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ICG Pulse Spectrophotometry for Perioperative Liver Function in Hepatectomy
Journal of Surgical Research 103, 109 –113 (2002) doi:10.1006/jsre.2001.6328, available online at http://www.idealibrary.com on
ICG Pulse Spectrophotometry for Perioperative Liver Function in Hepatectomy Osamu Okochi, M.D., 1 Tetsuya Kaneko, M.D., Hiroyuki Sugimoto, M.D., Soichiro Inoue, M.D., Shin Takeda, M.D., and Akimasa Nakao, M.D. Department of Surgery II, Nagoya University School of Medicine, Nagoya, Japan Submitted for publication July 23, 2001; published online January 22, 2002
Background. The indocyanine green (ICG) clearance test has been used to estimate liver functional reserve before hepatectomy. However, changes in ICG clearance after hepatectomy have not been investigated, and their extent remains unknown. Patients and methods. The ICG(K) value, signifying the ICG elimination rate constant, was measured with pulse-dye densitometry before operation and 1, 2, 3, 5, and 7 days postoperatively in 22 patients who underwent liver resection of various extent. CT volumetry was used to calculate the residual liver volume ratio. The relationship between the pre- and postoperative ICG(K) value and the residual liver volume ratio was examined statistically. Results. There was a significant drop in ICG(K) value, from 0.193 ⴞ 0.011 before operation to 0.160 ⴞ 0.013 on Postoperative Day 1, and then it remained significantly low at the postoperative examination times. The residual liver volume ratio was 70.2 ⴞ 5.4%. The estimated ICG(K) value, calculated by the preoperative ICG(K) value and the residual liver volume ratio, showed a significant correlation with the actual postoperative value (r ⴝ 0.859 on Postoperative Day 1, P < 0.0001). In five patients with prolonged jaundice, the estimated ICG(K) value was significantly lower than in those without it (0.077 ⴞ 0.028 versus 0.153 ⴞ 0.012, P ⴝ 0.0136). Conclusions. The perioperative ICG(K) value measured by pulse-dye densitometry revealed a significant decrease in ICG(K) after operation depending on the reduction in liver volume, and the estimated ICG(K) based on the residual liver volume was useful in predicting postoperative morbidity. © 2002 Elsevier Science (USA) 1 To whom correspondence should be addressed at Department of Surgery II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Fax: ⫹81-52-744-2255. E-mail: [email protected].
Key Words: indocyanine green; pulse spectrophotometry; CT volumetry; hepatectomy. INTRODUCTION
Liver resection is the only treatment with the potential to cure a patient of hepatocellular carcinoma. Despite progress in operative procedures and perioperative care, the possibility or extent of liver resection is still limited in many cases by liver dysfunction [1]. In addition, patients with biliary tract cancer or metastatic liver tumors who require extensive liver resection also run a high risk of postoperative liver failure, even if the liver function is normal [2, 3]. The outcome of liver resection is therefore affected by hepatic functional reserves and remnant liver volume as well as the surgical procedure and perioperative care [4, 5]. Although various preoperative assessments have been reported [6, 7], they alone are not enough to predict postoperative liver failure. The indocyanine green (ICG) clearance test has also been used to estimate liver function [8]. However, how this clearance actually changes after liver resection has not yet been fully clarified. The aim of this study is to determine quantitatively the changes in perioperative liver function by using newly developed ICG pulse spectrophotometry to clarify the relationship between the pre- and postoperative liver function. PATIENTS AND METHODS Twenty-two patients who underwent liver resection at Nagoya University Hospital from January 2000 to August 2000 were evaluated in the current study (Table 1). The mean age of the patients was 53 years, ranging from 23 to 78 years, and the ratio between males and females was 20 to 2. There were 12 hepatocellular carcinomas, 4 living related donors, 3 metastatic liver tumors, 1 cholangiocellular carcinoma, and 2 other benign lesions. Lobectomy or further resec-
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TABLE 1 Patient Profile All (n ⫽ 22) Age (year) Preoperative data ICG(K) (/min) Total bilirubin (mg/dl) Platelet (⫻10 4/l) AST (units/L) ALT (units/L) Prothrombin time (%) Operative data Operation time (min) Blood loss (ml)
Noncirrhotic (n ⫽ 11)
Cirrhotic (n ⫽ 11)
P value a
53.0 (2.9)
49.5 (4.6)
56.6 (3.5)
NS
0.193 (0.011) 0.73 (0.05) 19.9 (1.8) 48.8 (8.5) 62.6 (12.9) 88.2 (3.4)
0.224 (0.014) 0.78 (0.07) 24.9 (2.1) 28.7 (6.7) 40.1 (13.9) 93.7 (4.9)
0.161 (0.012) 0.68 (0.07) 14.9 (2.3) 68.9 (13.3) 85.0 (20.2) 81.5 (4.0)
0.0039 NS 0.0095 0.0053 0.0197 NS
347 (25) 938 (209)
406 (34) 1282 (369)
282 (24) 559 (81)
0.0112 NS
Note. Values are means (SE). ICG(K), indocyanine green elimination rate constant; AST, aspartate aminotransferase; ALT, alanine aminotransferase. a Mann-Whitney U test.
