Anesth Analg 2006;103:448-452
© 2006 International Anesthesia Research Society
doi: 10.1213/01.ane.0000223677.34513.88
GENERAL ARTICLES
Prolonged International Normalized Ratio Correlates with a Large Intravascular Fluid Balance After Major Abdominal Surgery
Michal Barak, MD*¶,
Oded Jurim, MD
,
Ronit Tal, MD
, and
Yeshayahu Katz, MD, DSc
¶
From the Departments of *Anesthesiology and Surgery B, Rambam Medical Center; Department of Surgery A, Carmel Medical Center; ¶Laboratory for Anesthesia, Pain and Neural Research, Rappaport Faculty of Medicine, Technion–Israel Institute of Technology, Haifa; Department of Anesthesiology, Haemek Medical Center, Afula, Israel.
Address correspondence and reprint requests to Yeshayahu Katz, MD, DSc, Chairman, Department of Anesthesiology, Haemek Medical Center, Afula 18101, Israel. Address e-mail to ykatz18{at}hotmail.com.
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Abstract
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We performed a prospective randomized study of 32 patients who had undergone pancreaticoduodenectomy and did not receive blood during and after surgery. The patients were prospectively assigned to two groups related to fluid balance in the immediate postoperative period. Group 1 (14 patients) were maintained at a positive intravascular fluid balance of 0–1000 mL; Group 2 (18 patients) were maintained at a positive balance of 1000–2000 mL. Complete blood counts and coagulation tests (International Normalized Ratio) and activated partial thromboplastin time (aPTT) were performed at three time points: the day before surgery, on arrival at the postanesthesia care unit, and on leaving the postanesthesia care unit (16 h later). There were significant differences in International Normalized Ratio values between the groups with deterioration during the time they were in the postanesthesia care unit but not in aPTT values. Positive correlation was found between the amount of positive fluid balance and International Normalized Ratio prolongation, but not with aPTT, suggesting that restricted intravascular fluid balance is beneficial for preservation of coagulation after major abdominal surgery.
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Introduction
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Massively transfused trauma patients may suffer from disordered hemostasis as a result of thrombocytopenia or coagulopathy (1–3). Earlier studies used transfusion with whole blood (1); however, a similar tendency was found in more recent studies in which packed red blood cells were used. In patients who lost more than 50% of their blood volume during elective surgery, dilution of coagulation factors, rather than dilution thrombocytopenia, was the initial cause of increased surgical bleeding (4). We hypothesized that the dilution effect of IV fluid is dependent on the volume infused. Previously, we (5) found significant correlation between deteriorating coagulation and the administration of more than 3 L of crystalloids during abdominal surgery. There was also correlation between administration of more than 500 mL of colloid and prolonged prothrombin time. The purpose of the present study was to investigate the effect of postoperative intravascular fluid balance on the coagulation profile after major abdominal surgery.
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METHODS
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We conducted a prospective study over 18 mo on adult patients scheduled for elective pancreaticoduodenectomy with combined epidural and general anesthesia. The study was approved by our local Ethics Committee and all the patients provided signed informed consent. Exclusion criteria were history of coagulopathy, treatment with anticoagulants, aspirin, or herbal medications, preoperative anemia, abnormal preoperative coagulation tests or platelet count, renal insufficiency (preoperative creatinine 
2.0 mg/dL), morbid obesity, and administration of blood or blood products (packed red blood cells, fresh-frozen plasma) before, during, or after surgery.
During the studied time period, 37 patients underwent pancreaticoduodenectomy. Five patients received blood during the operation and were excluded from the study. We collected demographic and medical information, surgical and anesthetic information, events during and after surgery, and blood tests for each patient.
