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Anesthesiology:
Clinical Investigations

Recombinant Coagulation Factor VIIa in Major Liver Resection: A Randomized, Placebo-controlled, Double-blind Clinical Trial

Lodge, J Peter A. M.D., F.R.C.S.*; Jonas, Sven M.D.†; Oussoultzoglou, Elie M.D.‡; Malagó, Massimo M.D.§; Jayr, Christian M.D.∥; Cherqui, Daniel M.D.#; Anthuber, Matthias M.D.**; Mirza, Darius F. M.S., F.R.C.S.††; Kuhlman, Luce M.D.‡‡; Bechstein, Wolf-Otto M.D.§§; Díaz, Juan Carlos Meneu M.D.∥∥; Tartiere, Jack M.D.##; Eyraud, Daniel M.D.***; Fridberg, Marianne M.Sc.†††; Erhardtsen, Elisabeth D.V.M.‡‡‡; Mimoz, Oliver M.D.§§§

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Abstract

Background: Prevention of bleeding episodes in noncirrhotic patients undergoing partial hepatectomy remains unsatisfactory in spite of improved surgical techniques. The authors conducted a randomized, placebo-controlled, double-blind trial to evaluate the hemostatic effect and safety of recombinant factor VIIa (rFVIIa) in major partial hepatectomy.
Methods: Two hundred four noncirrhotic patients were equally randomized to receive either 20 or 80 μg/kg rFVIIa or placebo. Partial hepatectomy was performed according to local practice at the participating centers. Patients were monitored for 7 days after surgery. Key efficacy parameters were perioperative erythrocyte requirements (using hematocrit as the transfusion trigger) and blood loss. Safety assessments included monitoring of coagulation-related parameters and Doppler examination of hepatic vessels and lower extremities.
Results: The proportion of patients who required perioperative red blood cell transfusion (the primary endpoint) was 37% (23 of 63) in the placebo group, 41% (26of 63) in the 20-μg/kg group, and 25% (15 of 59) in the 80-μg/kg dose group (logistic regression model; P = 0.09). Mean erythrocyte requirements for patients receiving erythrocytes were 1,024 ml with placebo, 1,354 ml with 20 μg/kg rFVIIa, and 1,036 ml with 80 μg/kg rFVIIa (P = 0.78). Mean intraoperative blood loss was 1,422 ml with placebo, 1,372 ml with 20 μg/kg rFVIIa, and 1,073 ml with 80 μg/kg rFVIIa (P = 0.07). The reduction in hematocrit during surgery was smallest in the 80-μg/kg group, with a significant overall effect of treatment (P = 0.04).
Conclusions: Recombinant factor VIIa dosing did not result in a statistically significant reduction in either the number of patients transfused or the volume of blood products administered. No safety issues were identified.
DESPITE improvements in surgical techniques during the past two decades, hepatic resection is often associated with significant intraoperative blood loss, primarily occurring from branches of the hepatic veins damaged during parenchymal transection or as a result of mobilization of tumors.1 Recent estimates show that perioperative blood transfusion is required in approximately 25–40% of unselected patients undergoing partial hepatectomy.2–6 In addition to the inherent difficulties in adequately replacing blood components especially in cases of severe bleeding, allogeneic blood transfusion constitutes a risk factor for intraoperative and postoperative morbidity, including viral disease transmission, transfusion reactions, and an increased risk of postoperative infectious complications.7–9 The existence of an adverse effect of blood transfusion on tumor recurrence is still controversial10,11 but may be a further argument for reducing the need for blood transfusions. The latter point is especially pertinent for major liver resection, which is mostly performed for malignant disease. Many surgical techniques for vascular control in hepatic resection have been advocated. Techniques such as partial and total vascular exclusion are routinely used but may induce ischemic liver injury and, in the latter case, hemodynamic complications.12–14 Therefore, there is a need for treatment modalities that may induce a primary hemostatic effect.
Recombinant activated coagulation factor VII (rFVIIa, NovoSeven®; NovoNordisk A/S, Copenhagen, Denmark) is currently registered for perioperative prophylaxis and treatment of bleeding episodes in hemophilia patients with inhibitors against coagulation factors VIII and IX and in the European Union for patients with acquired hemophilia, FVII deficiency, and Glanzmann thrombasthenia who are refractory to platelets. Pharmacologic doses of rFVIIa have been shown to enhance thrombin generation on locally activated platelets, thereby contributing to the formation of a stabilized and lysis-resistant fibrin plug at the site of vessel injury.15,16 Patients experiencing bleeding in any situation of potentially suboptimal thrombin generation, including intraoperative depression of the coagulation system, may thus potentially benefit from dosing with rFVIIa. A hemostatic effect of rFVIIa has recently been demonstrated in patients with normal coagulation systems in a double-blind, placebo-controlled trial in retropubic prostatectomy, where a single bolus of 40 μg/kg rFVIIa in the early operative phase significantly reduced blood loss, transfusion requirements, and operating time when compared with placebo.17
The current randomized, controlled, double-blind, multi-national trial was designed to evaluate the efficacy and safety of rFVIIa in noncirrhotic patients undergoing major liver resection.
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Materials and Methods

