Anesth Analg 2007;104:1475-1480
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000261256.88414.e4
CRITICAL CARE AND TRAUMA
The Coagulation Changes Induced by Rapid In Vivo Crystalloid Infusion Are Attenuated When Magnesium Is Kept at the Upper Limit of Normal
Thomas G. Ruttmann, MBChB, MMed, PhD, FCA*,
Luis F. Montoya-Pelaez, MBChB, FCA*, and
Michael F. M. James, MBChB, PhD, FRCA, FCA*
From the Department of Anaesthesiology, University of Cape Town Medical School, Cape Town, Republic of South Africa.
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Abstract
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BACKGROUND: Rapid crystalloid infusion enhances coagulation, regardless of electrolytes, pH or osmolality, an effect thought to be related to deep vein thrombosis and other clot formations. Altered serum magnesium may play a role in the balance of coagulation. In this in vivo study we investigated the coagulation response to rapid hemodilution when serum magnesium is maintained or partially increased.
METHODS: Twenty-five healthy volunteers were investigated on three occasions, randomly receiving normal saline, Balsol (magnesium 1.5 g/L), and Balsol plus additional magnesium (magnesium 3.0 g/L). Investigators were blinded to the solution’s identity. Baseline blood samples were taken measuring hematocrit, serum magnesium, and thrombelastography (TEG), whereafter 14 mL/kg (20% blood volume) was infused over 30 min, followed by a second blood sample. All results were compared to their own baseline values using ANOVA with LSD post hoc significance testing.
RESULTS: All groups had a similar postdilutional hematocrit decrease, with significant magnesium reduction in the saline group (0.81 ± 0.07 to 0.74 ± 0.07 (approximately –8.6%) (P < 0.003)), no change in the Balsol group and significant increase in the Balsol + magnesium group (0.84 ± 0.07 to 0.99 ± 0.06 (approximately 17.9%) (P < 0.001)). Postdilutional TEG results reflected no significant change from control in the Balsol + magnesium group. Both of the other two groups had statistically significant increased clot formation (reaction time to onset of clotting and clotting time shortened; 
-angle increased).
CONCLUSIONS: Rapid hemodilution-induced coagulation may be partially due to decreased magnesium, and the effect is attenuated by maintaining magnesium at the upper limit of normal. Crystalloid resuscitation fluids should possibly contain higher magnesium levels, around 3 mmol/L.
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Introduction
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Rapid crystalloid infusion generates enhanced coagulation (1). Janvrin et al. (2) demonstrated that postoperative deep vein thrombosis was related to intraoperative fluid administration-enhanced coagulability, which correlated with laboratory findings. These findings have never been refuted. Other authors have used saline-induced clotting as a test to define the risk of cerebrovascular accident (3). The laboratory findings have been confirmed in several previous studies (4), one in patients undergoing peripheral vascular surgery demonstrating enhanced coagulation after the rapid administration of crystalloids (5). The thrombelastograph (TEG) is more sensitive than routine coagulation assays for the detection of a hypercoagulable state (6). One study (7) in patients undergoing knee surgery demonstrated enhanced coagulation related to all fluids administered. Isovolemic hemodilution is reported to be associated with hypercoagulability due to a loss of antithrombin activity through dilution with simultaneous maintenance of Factor VIII complex activity when albumin, but not Hextend, is used (8). Hypertonic saline dextran (RescueFlow) also resulted in an initial mild procoagulant effect, followed by an anticoagulant effect at higher levels (9). While it is difficult to give an absolute figure of the clinical risk of coagulation based on hemodilution, previous work has shown the clotting after rapid hemodilution to be on a par with undiluted term pregnancy clotting, which is hypercoagulable and associated with an increased risk of deep vein thrombosis (10). The effect was attenuated by some colloids, but never completely abolished (11). The effect of gelatin on decreasing the final clot strength has been demonstrated (12), but this does not change the effect of hemodilution on the onset of clotting (13).
In the plasma contents, magnesium is involved in coagulation, and altered serum magnesium levels may play a role in modulating changes of coagulation brought on by rapid plasma dilution (14). Whereas there were no significant effects of the magnesium on coagulation at serum magnesium concentrations < 3 mmol/L (15) in a study evaluating the effect of increasing magnesium levels in undiluted blood, this study did not examine the effects of concomitant hemodilution. A similar finding was reported by Ames et al. (16). Choi et al. (17) commented on a decrease in magnesium-impairing coagulation. However, in their study the patients arrived for liver transplantation with severely impaired coagulation, as evidenced by the pre-magnesium TEG, and this may have biased the result. In addition, the article does not comment on any other fluid given to patients during the study. An interesting finding by Ravn et al. (18) was that magnesium infusion compared to placebo demonstrated no difference. It is, however, not clear how much volume was infused and at what rate this occurred, factors which would bias the result.
