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Anesth Analg 2002;94:378-384
© 2002 International Anesthesia Research Society


CRITICAL CARE AND TRAUMA

Are Lactated Ringer’s Solution and Normal Saline Solution Equal with Regard to Coagulation?

Joachim Boldt, MD, G. Haisch, MD, S. Suttner, MD, B. Kumle, MD, and F. Schellhase

Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany

Address correspondence and reprint requests to Prof. Dr. Joachim Boldt, Department of Anaesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany. Address e-mail to BoldtJ{at}gmx.net


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Crystalloids represent an attractive strategy to alleviate intravascular volume deficits. Crystalloid hemodilution was associated with hypercoagulability in in vitro and in vivo studies. The influence of different crystalloids on coagulation in the surgical patient is not well studied. In a prospective, randomized study in patients undergoing major abdominal surgery, we used either lactated Ringer’s solution (RL) (n = 21) or 0.9% saline solution (SS) (n = 21) exclusively for intravascular volume replacement over 48 h to maintain central venous pressure between 8 and 12 mm Hg. Activated thrombelastography (TEG®) using different activators (intrinsic TEG, extrinsic TEG, heparinase TEG, aprotinin TEG) was used to measure coagulation time, clot formation time, and maximum clot firmness. Measurements were performed after induction of anesthesia (T0), immediately after surgery (T1), 5 h after surgery (T2), and on the morning of the first (T3) and second (T4) postoperative days. RL 18750 ± 1890 mL and 17990 ± 1790 mL of SS were infused during the study period. Acidosis was seen only in the SS-treated group. Blood loss was not different between the groups. Fibrinogen and antithrombin III decreased similarly at T1 and T2 in both groups, most likely because of hemodilution. Differences in TEG® data from normal baseline were seen only immediately after surgery and 5 h thereafter, indicating mild hypercoagulability in the intrinsic TEG® (RL, from 147 ± 130 s to 130 ± 11 s; SS, from 146 ± 12 s to 131 ± 12 s). There were no differences in coagulation between RL- and SS-treated patients. We conclude that in major abdominal surgery intravascular volume replacement with crystalloids resulted in only moderate and abbreviated changes in coagulation. No differences in activated TEG® and blood loss were seen between an RL- and an SS-based intravascular volume replacement regimen.

IMPLICATIONS: In 42 patients undergoing major abdominal surgery, either lactated Ringer’s solution or 0.9% saline solution were exclusively used for volume therapy for 48 h. Activated thrombelastography revealed some mild hypercoagulability after surgery. No differences in coagulation were seen between the two intravascular volume replacement strategies.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Controversy still surrounds the type and regimen of fluids to be administered IV during major surgery. The long-standing debate on the ideal fluid for intravascular volume replacement includes a crystalloid/colloid versus a colloid/colloid controversy.

