BJA Advance Access originally published online on August 1, 2006
British Journal of Anaesthesia 2006 97(4):460-467; doi:10.1093/bja/ael191
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Efficacy of fibrinogen and prothrombin complex concentrate used to reverse dilutional coagulopathy—a porcine model
1 Division of General and Surgical Intensive Care Medicine, Innsbruck Medical University Anichstrasse 35, 6020 Innsbruck, Austria
2 Division of Anaesthesiology, Innsbruck Medical University Anichstrasse 35, 6020 Innsbruck, Austria
3 Department of Theoretical Surgery, Innsbruck Medical University Anichstrasse 35, 6020 Innsbruck, Austria
4 Department of Paediatrics, Innsbruck Medical University Anichstrasse 35, 6020 Innsbruck, Austria
5 Department of Histology and Embryology, Innsbruck Medical University Anichstrasse 35, 6020 Innsbruck, Austria
*Corresponding author. E-mail: dietmar.fries{at}uibk.ac.at
Accepted for publication May 10, 2006.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background. This study was conducted to assess whether the combined administration of fibrinogen and prothrombin complex concentrate (PCC) enables the reversal of dilutional coagulopathy resulting from intended blood loss and fluid replacement, and whether this treatment reduces further blood loss and mortality.
Methods. In 20 anaesthetized pigs, 
65% of the estimated blood volume was withdrawn and replaced with the same amount of hydroxyethyl starch (6% HES 130/0.4) to mimic blood loss and to develop a dilutional coagulopathy. Pigs (randomized) received either fibrinogen (200 mg kg–1) and PCC (35 IU kg–1) (n=10), or placebo (n=10). Thereafter, a standard liver laceration was performed to induce uncontrolled haemorrhage. The subsequent blood loss and survival time were determined as primary outcome variables. Throughout the experiment serial blood samples were obtained to assess the competence of the haemostatic system using standard coagulation tests, modified Thrombelastograph® measurements (ROTEM®) and electron microscopy clot imaging.
Results. As compared with baseline, after haemodilution both groups showed statistically significant impairment of haemostasis as measured with standard coagulation tests and thrombelastography. These parameters significantly improved after administration of the study drugs while aPPT measurements remained unchanged. Blood loss after liver injury was significantly less in the treatment group as compared with placebo: 240 ml (50–830) vs 1800 ml (1500–2500) (P<0.0001). All treated animals survived, whereas 80% of the placebo group died (P<0.0001).
Conclusion. During haemodilution, substitution of fibrinogen and PCC causes an enhancement of coagulation and final clot strength. This reversal of dilutional coagulopathy may reduce blood loss and mortality when large amounts of colloids are needed to maintain normovolaemia during huge blood losses.
Keywords: blood, prothrombin complex concentrate; complications, coagulopathy; complications, haemorrhage; fluid, therapy; measurement techniques, Thrombelastograph®; pig; protein, fibrinogen concentrate
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The concept of adequately administering crystalloid and colloid fluids to maintain normovolaemia in patients exhibiting blood loss and the restrictive use of plasma-free red cell concentrates are the reasons why anaesthesiologists are now more frequently confronted with patients developing severe coagulopathy. The i.v. fluids not only dilute clotting factor concentrations but also exert specific effects on the coagulation system which have been extensively investigated in vitro and in vivo.1–5 Generally, artificial and natural colloids impair coagulation to a larger extent than crystalloids.6 7 We have previously shown that colloids decrease clot strength primarily by impairing fibrin polymerization, the final pathway of the coagulation process.6 In our previous experiments we were able to show that administration of fibrinogen concentrate results in quick and effective reversal of decreased clot strength, while, as expected, initiation of coagulation mainly depending on thrombin generation remained prolonged.8 9
Therefore, using our animal model of dilutional coagulopathy and uncontrolled haemorrhage, we investigated the efficacy of fibrinogen and additional prothrombin complex concentrate (PCC) in reversing dilutional coagulopathy as measured by modified thrombelastography, blood loss and survival rate.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This project was approved by the Austrian Federal Animal Investigation Committee, and the animals were managed in accordance with the American Physiological Society institutional guidelines and the Position of the American Heart Association on Research Animal Use, as adopted on November 11, 1984. Animal care and use were performed by qualified individuals supervised by veterinarians, and all facilities and transportation comply with current legal requirements and guidelines. Anaesthesia was used in all surgical interventions, all unnecessary suffering was avoided, and research was terminated if unnecessary pain or distress resulted. Our animal facilities meet the standards of the American Association for Accreditation of Laboratory Animal Care.
