Transabdominal Intrapericardial Approach in Liver Transplantation for Unresectable Primary Hepatic Functioning Paraganglioma With Invasion Into Hepatic Veins and Suprahepatic Vena Cava: A Surgical and Anesthesia Management Challenge.

Primary hepatic functional paraganglioma is a rare form of extra-adrenal catecholamine-secreting tumor. Definitive treatment of functioning paraganglioma is challenging because of the critical location of the tumor frequently in close proximity to vital structures and risk of excessive catecholamine release during operative manipulation. We report the multidisciplinary management approach for a case of unresectable primary hepatic functional paraganglioma with invasion into the hepatic veins and suprahepatic vena cava. To our knowledge, this is the first report showing that orthotopic liver transplantation is curative for patients with unresectable primary hepatic paraganglioma. For locally advanced unresectable hepatic paraganglioma that involves the intrapericardial vena cava, a meticulous pre- and intraoperative medical management and transabdominal intrapericardial vascular control of the suprahepatic vena cava during orthotopic liver transplantation allows for complete extirpation of the tumor and achieves optimal outcome.

Fibrinogen supplementation ex vivo increasesclot firmness comparable to platelet transfusion in thrombocytopenia.

BACKGROUND: Fibrinogen concentrate can improve clot firmness and offers a better safety profile than platelet concentrates. Reduction or avoidance of blood transfusions represents a strategy to reduce associated risks. We investigated whether supplementation of fibrinogen concentrate ex vivo can compensate for clot strength as compared with platelet transfusion in vivo METHODS: One hundred patients in need of platelet transfusion (PT) were enrolled. Blood samples were collected immediately before PT and at 1 h and 24 h after PT. Fibrinogen concentrate was added to these citrated whole blood samples at concentrations of 50, 100, 200 and 400 mg kg-1 and the maximum clot firmness (MCF) was analysed using ROTEM thromboelastometry. RESULTS: Fibrinogen supplementation increased MCF significantly and dose-dependently before and after PT. The effect of fibrinogen concentrate (equivalent to doses of 100 and 200 mg kg-1) ex vivo was comparable to that of PT in vivo, whereas 400 mg kg-1 fibrinogen significantly improved MCF compared with PT (P < 0.001). CONCLUSIONS: Fibrinogen concentrate can match the effect of PT on MCF in thrombocytopenia. This potential alternative haemostatic intervention should be evaluated in clinical trials.

Fibrinogen concentrate improves clot strength in patients with haematological malignancies requiring platelet transfusion.

BACKGROUND: Patients with bone marrow failure secondary to chemotherapy often develop thrombocytopenia and require platelet transfusion. Fibrinogen plays an important role in platelet aggregation and the establishment of the primary haemostatic plug. OBJECTIVES: To compare the effects of in vivo platelet transfusion on clot firmness in thrombocytopenic patients with in vitro-performed fibrinogen concentrate substitution. MATERIALS AND METHODS: Thirty patients with haematological malignancy admitted for platelet transfusion were included. Haemostatic effects from platelet transfusion and ex vivo addition of fibrinogen concentrate at three different doses were evaluated by thromboelastometry, with clot firmness as the primary endpoint (A30 ExTEM assay). Secondary endpoints were other thromboelastometry parameters, thrombin generation parameters, activated partial thromboplastin time (APTT), prothrombin time PT, fibrinogen and factor XIII levels and a clinical bleeding score. RESULTS: Twenty patients (66%) had clinical bleeding signs by prior to transfusion. Platelets increased from 17 (range, 1-109) to 40 (range 2-139) × 10(9) L(-1) following transfusion, with a median corrected count increment of 16·7 (range, 0·8-43·5). The A30 value increased significantly by platelet transfusion from 35 ± 11 to 47 ± 10 mm, with no changes in thrombin generation. Fibrinogen concentrate dose-dependently increased A 30 (to 43 ± 10, 49 ± 9 and 50 ± 9 mm, respectively) and reduced parameters of thrombin generation at high doses. Platelet transfusion, together with fibrinogen concentrate, further increased clot firmness. APTT and PT were within normal range, whereas fibrinogen levels were slightly elevated. CONCLUSION: Fibrinogen concentrate increased clot firmness to the same degree as platelet transfusion in patients with low platelet count requiring platelet transfusion.

