Evaluation of the splanchnic circulation with indocyanine green pharmacokinetics in liver transplant patients

Evaluation of the Splanchnic CirculationWith Indocyanine G k e n Pharmacokinetics in Liver Transplant Patients

'

Claus U. Niemann, * C. Spencer Yost, * Susan Mandell, and Thomas K Henthorn' Although indocyanine green (ICG) can be used to estimate cardiac output (CO) and blood volume independently, a recirculatory multicomparunental ICG model enables description of theseand additionalintravascular factors. This model was used to describe the effect of end-stage liver disease (ESLD) on systemicand splanchnic hemodynamics in patients undergoing orthotopic liver transplantation. ICG disposition was determined during the dissection phasein six patients withESLD undergoing orthotopic liver transplantation andsix healthy adult living liver donors. M e r injecting ICG, plasma concentrations were obtained for approximately 10 to 12 minutes by noninvasive pulse dye densitometry. The recirculatory model characterizes three distinct intravascular circuits: lumped parallel fast (presumably nonsplanchnic circulation) and slow peripheral (splanchnic) circuits and acentral circuit(centralbloodvolume).Mean transit time ( M m ) in the fast peripheral circuit was not different in patients with ESLD and controls.However,ESLD resulted in a significant decrease in MTT in the central (0.11 k 0.028 [SDI v 0.24 k 0.094 minutes in controls; P < .001) and slowperipheralcircuit (0.67 & 0.41 v 1.37 2 0.37 minutes in controls; P < .001) because of increased flowsto the central and slow peripheral circuits. These findings are consistent with the described hyperdynamic systemic and splanchnic circulations in patients with ESLD. In conclusion, the ICG model is able to derive estimates of not only blood volume and CO, but also splanchnic hemodynamics under different physiological conditions. This model can be a useful toolto evaluate the effectofpharmacological manipulation ofsplanchnic hemodynamics. (Liver Transpl2002;8:476-481.)

From the "Department ofAnesthesia and Perioperative Care, University of California, San Francisco, CA; and the fDepartment ofAnesthesiology, University of Colorado Health Sciences Center, Denver, CO. Supported in partby grantsf i o m the Research Evaluation and Allocation Committee and the Academic Senate, University o f California, San Francisco. No reprints available. Addresscorrespondence to Clam U Niemann, MD, Dqartment of Anesthesia and Perioperative Care, Universityof Cal;fomh, San Francisco, 521 ParnassusAve, San Francisco, C4 94143-0648. Telephone: 415-5022 162; FAX: 415-476-951 6 E-mail.. [email protected]~edu Copyright 0 2002 by the American Association for the Study of Liver Diseases I527-6465/02/0805-0064$35.00/0 do;: IO.I053/jlt2002.33218

476

P

atients presenting for orthotopic liver transplantationin general have profound hemodynamic changes. Hyperdynamic circulation, characterizedby increased cardiacoutput (CO),decreased vascular resistance, mild tachycardia, and low to normal blood pressure, is seen commonly in patients with end-stage liver disease (ESLD). Although the hyperdynamic circulation appears to affect all vascular beds, the splanchnic circulation is of particular concern. Cirrhosis-induced increasedhepaticvascularresistance is viewed as an important factor for the development of portal hypertension. However, because pressureis dependent on the product of flow and resistance, a more dynamic view has emerged in which increased splanchnic blood flow itself can aggravate portal hypertension.2 Indocyanine green (ICG), awater-soluble tricarboncyanine, is irreversibly removedbyhepatocytes in a flow-dependent manner. Therefore, its elimination clearance (Cl,) can be used to estimate hepatic blood flow in humans.3 In addition, ICG is an intravascular marker because it binds to plasma proteins rapidly and completely, impeding its extravascular distribution. Thus, it can be usedto estimate both blood volumeand CO. The combined description of the monoexponential blood ICG concentration history and its first-pass and subsequent recirculatory peaks (the mixing phase) using a pharmacokineticmodel allows characterization of such intravascular factors as mixing by deriving estimates not only of blood volumeand CO, but also their systemic distribution (Fig. l).*-6 We hypothesized that therecirculatory pharmacokinetics of ICG would show significant differences between healthy patients undergoing hepatic dissection for right hepaticlobe donation versuspatients with ESLD undergoing similarsurgery as recipients, thus providing the basis of a potential clinical measure of splanchnic circulation.

