Hemostasis during low molecular weight heparin anticoagulation for continuous venovenous hemofiltration: a randomized cross-over trial comparing two hemofiltration rates

INTRODUCTION: Renal insufficiency increases the half-life of low molecular weight heparins (LMWHs). Whether continuous venovenous hemofiltration (CVVH) removes LMWHs is unsettled. We studied hemostasis during nadroparin anticoagulation for CVVH, and explored the implication of the endogenous thrombin potential (ETP). METHODS: This cross-over study, performed in a 20-bed teaching hospital ICU, randomized non-surgical patients with acute kidney injury requiring nadroparin for CVVH to compare hemostasis between two doses of CVVH: filtrate flow was initiated at 4 L/h and converted to 2 L/h after 60 min in group 1, and vice versa in group 2. Patients received nadroparin 2850 IU i.v., followed by 380 IU/h continuously in the extracorporeal circuit. After baseline sampling, ultrafiltrate, arterial (art) and postfilter (PF) blood was taken for hemostatic markers after 1 h, and 15 min, 6 h, 12 h and 24 h after converting filtrate flow. We compared randomized groups, and 'early circuit clotting' to 'normal circuit life' groups. RESULTS: Fourteen patients were randomized, seven to each group. Despite randomization, group 1 had higher SOFA scores (median 14 (IQR 11-15) versus 9 (IQR 5-9), p = 0.004). Anti-Xa art activity peaked upon nadroparin bolus and declined thereafter (p = 0.05). Anti-Xa PF did not change in time. Anti-Xa activity was not detected in ultrafiltrate. Medians of all anti-Xa samples were lower in group 1 (anti-Xa art 0.19 (0.12-0.37) vs. 0.31 (0.23-0.52), p = 0.02; anti-Xa PF 0.34 (0.25-0.44) vs. 0.51 (0.41-0.76), p = 0.005). After a steep decline, arterial ETPAUC tended to increase (p = 0.06), opposite to anti-Xa, while postfilter ETPAUC increased (p = 0.001). Median circuit life was 24.5 h (IQR 12-37 h). Patients with 'short circuit life' had longer baseline prothrombin time (PTT), activated thromboplastin time (aPTT), lower ETP, higher thrombin-antithrombin complexes (TAT) and higher SOFA scores; during CVVH, anti-Xa, and platelets were lower; PTT, aPTT, TAT and D-dimers were longer/higher and ETP was slower and depressed. CONCLUSIONS: We found no accumulation and no removal of LMWH activity during CVVH. However, we found that early circuit clotting was associated with more severe organ failure, prior systemic thrombin generation with consumptive coagulopathy, heparin resistance and elevated extracorporeal thrombin generation. ETP integrates these complex effects on the capacity to form thrombin. TRIAL REGISTRATION : Clinicaltrials.gov ID NCT00965328

Insulin treatment guided by subcutaneous continuous glucose monitoring compared to frequent point-of-care measurement in critically ill patients: a randomized controlled trial

Glucose measurement in intensive care medicine is performed intermittently with the risk of undetected hypoglycemia. The workload for the ICU nursing staff is substantial. Subcutaneous continuous glucose monitoring (CGM) systems are available and may be able to solve some of these issues in critically ill patients. In a randomized controlled design in a mixed ICU in a teaching hospital we compared the use of subcutaneous CGM with frequent point of care (POC) to guide insulin treatment. Adult critically ill patients with an expected stay of more than 24 hours and in need of insulin therapy were included. All patients received subcutaneous CGM. CGM data were blinded in the control group, whereas in the intervention group these data were used to feed a computerized glucose regulation algorithm. The same algorithm was used in the control group fed by intermittent POC glucose measurements. Safety was assessed with the incidence of severe hypoglycemia ( <2.2 mmol/L), efficacy with the percentage time in target range (5.0 to 9.0 mmol/L). In addition, we assessed nursing workload and costs. In this study, 87 patients were randomized to the intervention and 90 to the control group. CGM device failure resulted in 78 and 78 patients for analysis. The incidence of severe glycemia and percentage of time within target range was similar in both groups. A significant reduction in daily nursing workload for glucose control was found in the intervention group (17 versus 36 minutes; P <0.001). Mean daily costs per patient were significantly reduced with EUR 12 (95% CI -32 to -18, P = 0.02) in the intervention group. Subcutaneous CGM to guide insulin treatment in critically ill patients is as safe and effective as intermittent point-of-care measurements and reduces nursing workload and daily costs. A new algorithm designed for frequent measurements may lead to improved performance and should precede clinical implementation. Clinicaltrials.gov, NCT01526044. Registered 1 February 201