Patients
Noncirrhotic adults (≥ 18 yr of age) scheduled to undergo partial hepatectomy for liver cancer/metastasis, benign tumors, or both were recruited into the trial at 13 hospitals throughout France, Spain, Germany, and the United Kingdom (see appendix). A further requirement for inclusion was planned anatomical resection of three or more segments of the liver or planned nonanatomical resection of a volume equivalent to two or more segments of the liver parenchyma. Exclusion criteria included known hereditary bleeding disorders; the planned use of autologous blood transfusion, low-molecular-weight heparin before hepatectomy, tissue glue or hemodilution therapy during surgery, or hemostatic drugs for prophylactic purposes; renal insufficiency requiring dialysis; clinically documented portal vein or deep vein thrombosis or a history of the latter within the preceding 6 months; severe cardiovascular disease or previous myocardial/pulmonary infarction or stroke within the preceding 6 months; anticoagulation therapy not discontinued within 48 h before surgery; active bleeding; and the use of nonsteroidal antiinflammatory drugs within 7 days before surgery. The study protocol was approved by local ethics committees in the participating countries, and the trial was conducted according to standards of good clinical practice. All patients gave written informed consent.
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Study Drug Administration
Patients were equally randomized in center blocks to receive an injection of either 20 or 80 μg/kg rFVIIa or placebo. Randomization was computer-generated and was performed after patient eligibility assessments on the day of surgery by means of a central interactive voice response system set up by Novo Nordisk A/S. The trial drug was administered as a slow intravenous injection within 5 min before the first skin cut to ensure sufficient amounts of rFVIIa in the liver circulation during surgical procedures and before any clamping procedures were performed. A second identical dose was given 5 h after the first skin cut if the surgery time was anticipated to exceed 6 h. This was done to achieve adequate plasma concentrations of rFVIIa during extended surgical procedures, given the expected half-life of rFVIIa of approximately 2.5 h.18
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Blinding
To maintain blinding, an equal volume of trial drug per body weight was administered to all patients, irrespective of treatment group allocation. Furthermore, central laboratory analysis results for prothrombin time, which might reveal treatment allocation, were not transferred from the laboratory to the investigators or the sponsor before the trial was completed. Local laboratory results on prothrombin time or international normalized ratio were reviewed by an unblinded third party.
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Hepatectomy and Transfusion Procedures
Partial hepatectomy was performed according to local standard practice at the participating centers in France, Spain, Germany, and the United Kingdom. Unless deviations were clinically indicated, the following transfusion guidelines were adhered to: erythrocytes were administered when the hematocrit was less than 25%; fresh frozen plasma was administered when clinically indicated as evaluated by the attending surgeon; platelet concentrate was administered when the platelet count was less than 30,000/mm2; and cryoprecipitates or fibrinogen concentrate was administered when the fibrinogen concentration was less than 1.0 g/l. Prophylactic systemic administration of hemostatic drugs and low-molecular-weight heparin was not allowed before surgery, but treatment could be initiated if critical bleeding occurred during surgery. Topical administration of hemostatic drugs/agents was allowed in those cases where overt bleeding occurred even though transfusion guidelines were followed. During the postsurgical period, the hematocrit was to be kept above 28%. Blood samples were drawn at 15 and 60 min after the first skin cut and then at 1-hour intervals until completion of surgery for the determination of blood biochemistry, coagulation-related parameters, and plasma concentrations of rFVIIa. Treatment with low-molecular-weight heparin at maximum doses of 10,000 U every 24 h for at least 1 day was initiated at completion of surgery. Patients were monitored for 7 days after surgery or until discharge from the hospital, whichever came first.
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Endpoints
The primary endpoint was whether patients required erythrocyte transfusion during surgery or the 48-h period after surgery (perioperative period). Efficacy was furthermore assessed by the amount of erythrocytes transfused, change in hematocrit, the proportion of patients who required perioperative transfusions of fresh frozen plasma, and total surgery time (from first skin cut to wound closure). Blood loss during surgery was assessed as the volume collected in suction containers and sponges/dressings/swabs minus the irrigation volume, and blood loss after surgery was evaluated using surgical drain volume 0–24 h after surgery, as well as hematocrit measured herein, as endpoints. Safety was assessed by the occurrence of adverse events, focusing on thromboembolic adverse events and bleeding complications, the former evaluated by Doppler examination of the hepatic vessels (before surgery, within 48 h after surgery, and otherwise if indicated) and lower extremities (before surgery and every 24 h until 3 days after surgery). Also, changes in coagulation-related parameters (prothrombin time, platelet count, and the concentrations of fibrinogen, D-dimer, prothrombin fragments 1 and 2, thrombin-antithrombin complex, and antithrombin III) and blood biochemistry (serum creatinine, calcium, potassium, sodium, bilirubin, serum albumin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) were monitored.
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Statistics
The trial size was planned to detect a 50% relative reduction in the proportion of patients requiring perioperative erythrocyte transfusions from 40% in the placebo group to 20% in the rFVIIa groups with 80% statistical power at a significance level of 5%. This translated to a sample size of 180 patients, 60 per treatment group. The perioperative period was defined as spanning the intraoperative period and the 48-h postsurgical period.
The comparison of the three treatment groups with respect to the primary endpoint, i.e., the proportion of the patients requiring perioperative erythrocyte transfusions, was conducted with use of a logistic regression model. Treatment group, country, baseline hematocrit, whether clamping was performed (defined as portal triad, inferior vena cava clamping, or both), type of resection (according to the Brisbane 2000 terminology19), and surgery type (hepatectomy vs. rehepatectomy) were included as covariates in the model. Residual diagnostics were used to check the statistical assumptions of the model.
Analysis of the treatment effect on the proportion of patients requiring fresh frozen plasma during the perioperative period was conducted as for the primary endpoint. Amounts of erythrocytes transfused during the perioperative period were compared between treatment groups using a two-sided Jonckheere-Terpstra test. This test was also applied for comparisons of treatment effects on requirements for systemic hemostatic drug as well as for other secondary endpoints, with the one exception of changes in hematocrit, which were analyzed using F tests. In all the above-mentioned analyses, the type I error was set to 5%. All randomized patients who were dosed were included in the safety analyses, whereas efficacy data presented herein pertain to all randomized patients who were dosed and underwent liver resection.
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Results