All patients had standard identical care before and during the operation. One surgeon (OJ) performed the operation with the same team of assistants. The patient was allowed to drink clear water until 2 h before surgery. Oral premedication included diazepam 10 mg and metoclopramide 10 mg 1 h before anesthesia. On arrival in the operating room, an IV line was placed for fluid and drug administration. The patient was continuously monitored with electrocardiogram, pulse oximeter, end-tidal CO2 capnograph, invasive arterial blood pressure, central venous pressure, urinary catheter, and esophageal thermometer. Body temperature was kept within 35.8–36.8°C using an active air warming blanket. Warm lactated Ringer's solution was administered for maintenance based on the formula 4:2:1 mL · kg–1 · h–1, supplemented with an additional 5 mL · kg–1 · h–1 for external losses when the abdomen was open (6). In addition, each patient received 7 mL/kg of hydroxyethyl starch 6% in normal saline (HAES-steril® 6%, Mw 200 kDa, MS 0.5, C2/C6 ratio 5:1; Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany) during the operation. A thoracic epidural catheter (T5–7) was placed and analgesia was maintained continuously, using 6 mL/h of bupivacaine 0.125% with fentanyl 5 µg/mL during the surgery and for 3 days afterwards. General anesthesia was induced with midazolam 0.03 mg/kg, fentanyl 0.001 mg/kg, and thiopental 3–5 mg/kg followed by vecuronium 0.1 mg/kg for muscle relaxation. Isoflurane 0.7%–1.1% in a mixture of air and oxygen was used for maintenance of anesthesia. Operative blood loss was estimated by counting sponges and measuring the volume collected in the suction bottles. Blood loss of <500 mL was not replaced by additional fluids.
All patients were tracheally extubated at the end of the surgery while in the operating room and then transferred to the postanesthesia care unit (PACU) where they stayed for 16 h. Patients who experienced pain (visual analog score 3) received epidural supplements or IV meperidine 20 mg.
In the PACU, the basic standard fluid administration was lactated Ringer's solution 100 mL/h. In our previous experience, we observed a tendency towards diminished urinary output a few hours after surgery. Therefore, 6 h after the end of this surgery, each patient received HAES 6% 500 mL and furosemide 5 mg.
The intravascular fluid balance during the 16-h period was randomized to one of the following two options: a positive fluid balance of 0–(+1000) mL (Group 1) or a positive balance of (+1000)–(+2000) mL (Group 2). Patients were randomized according to an arbitrary discretion of one of four attending anesthesiologists in the PACU, who were not study investigators. Their instructions of intravascular fluid balance were primarily a set standard, regardless of the patient. The PACU nurses and the investigators were not blinded as to these variables. Every 4 h the PACU nurse calculated the intravascular fluid balance from arrival at the PACU as follows: input (standard fluid administration plus solutions given for drug administration) minus output (urine and drain output). If the balance was less than targeted, the nurse gave lactated Ringer's solution 250 mL in addition to the basic fluid protocol. If the balance was above the upper limit of the target, the patient received furosemide 5 mg. The final intravascular fluid balance on leaving PACU to the ward was recorded.
During surgery and PACU stay, mean arterial blood pressure was kept above 60 mm Hg. If lower, ephedrine 5 mg was administered. Urinary output was targeted to be more than 0.3 mL · kg–1 · h–1. The decision to give blood (packed red blood cells unit) was based on estimated blood loss, the patient's vital signs, and repeated blood tests (the lowest hemoglobin level allowed was 9.0 g%).
Complete blood count and coagulation tests were performed at the following time points: on the day before surgery, on arrival at PACU, and on leaving PACU to the ward (16 h apart). Blood samples were collected in EDTA tubes for complete blood count and citrate for coagulation assays. Analysis included hemoglobin and platelet counts (Technicor H3; Bayer, Germany), International Normalized Ratio (INR) (normal, 0.75–1.3), and activated partial thromboplastin time (aPTT) (normal, 27–40 s) (STA-compact; Diagnostica, Stago, France). Serum creatinine was measured every other day; for the study we used data before surgery and at discharge from hospital.
Statistical analysis was performed using Statistica 6 (StatSoft, Tulsa, OK). Intergroup frequency differences were compared using Pearson's 
2 test. Normally distributed parametric variables were compared with the Student's t-test or one-way analysis of variance. Data of the hemoglobin, platelet count, and coagulation tests were compared with repeated-measures analysis of variance univariate tests. Wherever normality was violated (by the Mauchley Sphericity Test), Greenhouse & Geisser and Huynh-Feldt adjustments were applied. Analysis of covariance of the remaining demographic and clinical variables, with each time point of the coagulation test data as dependant variable, was performed. Correlations were analyzed by Pearson's method. Significance level was set at P < 0.05.