Methods Experimental Protocol Institutional review board approvalwas obtained. All patients with ESLD caused by hepatitis C waiting for cadaveric liver transplantation were eligible to participate in this study. After writteninformedconsentwasobtained, six consecutive

Liver Transplantation, VoL 8, No 5 (May), 2002:pp 476-481

ICG MTTs inPatients UndergoingLiver Transplantation

DDG

Central Vein Injection

this study, only one dose of ICGwas administered to transplantrecipients.Afterapproximately IO to 12 minutes, recorded ICG concentrationsweredownloadedfromthe D D G analyzer to a personal computer (PC)-based laptop for further dataanalysis.

Physiological Measurements

VPC-F

I

477

CIPC-F VPC-S ClPC-S

Mean arterial blood pressure (MAP) was transduced from a radial arterial catheter, and central venous pressure (CVP), fromacentralcatheter. CO was obtainedusingthedyedilution method from data measuredby the D D G analyzer. This method has been validated for CO and blood volume measurements in recently publishedreports.7.8 Systemic vascular resistance (SVR) was calculated from the standard equation:

Figure 1. The model for recirculatory pharmacokinetics all CO and is of ICG.Thecentralcirculationreceives 'SVR = ( M A P - C V P / C O ) X 80 representedgenericallybyrectanglessurroundingfour compartments, although the actual numberof compartments neededto be varied. Beyond the central circulation, CO was determined at the moment of ICG injection. COdistributes to numerouscirculatorypathwaysthat Data Analysis lump, on the basis of blood volume to blood flow ratios ("ITS), into fast(equilibratingfastperipheralcircuit Arterial ICG concentration versus time data before evidence clearance [Cl,,-,] and volume v [-,)] and slow (equiliof recirculation (i.e., first-pass data) were weighted uniformly brating slow peripheral circuit clearance [Cl,,-,] and vol- and fit to the sum oftwo right-skewed gamma (Erlang) disume wPc-J) peripheral-blood circuits. ICG Cl, is modtribution functions using Tablecurve2 D (version 3.0; SPSS eled &om the slow peripheral compartment (splanchnic). Inc, Chicago, IL) on a Pentium-based PC (Inspiron 8000; Dell Computer Corp, Round Rock, TX). In subsequent phar-