Fig. 1
Fig. 1
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Table 1
Table 1
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Between January 2001 and January 2002, 204 eligible patients were included in the trial. Four patients were withdrawn before dosing, the reasons being the investigator’s decision not to perform a partial hepatectomy, noncompliance with the protocol, failure to obtain a drug dispensing form before surgery, and patient withdrawal of consent. A flow diagram of patient allocation is outlined in figure 1. Baseline characteristics and prognostic factors were similar across treatment groups (table 1). Six patients in the placebo group, five in the 20-μg/kg group, and two in the 80-μg/kg group received a second dose 5 h after the initial injection as a result of an extended surgery period.
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Efficacy
Table 2
Table 2
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Results are summarized in table 2. The proportion of patients who required perioperative transfusion of erythrocytes (the primary endpoint) was 37% (23 of 63) in the placebo group, 41% (26 of 63) in the 20-μg/kg group, and 25% (15 of 59) in the 80-μg/kg group. The overall effect of rFVIIa treatment was not statistically significant (logistic regression model; P = 0.09). Mean erythrocyte requirements for patients receiving erythrocytes were 1,024 ml in the placebo group, 1,354 ml in the 20-μg/kg rFVIIa group, and 1,036 ml in the 80-μg/kg rFVIIa group (P = 0.78).
The mean volume of blood loss during surgery was 1,422 ml in the placebo group, 1,372 ml in the 20-μg/kg group, and 1,073 ml in the 80-μg/kg group (P = 0.07). The reduction in hematocrit from before surgery to last observation during surgery was smallest in the 80-μg/kg group, with a statistically significant overall effect of treatment (P = 0.04), even though the amount of erythrocytes transfused during surgery was not greater in the 80-μg/kg group. However, the reduction in hematocrit during surgery was larger in the 20-μg/kg group than in the placebo group. No significant difference between treatment groups was found with respect to requirement for fresh frozen plasma or systemic hemostatic drug, operating time, total volume collected in surgical drains in the 24-h postsurgical period, or for the percentage of hematocrit measured herein (table 2).
Fig. 2
Fig. 2
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Fig. 3
Fig. 3
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Data on plasma FVII clotting activity are depicted in figure 2. As expected, measured maximum plasma concentration and area under the concentration curve seem to increase approximately proportionally with dose. Prothrombin time was significantly shortened with rFVIIa dosing, the effect being prolonged at the 80-μg/kg dose level when compared with the effect of 20 μg/kg (fig. 3).
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Safety
Table 3
Table 3
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Of the 200 dosed patients, 158 patients had 487 adverse events (table 3). The most frequently reported adverse events included nausea, constipation, fever, hypotension, and insomnia, and there were no apparent differences between dose groups in the types or frequencies of adverse events reported. All nonthromboembolic serious adverse events were considered by the investigators as unlikely to be related to trial drug treatment. Three thromboembolic events were observed in each of the three treatment groups. The total of nine events was comprised of the following.
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Four events of deep venous thrombosis.
All four events (two in the placebo group diagnosed at day 1 after dosing and two in the 80-μg/kg group diagnosed at days 2 and 3 after dosing, respectively) were without clinical symptoms and were thus only recognized through the protocol-specified routine Doppler examinations.
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Two events of pulmonary embolism.
A 62-yr-old patient of the 20-μg/kg group was diagnosed with a right basal segment arterial pulmonary embolism at day 2 after dosing. Doppler examination before the events showed no signs of deep vein thrombosis. A 58-yr-old patient of the 80-μg/kg group was diagnosed with a left apical pulmonary embolism at day 7 after dosing. Two days after the event, a Doppler ultrasound examination indicated a partial thrombosis of the left internal jugular vein corresponding to the site of central venous catheter placement. Doppler ultrasonography before the event and 4 days after the event did not indicate deep venous thrombosis in the lower extremities. Both patients recovered completely from the events.
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An event of partial portal vein thrombosis experienced by a patient in the placebo group.
Five days after extended hepatic resection and administration of trial drug, a 67-yr-old woman of the placebo group experienced fever, abdominal pain, and clouding of consciousness with signs of hepatic failure. A computed tomography scan indicated a partial portal venous thrombus at the stump of the ligated right portal vein. The thrombus was protruding into the main portal vein without impairment of the flow. Doppler ultrasonography confirmed good portal venous flow. The patient died of hepatic failure, most probably as a consequence of the extended hepatic resection performed 2 weeks previously.
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Two events of myocardial infarction experienced by patients in the 20-μg/kg group.
A 79-yr-old man experienced posterior myocardial infarction 1 day after administration of the trial drug. Subsequent angiography showed moderate left ventricle–apical hypokinesia and severe left main stem and triple vessel disease. The patient underwent coronary surgery and recovered completely. A 74-yr-old man experienced worsening of liver, renal, and respiratory function 4 days after receiving the trial drug and undergoing hepatic resection and extensive abdominal surgery. The patient subsequently had a hypotensive episode but recovered quickly after colloid therapy. An electrocardiogram showed a possible myocardial infarction, but this was unconfirmed because creatinine kinase concentrations were already increased. Renal, hepatic, and respiratory functions deteriorated over the course of the day, and chest radiographs suggested pulmonary edema. The condition of the patient continued to worsen, and he died from multiorgan failure 7 days later.
Seven adverse events recorded during the trial period had a fatal outcome, with death occurring on average 28 days after trial drug dosing (range, 9–92 days). Three deaths occurred in the placebo group, and four deaths occurred in the 20-μg/kg treatment group (causes of death were hepatic failure, pneumonia, pulmonary edema, and multiorgan failure). All seven deaths were evaluated by the investigators as unlikely to be related to the trial drug.
Bleeding complications, as defined by the investigators, occurred with similar frequencies across treatment groups (P = 0.73). Furthermore, no clinically significant adverse changes in the investigated coagulation-related parameters were observed, and there were no indications of systemic activation of the coagulation cascade. A statistically significantly greater increase from baseline to 1 h after dosing (P < 0.01) and to 24 h after dosing (P = 0.04) was observed for D-dimer when comparing rFVIIa groups to placebo, which is consistent with the expected mode of action of rFVIIa. No significant differences between dose groups were observed for platelets, fibrinogen, prothrombin fragments 1 and 2, thrombin–antithrombin complex, or antithrombin III, although it should be noted that data for prothrombin fragments 1 and 2 and thrombin–antithrombin complex were inconclusive because of methodologic problems related to drawing of blood at some of the trial centers.
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Discussion

