Abstract
An important challenge during orthotopic liver transplantation (OLT) is optimal coagulation management. There are diverse studies regarding effect of Mg sulfate on coagulation system. This study evaluates the impact of Mg sulfate on the coagulation parameters of the rotational thromboelastometry (ROTEM) in patients about to undergo OLT. In this randomized clinical trial, 60 patients who were going to undergo OLT were randomly allocated into two groups. In the Mg group, the patients received a 1.5 g infusion of Mg 5 min before the surgical incision. In the control group, patients received a physiological saline instead of Mg. Plasma Mg levels before and after the infusions were measured in both groups. Also, three ROTEM tests: EXTEM, INTEM and FIBTEM were performed before and after the infusions. Baseline mean plasma magnesium levels were within normal range in the control and Mg groups: 2.06 and 2.18 mg/dl, respectively. After magnesium therapy, the mean plasma Mg level in the Mg group increased to 2.78 mg/dl in compared to the control group that was 2.01 mg/dl (P < 0.000). Mean value of the clotting time (CT) in the magnesium group were significantly decreased from 129.50 ± 7.76, 381.86 ± 8.51 and 114.26 ± 6.80 to 86.13 ± 3.4, 209.33 ± 6.68 and 81.56 ± 5.01 in the EXTEM, INTEM, and FIBTEM respectively after intervention in the Mg group (P = 0.001). Among patients with end-stage liver diseases who have ROTEM evidence of hypocoagulability, magnesium could correct CT parameter of the ROTEM tests.
Keywords: Blood coagulation disorder, Blood coagulation test, End stage liver disease, Liver transplantation, Magnesium sulfate
Introduction
An important challenge during orthotopic liver transplantation (OLT) is optimal coagulation management [1, 2]. For a long time believes that patients with end-stage liver disease have hypocoagulopathy state in proportion to degree of liver dysfunction [3]. However, in end-stage liver disease there is a delicate balance between coagulation factors and anticoagulant factors, which prevents actual coagulopathy in these patients. When additional factors such as fibrinolysis, calcium and magnesium deficiencies, or massive transfusions are superimposed, the aforementioned balance is removed and coagulopathy occurs [4, 5]. This coagulopathy is multifactorial and results from underlying liver disease, massive bleeding during OLT, and primary non function of new grafts [6, 7].
Magnesium (Mg) has a crucial role in the coagulation system and this divalent ion is an important cofactor of the blood coagulation cascade [8]. However, this ion has diverse effects on coagulation system, some studies suggested that Mg has antithrombotic effect while other studies reported that Mg does not have effect on coagulation system [9, 10] and just one preliminary study is in the literature, which found that Mg improved coagulation profiles on a thromboeslatographic system prior to OLT [11].
The present study was a randomized clinical trial designed to evaluate the effects of Mg therapy on coagulation profiles prior to OLT. We surveyed the effect of magnesium therapy on parameters of the three different test of the rotational thromboelastometry (ROTEM): INTEM (which evaluates the intrinsic pathway after contact activation), EXTEM (which evaluates the extrinsic pathway after addition of tissue factor) and FIBTEM (assess fibrinogen level after tissue factor activation).
Materials and methods
Study design
This single-center, double-blind, placebo-controlled, parallel-group with balanced randomization clinical trial was conducted in the operating theater of the Department of Organ Transplantation at Namazi Hospital, Shiraz, Iran. The study is registered in the Iranian Registry of Clinical Trials (IRCT2016012911662N9).The eligible participants were patients with end-stage liver disease, ages 18 through 65 years, who were candidates for OLT under general anesthesia. The exclusion criteria were a history of hepatorenal syndrome types I and II, baseline serum potassium > 6 meq/l, ejection fraction < 60% and cirrhotic cardiomyopathy, INR (international normalization ratio) < 1.5 and platelet count < 50,000 × 103/µL.
