Treatment of end-stage peripheral artery disease by neuromodulation.

BACKGROUND: Neuromodulation is a therapeutic option to improve limb salvage in end-stage peripheral arterial disease (PAD), but there is no consensus on its indication for spinal cord stimulation (SCS) in PAD patients. OBJECTIVE: The aim of this study was to present the outcome of end-stage PAD patients treated with SCS. METHODS: This study is a retrospective analysis based on a local prospective registry. Neuromodulation was performed if there was: 1) no revascularisation option, 2) no septicemia, 3) and Rutherford stage 4-6. The primary endpoint of the study was limb salvage. Secondary endpoints were reduction in pain or simply pain reduction pain (assessed using a visual anlog scale/VAS) and improvement in walking distance. RESULTS: Limb salvage was reached in 30/34 patients (88%). Patients reported a significant reduction in pain on the 10-point VAS scale from baseline (median = 7.5, IQR = 7-8) to follow-up at 2 years (median = 0, IQR 0-2.75), p < 0.001. Walking distance also improved from preoperative (median = 50 m, IQR = 20-50 m) to follow-up at 2 years (median = 150 m, IQR 50-272 m), p < 0.001. RESULTS: SCS implantation in patients with end-stage PAD can enable limb salvage in a high percentage of cases and increase mobility due to pain reduction. The role of microcirculation in these improvements needs to be investigated in further studies.

Ice Sheet and Climate Processes Driving the Uncertainty in Projections of Future Sea Level Rise: Findings From a Structured Expert Judgement Approach.

The ice sheets covering Antarctica and Greenland present the greatest uncertainty in, and largest potential contribution to, future sea level rise. The uncertainty arises from a paucity of suitable observations covering the full range of ice sheet behaviors, incomplete understanding of the influences of diverse processes, and limitations in defining key boundary conditions for the numerical models. To investigate the impact of these uncertainties on ice sheet projections we undertook a structured expert judgement study. Here, we interrogate the findings of that study to identify the dominant drivers of uncertainty in projections and their relative importance as a function of ice sheet and time. We find that for the 21st century, Greenland surface melting, in particular the role of surface albedo effects, and West Antarctic ice dynamics, specifically the role of ice shelf buttressing, dominate the uncertainty. The importance of these effects holds under both a high-end 5°C global warming scenario and another that limits global warming to 2°C. During the 22nd century the dominant drivers of uncertainty shift. Under the 5°C scenario, East Antarctic ice dynamics dominate the uncertainty in projections, driven by the possible role of ice flow instabilities. These dynamic effects only become dominant, however, for a temperature scenario above the Paris Agreement 2°C target and beyond 2100. Our findings identify key processes and factors that need to be addressed in future modeling and observational studies in order to reduce uncertainties in ice sheet projections.

Long-Term Venovenous Connection for Extracorporeal Carbon Dioxide Removal (ECCO2R)-Numerical Investigation of the Connection to the Common Iliac Veins.

PURPOSE: Currently used cannulae for extracorporeal carbon dioxide removal (ECCO2R) are associated with complications such as thrombosis and distal limb ischemia, especially for long-term use. We hypothesize that the risk of these complications is reducible by attaching hemodynamically optimized grafts to the patient's vessels. In this study, as a first step towards a long-term stable ECCO2R connection, we investigated the feasibility of a venovenous connection to the common iliac veins. To ensure its applicability, the drainage of reinfused blood (recirculation) and high wall shear stress (WSS) must be avoided. METHODS: A reference model was selected for computational fluid dynamics, on the basis of the analysis of imaging data. Initially, a sensitivity analysis regarding recirculation was conducted using as variables: blood flow, the distance of drainage and return to the iliocaval junction, as well as the diameter and position of the grafts. Subsequently, the connection was optimized regarding recirculation and the WSS was evaluated. We validated the simulations in a silicone model traversed by dyed fluid. RESULTS: The simulations were in good agreement with the validation measurements (mean deviation 1.64%). The recirculation ranged from 32.1 to 0%. The maximum WSS did not exceed 5.57 Pa. The position and diameter of the return graft show the highest influence on recirculation. A correlation was ascertained between recirculation and WSS. Overall, an inflow jet directed at a vessel wall entails not only high WSS, but also a flow separation and thereby an increased recirculation. Therefore, return grafts aligned to the vena cava are crucial. CONCLUSION: In conclusion, a connection without recirculation could be feasible and therefore provides a promising option for a long-term ECCO2R connection.

Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab.

BACKGROUND: Some phase 2 trials had reported encouraging progression-free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma. METHODS: We used Immunochemical analysis on tumor samples and pretreatment and post-treatment perfusion-MRI to try to identify possible predictive angiogenesis-related biomarkers of response and survival in patients with glioblastoma treated with bevacizumab in the first recurrence. We analyzed histological parameters: vascular proliferation, mitotic number and Ki-67 index; molecular factors: MGMT promoter methylation, EGFR amplification and EGFR variant III; immunohistochemical: MET, Midkine, HIF1, VEGFA, VEGF-R2, CD44, Olig2, microvascular area and microvascular density; and radiological: rCBV. RESULTS: In the statistical analysis, no significant correlation of any histological, molecular, microvascular or radiological parameters could be demonstrated with the response rate, PFS or OS with bevacizumab treatment. CONCLUSION: Unfortunately, in this histopathological, molecular, immunohistochemical and neuroradiological study we did not find any predictive biomarker of response or survival benefit for Bevacizumab in glioblastoma.

Bringing obesity to light: Rev-erbα, a central player in light-induced adipogenesis in the zebrafish?

BACKGROUND: Recent studies have led to an expansion of potential factors capable of stimulating obesity. Increasing evidence indicates that environmental factors, including disturbance of circadian rhythms, also contribute to its etiology. OBJECTIVES: To determine the effects of altered circadian rhythms on adipogenesis and to better understand how circadian and adipogenic regulatory pathways are linked, zebrafish larvae were exposed to various light/dark cycles or hypercaloric feeding (HCF). METHODS: Clock and adipogenic gene expression was quantitative real time PCR. Adipogenesis was characterized using coherent anti-Stokes Raman scattering microscopy (CARS) and whole-mount lipid composition was analyzed by gas chromatography. The clock protein Rev-erbα and the adipogenesis-regulating protein Pparγ were localized by immunohistochemistry. RESULTS: Zebrafish larvae exposed to continuous light (LL) had a sevenfold higher prevalence of adipocytes compared with control fish under a 14 h light and 10 h dark cycle. It was also significantly higher compared with that in HCF larvae with control light/dark cycle, which showed a 5.5-fold increase compared with control animals. Although total fatty acid content was unaffected, adipocyte lipid composition was altered in LL zebrafish. In contrast, shifting the onset and duration of the light periods did not affect adipogenesis or total fatty acid content. Gene expression analysis revealed effects of LL and HCF on circadian cyclicity, with increased expression of the clock gene period2 and altered circadian rev-erbα expression in LL larvae. Immunostaining revealed for the first time that Rev-erbα and Pparγ colocalize in adipocytes, which together with the gene expression analysis suggests interplay between Rev-erbα and Ppar isoforms. CONCLUSIONS: The amount of light, but not shifted light/dark cycles, affected adipogenesis and lipid composition, possibly due to increased period2 expression, which, in turn, enhances Rev-erbα-regulated gene expression. As the pparßδ promoter includes three Rev-erbα binding sites, we hypothesize that pparßδ may be a direct target that ultimately activates Pparγ.

Inferior Mesenteric Artery Side Branch for Selected Patients with Endovascular Aortic Aneurysm Repair.

OBJECTIVE/BACKGROUND: To report on our experience of the treatment of aortic aneurysms by custom-made, branched stent-grafts with an additional inferior mesenteric artery (IMA) side branch to preserve IMA perfusion in patients at risk for colon ischemia. METHODS: Three male patients (mean age 60 years) with a thoracoabdominal, pararenal, and infrarenal aortic aneurysm (AA), respectively, were treated by endovascular aneurysm exclusion using custom-made, branched stent-grafts with a side branch to the IMA for prevention of colon ischemia. Indications for selective IMA side branch perfusion were occlusions or high-grade stenosis of the visceral or hypogastric arteries. RESULTS: No colon ischemia and no neurological deficit were observed. All three IMA side branches were perfused and patent, as documented by computed tomography scan and duplex ultrasound postoperatively and after 12 months. Patency after 24 months was documented as 2/3. CONCLUSION: Custom-made, branched stent-grafts are an endovascular option to preserve the IMA perfusion in selected, electively treated patients with an increased risk for insufficient colon perfusion due to stenosis or occlusions of visceral or hypogastric arteries.