Surgical preparations and measurements
This study was performed in 20 healthy, 12- to 16-week-old swine weighing 36–44 kg. The animals were fasted overnight, but had free access to water. The pigs were premedicated with azaperone (4 mg kg–1 i.m., neuroleptic agent, StresnilTM, Janssen, Vienna, Austria) and atropine (0.1 mg kg–1 i.m.) 1 h before surgery, and anaesthesia was induced with propofol (1–2 mg kg–1 i.v.). After intubation during spontaneous respiration, the pigs received pancuronium (0.2 mg kg–1) and were ventilated with a volume-controlled ventilator (Draeger, EV-A, Lübeck, Germany) with oxygen 35% at 20 bpm and with a tidal volume adjusted to maintain normocapnia. Anaesthesia was maintained with propofol (6–8 mg kg–1), and a single injection of piritramide (30 mg, 4–8 h half-life, DipidolorTM, Janssen, Vienna, Austria). If clinical assessment indicated a lessening of anaesthesia, the dosage of propofol and piritramide was increased. Ringer's lactate (250 ml) was administered in the preparation phase. Body temperature was maintained between 38.0 and 39.0°C. A 7.5 French catheter was advanced into the femoral artery for collection of blood samples and continuous arterial pressure measurement; two 7.5 French catheters were advanced into both femoral veins for blood withdrawal and hydroxyethyl starch (HES) administration.
Experimental protocol
After assessing baseline haemodynamic and coagulation values, a midline laparotomy was performed. Propofol infusion was then adjusted to 2 mg kg–1 h–1. The animals subsequently underwent an isovolaemic and normothermic exchange of 65% of their total blood volume of 2500 ml with HES 130/0.4 (Voluven®, Fresenius, Pharma Austria GmbH, Graz, Austria) over 30 min. The shed blood was processed using a cell saver device (CATS®, Fresenius, Frankfurt, Germany), and all animals received their washed autologous red cells after volume resuscitation with HES in order to avoid early death from severe anaemia. Animals were then randomly assigned to either fibrinogen (200 mg kg–1) concentrate and PCC (35 IU kg–1) (Haemocompletan P® and Beriplex P/N®, ZLB Behring, Marburg, Germany) (n=10) or to an equal amount of normal saline (n=10) (investigators were blinded to the drugs). A standardized incision was made in the right liver lobe (length, 12 cm; depth, 3 cm) to induce uncontrolled bleeding. Subsequently, no packing any other mechanical manipulation of the wound was performed. At the end of the study protocol, blood was suctioned out of the abdomen and total blood loss determined. After liver incision, observation was conducted for 120 min. If an animal died within these 120 min, the last blood sampling was performed immediately before death, which was defined as pulseless electrical activity, mean arterial pressure below 10 mm Hg and end tidal carbon dioxide below 10 mm Hg. Animals surviving for more than 120 min were euthanized with an overdose of fentanyl, propofol and potassium chloride.
Blood sampling and analytical methods
Arterial blood sampling was performed at baseline, after withdrawal of blood, after haemodilution, after administration of salvaged washed red blood cell concentrate and study drugs, and 120 min after liver injury or immediately before death. Fibrinogen concentration, prothrombin (PT) and activated partial thromboplastin time (aPTT) haemoglobin values and platelet cell count at corresponding time points were determined by standard laboratory methods. Further, antithrombin (AT) (Antithrom Stago, Boehringer Mannheim, Germany), D-dimer (Latex Immunoassay, Instrumental Laboratories) with good cross-reactivity to porcine fibrinogen, thrombin–AT (TAT, Elisa Test, Dade Behring) and Thrombelastograph® measurements (ROTEM®, Pentapharm, Munich, Germany) were performed. The parameters of ROTEM® analysis are ‘clotting time’ (CT in seconds) corresponding to the r-time in a conventional thrombelastogram, ‘clot formation time’ (CFT in seconds), the k-time, ‘maximum clot firmness’ (MCF, mm), which is equivalent to the maximum amplitude, and alpha angle, which describes the speed of clot formation (Fig. 1). In addition blood clots were examined by electron microscopy using fresh whole undiluted blood, and diluted blood and diluted blood after fibrinogen and PCC administration. Blood clots were initially fixed with glutaraldehyde 2.5%, buffered with sodium cacodylate containing CaCl2, washed in the same buffer and then fixed in osmium tetroxide for 1 h. Next, clots were washed, dissected into small pieces in ethanol 70%, dehydrated, critical point-dried and sputter coated with gold–palladium. All scanning electron microscopy specimens were examined with a Zeiss DSM 982 Gemini electron microscope.
