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© 2002 International Anesthesia Research Society
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Abstract |
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Potential overestimation of plasma volume (PV) determination by the conventional indocyanine green (ICG) dilution method (PV-ICG) can occur when generalized capillary protein leakage is present, because ICG binds to proteins. We recently reported that this overestimation can be recognized by simultaneous measurement of the initial distribution volume of glucose (IDVG). We examined whether overestimation of PV-ICG and further ICG-pulse dye densitometry-derived plasma volume (PV-PDD) can occur early after cardiac surgery by using the PV-ICG/IDVG ratio as an indicator. Possible overestimation was defined as a ratio higher than 0.45. Twenty-four consecutive postcardiac surgical patients were enrolled. PV-ICG, PV-PDD, and IDVG were calculated simultaneously after admission to the intensive care unit and on the first postoperative day. The mean ± SD PV-ICG/IDVG ratio for 47 recordings was 0.38 ± 0.05. Four had a PV-ICG/IDVG ratio higher than 0.45, and the highest was 0.48. The mean PV-PDD/IDVG ratio for a total of 47 recordings was 0.39 ± 0.10. There were extremely high or low ratios observed in PV-PDD determinations, but they were not observed in PV-ICG determinations. Results suggest that most of the PV-ICG measurements are accurate, but inaccuracy of PV-PDD can occur early after cardiac surgery.
IMPLICATIONS: Overestimation of indocyanine green-derived plasma volume can occur in the presence of generalized capillary protein leakage. This overestimation was examined early after cardiac surgery by using the simultaneous measurement of the initial distribution volume of glucose. We suggest that overestimation of the traditional dye dilution method is negligible, but apparent over- or underestimation of pulse dye densitometry-derived plasma volume cannot be negligible.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Indocyanine green (ICG) has been used for estimating plasma volume (PV-ICG) and subsequently circulating blood volume (CBV) calculated from PV-ICG and hematocrit (Hct) values and has been reported to be as accurate as the radioisotopic method (1). Recently, a relatively noninvasive ICG dilution method for measuring CBV with pulse dye densitometry (ICG-PDD) has also become clinically possible (2–5). However, there is potential inaccuracy with the PV-ICG determination when apparent generalized protein capillary leakage is present, because this dye binds mainly to plasma albumin (6). As judged by several reports, overestimation of plasma volume rather than an augmented disappearance rate of ICG from plasma seems likely (7,8). This phenomenon can occur during various pathological conditions, such as sepsis, burns, trauma, surgery, and immunotherapy for cancer patients (9). We have recently reported that overestimation can be detected by simultaneous measurement of initial distribution volume of glucose (IDVG) without repeated measurements (10–14) and that apparent overestimation of PV-ICG can frequently occur early after esophagectomy (approximately 30%–45%) (13,14).
Cardiac surgery with cardiopulmonary bypass is generally believed to be associated with altered vascular endothelial integrity and albumin leakage from the intravascular compartment (15), suggesting that overestimation of PV-ICG can also occur after cardiac surgery. The aim of this study was to test whether overestimation of either PV-ICG or ICG-PDD-derived plasma volume (PV-PDD) can occur after cardiac surgery as observed after esophagectomy, by using the PV-ICG/IDVG ratio as an indicator of the overestimation.
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Methods |
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The study was approved by our IRB, and each patient gave written informed consent. ICG and a glucose challenge test associated simultaneously with ICG-PDD were initially performed in 24 consecutive postcardiac surgical patients postoperatively admitted to the general intensive care unit (ICU) (Table 1). Surgical procedures consisted of 15 coronary artery bypass grafts, 7 aortic or mitral valve surgeries, and 2 total aortic arch replacements with cardiopulmonary bypass.
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IDVG, PV-ICG, and PV-PDD were assessed postoperatively twice: immediately after admission to the ICU and between 9:00 and 11:00 AM on the first postoperative day. PV-PDD was indirectly estimated from Hct (%) and CBV by using ICG-PDD (CBV-PDD) as follows:
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An optical sensor for ICG-PDD was attached to a nostril of each patient before ICG and the glucose challenge test. Each sensor was connected to a pulse dye densitometer (R470; Nihon-Kohden, Tokyo, Japan). Each of the dilution curves of ICG-PDD recorded from a nostril was reviewed by one of the authors (HI) to determine whether the ICG decay curve or the computed regression line was adequately recorded.