This was a placebo-controlled, double-blind study of the effect of a single presurgical bolus injection of either 20 or 80 μg/kg rFVIIa administered to noncirrhotic patients undergoing major liver resection. No statistically significant overall effect of rFVIIa treatment across treatment groups was observed with respect to the proportion of patients requiring perioperative erythrocyte transfusions (primary endpoint) or other endpoints on transfusion and blood loss. The trial was dimensioned to detect a 50% relative reduction with respect to the primary endpoint, and the number of patients included would thus be expected to be insufficient to statistically verify any smaller relative reduction on the primary endpoint. A larger trial, powered for a smaller but still clinically relevant effect on transfusion requirements, would be needed to better evaluate any hemostatic effect of rFVIIa in this patient population. Prothrombin time was significantly shortened with rFVIIa dosing. However, the clinical relevance of this in vitro effect of rFVIIa remains to be determined.
The administration of a procoagulant such as rFVIIa to patients with otherwise normal coagulation systems might raise concerns that patients would be exposed to a higher risk of thromboembolic events. In this trial, the prevalence of thromboembolic events in these immobilized, anesthetized, noncoagulopathic patients undergoing major liver surgery did not differ between placebo-treated and rFVIIa-treated patients. Although there was a tendency for the thromboembolic events to be more severe in the rFVIIa-treated patients, the number of events is too small to draw any conclusions. The 1% overall incidence of pulmonary embolism observed in the current study corresponds to the incidence previously observed in cancer surgery.20 Moreover, no indications of systemic activation of the coagulation cascade were observed. The absence of systemic activation of the coagulation system with rFVIIa may be explained by its mode of action, confining propagation of coagulation to the site of injury of the vessel wall.15,16 Given the localized effect of rFVIIa, an increased incidence of thromboembolic complications or intravascular coagulation after dosing with rFVIIa would not be expected and has indeed not been observed previously.17,21 The low trial-related mortality rate of 3.5% (0.0% in the 80-μg/kg dose group) is in line with previous observations, where operative mortality of less than 10% has been reported in many series6,22 and is to be expected in this noncirrhotic patient population. No statistically significant effect of rFVIIa on mortality was observed. However, the trial was not powered to investigate mortality.
It should be noted that routine monitoring of laboratory coagulation parameters during surgery could potentially reveal dose group allocation. The effect of such bias on trial results, however, is judged to be small because of the requirement of adherence to protocol-defined transfusion guidelines.
In conclusion, dosing with 20 or 80 μg/kg rFVIIa did not raise safety concerns in this patient population without preexisting coagulopathy undergoing major liver resection. No statistically significant effect of rFVIIa across treatment groups was observed for transfusion requirements or blood loss. Further trials are needed to establish the hemostatic potential of rFVIIa in this clinical setting.
The authors thank the patients and the hospital staff participating in the trial, as well as Allan Blemings, M.Sc. (Statistician), and Karsten Soendergaard, M.Sc. (Clinical Researcher), both at Novo Nordisk A/S, Copenhagen, Denmark.
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Appendix: Participating Principal Investigators and Hospitals
United Kingdom: J. Peter A. Lodge, M.D., F.R.C.S., Professor of Surgery, St. James’s University Hospital, Leeds; Darius F. Mirza, M.S., F.R.C.S., Consultant Hepatobiliary and Transplant Surgeon, The Queen Elizabeth Hospital, The Liver and Hepatobiliary Unit, Birmingham. Germany: Sven Jonas, M.D., Professor, Campus Virchow-Klinikum, Berlin; Massimo Malagó, M.D., Professor of Surgery and Transplantation, Essen University Clinic, Department of General Surgery and Transplantation, Essen; Matthias Anthuber, M.D., Professor, Regensburg University Clinic, Regensburg; Wolf-Otto Bechstein, M.D., Professor of Surgery, Chairman of the Department of General and Vascular Surgery, University Hospital Frankfurt am Main. France: Daniel Cherqui, M.D., Professor, Hospital Henri-Mondor, Department of General and Digestive Surgery, Paris; Christian Jayr, M.D., Research Director, Institut Gustave Rousy, Anesthesiology Department, Villejuif; Luce Kuhlman, M.D., Hospital Consultant in Anesthesiology, Paul Brousse University Hospital Center, Department of Hepatobiliary Surgery, Villejuif; Jack Tartiere, M.D., Hospital Practitioner in Anesthesiology and Intensive Care, CHU de la Côte de Nacre, Anesthesia and Intensive Care Department, Pr JL Gerard Unit, Caen; Daniel Eyraud, M.D., Associate Professor, Anesthesiology and Intensive Care Unit, Hospital Pitié Salpétriére, Paris; Elie Oussoultzoglou, M.D., Hospital Practitioner, Hospital Haute-Pierre, Strasbourg. Spain: Juan Carlos Meneu Díaz, M.D., Staff Surgeon, Hospital “12 de Octubre,” General and Digestive Surgery and Liver Transplantation Unit, Madrid. Cited Here...