tion was performed in 11 patients (3 right trisegmentectomies, 4 right lobectomies, and 4 left lobectomies) and lesser resection in 11 patients (5 left lateral segmentectomies and 6 partial resections). The type of hepatectomy was decided according to the location and extent of the tumor along with the decision-making chart of Midorikawa et al. using the ICG(K) value, serum total bilirubin level and the presence of ascites [9]. Eleven patients had liver cirrhosis, based on histological diagnosis of resected specimens. Informed consent was obtained from all patients before enrollment in the study. ICG pulse spectrophotometry. Pulse-dye densitometry (DDG2001, Nihon Kohden, Tokyo, Japan) was used to measure the blood ICG concentration. This apparatus makes such measurements continuously possible by monitoring the optical absorption at wavelengths of 805 and 890 nm, based on the principle of pulse spectrophotometry. The peak optical absorption of ICG occurs at 805 nm, while the absorption of ICG at 890 nm is negligible. In contrast, the difference between the absorption of oxyhemoglobin and deoxyhemoglobin is quite small at both 805 and 890 nm. The basic principle has been described in detail elsewhere [10]. A bolus of 20 mg ICG dissolved in 4 ml of distilled water (5 mg/ml) was injected intravenously, and blood ICG concentrations were monitored at every pulse interval via an optical probe attached to the patient’s finger. The ICG(K) value, which was the elimination rate constant, was calculated automatically by the blood ICG concentration time course. This measurement was performed before surgery and 1, 2, 3, 5, and 7 days after. CT volumetry. The liver volume was measured from the CT scan images acquired before liver resection [11]. Serial transverse CT scan images enhanced by an intravenous injection of contrast medium were obtained at 1-cm intervals from the dome to the most inferior part of the liver. Each slice of the liver was traced with a cursor, and the corresponding area was calculated by computer. The division between the right and the left lobe of the liver was defined as the line passing through the gallbladder and inferior vena cava, and the left lateral segment was defined as the area to the left side of the left sagittal fissure. The tumor area was excluded when the outline of the liver was traced. The resection line in a partial resection case was arranged so as to leave a 1-cm margin from the tumor edge. The total volumes of the whole liver and the remaining region were calculated by adding the volumes of each corresponding area, and the residual liver volume ratio was defined as the ratio of both calculated liver volumes. Statistical analysis. Data were expressed as means ⫾ standard error. Comparison analysis was performed with the Wilcoxon test
and Mann-Whitney U test. Correlation was tested by using linear regression analysis. Statistical significance was considered as P ⬍ 0.05.
RESULTS
All patients examined in the study underwent the planned liver resection. Total bilirubin level increased to more than 2.0 mg/dl after hepatectomy in 12 patients and remained elevated over 7 days after operation in 5 of them. No patient suffered hepatic encephalopathy and/or hospital death. Blood ICG concentrations were measured satisfactorily using pulse-dye densitometry in all examinations (Fig. 1a). The ICG(K) value decreased remarkably after operation and reached its lowest on Postoperative Day 2 (from 0.193 ⫾ 0.011 before operation to 0.145 ⫾ 0.013 on Postoperative Day 2). The decrease remained significantly low until the last period measured in the study. ICG(K) values throughout the study were significantly lower in patients with than without cirrhosis, but the profiles of postoperative changes in both patients greatly resembled one another (Fig. 1b). The mean volume of the whole liver excluding the tumor mass was calculated based on the liver CT as 1295 ⫾ 50 cm 3, and that of the remaining liver was 878 ⫾ 62 cm 3. The residual liver volume ratio was 70.2 ⫾ 5.4%. The estimated ICG(K) value was calculated as the product of the preoperative ICG(K) value and the residual liver volume ratio. Using this value, we first examined the relationship between ICG(K) values before and after hepatectomy. Correlation analysis between the estimated and the actual postoperative ICG(K) value (Fig. 2) revealed that the estimated ICG(K) value correlated closely with the actual postoperative ICG(K) values throughout the measured pe-
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FIG. 2. Correlation between estimated and actual ICG(K) values on Postoperative Day 1. Actual ICG(K) value was measured by pulse-dye densitometry (n ⫽ 22), and estimated ICG(K) value was calculated by the preoperative ICG(K) value and the residual liver volume ratio. There was a significant correlation between them. Y ⫽ 0.045 ⫹ 0.846 X (correlation coefficient, 0.859; P ⬍ 0.0001).