Aside from the efficacy of a specific solution, possible side effects have become an increasing concern. One of the most important issues for assessing the optimal intravascular volume replacement strategy is the influence on the hemostatic process and subsequent influence on bleeding or the development of thrombosis. When compared with colloids, crystalloids are frequently preferred because they are inexpensive and appear to be almost free of significant negative side effects (1). However, some in vitro studies have shown that crystalloid-based hemodilution can alter coagulation (2,3). Others have shown that infusion of a saline solution (SS), particularly in large doses, produces a marked acidosis with negative sequelae for some organ systems (4,5). Measuring plasma concentrations of specific markers of coagulation appears to be too simple to completely assess changes in the hemostatic process (6). Thrombelastography (TEG®; Haemoscope, Skokie, IL) is a widely established method to monitor the dynamic process of coagulation (68). By measuring reaction time, clot formation time, and maximum clot firmness, TEG® monitors the kinetic of the hemostatic process. TEG® examines total blood coagulation: the interplay of the protein coagulation cascade, fibrinogen, and platelet function. TEG® has even been assumed to correlate best with postoperative blood loss (9), and it may be helpful to reduce use of blood and blood products during surgery (10). We used modified, activated TEG® monitoring instead of conventional TEG® because different aspects of the coagulation process can be detected by using different activators (1114). Because the effects of different crystalloids on blood coagulation have not be shown in vivo, this study was designed to assess whether a lactated Ringer’s solution-based intravascular volume replacement strategy impacts TEG® differently than using a normal SS.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After approval by the Ethics Committee of the hospital, 42 consecutive patients undergoing elective major abdominal surgery for malignancies were studied. All patients gave written informed consent. Patients suffering from cardiac insufficiency (New York Heart Association class III-IV), renal insufficiency (serum creatinine >2 mg/dL), altered liver function (aspartate aminotransferase >40 U/L, alanine aminotransferase >40 U/L), preoperative anemia (hemoglobin [Hb] <10 g/dL), preoperative coagulation abnormalities (platelet count <100/nL; activated partial thromboplastin time [aPTT] >70 s; fibrinogen <2 g/dL; antithrombin [AT] III <40%), use of heparin, vitamin K-antagonists, corticosteroids, cyclooxygenase inhibitors, or chemotherapy before surgery were defined as exclusion criteria for participation in the study. Preoperatively, the patients were randomly assigned to one of two volume groups using a closed envelope system. Patients of Group 1 (n = 21) received exclusively lactated Ringer’s solution (RL), whereas patients of Group 2 (n = 21) exclusively received 0.9% SS. The specific volume was administered to keep central venous pressure (CVP) between 8 to 12 mm Hg. Volume replacement was started before induction of anesthesia (after baseline data were achieved) and continued during the next 48 h until the morning of the second postoperative day (POD). The patients were premedicated with midazolam 1 h before surgery. Epidural anesthesia was not used. Postoperatively, a patient-controlled analgesia pain regimen was used in all patients. General anesthesia was induced with thiopental (5 mg/kg) and fentanyl (3 µg/kg). Neuromuscular blockade was achieved with vecuronium (0.1 mg/kg). Anesthesia was maintained with fentanyl, desflurane, and vecuronium, titrated according to the patients’ needs. Mechanical ventilation was performed in all patients (50% air in oxygen) to keep SaO2 >95% and end-expiratory CO2 between 35 and 40 mm Hg. Electrocardiogram, arterial blood pressure, and CVP were monitored continuously. Cover blanket systems and fluid warmers were used to prevent decreases in body temperature during surgery. The patients were managed by anesthesiologists who were not involved in the study and were blinded to the grouping.

All patients were transferred to the intensive care unit after surgery. Controlled mechanical ventilation was continued when necessary (e.g., because of esophageal temperature <36°C or unstable hemodynamics). Tracheal extubation was performed when hemodynamics were stable, temperature was >36°C, and the patient breathed spontaneously with adequate blood gases. When mean arterial blood pressure was <50 mm Hg despite sufficient intravascular volume (CVP >10 mm Hg), dopamine was given. Norepinephrine was added when volume therapy and dopamine were not successful in keeping mean arterial blood pressure >50 mm Hg. Sodium bicarbonate was administered when base deficit (BD) was <-4.0 mmol/L. Packed red blood cells were given when Hb was <8 g/dL, fresh-frozen plasma was used when aPTT was >70 s, fibrinogen was <2 g/dL, AT III was <40%, and bleeding occurred.

Coagulation Measurements
Platelet count, AT III, fibrinogen, and aPTT were measured from arterial blood samples using routine laboratory methods. Another 5 mL of citrated blood was taken for performing activated TEG® using a four-channel analyzer (roTEGTM®, Nobis Diagnostics, Edingen, Germany). TEG® measurements were performed within 10 min after blood sampling using a semiautomatic pipetting system. The roTEGTM system uses a different power transduction system than conventional TEG® machines that makes it less susceptible to mechanical stress, movement, and vibration (15). RoTEGTM analysis relies on the continuous assessment of clot firmness, allowing the determination of the onset of coagulation (coagulation time [CT] - standard TEG® = reaction time [r]), kinetics of clot formation (clot formation time [CFT] - standard TEG® = coagulation time [k]), and maximum clot firmness [MCF] (standard TEG® = maximal amplitude [MA]). All measurements were performed after induction of anesthesia before surgery (T0), immediately after surgery (T1), 5 h after surgery (T2), and at the morning of POD 1 (T3) and POD 2 (T4).