Post-operative bilateral adrenal haemorrhage: A case report.

INTRODUCTION: Bilateral adrenal haemorrhage is a rare, but serious, illness carrying an estimated 15% mortality.(1,2) The majority of cases occur in patients with acute, stressful illness, however the exact mechanism underlying adrenal haemorrhage remains unclear. This medical emergency carries significant diagnostic difficulty(4) with non-specific clinical symptoms and variations in electrolyte abnormalities. Timely treatment is important as it prevents both the acute and long-term sequelae of adrenal failure. PRESENTATION OF CASE: This report describes a medical emergency in a surgical patient following emergency surgery for intra-abdominal sepsis. The patient reported non-specific symptoms of confusion, mild pyrexia and vague abdominal pain during the post-operative phase, with subtle electrolyte abnormalities and a low serum cortisol suggestive of adrenal crisis. Timely medical treatment, with intravenous hydrocortisone and intensive monitoring, and appropriate medical follow-up with addition of long-term fludrocortisone resulted in a satisfactory outcome. DISCUSSION: This report describes a potentially life-threatening complication of intra-abdominal sepsis with adrenal crisis secondary to bilateral adrenal haemorrhage. In particular, this case highlights the diagnostic difficulty in such surgical patients due to vague symptoms and, in this case, the presence of a presentation variant with acute hyponatraemia and normal potassium. CONCLUSION: This case highlights the importance of awareness of both the symptoms and signs and variation in electrolyte profile when assessing surgical patients post-operatively. In addition, this case highlights the benefit of early recognition and initiation of treatment and the importance of follow-up as long-term medical management is often required to prevent further relapse.

Systemic stiffening of mouse tail tendon is related to dietary advanced glycation end products but not high-fat diet or cholesterol.

Tendon pathology is related to metabolic disease and mechanical overloading, but the effect of metabolic disease on tendon mechanics is unknown. This study investigated the effect of diet and apolipoprotein E deficiency (ApoE(-/-)) on mechanical properties and advanced glycation end product (AGE) cross-linking of non-weight-bearing mouse tail tendons. Twenty ApoE(-/-) male mice were used as a model for hypercholesterolemia along with 26 wild-type (WT) mice. One-half of the mice from each group was fed a normal diet (ND) and the other half was fed a high-fat diet (HFD) to induce obesity. All were killed at 40 wk, and tail tendon fascicles were mechanically tested to failure and analyzed for AGEs. Diets were also analyzed for AGEs. ApoE(-/-) mice displayed a 14% increase in plateau modulus compared with WT mice (P < 0.05), whereas HFD mice displayed a 13% decrease in plateau modulus (P < 0.05) and a 12% decrease in total modulus (P < 0.05) compared with ND mice. Tail tendons of HFD mice had significantly lower concentrations of AGEs [carboxymethyllysine (CML): 26%, P < 0.0001; methylglyoxal-derived hydroimidazolone 1 (MG-H1): 15%, P < 0.005; pentosidine: 13%, P < 0.0005]. The HFD had ∼44-fold lower content of CML (P < 0.01), ∼29-fold lower content of carboxyethyllysine (P < 0.005), and ∼16-fold lower content of MG-H1 (P < 0.05) compared with ND. ApoE(-/-) increased, whereas HFD decreased mouse tail tendon stiffness. Dietary AGE content may be a crucial determinant for accumulation of AGE cross-links in tendons and for tissue compliance. The results demonstrate how systemic metabolic factors may influence tendon health.

New oral anticoagulants: clinical indications, monitoring and treatment of acute bleeding complications.