macokinetic analysis, the description of the central circulation patients with hepatitis C were studied during the dissection was incorporated into an independent recirculatory model phase. using SAAM I1 (version 1.1; SAAM Institute, Seattle, WA) For comparison, we studiedsix consecutive healthy living implemented on a Pentium-based PC.539 First-pass data were liver donors during hepatic dissection. Induction and mainexcluded from further data fitting; results of the Erlang model tenance of anesthesia were similar in both groups, except of central circulation were placed as fixed parameters into the dopamine was administered at a low dose (3 pg/kg/min) to recirculatory model, thereby reducing the number of paramstimulate renal blood flow in the recipient group. eters to be optimized. In the recirculatory model, measured Donors were studied before resection of the right hepatic concentration values were weighted using relative reciprocal lobe. T o ensure similar conditions during all study periods, weighting, computed as the square of the reciprocal of the the following criteria had to be fulfilled. The study was not product of the fractional standard deviation (FSD) and the started until the study subjectwas determined to be hemodyobserved datum (y) with a scaling factor (v) estimated from namically stable. Thiswas defined as less than 20% variation the dataso the average weighted residual has a value of one for in heart rate and blood pressure over a 15-minute period. the data set with the FSD set to 0.5: Intravenous fluids were restricted before and during the study period to minimize intravascular volume changes. mi = v/(FSD X A noninvasive densitometer (DDG-2001; Nihon Kohden CO, Saitama, Japan) was used to measure arterial ICG conPharmacokinetic Model two light-emitcentrations in our study subjects. Probes with Central circulation (heart, lung, great vessels) was described ting diode infrared sources (wavelengths, 805 and 940 nm) by the sum of two Erlang frequency distribution functions. were placed on the external nares ofall study subjects. RealThose functions were added to lumpedparallel fast and slow time arterial ICG concentrationwas computed on a beat-byperipheral circuits or compartments and elimination clearbeat basis by reference to the previously determined blood ance by using SAAM I1 to describe a full recirculatory model.5 20 mg of ICG (IC hemoglobin concentration.7 Fifteen or A compartment can be defined as a space in which a substance Green; Akorn Inc, Buffalo Grove, IL) was injected through (e.g., ICG) is well mixed, kinetically homogeneous, and disthe central catheter into recipients or donors and immediately tinct from other compartments. Fast and slow peripheral cirflushed with normal saline, respectively. Because transplant cuits have identifiable volumes (V) and flows or intercompartrecipients were part of a larger ongoing study and may have mental clearances. I C G Cl, was assumed to occur from the been administered multiple doses of ICG, a smaller dose of I C G was chosen to avoid accumulation of ICG. However, forsplanchnic compartment. Mean transit times (MTTs) of var-

478

et

Niemann

ious circuits were calculatedas the ratio of V toC1 ( M T T = v/c1).5,10

Statistical Analysis

al

'"I

All data are presented as mean ? SD. For analysis between groups, unpaired data were compared using the two-tailed unpaired t-test. T h e criterion for rejectionof the null hypothesis was P less than .05. All calculations were performed using Primer of Statistics (version 4.0; McGraw-Hill, San Francisco, CA).

t

Results

0.1 1

All patients were United Network for Organ Sharing status IIb or 111. Three patients were Child-Pugh classification B; two patients, Child-Pugh classification A; and one patient, Child-Pugh classification C. All studl. ies wereperformed within8 months in 2000 and 200 The relationship between ICG blood concentration measured by DDG analyzer and time was well characterized by the model from the moment of injection (Figs. 2 and 3). Patients with ESLD had COSalmost double those estimated for healthy donors (12.18 t 2.91 v 7.01 L 0.54 L/min;P < .O l),whereas ICG Cl, was reduced by more than 50% (0.44 2 0.21 v 1.00 t 0.21 L/min; P < .OO l ;Tables 1 and 2).Greater CO was reflected in the smaller areaunder first-pass ICG concentration history (Fig. 2). Lower ICG Cl, was reflected in the flatter terminal slope of the ICG concentration versus time relationship (Fig. 3). Systemic vascular resistance and

7 10-

1-

0.1

0.2 0

0.4

0.6 0.8 Time (nin)

1.0

1.2

Figure 2. Arterial blood ICG concentration histories for the first minute (showing first- and second-pass peaks) after rapid venous injection in two subjects; one subject with ESLD (solid line, closed symbols) and one living donor(dashedline,opensymbols).Symbolsrepresent drug concentrations, whereas lines represent concentrations predicted by the models.

0

n

I

I

I

2

4

6

I

I

I

8 1 0 1 2

Tim (mn) Figure 3. Arterial blood ICG concentration histories for 10 to 12 minutes after rapid venous injection two in subjects; one subject with ESLD (solid line, closed symbols) and one living donor (dashed line, open symbols). Symbols represent drug concentrations, whereas lines represent concentrations predicted by the models.