DISCUSSION
FIG. 1. Changes in ICG(K) values after hepatectomy. Panel 1a shows changes in all patients (n ⫽ 22). Values decreased significantly after operation and remained low until Postoperative Day 7. Panel 1b is divided into two groups, patients with cirrhosis (open circle, n ⫽ 11) and without cirrhosis (closed circle, n ⫽ 11). ICG(K) values of the two groups show significant differences throughout the examination periods, but the profiles of changes tend to resemble each other. *P ⬍ 0.01 and **P ⬍ 0.05 compared with preoperative value by the Wilcoxon test. †P ⬍ 0.01 and ††P ⬍ 0.05 by MannWhitney U test.
riod (Table 2). The correlation coefficient was highest on Postoperative Day 1 (r ⫽ 0.859, P ⬍ 0.0001). Subsequently, we investigated the relationship between the estimated ICG(K) value and the postoperative morbidity. In five cases with prolonged jaundice whose total bilirubin level increased to more than 2.0 mg/dl over 7 days after hepatectomy, the estimated ICG(K) value was significantly lower than in the patients without prolonged jaundice (0.077 ⫾ 0.028 in 5 cases with prolonged jaundice versus 0.153 ⫾ 0.012 in 17 cases without prolonged jaundice, P ⫽ 0.0136) (Fig. 3). There was no significant difference in the preoperative ICG(K) values of these two groups (0.189 ⫾ 0.027 in patients with prolonged jaundice versus 0.194 ⫾ 0.013 in patients without prolonged jaundice, P ⫽ 0.6952).
As liver failure is the major cause of morbidity and mortality after hepatectomy [12, 13], a variety of methods have been proposed to estimate the liver functional reserve before operation [6, 7]. ICG is a synthetic dye that is eliminated by the liver without extrahepatic metabolism and excretion, and its blood clearance has been applied to determine the operative risk before hepatectomy and recently to evaluate the donor liver function in liver transplantation [14 –16]. Although most of the studies assessing liver function before hepatectomy by ICG clearance have suggested a relationship between the preoperative ICG clearance test and the postoperative outcome [12, 17], it remains unknown just how the clearance of ICG actually changes after liver resection. Pulse-dye densitometry based on the principle of TABLE 2 Correlation Coefficient between Estimated ICG(K) Value and Data after Hepatectomy ICG(K) value after hepatectomy On On On On On
Day Day Day Day Day
1 2 3 5 7
Correlation coefficient
P value
0.859 0.806 0.820 0.826 0.829
⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
Note. Estimated ICG(K) value ⫽ preoperative ICG(K) value ⫻ residual liver volume ratio; residual liver volume ratio ⫽ remaining liver volume/whole liver volume (excluded tumor volume).
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FIG. 3. Comparison of estimated ICG(K) values between patients with prolonged jaundice (n ⫽ 5) and those without it (n ⫽ 17). The estimated ICG(K) value in the patients with prolonged jaundice is significantly lower than in those without it. * P ⫽ 0.0136 by Mann-Whitney U test.