|
Statistical analysis
Differences at baseline and between baseline and the following measurement points were compared between groups using the Wilcoxon test for unpaired observations. A non-parametric Friedman ANOVA was applied to analyse a possible time effect within each group. Thrombelastographic parameters are presented in box plots (minimum, first quartile, median, third quartile, maximum). A P-value <5% was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
At baseline, pigs were comparable for haemodynamic and coagulation measurements and for red blood cell count (Tables 1 and 2). All coagulation tests were within the normal reference interval described for pigs.10 The only exception was that baseline measurements of CFT were statistically significantly higher and those of alpha angle significantly lower in the treatment group, but, were still within the reference range (Fig. 2B and D).
|
|
|
All variables changed significantly within both groups over time (Friedmann ANOVA analysis) with the exception that concentrations of DD remained unchanged in the placebo group only (Table 1). After intended blood loss (median, Q1, Q3; 1700 ml, 1500 ml, 2000 ml; NS different between groups) and after volume replacement no differences between groups were observed for any variables except central venous pressure, which was slightly decreased in the placebo group after volume replacement (Table 2). After volume replacement in both groups measurements of CT and CFT were significantly prolonged, those of MCF and alpha angle decreased (Fig. 2A–D), concentrations of fibrinogen, haemoglobin, platelets and AT were significantly decreased, as were measurements of PT and aPTT (Table 1). Concentrations of lactate did not significantly differ from baseline. Measurements of haemodynamic variables are given in Table 2.
After administration of salvaged red blood cell concentrate and study drugs, ROTEM parameters improved not only in the animals treated with PCC and fibrinogen but also in the animals in the placebo group. However, normalization of parameters was seen in the treatment group only.
Between groups differences in coagulation parameters were detected after randomized administration of fibrinogen and PCC, immediately and at the end of the observation period, which was set at 120 min, or immediately before death.
In the treatment group CT was significantly shorter than in the placebo group (Fig. 2A). Similarly, CFT measurements decreased and values of MCF and alpha angle increased towards baseline concentrations (Fig. 2B–D). In addition, concentrations of fibrinogen and measurements of PT increased and did not significantly differ from baseline in the treatment group only. Concentrations of DD and TAT were significantly increased in the treatment group at the end of the observation period, while a non-significant decrease was observed for the placebo group (Table 1).
Median (Q1, Q3) blood loss of 1800 ml (1800–2200 ml) occurring after liver incision was significantly greater in the placebo group than in the treatment group; 240 ml (50–700 ml) (P=0.002). All animals in the treatment group survived. However, only 2 of the 10 animals in the placebo group survived (P=0.0003).
Electron microscopic pictures (which cannot by analysed by statistical methods), impressively expose the consequences of blood loss and volume replacement on clot architecture and the ability of the tested therapy to restore the density of the fibrin network even under conditions of uncontrolled haemorrhage (Fig. 3A–C).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This is the first study to investigate the effect of fibrinogen and PCC under conditions of haemodilution and uncontrolled haemorrhage in a porcine model. After major blood loss of
65% of the estimated total blood volume, volume resuscitation with HES (2500 ml) resulted in dilutional coagulopathy as measured by conventional coagulation tests and modified Thrombelastograph®. In the animals receiving salvaged red blood cell concentrate only and in the placebo group, there was a small improvement in Thrombelastograph® parameters. This was statistically significant. However, in the treatment group additional substitution of fibrinogen and PCC resulted in normalization of coagulation parameters. Blood loss and mortality after standardized liver injury were significantly diminished in animals treated with clotting factors as compared with placebo. There is no doubt that aggressive fluid resuscitation is crucial in the case of massive blood loss, at least in blunt and multiple traumatized patients. Nevertheless, haemodynamic stabilization by administration of large amounts of crystalloid and colloid solutions results in dilutional coagulopathy. The clinical effects of impaired plasma clotting caused by normovolaemic haemodilution were studied by Murray and colleagues:3 17 of 32 patients studied intraoperatively showed an increased bleeding tendency that correlated with prolonged PT and aPTT. The authors concluded that a 1.5-fold prolongation of PT and aPTT is associated with an increased bleeding tendency. Furthermore, an absolute increase of 4% in mortality after colloid fluid resuscitation was found in a systematic review of randomized controlled trauma resuscitation trials investigating colloid vs crystalloid solutions in critically injured patients.11 The increased mortality in these patients was probably not