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From the Department of Anesthesiology, School of Medicine, The Catholic University of Korea, Seoul, Korea.
Address correspondence to: Dr. Jaemin Lee, Department of Anesthesiology, School of Medicine, The Catholic University of Korea, Kangnam Saint Mary’s Hospital, 505 Banpo-Dong, Seocho-Gu, Seoul, Korea 137-040. Phone: 82-2-590-1545; Fax: 82-2-537-1951; E-mail: jmlee{at}catholic.ac.kr
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Abstract |
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Methods: 27 patients scheduled for liver transplantation were enrolled. 1.5 g of magnesium sulfate, diluted in normal saline, were infused to all patients over five minutes in the operating room, before skin incision. The TEG findings immediately before and ten minutes after the magnesium infusion were compared.
Results: The TEG findings showed general hypocoagulability before magnesium therapy. The K time and coagulation times (r+k) were shortened significantly from 641.6 ± 505.9 (mean ± SD) to 464.6 ± 387.7 sec and from 1664.7 ± 772.5 to 1362.2 ± 487.1 sec respectively (P < 0.05); the maximal amplitude, and TEG index showed significant increases from 38.5 ± 13.5 to 45.3 ± 12.2 mm and from –3.4 ± 2.6 to –1.9 ± 1.8 respectively after magnesium therapy (P < 0.01). R time, alpha angle and LY60 were not different after magnesium therapy.
Conclusion: Magnesium therapy significantly improved TEG findings suggestive of a general hypocoagulable state towards normal in patients about to receive liver transplantation.
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Introduction |
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Magnesium is known to be crucial physiologically in the coagulation cascade. According to recent studies, magnesium is an essential factor in the activation of coagulation factors and functions as a promoter of coagulation.4–6 Coagulation is impaired in patients with end-stage liver disease due to various factors such as decreased production of coagulation factors, gastrointestinal bleeding, splenomegaly, malnutrition and massive blood transfusion during liver transplantation. Considering the effect of magnesium on coagulation, we assumed that hypomagnesemia in patients with end-stage liver disease could impair coagulation and increase their tendency to bleed.
In this preliminary study, we examined the changes brought about by magnesium therapy on coagulation in patients about to undergo liver transplantation, using thromboelastography (TEG).
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Methods |
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After induction of anesthesia, a 20-gauge catheter was inserted in the right radial artery to monitor arterial pressure and to obtain blood samples for arterial blood gas analysis and TEG. Heparin was not added to the pressurized infusion system to prevent changes in TEG. Two millilitres of whole blood were obtained through the right radial artery using the two-syringe technique after anesthesia induction. TEG analysis was performed using 0.36 mL of this blood sample. After 1.5 g of magnesium sulfate (MgSO4) mixed in 100 mL of normal saline were infused iv in five minutes, a blood sample was obtained ten minutes later to determine TEG changes. Other than magnesium, no drug was infused between blood samples. Furthermore, since the surgical procedure itself could promote blood coagulation,7 blood sampling for TEG analysis before and after magnesium therapy was completed before skin incision. The remaining blood samples were sent to the laboratory to measure the serum magnesium concentration before and after magnesium therapy.
Statistical treatment of all data was done using SPSS 11.0 (SPSS Inc., Chicago, IL, USA). The TEG variables including R time, K time, coagulation time (r+k), alpha angle, maximal amplitude (MA), TEG index and serum magnesium concentration were analyzed using Bonferroni t tests. Non-parametric data including LY60 were analyzed using Wilcoxon sign test. P values less than 0.05 were considered statistically significant.
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. Numerical values are presented in the Table.
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; Table). The serum magnesium concentration increased significantly after magnesium therapy to 2.8 ± 0.9 mg·dL–1 from 1.8 ± 0.8 mg·dL–1 before magnesium therapy (normal ranges of serum magnesium concentration are 1.9 to 3.1 mg·dL–1; P < 0.01).
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Discussion |
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Magnesium is an important factor inhibiting cardiac cell excitation and maintaining stability of the cardiovascular system by controlling the migration of ions including sodium, calcium and potassium through the cell membrane.8 Hypomagnesemia is induced in patients with end-stage liver disease due to various reasons; thus, in order to avoid adverse effects of this condition on the cardiovascular system, magnesium supplementation during liver transplantation is considered positively.1,2
Magnesium is known to play an important role in the coagulation cascade. Sekiya et al.4 reported that magnesium at physiologic concentrations activates all processes related to factor IX by promoting the biochemical function of factor IX and the activity of factor X under the presence of factor IXa and described that magnesium is an important factor promoting coagulation by activating the factor VIIa·tissue factor complex. Matsuno et al.5 also reported that magnesium is an essential element in the activation of thrombin and collagen, promoting platelet aggregation and having coagulation activity. In a clinical study, Serebruany et al.6 reported that magnesium therapy improved coagulation by promoting platelet aggregation and decreasing the concentrations of protein S and protein C.
