S. Piepenbrock

The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia.

BACKGROUND: The binding of fibrinogen and fibrin to platelets is important in normal hemostasis. The extent of platelet-fibrin interaction can be measured as the viscoelastic strength of clot by rotational thromboelastometry (ROTEM®). In this study, we investigated the effect of fibrinogen concentration and its relative contribution to overall clot strength using ROTEM. METHODS: Blood samples were collected from healthy volunteers. The effects of platelet count on clot strength, determined by maximum clot elasticity (MCE), were evaluated on ROTEM using platelet-rich plasma (PRP) adjusted with autologous plasma to generate a range of platelet counts. PRPs were adjusted to 10 × 103 mm−3, 50 × 103 mm−3, and 100 × 103 mm−3 and spiked with fibrinogen concentrates at 550 and 780 mg/dL. The effect of fibrin polymerization on clot strength, independent of platelet attachment, was analyzed by the cytochalasin D-modified thromboelastometry (FIBTEM®) method. Additional retrospective analysis of clot strength (MCE) in two groups of thrombocytopenic patients was conducted. RESULTS: Clot strength (MCE) decreased at a platelet count below 100 × 103 mm−3, whereas increases in MCE peaked and reached a plateau at platelet counts from 400 × 103 mm−3. Increasing fibrinogen concentrations in PRP increased clot strength in a concentration-dependent manner, even at low platelet counts (10 × 103 mm−3). The positive correlation between clot strength and plasma fibrinogen level was also confirmed in the analysis of the data obtained from 904 thrombocytopenic patients. CONCLUSIONS: These in vitro and clinical data indicate that the clot strength increases in a fibrinogen concentration-dependent manner independent of platelet count, when analyzed by ROTEM. The maintenance of fibrinogen concentration is critical in the presence of thrombocytopenia. EXTEM® (extrinsic activation) and FIBTEM may be useful in guiding fibrinogen repletion therapy.

Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study

Background Bleeding diathesis after aortic valve operation and ascending aorta replacement (AV–AA) is managed with fresh-frozen plasma (FFP) and platelet concentrates. The aim was to compare haemostatic effects of conventional transfusion management and FIBTEM (thromboelastometry test)-guided fibrinogen concentrate administration. Methods A blood products transfusion algorithm was developed using retrospective data from 42 elective patients (Group A). Two units of platelet concentrate were transfused after cardiopulmonary bypass, followed by 4 u of FFP if bleeding persisted, if platelet count was ≤100×103 µl−1 when removing the aortic clamp, and vice versa if platelet count was >100×103 µl−1. The trigger for each therapy step was ≥60 g blood absorbed from the mediastinal wound area by dry swabs in 5 min. Assignment to two prospective groups was neither randomized nor blinded; Group B (n=5) was treated according to the algorithm, Group C (n=10) received fibrinogen concentrate (Haemocomplettan® P/Riastap, CSL Behring, Marburg, Germany) before the algorithm-based therapy. Results A mean of 5.7 (0.7) g fibrinogen concentrate decreased blood loss to below the transfusion trigger level in all Group C patients. Group C had reduced transfusion [mean 0.7 (range 0–4) u vs 8.5 (5.3) in Group A and 8.2 (2.3) in Group B] and reduced postoperative bleeding [366 (199) ml vs 793 (560) in Group A and 716 (219) in Group B]. Conclusions In this pilot study, FIBTEM-guided fibrinogen concentrate administration was associated with reduced transfusion requirements and 24 h postoperative bleeding in patients undergoing AV–AA.

Thromboelastometry-guided administration of fibrinogen concentrate for the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm surgery

OBJECTIVE Thoracoabdominal aortic aneurysm operations are associated with extensive blood loss and high requirements for allogeneic blood product transfusion. We assessed the efficacy of intraoperative post-cardiopulmonary bypass administration of fibrinogen concentrate in elective thoracoabdominal aortic aneurysm surgery. METHODS In a retrospective group (group A, n = 12) of patients undergoing elective thoracoabdominal aortic aneurysm surgery, clinically relevant diffuse bleeding after weaning from cardiopulmonary bypass was treated with allogeneic blood products (platelet concentrates, followed by fresh frozen plasma) according to a predetermined algorithm. In a prospective group (group F, n = 6) a first therapy step with fibrinogen concentrate was added to the algorithm. The dose of fibrinogen concentrate was estimated by using thromboelastometric data (ROTEM FIBTEM). Before each step of hemostatic therapy, blood loss in the range of 60 to 250 g per 5 minutes was confirmed. RESULTS In group F, administration of 7.8 +/- 2.7 g of fibrinogen concentrate established hemostasis, completely avoiding intraoperative transfusion of fresh frozen plasma and platelet concentrates. Transfusion of blood products after cardiopulmonary bypass and during the 24 hours after surgical intervention was markedly lower in group F than in group A (2.5 vs 16.4 units; 4/6 patients in group F required no transfusion of blood products), as was 24-hour drainage volume (449 vs 1092 mL). Fibrinogen plasma levels, standard coagulation parameters, and hemoglobin and hematocrit values were comparable between the 2 groups on the first postoperative day. CONCLUSIONS FIBTEM-guided post-cardiopulmonary bypass administration of fibrinogen concentrate resulted in improved intraoperative management of coagulopathic bleeding in thoracoabdominal aortic aneurysm operations and reduced transfusion and 24-hour drainage volume.

Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol.

BACKGROUND AND OBJECTIVE Thymol is a naturally occurring phenol derivative used in anaesthetic practice as a stabilizer and preservative of halothane, usually at a concentration of 0.01%. Although analgesic effects have long been described for thymol and its structural homologue menthol, a molecular basis for these effects is still lacking. We studied the blocking effects of thymol and menthol on voltage-activated sodium currents in vitro as possible molecular target sites. METHODS Whole cell sodium inward currents via heterologously (HEK293 cells) expressed rat neuronal (rat type IIA) and human skeletal muscle (hSkM1) sodium channels were recorded in the absence and presence of definite concentrations of either thymol or menthol. RESULTS When depolarizing pulses to 0 mV were started from a holding potential of -70 mV, half-maximum blocking concentrations (IC50) for the skeletal muscle and the neuronal sodium channel were 104 and 149 mumol for thymol and 376 and 571 mumol for menthol. The blocking potency of both compounds increased at depolarized holding potentials with the fraction of inactivated channels. The estimated dissociation constant Kd for thymol and menthol from the inactivated state was 22 and 106 mumol for the neuronal and 23 and 97 mumol for the skeletal muscle sodium channel, respectively. CONCLUSIONS The results suggest that antinociceptive and local anaesthetic effects of thymol and menthol might be mediated via blockade of voltage-operated sodium channels with the phenol derivative thymol being as potent as the local anaesthetic lidocaine.

Platelet concentrates transfusion in cardiac surgery and platelet function assessment by multiple electrode aggregometry.

Background: Platelet dysfunction contributes to the pathophysiology of bleeding complications during and after cardiac surgery. In most surgical institutions, no peri‐operative point‐of‐care monitoring of platelet function is used. We evaluated the usefulness of the Multiplate® platelet function analyser based on impedance aggregometry for identifying groups of patients at a high risk of transfusion of platelet concentrates (PC).

Pressure pain threshold and needle acupuncture in chronic tension-type headache – a double-blind placebo-controlled study

&NA; In order to examine the role of muscular mechanisms in chronic tension‐type headache a study with needle acupuncture was performed. Needle acupuncture could be of therapeutic value because it has shown some positive effects in myofascial pain syndromes. We performed a double‐blind, placebo‐controlled study with 39 patients (mean age 49.0 years, SD=14.8) fulfilling the International Headache Society criteria for chronic tension‐type headaches. Participants were randomly assigned to verum or placebo condition. Six weeks after end of treatment no significant differences between placebo and verum could be observed with respect to visual analogue scale and frequency of headache attacks. Nevertheless, pressure pain thresholds significantly increased for the verum group. The findings of our study support the hypothesis that peripheral mechanisms – such as increased muscle tenderness – only play a minor role in the pathogenesis of chronic tension‐type headache.

Comparison of inhaled iloprost and nitric oxide in patients with pulmonary hypertension during weaning from cardiopulmonary bypass in cardiac surgery: a prospective randomized trial.

OBJECTIVE The objective of this study was to compare the efficacy of inhaled iloprost and nitric oxide (iNO) in reducing pulmonary hypertension (PHT) during cardiac surgery immediately after weaning from cardiopulmonary bypass (CPB). DESIGN A prospective randomized study. SETTING A single-center university hospital. PARTICIPANTS Forty-six patients with PHT (mean pulmonary artery pressure (mPAP) > or = 26 mmHg preoperatively at rest, after anesthesia induction, and at the end of CPB) scheduled to undergo cardiac surgery were enrolled. INTERVENTIONS Patients were randomly allocated to receive iloprost (group A, n = 23) or iNO (group B, n = 23) during weaning from CPB. MEASUREMENTS AND MAIN RESULTS Heart rate, mean arterial pressure, central venous pressure, pulmonary artery pressure (PAP), pulmonary capillary wedge pressure, and left atrial pressure were recorded continuously. Iloprost and iNO were administered immediately after the end of CPB before heparin reversal. Both substances caused significant reductions in mean PAP (mPAP) and pulmonary vascular resistance (PVR) and significant increases in cardiac output 30 minutes after administration (p < 0.0001). However, in a direct comparison, iloprost caused significantly greater reductions in PVR (p = 0.013) and mPAP (p = 0.0006) and a significantly greater increase in cardiac output (p = 0.002) compared with iNO. CONCLUSIONS PHT after weaning from CPB was significantly reduced by the selective pulmonary vasodilators iNO and iloprost. However, in a direct comparison of the 2 substances, iloprost was found to be significantly more effective.