only a result of increased perfusion pressure after volume resuscitation with colloid solutions, but also a consequence of impaired haemostasis because of dilutional coagulopathy. The severity of dilutional coagulopathy is determined by the volume and the type of fluid. In addition to their dilutional effect, gelatin preparations also exert specific effects on the coagulation system. Above all, they impair fibrin polymerization and disturb the network of fibrin monomers. Moreover, reduced clot elasticity and clot weight have been reported in the presence of gelatin.12 13 HES has been shown to be associated with an increased tendency to bleed.14 HES causes a von Willebrand type 1-like syndrome characterized by diminished FVIII activity and diminished plasma vWF concentrations.15 In addition, HES also impairs fibrin polymerization.6 A relatively new preparation is 6% HES 130/0.4 (Voluven®, Fresenius, Pharma Austria GmbH); it has a medium molecular weight and a low degree of substitution and thus probably does not as strongly affect the coagulation system.16 17 However, recent data show that the molecular weight mainly determines duration of intravascular persistence, but is not the determining factor in compromising coagulation.18
In clinical routine coagulopathy is usually treated with fresh frozen plasma (FFP) and, if available, with cryoprecipitate. It has been shown that critically reduced clotting factor concentrations can barely be corrected by administering FFP because of its low concentrations of coagulation factors and its volume-expanding effects, which counterbalances the intended increase in concentration of any protein of interest.19 20 In addition, the necessary thawing process delays immediate treatment, which is of special importance in multiple traumatized patients. If sufficient amounts of FFP are not available within a reasonable time, the administration of clotting factor concentrates such as, for example, fibrinogen concentrate and PCC should be considered.21
However, administration of neither FFP nor coagulation factor concentrates has been adequately studied in this context. The guidelines for therapy with blood components and plasma derivatives issued by the German Medical Association recommend that fibrinogen and PCC be administered only in the case of proven deficiencies. For example, PCC should be administered for perioperative bleeding only when the residual activity of factors II, VII, IX and X is <40%.22 Factor analysis is extremely time-consuming and thus useless to a clinician. In such a situation a Thrombe-lastograph® analyses might be very helpful. On the one hand, it facilitates fast diagnosis of the actual coagulation status within a few minutes and, on the other hand, it can help check the efficacy of current therapy. Moreover, Thrombelastograph® data can be helpful in detecting isolated factor deficiencies and in some cases in treating them with coagulation factors, so that FFP may not be needed.23 24
The influence of only fibrinogen concentrate on dilutional coagulopathy was previously examined in vitro and in an animal model. Specimens were obtained from healthy controls and diluted by 55% with crystalloids, with different HES solutions including the newly developed 6% HES 130/0.4 and with dextrans in vitro and monitored by a Thrombelastograph® analyser. The diminished clot strength was thrombelastographically compensated by administering fibrinogen concentrate, but not factor VIII concentrate or platelets.25 In an animal model previously performed by us, 65% of the estimated total blood volume was withdrawn from pigs and compensated with gelatin. Fibrinogen concentrate or a placebo was subsequently administered. Here too, compensation exclusively with fibrinogen concentrate normalized the impaired clot strength. Moreover, uncontrolled bleeding was induced in the animals by means of a stab incision to the liver. The animals who received fibrinogen concentrate showed statistically significantly less blood loss after the liver injury.8
PCC usually contains factors II, VII, IX and X and protein C and trace amounts of heparin and have been used for years in the treatment of hereditary coagulation deficiencies and as an antagonist to warfarin-like anticoagulants.26 A further indication for the administration of PCC is the acquired factor deficiency, but there are only limited in vivo data on the use of modern PCC preparations in patients exhibiting acquired coagulation factor deficiencies caused by massive blood loss, massive transfusion or both. It is known that 1 U kg–1 PCC body weight increases PT by 1%. Staudinger and colleagues27 investigated the effect of PCC on plasma coagulation in critically ill patients and found that a dose of 2000 factor IX units of PCC (mean 30 U kg–1 body weight) normalized PT by raising the plasma concentration of coagulation factors II, VII, IX and X in patients with moderately reduced coagulation activity. PCC preparations contain defined amounts of clotting factors and is able to quickly compensate imbalances in the coagulation system caused by clotting factor deficiencies. In contrast, FFP, which are prepared from healthy blood donors, contain large amounts of albumin and water, while the procoagulatory factors and their inhibitors too are present in their normal physiologically low concentrations, which, however, can vary considerably with the individual donor.
