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How to investigate regional blood flow
H O W TO I N V E S T I G A T E R E G I O N A L B L O O D F L O W TAKALA
Blood flow is the major determinant of oxygen supply to the tissues. Changes of both systemic and regional blood flows are important in the evaluation of the pathophysiology of tissue oxygenation and the responses to therapy. Measurements of systemic blood flow have been readily available and extensively used in the clinical setting. Assessment of regional blood flows has gained increased interest in intensive care patients for several reasons. Inadequate regional blood flow and oxygen supply has been suspected to contribute to the pathogenesis and clinical course of organ dysfunction; specifically, inadequate splanchnic tissue perfusion has been associated with increased risk of multiple organ failure and mortality [1, 2]. Changes in regional tissue perfusion and oxygen uptake can easily be masked in whole body measurements, especially in the presence of impaired vasoregulation and abnormal blood flow distribution. Several common clinical events and routine therapeutic modalities may modify regional blood flows: for example, hypovolemia and low cardiac output tend to reduce all regional blood flows, whereas sepsis, use of vasoactive drugs, and positive pressure ventilation may redistribute cardiac output in an unpredictable way [1-4]. The blood flow responses may also be modified by the underlying clinical condition. All these factors may induce a mismatch between regional oxygen delivery and demand. Methods to directly measure regional blood flows are not available for routine clinical use. A number of clinical studies focusing on regional, and especially splanchnic perfusion has recently been published, and measurements of various regional blood flows in clinical studies is likely to become more common in the future. Since these methods have so far
CriticalCare ResearchProgram,Departmentof IntensiveCare, Kuopio UniversityHospital, FIN-70210 Kuopio, Finland. R#an. Urg., 1996, 5 (2 bis), 220-223
only rarely been used in intensive care patients, the theoretical basis, limitations, and practical aspects of regional blood flow measurements in intensive care patients deserve consideration. This review focuses on dye dilution techniques based on the Fick principle with specific reference to splanchnic blood flow. More indirect techniques and functional assessments will also be briefly addressed.
•
Indicator dilution t e c h n i q u e s (Fick principle)
According to the Fick principle, the blood flow to any organ can be measured, when the following data is available: -- the concentration of an indicator substance in the blood entering the organ; -- the concentration of the indicator substance in the mixed venous blood leaving the organ; -- the total amount of the indicator substance removed from the blood by the organ [5, 6]. The indicator must remain within the intravascular compartment during the measurement. Concentration of the indicator in the blood entering the organ can usually be assumed to be equal to the arterial concentration of the substance. Since the regional extraction of an indicator substance is in practice never 100%, the concentration of the indicator in the blood leaving the organ has to be obtained by regional venous catheterization. If the total amount of indicator removed cannot be measured directly, it can be estimated indirectly by obtaining steady-state indicator blood concentration during constant infusion of indicator. Under these conditions, the total removal rate equals the rate of indicator infusion. The typical examples of regions or organs, where the Fick principle can be applied are the hepatosplanchnic
H o w to investigate regional b l o o d flow? - 221 -
region and the kidney. If the regional extraction is not measured and only the clearance of the indicator is measured, this is reperred to as the effective regional blood flow. It has to be emphasized that changes in clearance cannot distinguish between changes in blood flow and extraction. If blood flow of organs or regions with no suitable indicator uptake is to be studied, the indicator has to be infused to the regional artery, and the Fick principle replaced by mass balance calculations [7]. The following data is required: -- the rate and the concentration of the indicator infusion into the artery supplying the organ; -- the concentration of the indicator substance in the mixed venous blood leaving the organ; -- the concentration of the indicator in the blood recirculating to the organ. The following demonstrates the application of these principles for the m e a s u r e m e n t of hepatosplanchnic and femoral blood flow [6-11]. Steady-state indicator blood concentrations are obtained by primed, continuous infusion of the indicator substance. Currently, indocyanine green (ICG) is the most commonly used indicator for the assessment of hepatosplanchnic blood flow. The substance is exclusively metabolized by the liver, but the extraction is never 100%. It is also suitable for blood flow measurement of other organs, since it remains within the intravascular compartment bound in plasma proteins. Other indicators that have been used include bromsulphalein [5, 9], galactose [12], and more recently, sorbitol [13]. Since the hepat0splanchnic venous efflux in the hepatic vein contains blood supplied by both the portal vein and the hepatic artery, the blood flow measured represents the total blood flow through the liver and the