Patient grouping and randomization
The study protocol was approved by our University Institutional Ethics Committee. After written informed consent was obtained from the patients, the eligible patients were randomly assigned to two groups through simple randomization using computer-generated random numbers. This randomization was performed by a nurse anesthetist who had no role in administering the study.
Application of interventions
Also, the nurse anesthetist prepared two groups of labeled 50 ml syringes. The 50 ml syringes contained either magnesium sulfate or normal saline (as placebo). Both types of syringes were identical in appearance, and differed only in their label. The syringes with the A label contained 1.5 g magnesium sulfate (Infu-magnesol® 20%, 10 ml amp, Shahid Ghazi Pharmaceutical Co., Tehran, Iran) with saline added to a total volume of 50 ml, while syringes with the B label contained 50 ml saline. We used this dose of magnesium sulfate according to previous study [12]. The patients and the research associate were not aware of the contents of these syringes. Each patient was assigned to one of the two parallel groups in a 1:1 allocation ratio. Each patient in group A received an IV infusion over 5 min with a 50 ml syringe with the A label, while each patient in group B received an IV infusion over 5 min with a 50 ml syringe with the B label.
Anesthesia application
Then, each patient received fentanyl (2 mg/kg) and midazolam (0.03 mg/kg) as premedication, induction of anesthesia was performed with propofol (2 mg/kg), and pancuronium (0.1 mg/kg) was used to achieve neuromuscular blockade. Anesthesia was maintained with isoflurane plus a 50% air–50% oxygen mixture with controlled ventilation to maintain an end-tidal CO2 of 30–35 mm Hg.
Before induction of anesthesia, 4 ml of whole blood was obtained through venipuncture from each patient, 2 ml for ROTEM analysis and the remaining 2 ml, that was without citrate, was sent to the laboratory to measure the plasma Mg concentrations. Then, again before surgical incision, 4 ml of whole blood was obtained through venipuncture from each patient for ROTEM analysis and plasma Mg level measurement.
Outcome measures
In this study, we examined the three ROTEM tests: INTEM (which evaluates the intrinsic pathway after contact activation), EXTEM (which evaluates the extrinsic pathway after addition of tissue factor) and FIBTEM (assess fibrinogen level after tissue factor activation). The following ROTEM parameters; CT: clotting time, CFT: clot formation time, ALFA: α angle, MCF: Maximum clot firmness of the INTEM, EXTEM and FIBTEM test were analyzed according to the manufacturer’s recommendations. Each test was done with 300 µl citrated whole blood and the specific agent of the test. All ROTEM parameters were analyzed within 5 min of obtaining the blood sample.
The primary outcome included ROTEM parameters changes in the three different test of ROTEM: ETEM, INTEM and FIBTEM following infusions. Secondary outcomes included changes in plasma magnesium concentrations following infusions.
Sample size
According to the previous studies, we assumed a mean difference (SD) of 7(8) mm in the MCF of EXTEM and INTEM following the infusions between two groups. Considering this difference in MCF between two group and aiming for a statistical power of 80% and risk of 5% for type I error, 30 patients were considered sufficient in each group to detect a 5% difference.
Statistical analysis
Shapiro–Wilk test was used to detect normal distribution in the variable data. Student’s t test or Mann–Whitney U test was performed for demogheraphic and base line data, where appropriate. Pre- and post-infusion values in each group were compared with Wilcoxon signed rank test and Tukey test for post hoc analysis. In all analyses, data were calculated using SPSS 21.0 software (SPSS Inc., Chicago, IL, USA) and a P value of < 0.05 was considered statistically significant.
Results
Among the 80 adult patients with end-stage liver disease who were scheduled to receive OLT surgery from August 2015 to February 2016, a total of 20 patients were excluded from the study due to hepatopulmonary syndrome (n = 3), hepatorenal syndrome (n = 5), and INR < 1.5 (n = 5) serum potassium > 6 meq/l (n = 1) and platelets count < 50,000 × 103 (n = 6). In total, 60 patients were enrolled into this study and randomly allocated into control and intervention groups (Fig. 1).
Fig. 1.