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ARTN R104
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European Journal of Obstetrics Gynecology and Reproductive Biology
Use of recombinant activated factor VII in massive postpartum haemorrhage
Bouma, LS; Bolte, AC; van Geijn, HR
European Journal of Obstetrics Gynecology and Reproductive Biology, 137(2): 172-177.
10.1016/j.ejogrb.2007.06.022
CrossRef
Military Medicine
Use of Recombinant Factor VIIa in Operation Iraqi Freedom and Operation Enduring Freedom: Survey of Army Surgeons
Kembro, RJ; Horton, JD; Wagner, M
Military Medicine, 173(): 1057-1059.

British Journal of Anaesthesia
Is recombinant FVIIa the magic bullet in the treatment of major bleeding?
Spahn, DR; Tucci, MA; Makris, M
British Journal of Anaesthesia, 94(5): 553-555.
10.1093/bja/aei103
CrossRef
Liver Transplantation
Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease
Planinsic, RM; van der Meer, J; Testa, G; Grande, L; Candela, A; Porte, RJ; Ghobrial, RM; Isoniemi, H; Schelde, PB; Erhardtsen, E; Klintmalm, G; Emre, S
Liver Transplantation, 11(8): 895-900.
10.1002/lt.20458
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British Journal of Anaesthesia
Predicting response to recombinant factor VIIa in non-haemophiliac patients with severe haemorrhage
Bowles, KM; Callaghan, CJ; Taylor, AL; Harris, RJ; Pettigrew, GJ; Baglin, TP; Park, GR
British Journal of Anaesthesia, 97(4): 476-481.
10.1093/bja/ael205
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Medizinische Klinik
Clinical assessment of potential fields of application of recombinant factor VIIa in internal and pediatric diseases. Recommendations of an expert group
Dempfle, CE; Gulba, D; Kirchmaier, CM; Klamroth, R; Korte, W; Lorenz, R; Peck-Radosavljevic, M; Veldman, A; Zotz, RB
Medizinische Klinik, 102(1): 70-81.
10.1007/s00063-007-1012-9
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Annales Francaises D Anesthesie Et De Reanimation
Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding. A European perspective
Vincent, JL; Rossaint, R; Riou, B; Ozier, Y; Zideman, D; Spahn, DR
Annales Francaises D Anesthesie Et De Reanimation, 26(2): 145-156.
10.1016/j.annfar.2006.10.008
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Thrombosis and Haemostasis
Recombinant human activated factorVII is thrombogenic in a rabbit model of cyclic flow reduction and does not reduce intra-abdominal bleeding
Charbonneau, S; Girard, F; Boudreault, D; Ruel, M; Blais, N; Hardy, JF
Thrombosis and Haemostasis, 97(2): 296-303.
10.1160/TH06-08-0429
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Annales Francaises D Anesthesie Et De Reanimation
Off label use of recombinant activated factor VII: a practice survey
Delannoy, B; Levrat, A; Chamouard, V; Aulagner, G; Perdrix, JP; Negrier, C; Allaouchiche, B
Annales Francaises D Anesthesie Et De Reanimation, 26(9): 774-779.
10.1016/j.annfar.2007.06.001
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European Journal of Cardio-Thoracic Surgery
Treatment of refractory bleeding after cardiac operations with low-dose recombinant activated factor VII (NovoSeven (R)): a propensity score analysis
Gelsomino, S; Lorusso, R; Romagnoli, S; Bevilacqua, S; De Cicco, G; Bille, G; Stefano, P; Gensini, GF
European Journal of Cardio-Thoracic Surgery, 33(1): 64-71.
10.1016/j.ejcts.2007.10.004
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Critical Care
Recombinant activated factor VIIa for the treatment of bleeding in major abdominal surgery including vascular and urological surgery: a review and meta-analysis of published data
von Heymann, C; Jonas, S; Spies, C; Wernecke, KD; Ziemer, S; Janssen, D; Koscielny, J
Critical Care, 12(1): -.
ARTN R14
CrossRef
Current Drug Targets
Uncontrolled Bleeding in Surgical Patients: The Role of Recombinant Activated Factor VIIa
Phillips, LE; Zatta, AJ; Schembri, NL; Noone, AK; Isbister, J
Current Drug Targets, 10(8): 744-770.

Canadian Medical Association Journal
Blood conservation strategies to reduce the need for red blood cell transfusion in critically ill patients
Tinmouth, AT; McIntyre, LA; Fowler, RA
Canadian Medical Association Journal, 178(1): 49-57.
10.1503/cmaj.071298
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Journal of the American College of Surgeons
The "Off-Label" Role of Recombinant Factor Vlla in Surgery: Is the Problem Deficient Evidence or Defective Concept?
Al-Ruzzeh, S; Navia, JL
Journal of the American College of Surgeons, 209(5): 659-667.
10.1016/j.jamcollsurg.2009.07.018
CrossRef
Journal of Surgical Research
Factors influencing perioperative blood transfusions in patients with gastrointestinal cancer
Verma, V; Schwarz, RE
Journal of Surgical Research, 141(1): 97-104.
10.1016/j.jss.2007.03.032
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European Journal of Anaesthesiology
Recombinant activated factor VII in cardiac surgery
Ranucci, M; Isgro, G
European Journal of Anaesthesiology, 24(): 83-88.
10.1017/S0265021507000634
CrossRef
Anz Journal of Surgery
Laparoscopic cholecystectomy in cirrhotic patients with symptomatic gallstone disease
Leandros, E; Albanopoulos, K; Tsigris, C; Archontovasilis, F; Panoussopoulos, SG; Skalistira, M; Bramis, C; Konstandoulakis, MM; Giannopoulos, A
Anz Journal of Surgery, 78(5): 363-365.
10.1111/j.1445-2197.2008.04478.x
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Drugs
An evaluation of eptacog alfa in nonhaemophiliac conditions
Mallarkey, G; Brighton, T; Thomson, A; Kaye, K; Seale, P; Gazarian, M
Drugs, 68(): 1665-1689.