In accordance with our hypothesis and based on previous data, we found that magnesium therapy improved coagulation in patients about to undergo liver transplantation who showed TEG evidence of hypocoagulability. The fact that end-stage liver disease patients show TEG findings of general hypocoagulability had already been reported.9–11 Our finding of decreased K and coagulation times (r+k) after magnesium therapy was considered the result of increased early fibrin formation and improved speed of cross-linking. Increased MA was thought to be a result of improved clot strength secondary to improved function of platelets. The increased TEG index suggests an overall improvement in coagulation.
No significant change was seen on the TEG when healthy volunteers were treated with magnesium.12 The claim that the effect of magnesium on the coagulation system is insignificant is based on an in vitro study.13 On the other hand, the R time decreased significantly after magnesium therapy in pre-eclamptic women.14 Thus, the effect of magnesium therapy on the TEG is still debated. These differing results suggest that magnesium may have different actions when coagulation is normal and abnormal. As shown in our study, magnesium improves TEG variables in patients with end-stage liver disease and hypomagnesemia.
We diluted 1.5 g of MgSO4 with 100 mL of normal saline and infused the solution in five minutes. Magnesium was mixed into a small volume of saline because large volumes may either induce bleeding by diluting coagulation factors or promote coagulation by destroying the thrombin and antithrombin balance, as reported by Ruttmann et al.15
Our results must be interpreted with caution. First, ionized magnesium is important physiologically among the different forms of magnesium present in the body. However, we did not measure ionized magnesium so that we could not confirm whether TEG changes after magnesium therapy were due to ionized or non-ionized magnesium. Second, TEG used to monitor changes in coagulation after magnesium therapy cannot measure the physiologic and biochemical interactions occurring between platelets and the vascular endothelium. Third, this study was performed to examine the effect of the magnesium therapy on TEG while ruling out the effect of other various factors affecting TEG. Thus, TEG findings prior to (control) and after magnesium therapy in the same patient were compared. However, we must admit that this study was not randomized, and does not give any details on clinical outcome. As such, it should be considered preliminary to a formal randomized controlled study.
In conclusion, we found that magnesium therapy improved the overall TEG findings in patients about to undergo liver transplantation. Further studies will be needed to investigate the effect of magnesium therapy and the improvement of TEG variables on blood product requirements during liver transplantation.
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Footnotes |
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References |
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2 Bennett MW, Webster NR, Sadek SA. Alterations in plasma magnesium concentrations during liver transplantation. Transplantation 1993; 56: 859–61.[Medline]
3 Ranasinghe DN, Mallett SV. Hypomagnesaemia, cardiac arrhythmias and orthotopic liver transplantation. Anaesthesia 1994; 49: 403–5.[Medline]
4 Sekiya F, Yoshida M, Yamashita T, Morita T. Magnesium (II) is a crucial constituent of the blood coagulation cascade. Potentiation of coagulant activities of factor IX by Mg2+ ions. J Biol Chem 1996; 271: 8541–4.
5 Matsuno K, Koyama M, Takeda H, et al. Cytosolic free magnesium concentration in human platelets. Thromb Res 1993; 69: 131–7.[Medline]
6 Serebruany VL, Herzog WR, Schlossberg ML, Gurbel PA. Bolus magnesium infusion in humans is associated with predominantly unfavourable changes in platelet aggregation and certain haemostatic factors. Pharmacol Res 1997; 36: 17–22.[Medline]
7 Samama CM, Thiry D, Elalamy I, et al. Perioperative activation of hemostasis in vascular surgery patients. Anesthesiology 2001; 94: 74–8.[Medline]
8 Fawcett WJ, Haxby EJ, Male DA. Magnesium: physiology and pharmacology. Br J Anaesth 1999; 83: 302–20.
9 Kang YG, Martin DJ, Marquez J, et al. Intraoperative changes in blood coagulation and thrombelastographic monitoring in liver transplantation. Anesth Analg 1985; 64: 888–96.
10 McNicol PL, Liu G, Harley ID, et al. Patterns of coagulopathy during liver transplantation: experience with the first 75 cases using thrombelastography. Anaesth Intens Care 1994; 22: 659–65.[Medline]
11 Gillies BS. Thromboelastography and liver transplantation. Semin Thromb Hemost 1995; 21(Suppl 4): 45–9.
12 Ames WA, McDonnell N, Potter D. The effect of ionised magnesium on coagulation using thromboelastography. Anaesthesia 1999; 54: 999–1006.[Medline]
13 James MF, Neil G. Effect of magnesium on coagulation as measured by thrombelastography. Br J Anaesth 1995; 74: 92–4.
14 Harnett MJ, Datta S, Bhavani-Shankar K. The effect of magnesium on coagulation in parturients with preeclampsia. Anesth Analg 2001; 92: 1257–60.
15 Ruttmann TG, James MF, Viljoen JF. Haemodilution induces a hypercoagulable state. Br J Anaesth 1996; 76: 412–4.
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  T. G. Ruttmann, L. F. Montoya-Pelaez, and M. F. M. James The Coagulation Changes Induced by Rapid In Vivo Crystalloid Infusion Are Attenuated When Magnesium Is Kept at the Upper Limit of Normal Anesth. Analg., June 1, 2007; 104(6): 1475 - 1480. [Abstract] [Full Text] [PDF]
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