splanchnic region. Neither differentiation between the hepatic arterial and portal venous blood nor detection of flow redistribution within the splanchnic bed is possible using this method. Once steady-state blood concentrations have been obtained, the total hepatosplanchnic blood flow can be calculated as follows: total hepatosplanchnic blood flow = infusion rate (L/min) x Ci/(Ca-Chv) x ( l - H c r ) , where Ci is the ICG-concentration of infusate (mg/L), and Ca and Chv are the ICG-concentrations in a sys -' temic artery and hepatic vein (mg/L), respectively. When the indicator (ICG) is infused to the femoral artery, the femoral blood flow can be calculated as follows: femoral blood flow = infusion rate (L/rain) x (Ci-Cfv)/(Cfv- Ca) x (1-Hcr), where cry is the ICG-concentration in the femoral vein (mg/L). This formula takes into account the ef-
fect of the rate of dye infusion into the femoral artery. The same principle has also been applied to measure e.g. the forearm and the renal blood flow [7, 14]. These two techniques can be combined to simultaneously measure the total hepatosplanchnic and femoral blood flow [8, 10]. We have used the primed, continuous infusion of indocyanine green into the femoral artery with hepatic venous, femoral venous, and systemic arterial blood sampling to estimate the hepatosplanchnic and femoral blood flow in intensive care patients. The simultaneous measurement of hepatosplanchnic and femoral blood flow has originally been described in detail by Jorfeldt and JuhlinDannefelt in 1978, as a modification of the original techniques of Leery et al., and Johrfeldt and Wahren [8, 9]. We have previously described the method and its evaluation in intensive care patients in detail [10]. Briefly, the femoral artery is catheterized for dye infusion, and the ipsilateral femoral vein, a hepatic vein, and a radial artery for blood sampling. The correct, non-wedged position of the hepatic venous catheter is verified with fluoroscopy using a small amount of contrast dye. After a priming dose of 12 mg of ICG, a constant infusion of 1.1 mg/min is commenced and continued for 30 minutes. Blood is sampled for the measurement of arterial, and hepatic and femoral vein ICG concentrations after 20, 25, and 30 minutes of infusion. As pointed out earlier, steady-state dye concentrations and sufficient (> 10%, preferably (> 20%) hepatic dye extraction are necessary for the valid application of the continuous infusion method. Methods to correct for non-steady state indicator concentrations have been described, but these have not been evaluated in intensive care patients. Lack of steady-state, especially during prolonged infusions have been reported by some authors. This may be due to the back diffusion of the dye from the hepatocytes [14]. In our experience, this has not been a problem with the 30-minutes infusion periods, even if repeated measurements have been performed. In our studies, the mean coefficient of variation of both splanchnic and femoral blood flow was 6% within each 30-minutes measurement period in 240 regional blood flow measurements. This is similar to the variability of cardiac output measurements in optimum conditions using the thermodilution method [15]. Sufficient hepatic extraction of indocyanine green has also been achieved in a variety of patient groups: in septic shock, postoperative cardiac surgery, ARDS, and acute pancreatitis [10]. In order to avoid hepatic venous catheterization, techniques using only systemic sampling have been proposed [6, 16-19]. These methods are based on either the assumption of constant hepatic dye extraction or estimation of the extraction using pharmacokinetic models. The hepatic extraction may remain relatively stable under specific conditions in normal Rean. Urg., 1996, 5 (2 bis), 220-223
- 222 - How to investigate regional blood flow? subjects, so that acute changes in hepatosplanchnic blood flow may possibly be estimated with some reliability using systemic sampling alone. Unstable hemodynamics and hepatic dysfunction may interfere with the splanchnic blood flow measurement by causing unstable or insufficient hepatic extraction and lack of steady state dye concentration [12, 20]. Also, vasoactive drugs may acutely alter the hepatic dye extraction [10]. All these interfering factors are common in intensive care patients, and the use of dye dilution techniques based on systemic sampling alone to estimate the hepatosplanchnic blood flow cannot be justified.
•
Noninvasive assessment of h e p a t o s p l a n c h n i c p e r f u s i o n
Systemic clearance of substances metabolized by the liver (ICG, bromsuphalein, galactose, sorbitol) have been used to estimate "functional" liver blood flow. While the clearance values certainly reflect in part the hepatic function, they cannot be used as surrogate measures of splachnic blood flow due to the unpredictable hepatic extraction of these substances. The production of monoethylglycinexylidide (MEGX) from lidocaine was initially introduced as a sensitive indicator of liver function, which may be influenced by major changes in hepatic blood flow (20). Measurement of the plasma concentration of MEGX after a bolus injection of lidocaine has been proposed as a surrogate measure of hepatosplanchnic blood flow. MEGX is formed from lidocaine via the hepatic cytochrome P-450 system. Whether this process is blood flow dependent and under which conditions remains to be demonstrated. Currently, the use of MEGX as a surrogate measure of hepatic blood flow cannot be justified.