MAP were significantly lower in patients with ESLD than living donors(439 5 163 v 1,020 t 202 P < .001; 69 t 6 v 83 t 10 mm Hg; dyne~.s.cm-~;

P < .05, respectively; Table 1). The division of total flow (CO) between intercompartmental clearances was not statistically different between patients with ESLD and living donors. Central, slow peripheral, and total distribution volumes ofICG were not statistically different between the two study groups.However, fast peripheral circuit volume was significantly greater in patients with ESLD than living donors (1.03 t 0.27 v 0.56 t 0.30 L; P < .05; Table 2). The shorter MTT of the central circuit in patients with ESLD (0.1 l L 0.03 v 0.24 L 0.09 minutes in donors; P < .05; Table 3) is proportional to the greater CO. The MTT of the fast peripheral circuit was similar in both groups (0.21 L 0.06 v 0.19 t 0.06 minutes; P > .05; Table 3) because the greater volume of this circuit in patients with ESLDwas matched by reciprocal changesin flow in this circuit (2.95 t 0.75 v 5.18 ? 1.76 L/min; P < .OS). Splanchnic MTT also was significantly shorter in transplant recipients (0.67 2 0.41 v 1.37 t 0.37 minutes; P < .001; Table 3), with clearance as the major factor, because slow peripheral circuit volumes werevirtually identical between groups.

Discussion Patients enrolledonourcontrolgroup (livingliver donors) were healthy, with no significant medical dis-

ICGin MTTs

Patients Undergoing

479

Liver Transplantation

T a b 1, S&jm

Living donors Liver transplant recipients

MAP*

SV*II H(bm u

Sn$§

Weight (kg)

HR* (beatdmin)

(mm Hg)

cot$ (dynes (Umin)

82 2 9

62 2 9

83 2 10

7.01 2 0.54

1,020 2 202

l 1 1 f- 17

12 2 0.9

87 2 22

83 2 16

69 2 6

12.18 2 2.91

439 2 163 147

2 21

10.4 2 2.6

* S *

(g/dL)

NOTE. Values expressedas mean 2 SD. Abbreviations: S W , systemic vascular resistance; SV, stroke volume; Hb, hemoglobin; HR, heart rate. *Significantly different betweenthe two groups, P < .05. ?Determined at the moment of marker injection. $Significantly different betweenthe two groups, P < .001. $Central venous pressure measured by central venous catheter. (IDetermined byC O divided by heart rate.

ease or physical impairment. CO and heart rate under general anesthesia were significantly lower in these (7.0 t 0.5 v 12.18 2 patients than in those with ESLD 2.9 L/min; 62 t 9 v 83 ? 16 beadmin, respectively). These circulatory parameters, as well as a lower systemic vascular resistance and MAP in transplant recipients (439 t 163 v 1,020 t 202 d y n e ~ ~ c m P - ~< ; .001; 69 t 6 v 83 ? 10 mm Hg; P < .05; Table l), are similar to previously published data.’ Lessis known about regional alteration in hemodynamics and whether changes in flow, for example, occur uniformly and are entirely proportional to changes in cardiac index in all vascular beds. To investigate potential changes in regional hemodynamics, we used a kinetic model to characterize the blood ICG concentration versus time curve from the moment of rapidintravenous injection. The model incorporates data from both the initial transient oscillations and later postmixing portions of curves to provide estimates of not only blood volume andCO, but

Clearances

(L)

VC Livingdonors Liver transplant recipients

also their distribution among central and two peripheral circuits. These parallel peripheral circulations are characterized by time constants that reflect (1) a lowcapacitance low-volume (fast) circuit and (2) a highcapacitance larger volume (slow) circuit and represent the nonsplanchnic and splanchniccirculations, respectively.12-14Despite awide range ofC o s between study groups, the regional blood A ow (intercompartmental clearance) to different peripheral circuits remained remarkably proportional (Table 1). There was a trend to a greater proportion of total flow to theslow peripheral circuit in patients with ESLD, butit did not reach statistical significance. ICG elimination clearance has been used extensively as an index of liver function.l5-” As expected, on our study, ICG clearance was significantly reducedin patients with ESLD in comparison to living donors (Table 2). However, it is important to note that the hepatic extractionratio of ICG can varyin patients with advanced liver disease because of intrahepatic shunts,

