Fabrizio Gronchi

Comparison of porcine and human coagulation by thrombelastometry

INTRODUCTION Although the pig is a standard model for the evaluation of various diseases in humans, including coagulopathy, it is not clear whether results in animals can be extrapolated to man. MATERIALS AND METHODS In 75 anesthetized pigs, we assessed reagent-supported thrombelastometry (ExTEM®), platelet-blocked thrombelastometry (FibTEM®), and aprotinin thrombelastometry (ApTEM®). Results were compared to values from 13 anesthetized humans. RESULTS (MEDIAN, 95% CI): ExTEM®: While clot strength was comparable in pigs (66 mm, 65-67 mm) and in humans (64 mm, 60-68 mm; NS), clotting time in animals was longer (pigs 64 s, 62-66 s; humans 55 s, 49-71 s; P<0.05) and clot formation time shorter (pigs 52 s, 49-54 s; humans 83 s, 67-98 s, P<0.001). The clot lysis index at 30 minutes was lower in animals (96.9%, 95.1-97.3%) than in humans (99.5%, 98.6-99.9%; P<0.001). ApTEM® showed no hyperfibrinolysis in animals. Modification of the anesthesia protocol in animals resulted in significant ExTEM® changes. FibTEM®: Complete platelet inhibition yielded significantly higher platelet contribution to clot strength in pigs (79%, 76-81%) than in humans (73%, 71-77%; P<0.05), whereas fibrinogen contribution to clot strength was higher in humans (27%, 24-29%) than in animals (21%, 19-24%; P<0.05). CONCLUSIONS Maximum clot firmness is comparable in human and porcine blood. However, clot lysis, platelet and fibrinogen contribution to clot strength, as well as initiation and propagation of clotting, are considerably different between pigs and humans. In addition, anesthesic drugs seem to influence thrombelastometry in animals. Accordingly, coagulation abnormalities in pigs subjected to diseases may not necessarily represent the coagulation profile in sick patients.

Validation of rotational thromboelastometry during cardiopulmonary bypass A prospective, observational in-vivo study

BACKGROUND Rotational thromboelastometry (ROTEM) is a whole blood point-of-test used to assess the patients coagulation status. Three of the available ROTEM tests are EXTEM, INTEM and HEPTEM. In the latter, heparinase added to the INTEM reagent inactivates heparin to reveal residual heparin effect. Performing ROTEM analysis during cardiopulmonary bypass (CPB) might allow the anaesthesiologist to anticipate the need for blood products. OBJECTIVE The goal of this study was to validate ROTEM analysis in the presence of very high heparin concentrations during CPB. DESIGN Prospective, observational trial. SETTING Single University Hospital. PARTICIPANTS Twenty patients undergoing coronary artery bypass grafting. MAIN OUTCOME MEASURE ROTEM analysis was performed before heparin administration (T0), 10 min after heparin (T1), at the end of CPB (T2) and 10 min after protamine (T3). The following tests were performed: EXTEM, INTEM, and HEPTEM. Heparin concentrations were measured at T1 and at the end of bypass (T2). RESULTS At T1, EXTEM differed from baseline for coagulation time: +26.7 s (18.4 to 34.9, P < 0.0001), &agr;: −3° (1.0 to 5.4, P = 0.006) and A10: −4.4 mm (2.3 to 6.5, P = 0.0004). INTEM at T0 was different from HEPTEM at T1 for coagulation time: + 47 s (34.3 to 59.6, P >0.0001), A10: −2.3 mm (0.5 to 4.0, P = 0.01) and &agr; −2° (1.0 to 3.0; P = 0.0007). At T2, all parameters in EXTEM and HEPTEM related to fibrin-platelet interaction deteriorated significantly compared to T1. At T3, EXTEM and INTEM were comparable to EXTEM and HEPTEM at T2. CONCLUSION HEPTEM and EXTEM measurements are valid in the presence of very high heparin concentrations and can be performed before protamine administration in patients undergoing cardiac surgery with CPB. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01455454.

Pharmacological Reconditioning of Marginal Donor Rat Lungs Using Inhibitors of Peroxynitrite and Poly (ADP-ribose) Polymerase During Ex Vivo Lung Perfusion.