An analysis of the association between prostate cancer risk loci, PSA levels, disease aggressiveness and disease-specific mortality.

BACKGROUND: Genome-wide association studies have identified multiple single-nucleotide polymorphsims (SNPs) associated with prostate cancer (PCa). Although these SNPs have been clearly associated with disease risk, their relationship with clinical outcomes is less clear. Our aim was to assess the frequency of known PCa susceptibility alleles within a single institution ascertainment and to correlate risk alleles with disease-specific outcomes. METHODS: We genotyped 1354 individuals treated for localised PCa between June 1988 and December 2007. Blood samples were prospectively collected and de-identified before being genotyped and matched to phenotypic data. We investigated associations between 61 SNPs and disease-specific end points using multivariable analysis and also determined if SNPs were associated with PSA at diagnosis. RESULTS: Seven SNPs showed associations on multivariable analysis (P<0.05), rs13385191 with both biochemical recurrence (BR) and castrate metastasis (CM), rs339331 (BR), rs1894292, rs17178655 and rs11067228 (CM), and rs11902236 and rs4857841 PCa-specific mortality. After applying a Bonferroni correction for number of SNPs (P<0.0008), the only persistent significant association was between rs17632542 (KLK3) and PSA levels at diagnosis (P=1.4 × 10(-5)). CONCLUSIONS: We confirmed that rs17632542 in KLK3 is associated with PSA at diagnosis. No significant association was seen between loci and disease-specific end points when accounting for multiple testing. This provides further evidence that known PCa risk SNPs do not predict likelihood of disease progression.

Magnetic properties of uncultivated magnetotactic bacteria and their contribution to a stratified estuary iron cycle.

Of the two nanocrystal (magnetosome) compositions biosynthesized by magnetotactic bacteria (MTB), the magnetic properties of magnetite magnetosomes have been extensively studied using widely available cultures, while those of greigite magnetosomes remain poorly known. Here we have collected uncultivated magnetite- and greigite-producing MTB to determine their magnetic coercivity distribution and ferromagnetic resonance (FMR) spectra and to assess the MTB-associated iron flux. We find that compared with magnetite-producing MTB cultures, FMR spectra of uncultivated MTB are characterized by a wider empirical parameter range, thus complicating the use of FMR for fossilized magnetosome (magnetofossil) detection. Furthermore, in stark contrast to putative Neogene greigite magnetofossil records, the coercivity distributions for greigite-producing MTB are fundamentally left-skewed with a lower median. Lastly, a comparison between the MTB-associated iron flux in the investigated estuary and the pyritic-Fe flux in the Black Sea suggests MTB play an important, but heretofore overlooked role in euxinic marine system iron cycle.

Outcomes of fenestrated/branched endografting in post-dissection thoracoabdominal aortic aneurysms.

OBJECTIVES: Fenestrated/branched thoracic endovascular repair (F/Br-TEVAR) is increasingly applied for atherosclerotic thoracoabdominal aortic aneurysm (TAAA); however, use in post-dissection TAAAs is still very limited. Experience with F/Br-TEVAR in the treatment of post-dissection TAAA is presented. METHODS: Data were analysed from prospectively maintained databases including all patients with post-dissection TAAAs that underwent F/Br-TEVAR within the period January 2010 to July 2013 in two vascular institutions. Evaluated outcomes included initial technical success, operative mortality and morbidity, late survival, endoleak, aneurysm diameter regression, renal function, and reintervention during follow-up (FU). RESULTS: A total of 31 patients (25 male, mean age 65 ± 11.4 years) were treated. Technical success was 93.5% and 30-day mortality 9.6%. Temporary spinal cord ischaemia occurred in four (12.6%) patients, with no case of permanent paraplegia. Mean FU was 17.0 ± 10 months. There were seven late deaths, all aneurysm unrelated. Estimated overall survival rates were 83.9 ± 6.7, 76.4 ± 7.9 and 71.6 ± 8.7% at 6, 12, and 18 months, respectively. Impairment of renal function occurred in two (6.4%) patients. Endoleaks were diagnosed in 12 patients during FU, including six type IB endoleaks and six type II endoleaks. Reintervention was required in seven (22.5%) patients. Mean aneurysm sac regression was 9.3 ± 8.7 mm, with a false lumen thrombosis rate of 66.7% and 88.2% for patients with a FU longer than 6 and 12 months respectively. CONCLUSIONS: F/Br-EVAR is feasible for patients with a post-dissection TAAA. Although associated with additional technical challenges, and a significant need for reintervention, it leads to favourable aneurysm morphologic changes, and may play a more prominent role in the future for this type of pathology if long-term results confirm the good initial outcome.