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RESULTS
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The clinical characteristics of the patients, anesthesia, and surgical details are shown in Table 1. No significant difference was found between groups in these variables. No patient had bleeding complications or required reoperation. There was no in-hospital mortality. Postoperative complications are shown in Table 1. On discharge from hospital, no patient had a serum creatinine above 2.0 mg/dL.
Blood test results (hemoglobin and platelet count) are summarized in Table 2. On arriving at PACU, hemoglobin was significantly less than preoperative hemoglobin for each study group (P < 0.01 for both groups). Also, on leaving PACU hemoglobin was significantly less than preoperative hemoglobin (P < 0.01 for both groups). In each time point there was no significant difference in hemoglobin values between Group 1 and Group 2. There was a similar trend in the platelet count, with no significant difference between groups
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Table 2. Hemoglobin and Platelet Count on Day Before Surgery, on Arrival at PACU and on Leaving PACU for the Ward
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INR and aPTT changed significantly in each group over time. The preoperative mean INR was 1.04 for both groups. On arriving at the PACU, it was 1.10 and 1.11 for Groups 1 and 2, respectively. On leaving the PACU, the mean INR was 1.15 for Group 1 and 1.27 for Group 2 (Fig. 1). Comparing INR on arriving at the PACU to INR on leaving the PACU, the change was significant within each group (P < 0.01).
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Figure 1. International Normalized Ratio (INR) at three time points: on the day before surgery, on arrival in the postanesthesia care unit (PACU), and on leaving the PACU for two study groups. Data are mean ± 95% confidence interval. *P < 0.01 Group 1 versus Group 2.
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The same trend was found in aPTT values. The preoperative mean aPTT was 33.0 s for Group 1 and 32.9 s for Group 2. On arrival at the PACU, it was 33.9 and 34.2 for Groups 1 and 2, respectively. On leaving the PACU, aPTT was 37.8 for Group 1 and 40.0 for Group 2 (Fig. 2). There were significant differences between preoperative aPTT and aPTT on leaving the PACU and between aPTT on arrival at the PACU and on leaving the PACU within each group (P < 0.01).
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Figure 2. Activated partial thromboplastin time (aPTT) at three time points: on the day before surgery, on arrival at the postanesthesia care unit (PACU), and on leaving the PACU for two study groups. Data are mean ± 95% confidence interval. No statistical significance was found.
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At two time points, preoperatively and on arrival at the PACU, INR values were similar in both groups (P = 0.90 and 0.52, respectively). However, on leaving the PACU, there was a significant difference between groups (P = 0.001) (Fig. 1). No significant difference was found in the aPTT values of the groups at the 3 time points (P = 0.95, 0.83, and 0.51, respectively) (Fig. 2).
We defined the change in INR during PACU stay (INR on leaving PACU/INR at PACU arrival) as INR quotient. We found significant correlation between the total intravascular fluid balance on leaving the PACU and the INR quotient (r = 0.54, P = 0.004) (Fig. 3). No correlation was found between total fluid balance on leaving PACU and aPTT quotient (aPTT on leaving PACU/aPTT on PACU arrival) (r = 0.04; P = 0.8).
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Figure 3. Correlation between International Normalized Ratio (INR) quotient (INR on leaving the postanesthesia care unit [PACU]/INR on arrival to PACU) and total fluid balance on leaving the PACU. The correlation is statistically significant (r = 0.54; P = 0.004).