standard blood gas analyzer. The gastric pHi is calculated by applying a modified HendersonHasselbalch equation: pH i = 6.1 + log arterial[HCO3-] PCO2(tonometer)x k where k is a time-dependent equilibration constant provided by the manufacturer [23]. Alternatively, the pH-gap (arterial pH-pHi) or the PCO2 -gap (gastric-arterial PCO~) can be used, with a widening gap suggesting insufficient perfusion of the gastric mucosa. The relationship between changes in pHi and hepatosplanchnic blood flow is inconsistent [27, 28]. Despite major increase in splanchnic blood flow, the pHi may markedly decrease [27, 28]. This inconsistency may reflect redistribution within the splanchnic region of either blood flow, metabolism or both. How well changes in gastric pHi or gastric mucosal PCO~ reflect changes in various parts of the splanchnic region is still unclear. Sources of error in tonometry include the analysis of the saline PCO~ and increased intraluminal production of CO~. Different blood gas analyzers may induce marked errors in the calculated gastric pHi due to variable accuracy in the analysis of PCO2 [29, 30]. H~-blockers have been recommended to reduce the generation of intraluminal CO~, and to improve the reproducibility of measurements of pH~ [31, 32], but this concept has not been validated in intensive care patients. In contrast, preliminary studies in critically ill patients suggest that the use of H2-blockers has no effect on the calculated gastric pHi [33, 34]. The very recent development of tonometry using samples of air from the gastric balloon and measurement of the PCO~ of the air sample by capnometry may reduce both the response time and sources of error of tonometry.
• •
Gastrointestinal tonometry
Assessment of gastric intramucosal pH (pHi) by gastric tonometry has been used to estimate the adequacy of splanchnic tissue perfusion [22-26]. While low pHi may be associated with poor prognosis in critically ill patients [24-26], the relevance of monitoring transient changes in phi in response therapeutic interventions has not been established. A saline sample is injected in a silicone balloon located at the tip of a special nasogatric tube. The balloon is permeable to CO~, and the PC02 of the saline will equilibrate with the intraluminal PCO~, which is taken to reflect the intramucosal PCO~. Simultaneously with the saline sample, an arterial blood sample is taken and both samples are analyzed in a R~an. Urg., 1996, 5 (2 bis), 220-223
Other methods
Several other methods have been used to assess various regional blood flows in intensive care patients. Venous occlusion plethysmography [35] is suitable for both leg and forearm blood flow measurement, but calibration remains a problem. Doppler ultrasound can be used to measure the blood flow in various vessels, including the viscera [36]. Measurement of the diameter of the vessel and the insoniflcation angle, the inhomogeneity of the flow velocity profile, reproducibility (especially between-user variability) and validation are the main problems. Laser Doppler flowmetry [37] has been used to measure peripheral capillary blood flow and gastric mucosal blood flow. This technique allows the detection of relative flow changes in small tissue volumes.
H o w to investigate regional blood flow? -
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[20] WILMORE D.W., GOODWIN C.W., AULICK L.H., POWANDA M.C., MASON A.D., PRUITr Jr M.D. - - Effect of injury and infection on visceral metabolism and circulation. Ann. Surg., 1980, 192, 491-500. [21] OELLERICH M., RAUDE E, BURDELSKI M., SCRULZ M., SCHMIDT F.W. et aL - - Monoethylglycineglycidide formulation kinetics: a novel approach to assessment of liver function. J. Clin. Chem. Clin. Biochem., 1987, 25, 845-853. [22] GRUM C., FIDDIAN-GREEN R., PITTENGER G. - - Adequacy of tissue oxygenation in the intact dog intestine. J. Applied PhysioL, 1984, 56, 1065-1069. [23] FIDBIAN-GREEN R.G., BAKER S. - - Predictive value of stomach wall pH for complications after cardiac operations: Comparison with other monitoring. Grit. Care Med., 1987, 15, 153-156. [24] GYST., HUBENS A., HEELS H., LAUWERS