Background Donor lungs obtained after prolonged warm ischemia (WI) may be unsuitable for transplantation due to the risk of reperfusion injury, but could be reconditioned using ex-vivo lung perfusion (EVLP). Key processes of reperfusion injury include the formation of reactive oxygen species (ROS)/nitrogen species (RNS) and the activation of poly(adenosine diphosphate-ribose) polymerase (PARP). We explored whether rat lungs obtained after WI could be reconditioned during EVLP using the ROS/RNS scavenger Mn(III)-tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) or the PARP inhibitor 3-aminobenzamide (3-AB). Methods Rat lungs obtained after 3 hours cold ischemia (CI group, control), or 1 hour WI plus 2 hours CI (WI group) were placed in an EVLP circuit for normothermic perfusion for 3 hours. Lungs retrieved after WI were treated or not with 3-AB (1 mg/mL) or MnTBAP (0.3 mg/mL), added to the perfusate. Measurements included physiological variables (lung compliance, vascular resistance, oxygenation capacity), lung weight gain, levels of proteins, lactate dehydrogenase, protein carbonyl (marker of ROS), 3-nitrotyrosine (marker of RNS), poly(adenosine diphosphate-ribose) (PAR, marker of PARP activation) and IL-6, in the bronchoalveolar lavage or the lung tissue, and histology. Results In comparison to the CI group, the lungs from the WI group displayed higher protein carbonyls, 3-nitrotyrosine, PAR, lactate dehydrogenase and proteins in bronchoalveolar lavage, lung weight gain, perivascular edema, as well as reduced static compliance, but similar oxygenation. All these alterations were markedly attenuated by 3-AB and MnTBAP. Conclusions After EVLP, lungs obtained after WI exhibit oxidative stress, PARP activation, and tissue injury, which are suppressed by pharmacological inhibitors of ROS/RNS and PARP.

Extracorporeal support for pulmonary resection: current indications and results

Extracorporeal assistances are exponentially used for patients, with acute severe but reversible heart or lung failure, to provide more prolonged support to bridge patients to heart and/or lung transplantation. However, experience of use of extracorporeal assistance for pulmonary resection is limited outside lung transplantation. Airways management with standard mechanical ventilation system may be challenging particularly in case of anatomical reasons (single lung), presence of respiratory failure (ARDS), or complex tracheo-bronchial resection and reconstruction. Based on the growing experience during lung transplantation, more and more surgeons are now using such devices to achieve good oxygenation and hemodynamic support during such challenging cases. We review the different extracorporeal device and attempt to clarify the current practice and indications of extracorporeal support during pulmonary resection.

Pyrrolidine dithiocarbamate administered during ex-vivo lung perfusion promotes rehabilitation of injured donor rat lungs obtained after prolonged warm ischemia

Damaged lung grafts obtained after circulatory death (DCD lungs) and warm ischemia may be at high risk of reperfusion injury after transplantation. Such lungs could be pharmacologically reconditioned using ex-vivo lung perfusion (EVLP). Since acute inflammation related to the activation of nuclear factor kappaB (NF-κB) is instrumental in lung reperfusion injury, we hypothesized that DCD lungs might be treated during EVLP by pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB. Rat lungs exposed to 1h warm ischemia and 2 h cold ischemia were subjected to EVLP during 4h, in absence (CTRL group, N = 6) or in presence of PDTC (2.5g/L, PDTC group, N = 6). Static pulmonary compliance (SPC), peak airway pressure (PAWP), pulmonary vascular resistance (PVR), and oxygenation capacity were determined during EVLP. After EVLP, we measured the weight gain of the heart-lung block (edema), and the concentration of LDH (cell damage), proteins (permeability edema) and of the cytokines IL-6, TNF-α and CINC-1 in bronchoalveolar lavage (BAL), and we evaluated NF-κB activation by the degree of phosphorylation and degradation of its inhibitor IκBα in lung tissue. In CTRL, we found significant NF-κB activation, lung edema, and a massive release of LDH, proteins and cytokines. SPC significantly decreased, PAWP and PVR increased, while oxygenation tended to decrease. Treatment with PDTC during EVLP inhibited NF-κB activation, did not influence LDH release, but markedly reduced lung edema and protein concentration in BAL, suppressed TNFα and IL-6 release, and abrogated the changes in SPC, PAWP and PVR, with unchanged oxygenation. In conclusion, suppression of innate immune activation during EVLP using the NF-κB inhibitor PDTC promotes significant improvement of damaged rat DCD lungs. Future studies will determine if such rehabilitated lungs are suitable for in vivo transplantation.

A New Combined Technique Reducing the Risk of Paraplegia during Thoracoabdominal Aorta Replacement

Acute spinal cord ischemia during thoracoabdominal aorta replacement is a dreadful complication. Existing tools (motor evoked potential [MEP] and somatosensory evoked potential [SSEP]) do not allow differentiating between central and peripheral paraplegia. Therefore, the surgeon often performs unnecessary reimplantation of intercostal arteries: this is time consuming, and significantly increases bleeding complications. We present a simple technique combining MEP and peripheral compound muscle action potential induced by posterior tibialis nerve stimulation, enabling the surgeon to quickly discriminate between central and peripheral neurologic injury. The surgeon has one more tool to drive in real time the optimal surgical strategy. This strategy guides the decision as to which side branches ought to be reimplanted, thus minimizing the risk of paraplegia.

The influence of drugs used in cardiac anaesthesia and critical care on multiple electrode aggregometry: an in-vitro volunteer study.