All of these findings have essentially examined only the relationship between magnesium and coagulation, rather than examining the relationship between increased coagulation due to dilution and the alteration of magnesium levels brought about by the dilution. These findings do not counter the theory that when the dilution of blood decreases the plasma magnesium level, the onset of coagulation is enhanced. In our own findings, when including dilution in an in vitro study examining the effect of hemodilution on coagulation with different levels of magnesium in the diluent (unpublished data), it was found that, with magnesium levels maintained at normal or slightly increased levels, the enhanced coagulation brought on by rapid hemodilution is attenuated.
It is postulated that hemodilution influences the magnesium level, and that this may contribute to the enhanced onset of coagulation. Our in vivo study investigates the response of coagulation to rapid IV infusion with crystalloid solutions containing sufficient magnesium to maintain, or slightly increase, the serum magnesium concentration.
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METHODS
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Twenty-five healthy volunteers gave written, informed consent to be included in the study, which was approved by the Ethics Committee at the University of Cape Town Medical School. The volunteers had not taken aspirin, any nonsteroidal analgesics, or any other drugs that might affect coagulation, during the previous 7 days. Any subject with a history of coagulation abnormalities was excluded.
The effect of magnesium on crystalloid hemodilution-induced hypercoagulability was investigated in the same group of volunteers on three occasions, three days apart. On one occasion volunteers received a rapid IV dilution with saline, on another with Balsol (magnesium 1.5 g/L) and on the third with Balsol plus additional magnesium (magnesium 3.0 g/L) (Table 1). The solutions were marked "Solution A," "Solution B" or "Solution C," and investigators and subjects were blinded to the identity of the solutions. The order of administration of the solutions was randomized for each volunteer to exclude any bias.
A large gauge cannula was inserted into the forearm under local anesthesia and a venous baseline blood sample was taken for the measurement of the hematocrit (Hct) and serum magnesium levels and for TEG coagulation analysis, using the standard two syringe technique to eliminate tissue factor or contamination from catheter lines (3–5 mL of blood drawn in a separate syringe and discarded before the test sample is taken).
The chosen solution (14 mL/kg) was then infused over 30 min. This fluid load constitutes approximately 20% of the blood volume. Immediately after completion of the infusion a second venous sample was taken for repeat hemoglobin, magnesium, and TEG analysis. The same sequence was repeated twice in all of the volunteers, at which time they received the other two solutions. All results were compared to their own baseline values.
The TEG pattern is divided into component variables: r-time (reaction time to onset of clotting) represents predominantly the activity of the clotting factors; k-time (clotting time) is shortened by increased fibrinogen level and, to a lesser extent, by platelet function; the -angle (rate of clotting) is closely related to k-time, since they both are a function of the rate of fibrin polymerization; and maximum amplitude (MA) is the measurement of maximum clot strength with a modest contribution of fibrin and much more significant contribution of the platelets (19). Hypercoagulability is detected highly effectively by TEG techniques (20,21).
Statistics
Statistical analysis was performed using a two-way analysis of variance (ANOVA), with the solution type and timing of the sample (pre- or post-dilution) as the independent variables. Where this analysis showed significant differences, post hoc analysis was performed using the least significant difference (LSD) technique to identify significantly different individual groups. The percentage change from baseline in each group was also calculated and compared among groups using a one-way ANOVA with LSD post hoc significance testing.
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RESULTS
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In all three groups (A, B and C) a significant, similar decrease in Hct after dilution was seen (Table 2). As expected, this was around 10%. There were no significant differences among the groups.
The magnesium values were revealed after the study was completed and the solutions had been identified. These are shown in Table 3. There was a statistically significant reduction in magnesium concentration with dilution in the saline group (Solution B), from 0.81 ± 0.07 to 0.74 ± 0.07 (P < 0.003), which was lower than the value in all of the other groups. There was no change of magnesium with dilution in the Balsol group (Solution C). There was a significant increase in serum magnesium from 0.84 ± 0.07 to 0.99 ± 0.06 after dilution with Balsol + magnesium (P < 0.001) (Solution A), which was higher than the value in all of the other groups, but all absolute levels remained within the normal range.
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Table 3. The Change in Serum Magnesium with Dilution in the Three Groups (Normal Range of Serum Magnesium is 0.7–1.1 mmol/L)
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The postdilutional TEG results in the three groups were compared to their own undiluted controls, and are shown in Figure 1. They reflect no significant change from control in the Balsol + magnesium group in any of the TEG parameters. Both of the other two groups, saline and Balsol, had an increased rate of clot formation, with a statistically significant shortening of r- and k-times. There was also a statistically significant increase in the -angle in both of these groups after dilution. The final clot strength, or MA, was not significantly different from control in any of the groups.
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Figure 1. The change in thrombelastography (TEG) values from control in the three solutions: A (Balsol + magnesium), B (saline), and C (Balsol) after 20% dilution. Asterisk (*) denotes significant differences from undiluted control.
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The percentage changes in r-time were significantly different between the Balsol + magnesium and saline groups. The percentage changes in the k-time, -angle and MA were all significantly larger in both the saline and Balsol groups compared to the Balsol + magnesium group (Table 4).