L.F., PELTERS R. - Prognostic value of gastric intramural pH in surgical intensive care patients. Crit. Care Med., 1988, 16, 1222-1224. [25] DOGLIO G.R., PUSAJO J.F., EGURROLA M.A., BONFIGLI G.C., PARRA C., VETERE L , HERNANDEZ M.S., FERNANDEZS., PALIZAS F., GUTIERREZG. - - Gastric mucosal pH as a prognostic index of mortality in critically ill patients. Grit. Care Med., 1991, 19, 1037-1040. [26] MAYNARDN., BIHARI O., BEALER., SMITHIES M., BALDOCK G., MASON R., McCOLL I. - - Assessment of splanchnic oxygenation by gastric tonometry in patients with acute circulatory failure. JAMA, 1993, 270, 1203-1210. [27] UUSAROA., RUOKONEN E., TAKALA J. - - Gastric mucosal pH does not reflect change in splanchnic blood flow after cardiac surgery. Br. J. Anaesth., 1995, 74, 149-154. [28] PARVIAINEN I., RUOKONEN E., TAKALA J. - - Dobutamineinduced dissociation between changes in splanchnic blood flow and gastric intramucosal pH after cardiac surgery. Br. J. Anaesth., 1995, 74, 277-282. [29] RIDDINGTOND., BALASUBRAMANIANVENKATESH K., GLUTTONBROCK T., BION J. - - Measuring carbon dioxide tension in saline and alternative solutions: Quantification of bias and precision in two blood gas analyzers. Grit. Care Med., 1994, 22, 96-100. [30] TAKALA J., PARVIAINEN I., SILOHAHO M., RUOKONEN E., H.~M.~.L.~.INENE. - - Saline PCO2 is an important source of error in the assessment of gastric intramucosal pH. Grit. Care Med., 1994, 22, 1877-1879. [31] HEARD S.C., HELSMOORTELC.M., KENT J.C., SHAHNARIANA., FINCK M.P. - - Gastric tonometry in healthy volunteers: effect of ranitidine on calculated intramural pH. Grit. Care Med., 1991, 19, 271-274. [32] KOLKMAN J., GROENEVELD A., MEUWlSSEN S. - - Effect of ranitidine on basal and bicarbonate enhanced intragastric PCO2: a tonometric study. Gut, 1994, 35, 737-741. [33] MAYNARDN., ATKINSON S., MASON R., SMITHIES M., BIHARI D. - - Influence of intravenous ranitidine on gastric intramucosal pH in critically ill patients. Grit. Care Med., 1994, 22, A79. [34] BAIGORRI F., CALVET X., DUARTE M., SAURA P., JUBERT P., ROYO C., JOSEPH D., ARTIGAS A. - - Effect of ranitidine treatment in gastric intramucosal pH determinations in critical patients. Intensive Care Med., 1994, 20, $2. [35] GREENFIELDA.D.M., WHITNEY R.J., MOWBRAY J. - - Methods for the investigation of peripheral blood flow. Br. Med. Bull., 1963, 19, 101-112. [36] GILL RW. - - Measurement of blood flow by ultrasound: accuracy and sources of error. Ultrasound Med. BioL, 1985, 11, 625-641. [37] LUNDE O.C., KVERNEBO K., LARSEN S. - - Evaluation of en. doscopic laser doppler flowmetry for measurement of human gastric blood flow. Scand. J. Gastroenterol, 1988, 23, 1072-1078.
References
[1] MATUSCHAKG.M. - - Liver-lung interactions in critical illness. New Horizons, 1994, 2, 488-504. [2] TAKALAJ. - - Splanchnic perfusion in shock. Intensive Care Med., 1994, 20, 403-404. [3] RUOKONENE., TAKALAJ., KARl A., SAXENH., MERTSOLAJ., HANSEN E.J. - - Regional blood flow and oxygen transport in septic shock. Grit. Care Med., 1993, 21, 1296-1303. [4] RUOKONEN E., TAKALAJ., KARl A. - - Regional blood flow and oxygen transport in patients with the low cardiac output syndrome after cardiac surgery. Grit. Care Med., 1993, 21, 1304-1311. [5] BRADLEY S.E., INGELFINGERF.J., BRADLEY G.P., CURRY J.J. - - The estimation of hepatic blood flow in man. J. Clin. Invest., 1945, 24, 890-897. [6] SHAK C., KEIDING S. - - Methodological problems in the use of indocyanine green to estimate hepatic blood flow and ICG clearence in man. Liver, 1987, 7, 155-162. [7] WARREN J. - - Quantitative aspects of blood flow and oxygen uptake in the human forearm during rhythmic exercise. Stockholm, Kungl. Boktryckeriet P. A. Norstedt & SGner, 1966. [8] JORFELDTL., JURLIN-DANNFELTA. - - The influence of ethanol on splanchnic and skeletal muscle metabolism in man. Metabolism, 1978, 27, 97-106. [9] LEEVYC.V., MENDEHALLC.L., LESKOW., HOWARD M.K. - - Estimation of hepatic blood flow with indocyanine green. J. Clin. Invest., 1962, 41, 1169-1179. [10] UUSARO A., RUOKONEN E., TAKALA J. - - Estimation of splanchnic blood flow by the Fick principle in man and problems in the use of