Cochrane Database of Systematic Reviews
Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia
Stanworth, SJ; Birchall, J; Doree, CJ; Hyde, C
Cochrane Database of Systematic Reviews, (2): -.
ARTN CD005011
CrossRef
Canadian Journal of Cardiology
Safety and efficiency of recombinant activated factor VII in postcardiotomy massive hemorrhage
Lamarche, Y; Demers, P; Poirier, NC; Robitaille, D; Cartier, R
Canadian Journal of Cardiology, 23(): 809-813.

Anesthesia and Analgesia
Recombinant Activated Factor VII in Obstetric Hemorrhage: Experiences from the Australian and New Zealand Haemostasis Registry
Phillips, LE; McLintock, C; Pollock, W; Gatt, S; Popham, P; Jankelowitz, G; Ogle, R; Cameron, PA
Anesthesia and Analgesia, 109(6): 1908-1915.
10.1213/ANE.0b013e3181c039e6
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Journal of Gastrointestinal Surgery
Anesthetic management for liver resection
Walia, A
Journal of Gastrointestinal Surgery, 10(2): 168-169.
10.1016/j.gassur.2005.09.024
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Haemophilia
Utilization of recombinant activated factor VII in southern Ontario in 85 patients with and without haemophilia
Webert, KE; Arnold, DM; Carruthers, J; Molnar, L; Almonte, T; Decker, K; Seroski, W; Reed, J; Chan, AK; Pai, M; Walker, IR
Haemophilia, 13(5): 518-526.
10.1111/j.1365-2516.2007.01490.x
CrossRef
Isbt Science Series, Vol 2, No 2
The Australasian haemostasis register for clinical use of recombinant activated factor VII
Isbister, J; Dunkley, S; Cameron, P; Phillips, L
Isbt Science Series, Vol 2, No 2, 2(2): 110-112.

Injury-International Journal of the Care of the Injured
Low-dose recombinant factor VIIa for trauma patients with coagulopathy
Stein, DM; Dutton, RP; Hess, JR; Scalea, TM
Injury-International Journal of the Care of the Injured, 39(9): 1054-1061.
10.1016/j.injury.2008.03.032
CrossRef
Liver Transplantation
Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation
Lodge, JPA; Jonas, S; Jones, RM; Olausson, M; Mir-Pallardo, J; Soefelt, S; Garcia-Valdecasas, JC; McAlister, V; Mirza, DF
Liver Transplantation, 11(8): 973-979.
10.1002/lt.20470
CrossRef
Archives of Surgery
Administration of Recombinant Activated Factor VII in Major Thoracic Operations In reply
Ranucci, M
Archives of Surgery, 143(): 1021.

Critical Care Clinics
Emerging off-label uses for recombinant activated factor VII: Grading the evidence
Enomoto, TM; Thorborg, P
Critical Care Clinics, 21(3): 611-+.
10.1016/j.ccc.2005.04.001
CrossRef
Expert Opinion on Pharmacotherapy
Management of bleeding emergencies: when to use recombinant activated Factor VII
DeLoughery, TG
Expert Opinion on Pharmacotherapy, 7(1): 25-34.
10.1517/14656566.7.1.25
CrossRef
Anaesthesia and Intensive Care
Thrombogenic side-effects of recombinant factor VIIa after use in coronary artery bypass surgery
White, MC; Pryn, SJ; Monk, CR
Anaesthesia and Intensive Care, 34(5): 664-667.

New England Journal of Medicine
Drug therapy: Prevention and treatment of major blood loss
Mannucci, PM; Levi, M
New England Journal of Medicine, 356(): 2301-2311.

Internal Medicine Journal
Recombinant activated factor VII in critical bleeding: experience from the Australian and New Zealand Haemostasis Register
Isbister, J; Phillips, L; Dunkley, S; Jankelowitz, G; McNeil, J; Cameron, P
Internal Medicine Journal, 38(3): 156-165.
10.1111/j.1445-5994.2007.01472.x
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Pharmacological approaches to reducing blood loss and transfusions in the surgical patient
Ozier, Y; Schlumberger, S
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 53(6): S21-S29.

Minerva Anestesiologica
Intraoperative use of recombinant activated factor VII (rFVIIa)
De Gasperi, A
Minerva Anestesiologica, 72(6): 489-494.

Transfusion
How we manage requests for recombinant factor VIIa (NovoSeven)
Mathew, P; Simon, TL; Hunt, KE; Crookston, KP
Transfusion, 47(1): 8-14.
10.1111/j.1537-2995.2007.01058.x
CrossRef
Journal of Cardiothoracic Surgery
Use of activated recombinant factor VII for severe coagulopathy post ventricular assist device or orthotopic heart transplant
Gandhi, MJ; Pierce, RA; Zhang, L; Moon, MR; Despotis, GJ; Moazami, N
Journal of Cardiothoracic Surgery, 2(): -.
ARTN 32
CrossRef
British Journal of Clinical Pharmacology
Overview of the human pharmacokinetics of recombinant activated factor VII
Klitgaard, T; Nielsen, TG
British Journal of Clinical Pharmacology, 65(1): 3-11.
10.1111/j.1365-2125.2007.03030.x
CrossRef
Texas Heart Institute Journal
Systemic venous thrombosis after recombinant factor VIIa in the control of bleeding after cardiac surgery
Mahmoud, A; Al-Ruzzeh, S; McKeague, H; Cross, M
Texas Heart Institute Journal, 34(4): 485-488.

Anasthesiologie & Intensivmedizin
The importance of the recombinant factor VIIa in major bleeding: contra
Rump, G; Potzsch, B; Frietsch, T
Anasthesiologie & Intensivmedizin, 48(): S180-S183.