Volumes VPC-F*

(L/min)

v,,-,

1.47 2 0.64 0.56 2 0.30 4.00 2 0.616.05

vs, 2 0.832.95

CIPC-F* Cl,$

2 0.753.04

ClPC-St 2 0.651.00

CClt 2 0.217.01

2 0.54

1.22 2 0.28 1.03 2 0.27 3.77 2 0.75 6.05 2 0.37 5.18 2 1.76 6.55 2 2.41 0.44 2 0.21 12.18 2 2.91

NOTE. Values expressedas mean 2 SD. Abbreviations: V,, central circuit volume; VPC-F, fast peripheral circuit volume; VPc-,, slow peripheral circuit volume;V,,, distribution volume at steadystate (the sumof allvolumes);(fast)equilibratingperipheralcircuitclearance; Cl,,_,, (slow)equilibrating peripheral circuit clearance;Cl,, elimination clearance; X I , ICG (dye dilution) C O determined at the moment of marker injection(the sum of all clearances). *Significantly different betweenthe two groups, P < .05. tsignificantly different between the two groups, P < .01. $Significantly different betweenthe two groups, P < .001.

480

et

Table 3.

Niemann

for Compments of the Recirculatory ICG Pharmacokinetic Mod&

"ITS

(min)

MTTpc., MTTpc.,' (min)

(min)

Living liver donors 0.24 2 0.09 0.19 2 0.06 1.37 0.37 Liver transplant recipients 0.1 1 2 0.03 0.21 0.06 0.67 2 0.41

*

*

NOTE. Values expressed as mean 2 SD. Abbreviations: MTT,, central circuit MTT; MTTPC-F,fast peripheral circuit MTT; MTT,,-,, slow peripheral circuit MTT. *Significantly different betweenthe two groups, P < 0.05. 'Significantly different between the two groups, P < 0.00 1.

capillarization, and reduction in membranepermeability and surface area.20 Consequently, interpretation of hepatic ICG Cl,, particularly in patients with liver disease, isdifficult without knowing theextraction ratio of ICG in each patient. Because we did not measure the hepatic extraction ratio in our transplant recipients, ICG clearance as a surrogatefor hepatocellular function should be interpreted with caution in patients with ESLD.Nevertheless, ICG clearance in living liver donors is similar to previous published results.6 Volumes ofthe different circuits, with theexception of the fast peripheral compartment, were not statistically significantly different between donors and recipients. Whether central blood volume is increased or decreased in cirrhosis is a subject of controversy. The trend, which might have becomestatisticallysignificant with a larger number of subjects, of lower central blood volumes in our patients with ESLD is consistent with findings of some previous studies.21,22 However, other investigators have found increased central blood volume in patients with cirrh0sis.~3 The close agreement of volumes in theslow peripheral circuit between patients with ESLD and controls (4.00t 0.61 v 3.77 t 0.75 L in ESLD) may be explained by recruitment or increased vasodilatation of splanchnic conduction vessels in the ESLD population.These effects would offset the diminished capacity of the liver as a blood reservoir because of fibrosis. Similarly, the statistically significant increased volume in fastperipheral circuits (1.03 2 0.27 v 0.56 t 0.3 L; P < .OS) may be explained by generalized increased arterial and venous vascular compliance caused by vasodilatation.24-26 The kinetics of ICG in a givencompartment is influenced by its size (volume) and flow (clearance). Hence, kinetically distinct compartmentscan be best described

