Barbara Steinlechner

Platelet Dysfunction in Outpatients With Left Ventricular Assist Devices

BACKGROUND Thromboembolic and bleeding complications in outpatients with a left ventricular assist device are common and can be detrimental. A meticulous balance between anticoagulant and procoagulant factors is therefore crucial. However, in contrast to routinely performed plasmatic coagulation tests, platelet function is hardly ever monitored although recent reports indicated platelet dysfunction. We therefore differentially evaluated platelet function with four commonly used point-of-care devices. METHODS In a cross-sectional design platelet function was assessed in 12 outpatients and 12 healthy matched volunteers using thrombelastography platelet mapping, thromboelastometry, platelet function analyzer, and a new whole blood aggregometer (Multiplate). RESULTS Phenprocoumon produced an international normalized ratio of 3.5. It was associated with a twofold prolongation in the thromboelastometry clotting time (p < 0.001). Platelet function under high shear was severely compromised: collagen adenosine diphosphate closure times were 2.5-fold longer in patients than in volunteers (p < 0.001), and 50% of patients had maximal collagen adenosine diphosphate closure time values. Although antigen levels of von Willebrand factor were 80% higher in patients (p < 0.001), von Willebrand factor-ristocetin was subnormal in 5 of 12 patients. Ristocetin-induced aggregation was also threefold higher in volunteers (p < 0.001), indicating an additional functional defect of platelets affecting the glycoprotein Ib-von Willebrand factor axis. The von Willebrand factor multimer pattern in patients also appeared abnormal. CONCLUSIONS Multimodal antiplatelet monitoring showed markedly impaired platelet function in patients with a left ventricular assist device. Platelet dysfunction under high shear rates and abnormal ristocetin-induced aggregation is only partly attributable to low von Willebrand factor activity. These findings resemble the acquired von Willebrand syndrome that is associated with microaggregate formation and enhanced bleeding.

Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia

We hypothesized that infusion of recombinant human antithrombin without concomitant heparin would have dose‐dependent anticoagulant properties and potentially decrease endotoxin (lipopolysaccharide [LPS])–induced cytokine production. This was a randomized, double‐blind, placebo‐controlled study in parallel groups enrolling 30 healthy male volunteers. The active treatment groups received infusions of recombinant human antithrombin to increase antithrombin levels to 200% and 500% before infusion of 2 ng/kg endotoxin (LPS). Infusion of antithrombin dose‐dependently decreased coagulation (P<.01 by repeated‐measures ANOVA): peak levels of prothrombin fragment (1.8 nmol/L [95% confidence interval (CI), 1.3–2.3 nmol/L] in the 500% antithrombin group and 4.4 nmol/L [95% CI, 2.7–6.2 nmol/L] in the placebo group at 4 hours), thrombin antithrombin complexes (12 μg/L [95% CI, 8–16 μg/L] in the 500% antithrombin group and 34 μg/L [95% CI, 20–48 μg/L] in the placebo group at 4 hours), and D‐dimer (0.2 μg/L [95% CI, 0.1–0.2 μg/L] in the 500% antithrombin group and 0.5 μg/L [95% CI, 0.4–0.7 μg/L] in the placebo group). Recombinant human antithrombin decreased peak interleukin‐6 levels by 40% (222 pg/mL [95% CI, 148–295 pg/mL] and 216 pg/mL [95% CI, 112–320 pg/mL] in the 500% and 200% antithrombin groups, respectively, versus 357 pg/mL [95% CI, 241–474 pg/mL] in the placebo group; P<.001 by ANOVA). Finally, infusion of recombinant human antithrombin rapidly and transiently decreased neutrophil counts (by 19% [95% CI, 8%–30%] in the 500% antithrombin group versus 6% [95% CI, 1%–10%] in the placebo group, P = .002 by Kruskal‐Wallis ANOVA) and monocyte counts (by 30% [95% CI, 16%–44%] in the 500% antithrombin group and 18% [95% CI, 9%‐28%] in the 200% antithrombin group versus 8% [95% CI, 5%‐20%] in the placebo group, P = .04) before LPS challenge, indicating that recombinant human antithrombin directly interacts with these leukocyte subsets. In summary, recombinant human antithrombin dose‐dependently inhibited tissue factor‐triggered coagulation. Effects on leukocytes and inhibition of interleukin‐6 release seem to represent specific pharmacodynamic properties of recombinant human antithrombin.