TEG® was performed after different activators were added to the blood sample (activated TEG®). For intrinsic TEG®, clot formation was measured after recalcification of 300 µL of whole blood with 20 µL of 0.2 M calcium chloride and adding a surface activator (partial thromboplastin from rabbit brain [20 µL]) for monitoring the intrinsic system. For extrinsic TEG®, clot formation was monitored after adding tissue thromboplastin (rabbit brain extract) for monitoring the extrinsic system. For Heparinase-modified TEG®, intrinsic TEG® plus heparin inactivation using heparinase (2 µL) was used to eliminate trace amounts of heparin and to exclude residual heparinization. For aprotinin TEG®, extrinsic TEG® + in vitro inhibition of fibrinolytic activity through aprotinin (aprotinin solution equals 10,000 kallikrein inhibitor units/mL). Compared with extrinsic TEG® results, this shows evidence of hyperfibrinolytic activity after 5 min.

Statistics
The appropriate sample size was determined before the study by performing a power analysis using data of a previously published TEG® study (16). A 50% increase in r was assumed to be the minimum clinically important difference we wished to detect. Using the given SD, an {alpha} error of 0.05 (two-sided) and type II error of 0.2, a total of 21 patients per group was assumed to be necessary. Statistical analysis was performed with the SPSS/PC+ software package (SPSS, Chicago, IL). Data are presented as mean ± SD unless otherwise indicated. Normal distribution of the data was tested using the Kolmogorov-Smirnov test. Continuous, normally distributed data were compared using paired and unpaired Student’s t-tests or analysis of variance for repeated measures followed by Scheffé’s test. Bonferroni correction was applied when multiple comparisons were made. Continuous, nonnormally distributed data were compared using Wilcoxon’s test. Binomial data were compared using {chi}2 analysis and Fisher’s exact test when appropriate. P values <0.05 were considered significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient characteristics and surgical procedures were without differences between the two groups (Table 1). Use of blood/blood products (Table 1) and blood loss (Table 2) also did not differ between the two volume groups. A total of 18750 ± 1890 mL of RL and 17990 ± 1790 mL of SS were used within the study period (Table 2). Eighteen patients of the SS group needed sodium bicarbonate (total, 215 ± 50 mL), whereas only 1 patient of the RL group needed 100 mL of sodium bicarbonate (Table 2). Hemodynamics were similar in the two groups within the entire study period and degree of dilution (Hb) was comparable in the two groups (Table 3). None of the patients showed a body temperature of <36°C. Fibrinogen and AT III decreased significantly in both groups after surgery and 5 h after surgery and returned to baseline data on the first POD (Table 3). BD and Cl- in the patients treated with SS were significantly higher than in the RL-treated patients (Table 4).


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Table 1. Patient Characteristics and Data From the Perioperative Period
 

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Table 2. Volume In- and Output (Cumulative)
 

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Table 3. Coagulation Data
 

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Table 4. Electrolytes and Acid-Base Status
 
All TEG® variables were within normal range and without group differences at baseline. Intrinsic TEG® showed shorter CT (P < 0.05) after surgery and 5 h after surgery in both group (RL, from 147 ± 130 s to 130 ± 11 s; SS, from 146 ± 12 s to 131 ± 12 s) (Fig. 1). Extrinsic TEG®-CT was also slightly decreased, whereas CFT was significantly increased at the end of surgery and 5 h after surgery (Fig. 2). No significant differences between the two groups were seen. In heparinase TEG®, CFT was slightly increased at the end of surgery and 5 h after surgery in both groups (Fig. 3). Aprotinin TEG® showed a significant prolongation of CFT in both groups at the end of surgery and 5 h after surgery without showing group differences (Fig. 4). All changes of TEG® data were within normal range throughout the study. MCF remained unchanged in all activated TEG® traces throughout the study period. All TEG® data had returned to baseline by the morning of POD 1 at the latest.



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Figure 1. Changes in coagulation time (CT) (onset of coagulation; normal, <50 s), clot formation time (CFT) (kinetics of clot formation; normal, <180 s), and maximum clot firmness (MCF) (normal, 53–74 mm) using (extrinsic) activation by tissue-thromboplastin (extrinsic TEG®). Values expressed as mean ± SD. POD = postoperative day.