The effect of coagulation therapy achieved by administering clotting factor concentrates to counteract uncontrolled haemorrhage was previously examined in several animal studies using recombinant activated factor VII (rFVIIa, NovoSeven®, Novo Nordisk, Copenhagen, Denmark). In contrast to our findings, these studies mainly found no effect of rFVIIa on blood loss after liver injury28–31 although mortality was reduced. However, formation of polymerized fibrin, the final product of the coagulation cascade, was not considered in these investigations. Probably, the combined administration of fibrinogen with rFVIIa will achieve better results with regard to blood loss in uncontrolled haemorrhage.
One concern associated with the combined administration of PCC and fibrinogen concentrate is thrombosis and thromboembolic complications and the dosage of PCC and fibrinogen used in our study seems to be quite high. However, the fibrinogen dosage needed to improve clot firmness during profound dilutional coagulopathy and ongoing haemorrhage relies on results of our previous animal study. In addition, recently published results from an animal model show that even during moderate blood loss synthesis of fibrinogen cannot exceed the markedly increased fibrinogen breakdown.32 The PT complex dosage was calculated to reach concentrations of coagulation factors around 50%. According to the manufacturers instructions 1IU kg–1 increases coagulation factors by 1% (and also PT measurements by 1%) and it is our experience that pronounced increased CT-times are associated with clotting factor concentrations of 20–30%. Few publications describing thromboembolic complications after clotting factor administration exist and refer mainly to the use of activated preparations. Recent preparation of clotting factor concentrates differs from those used earlier and to our knowledge no data are available for their use in severe coagulopathic bleeding. D-dimer as a laboratory parameter of a thromboembolic phenomenon was elevated at the end of the observation period in the animals treated with coagulation factors, while TAT did not differ between the groups. Autopsy showed no evidence of thromboembolic problems in our animals. Elevated D-dimer values are also a marker for disseminated intravascular coagulopathy. Histological examination did not detect any microvascular thrombosis in the lungs, heart, gut, spleen or liver. However, D-dimer values between 200 and 300 ng ml–1 can be interpreted as an adequate response to liver injury. Furthermore, Thrombe-lastograph® measurements after fibrinogen and PCC administration did not show any signs of hypercoagulopathy.
There are some limitations to our study that need to be noted: in order to enable exact measurement of study end points, haemodilution and coagulation factor administration had to be induced before liver injury. However, withdrawal of whole blood and consequent administration of colloids corresponds with clinical practice of treating blood loss so that the administration of clotting factor concentrates was not prophylactic but therapeutic.
In conclusion, correction of dilutional coagulopathy with fibrinogen concentrate and PCC was able to restore impaired clot formation and reduced blood loss and mortality after standardized liver injury in a porcine model of dilutional coagulopathy and uncontrolled haemorrhage.
Clinical studies are needed to confirm our hypothesis that administration of fibrinogen and PCC may be a useful first step toward reversing dilutional coagulopathy, thereby accelerating effective therapy, reducing FFP requirements and the undesirable side-effects such as development of transfusion associated lung injury (TRALI), total blood loss and further volume demand.