Editor's choice--Temporary aneurysm sac perfusion as an adjunct for prevention of spinal cord ischemia after branched endovascular repair of thoracoabdominal aneurysms.

OBJECTIVE: To report experience with the concept of temporary aneurysm sac perfusion (TASP) and second stage side branch completion to prevent severe spinal cord ischemia (SCI) after branched endovascular aortic repair (bEVAR) for thoracoabdominal aortic aneurysm (TAAA). METHODS: Patients were treated for TAAA with bEVAR between January 2009 and September 2012. TASP was performed by non-completion of side branches to one of the reno-visceral arteries, distal aortic or iliac extensions with secondary side branch completion. Primary endpoints of the study were overall technical success, side branch patency, perioperative mortality, and the rate of severe SCI. RESULTS: Eighty-three patients were treated for TAAA with branched aortic stent grafts with (n = 40) or without (n = 43) TASP. Overall technical success, including aneurysm exclusion, absence of persistent type I or III endoleak, TASP side branch patency, and secondary side branch completion was 35/40 (88%). Secondary TASP side branch completion was performed after a median of 48 days (range 1-370 days). The rate of early re-interventions for reno-visceral side branch complications was 8/283 (3%) and 6/83 (7%) for perioperative mortality, with three patients in both groups. Severe SCI or paraplegia was observed in 11/83 (13%) of the patients and reduced in the TASP group (2/40) compared with the non-TASP group (9/43; p = .03), especially in Crawford I-III aneurysms (1/29 vs. 7/24; p = .01). However, one TASP patient died 4 months after bEVAR during the TASP interval from suspected aorto-bronchial fistula. CONCLUSION: The concept of TASP after bEVAR for TAAA is feasible and seems to reduce the risk of SCI. Early side TASP branch completion within 4 weeks is recommended to reduce the risk of rupture, although, according to the individual clinical presentation, a longer TASP interval might improve neurological rehabilitation from SCI.

[The significance of contrast-enhanced ultrasound in vascular surgery]. / Stellenwert der Kontrastmittelsonografie in der Gefäßchirurgie.

BACKGROUND: Vascular contrast-enhanced ultrasound (CEUS) is a special ultrasound application without the harmful side effects of nephrotoxicity and radiation exposure. CEUS can be used for advanced diagnosis of carotid stenosis and follow-up checks of endovascular repair of abdominal aortic aneurysms (EVAR). Low-flow phenomenon in peripheral vascular disease can easily be detected by enhanced colour-coded duplex sonography (CCDS). METHODS: The technical requirements of CEUS are explained here for the aorta, carotid, and peripheral arteries. The benefits and risks compared to computed tomography (CT), magnetic resonance (MR) and angiography are evaluated. Based on a selective review of the literature and the authors' personal experiences, CEUS is recommended for routine surveillance after EVAR. RESULTS: CEUS is a safe method using SonoVue® (Bracco) as the only approved agent for vascular examination. Special equipment and training is necessary. In prospective studies and meta-analyses the detection and characterisation of endoleaks is comparable to that of CT imaging. Neovascularisation as a sign of carotid plaques at risk can be seen without the need for invasive treatment. Imaging of crural vessels with enhanced CCDS is a promising but rarely needed option in diabetic and renally insufficient patients. CONCLUSION: CEUS in vascular medicine should be performed prior to other methods to avoid nephrotoxic contrast agents for the patients, especially in follow-up checks after EVAR. The time and effort required are still limiting its practical breakthrough.

Pumpless arterio-venous extracorporeal lung assist compared with veno-venous extracorporeal membrane oxygenation during experimental lung injury.