ICG (25 mg) in 10 mL of a glucose 50% (5 g) solution was administered as a single-bolus injection through the proximal port of a flow-directed pulmonary artery catheter (Swan-Ganz CCOmbo CCO/SVO2, 744HF75; Baxter Healthcare Corporation, Edwards Critical Care Division, Irvine, CA). Injections were manual and not coordinated with the respiratory cycle. No patient had excessive hyperglycemia (>300 mg/100 mL) present immediately before each glucose challenge. Serial blood samples were obtained through an indwelling radial or femoral artery catheter at the following times: immediately before and 1, 2, 3, 4, 5, 7, 9, and 11 min after the completion of both ICG and glucose injections. Isotonic saline with small amounts of heparin was used to flush the arterial line. Each 2-mL blood sample was collected in a heparinized syringe. Plasma was separated immediately, and measurements of glucose and ICG concentrations were performed within 15 min of sampling.
Plasma glucose concentrations were measured with the glucose oxidase method (glucose analyzer GA-1150; Kyoto Daiichi Kagaku Co. Ltd., Kyoto, Japan), and plasma ICG concentrations were measured with a spectrophotometric technique at wavelength of 805 nm (DU530 Spectrophotometer; Beckman Instruments, Inc., Fullerton, CA). Each value was measured in duplicate and averaged. Coefficients of variation for repeated measurements were 2% or less for plasma glucose (range, 55–350 mg/100 mL) and plasma ICG (range, 0.01–1.5 mg/100 mL).
IDVG and PV-ICG were calculated with a one-compartment model from the increased plasma value between 3 and 7 min postinjection for the former and between 3 and 9 or 11 min postinjection for the latter. A microcomputer-based least-squares program was used to analyze plasma glucose and ICG concentrations as described previously (10–14). Akaike’s information criterion (AIC) (16) was examined as described previously (10–14) to evaluate the exponential term of the pharmacokinetic model as follows:
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where n is the number of data points, P is the number of parameters identified in the model, and SSQw is the weighted residual sum of squares. Low AIC values indicate a superiority of the selected model. AIC was -23.7 ± 4.4 (SD) for the IDVG curve and -48.8 ± 6.0 for the PV-ICG curve, respectively. As indicated in the AIC values, convergence was assumed in each curve in this study, as observed previously (10,11,13,14). Possible overestimation was defined as a ratio higher than 0.45 (10,11,17,18).
Continuous thermodilution cardiac output (CO-TD) (Vigilance Monitor, Model VGSSYS; Baxter Healthcare Corporation), Hct, and other routine clinical variables were recorded immediately before each ICG and glucose challenge. Body weight was measured immediately after admission to the ICU and subsequently on the first postoperative day at 8:30 AM. A glucose-containing crystalloid solution, glucose 4.3%, was infused continuously for routine postoperative fluid management through a central venous line by using an electric pump at a constant rate (1.5 mL · kg-1 · h-1). Lactated Ringer’s solution, plasma protein fraction, packed red blood cells, or a combination of these was further administered as clinically required. Additionally, as part of therapy, all but one occasion required an infusion of dopamine, dobutamine, norepinephrine, or a combination of these. Five occasions required intraaortic balloon pumping. Nineteen occasions required an infusion of insulin ranging from 0.5 to 5.0 U/h. Although all patients required mechanical ventilatory support without applying positive end-expiratory pressure immediately after admission to the ICU, the trachea had been extubated before the second determination in 19 patients, and these patients were discharged from the ICU on the first postoperative day.
One patient had obvious cardiovascular instability during data collection on the first postoperative day. Thus, the remaining 47 determinations had comparison of PV-ICG, PV-PDD, and IDVG. CO-TD was not obtained in one patient on the first postoperative day because of failure of the cardiac output monitor.
Unless otherwise stated, data are presented as mean ± SD. When examining for the agreement of two methods, the statistical method described by Bland and Altman (19) was used. Regression analysis was also used to determine the relationship between fluid volumes. Values on the operative day and the first postoperative day were compared by using paired Student’s t-tests. A P value of <0.05 identified statistically significant differences.
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Results |
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Fluid volume status on the two study days is shown in Table 2. Body weight and routine cardiovascular variables, including CO-TD, remained statistically unchanged. PV-ICG and IDVG on the first postoperative day were higher than those on the operative day (P < 0.001 and P = 0.001, respectively). The Hct value on the first postoperative day was lower than that on the operative day (P < 0.001).