pulse spectrophotometry has been developed in recent years to enable the blood ICG concentration to be measured easily, less invasively, and continuously. The earlier developed method of measuring the ICG concentration by means of spectrophotometry [18] has not shown sufficient accuracy. However, a newer approach, based on pulse spectrophotometry, is able to continuously measure the arterial ICG concentration alone because of its ability to detect pulse waves, greatly improving accuracy [19]. The ICG(K) value, meaning the ICG elimination rate constant, has a high correlation with that of the conventional method determined by collecting blood samples [20]. For these reasons, we attempted to measure the ICG(K) values perioperatively using pulse-dye densitometry. The postoperative ICG(K) values diminished significantly compared with the preoperative one and remained low until a week after operation. This significant decrease after liver resection is supposed to mainly depend on a reduction in hepatocellular volume, because adequate operation and anesthesia were performed in all patients enrolled in this study, and under this condition, the change in hepatocellular volume seems to be more significant than the other changes affecting ICG(K), such as hepatic blood flow and plasma volume. In contrast, the postoperative ICG(K) profiles revealed that its value fell to its lowest on Postoperative Day 2. The previous study reported that ICG(K) was mainly affected by hepatocellular volume, hepatic blood flow, and plasma volume [21], and another study reported that the portal blood flow in remnant liver increased in the immediate postoperative period and decreased thereafter [22]. The current
results and other observations may indicate that we should pay closer attention to postoperative care at an early period after hepatectomy, especially Postoperative Day 2. In practice, treatment with vasoreactive agents may be necessary to increase hepatic blood flow, possibly with fluid and blood supplementation in these periods to support residual liver function [23]. It should be possible to predict the decrease in postoperative ICG(K) before hepatectomy, if it is due mainly to the reduction in hepatocellular volume by liver resection. Then, we attempted to examine the relationship between the pre- and postoperative ICG(K) level and the residual liver volume. Consequently, the estimated ICG(K) value based on the preoperative ICG(K) value and the residual liver volume ratio from the preoperative CT images showed a high correlation with the actual postoperative ICG(K) value. This result indicates that we may be able to know the residual liver function corresponding to each type of liver resection before operation and predict the risk for postoperative liver failure. In fact, the estimated ICG(K) value described in the study was significantly lower in the patients with prolonged jaundice than in those without it, despite no significant difference in preoperative ICG(K) values between both groups. This estimated value, of course, may turn out to be at odds with the actual outcome due to inadequate perioperative care or some discrepancy between the planned operation and the performed one, but such problems have become less likely because of the recent progress in surgical procedures and perioperative care. Admittedly, the small population in the current study makes it difficult to determine the cutoff point of the estimated ICG(K) for morbidity and mortality after hepatectomy. More extensive examinations may serve to clarify the association between estimated ICG(K) and the liver failure, which could lead to more accurately determination of the extent of the resection needed to prevent liver failure before hepatectomy. In conclusion, we clarified the dynamic liver function after hepatectomy using ICG pulse spectrophotometry. The ICG(K) values decreased significantly after operation depending on the reduction in liver volume, and the estimated ICG(K) value based on the residual liver volume may be useful in predicting the postoperative morbidity. REFERENCES 1.
Miyagawa, S., Makuuchi, M., Kawasaki, S., and Kakazu, T. Criteria for safe hepatic resection. Am. J. Surg. 169: 589, 1995. 2. Thompson, H. H., Tompkins, R. K., and Longmire, W. P. Major hepatic resection. A 25-year experience. Ann. Surg. 197: 375, 1983. 3. Nagino, M., Nimura, Y., Hayakawa, N., Kamiya, J., Kondo, S., Sasaki, R., and Hamajima, N. Logistic regression and discriminant analyses of hepatic failure after liver resection for carcinoma of the biliary tract. World J. Surg. 17: 250, 1993.
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Kubota, K., Makuuchi, M., Kusaka, K., Kobayashi, T., Miki, K., Hasegawa, K., Harihara, Y., and Takayama, T. Measurement of liver volume and hepatic functional reserve as a guide to decision-making in resectional surgery for hepatic tumors. Hepatology 26: 1176, 1997. Okamoto, E., Kyo, A., Yamanaka, N., Tanaka, N., and Kuwata, K. Prediction of the safe limits of hepatectomy by combined volumetric and functional measurements in patients with impaired hepatic function. Surgery 95: 586, 1984. Gill, R. A., Goodman, M. W., Golfus, G. R., Oustod, G. R., and Budrick, M. P. Aminopyrine breath test predicts surgical risk for patients with liver disease. Ann. Surg. 198: 701, 1983. Ozawa, K. Hepatic function and liver resection. J. Gastroenterol. Hepatol. 5: 296, 1990. Lau, H., Man, K., Fan, S. T., Yu, W. C., Lo, C. M., and Wong, J. Evaluation of preoperative hepatic function in patients with hepatocellular carcinoma undergoing hepatectomy. Br. J. Surg. 84: 1255, 1997. Midorikawa, Y., Kubota, K., Takayama, T., Toyoda, H., Ijichi, M., Torzilli, G., Mori, M., and Makuuchi, M. A comparative study of postoperative complications after hepatectomy in patients with and without chronic liver disease. Surgery 126: 484, 1999. Aoyagi, T., Fuse, M., Kanemoto, M., Xie, C. T., Kobayashi, N., Hirabara, H., Hosaka, H., Iijima, T., Sankawa, H., Haruna, M., Tanigami, H., and Kumon, K. Pulse dye-densitometry. Jpn. J. Clin. Monit. 5: 371, 1994. Heymsfield, S. B., Fulenwider, T., Nordlinger, B., Barlow, R., Sones, P., and Kutner, M. Accurate measurement of liver, kidney, and spleen volume and mass by computerized axial tomography. Ann. Intern. Med. 90: 185, 1979. Fan, S. T., Lai, E. C. S., Lo, C. M., Ng, I. O. L., and Wong, J. Hospital mortality of major hepatectomy for hepatocellular carcinoma associated with cirrhosis. Arch. Surg. 130: 198, 1995. Wu, C. C., Ho, W. L., Lin, M. C., Yeh, D. C., Wu, H. S., Hwang, C. J., Liu, T. J., and Peng, F. K. Hepatic resection for bilobar multicentric hepatocellular carcinoma: Is it justified? Surgery 123: 270, 1998.