The N-Terminal DH-PH Domain of Trio Induces Cell Spreading and Migration by Regulating Lamellipodia Dynamics in a Rac1-Dependent Fashion

The guanine-nucleotide exchange factor Trio encodes two DH-PH domains that catalyze nucleotide exchange on Rac1, RhoG and RhoA. The N-terminal DH-PH domain is known to activate Rac1 and RhoG, whereas the C-terminal DH-PH domain can activate RhoA. The current study shows that the N-terminal DH-PH domain, upon expression in HeLa cells, activates Rac1 and RhoG independently from each other. In addition, we show that the flanking SH3 domain binds to the proline-rich region of the C-terminus of Rac1, but not of RhoG. However, this SH3 domain is not required for Rac1 or RhoG GDP-GTP exchange. Rescue experiments in Trio-shRNA-expressing cells showed that the N-terminal DH-PH domain of Trio, but not the C-terminal DH-PH domain, restored fibronectin-mediated cell spreading and migration defects that are observed in Trio-silenced cells. Kymograph analysis revealed that the N-terminal DH-PH domain, independent of its SH3 domain, controls the dynamics of lamellipodia. Using siRNA against Rac1 or RhoG, we found that Trio-D1-induced lamellipodia formation required Rac1 but not RhoG expression. Together, we conclude that the GEF Trio is responsible for lamellipodia formation through its N-terminal DH-PH domain in a Rac1-dependent manner during fibronectin-mediated spreading and migration

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Critical illness onychomadesis

Objective: To present our observation of the development of a rare nail deformity in the prolonged course of disease of a critically ill patient with a pulmonary abscess. Design: Case report. Setting: Tertiary referral, 16-bed, level I surgical ICU in an academic hospital. Patient: A 48-year-old Caucasian male was treated with penicillin for a pneumococcal meningitis and pneumonia. He developed a large pulmonary abscess of the right upper lobe and needed prolonged mechanical ventilation. Extensive surgical treatment was successful eventually. A remarkable feature concerned the occurrence of onycholysis of all finger nails and toe nails resulting in complete shedding of the nails (onychomadesis). This phenomenon can be regarded as an extreme manifestation of Beau's lines precipitated by a severe systemic insult. Conclusion: We observed the development of onychomadesis in a critically ill patient with a large pulmonary abscess. This association has not been described before

Percutaneous dilatational tracheostomy in the ICU: Optimal organization, low complication rates, and description of a new complication

Study objectives: To assess short-term and long-term complications of bronchoscopy-guided, percutaneous dilatational tracheostomy (PDT) and surgical tracheostomy (ST) and to report a complication of PDT that has not been described previously. Design: Prospective survey. Setting: University teaching hospital. Patients: Two hundred eleven critically ill patients in our ICU. Interventions: PDT was performed in 174 patients, under bronchoscopic guidance in most cases. ST was performed in 40 patients. Results: No procedure-related fatalities occurred during PDT or ST. The incidence of significant complications (eg, procedure-related transfusion of fresh-frozen plasma, RBCs, or platelets, malpositioning or kinking of the tracheal cannula, deterioration of respiratory parameters lasting for < 36 h following the procedure, or stomal infection) in patients undergoing PDT was 4.0% overall and 3.0% when bronchoscopic guidance was used. No cases of paratracheal insertion, pneumothorax, pneumomediastinum, tracheal laceration, or clinically significant tracheal stenosis occurred in patients undergoing PDT. We attribute this low rate of complications to procedural and organizational factors such as bronchoscopic guidance, performance by or supervision of all PDTs by physicians with extensive experience in this procedure, and airway management by physicians who were well-versed in (difficult) airway management. In addition, an ear-nose-throat surgeon participated in the procedure in case conversion of the procedure to an ST should become necessary. We observed a complication that, to our knowledge, has not been reported previously. Five patients developed intermittent respiratory difficulties 2 to 21 days (mean, 8 days) after undergoing PDT. The cause turned out to be the periodic obstruction of the tracheal cannula by hematoma and the swelling of the posterior tracheal wall, which had been caused by intermittent pressure and chafing of the cannula on the tracheal wall. In between the episodes of obstruction, the cannula was open and functioning normally, which made the diagnosis difficult to establish. Conclusions: Bronchoscopy-assisted PDT is a safe and effective procedure when performed by a team of experienced physicians under controlled circumstances. The intermittent obstruction of the cannula caused by swelling and irritation of the posterior tracheal wall should be considered in patients who develop unexplained paroxysmal respiratory problems some time after undergoing PDT or ST