American Journal of Surgery
Safety and hemostatic effect of recombinant activated factor VII in cirrhotic patients undergoing partial hepatectomy: a multicenter, randomized, double-blind, placebo-controlled trial
Shao, YF; Yang, JM; Chau, GY; Sirivatanauksorn, Y; Zhong, SX; Erhardtsen, E; Nivatvongs, S; Lee, PH
American Journal of Surgery, 191(2): 245-249.
10.1016/j.amjsurg.2005.10.019
CrossRef
Archives of Surgery
Efficacy and safety of recombinant activated factor VII in major surgical procedures
Ranucci, M; Isgro, G; Soro, G; Conti, D; De Toffol, B
Archives of Surgery, 143(3): 296-304.

Annals of Thoracic Surgery
Efficacy and safety of recombinant activated factor VII to control bleeding in nonhemophiliac patients: A review of 17 randomized controlled trials
Hardy, JF; Belisle, S; Van der Linden, P
Annals of Thoracic Surgery, 86(3): 1038-1048.
10.1016/j.athoracsur.2008.05.013
CrossRef
Transfusion Medicine
Recombinant factor VIIa reduces transfusion requirements in liver transplant patients with high MELD scores
Niemann, CU; Behrends, M; Quan, D; Eilers, H; Gropper, MA; Roberts, JP; Hirose, R
Transfusion Medicine, 16(2): 93-100.
10.1111/j.1365-3148.2006.00653.x
CrossRef
British Journal of Haematology
A critical appraisal of the use of recombinant factor VIIa in acquired bleeding conditions
Mittal, S; Watson, HG
British Journal of Haematology, 133(4): 355-363.
10.1111/j.1365-2141.2006.06023.x
CrossRef
Critical Care
Mechanistic implications for the use and monitoring of recombinant activated factor VII in trauma
Pusateri, AE; Park, MS
Critical Care, 9(): 15-24.
10.1186/cc3781
CrossRef
Injury-International Journal of the Care of the Injured
The use of factor VIIa in haemorrhagic shock and intracerebral bleeding
Dutton, RP; Stein, DM
Injury-International Journal of the Care of the Injured, 37(): 1172-1177.
10.1016/j.injury.2006.09.001
CrossRef
Archives of Pathology & Laboratory Medicine
Blood management
Goodnough, LT; Shander, A
Archives of Pathology & Laboratory Medicine, 131(5): 695-701.

Transplantation Proceedings
Recombinant factor VIIa in major abdominal surgery and liver transplantation
Viana, JD
Transplantation Proceedings, 38(3): 818-819.
10.1016/j.transproceed.2006.01.045
CrossRef
Hepato-Gastroenterology
Recent randomized controlled trials in hepatectomy
Kaido, T
Hepato-Gastroenterology, 54(): 1825-1830.

Transfusion Medicine Reviews
Evidence for the use of recombinant factor VIIa in the prevention and treatment of bleeding in patients without hemophilia
Birchall, J; Stanworth, SJ; Duffy, MR; Doree, CJ; Hyde, C
Transfusion Medicine Reviews, 22(3): 177-187.
10.1016/j.tmrv.2008.02.007
CrossRef
Annals of Thoracic Surgery
Effective management of refractory postcardiotomy bleeding with the use of recombinant activated factor VII
Filsoufi, F; Castillo, JG; Rahmanian, PB; Scurlock, C; Fischer, G; Adams, DH
Annals of Thoracic Surgery, 82(5): 1779-1783.
10.1016/j.athoracsur.2006.05.076
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Critical Care
Recommendations on the use of recombinant activated factor VII as an adjunctive treatment for massive bleeding - a European perspective
Vincent, JL; Rossaint, R; Riou, B; Ozier, Y; Zideman, D; Spahn, DR
Critical Care, 10(4): -.
ARTN R120
CrossRef
Vox Sanguinis
Off-label use of recombinant factor VIIa for treatment of haemorrhage: results from randomized clinical trials
Johansson, PI
Vox Sanguinis, 95(1): 1-7.
10.1111/j.1423-0410.2008.01063.x
CrossRef
Cochrane Database of Systematic Reviews
Pharmacological interventions to decrease blood loss and blood transfusion requirements for liver resection
Gurusamy, KS; Li, J; Sharma, D; Davidson, BR
Cochrane Database of Systematic Reviews, (4): -.
ARTN CD008085
CrossRef
Annals of Emergency Medicine
The Efficacy of Recombinant Activated Factor VII in Severe Trauma
Nishijima, DK; Zehtabchi, S
Annals of Emergency Medicine, 54(5): 737-744.
10.1016/j.annemergmed.2009.01.027
CrossRef
British Journal of Anaesthesia
Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study
Diprose, P; Herbertson, MJ; O'Shaughnessy, D; Gill, RS
British Journal of Anaesthesia, 95(5): 596-602.

Anaesthesia and Intensive Care
The use of recombinant activated factor VII for refractory bleeding post complex cardiothoracic surgery
Walsham, J; Fraser, JF; Mullany, D; Ziegenfus, M; Chinthamuneedi, M; Dunning, J; Tesar, P
Anaesthesia and Intensive Care, 34(1): 13-20.

Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
The role of recombinant factor VIIa in on-pump cardiac surgery: Proceedings of the Canadian Consensus Conference
Karkouti, K; Beattie, S; Crowther, MA; Callum, JL; Chun, R; Fremes, SE; Lemieux, J; McAlister, VC; Muirhead, BD; Murkin, JM; Nathan, HJ; Wong, BI; Yau, TM; Yeo, EL; Hall, RI
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 54(7): 573-582.

Journal of Pediatric Surgery
Recombinant factor VIIa for intraoperative bleeding in a child with hepatoblastoma and review of recombinant activated factor VIIa use in children undergoing surgery
Al-Said, K; Anderson, R; Wong, A; Le, D
Journal of Pediatric Surgery, 43(4): -.
ARTN E15
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Revista Medica De Chile
Recombinant activated factor VII for perioperative bleeding
Lopez, R; Aeschlimann, N; Carvajal, C; Lema, G
Revista Medica De Chile, 137(6): 837-843.