Flowchart of the patients according to the consort guidelines
There were no significant differences in the demographic data, baseline INR, or platelet counts between the two groups (P > 0.05; Table 1). Table 2 showed the ROTEM parameters before infusion in the both groups. There were no significant differences between-groups in baseline parameters for the three different ROTEM tests: EXTEM, INTEM, and FIBTEM (P > 0.05; Table 2). However, six patients in Mg group and five patients in the control group have normal ROTEM findings (P > 0.05; Table 2).
Table 1.
Demographics data and base line data of the both study’s groups
| Mg Group (n = 30) |
Control Group (n = 30) |
P value | |
|---|---|---|---|
| Weight (kg) | 69.71 ± 12.28 | 72.43 ± 17.45 | 0.61 |
| Age(year) | 41.50 ± 12.94 | 45.80 ± 15.19 | 0.47 |
| Sex (M/F) | 16/14 | 19/11 | 0.85 |
| Meld score | 23.60 ± 5.75 | 25.33 ± 5.97 | 0.74 |
| INR | 2.96 ± 1.44 | 2.93 ± 1.06 | 0.22 |
| Platelet count (× 103/µL) | 76.80 ± 14.36 | 79.10 ± 15.27 | 0.58 |
All data in mean ± standard deviation
Table 2.
Base line parameters of the three different tests of the ROTEM in the control and Mg group
| Control group subgroup1 (n = 25) |
Mg group subgroup 1 (n = 24) |
P value | Control group subgroup2 (n = 5) |
Mg group subgroup2 (n = 6) |
P Value | |
|---|---|---|---|---|---|---|
| CT (EXTEM) | 127.23 ± 6.08 | 129.50 ± 7.76 | 0.77 | 68.34 ± 2.50 | 66.79 ± 2.65 | 0.98 |
| CFT (EXTEM) | 199.36 ± 8.27 | 195.76 ± 4.33 | 0.65 | 131.28 ± 5.8 | 129.43 ± 4.31 | 0.82 |
| ALFA (EXTEM) | 59.43 ± 3.17 | 61.37 ± 2.87 | 0.97 | 60.13 ± 1.50 | 61.00 ± 2.83 | 0.10 |
| MCF (EXTEM) | 49.47 ± 2.67 | 47.31 ± 3.14 | 0.35 | 59.45 ± 2.53 | 61.87 ± 1.99 | 0.75 |
| CT (INTEM) | 378.10 ± 2.75 | 381.86 ± 8.51 | 0.37 | 189.54 ± 7.69 | 190.44 ± 3.11 | 0.82 |
| CFT (INTEM) | 187.76 ± 3.74 | 186.66 ± 5.74 | 0.51 | 65.39 ± 4.21 | 63.57 ± 0.66 | 0.38 |
| ALFA (INTEM) | 60.17 ± 3.17 | 64.13 ± 3.27 | 0.67 | 60.26 ± 2.11 | 62.01 ± 1.09 | 0.74 |
| MCF (INTEM) | 51.13 ± 2.66 | 50.46 ± 1.81 | 0.49 | 60.26 ± 3.21 | 61.33 ± 1.68 | 0.49 |
| CT (FIBTEM) | 113.70 ± 9.57 | 114.26 ± 6.80 | 0.75 | 65.34 ± 2.11 | 63.67 ± 1.29 | 0.59 |
| CFT (FIBTEM) | – | – | – | – | – | – |
| ALFA (FIBTEM) | 58.80 ± 0.54 | 59.13 ± 0.23 | 0.91 | 58.11 ± 0.31 | 59.15 ± 0.41 | 0.39 |
| MCF (FIBTEM) | 9.66 ± 0.04 | 8.99 ± 0.64 | 0.11 | 9.810 ± 0.11 | 9.11 ± 0.25 | 0.29 |
All data in mean ± standard deviation. CT clotting time, CFT clot formation time, ALFA α angle, MCF maximum clot firmness. Subgroup1: patients with abnormal ROTEM findings. Subgroup2: patients with normal ROTEM findings
Furthermore, there were no significant differences in pre-infusion plasma magnesium levels between the two groups (P > 0.05; Table 3). After Mg therapy in the Mg group, mean plasma Mg increased from 2.18 to 2.87 mg/dl. Therefore, after infusion, the plasma Mg level of the Mg group was significantly higher than that of the control group (P < 0.05; Table 3).