indocyanine green. Cardiovasc. Res., in press. [11] VILLENEUVEJ.e., HUOT R., MARLEAU D., HUET P.M. - - The estimation of hepatic blood flow with indocyanine green: Comparison between the continuous infusion and single injection methods. Am. J. Gastroent., 1982, 77, 233-237. [12] DARN M.S., LANCE e., WILSON R.F., JACOBS L.A., MITCHELLR.A. - - Hepatic blood flow and splanchnic oxygen consumption measurements in clinical sepsis. Surgery, 1990, 107, 295-301. [13] ZEEH J., LANCE H;, BOSCH J., POHL S., LOESGEN H., EGGERS a., NAVASA M., CHESTA J., BIRCHER J. - - Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow. Gastroenterology, 1988, 95, 749-759. [14] REUBI E.G., VORBURGER C. - - Renal hemodynamics and physiopathology of acute renal failure after shock in man. Basel, Karger, 1976. [15] PINSKY M.R. - - The meaning of cardiac output. Int. Care Med., 1990, 16, 415-417. [16] CLEMENTSD., WEST R., ELIAS E. - - Comparison of bolus and infusion methods for estimating hepatic blood flow in patients with liver disease using indocyanine green. J. Hepat., 1987, 5, 282-287. [17] GRAINGER S.L., KEELING P.W.N., BROWN I.M.H., MARIGOLD J.H., THOMPSON R.P.H. - - Clearance and noninvasive determination of the hepatic extraction of indocyanine green in baboons and man. Clin. Sci., 1983, 64, 207-212. [18] WANG P., ZHENG F., CRAUDRY I.H. - - Hepatic extraction of indocyanine green is depressed early in sepsis despite increased hepatic blood flow and cardiac output. Arch. Surg., 1991, 126, 219-224. [19] KHOLOUSSYA.M., POLLACK D., MATSMUTO T. - - Prognostic significance of indocyanine green clearance in critically ill surgical patients. Grit. Care Med., 1984, 12, 115-116.
i
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l
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R#an. Urg., 1996, 5 (2 bis), 220-223
Blood flow is the major determinant of oxygen supply to the tissues. Changes of both systemic and regional blood flows are important in the evaluation of the pathophysiology of tissue oxygenation and the responses to therapy. Measurements of systemic blood flow have been readily available and extensively used in the clinical setting. Assessment of regional blood flows has gained increased interest in intensive care patients for several reasons. Inadequate regional blood flow and oxygen supply has been suspected to contribute to the pathogenesis and clinical course of organ dysfunction; specifically, inadequate splanchnic tissue perfusion has been associated with increased risk of multiple organ failure and mortality [1, 2]. Changes in regional tissue perfusion and oxygen uptake can easily be masked in whole body measurements, especially in the presence of impaired vasoregulation and abnormal blood flow distribution. Several common clinical events and routine therapeutic modalities may modify regional blood flows: for example, hypovolemia and low cardiac output tend to reduce all regional blood flows, whereas sepsis, use of vasoactive drugs, and positive pressure ventilation may redistribute cardiac output in an unpredictable way [1-4]. The blood flow responses may also be modified by the underlying clinical condition. All these factors may induce a mismatch between regional oxygen delivery and demand. Methods to directly measure regional blood flows are not available for routine clinical use. A number of clinical studies focusing on regional, and especially splanchnic perfusion has recently been published, and measurements of various regional blood flows in clinical studies is likely to become more common in the future. Since these methods have so far
CriticalCare ResearchProgram,Departmentof IntensiveCare, Kuopio UniversityHospital, FIN-70210 Kuopio, Finland. R#an. Urg., 1996, 5 (2 bis), 220-223
only rarely been used in intensive care patients, the theoretical basis, limitations, and practical aspects of regional blood flow measurements in intensive care patients deserve consideration. This review focuses on dye dilution techniques based on the Fick principle with specific reference to splanchnic blood flow. More indirect techniques and functional assessments will also be briefly addressed.