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Yamanaka, N., Okamoto, E., Kato, T., Fujihara, S., Sasase, S., Oriyama, T., Fujimoto, J., Furukawa, K., Kawamura, E., Tomoda, F., Tanaka, T., Tanaka, W., and Ichikawa, N. Usefulness of monitoring the ICG retention rate as an early indicator of allograft function in liver transplantation. Transplant. Proc. 24: 1614, 1992. Koneru, B., Leevy, C. B., Klein, K. M., and Zweil, P. Clearance of indocyanine green in the evaluation of liver donors. Transplantation 58: 729, 1994. Tsubono, T., Todo, S., Jabbour, N., Mizoe, A., Warty, V., Demetris, A. J., and Starzl, T. E. Indocyanine green elimination test in orthotopic liver recipients. Hepatology 24: 1165, 1996. Hemming, A. W., Scudamore, C. H., Shackleton, C. R., Rudek, M., and Erb, S. R. Indocyanine green clearance as a predictor of successful hepatic resection in cirrhotic patients. Am. J. Surg. 163: 515, 1992. Leavy, C. M., Smith, F., Longneville, J., Paumgartner, G., and Howard, M. M. Indocyanine green clearance as a test for hepatic function. Evaluation by dichromatic ear densitometry. J. Am. Med. Assoc. 200: 236, 1967. Iijima, T., Aoyagi, T., Iwao, Y., Masuda, J., Fuse, M., Kobayashi, N., and Sankawa, H. Cardiac output and circulating blood volume analysis by pulse dye-densitometry. J. Clin. Monit. 13: 81, 1997. Imai, T., Takahashi, K., Goto, F., and Morishita, Y. Measurement of blood concentration of indocyanine green by pulse dye densitometry—Comparison with the conventional spectrophotometric method. J. Clin. Monit. 14: 477, 1998. Wilkinson, G. R., and Shand, D. G. A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther. 18: 377, 1975. Kin, Y., Nimura, Y., Hayakawa, N., Kamiya, J., Kondo, S., Nagino, M., Miyachi, M., and Kanai, M. Doppler analysis of hepatic blood flow predicts liver dysfunction after major hepatectomy. World J. Surg. 18: 143, 1994. Nonami, T., Asahi, K., Harada, A., Nakao, A., and Takagi, H. Effect of hyperdynamic circulatory support on hepatic hemodynamics, oxygen supply and demand after massive hepatectomy. Surgery 109: 277, 1991.
ICG Pulse Spectrophotometry for Perioperative Liver Function in Hepatectomy Osamu Okochi, M.D., 1 Tetsuya Kaneko, M.D., Hiroyuki Sugimoto, M.D., Soichiro Inoue, M.D., Shin Takeda, M.D., and Akimasa Nakao, M.D. Department of Surgery II, Nagoya University School of Medicine, Nagoya, Japan Submitted for publication July 23, 2001; published online January 22, 2002
Background. The indocyanine green (ICG) clearance test has been used to estimate liver functional reserve before hepatectomy. However, changes in ICG clearance after hepatectomy have not been investigated, and their extent remains unknown. Patients and methods. The ICG(K) value, signifying the ICG elimination rate constant, was measured with pulse-dye densitometry before operation and 1, 2, 3, 5, and 7 days postoperatively in 22 patients who underwent liver resection of various extent. CT volumetry was used to calculate the residual liver volume ratio. The relationship between the pre- and postoperative ICG(K) value and the residual liver volume ratio was examined statistically. Results. There was a significant drop in ICG(K) value, from 0.193 ⴞ 0.011 before operation to 0.160 ⴞ 0.013 on Postoperative Day 1, and then it remained significantly low at the postoperative examination times. The residual liver volume ratio was 70.2 ⴞ 5.4%. The estimated ICG(K) value, calculated by the preoperative ICG(K) value and the residual liver volume ratio, showed a significant correlation with the actual postoperative value (r ⴝ 0.859 on Postoperative Day 1, P < 0.0001). In five patients with prolonged jaundice, the estimated ICG(K) value was significantly lower than in those without it (0.077 ⴞ 0.028 versus 0.153 ⴞ 0.012, P ⴝ 0.0136). Conclusions. The perioperative ICG(K) value measured by pulse-dye densitometry revealed a significant decrease in ICG(K) after operation depending on the reduction in liver volume, and the estimated ICG(K) based on the residual liver volume was useful in predicting postoperative morbidity. © 2002 Elsevier Science (USA) 1 To whom correspondence should be addressed at Department of Surgery II, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Fax: ⫹81-52-744-2255. E-mail: [email protected].