|
Acknowledgments |
|---|
This study was supported in part by the Science Foundation of the Austrian National Bank grant 11448, Vienna, Austria and by ZLB Behring, Marburg, Germany.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1 Hippala S. Replacement of massive blood loss. Vox Sang 1998; 74:Suppl 2, 399–407
2 Leslie SD and Toy PT. Laboratory hemostatic abnormalities in massively transfused patients given red blood cells and crystalloid. Am J Clin Pathol 1991; 96:770–3[Web of Science][Medline]
3 Murray DJ, Olson J, Strauss R, Tinker JH. Coagulation changes during packed red cell replacement of major blood loss. Anesthesiology 1988; 69:839–45[Web of Science][Medline]
4 Counts RB, Haisch C, Simon TL, et al. Hemostasis in massively transfused trauma patients. Ann Surg 1979; 190:91–9[Web of Science][Medline]
5 Hiippala ST, Myllylä GJ, Vahtera EM. Hemostatic factors and replacement of major blood loss with plasma-poor red cell concentrates. Anesth Analg 1995; 81:360–5[Abstract]
6 Innerhofer P, Fries D, Margreiter J, et al. The effects of perioperatively administered colloids and crystalloids on primary platelet-mediated hemostasis and clot formation. Anaesth Analg 2002; 95:858–65
7 Fries D, Innerhofer P, Klingler A, et al. The effect of the combined administration of colloids and lactated Ringer's solution on the coagulation system: an in vitro study using thrombelastograph coagulation analysis (ROTEG). Anesth Analg 2002; 94:1280–7
8 Fries D, Krismer A, Klingler A, et al. Effect of fibrinogen on reversal of dilutional coagulopathy: a porcine model. Br J Anaesth 2005; 95:172–7
9 Fries D, Innerhofer P, Reif C, et al. The effect of fibrinogen substitution on reversal of dilutional coagulopathy: an in vitro study. Anesth Analg 2006; 102:347–51
10 Velik-Salchner C, Schnürer C, Fries D, et al. Normal values for thrombelastography and selected coagulation parameters in porcine blood. Thromb Res 2006. 35: pp. 310–16
11 Schierhout G and Roberts I. Fluid resuscitation with colloid or crystalloid solution in critically ill patients: a systemic review of randomized trials. Br Med J 1998; 316:961–4
12 Mardel SN, Saunders FM, Allen H, et al. Reduced quality of clot formation with gelatin-based plasma substitutes. Br J Anaesth 1998; 80:204–7
13 Engvall E, Ruoslahti E, Miller EJ. Affinity of fibronectin to collagens of different genetic types and fibrinogen. J Exp Med 1978; 147:1584–95
14 Treib J, Baron JF, Grauer MT, Strauss RG. An international view of hydroxyethyl starches. Int Care Med 1999; 25:258–68[CrossRef][Web of Science][Medline]
15 Vogt NH, Bothner U, Lerch G, Lindner KH, Georgieff M. Large dose administration of 6% hydroxyethyl starch 200/0.5 for total hip arthroplasty: plasma homeostasis, hemostasis and renal function compared to use of 5% human albumin. Anesth Analg 1996; 83:262–8[Abstract]
16 Entholzer EK, Mielke LL, Calatzis AN, et al. Coagulation effects of a recently developed hydroxyethyl starch (HES 130/0.4) compared to hydroxyethyl starches with higher molecular weight. Acta Anaesthesiol Scand 2000; 44:1116–21[CrossRef][Web of Science][Medline]
17 Gallandat R, Siemons A, Baus D, et al. A novel hydroxyethyl starch (Voluven®) for effective perioperative plasma volume substitution in cardiac surgery. Can J Anesth 2000; 47:1207–15[Web of Science][Medline]
18 Madjdpour C, Dettori N, Frascarolo P, et al. Molecular weight of hydroxyethyl starch: is there an effect on blood coagulation and pharmacokinetics? Br J Anaesth 2005; 94:569–76
19 Stanworth S, Brunskill S, Hyde C, McClelland D, Murphy M. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol 2004; 126:139–52[CrossRef][Web of Science][Medline]
20 Chowdhury P, Saayman A, Paulus U, Findlay G, Collins P. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol 2004; 125:69–73[CrossRef][Web of Science][Medline]
21 Fries D, Haas T, Velik-Salchner C, Innerhofer P. Gerinnungsmanagement beim polytraumatisierten Patienten. Anaesthesist 2005; 54:137–44[CrossRef][Web of Science][Medline]
22 Vorstand und wissenschaftlicher Beirat der Bundesärztekammer. Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten. Z. Ausgabe Deudnaker Ârzteverlag Kölm 2001. pp. 95–146