•
Indicator dilution t e c h n i q u e s (Fick principle)
According to the Fick principle, the blood flow to any organ can be measured, when the following data is available: -- the concentration of an indicator substance in the blood entering the organ; -- the concentration of the indicator substance in the mixed venous blood leaving the organ; -- the total amount of the indicator substance removed from the blood by the organ [5, 6]. The indicator must remain within the intravascular compartment during the measurement. Concentration of the indicator in the blood entering the organ can usually be assumed to be equal to the arterial concentration of the substance. Since the regional extraction of an indicator substance is in practice never 100%, the concentration of the indicator in the blood leaving the organ has to be obtained by regional venous catheterization. If the total amount of indicator removed cannot be measured directly, it can be estimated indirectly by obtaining steady-state indicator blood concentration during constant infusion of indicator. Under these conditions, the total removal rate equals the rate of indicator infusion. The typical examples of regions or organs, where the Fick principle can be applied are the hepatosplanchnic
H o w to investigate regional b l o o d flow? - 221 -
region and the kidney. If the regional extraction is not measured and only the clearance of the indicator is measured, this is reperred to as the effective regional blood flow. It has to be emphasized that changes in clearance cannot distinguish between changes in blood flow and extraction. If blood flow of organs or regions with no suitable indicator uptake is to be studied, the indicator has to be infused to the regional artery, and the Fick principle replaced by mass balance calculations [7]. The following data is required: -- the rate and the concentration of the indicator infusion into the artery supplying the organ; -- the concentration of the indicator substance in the mixed venous blood leaving the organ; -- the concentration of the indicator in the blood recirculating to the organ. The following demonstrates the application of these principles for the m e a s u r e m e n t of hepatosplanchnic and femoral blood flow [6-11]. Steady-state indicator blood concentrations are obtained by primed, continuous infusion of the indicator substance. Currently, indocyanine green (ICG) is the most commonly used indicator for the assessment of hepatosplanchnic blood flow. The substance is exclusively metabolized by the liver, but the extraction is never 100%. It is also suitable for blood flow measurement of other organs, since it remains within the intravascular compartment bound in plasma proteins. Other indicators that have been used include bromsulphalein [5, 9], galactose [12], and more recently, sorbitol [13]. Since the hepat0splanchnic venous efflux in the hepatic vein contains blood supplied by both the portal vein and the hepatic artery, the blood flow measured represents the total blood flow through the liver and the splanchnic region. Neither differentiation between the hepatic arterial and portal venous blood nor detection of flow redistribution within the splanchnic bed is possible using this method. Once steady-state blood concentrations have been obtained, the total hepatosplanchnic blood flow can be calculated as follows: total hepatosplanchnic blood flow = infusion rate (L/min) x Ci/(Ca-Chv) x ( l - H c r ) , where Ci is the ICG-concentration of infusate (mg/L), and Ca and Chv are the ICG-concentrations in a sys -' temic artery and hepatic vein (mg/L), respectively. When the indicator (ICG) is infused to the femoral artery, the femoral blood flow can be calculated as follows: femoral blood flow = infusion rate (L/rain) x (Ci-Cfv)/(Cfv- Ca) x (1-Hcr), where cry is the ICG-concentration in the femoral vein (mg/L). This formula takes into account the ef-
fect of the rate of dye infusion into the femoral artery. The same principle has also been applied to measure e.g. the forearm and the renal blood flow [7, 14]. These two techniques can be combined to simultaneously measure the total hepatosplanchnic and femoral blood flow [8, 10]. We have used the primed, continuous infusion of indocyanine green into the femoral artery with hepatic venous, femoral venous, and systemic arterial blood sampling to estimate the hepatosplanchnic and femoral blood flow in intensive care patients. The simultaneous measurement of hepatosplanchnic and femoral blood flow has originally been described in detail by Jorfeldt and JuhlinDannefelt in 1978, as a modification of the original techniques of Leery et al., and Johrfeldt and Wahren [8, 9]. We have previously described the method and its evaluation in intensive care patients in detail [10]. Briefly, the femoral artery is catheterized for dye infusion, and the ipsilateral femoral vein, a hepatic vein, and a radial artery for blood sampling. The correct, non-wedged position of the hepatic venous catheter is verified with fluoroscopy using a small amount of contrast dye. After a priming dose of 12 mg of ICG, a constant infusion of 1.1 mg/min is commenced and continued for 30 minutes. Blood is sampled for the measurement of arterial, and hepatic and femoral vein ICG concentrations after 20, 25, and 30 minutes of infusion. As pointed out earlier, steady-state dye concentrations and sufficient (> 10%, preferably (> 20%) hepatic dye extraction are necessary for the valid application of the continuous infusion method. Methods to correct for non-steady state indicator concentrations have been described, but these have not been evaluated in intensive care patients. Lack of steady-state, especially during prolonged infusions have been reported by some authors. This may be due to the back diffusion of the dye from the hepatocytes [14]. In our experience, this has not been a problem with the 30-minutes infusion periods, even if repeated measurements have been performed. In our studies, the mean coefficient of variation of both splanchnic and femoral blood flow was 6% within each 30-minutes measurement period in 240 regional blood flow measurements. This is similar to the variability of cardiac output measurements in optimum conditions using the thermodilution method [15]. Sufficient hepatic extraction of indocyanine green has also been achieved in a variety of patient groups: in septic shock, postoperative cardiac surgery, ARDS, and acute pancreatitis [10]. In order to avoid hepatic venous catheterization, techniques using only systemic sampling have been proposed [6, 16-19]. These methods are based on either the assumption of constant hepatic dye extraction or estimation of the extraction using pharmacokinetic models. The hepatic extraction may remain relatively stable under specific conditions in normal Rean. Urg., 1996, 5 (2 bis), 220-223
- 222 - How to investigate regional blood flow? subjects, so that acute changes in hepatosplanchnic blood flow may possibly be estimated with some reliability using systemic sampling alone. Unstable hemodynamics and hepatic dysfunction may interfere with the splanchnic blood flow measurement by causing unstable or insufficient hepatic extraction and lack of steady state dye concentration [12, 20]. Also, vasoactive drugs may acutely alter the hepatic dye extraction [10]. All these interfering factors are common in intensive care patients, and the use of dye dilution techniques based on systemic sampling alone to estimate the hepatosplanchnic blood flow cannot be justified.