International Journal of Hematology
Recombinant factor VIIa: A review on its clinical use
Franchini, M
International Journal of Hematology, 83(2): 126-138.
10.1532/IJH97.E0517
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Critical Care
Clinical experiences and current evidence for therapeutic recombinant factor VIIa treatment in nontrauma settings
Grounds, RM; Bolan, C
Critical Care, 9(): S29-S36.
10.1186/cc3783
CrossRef
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie
Reversal of vitamin K antagonists prior to urgent surgery
Grobler, C; Callum, J; McCluskey, SA
Canadian Journal of Anaesthesia-Journal Canadien D Anesthesie, 57(5): 458-467.
10.1007/s12630-009-9250-3
CrossRef
Journal of Thrombosis and Haemostasis
Recombinant activated factor VII in treatment of bleeding complications following hematopoietic stem cell transplantation
Pihusch, M; Bacigalupo, A; Szer, J; Prondzinski, MV; Gaspar-Blaudschun, B; Hyveled, L; Brenner, B
Journal of Thrombosis and Haemostasis, 3(9): 1935-1944.

Vox Sanguinis
The coagulopathy of massive transfusion
Hardy, JF; de Moerloose, P; Samama, CM
Vox Sanguinis, 89(3): 123-127.
10.1111/j.1423-0410.2005.00678.x
CrossRef
Anaesthesia
Recombinant activated factor VII and the anaesthetist
Welsby, IJ; Monroe, DM; Lawson, JH; Hoffmann, M
Anaesthesia, 60(): 1203-1212.
10.1111/j.1365-2044.2005.04376.x
CrossRef
Acta Anaesthesiologica Scandinavica
Transfusion vs. alternative treatment modalities in acute bleeding: a systematic review
Heier, HE; Bugge, W; Hjelmeland, K; Soreide, E; Sorlie, D; Haheim, LL
Acta Anaesthesiologica Scandinavica, 50(8): 920-931.
10.1111/j.1399-6576.2006.01089.x
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Chirurg
Local and systemic hemostasis in surgery
Bechstein, WO; Strey, C
Chirurg, 78(2): 95-+.
10.1007/s00104-006-1289-x
CrossRef
Annals of Pharmacotherapy
Recombinant Activated Factor VII Use in Critically Ill Patients: Clinical Outcomes and Thromboembolic Events
Brophy, GM; Candeloro, CL; Robles, JR; Brophy, DF
Annals of Pharmacotherapy, 47(4): 447-454.
10.1345/aph.1R729
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Annals of Surgery
Use of Recombinant Activated Factor VII in Patients Without Hemophilia: A Meta-Analysis of Randomized Control Trials
Hsia, CC; Chin-Yee, IH; McAlister, VC
Annals of Surgery, 248(1): 61-68.
10.1097/SLA.0b013e318176c4ec
PDF (844) | CrossRef
Blood Coagulation & Fibrinolysis
Recombinant activated factor VII in liver patients: a retrospective cohort study from Australia and New Zealand
Flower, O; Phillips, LE; Cameron, P; Gunn, K; Dunkley, S; Watts, A; Rajbhandari, D
Blood Coagulation & Fibrinolysis, 21(3): 207-215.
10.1097/MBC.0b013e3283333589
PDF (239) | CrossRef
Blood Coagulation & Fibrinolysis
The use of recombinant factor VIIa in liver diseases
Franchini, M; Montagnana, M; Targher, G; Zaffanello, M; Lippi, G
Blood Coagulation & Fibrinolysis, 19(5): 341-348.
10.1097/MBC.0b013e32830496a7
PDF (132) | CrossRef
Critical Care Medicine
Recombinant activated factor VII in cardiac surgery—Will we ever know for sure?*
Silver, DA; D’Ambra, MN
Critical Care Medicine, 35(7): 1782-1783.
10.1097/01.CCM.0000269395.46821.EF
PDF (967) | CrossRef
Critical Care Medicine
Massive transfusion and nonsurgical hemostatic agents
Perkins, JG; Cap, AP; Weiss, BM; Reid, TJ; Bolan, CE
Critical Care Medicine, 36(7): S325-S339.
10.1097/CCM.0b013e31817e2ec5
PDF (528) | CrossRef
Current Opinion in Anesthesiology
The role of recombinant-activated factor VII in bleeding trauma patients
Dutton, RP; Conti, BM
Current Opinion in Anesthesiology, 22(2): 299-304.
10.1097/ACO.0b013e32832678c6
PDF (100) | CrossRef
Current Opinion in Hematology
Recombinant factor VIIa: safety and efficacy
Goodnough, LT; Shander, AS
Current Opinion in Hematology, 14(5): 504-509.
10.1097/MOH.0b013e32826388c3
PDF (126) | CrossRef
Journal of Trauma and Acute Care Surgery
The Effect of Recombinant Activated Factor VII on Mortality in Combat-Related Casualties With Severe Trauma and Massive Transfusion
Spinella, PC; Perkins, JG; McLaughlin, DF; Niles, SE; Grathwohl, KW; Beekley, AC; Salinas, J; Mehta, S; Wade, CE; Holcomb, JB
Journal of Trauma and Acute Care Surgery, 64(2): 286-294.
10.1097/TA.0b013e318162759f
PDF (410) | CrossRef
Pediatric Critical Care Medicine
Activated recombinant factor VII for refractory bleeding during extracorporeal membrane oxygenation*
Niebler, RA; Punzalan, RC; Marchan, M; Lankiewicz, MW
Pediatric Critical Care Medicine, 11(1): 98-102.
10.1097/PCC.0b013e3181b0620b
PDF (176) | CrossRef
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