New oral anticoagulants like the direct thrombin inhibitor, dabigatran (Pradaxa®), and factor Xa-inhibitors, rivaroxaban (Xarelto®) and apixaban (Eliquis®) are available for prophylaxis and treatment of thromboembolic disease. They are emerging alternatives to warfarin and provide equal or better clinical outcome together with reduced need for routine monitoring. Methods for measuring drug concentrations are available, although a correlation between plasma drug concentrations and the risk of bleeding has not been firmly established. Standard laboratory measures like prothrombin time and activated partial thromboplastin time are not sensitive enough to detect thrombin or factor Xa inhibition provided by new oral anticoagulants. Thus, these standard tests may only be used as a crude estimation of the actual anticoagulation status. Further challenges regarding patients receiving new oral anticoagulants who presents with major bleeding or need for emergency surgery pose a unique problem. No established agents are clinically available to reverse the anticoagulant effect, although preclinical data report prothrombin complex concentrate as more efficient than fresh frozen plasma or other prohaemostatic agents. This review summaries current knowledge on approved new oral anticoagulants and discusses clinical aspects of monitoring, with particular focus on the management of the bleeding patient.

Platelet activation and aggregation: the importance of thrombin activity--a laboratory model.

This study introduces a new laboratory model of whole blood platelet aggregation stimulated by endogenously generated thrombin, and explores this aspect in haemophilia A in which impaired thrombin generation is a major hallmark. The method was established to measure platelet aggregation initiated by tissue factor evaluated by means of impedance aggregometry. Citrated whole blood from healthy volunteers and haemophilia A patients with the addition of inhibitors of the contact pathway and fibrin polymerization was evaluated. In healthy persons, a second wave of platelet aggregation was found to coincide with the thrombin burst and to be abolished by thrombin inhibitors. In this system, platelet aggregation in severe haemophilia A (n = 10) was found to be significantly decreased as compared with healthy individuals (912 ± 294 vs. 1917 ± 793 AU × min, P = 0.003), most probably due to the weak level of thrombin generation. For the first time, analysis of platelet aggregation as induced by endogenously generated thrombin was demonstrated. The new method makes it possible to explore the influence of the coagulation system on platelet function. In contrast to the general understanding, the data suggest that the impaired thrombin generation in haemophilia may affect platelet activation. Future studies will address whether our results may contribute to understanding differences in bleeding phenotypes and response to haemostatic substitution observed among patients.

Breast surgeons performing immediate breast reconstruction with implants - assessment of resource-use and patient-reported outcome measures.

Oncoplastic surgery, including immediate breast reconstruction (IBR), is expanding as a result of public demand. IBR in women with breast carcinoma is resource intense and the reconstruction is often completed concurrently with adjuvant oncological treatment. A series of 223 patients with implant-based IBRs, performed by breast surgeons 2005-2008, were analysed for use of resources and outcome. Low overall major complication rates (19,7%) were identified, even though 41% of the patients had received post-mastectomy radiation. A total of 1.1 reoperations per patient were required. Patient-reported outcomes using the EQ-5D and a disease-specific questionnaire at a median of four years follow-up were analysed. Patients' general health-state was high (0.83), whereas negative impact on intimate situations and the sensibility of the breast was reported. Our audit concludes that trained breast surgeon specialists perform implant-based IBRs with a satisfactory outcome when evaluated by subjective and objective analyses.

Immediate reconstruction with implants in women with invasive breast cancer does not affect oncological safety in a matched cohort study.

Physicians are still concerned about the oncological safety regarding immediate breast reconstruction (IBR) in breast cancer patients. This study aimed to evaluate possible differences between local, regional, and distant recurrences between women having implant-based reconstruction versus women operated with mastectomy alone. Secondary aims were to evaluate time to oncological treatment as well as disease-free and breast-cancer-specific survival. In a retrospective cohort designed study, 300 reconstructed patients with invasive breast cancer were matched with 300 patients from the population-based Regional Breast Cancer Register of the Stockholm-Gotland health-care region operated with mastectomy alone. They were matched for age, tumor size, nodal stage, and year of operation. Also included were patients treated with neoadjuvant chemotherapy and postoperative radiotherapy. The median follow-up for both the groups was 11.5 years (range 2-20). There were no significant differences in the local recurrence rate, 8.2% in the IBR group and 9.0% in the control group or in the regional recurrence rate, 8.2% versus 9.7%. Distant metastases occurred more frequently in the control group (27.1%) when compared to the IBR group (20.3%). There were no significant differences in time to treatment or in complications rate. Breast cancer mortality was 17% for the IBR group and 23% in the control group during follow-up. This long-term follow-up survey with a well-matched control group demonstrates that IBR with implants is safe to offer patients with invasive breast cancer without any negative effect on the oncological safety.