Key Words: indocyanine green; pulse spectrophotometry; CT volumetry; hepatectomy. INTRODUCTION
Liver resection is the only treatment with the potential to cure a patient of hepatocellular carcinoma. Despite progress in operative procedures and perioperative care, the possibility or extent of liver resection is still limited in many cases by liver dysfunction [1]. In addition, patients with biliary tract cancer or metastatic liver tumors who require extensive liver resection also run a high risk of postoperative liver failure, even if the liver function is normal [2, 3]. The outcome of liver resection is therefore affected by hepatic functional reserves and remnant liver volume as well as the surgical procedure and perioperative care [4, 5]. Although various preoperative assessments have been reported [6, 7], they alone are not enough to predict postoperative liver failure. The indocyanine green (ICG) clearance test has also been used to estimate liver function [8]. However, how this clearance actually changes after liver resection has not yet been fully clarified. The aim of this study is to determine quantitatively the changes in perioperative liver function by using newly developed ICG pulse spectrophotometry to clarify the relationship between the pre- and postoperative liver function. PATIENTS AND METHODS Twenty-two patients who underwent liver resection at Nagoya University Hospital from January 2000 to August 2000 were evaluated in the current study (Table 1). The mean age of the patients was 53 years, ranging from 23 to 78 years, and the ratio between males and females was 20 to 2. There were 12 hepatocellular carcinomas, 4 living related donors, 3 metastatic liver tumors, 1 cholangiocellular carcinoma, and 2 other benign lesions. Lobectomy or further resec-
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TABLE 1 Patient Profile All (n ⫽ 22) Age (year) Preoperative data ICG(K) (/min) Total bilirubin (mg/dl) Platelet (⫻10 4/l) AST (units/L) ALT (units/L) Prothrombin time (%) Operative data Operation time (min) Blood loss (ml)
Noncirrhotic (n ⫽ 11)
Cirrhotic (n ⫽ 11)
P value a
53.0 (2.9)
49.5 (4.6)
56.6 (3.5)
NS
0.193 (0.011) 0.73 (0.05) 19.9 (1.8) 48.8 (8.5) 62.6 (12.9) 88.2 (3.4)
0.224 (0.014) 0.78 (0.07) 24.9 (2.1) 28.7 (6.7) 40.1 (13.9) 93.7 (4.9)
0.161 (0.012) 0.68 (0.07) 14.9 (2.3) 68.9 (13.3) 85.0 (20.2) 81.5 (4.0)
0.0039 NS 0.0095 0.0053 0.0197 NS
347 (25) 938 (209)
406 (34) 1282 (369)
282 (24) 559 (81)
0.0112 NS
Note. Values are means (SE). ICG(K), indocyanine green elimination rate constant; AST, aspartate aminotransferase; ALT, alanine aminotransferase. a Mann-Whitney U test.
tion was performed in 11 patients (3 right trisegmentectomies, 4 right lobectomies, and 4 left lobectomies) and lesser resection in 11 patients (5 left lateral segmentectomies and 6 partial resections). The type of hepatectomy was decided according to the location and extent of the tumor along with the decision-making chart of Midorikawa et al. using the ICG(K) value, serum total bilirubin level and the presence of ascites [9]. Eleven patients had liver cirrhosis, based on histological diagnosis of resected specimens. Informed consent was obtained from all patients before enrollment in the study. ICG pulse spectrophotometry. Pulse-dye densitometry (DDG2001, Nihon Kohden, Tokyo, Japan) was used to measure the blood ICG concentration. This apparatus makes such measurements continuously possible by monitoring the optical absorption at wavelengths of 805 and 890 nm, based on the principle of pulse spectrophotometry. The peak optical absorption of ICG occurs at 805 nm, while the absorption of ICG at 890 nm is negligible. In contrast, the difference between the absorption of oxyhemoglobin and deoxyhemoglobin is quite small at both 805 and 890 nm. The basic principle has been described in detail elsewhere [10]. A bolus of 20 mg ICG dissolved in 4 ml of distilled water (5 mg/ml) was injected intravenously, and blood ICG concentrations were monitored at every pulse interval via an optical probe attached to the patient’s finger. The ICG(K) value, which was the elimination rate constant, was calculated automatically by the blood ICG concentration time course. This measurement was performed before surgery and 1, 2, 3, 5, and 7 days after. CT volumetry. The liver volume was measured from the CT scan images acquired before liver resection [11]. Serial transverse CT scan images enhanced by an intravenous injection of contrast medium were obtained at 1-cm intervals from the dome to the most inferior part of the liver. Each slice of the liver was traced with a cursor, and the corresponding area was calculated by computer. The division between the right and the left lobe of the liver was defined as the line passing through the gallbladder and inferior vena cava, and the left lateral segment was defined as the area to the left side of the left sagittal fissure. The tumor area was excluded when the outline of the liver was traced. The resection line in a partial resection case was arranged so as to leave a 1-cm margin from the tumor edge. The total volumes of the whole liver and the remaining region were calculated by adding the volumes of each corresponding area, and the residual liver volume ratio was defined as the ratio of both calculated liver volumes. Statistical analysis. Data were expressed as means ⫾ standard error. Comparison analysis was performed with the Wilcoxon test
and Mann-Whitney U test. Correlation was tested by using linear regression analysis. Statistical significance was considered as P ⬍ 0.05.