Table 3.
Plasma Mg level in the both groups before and after infusions
| Mg sulfate Group (n = 30) | Control Group (n = 30) |
P value | |
|---|---|---|---|
| Base line plasma Mg (mg/dl) | 2.18 ± 0.75 | 2.06 ± 0.46 | 0.76 |
| Plasma Mg after infusions (mg/dl) | 2.78 ± 0.49 | 2.01 ± 0.46 | 0.003 |
| P value | 0.000 | 0.46 |
All data in mean ± standard deviation
In the control group, there were no significant differences within-group in pre- and post-intervention parameters for the three ROTEM tests: EXTEM, INTEM, and FIBTEM in the patients with normal and abnormal base line ROTEM findings (P > 0.05; Table 4). However, in the Mg group, there were significant differences within-group in pre- and post-intervention, CT parameter of the three ROTEM tests: EXTEM, INTEM, and FIBTEM was significantly decreased in the patients with abnormal base line ROTEM findings (P = 0.001; Table 5), but CT parameter did not significantly change in the patients with normal ROTEM findings (P > 0.05; Table 5).
Table 4.
ROTEM parameters in three different tests of the ROTEM in the control group, before and after infusion
| Before placebo Subgroup1 (n = 25) |
After placebo Subgroup2 (n = 25) |
P value | Before placebo Subgroup1 (n = 5) |
After placebo Subgroup2 (n = 5) |
P value | |
|---|---|---|---|---|---|---|
| CT (EXTEM) | 127.23 ± 6.08 | 125.43 ± 10.33 | 0.35 | 68.34 ± 2.50 | 67.39 ± 1.98 | 0.71 |
| CFT (EXTEM) | 199.36 ± 8.27 | 197.32 ± 35.96 | 0.74 | 131.28 ± 5.8 | 129.11 ± 1.23 | 0.65 |
| ALFA (EXTEM) | 59.43 ± 3.17 | 58.33 ± 3.31 | 0.88 | 60.13 ± 1.50 | 61.12 ± 1.64 | 0.91 |
| MCF (EXTEM) | 49.47 ± 2.67 | 47.46 ± 3.17 | 0.93 | 59.45 ± 2.53 | 60.34 ± 1.67 | 0.79 |
| CT (INTEM) | 378.10 ± 2.75 | 376.16 ± 5.44 | 0.70 | 189.54 ± 7.69 | 191.11 ± 6.44 | 0.75 |
| CFT (INTEM) | 187.76 ± 3.74 | 185.13 ± 3.16 | 0.94 | 65.39 ± 4.21 | 66.11 ± 0.89 | 0.86 |
| ALFA (INTEM) | 60.17 ± 3.17 | 61.13 ± 2.50 | 0.76 | 60.26 ± 2.11 | 61.16 ± 1.21 | 0.94 |
| MCF (INTEM) | 51.13 ± 2.66 | 49.96 ± 2.72 | 0.72 | 60.26 ± 3.21 | 61.11 ± 2.11 | 0.98 |
| CT (FIBTEM) | 113.70 ± 9.57 | 118.30 ± 7.34 | 0.21 | 65.34 ± 2.11 | 66.82 ± 2.54 | 0.69 |
| CFT (FIBTEM) | – | – | – | – | – | – |
| ALFA (FIBTEM) | 58.80 ± 0.54 | 57.06 ± 1.92 | 0.74 | 58.11 ± 0.31 | 57.42 ± 1.65 | 0.84 |
| MCF (FIBTEM) | 9.66 ± 0.04 | 9.46 ± 2.95 | 0.81 | 9.810 ± 0.11 | 9.34 ± 0.79 | 0.99 |
All data in mean ± standard deviation. CT clotting time, CFT clot formation time, ALFA α angle, MCF maximum clot firmness. Subgroup1: patients with abnormal ROTEM findings. Subgroup2: patients with normal ROTEM findings
Table 5.