Mechanisms of hydroxyethyl starch-induced dilutional coagulopathy.

BACKGROUND: The biochemical mechanisms causing dilutional coagulopathy following infusion of hydroxyethyl starch 130/0.4 (HES) are not known in detail. OBJECTIVES: To give a detailed biochemical description of the mechanism of coagulopathy following 30%in vivo dilution with HES, to present a systematic ex vivo test of various hemostatic agents, and to investigate the hypothesis that acquired fibrinogen deficiency constitutes the most important determinant of the coagulopathy. METHODS: Dynamic whole blood clot formation assessed by thromboelastometry, platelet count, thrombin generation, and the activities of von Willebrand factor, coagulation factor II, FVII, FVIII, FIX, FX and FXIII were measured in 20 bleeding patients enrolled in a prospective clinical study investigating in vivo substitution of blood loss with HES up to a target level of 30%. Thromboelastometry parameters were further evaluated after ex vivo spiking experiments with fibrinogen, prothrombin complex concentrate (PCC), FXIII, activated recombinant FVIIa (rFVIIa), fresh frozen plasma, and platelets. RESULTS: Hemodilution reduced maximum clot firmness (MCF), whereas whole blood clotting time (CT) and maximum velocity remained unaffected. All coagulation factor activities were reduced. Fibrinogen, FII, FXIII and FX activities decreased significantly below the levels expected from dilution. The endogenous thrombin potential was unchanged. Ex vivo addition of fibrinogen normalized the reduced MCF and increased the maximum velocity, whereas PCC, rFVIIa and platelets shortened the CT but showed no effect on the reduced MCF. CONCLUSIONS: Acquired fibrinogen deficiency seems to be the leading determinant in dilutional coagulopathy, and ex vivo addition corrected the coagulopathy completely.

Fibrinogen substitution improves whole blood clot firmness after dilution with hydroxyethyl starch in bleeding patients undergoing radical cystectomy: a randomized, placebo-controlled clinical trial.

SUMMARY BACKGROUND: Infusion of artificial colloids such as hydroxyethyl starch (HES) induces coagulopathy to a greater extent than simple dilution. Several studies have suggested that the coagulopathy could be corrected by substitution with a fibrinogen concentrate. OBJECTIVES: The aims of the present prospective, randomized, placebo-controlled trial were to investigate the hemostatic effect of a fibrinogen concentrate after coagulopathy induced by hydroxyethyl starch in patients experiencing sudden excessive bleeding during elective cystectomy. METHODS: Twenty patients were included. Blood loss was substituted 1:1 with HES 130/0.4. At a dilution level of 30%, patients were randomly selected for intra-operative administration of a fibrinogen concentrate or placebo. The primary endpoint was maximum clot firmness (MCF), as assessed by thromboelastometry. Secondary endpoints were blood loss and transfusion requirements, other thromboelastometry parameters, thrombin generation and platelet function. RESULTS: Whole-blood MCF was significantly reduced after 30% dilution in vivo with HES. The placebo resulted in a further decline of the MCF, whereas randomized administration of fibrinogen significantly increased the MCF. Furthermore, only 2 out of 10 patients randomly chosen to receive fibrinogen substitution required postoperative red blood cell transfusions, compared with 8 out of 10 in the placebo group (P = 0.023). Platelet function and thrombin generation were reduced after 30% hemodilution in vivo, and fibrinogen administration caused no significant changes. CONCLUSIONS: During cystectomy, fluid resuscitation with HES 130/0.4 during sudden excessive bleeding induces coagulopathy that shows reduced whole-blood maximum clot firmness. Randomized administration of fibrinogen concentrate significantly improved maximum clot firmness and reduced the requirement for postoperative transfusion.

