Helfried Metzler

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.

Platelet Function Measurement–Based Strategy to Reduce Bleeding and Waiting Time in Clopidogrel-Treated Patients Undergoing Coronary Artery Bypass Graft Surgery The Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG (TARGET-CABG) Study

Background— Aspirin and clopidogrel therapy is associated with a variable bleeding risk in patients undergoing coronary artery bypass graft surgery (CABG). We evaluated the role of platelet function testing in clopidogrel-treated patients undergoing CABG. Methods and Results— One hundred eighty patients on background aspirin with/without clopidogrel therapy undergoing elective first time isolated on-pump CABG were enrolled in a prospective single-center, nonrandomized, unblinded investigation (Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG [TARGET-CABG] study) between September 2008 and January 2011. Clopidogrel responsiveness (ADP-induced platelet-fibrin clot strength [MAADP]) was determined by thrombelastography; CABG was done within 1 day, 3–5 days, and >5 days in patients with an MAADP >50 mm, 35–50 mm, and <35 mm, respectively. The primary end point was 24-hour chest tube drainage and key secondary end point was total number of transfused red blood cells. Equivalence was defined as ⩽25% difference between groups. ANCOVA was used to adjust for confounders. Mean 24-hour chest tube drainage in clopidogrel-treated patients was 93% (95% confidence interval, 81–107%) of the amount observed in clopidogrel-naive patients, and the total amount of red blood cells transfused did not differ between groups (1.80 U versus 2.08 U, respectively, P=0.540). The total waiting period in clopidogrel-treated patients was 233 days (mean, 2.7 days per patient). Conclusions— A strategy based on preoperative platelet function testing to determine the timing of CABG in clopidogrel-treated patients was associated with the same amount of bleeding observed in clopidogrel-naive patients and ≈50% shorter waiting time than recommended in the current guidelines. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00857155.

Thromboelastography for monitoring prolonged hypercoagulability after major abdominal surgery

Despite clinical and laboratory evidence of perioperative hypercoagulability, there are no consistent data evaluating the extent, duration, and specific contribution of platelets and procoagulatory proteins by in vitro testing. We tested the hypothesis that the parallel use of standard and abciximab-cytochalasin D-modified thromboelastography (TEG®) can assess 7 days’ postoperative hypercoagulability and can estimate the independent contribution of procoagulatory proteins and platelets. Thromboelastograms were performed before surgery, at the end of surgery, 6 h after surgery, and on postoperative days 1, 2, 3, and 7; they were analyzed for the reaction time and the maximal amplitude (MA). We calculated the elastic shear modulus of standard MA (Gt) and modified MA (Gc), which reflect total clot strength and procoagulatory protein component, respectively. The difference was an estimate of the platelet component (Gp). There was a 10% perioperative increase of standard MA, corresponding to a 50% increase of Gt (P < 0.0001) and an 86%–90% contribution of the calculated Gp to Gt. We conclude that serial standard and modified thromboelastography may reveal prolonged postoperative hypercoagulability and the independent contribution of platelets and procoagulatory proteins to clot strength.

Remifentanil versus morphine analgesia and sedation for mechanically ventilated critically ill patients: A randomized double blind study

Background: The rapid onset and offset of action of remifentanil could make it quickly adjustable to the required level of sedation in critically ill patients. The authors hypothesized that the efficacy of a remifentanil-based regimen was greater than that of a morphine-based regimen. Methods: Forty intent-to-treat patients were randomly allocated to receive a blinded infusion of either remifentanil 0.15 &mgr;g·kg−1·min−1 or morphine 0.75 &mgr;g·kg−1·min−1. The opioid infusion was titrated, in the first intent, to achieve optimal sedation defined as Sedation Agitation scale of 4. A midazolam open-label infusion was started if additional sedation was required. Results: The mean percentage hours of optimal sedation was significantly longer in the remifentanil group (78.3 ± 6.2) than in the morphine group (66.5 ± 8.5). This was achieved with less frequent infusion rate adjustments (0.34 ± 0.25 changes/h) than in the morphine group (0.42 ± 0.22 changes/h). The mean duration of mechanical ventilation and extubation time were significantly longer in the morphine group (18.1 ± 3.4 h, 73 ± 7 min) than in the remifentanil group (14.1 ± 2.8 h, 17 ± 6 min), respectively. Remifentanil mean infusion rate was 0.13 ± 0.03 &mgr;g·kg−1·min−1, whereas morphine mean infusion rate was 0.68 ± 0.28 &mgr;g·kg−1·min−1. More subjects in the morphine group (9 of 20) than in the remifentanil group (6 of 20) required midazolam. The incidence of adverse events was low and comparable across the two treatment groups. Conclusions: A remifentanil-based regimen was more effective in the provision of optimal analgesia-sedation than a standard morphine-based regimen. The remifentanil-based regimen allowed a more rapid emergence from sedation and facilitated earlier extubation.