ROTEM parameters in three different tests of the ROTEM in the Mg group, before and after infusion
| Before Mg sulfate in the subgroup1 (n = 24) |
After Mg sulfate in the subgroup1 (n = 24) |
P value | Before Mg sulfate in the sub group 2 (n = 6) | After Mg sulfate in the sub group 2 (n = 6) |
P Value | |
|---|---|---|---|---|---|---|
| CT (EXTEM) | 129.50 ± 7.76 | 86.13 ± 3.40 | 0.001 | 66.79 ± 2.65 | 64.99 ± 3.45 | 0.89 |
| CFT(EXTEM) | 195.76 ± 4.33 | 191.53 ± 4.10 | 0.61 | 129.43 ± 4.31 | 127.56 ± 4.89 | 0.71 |
| ALFA(EXTEM) | 61.37 ± 2.87 | 62.13 ± 2.54 | 0.89 | 61.00 ± 2.83 | 60.14 ± 1.18 | 0.75 |
| MCF(EXTEM) | 47.31 ± 3.14 | 49.03 ± 1.84 | 0.28 | 61.87 ± 1.99 | 60.56 ± 2.89 | 0.80 |
| CT (INTEM) | 381.86 ± 8.51 | 209.33 ± 6.68 | 0.001 | 190.44 ± 3.11 | 188.56 ± 2.49 | 0.64 |
| CFT(INTEM) | 186.66 ± 5.74 | 184.56 ± 4.98 | 0.35 | 63.57 ± 0.66 | 64.11 ± 2.90 | 0.90 |
| ALFA(INTEM) | 64.13 ± 3.27 | 65.23 ± 2.89 | 0.22 | 62.01 ± 1.09 | 61.78 ± 1.01 | 0.82 |
| MCF(INTEM) | 50.46 ± 1.81 | 51.87 ± 2.1 | 0.39 | 61.33 ± 1.68 | 60.11 ± 0.99 | 0.75 |
| CT (FIBTEM) | 114.26 ± 6.80 | 81.56 ± 5.01 | 0.001 | 63.67 ± 1.29 | 64.55 ± 2.01 | 0.66 |
| CFT(FIBTEM) | – | – | – | – | – | – |
| ALFA(FIBTEM) | 59.13 ± 0.23 | 60.16 ± 2.57 | 0.23 | 59.15 ± 0.41 | 60.03 ± 1.65 | 0.86 |
| MCF(FIBTEM) | 8.99 ± 0.64 | 9.11 ± 1.13 | 0.79 | 9.11 ± 0.25 | 8.99 ± 1.99 | 0.91 |
All data in mean ± standard deviation. CT clotting time, CFT clot formation time, ALFA α angle, MCF maximum clot firmness. Subgroup1: patients with abnormal ROTEM findings. Subgroup2: patients with normal ROTEM findings
Discussion
In this randomized clinical trial, we found that magnesium therapy in patients with end stage liver diseases who have ROTEM evidence of hypocoagulability about to undergo liver transplantation improved CT parameter of different ROTEM tests.
Traditional plasma-based coagulation tests such as PT (International normalization ratio = INR) PTT have limited value in the assessment of the in vivo coagulation pathway. However, during OLT, viscoelastic tests measure the continuous process of clotting in whole blood, and therefore provide global information on the dynamics of coagulation system from clotting initiation through clot development, stabilization, and dissolution [12–14]. Furthermore, ROTEM could be run as several parallel tests to compare different pathways of the coagulation system. For example, INTEM analysis gives data similar to that of PTT, EXTEM analysis gives data similar to that of PT (INR), and FIBTEM is suitable for detecting fibrinogen levels and functions [15, 16]. During OLT surgery, ROTEM allows for reliable monitoring of the coagulation system that could not be accomplished using plasma-based coagulation tests [17].