Recombinant factor VIIa and fibrinogen display additive effect during in vitro haemodilution with crystalloids.

BACKGROUND: Major blood loss requires fluid resuscitation for maintaining hemodynamic stability. Excessive volume infusions predispose to dilutional coagulopathy through loss, consumption and dilution of cells and proteins involved in haemostasis. Further treatment with fibrinogen concentrate and/or recombinant activated factor VII (rFVIIa) may be initiated, although the haemostatic effects in a situation with haemodilution are not fully detailed. The present study evaluates haemostatic effect of fibrinogen and rFVIIa and their combination in an in vitro model of haemodiluted whole blood with two commonly used crystalloids. METHODS: Eight healthy, male volunteers were enrolled. Outcome variables were clot initiation, propagation and strength assessed by thrombelastographic parameters: clotting time, clot formation time, maximum velocity, time until maximum velocity, maximum clot firmness evaluated at dilution levels of 0% (control), 10%, 30% and 50% with isotonic saline and Ringer's lactate in a model of tissue factor-activated whole blood. Fibrinogen and rFVIIa were additional final reaction concentrations, reflecting commonly used clinically therapeutic dosages. RESULTS: Dose-dependent coagulopathy developed following haemodilution with isotonic saline and Ringer's lactate, characterised by a prolonged clot initiation, reduced clot propagation and reduced clot strength. Fibrinogen improved clot strength and propagation phase while rFVIIa shortened clot initiation, both with a positive dose dependency. CONCLUSIONS: The combination of fibrinogen and rFVIIa displays an additive effect and improves overall in vitro whole blood clot formation in a model of in vitro crystalloid-induced haemodilution.

Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations.

BACKGROUND: Patients experiencing massive haemorrhage are at high risk of developing coagulopathy through loss, consumption, and dilution of coagulation factors and platelets. It has been reported that plasma fibrinogen concentrations may reach a critical low level relatively early during bleeding, calling for replacement fibrinogen therapy. Cryoprecipitate has been widely used in the past, but more recently, a pasteurized fibrinogen concentrate has become available. We audited the effects of fibrinogen concentrate therapy on laboratory and clinical outcome in patients with massive haemorrhage. METHODS: We identified 43 patients over the previous 2 yr to whom a fibrinogen concentrate had been administered as treatment for hypofibrinogenaemia during serious haemorrhage. Platelet count, P-fibrinogen, activated partial thromboplastin time (APTT), prothrombin time (PT), D-dimer, and volume of blood lost were obtained from medical and laboratory records. Numbers of units of red blood cells (RBC), fresh frozen plasma (FFP), and pooled platelet concentrates were recorded before and after fibrinogen substitution. RESULTS: A significant increase in plasma fibrinogen concentration was observed after fibrinogen concentrate therapy. Platelet counts and fibrin D-dimer values remained unchanged, whereas the APTT and PT improved significantly. Requirements for RBC, FFP, and platelets were significantly reduced. Blood loss decreased significantly. CONCLUSIONS: Off-label substitution therapy with a fibrinogen concentrate generally improved global laboratory coagulation results and as supplementary intervention, appeared to diminish the requirements for RBC, FFP, and platelet substitution in this patient cohort.

Renal effects of hypotensive anaesthesia in combination with acute normovolaemic haemodilution with hydroxyethyl starch 130/0.4 or isotonic saline.