al

by blood volume to blood flow ratios (V/CL), which defines MTTs through given circuits (MTTs).4,5,27 This parameter allows more rigorous examination of compartmental kinetics than clearance or volume measurements alone and affords a more complete description of the kinetic behavior ofcircuits. Although increased hepatic resistance initially may be responsible for the development of portal hypertension, subsequent splanchnic vasodilatationaccompaniedbyincreasedportalbloodflowworsensportal hypertension and appears to be especially important in advancedstages.2 Thisdynamic viewsuggestswhy pharmacological manipulation ameliorates detrimental effects of portal hypertension. In thecase of splanchnic circulation, decreased blood flow to this vascular bed canbe produced byusingnonselectiveP-blockers, vasopressin and its analogues, or somatostatin and its analogues. However, determining a beneficial effect of decreasedbloodflowproves difficult. In aselected patient population, nonselective P-blockers have decreased the incidence of recurrent upper gastrointestinal bleeding.2*,29However, this clinical endpoint provides no direct information withregard to splanchnic circulation. Similarly, somatostatin or its analogues are used perioperatively to decrease surgical blood loss and attenuate reperfusion injury to the liver, which is believed to be caused in part by excessive splanchnic blood flow. Again, no clear measure of the efficacy of this treatment is currently available.30 Patients undergoing liver transplantation had significantly shorter MTTs in central and slow peripheral circuits than healthy controls (0.11 t 0.03 v 0.24 t 0.09 minutes; P < .05; 0.67 t 0.41 v 1.37 t 0.37 minutes; P < .OO 1, respectively). Of note, the relative largeSD in the slow peripheral compartment in patients withESLD is caused entirely byone outlying patient. MTTs were cluspatient who was tered around0.5 minutes, except for one under strong beta-blockade (heart rate, 52 beats/min; CO, 6.95 L/min) and had an estimatedMTT of 1.5 minutes. The change in MTTs in this patient was caused entirely by decreased systemic flowand is consistent with previously documentedalterations in healthyvolunteersunder P-blockade.6 Of further interest, MTTs of the slow compartment (splanchnic circulation) do not overlap between living liver donors andpatients with ESLD (data not shown). Although the robustness and sensitivity of the ICG recirculatory model needs to be investigated further, this model may allow longitudinal assessment of the severity of splanchnic pathophysiological states in patients with ESLD before liver transplantation. Because of the small size of this study, a correlation between disease severity

ICGin MTTs

Patients UndergoingLiver Transplantation

481

rine on pressure, flow, and volume relationships in the systemic (e.g., Child-Pugh classification) and MTTs has not been circulation of dogs.Circ Res 1974;34:606-623. attempted. Nevertheless, determination of MTTs may 14. Green JF, Jackman AP, ParsonsG. The effects of morphineon provide an excellent measure for evaluation of such pharthe mechanical propertiesof the systemic circulationin the dog. macological interventionas octreotide forthe treatment of Circ Res 1978;42:474-478. portal hypertension.30 15. Tsubono T, Todo S, Jabbour N, Mizoe A, Warty V, Demetris AJ, Starzl TE. Indocyanine green elimination test in orthotopic In conclusion, we show that a recirculatory pharmacoliver recipients. Hepatology 1996;24:1165-1171. ICG is able to characterize hyperdynamic kinetic model of 16. Igea J, Nuno J, Lopez-Hervas P, Quijano Y, Honrubia A, Candela circulation in patients withESLD. Because the methodof as a marker of graft function in A, etal. Indocyanine green clearance this kinetic analysis is relatively noninvasive, it may be used liver transplantation. Transplant Proc 1999;3 1 :2447-2448. serially in patients withESLD to assess both progression of 17. Plevris JN, Jalan R, BzeiziKI, Dollinger MM, Lee A, GardenOJ, HayesPC.Indocyaninegreenclearancereflectsreperfusion disease and therapeutic interventions.

Acknowledgment

18.

The DDG analyzer ison loan from Nihon Kohden Corporation. 19.

References

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