BACKGROUND Multiple electrode aggregometry (MEA) is a point-of-care test evaluating platelet function and the efficacy of platelet inhibitors. In MEA, electrical impedance of whole blood is measured after addition of a platelet activator. Reduced impedance implies platelet dysfunction or the presence of platelet inhibitors. MEA plays an increasingly important role in the management of perioperative platelet dysfunction. In vitro, midazolam, propofol, lidocaine and magnesium have known antiplatelet effects and these may interfere with MEA interpretation. OBJECTIVE To evaluate the extent to which MEA is modified in the presence of these drugs. DESIGN An in-vitro study using blood collected from healthy volunteers. SETTING Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, 2010 to 2011. PATIENTS Twenty healthy volunteers. INTERVENTION Measurement of baseline MEA was using four activators: arachidonic acid, ADP, TRAP-6 and collagen. The study drugs were then added in three increasing, clinically relevant concentrations. MAIN OUTCOME MEASURE MEA was compared with baseline for each study drug. RESULTS Midazolam, propofol and lidocaine showed no effect on MEA at any concentration. Magnesium at 2.5 mmol l−1 had a significant effect on the ADP and TRAP tests (31 ± 13 and 96 ± 39 AU, versus 73 ± 21 and 133 ± 28 AU at baseline, respectively), and a less pronounced effect at 1 mmol l−1 on the ADP test (39 ± 0 AU). CONCLUSION Midazolam, propofol and lidocaine do not interfere with MEA measurement. In patients treated with high to normal doses of magnesium, MEA results for ADP and TRAP-tests should be interpreted with caution. TRIAL REGISTRATION Clinicaltrials.gov (no. NCT01454427)

An enhanced recovery after surgery program for video-assisted thoracoscopic surgery anatomical lung resections is cost-effective

Background Enhanced recovery after surgery (ERAS) programs have been reported to decrease complications and shorten hospital stays after lung resections, but their implementation requires time and financial investment with dedicated staff. The aim of this study was to evaluate the clinical and economic outcomes of video-assisted thoracoscopic surgery (VATS) anatomical pulmonary resections before and after implementation of an ERAS program. Methods The first 50 consecutive patients undergoing VATS lobectomy or segmentectomy for malignancy after implementation of an ERAS program were compared with 50 consecutive patients treated before its introduction. The ERAS protocol included preoperative counseling, reduced preoperative fasting with concomitant carbohydrate loading, avoidance of premedication, standardized surgery, anesthesia and postoperative analgesia, early removal of chest tube, nutrition and mobilization. Length of stay, readmissions and cardio-pulmonary complications within 30 days were compared. Total costs were collected for each patient and a cost-minimization analysis integrating ERAS-specific costs was performed. Results Both groups were similar in terms of demographics and surgical characteristics. The ERAS group had significantly shorter postoperative length of stay (median: 4 vs. 7 days, P<0.0001), decreased pulmonary complications (16% vs. 38%; P=0.01) and decreased overall post-operative complications (24% vs. 48%, P=0.03). One patient in each group was readmitted and there was no 30-day mortality. ERAS-specific costs were calculated at €729 per patient including the clinical nurse and database costs. Average total hospitalization costs were significantly lower in ERAS group (€15,945 vs. €20,360, P<0.0001), mainly due to lower costs during the post-operative period (€7,449 vs. €11,454, P<0.0001) in comparison with the intra-operative period (€8,496 vs. €8,906, P=0.303). Cost-minimization analysis showed a mean saving in the ERAS group of €3,686 per patient. Conclusions An ERAS program for VATS anatomical lung resection is cost-effective and is associated with a lower complication rate and a shorter postoperative hospitalization.

Extracorporeal total artificial heart as bailout surgery

We report the use of a total extracorporeal heart for uncontrolled bleeding following a proximal left anterior descending artery perforation, using two centrifugal ventricular assist devices after heart explantation. The literature describing similar techniques and patient outcomes for this “bailout” technique are reviewed.

Perioperative Coagulation in Cardiovascular Surgery

The evolution of scientific knowledge in cardiac surgery and cardiopulmonary bypass has enabled the reduction of perioperative complications, despite an increase in patient-related risks and in the complexity of surgical procedures. However, the management of hemostasis and coagulation remains a difficult issue, and it is of note that the rates of allogeneic blood transfusion and surgical revision in bleeding patients have not declined in recent years. The perioperative coagulopathy in patients undergoing cardiac surgical procedures is a highly complex and challenging field, and appropriate management is essential to improve morbidity and mortality. Identifying the patient’s preoperative hemorrhagic risk factors and understanding the mechanisms involved in coagulopathy and fibrinolysis during cardiopulmonary bypass are crucial for the patient’s care. Today, the use of practice guidelines and point-of-care testing is an established part of the management of the bleeding patient. In this chapter, we review the state of knowledge on perioperative hemostasis management in cardiac surgery and describe some specific points on the pathophysiology and pharmacology of CPB-related coagulopathies.