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DISCUSSION
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For many years IV fluid administration has been one of the fundamentals of patient management, intended to maintain hemodynamic stability and prevent hypotension and hypoperfusion (7). Solutions used as intravascular volume replacement leak to the extravascular space (nonfunctional fluids), resulting in increased total body water (8). This impaired homeostasis is further exacerbated by perioperative events, such as decreased blood oncotic pressure, aldosterone and antidiuretic hormone secretion triggered by stress, third space in the traumatized/surgical compartment, and patient immobilization (9,10). Excess extravascular fluid may decrease tissue oxygenation, deteriorate pulmonary function, and disrupt wound and anastomosis healing (11). These pathophysiologic events have clinical implications, as has been demonstrated (12–14). Brandstrup et al. (14) showed that generous fluid administration resulted in increased postoperative cardiopulmonary complications, tissue-healing complications, and mortality. In contrast, Holte et al. (15) showed that generous crystalloid administration improved postoperative organ function and recovery and shortened hospital stay after laparoscopic cholecystectomy. Although relating to many aspects of perioperative outcome, coagulation has not been dealt with (12–15).
Our study focused on the effect of intravascular fluid balance on coagulation during the immediate postsurgical period. Several perioperative factors, such as mild or moderate hypothermia, blood administration, and trauma per se may affect coagulation (3,16–18). Hemodynamic instability with low hepatic perfusion during surgery reduces production of coagulation factors and degradation of activated factors (19). Earlier studies examined the influence of various types of solutions on hemostasis. It was found that colloids reduce clot strength and platelet function (20–23). In patients who lost 50% of their blood volume during surgery, the use of crystalloid solutions and packed red blood cells caused coagulation factor dilution (4). Indeed, there is no scientific evidence for the occurrence of "dilution coagulopathy" in minor bleeding, where no blood products are used (24,25). In our study, we excluded patients who received blood products and used a uniform composition of solutions to determine the net effect of the amount of infused solutions on coagulation. The body temperature of all patients was kept strictly within normal limits to avoid the effect of hypothermia. We found that the patients who had restricted intravascular fluid balance exhibited preserved INR compared with those who had a larger fluid balance. Moreover, we showed correlation between the fluid balance and deterioration of INR during the PACU stay. On leaving the PACU, 4 patients would have been considered to have an increased INR in Group 2 compared with none in Group 1. It should be noted that the limit of normal INR is somewhat arbitrary, as INR is a continuous scale. Knowing the dose (fluid) versus response (INR) relationship is the key point, and the number that crosses a particular threshold value is less important. We believe that understanding the sensitivity of INR to extra intravascular fluid is important; without it the treatment might be fresh-frozen plasma instead of waiting and avoiding excessive fluid.
The aPTT values were similar between our two patient groups. In earlier studies, the infusion of large volumes of fluids resulted in significant increase of both PT and aPTT (2,4,5). However, our study was designed to test the effect of relatively small volumes. We propose that the extrinsic pathway (INR) is more vulnerable to the negative effect of fluid administration than the intrinsic pathway (aPTT). Factor VII may be responsible for the susceptibility to fluids because of its short half-life being the rate-limiting component of the clotting cascade and the main noncellular humoral factor of the extrinsic pathway (26). Conversely, a hypercoagulable state occasionally occurs after surgery, apparent by postoperative deep vein thrombosis and pulmonary embolism and by abnormal thromboelastogram (27,28). The contradiction between hypercoagulability and prolonged INR may be explained by the fact that both coagulation cascade and the fibrinolytic system are damaged simultaneously.
A major concern in managing the patient with a restricted fluid regimen is maintaining renal function (29). Data regarding renal function in controlled hypovolemic conditions is found in studies of liver resections and thoracotomies, where a restricted fluid regimen is the standard of care. From these studies it is apparent that the risk of renal damage in "dry" regimen is very small (30–33). In our study, we had no case of renal failure or permanently increased serum creatinine. Thus, we conclude that the risk of causing renal failure by fluid restriction is not high.
In summary, we found that there is correlation between a positive intravascular fluid balance and deterioration of INR in the immediate postoperative period. It is reasonable to believe that policy should aim at a restricted fluid regimen if preserved coagulation is desired. Further investigation is necessary to establish definitive end-points for fluid management.
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Footnotes
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Accepted for publication April 11, 2006.
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Abstract
Introduction