•
Noninvasive assessment of h e p a t o s p l a n c h n i c p e r f u s i o n
Systemic clearance of substances metabolized by the liver (ICG, bromsuphalein, galactose, sorbitol) have been used to estimate "functional" liver blood flow. While the clearance values certainly reflect in part the hepatic function, they cannot be used as surrogate measures of splachnic blood flow due to the unpredictable hepatic extraction of these substances. The production of monoethylglycinexylidide (MEGX) from lidocaine was initially introduced as a sensitive indicator of liver function, which may be influenced by major changes in hepatic blood flow (20). Measurement of the plasma concentration of MEGX after a bolus injection of lidocaine has been proposed as a surrogate measure of hepatosplanchnic blood flow. MEGX is formed from lidocaine via the hepatic cytochrome P-450 system. Whether this process is blood flow dependent and under which conditions remains to be demonstrated. Currently, the use of MEGX as a surrogate measure of hepatic blood flow cannot be justified.
standard blood gas analyzer. The gastric pHi is calculated by applying a modified HendersonHasselbalch equation: pH i = 6.1 + log arterial[HCO3-] PCO2(tonometer)x k where k is a time-dependent equilibration constant provided by the manufacturer [23]. Alternatively, the pH-gap (arterial pH-pHi) or the PCO2 -gap (gastric-arterial PCO~) can be used, with a widening gap suggesting insufficient perfusion of the gastric mucosa. The relationship between changes in pHi and hepatosplanchnic blood flow is inconsistent [27, 28]. Despite major increase in splanchnic blood flow, the pHi may markedly decrease [27, 28]. This inconsistency may reflect redistribution within the splanchnic region of either blood flow, metabolism or both. How well changes in gastric pHi or gastric mucosal PCO~ reflect changes in various parts of the splanchnic region is still unclear. Sources of error in tonometry include the analysis of the saline PCO~ and increased intraluminal production of CO~. Different blood gas analyzers may induce marked errors in the calculated gastric pHi due to variable accuracy in the analysis of PCO2 [29, 30]. H~-blockers have been recommended to reduce the generation of intraluminal CO~, and to improve the reproducibility of measurements of pH~ [31, 32], but this concept has not been validated in intensive care patients. In contrast, preliminary studies in critically ill patients suggest that the use of H2-blockers has no effect on the calculated gastric pHi [33, 34]. The very recent development of tonometry using samples of air from the gastric balloon and measurement of the PCO~ of the air sample by capnometry may reduce both the response time and sources of error of tonometry.
• •
Gastrointestinal tonometry
Assessment of gastric intramucosal pH (pHi) by gastric tonometry has been used to estimate the adequacy of splanchnic tissue perfusion [22-26]. While low pHi may be associated with poor prognosis in critically ill patients [24-26], the relevance of monitoring transient changes in phi in response therapeutic interventions has not been established. A saline sample is injected in a silicone balloon located at the tip of a special nasogatric tube. The balloon is permeable to CO~, and the PC02 of the saline will equilibrate with the intraluminal PCO~, which is taken to reflect the intramucosal PCO~. Simultaneously with the saline sample, an arterial blood sample is taken and both samples are analyzed in a R~an. Urg., 1996, 5 (2 bis), 220-223
Other methods
Several other methods have been used to assess various regional blood flows in intensive care patients. Venous occlusion plethysmography [35] is suitable for both leg and forearm blood flow measurement, but calibration remains a problem. Doppler ultrasound can be used to measure the blood flow in various vessels, including the viscera [36]. Measurement of the diameter of the vessel and the insoniflcation angle, the inhomogeneity of the flow velocity profile, reproducibility (especially between-user variability) and validation are the main problems. Laser Doppler flowmetry [37] has been used to measure peripheral capillary blood flow and gastric mucosal blood flow. This technique allows the detection of relative flow changes in small tissue volumes.