Despite many in vitro and in vitro studies regarding the effect of Mg on coagulation system, the results of studies have been inconclusive [17–19]. In vitro investigations have been reported that Mg augments the activity of the factor X and VIII, decreases the level of the factor S and C and increases platelet aggregation and finally induces hypercoagulopathy [10, 20]. Sekiya et al. showed that magnesium has an important role in the amplification of the biological activities of factor IX. They found that activation of factor X by factor IXa was accelerated by magnesium [21].
Furthermore, based on some in vitro studies, magnesium does not appear to have significant effects on the coagulation system. James et al. found that in healthy person at low therapeutic levels, magnesium sulfate does not have effects on thromboelastographic (TEG) parameters. At higher therapeutic levels, magnesium could increase the r and k times on TEG that means higher therapeutic levels could prolong initiation of coagulation measured by TEG, but those effects do not seem to be clinically significant [22]. Also, Ames et al. found that, in healthy volunteers treated with magnesium, TEG parameters did not change significantly [23]. Harnett et al., found in parturients with preeclampsia, administration of magnesium (a 6-g bolus followed by 2 g/h) did not have effect on coagulation system [24].
Choi et al., in their preliminary study on 27 patients who were candidates for OLT, found that 1500 mg doses of magnesium not only changed plasma magnesium levels, but also K time and coagulation time (k + r) were shortened significantly and maximal amplitude was increased in the TEG findings toward normal levels in patients with end-stage liver disease that means Mg sulfate therapy in this patients could increase activity of coagulation factors and formation of thrombin. However, the sample size of that study was small, and it was not a randomized controlled trial [11]. In another in vivo study by Hammouda et al., ROTEM was used to survey the effects of magnesium on different pathways of the coagulation system. They found that magnesium therapy in patients with end-stage liver disease prior to starting OLT could improve CT parameter in different ROTEM tests, CFT parameter in the EXTEM test, A10, α angle in the FIBTEM. Although, they found Mg sulfate could improved ROTEM finding, but they had a discrepancy in their results. Furthermore, that study’s sample size was also small, and they used 2 g doses of magnesium sulfate. They did not report baseline plasma Mg levels or possible changes after magnesium sulfate therapy [25].
In our study, we found that patients with end-stage liver disease who had INR > 1.5, platelet counts > 50,000 and their ROTEM parameters showed hypocoagulability, magnesium sulfate administration as 1.5 g per dose not only could change the plasma Mg level but also, improved CT parameter in different ROTEM tests, including EXTEM, INTEM, and FIBTEM. However, finding of our study were more consistent than results of study by Hammouda et al., in our study Mg sulfate just improved CT parameter (interval between the start of the test and appearance of the first clot) this means Mg sulfate could improve coagulation factors activity and confirmed the results of study by the Sekiya et al. which has shown that Mg sulfate augments coagulation factors activity [21], and also confirmed the results of study of the Choi et al., who found that K time and coagulation time (k + r) in the TEG were improved by Mg sulfate [11].
This study has some limitations. In the future studies it is better to measure ionized serum magnesium instead of total serum magnesium. Also, in another study should select a group of patients with low level of serum magnesium as third group of study.
Conclusion
In conclusion, we found that, in patients with end-stage liver disease who had hypocoagulability, magnesium therapy could improve CT parameter in different ROTEM tests, including EXTEM, INTEM, and FIBTEM. This means Mg sulfate could improve coagulation factors activity in patients with end-stage liver disease.
Acknowledgements
The present article was extracted from the thesis written by Ashkan Taghizadeimani and was financially supported by Shiraz University of Medical Sciences Grants No: 10143.
Author contributions
All authors were involved in the preparation of the manuscript, have read the manuscript, agree with the analyses of the data and the conclusions reached in the manuscript, and are accountable for all aspects of the work.
Funding
This study received no specific funding.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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