Patients With Severe Aortic Valve Stenosis and Impaired Platelet Function Benefit From Preoperative Desmopressin Infusion

BACKGROUND Patients with severe aortic valve stenosis have a markedly reduced platelet function as measured by a prolonged collagen adenosine diphosphate closure time (CADP-CT) determined by the platelet function analyzer PFA-100. We hypothesized that such patients may benefit from desmopressin when they present with prolonged CADP-CT due to the specific action of desmopressin on von Willebrand factor (VWF) and CADP-CT. METHODS In this double-blind, randomized placebo controlled trial, 43 patients undergoing aortic valve replacement (due to severe aortic valve stenosis with CADP-CT>170 seconds) were given desmopressin 0.3 μg/kg or saline intravenously after induction of anesthesia. Measurement of CADP-CT, factor VIII activity, von Willebrand factor antigen, GpIb binding activity, ristocetin cofactor activity, collagen-binding activity, and multimers were performed after induction of anesthesia, one hour after desmopressin infusion, and 24 hours postoperatively. RESULTS In the majority of patients, baseline values of von Willebrand factor related indices were normal, but increased one hour after infusion of desmopressin by 73% to 90% as compared with placebo. Selective loss of high molecular weight multimers was seen only in a minority of patients. The CADP-CT was greater than 170 seconds in 92% of screened patients, and desmopressin shortened CADP-CT by 48% versus baseline and reduced postoperative blood loss by 42% (p<0.001). CONCLUSIONS Prolonged CADP-CT indicates platelet dysfunction in severe aortic valve stenosis, and can guide the use of desmopressin as an effective prohemostatic agent in patients with severe aortic valve stenosis.

Preoperative patient optimization using extracorporeal life support improves outcomes of INTERMACS Level I patients receiving a permanent ventricular assist device.

OBJECTIVES Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS) Level I patients have the highest early mortality after ventricular assist device (VAD) implantation. This is determined by the exposure of patients in shock with acutely damaged end-organs and high catecholamine support to a significant surgical trauma. We report our experience with a bridge-to-bridge concept consisting of initial veno-arterial extracorporeal life support (ECLS) and deferral of VAD implantation to recovery of end-organ function in INTERMACS Level I patients. METHODS We reviewed the concept of initial ECLS implantation and deferral of VAD implantation to end-organ recovery in 22 consecutive patients (mean age 54 ± 14 years; 72.2% males; 50% ischemic cardiomyopathy; 100% INTERMACS Level I; 18.2% Heartmate II, 68.2% Heartware HVAD, 4.5% Heartware BiVAD, 9.1% DeBakey LVAD) receiving a VAD for refractory cardiogenic shock between June 2004 and February 2013. Study endpoints were end-organ recovery during ECLS and survival. RESULTS ECLS significantly improved renal (creatinine 1.86 ± 0.91 vs 1.32 ± 0.52 mg/dl, P = 0.02), hepatic (aspartate aminotransferase 1426 ± 2176 vs 277 ± 259 U/l, P = 0.04; alanine aminotransferase 982 ± 1466 vs 357 ± 447 U/l, P = 0.04) and pulmonary functions (fraction of inspired oxygen 52 ± 18 vs 26 ± 23%, P < 0.01; positive end-expiratory pressure 7 ± 3 vs 5 ± 4 mbar, P = 0.02) over a period of 8 ± 7 days. Catecholamines could be reduced during ECLS (levosimendan 0.056 ± 0.085 vs 0.010 ± 0.032 μg/kg/min, P = 0.06; dobutamine 4.362 ± 5.268 vs 0.056 ± 0.097 μg/kg/min, P = 0.06; noradrenaline 0.408 ± 0.355 vs 0.056 ± 0.097 μg/kg/min, P < 0.01). Thirty-day and in-hospital mortality after VAD implantation were 4.5 and 9.1%, respectively, and 1-year survival was 86.4%. CONCLUSIONS Preoperative patient optimization using ECLS improves outcomes of INTERMACS Level I patients receiving a permanent VAD.