RESULTS
All patients examined in the study underwent the planned liver resection. Total bilirubin level increased to more than 2.0 mg/dl after hepatectomy in 12 patients and remained elevated over 7 days after operation in 5 of them. No patient suffered hepatic encephalopathy and/or hospital death. Blood ICG concentrations were measured satisfactorily using pulse-dye densitometry in all examinations (Fig. 1a). The ICG(K) value decreased remarkably after operation and reached its lowest on Postoperative Day 2 (from 0.193 ⫾ 0.011 before operation to 0.145 ⫾ 0.013 on Postoperative Day 2). The decrease remained significantly low until the last period measured in the study. ICG(K) values throughout the study were significantly lower in patients with than without cirrhosis, but the profiles of postoperative changes in both patients greatly resembled one another (Fig. 1b). The mean volume of the whole liver excluding the tumor mass was calculated based on the liver CT as 1295 ⫾ 50 cm 3, and that of the remaining liver was 878 ⫾ 62 cm 3. The residual liver volume ratio was 70.2 ⫾ 5.4%. The estimated ICG(K) value was calculated as the product of the preoperative ICG(K) value and the residual liver volume ratio. Using this value, we first examined the relationship between ICG(K) values before and after hepatectomy. Correlation analysis between the estimated and the actual postoperative ICG(K) value (Fig. 2) revealed that the estimated ICG(K) value correlated closely with the actual postoperative ICG(K) values throughout the measured pe-
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OKOCHI ET AL.: ICG PULSE SPECTROPHOTOMETRY
FIG. 2. Correlation between estimated and actual ICG(K) values on Postoperative Day 1. Actual ICG(K) value was measured by pulse-dye densitometry (n ⫽ 22), and estimated ICG(K) value was calculated by the preoperative ICG(K) value and the residual liver volume ratio. There was a significant correlation between them. Y ⫽ 0.045 ⫹ 0.846 X (correlation coefficient, 0.859; P ⬍ 0.0001).
DISCUSSION
FIG. 1. Changes in ICG(K) values after hepatectomy. Panel 1a shows changes in all patients (n ⫽ 22). Values decreased significantly after operation and remained low until Postoperative Day 7. Panel 1b is divided into two groups, patients with cirrhosis (open circle, n ⫽ 11) and without cirrhosis (closed circle, n ⫽ 11). ICG(K) values of the two groups show significant differences throughout the examination periods, but the profiles of changes tend to resemble each other. *P ⬍ 0.01 and **P ⬍ 0.05 compared with preoperative value by the Wilcoxon test. †P ⬍ 0.01 and ††P ⬍ 0.05 by MannWhitney U test.
riod (Table 2). The correlation coefficient was highest on Postoperative Day 1 (r ⫽ 0.859, P ⬍ 0.0001). Subsequently, we investigated the relationship between the estimated ICG(K) value and the postoperative morbidity. In five cases with prolonged jaundice whose total bilirubin level increased to more than 2.0 mg/dl over 7 days after hepatectomy, the estimated ICG(K) value was significantly lower than in the patients without prolonged jaundice (0.077 ⫾ 0.028 in 5 cases with prolonged jaundice versus 0.153 ⫾ 0.012 in 17 cases without prolonged jaundice, P ⫽ 0.0136) (Fig. 3). There was no significant difference in the preoperative ICG(K) values of these two groups (0.189 ⫾ 0.027 in patients with prolonged jaundice versus 0.194 ⫾ 0.013 in patients without prolonged jaundice, P ⫽ 0.6952).