BACKGROUND: Hypotensive anaesthesia (HA) and acute normovolaemic haemodilution (ANH) are used separately to decrease per-operative blood loss. Reducing blood viscosity by adding ANH to HA may appear profitable in a situation with lowered perfusion pressure and concern about organ ischemia. The aim of this study was to clarify the influence of HA in combination with ANH using crystalloid or colloid as replacement fluid on renal function. METHODS: Hypotensive anaesthesia was induced in 11 patients referred to major spine surgery using sevoflurane in combination with fentanyl/remifentanil. Acute normovolaemic haemodilution was carried out by drawing venous blood into standard blood bags and replacing it by isotonic saline 0.9% (Group S) or HES 130/0.4 (Group V). Renal function was evaluated before, during and up to 8 h after hypotension as the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) by means of 51Cr-EDTA and 125I-Hippuran clearances. RESULTS: Lowering mean arterial blood pressure decreased GFR and ERPF in both groups. During hypotension ERPF was lower in Group S (n = 5) than Group V (n = 6). Renal function was normalized postoperatively. We found a positive but non-significant correlation between the relative GFR change and the duration of hypotension. CONCLUSION: In conclusion, our study demonstrated that renal function, assessed by GFR and ERPF, is transiently reduced during the combination of hypotensive anaesthesia and acute normovolaemic haemodilution. A colloid-based fluid regime (HES 130/0.4) used for haemodilution may preserve renal function to a greater extent than a crystalloid-based regime (0.9% saline).

Acoustics and psychosocial environment in intensive coronary care.

BACKGROUND: Stress, strain, and fatigue at the workplace have previously not been studied in relation to acoustic conditions. AIMS: To examine the influence of different acoustic conditions on the work environment and the staff in a coronary critical care unit (CCU). METHOD: Psychosocial work environment data from start and end of each individual shift were obtained from three shifts (morning, afternoon, and night) for a one-week baseline period and for two four-week periods during which either sound reflecting or sound absorbing tiles were installed. RESULTS: Reverberation times and speech intelligibility improved during the study period when the ceiling tiles were changed from sound reflecting tiles to sound absorbing ones of identical appearance. Improved acoustics positively affected the work environment; the afternoon shift staff experienced significantly lower work demands and reported less pressure and strain. CONCLUSIONS: Important gains in the psychosocial work environment of healthcare can be achieved by improving room acoustics. The study points to the importance of further research on possible effects of acoustics in healthcare on staff turnover, quality of patient care, and medical errors.

Thrombelastographic whole blood clot formation after ex vivo addition of plasma substitutes: improvements of the induced coagulopathy with fibrinogen concentrate.

BACKGROUND: Plasma substitutes such as hydroxyethyl starch (HES) and various dextrans may compromise the haemostatic system, thereby causing potentially dangerous bleeding. Whilst several mechanisms have been advanced to explain the nature of the coagulopathy induced by this colloid, there has been comparably little interest in devising ways to optimize haemostasis after a relative colloid overdose. METHODS: Real-time whole blood (WB) clot formation profiles were recorded using a thrombelastographic method employing activation with tissue factor. The coagulation tracings were transformed into dynamic velocity profiles of WB clot formation. WB from healthy individuals (n=20) was exposed to haemodilution of approximately 55% with isotonic saline, HES 200/0.5, HES 130/0.4, and dextran 70, respectively. Possible modalities for improvement of the induced coagulopathy were explored, in particular ex vivo addition of a fibrinogen concentrate. RESULTS: WB coagulation profiles changed significantly with decreased clot strength, and a compromised propagation phase of clot formation. The duration of the initiation phase of WB coagulation was unchanged. No statistical differences were detected amongst the HES solutions and dextran 70. However, dextran 70 returned a more suppressed clot development and strength compared with the HES solutions. Ex vivo haemostatic addition of washed platelets (75 x 10(9) litre(-1)) and factor VIII (0.6 IU ml(-1)) produced insignificant changes in clot initiation, propagation, and in the clot strength. In contrast, ex vivo addition of a fibrinogen concentrate (1 g litre(-1)) improved the coagulopathy induced by all of the three individual plasma expanders tested. CONCLUSION: Coagulopathy induced by haemodilution with either HES 200/0.5, HES 130/0.4, and dextran 70 may be improved by fibrinogen supplementation.