 


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Figure 2. Changes in coagulation time (CT) (onset of coagulation; normal, <160 s), clot formation time (CFT) (kinetics of clot formation; normal, <180 s), and maximum clot firmness (MCF) (normal, 53–74 mm) using activation by surface activator (activation of the intrinsic system [intrinsic TEG®]). Values expressed as mean ± SD. POD = postoperative day.

 


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Figure 3. Changes in coagulation time (CT) (onset of coagulation; normal, <50 s), clot formation time (CFT) (kinetics of clot formation; normal, <180 s), and maximum clot firmness (MCF) (normal, 53–74 mm) using extrinsic activation + in vitroinhibition of fibrinolytic activity through aprotinin (aprotinin TEG®). Values expressed as mean ± SD. POD = postoperative day.

 


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Figure 4. Changes in coagulation time (CT) (onset of coagulation; normal, <160 s), clot formation time (CFT) (kinetics of clot formation; normal, <180 s), and maximum clot firmness (MCF) (normal, 53–74 mm) using intrinsic activation + heparin inactivation with heparinase for detection of heparin effects (heparinase TEG®). Values expressed as mean ± SD. POD = postoperative day.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Crystalloids are widely used for intravascular volume replacement therapy, most likely because of their low acquisition costs. Additionally, side effects are very rare when using a crystalloid-based intravascular volume replacement strategy.

The influence of a crystalloid-based intravascular volume replacement regimen on coagulation is not definitely known. In an in vitro TEG® study, Ruttman et al. (2) showed that hemodilution per se increased coagulability of whole blood (decrease in r- and k-values; increase in MA-value) most likely as a result of induction of thrombin formation (3). This hypercoagulability was more frequent in saline-diluted than in gelatin-diluted samples. By contrast, others did not find a hypercoagulability state by hemodilution (17). In an in vitro TEG® study from Petroianu et al. (18), only extreme hemodilution with RL (10:10) resulted in a significant increase in k- and MA-value, whereas r-value remained always unchanged. It is increasingly evident that the pathophysiologic characteristic of in vitro studies on coagulation does not always reflect the in vivo condition (17,19). In the present study we found a slight hypercoagulability after surgery seen by shortening in CT measured by the intrinsic TEG®, whereas CFT was slightly increased in the extrinsic TEG®. Others also showed a saline-induced increased coagulability in vivo and suggested that there might be a correlation between the use of crystalloid solutions and the risk of development of deep vein thrombosis (20). Aprotinin TEG® in our study showed a prolongation of CFT in both groups at the end of surgery and five hours after surgery indicating some (reactive) impact on the fibrinolytic system.

The definite mechanism that may be responsible for the hypercoagulability after hemodilution with crystalloids is not well defined. In 1959 Monkhouse (21) has shown that diluting plasma with saline increases the thrombin activity of the mixture two- to threefold. This increase in thrombin activity in diluted samples was suggested to be a result of decreasing the antithrombin action rather than because of any real increase in thrombin generation. Similar changes in thrombin generation occur in vivo as shown after infusion of large amounts of SS in acute hemorrhage (21).

The influence of different types of crystalloids on coagulation in humans is far from clear. In a study in patients undergoing gynecologic surgery, hyperchloremic acidosis was associated with a larger blood loss (22). Ng et al. (23) demonstrated increased blood coagulability when surgical blood loss was replaced by crystalloids. In our study we found no group differences in standard coagulation variables, activated TEG®, blood loss, or use of blood or blood products. Thus it can be assumed that the type of crystalloid does not significantly influence coagulation in patients undergoing major abdominal surgery.

Negative consequences of hyperchloremic acidosis on organ function have been elucidated by some studies (4,5). This has led to development of more balanced fluid solutions for volume replacement (24). (Hyperchloremic) acidosis was seen only in our SS-patients. Some patients even showed very low BD (e.g., BD of -12 mmol/L). BD of >-4.0 mmol/L was always treated with sodium bicarbonate; thus hyperchloremic acidosis was not present for long. Whether long-lasting hyperchloremic acidosis may influence coagulation cannot be determined from the present data.

We conclude that intravascular volume therapy with two different kinds of crystalloids, RL and SS, in patients undergoing major abdominal surgery showed significant differences on acid-base physiology, whereas no relevant impact on hemostasis monitored by activated TEG® was seen.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 14, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2002 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press