml/kg/min; p=0.08), whereas an effect on HRR-1 [20 (15-23) vs. 21 (16-26) bpm; p=0.03] and HRR-2 [38 (29-42) vs. 42 (33-47) bpm; p=0.004] was observed only in those with severe OSA. NT-proBNP levels remained unchanged [21 (11-45) vs. 26 (5-52) pg/ml; p=0.6].nnnCONCLUSIONSnTreatment with nCPAP is associated with an improvement in peak VO(2) and heart rate recovery in patients with OSA.

Perioperative course of FXIII in children undergoing major surgery

Background:u2002 Acquired deficiency of FXIII because of perioperative hemodilution has been described several times in adults; however, data in children are scarce. We performed a prospective observational trial to evaluate the intraoperative course of FXIII in children undergoing elective major surgery.

N-terminal pro-B-type natriuretic peptide and functional capacity in patients with obstructive sleep apnea

The obstructive sleep apnea syndrome (OSAS) is associated with cardiovascular abnormalities including left ventricular hypertrophy, left ventricular diastolic dysfunction, and endothelial dysfunction. The present study evaluated whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) and peak oxygen consumption (peak VO2), both integral markers of cardiovascular function, are related to OSAS severity. In addition, we tested whether NT-proBNP levels depend on body composition in OSAS patients, similar to what has been reported in patients without OSAS. Eighty-nine patients with untreated OSAS underwent NT-proBNP measurement, dual X-ray absorptiometry, and cardiopulmonary exercise testing. In a representative subgroup (nu2009=u200932), transthoracic echocardiography was performed. The severity of OSAS was classified based on apnea–hypopnea index (AHI) values as mild (AHI 5–15xa0h−1), moderate (AHI 15–30xa0h−1), and severe (AHI >30xa0h−1). OSAS was mild in 19 (21%), moderate in 21 (24%), and severe in 49 (55%) patients. NT-proBNP levels did not differ among patients with mild [30 (10–57)], moderate [37 (14–55)], and severe [24 (13–49) pg/ml; pu2009=u20090.8] OSAS and were not related to body mass index (ru2009=u20090.07; pu2009=u20090.5), percent lean body mass (ru2009=u2009−0.17; pu2009=u20090.1), and percent fat mass (ru2009=u20090.18; pu2009=u20090.1). Percent predicted peak VO2 was on average normal and did not differ among patients with mild (115u2009±u200926), moderate (112u2009±u200923), and severe OSAS (106u2009±u200929%; pu2009=u20090.4). Body weight-indexed peak VO2 did not differ among patients with mild (31.9u2009±u200910.3), moderate (32.1u2009±u20097.9), and severe OSAS (30.0u2009±u20099.9xa0ml kg−1 min−1; pu2009=u20090.6) either. Lower NT-proBNP (βu2009=u2009−0.2; pu2009=u20090.02) was independently but weakly associated with higher body weight-indexed peak VO2. In the echocardiography subgroup, NT-proBNP was not significantly related to left ventricular mass index (ru2009=u20090.26; pu2009=u20090.2). In conclusion, NT-proBNP and peak VO2 are not related to OSAS severity, and NT-proBNP poorly reflects left ventricular hypertrophy in OSAS. The lack of a relationship between NT-proBNP and OSAS severity is not due to a significant influence of body composition on NT-proBNP. There is an association between higher NT-proBNP and lower peak VO2, indicating that NT-proBNP is a marker of cardiorespiratory fitness in patients with OSAS. However, the association is too weak to be clinically useful.