N-Terminal Pro-brain Natriuretic Peptide Identifies Patients at High Risk for Adverse Cardiac Outcome after Vascular Surgery

Background:Preoperative N-terminal pro-BNP (NT-proBNP) is independently associated with adverse cardiac outcome but does not anticipate the dynamic consequences of anesthesia and surgery. The authors hypothesized that a single postoperative NT-proBNP level provides additional prognostic information for in-hospital and late cardiac events. Methods:Two hundred eighteen patients scheduled to undergo vascular surgery were enrolled and followed up for 24–30 months. Logistic regression and Cox proportional hazards model were performed to evaluate predictors of in-hospital and long-term cardiac outcome. The optimal discriminatory level of preoperative and postoperative NT-proBNP was determined by receiver operating characteristic analysis. Results:During a median follow-up of 826 days, 44 patients (20%) experienced 51 cardiac events. Perioperatively, median NT-proBNP increased from 215 to 557 pg/ml (interquartile range, 83/457 to 221/1178 pg/ml; P < 0.001). The optimum discriminate threshold for preoperative and postoperative NT-proBNP was 280 pg/ml (95% confidence interval, 123–400) and 860 pg/ml (95% confidence interval, 556–1,054), respectively. Adjusted for age, previous myocardial infarction, preoperative fibrinogen, creatinine, high-sensitivity C-reactive protein, type, duration, and surgical complications, only postoperative NT-proBNP remained significantly associated with in-hospital (adjusted hazard ratio, 19.8; 95% confidence interval, 3.4–115) and long-term cardiac outcome (adjusted hazard ratio, 4.88; 95% confidence interval, 2.43–9.81). Conclusion:A single postoperative NT-proBNP determination provides important additional prognostic information to preoperative levels and may support therapeutic decisions to prevent subsequent structural myocardial damage.

The effect of different stages of neuromuscular block on the bispectral index and the bispectral index-XP under remifentanil/propofol anesthesia.

Facial electromyographic activity and neuromuscular block could influence bispectral index (BIS) depth of anesthesia monitoring. In this study we examined, in 30 patients undergoing general surgical procedures, the effect of different stages of neuromuscular block on BIS monitoring and compared the conventional A-2000 BIS™ (BIS3.4) with the new BIS-XP™ (BISXP). At deep surgical anesthesia BIS3.4 of approximately 40, under a propofol 3.61 μg/mL target-controlled infusion and a 0.15–0.3 μg·kg−1·min−1 remifentanil infusion, mivacurium 0.15 mg/kg was administered. The onset of neuromuscular block triggered a brief transient odd divergence in response that manifested as a BIS3.4 increase from 43 ±4 to 49±7 (P = 0.007) and a BISXP decline from 41 ±3 to 35 ±3 (P = 0.003) at 1 ±0.2 min. Then, 2.5 ±1 min after mivacurium administration, both monitors returned to baseline values of 43 ±5 and 40 ± 4, respectively. After that, BIS3.4 and BISXP did not significantly change during complete neuromuscular block or during various levels of neuromuscular recovery. At all phases, BISXP was significantly lower than BIS3.4. Our study indicated that the BIS3.4/BISXP bias and the wide limits of agreement do not allow values given by the two monitors to be used interchangeably.

Inhaled nitric oxide in patients with critical pulmonary perfusion after fontan-type procedures and bidirectional glenn anastomosis

OBJECTIVE The aim of this study was to evaluate the effects of inhaled nitric oxide in patients with critical pulmonary perfusion after Fontan-type procedures and bidirectional Glenn anastomosis. METHODS Inhaled nitric oxide (mean 4.1 +/- 0.7 ppm, 1.5 to 10 ppm) was administered in 13 patients (mean age 5.6 +/- 1.6 years, 1.5 to 17 years) with critical pulmonary perfusion (central venous pressure > 20 mm Hg or transpulmonary pressure gradient > 10 mm Hg) in the early postoperative period after total cavopulmonary connection (n = 9) or after bidirectional Glenn anastomosis (n = 4). RESULTS In patients after total cavopulmonary connection inhaled nitric oxide therapy decreased central venous pressure by 15.3% +/- 1.4% (p = 0.0001) and transpulmonary pressure gradient by 42% +/- 8% (p = 0.0008) and increased mean systemic arterial and left atrial pressures by 12% +/- 3.6% (p = 0.011) and 28% +/- 8% (p = 0.007), respectively. Arterial and venous oxygen saturations improved by 8.2% +/- 1% (p = 0.005) and 14% +/- 4.3% (p = 0.03), respectively. In patients after bidirectional Glenn anastomosis inhaled nitric oxide therapy resulted in a decrease of central venous pressure by 22% +/- 1% and of the transpulmonary pressure gradient by 55% +/- 6% and improved arterial and venous oxygen saturations by 37% +/- 29% and 11% +/- 3%, respectively. Mean systemic arterial and left atrial pressures remained nearly unchanged. No toxic side effect was observed in any patient. CONCLUSION Inhaled nitric oxide may play an important role in the management of transient critical pulmonary perfusion caused by reactive elevated pulmonary vascular resistance in the early postoperative period after Fontan-type operations and bidirectional Glenn anastomosis.