H o w to investigate regional blood flow? -
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[20] WILMORE D.W., GOODWIN C.W., AULICK L.H., POWANDA M.C., MASON A.D., PRUITr Jr M.D. - - Effect of injury and infection on visceral metabolism and circulation. Ann. Surg., 1980, 192, 491-500. [21] OELLERICH M., RAUDE E, BURDELSKI M., SCRULZ M., SCHMIDT F.W. et aL - - Monoethylglycineglycidide formulation kinetics: a novel approach to assessment of liver function. J. Clin. Chem. Clin. Biochem., 1987, 25, 845-853. [22] GRUM C., FIDDIAN-GREEN R., PITTENGER G. - - Adequacy of tissue oxygenation in the intact dog intestine. J. Applied PhysioL, 1984, 56, 1065-1069. [23] FIDBIAN-GREEN R.G., BAKER S. - - Predictive value of stomach wall pH for complications after cardiac operations: Comparison with other monitoring. Grit. Care Med., 1987, 15, 153-156. [24] GYST., HUBENS A., HEELS H., LAUWERS L.F., PELTERS R. - Prognostic value of gastric intramural pH in surgical intensive care patients. Crit. Care Med., 1988, 16, 1222-1224. [25] DOGLIO G.R., PUSAJO J.F., EGURROLA M.A., BONFIGLI G.C., PARRA C., VETERE L , HERNANDEZ M.S., FERNANDEZS., PALIZAS F., GUTIERREZG. - - Gastric mucosal pH as a prognostic index of mortality in critically ill patients. Grit. Care Med., 1991, 19, 1037-1040. [26] MAYNARDN., BIHARI O., BEALER., SMITHIES M., BALDOCK G., MASON R., McCOLL I. - - Assessment of splanchnic oxygenation by gastric tonometry in patients with acute circulatory failure. JAMA, 1993, 270, 1203-1210. [27] UUSAROA., RUOKONEN E., TAKALA J. - - Gastric mucosal pH does not reflect change in splanchnic blood flow after cardiac surgery. Br. J. Anaesth., 1995, 74, 149-154. [28] PARVIAINEN I., RUOKONEN E., TAKALA J. - - Dobutamineinduced dissociation between changes in splanchnic blood flow and gastric intramucosal pH after cardiac surgery. Br. J. Anaesth., 1995, 74, 277-282. [29] RIDDINGTOND., BALASUBRAMANIANVENKATESH K., GLUTTONBROCK T., BION J. - - Measuring carbon dioxide tension in saline and alternative solutions: Quantification of bias and precision in two blood gas analyzers. Grit. Care Med., 1994, 22, 96-100. [30] TAKALA J., PARVIAINEN I., SILOHAHO M., RUOKONEN E., H.~M.~.L.~.INENE. - - Saline PCO2 is an important source of error in the assessment of gastric intramucosal pH. Grit. Care Med., 1994, 22, 1877-1879. [31] HEARD S.C., HELSMOORTELC.M., KENT J.C., SHAHNARIANA., FINCK M.P. - - Gastric tonometry in healthy volunteers: effect of ranitidine on calculated intramural pH. Grit. Care Med., 1991, 19, 271-274. [32] KOLKMAN J., GROENEVELD A., MEUWlSSEN S. - - Effect of ranitidine on basal and bicarbonate enhanced intragastric PCO2: a tonometric study. Gut, 1994, 35, 737-741. [33] MAYNARDN., ATKINSON S., MASON R., SMITHIES M., BIHARI D. - - Influence of intravenous ranitidine on gastric intramucosal pH in critically ill patients. Grit. Care Med., 1994, 22, A79. [34] BAIGORRI F., CALVET X., DUARTE M., SAURA P., JUBERT P., ROYO C., JOSEPH D., ARTIGAS A. - - Effect of ranitidine treatment in gastric intramucosal pH determinations in critical patients. Intensive Care Med., 1994, 20, $2. [35] GREENFIELDA.D.M., WHITNEY R.J., MOWBRAY J. - - Methods for the investigation of peripheral blood flow. Br. Med. Bull., 1963, 19, 101-112. [36] GILL RW. - - Measurement of blood flow by ultrasound: accuracy and sources of error. Ultrasound Med. BioL, 1985, 11, 625-641. [37] LUNDE O.C., KVERNEBO K., LARSEN S. - - Evaluation of en. doscopic laser doppler flowmetry for measurement of human gastric blood flow. Scand. J. Gastroenterol, 1988, 23, 1072-1078.
References
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