BACKGROUND: Extracorporeal lung support is effective to prevent hypoxaemia and excessive hypercapnia with respiratory acidosis in acute respiratory distress syndrome. Miniaturized veno-venous extracorporeal membrane oxygenation (mECMO) and arterio-venous pumpless extracorporeal lung assist (pECLA) were compared for respiratory and haemodynamic response and extracorporeal gas exchange and device characteristics. METHODS: After induction of acute lung injury by repeated lung lavage, 16 anaesthetized and mechanically ventilated pigs were randomized to mECMO (Medos Hilite/Deltastream) or pECLA (iLA Novalung) for 24 h. RESULTS: Improved gas exchange allowed reduced ventilation and plateau pressure in both groups. An arterio-venous shunt flow of up to 30% of cardiac output resulted in a left cardiac work of 6.8 (2.0) kg m for pECLA compared with 5.0 (1.4) kg m for mECMO after 24 h (P<0.05). Both devices provided adequate oxygen delivery to organs. The oxygen transfer of pECLA was lower than mECMO due to inflow of arterial oxygenated blood [16 (5) compared with 64 (28) ml min(-1) after 24 h, P<0.05]. Unexpectedly, the carbon dioxide transfer rate was also lower [58 (28) compared with 111 (42) ml min(-1) after 24 h, P<0.05], probably caused by a Haldane effect preventing higher transfer rates in combination with lower extracorporeal blood flow. CONCLUSIONS: Both devices have the potential to unload the lungs from gas transfer sufficiently to facilitate lung-protective ventilation. Although technically less complex, oxygen uptake and carbon dioxide removal are limited in pECLA, and cardiac work was increased. mECMO overcomes these limitations and might provide better cardiopulmonary protection.

Prostate atypia: clinical and pathological variables associated with cancer diagnosis on repeat biopsy.

The clinical significance of atypical glands suspicious for malignancy (atypia) on prostate biopsy is unclear. We studied a cohort of 139 patients with atypia who underwent repeat prostate biopsy. We analyzed clinical and pathological variables that may be associated with cancer on repeat biopsy. Cancer was diagnosed in 41 (29%) of patients with atypia: 26 of 41 (66%) were Gleason 6, 20% were Gleason 7 and 7% were Gleason 8 (Gleason < 6 not reported). There were no significant associations of age, race, family history, PSA, PSA density (PSAd), number of previous biopsies or time to repeat biopsy with cancer diagnosis. In multivariate regression, histological inflammation was associated with an 85% decreased probability of cancer on repeat biopsy (odds ratio; OR 0.15; 95% confidence interval; CI 0.04-0.57; P=0.04). Radical prostatectomy was performed in 14 of 41 (34%) patients with cancer; 6 (43%) were Gleason sum ≥7, 3 (21%) were pT3a and 1 (7%) had lymph node metastases. In conclusion, inflammation was independently associated with a significantly decreased risk of cancer on repeat biopsy. However, some patients with initial atypia have higher-risk prostate cancer. Additional studies are needed to elucidate these associations.

Haematological indices are modulated in juvenile carp, Cyprinus carpio L., exposed to microcystins produced by cyanobacterial water bloom.

This study evaluated the influence of toxic cyanobacterial water blooms on the blood indices of the common carp, Cyprinus carpio L. Experimental fish were exposed to a natural population of cyanobacterial water blooms (mainly Microcystis aeruginosa and M. ichthyoblabe), which contained microcystins [total concentration 133-284 µg g⁻¹ (DW), concentration in water 2.8-7.4 µg L⁻¹]. Haematological indices showed marked changes in fish exposed to the cyanobacterial population in comparison with the control group. Statistical evaluation of the influence of cyanobacterial water blooms on biochemical indices of the juvenile carp showed a distinct decrease in albumin, alanine aminotransferase, total bilirubin, calcium, cholesterol, glucose, phosphorus and iron when compared to controls. Values of red blood counts [haemoglobin, haematocrit (PCV), mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration] and lactate were significantly increased compared to controls. After exposure to cyanobacterial water bloom, the carp were kept in clean water to monitor the persistence of biochemical indices. The influence of cyanobacterial populations on calcium, cholesterol, glucose, lactate, phosphorus and PCV persisted up to 28 days after conclusion of the experiment. Duration of exposure, toxicity and density of cyanobacterial water blooms had an important impact on individual haematological indices.