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Table 4. Percentage Change in Thrombelastography (TEG®) Variables from Predilution to Postdilution in the Three Groups (Mean and [sd])
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DISCUSSION
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While primary inhibitors of platelet aggregation are good for prevention of arterial hemostasis, they do not inhibit the procoagulant effect of hemodilution (22). The stasis-induced venous "thrombus" is not affected by antiplatelet drugs, but is rather prevented by the action of the plasma factor inhibitors (23), which are diluted by rapid hemodilution (23). Conversely, a decreasing of Hct has been described as decreasing coagulation on the basis of decreased blood viscosity, leading to a faster arterial bloodflow (24). However, there is a difference between aggregating platelets at the site of an arterial plaque fissure ("white" clot) and the development of a meshwork of fibrin, thrombin, and entrapped blood cells ("red" clot) (25), the latter occurring predominantly on the venous side. The process of red clot formation in the microvascular circulation is not greatly dependent on rheology, as flow does not affect the intrinsic ability of blood to clot at this level.
The coagulation tests were done with the subject’s own predilution coagulation test as the control against which the postdilutional result was compared; therefore, regardless of the state of the coagulation of the volunteers, any change in coagulation between the control and test sample is related to the fluid diluent (22). The TEG is a global, noninvasive diagnostic instrument designed to analyze the viscoelastic coagulation state of a blood sample; it displays a graphic measure of the kinetics of the clot formation process from the onset of clot formation to clot lysis, rather than end-points (26). It is particularly useful in the detection of hypercoagulable states, with excellent reproducibility for all parameters (19,27–29). Whereas standard tests of coagulation stop measuring at the first onset of clot formation, the TEG measures interactive dynamic coagulation, and provides information on the dynamics of clot formation, strength and stability (30).
Coagulation onset induced through dilution has been investigated at length, and various parameters have been excluded (4). It has been documented that calcium will cause bleeding if the ionized level is <0.55 mmol/L. Above that, however, calcium does not affect coagulation (31). The pH (H+), as well as other ions, have also been discussed in the literature (32).
In this study, both the saline and Balsol groups demonstrated the expected increase in coagulation onset with rapid hemodilution, whereas the Balsol + magnesium group showed an almost complete attenuation of the enhanced coagulation onset associated with rapid hemodilution. The serum magnesium was significantly increased in this group, but it was still within the normal range and well under a serum level of 3 mmol/L, a level below which no complications such as bleeding or neuromuscular weakness will occur (15).
Conversely, the magnesium level decreased significantly to the lower limit of normal after the rapid saline infusion and demonstrated a significant increase in coagulation. Keeping the magnesium unchanged did not attenuate the dilution-triggered effect on coagulation. These results suggest that when magnesium levels are slightly increased with rapid hemodilution, coagulation is maintained at normal values. The exact mechanism of this is not clear. However, the magnesium level may be related to the functioning of anticoagulants such as antithrombin.
A low dietary intake of magnesium appears to be related to a frequent incidence of ischemic heart disease and other cardiovascular diseases (33), and if the dietary Ca2+/Mg2+ ratio of 2/1 is exceeded a relative or absolute magnesium deficiency may occur, increasing the risk of intravascular coagulation (34). Research has shown that magnesium seems to counter the coagulation brought on by calcium (34). In fact, magnesium depletion can influence coronary bloodflow, blood clotting, and atherogenesis (35), and serum magnesium has been found to be inversely correlated with thrombus weight, suggesting that magnesium may be effective for preventing acute stent thrombosis (36,37). A Medical Research Council trial, published in The Lancet, has shown that magnesium sulfate may reduce disability and death after a stroke (38). IV magnesium sulfate has been shown to reduce early mortality of myocardial infarction, comparable to, but independent of, that of thrombolytic or antiplatelet therapy (39), with the mortality rate from ischemic heart disease being reduced by 21% (40).
On the one hand, magnesium sulfate has been described as being associated with enhanced platelet aggregation (41), accelerated activation of Factor X by Factor VII-TF independently of Factor IX (42), and activation of Factor X by Factor IXa (43). Conversely, however, magnesium, which is an anticoagulant physiological electrolyte (44), has been found to induce a significant prolongation of bleeding time, an effect that is mediated neither by changes in platelet count or aggregation pattern, nor by changing the level or ratios of serum arachidonic acid metabolites (45). Magnesium sulfate slightly reduces platelet aggregation ex vivo, with in vivo blood clotting time being markedly prolonged (14).
In summary, enhanced coagulation brought on by rapid hemodilution may be partially due to decreased levels of magnesium—an effect that can be attenuated by maintaining magnesium levels at the upper limit of the normal range when rapid hemodilution occurs. IV crystalloid resuscitation fluids should possibly contain higher magnesium levels, around 3 mmol/L. This carries a great potential benefit and no risk.
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Footnotes
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Accepted for publication February 6, 2007.
Financial support from Fresenius-Kabi SA.
Address correspondence and reprint requests should be addressed to Prof. T.G. Ruttmann, Department of Anaesthesiology, University of Cape Town, 7925 Observatory, Cape Town, Republic of South Africa. Address e-mail to ruttman{at}cormack.uct.ac.za.
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Abstract
Introduction