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There was a wide variability of PV-ICG and IDVG, as shown in Table 3. IDVG correlated linearly with PV-ICG on the operative day (r = 0.68, n = 24, P = 0.00023) and on the first postoperative day (r = 0.78, n = 23, P = 0.000013) (Fig. 1). IDVG correlated linearly with PV-ICG using all data (r = 0.74, n = 47, P < 0.000001). The mean PV-ICG/IDVG ratio was 0.38 ± 0.05, ranging from 0.27 to 0.48. Four recordings had a PV-ICG/IDVG ratio higher than 0.45: 0.46, 0.46, 0.47, and 0.48.
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Reviewing each dye dilution curve of ICG-PDD associated with the computed regression line revealed that 20 of these 47 recordings were judged as completely adequate because the curve and the line looked identical, 23 recordings were judged as adequate because they looked close, and the remaining 4 recordings were judged as inadequate because they looked different. However, as indicated by a scatterplot of the difference between PV-PDD and PV-ICG according to Bland and Altman’s method (19) (Fig. 2), a clear difference in the relationship seems unlikely regardless of the magnitude of the adequate recording. PV-PDD was found to overestimate PV-ICG by an average of 0.04 L. The standard deviation of the difference between the two volumes was 0.44 L. Therefore, the 95% confidence limits for agreement between the two volumes were from -0.84 to 0.92 L. Simultaneously recorded ICG-PDD-derived cardiac output (CO-PDD) was found to overestimate CO-TD by an average of 0.5 ± 2.1 L/min. With use of PV-ICG and CO-TD as references, the relationship of inaccuracy between PV-PDD and CO-PDD was examined. The over- and underestimation of PV-PDD correlated with those of CO-PDD (r = 0.57, n = 46, P = 0.000043) (Fig. 3). Oxygen saturation at a nostril in 47 determinations ranged from 92% to 100% immediately before ICG and glucose challenge. Five of 47 determinations had oxygen saturations of <95%, but the corresponding PaO2 remained higher than 77 mm Hg. No correlation was found between the PV-PDD/PV-ICG ratio and the oxygen saturation (r = -0.27, P = 0.066). There was a wide variability of the PV-PDD/IDVG ratio, ranging from 0.22 to 0.73 (Table 3), and the mean PV-PDD/IDVG ratio was 0.39 ± 0.10. Nine (19%) of 47 recordings had a PV-PDD/IDVG ratio higher than 0.45, and only one patient had such a high ratio in both measurements. Seven (15%) recordings had ratios >0.48, and 3 (6%) of 47 recordings had a ratio <0.27. These extremely high or low ratios were not observed in PV-ICG determination.
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), adequate (
), or inadequate (
). PV-ICG = the conventional indocyanine green dilution-derived plasma volume requiring repeated blood sampling; PV-PDD = indocyanine green pulse dye densitometry-derived plasma volume. Dashed lines represent 95% confidence limits.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We have reported that IDVG indicates the fluid volume status of the central extracellular fluid, namely, plasma and the highly perfused interstitial fluid compartment, in various critical conditions regardless of the presence or absence of generalized capillary protein leakage (10–14). Although IDVG is not proportionally larger than plasma volume, we have proposed that a PV-ICG/IDVG ratio higher than 0.45 would indicate overestimation of plasma volume (10,11,17,18). Only 4 of 47 recordings in this study had a PV-ICG/IDVG ratio >0.45 but <0.50. Assuming that preoperative the body weight is 60 kg and is associated with the normal IDVG of 120 mL/kg, and if the threshold ratio of the leakage is set at 0.45, the PV-ICG/IDVG ratio of 0.48, which was the highest ratio in this study, would yield overestimation of PV-ICG by approximately 150 mL. Presumably the overestimation can be clinically negligible, even if present.
Judging from the AIC values (16), convergence of the ICG curve was superior to that of the glucose curve, partly reflecting a smaller sampling size for the latter. However, convergence was consistently assumed in each curve in this study, as observed previously (10–14), even on four occasions in which simultaneously recorded ICG-PDD curves were judged as inadequate. Additionally, although a considerable number of patients were receiving an infusion of insulin, vasoactive drugs, or both in this study, our previous studies found that these therapeutic measures do not play a significant role in determining IDVG (11,17). Moreover, we have previously reported that a low cardiac output state (<2.5 L · min-1 · m-2) or a low disappearance rate of ICG from plasma (Ke-ICG) (<0.1/min) does not significantly affect the result of PV-ICG (17), even though five recordings in this study were associated with a low cardiac output state and one recording with a low Ke-ICG. In contrast, the higher the Ke-ICG, the greater the error of PV-ICG, because recirculation of ICG within 60 seconds postinjection significantly affects its pharmacokinetic behavior (20). In fact, we have observed that the relationship between PV-ICG and IDVG with Ke-ICG higher than 0.30 seems different compared with Ke-ICG <0.30, even though a statistically significant difference was not reached (17). However, only one recording in this study had a Ke-ICG higher than 0.30: Ke-ICG was 0.33, associated with the PV-ICG/IDVG ratio 0.29. Presumably, the high Ke-ICG does not yield a significant error in this study. Thus, we believe that the measurement of these two fluid volumes in this study was reliable.