Laparoscopic and percutaneous cryotherapy for renal neoplasms.

Incidence of renal cell carcinoma is increasing. There has been a shift towards utilization of nephron sparing surgery when feasible. Minimally invasive ablative treatments such as laparoscopic and percutaneous renal cryoablation aim to treat renal tumors with the two goals of cancer eradication and reduced morbidity compared to excisional surgical approaches. In this article, we review the basis of cryobiology and examine the current role of renal cryoablation and analyze the current literature focusing on laparoscopic and percutaneous approaches and discuss future directions and refinements in cryosurgical technology. While renal cryoablation is associated with higher local retreatment rates compared to radical or partial nephrectomy, emerging reports of intermediate-term oncological outcomes suggest disease-specific survival approaching that of extirpative surgery. Further follow up is needed to elucidate the long-term oncologic outcomes of and effects on renal function by renal cryoablation.

Compliance with hand hygiene in patients with meticillin-resistant Staphylococcus aureus and extended-spectrum ß-lactamase-producing enterobacteria.

Hand hygiene is considered to be the single most effective measure to prevent healthcare-associated infection. Although there have been several reports on hand hygiene compliance, data on patients with multidrug-resistant (MDR) organisms in special isolation conditions are lacking. Therefore, we conducted a prospective observational study of indications for, and compliance with, hand hygiene in patients colonised or infected with meticillin-resistant Staphylococcus aureus (MRSA) or extended-spectrum ß-lactamase (ESBL)-producing enterobacteria in surgical intensive and intermediate care units. Hand disinfectant used during care of patients with MRSA was measured. Observed daily hand hygiene indications were higher in MRSA isolation conditions than in ESBL isolation conditions. Observed compliance rates were 47% and 43% for the MRSA group and 54% and 51% for the ESBL group in the surgical intensive care unit and the intermediate care unit, respectively. Compliance rates before patient contact or aseptic tasks were significantly lower (17-47%) than after contact with patient, body fluid or patient's surroundings (31-78%). Glove usage instead of disinfection was employed in up to 100% before patient contact. However, compliance rates calculated from disinfectant usage were two-fold lower (intensive care: 24% vs 47%; intermediate care: 21% vs 43%). This study is the first to provide data on hand hygiene in patients with MDR bacteria and includes a comparison of observed and calculated compliance. Compliance is low in patients under special isolation conditions, even for the indications of greatest impact in preventing healthcare-associated infections. These data may help to focus measures to reduce transmission of MDR bacteria and improve patient safety.

Recombinant factor VIIa reduces bleeding after blunt liver injury in coagulopathic, hypofibrinogenaemic pigs.

BACKGROUND: Recombinant factor VIIa (rFVIIa) has been successfully used in various clinical conditions to treat severe coagulopathy, but its efficacy may be affected by the underlying conditions. We therefore investigated the efficacy of rFVIIa treatment under conditions of hypofibrinogenaemia in a pig model of blunt liver injury. METHODS: Severe haemodilution was instigated in four groups of seven anaesthetized pigs. Before inflicting liver injury, animals were assigned to receive either 70 mg kg(-1) fibrinogen (fibrinogen group) or placebo (control group). Thirty seconds after injury, rFVIIa (180 µg kg(-1)) (rFVIIa and fibrinogen+rFVIIa groups) or vehicle (control and fibrinogen groups) was administered. Haemodynamic variables, coagulation parameters, and blood loss were monitored for 2 h. Histology was examined to evaluate the presence of thrombi and the consistency of liver injury. RESULTS: At the end of the observation period, total blood loss [median (range)] decreased in all intervention groups [fibrinogen: 1275 (1221-1439) ml, P=0.036; rFVIIa: 966 (923-1136) ml, P=0.008; fibrinogen+rFVIIa: 678 (475-756) ml, P=0.008] when compared with control animals [blood loss: 1752 (1735-2221) ml]. The mortality rate in the control group was 100%, whereas only 42% of fibrinogen-substituted animals died (P=0.023). All animals treated with rFVIIa or fibrinogen+rFVIIa (P<0.001) survived and no signs of thromboembolism were observed. CONCLUSIONS: rFVIIa under conditions of hypofibrinogenaemia exhibited a positive impact on coagulation parameters and a reduction in blood loss. These effects were significantly improved after prior substitution with fibrinogen.