As liver failure is the major cause of morbidity and mortality after hepatectomy [12, 13], a variety of methods have been proposed to estimate the liver functional reserve before operation [6, 7]. ICG is a synthetic dye that is eliminated by the liver without extrahepatic metabolism and excretion, and its blood clearance has been applied to determine the operative risk before hepatectomy and recently to evaluate the donor liver function in liver transplantation [14 –16]. Although most of the studies assessing liver function before hepatectomy by ICG clearance have suggested a relationship between the preoperative ICG clearance test and the postoperative outcome [12, 17], it remains unknown just how the clearance of ICG actually changes after liver resection. Pulse-dye densitometry based on the principle of TABLE 2 Correlation Coefficient between Estimated ICG(K) Value and Data after Hepatectomy ICG(K) value after hepatectomy On On On On On
Day Day Day Day Day
1 2 3 5 7
Correlation coefficient
P value
0.859 0.806 0.820 0.826 0.829
⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001
Note. Estimated ICG(K) value ⫽ preoperative ICG(K) value ⫻ residual liver volume ratio; residual liver volume ratio ⫽ remaining liver volume/whole liver volume (excluded tumor volume).
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FIG. 3. Comparison of estimated ICG(K) values between patients with prolonged jaundice (n ⫽ 5) and those without it (n ⫽ 17). The estimated ICG(K) value in the patients with prolonged jaundice is significantly lower than in those without it. * P ⫽ 0.0136 by Mann-Whitney U test.
pulse spectrophotometry has been developed in recent years to enable the blood ICG concentration to be measured easily, less invasively, and continuously. The earlier developed method of measuring the ICG concentration by means of spectrophotometry [18] has not shown sufficient accuracy. However, a newer approach, based on pulse spectrophotometry, is able to continuously measure the arterial ICG concentration alone because of its ability to detect pulse waves, greatly improving accuracy [19]. The ICG(K) value, meaning the ICG elimination rate constant, has a high correlation with that of the conventional method determined by collecting blood samples [20]. For these reasons, we attempted to measure the ICG(K) values perioperatively using pulse-dye densitometry. The postoperative ICG(K) values diminished significantly compared with the preoperative one and remained low until a week after operation. This significant decrease after liver resection is supposed to mainly depend on a reduction in hepatocellular volume, because adequate operation and anesthesia were performed in all patients enrolled in this study, and under this condition, the change in hepatocellular volume seems to be more significant than the other changes affecting ICG(K), such as hepatic blood flow and plasma volume. In contrast, the postoperative ICG(K) profiles revealed that its value fell to its lowest on Postoperative Day 2. The previous study reported that ICG(K) was mainly affected by hepatocellular volume, hepatic blood flow, and plasma volume [21], and another study reported that the portal blood flow in remnant liver increased in the immediate postoperative period and decreased thereafter [22]. The current
results and other observations may indicate that we should pay closer attention to postoperative care at an early period after hepatectomy, especially Postoperative Day 2. In practice, treatment with vasoreactive agents may be necessary to increase hepatic blood flow, possibly with fluid and blood supplementation in these periods to support residual liver function [23]. It should be possible to predict the decrease in postoperative ICG(K) before hepatectomy, if it is due mainly to the reduction in hepatocellular volume by liver resection. Then, we attempted to examine the relationship between the pre- and postoperative ICG(K) level and the residual liver volume. Consequently, the estimated ICG(K) value based on the preoperative ICG(K) value and the residual liver volume ratio from the preoperative CT images showed a high correlation with the actual postoperative ICG(K) value. This result indicates that we may be able to know the residual liver function corresponding to each type of liver resection before operation and predict the risk for postoperative liver failure. In fact, the estimated ICG(K) value described in the study was significantly lower in the patients with prolonged jaundice than in those without it, despite no significant difference in preoperative ICG(K) values between both groups. This estimated value, of course, may turn out to be at odds with the actual outcome due to inadequate perioperative care or some discrepancy between the planned operation and the performed one, but such problems have become less likely because of the recent progress in surgical procedures and perioperative care. Admittedly, the small population in the current study makes it difficult to determine the cutoff point of the estimated ICG(K) for morbidity and mortality after hepatectomy. More extensive examinations may serve to clarify the association between estimated ICG(K) and the liver failure, which could lead to more accurately determination of the extent of the resection needed to prevent liver failure before hepatectomy. In conclusion, we clarified the dynamic liver function after hepatectomy using ICG pulse spectrophotometry. The ICG(K) values decreased significantly after operation depending on the reduction in liver volume, and the estimated ICG(K) value based on the residual liver volume may be useful in predicting the postoperative morbidity. REFERENCES 1.
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