It is interesting to note that two patients in this study who underwent prolonged surgical procedures that lasted more than 10 hours and were associated with massive intraoperative hemorrhage did not have a ratio higher than 0.45. Similarly, patients with acute myocardial infarction severe enough to require mechanical cardiac support, such as intraaortic balloon pumping, had a ratio <0.45 immediately after percutaneous angioplasty (10,11). These findings allow speculation that the protein leakage in either surgical or medical cardiac patients would not be severe enough to produce apparent overestimation of PV-ICG, as observed in our previous studies, in which the highest PV-ICG/IDVG ratio was more than 0.6 (10,11,13).
There are two reports suggesting that ICG-PDD is not influenced by the presence of generalized capillary protein leakage (4,5). However, no ICG-PDD study was performed in any underlying pathology producing generalized capillary protein leakage. The extremely high or low PV-PDD/IDVG ratios observed in this study cannot be clinically negligible compared with PV-ICG. Haruna et al. (2) compared PDD-derived CBV by using a nostril probe with the conventional blood sampling method for ICG determination in 27 cardiac surgical patients. They found that the difference of CBV in the two methods was -0.23 ± 0.37 L (SD). Imai et al. (5) have reported blood volume measured both by ICG-PDD at a nostril and by 51Cr-labeled red blood cells after cardiac surgery. The difference between the two blood volumes was 0.26 ± 0.49 L (SD). Although they concluded that ICG-PDD can measure blood volume with a small bias compared with the radioisotopic method, there was a similar bias as observed in this study (0.04 ± 0.44 L [SD]).
Considering a linear correlation of inaccuracies between PV-PDD and CO-PDD, over- or underestimation of PV-PDD would occur simultaneously with those of CO-PDD. There were a considerable number of recordings (13%) associated with a relatively low oxygen saturation at a nostril compared with the corresponding PaO2. An infusion of vasoactive drugs was also required in all but one occasion. Furthermore, subsequent hypovolemic hypotension requiring volume loading frequently developed within two hours after the first measurement. Considering these findings, there would be possible poor peripheral circulation at a nostril during data collection in this study, leading to inaccurate estimation of absolute values of the blood ICG concentration, even though the disappearance rate of ICG from blood using ICG-PDD has been recently reported to be reliable in critical conditions (21). The inaccuracy is probably due to a lack of high and stable oxygen saturation, adequate peripheral circulation, or unchanged probe position during data collection. Additionally, tissue factors that would affect the measurement of the dye concentration at each detection site may also play a role (5). Thus, these undesirable underlying conditions would limit the effectiveness and accuracy of the currently available ICG-PDD, and reviewing each ICG dilution curve alone does not consistently identify the inaccuracy. On the basis of this finding, the difference between CO-PDD and CO-TD and oxygen saturation should also be checked in each PV-PDD measurement. However, more sophisticated ICG-PDD is required to be used as a clinically relevant bedside monitor, even though the present ICG-PDD is useful in the operating room (2,4).
A reduction of Hct value observed on the first postoperative day would not consistently indicate an increase in plasma volume, because fluid therapy, blood transfusion, or postoperative blood loss may considerably affect the intravascular volume status. However, PV-ICG and IDVG on the first postoperative day were higher than those on the operative day, confirming significant increases in fluid volumes, which cannot be consistently identified by routine cardiovascular variables. Thus, measurement of fluid volumes would help provide more rational therapy than that of routine cardiovascular variables alone.
In conclusion, we measured PV-ICG, PV-PDD, and IDVG simultaneously early after cardiac surgery. Results suggest that ICG can accurately measure plasma volume early after cardiac surgery by using the traditional blood sampling method, but not ICG-PDD.
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Acknowledgments |
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We thank Dr. P. Hollister (Misawa, Japan) for his valuable comments and Professor A. H. Giesecke (Dallas, TX) for his continued support of this study.
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References |
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