23 Nielsen V, Cohen B, Cohen E. Effects of coagulation factor deficiency on plasma coagulation kinetics determined via thrombelastography: critical roles of fibrinogen and factors II, VII, X and XII. Acta Anaesthesiol Scand 2005; 49:222–31[CrossRef][Web of Science][Medline]
24 O'Shaughnessy D, Atterbury C, Bolton Maggs P, et al. Guidelines for the use of fresh-frozen-plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004; 126:11–28[CrossRef][Web of Science][Medline]
25 Fenger-Eriksen C, Anker-Moller E, Heslop J, Ingerslev J, Sorensen B. Thrombelastographic whole blood clot formation after ex vivo addition of plasma substitutes: improvements of the induced coagulopathy with fibrinogen concentrate. Br J Anaesth 2005; 94:324–9
26 Menache D. Prothrombin complex concentrates: clinical use. Ann N Y Acad Sci 1981; 370:747–56[Medline]
27 Staudinger T, Frass M, Rintelen C, et al. Influence of prothrombin complex concentrates on plasma coagulation in critically ill patients. Intensive Care Med 1999; 25:1105–10[CrossRef][Web of Science][Medline]
28 Lynn M, Jerokhimov I, Jewelewicz D, et al. Early use of recombinant factor VIIa improves mean arterial pressure and may potentially decrease mortality in experimental hemorrhagic shock: a pilot study. J Trauma 2002; 52:703–7[Web of Science][Medline]
29 Schreiber M, Holocomb JB, Hedner U, et al. The effect of rFIIa on noncoagulopathic pigs with grade V liver injuries. J Am Coll Surg 2003; 196:691–7[CrossRef][Web of Science][Medline]
30 Schreiber M, Holocomb JB, Hedner U, et al. The effect of rFIIa on coagulopathic pigs with grade V liver injuries. J Trauma 2002; 53:252–7[Web of Science][Medline]
31 Sondeen J, Pusateri A, Hedner U, Yantis L, Holocomb J. rFVIIa increases the pressure at which rebleeding occurs in porcine uncontrolled hemorrhage model. Shock 2004; 22:163–8[CrossRef][Web of Science][Medline]
32 Martini WZ, Chinkes DL, Pusateri AE, et al. Acute changes in fibrinogen metabolism and coagulation after hemorrhage in pigs. AJP-Endo 2005; 289:930–4
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. Bolliger, F. Szlam, R. J. Molinaro, N. Rahe-Meyer, J. H. Levy, and K. A. Tanaka Finding the optimal concentration range for fibrinogen replacement after severe haemodilution: an in vitro model Br. J. Anaesth., June 1, 2009; 102(6): 793 - 799. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Dickneite and I. Pragst Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model Br. J. Anaesth., March 1, 2009; 102(3): 345 - 354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fenger-Eriksen, M. Lindberg-Larsen, A. Q. Christensen, J. Ingerslev, and B. Sorensen Fibrinogen concentrate substitution therapy in patients with massive haemorrhage and low plasma fibrinogen concentrations Br. J. Anaesth., December 1, 2008; 101(6): 769 - 773. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. T. Ganter and C. K. Hofer Coagulation Monitoring: Current Techniques and Clinical Use of Viscoelastic Point-of-Care Coagulation Devices Anesth. Analg., May 1, 2008; 106(5): 1366 - 1375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Dickneite, B. Doerr, and F. Kaspereit Characterization of the Coagulation Deficit in Porcine Dilutional Coagulopathy and Substitution with a Prothrombin Complex Concentrate Anesth. Analg., April 1, 2008; 106(4): 1070 - 1077. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Haas, D. Fries, C. Holz, P. Innerhofer, W. Streif, A. Klingler, A. Hanke, and C. Velik-Salchner Less Impairment of Hemostasis and Reduced Blood Loss in Pigs After Resuscitation from Hemorrhagic Shock Using the Small-Volume Concept with Hypertonic Saline/Hydroxyethyl Starch as Compared to Administration of 4% Gelatin or 6% Hydroxyethyl Starch Solution Anesth. Analg., April 1, 2008; 106(4): 1078 - 1086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. G. Nielsen and J. H. Levy Fibrinogen and Bleeding: Old Molecule New Ideas Anesth. Analg., October 1, 2007; 105(4): 902 - 903. [Full Text] [PDF]
|
|
|
|
|
|
M. Mittermayr, W. Streif, T. Haas, D. Fries, C. Velik-Salchner, A. Klingler, E. Oswald, C. Bach, M. Schnapka-Koepf, and P. Innerhofer Hemostatic Changes After Crystalloid or Colloid Fluid Administration During Major Orthopedic Surgery: The Role of Fibrinogen Administration Anesth. Analg., October 1, 2007; 105(4): 905 - 917. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||