Intestinal motility disturbances in intensive care patients pathogenesis and clinical impact

BackgroundGastrointestinal motility disturbances in critically ill patients are frequent in the ICU setting, causing considerable discomfort and are associated with increased rates of morbidity and mortality. This review focuses on the pathophysiological basis of intestinal motility, the major patterns of pathological motility alterations, the impact on patient outcome, and current therapeutic options.DiscussionIntestinal motility is controlled by the enteric nervous system, modulated by hormones and extrinsic afferent and efferent neurons. Pathological motility disturbances can affect the stomach, small bowel, and colon separately or in combination. Changes in esophageal motor activity contribute to the aspiration of gastric juice, whereas early enteral feeding most frequently fails due to gastric intolerance. Disturbances in digestive and interdigestive motility patterns and the inability to switch motor activity from the interdigestive to the digestive pattern also contribute to feeding disability and thus to increased morbidity and mortality as well.ConclusionsThe therapeutic options for motility disturbances in critically ill patients include the adjustment of electrolyte imbalances, tailored fluid management, early enteral feeding, appropriate management of catecholamines and drugs used for analgosedation, and prokinetic drugs. Unfortunately, the therapeutic options for treating motility disturbances in ICU patients are still limited. This situation requires careful assessment of ICU patients with respect to gut motility disturbances and their pathophysiological mechanisms and an individually tailored treatment to prevent further aggravation of existing motility disturbances.

Catecholamines potentiate LPS-induced expression of MMP-1 and MMP-9 in human monocytes and in the human monocytic cell line U937: possible implications for peri-operative plaque instability

Plaque destabilization leading to myocardial infarction is observed after surgery even if the intervention is of noncardiovascular nature. Mediators of peri‐ or postoperative stress responsible for such events could include catecholamines and lipopolysaccharide (LPS). Monocytes may be involved in destabilization of atherosclerotic plaques by production of matrix metalloproteinases (MMP). We examined whether catecholamines could affect the expression of MMPs in human monocytes/macrophages and whether catecholamines could modulate LPS‐stimulated expression of particular MMPs in these cells. Epinephrine and norepinephrine up‐regulated MMP‐1 and potentiated LPS‐induced expression of MMP‐1 in peripheral blood monocytes and monocyte‐ derived macrophages. We further characterized this effect employing the monocytic cell line U937 and showed that catecholamines potentiate LPS‐induced effects on MMP‐1 and MMP‐9 antigen and activity. mRNA levels of the respective MMPs also increased. These effects did not result from higher mRNA stability but rather from increased transcription possibly induced by enhanced DNA binding of AP‐1 and were mediated by either β1‐ or β2‐receptors. If this mechanism is also effective in vivo, our findings might, at least in part, help to explain the observation that cardiac events are important causes of morbidity and mortality after noncardiac surgery and support the findings that peri‐operative β‐blockade has been shown to reduce postoperative mortality from cardiac events.

Subcutaneous recombinant human erythropoietin and autologous blood donation before coronary artery bypass surgery

Conventional therapies with recombinant human erythropoietin (rHuEPO) to sustain preoperative autologous blood collection entail high doses of the drug at short intervals. To evaluate the efficacy of a single weekly dose of rHuEPO for autologous blood collection, we randomly assigned 24 male patients scheduled for coronary artery bypass surgery to receive 400 IU/kg rHuEPO subcutaneously once a week or iron only. Patients were examined weekly and a total of up to 4 units of autologous blood were obtained if the hemoglobin level exceeded 12 g/dL. Patients receiving rHuEPO had consistently higher hemoglobin values than those receiving iron only (P < 0.001). Consequently, more autologous red cells were obtained from this group (776 +/- 49 mL vs 682 +/- 91 mL; P < 0.05). One patient receiving rHuEPO and eight in the control group required homologous blood at surgery (P < 0.01). These results suggest that 400 IU/kg rHuEPO administered subcutaneously once a week efficiently stimulates erythropoiesis and compensates the hemoglobin decrease after autologous blood donation.