Effects and limitations of an AED with audiovisual feedback for cardiopulmonary resuscitation: a randomized manikin study.

PURPOSE Correctly performed basic life support (BLS) and early defibrillation are the most effective measures to treat sudden cardiac arrest. Audiovisual feedback improves BLS. Automated external defibrillators (AED) with feedback technology may play an important role in improving CPR quality. The aim of this simulation study was to investigate if an AED with audiovisual feedback improves CPR parameters during standard BLS performed by trained laypersons. METHODS With ethics committee approval and informed consent, 68 teams (2 flight attendants each) performed 12 min of standard CPR with the AEDs audiovisual feedback mechanism enabled or disabled. We recorded CPR quality parameters during resuscitation on a manikin in this open, prospective, randomized controlled trial. Between the feedback and control-group we measured differences in compression depth and rate as main outcome parameters and effective compressions, correct hand position, and incomplete decompression as secondary outcome parameters. An effective compression was defined as a compression with correct depth, hand position, and decompression. RESULTS The feedback-group delivered compression rates closest to the recommended guidelines (101 ± 9 vs. 109 ± 15/min, p=0.009), more effective compressions (20 ± 18 vs. 5 ± 6%, p<0.001), more compressions with correct hand position (96 ± 13 vs. 88 ± 16%, p<0.001), and less leaning (21 ± 31 vs. 77 ± 33%, p<0.001). However, only the control-group adhered to the recommended compression depth (44 ± 7 mm vs. 39 ± 6, p=0.003). CONCLUSION Use of an AEDs audiovisual feedback system improved some CPR-quality parameters, thus confirming findings of earlier studies with the notable exception of decreased compression depth, which is a key parameter that might be linked to reduced cardiac output.

Low molecular weight heparin as an alternative to unfractionated heparin in the immediate postoperative period after left ventricular assist device implantation.

We present a regimen for anticoagulation in the immediate postoperative period after left ventricular assist device (LVAD) implantation using low molecular weight heparin (LMWH) as an alternative to unfractionated heparin. Between May and September 2007, eight consecutive patients undergoing LVAD implantation for advanced heart failure received the LMWH nadroparin. Nadroparin was given twice daily to achieve anti-Factor Xa activity target peak levels of 0.4 +/- 0.1 U/mL. The antiplatelet therapy consisted of aspirin (100 mg/day) and dipyridamole (3 x 75 mg/day). One patient underwent heart transplantation, three patients died, and four patients continued to receive device support. The median duration of support was 78 days (range, 46 to 174). No major bleeding was observed; minor bleeding occurred in three patients. In two patients, pump thrombosis was suspected. There were two ischemic and no hemorrhagic strokes. The use of LMWH may provide a new anticoagulation treatment option in the immediate postoperative period after LVAD implantation.

Neuronal injury after repeated brief cardiac arrests during internal cardioverter defibrillator implantation is associated with deterioration of cognitive function.

To determine the degree of neurocognitive dysfunction after placement of internal cardioverter defibrillators (ICD) and its relationship to the extent of neuronal injury, we studied 42 patients undergoing ICD (n = 21) or pacemaker (PM) insertion (control patients, n = 21). The Mini Mental State Examination, the Trailmaking A test and the forward and backward Digit Span tests were used and P300 latencies were determined preoperatively and postoperatively. Serum neuron-specific enolase (NSE) was determined before and at the end of, as well as 2, 6, and 24 h after surgery. Preoperatively, PM patients scored worse in the Digit Span backward and the Trailmaking tests and showed prolonged P300 latencies. Postoperatively, the Digit Span backward scores declined and NSE levels increased only in the ICD group (P ≤ 0.05). The difference between preoperative and postoperative Digit Span backward scores correlated with the increase in serum NSE levels (r2 = 0.3, P ≤ 0.05). Moreover, P300 latencies increased in 13 of 17 ICD patients, but decreased in 7 of 10 PM patients (P ≤ 0.05). PM patients even improved in the Trailmaking test (P ≤ 0.05). Neuronal injury from even brief periods of global brain ischemia seems to be associated with deteriorating neurocognitive function.