Propofol Blocks Human Skeletal Muscle Sodium Channels in a Voltage-Dependent Manner

Propofol decreases muscle tone in the absence of neuromuscular blocking drugs. This effect probably cannot be attributed solely to central nervous depression. We studied the effects of propofol on heterologously expressed skeletal muscle sodium channels. Our hypothesis was that the decrease in muscle tone may partly be attributed to an interaction of propofol with sarcolemmal sodium channels. Cells were voltage clamped and whole-cell sodium inward currents were recorded in the absence and presence of propofol. When depolarizing pulses to 0 mV were started from a holding potential close to the normal resting potential of muscle (−70 mV), or when a 2.5-s prepulse inducing slow inactivation was applied before the test pulse at −100 mV, a significant reduction in the peak current amplitude was achieved by 10 and 5 &mgr;M propofol, respectively (P < 0.001). Half-maximum blocking concentrations with these protocols were 23 and 22 &mgr;M. Blocking potency increased at depolarized membrane potentials with the fraction of inactivated channels; the estimated dissociation constant Kd from the inactivated state was 4.6 &mgr;M. These results suggest that propofol significantly blocks sarcolemmal sodium channels at clinically relevant concentrations while maintaining potentials close to the physiological resting potential.

Endocrine stress response and inflammatory activation during CABG surgery. A randomized trial comparing remifentanil infusion to intermittent fentanyl

Background and objective: Our aim was to compare a continuous infusion of remifentanil with intermittent boluses of fentanyl as regards the perioperative hormonal stress response and inflammatory activation in coronary artery bypass graft patients under sevoflurane‐based anaesthesia. Methods: In all, 42 patients undergoing coronary artery bypass grafting with cardiopulmonary bypass were prospectively randomized to a fentanyl group (n = 21, total fentanyl dose 2.6 ± 0.3 mg), or a remifentanil group (n = 21, infusion rate 0.25 &mgr;g kg−1 min−1). Haemodynamics, plasma levels of epinephrine, norepinephrine, antidiuretic hormone, adrenocorticotropic hormone, cortisol, complement activation (C3a, C5b‐9), interleukin (IL)‐6, IL‐8 and tumour necrosis factor‐&agr; were measured at T1: baseline, T2: intubation, T3: sternotomy, T4: 30 min on cardiopulmonary bypass, T5: end of surgery and T6: 8 h postoperatively. Troponin T and creatine kinase‐MB were measured postoperatively. Results: Patients in the remifentanil group were extubated significantly earlier than fentanyl patients (240 ± 182 min vs. 418 ± 212 min, P = 0.006). Stress hormones 30 min after start of cardiopulmonary bypass showed higher values in the fentanyl group compared to the remifentanil group (antidiuretic hormone (ADH): 39.94 ± 30.98 vs. 11.7 ± 22.8 pg mL−1, P = 0.002; adrenocorticotropic hormone: 111.5 ± 116.8 vs. 21.81 ± 24.71 pg mL−1, P = 0.01; cortisol 185 ± 86 vs. 131 ± 82 ng mL−1, P = 0.04). The interleukins were significantly higher at some perioperative time points in the fentanyl group compared to the remifentanil group (tumour necrosis factor: T5: 3.57 vs. 2.37; IL‐6: T5: 4.62 vs. 3.73; and IL‐8: T5: 4.43 vs. 2.65 and T6: 2.61 vs. 1.13). However, cardiopulmonary bypass times and aortic cross‐clamp times were longer in the fentanyl group, which may to some extent account for the differences. Conclusions: The perioperative endocrine stress response was attenuated in patients supplemented with continuous remifentanil infusion as compared to intermittent fentanyl.

In vivo myograph measurement of muscle contraction at optimal length

BackgroundCurrent devices for measuring muscle contraction in vivo have limited accuracy in establishing and re-establishing the optimum muscle length. They are variable in the reproducibility to determine the muscle contraction at this length, and often do not maintain precise conditions during the examination. Consequently, for clinical testing only semi-quantitative methods have been used.MethodsWe present a newly developed myograph, an accurate measuring device for muscle contraction, consisting of three elements. Firstly, an element for adjusting the axle of the device and the physiological axis of muscle contraction; secondly, an element to accurately position and reposition the extremity of the muscle; and thirdly, an element for the progressive pre-stretching and isometric locking of the target muscle.Thus it is possible to examine individual in vivo muscles in every pre-stretched, specified position, to maintain constant muscle-length conditions, and to accurately re-establish the conditions of the measurement process at later sessions.ResultsIn a sequence of experiments the force of contraction of the muscle at differing stretching lengths were recorded and the forces determined. The optimum muscle length for maximal force of contraction was established. In a following sequence of experiments with smaller graduations around this optimal stretching length an increasingly accurate optimum muscle length for maximal force of contraction was determined. This optimum length was also accurately re-established at later sessions.ConclusionWe have introduced a new technical solution for valid, reproducible in vivo force measurements on every possible point of the stretching curve. Thus it should be possible to study the muscle contraction in vivo to the same level of accuracy as is achieved in tests with in vitro organ preparations.