Intravenous immunoglobulins induce CD32-mediated platelet aggregation in vitro.

Background  Intravenous immunoglobulins (IVIg) and cytomegalovirus immunoglobulins (CMVIg) are currently finding increased acceptance in clinical states of high immune activity and in transplant recipients. A rare side‐effect of their application is intravascular thrombosis, which is thought to be related to pre‐existing hyperviscosity. In a previous study we have shown that rabbit antithymocyte globulin causes platelet aggregation in vitro via the Fc IgG receptor (CD32).

Performance of supraglottic airway devices and 12 month skill retention: A randomized controlled study with manikins

PURPOSE Airway management for successful ventilation by laypersons and inexperienced healthcare providers is difficult to achieve. Bag-valve mask (BVM) ventilation requires extensive training and is performed poorly. Supraglottic airway devices (SADs) have been successfully introduced to clinical resuscitation practice as an alternative. We evaluated recently introduced (i-gel™ and LMA-Supreme™) and established SADs (LMA-Unique™, LMA-ProSeal™) and BVM used by laypeople in training sessions on manikins. METHODS In this randomized controlled study, 267 third-year medical students participated with informed consent and IRB approval. After brief standardized training, each participant applied all devices in a randomized order. Success of device application and ventilation was recorded. Without further training, skill retention was assessed in the same manner 12 months later. Outcome parameters were the number of application attempts, application time, tidal volume and gastric inflation rate recorded at successful attempts, and subjective ease-of-use rating by the participants. RESULTS i-gel™ and LMA-Supreme™ were the most successful in the first attempt at both assessments and in the subjective ease-of-use rating. The shortest application time was found with BVM (8 ± 5s in 2008 vs. 9 ± 5s in 2009) and i-gel (10 ± 3s vs. 12 ± 5s). Tidal volumes were disappointing with no device reaching 50% volume within the recommended range (0.4-0.6L). Gastric inflation rate was highest with BVM (18% vs. 20%) but significantly lower with all SADs (0.4-6%; p < 0.001 for 2008 and 2009). CONCLUSION SADs showed clear advantages over BVM. Compared with LMA-Unique™ and LMA-ProSeal™, i-gel™ and LMA-Supreme™ led to higher first-attempt success rates and a shorter application time.

A randomized controlled trial of femoral nerve blockade administered preclinically for pain relief in femoral trauma.

BACKGROUND:Analgesia at the location of the accident and on transport for femoral trauma is often delayed or insufficient. In this prospective, randomized, controlled study, we evaluated the preclinical use of femoral nerve blockade for reducing pain and anxiety compared with IV analgesia using metamizol. METHODS:Patients with painful femoral trauma, such as fracture or severe contusion, were randomized to receive at the site of the accident a femoral nerve blockade (n = 31) or IV analgesia with metamizol (n = 31). A visual analog scale (VAS) was used to assess pain and anxiety. Variables were assessed at baseline, during transport and upon arrival at the hospital. RESULTS:In patients receiving the femoral nerve blockade, pain values decreased by half from VAS 86 ± 6 mm at the site of the accident to VAS 41 ± 15 mm during transport. Anxiety decreased by half from VAS 84 ± 11 mm to VAS 39 ± 14 mm. Heart rate decreased by 20 ± 5 bpm. In the metamizol group, pain, anxiety, and heart rate did not decrease (P < 0.001). Time of treatment was 7.4 ± 3.5 min longer in the femoral nerve blockade group. CONCLUSION:Preclinically administered femoral nerve blockade effectively decreases pain, anxiety, and heart rate after femoral trauma. Regional blockade is an option for out-of-hospital analgesia administered by a trained physician.