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The Bradykinin Response and EarlyHypotension at the Introduction of

Continuous Renal Replacement Therapyin the Intensive Care Unit

J. Stoves, N.P. Goode, R. Visvanathan, C.H. Jones,M. Shires, E.J. Will, and A.M. Davison,

Department of Renal Medicine, St. James’sUniversity Hospital, Leeds, United Kingdom

Abstract: We assessed the relationship of certain clinicalvariables (including bradykinin [BK] release and dialysismembrane) to initial mean arterial pressure (MAP) reduc-tion in 47 patients requiring continuous renal replacementtherapy (CRRT) in an intensive care unit. The pretreat-ment MAP was 84 ± 14 mm Hg for the group as a whole.The initial MAP reduction was 11.5 (7–20) mm Hg, occur-ring 4 to 8 min after connection. MAP reduction was 9(6–15) mm Hg with polyacryonitrile (PAN) membranesversus 14 (5-19) mm Hg with polysulfone (PS) (not signifi-cant). There were positive correlations between MAP re-duction and BK concentration at 3 (BK3; r � 0.58, p <0.01) and 6 (BK6; r � 0.67, p < 0.001) min with PAN butnot with PS. A greater reduction in MAP was seen inpatients who were not receiving inotropic support (Mann-Whitney test, p < 0.01). BK3 and BK6 values for the PANand PS groups were not significantly different. However,BK concentrations greater than 1,000 pg/ml were onlyseen with PAN (6 patients, MAP reduction 27 [17–31] mmHg). There were positive (albumin) and negative (age;acute physiology, age, and chronic health evaluationscore; C-reactive protein [CRP]; calcium) correlationswith BK3/BK6 in the PAN and PS groups, some of which(albumin, CRP) reached statistical significance. In sum-mary, MAP reduction at the start of CRRT correlates withBK concentration. The similarity of response with PANand PS suggests an importance for other clinical factors. Inthis study, hemodynamic instability was more likely in pa-tients with evidence of a less severe inflammatory or sep-tic illness. Key Words: Bradykinin activation—Hemo-dynamic instability—Mean arterial pressure—Continuousrenal replacement therapy—Inotropes—Intensive care unit.

Hemodynamic instability may occur at the start ofcontinuous renal replacement therapy (CRRT) in

acutely ill patients. This is particularly important inpatients with intracranial hypertension (as seen inacute hepatic encephalopathy), where cerebral per-fusion may become critically reduced (1). Transienthypotension may provoke otherwise unnecessarymeasures such as the infusion of intravenous fluidsand increased doses of inotropic and vasoconstrictormedications.

Previous work has shown that the vasoactive pep-tide bradykinin (BK) contributes to a reduction incardiac output and peripheral vascular resistance inseptic shock (2,3). Blood contact with negativelycharged polyacrylonitrile (PAN) membranes is alsoknown to stimulate BK release via the “contact sys-tem” (Factor XII, prekallikrein, and high molecularweight kininogen) (4). This is of obvious relevance tothe possible systemic effects of extracorporeal dialy-sis circuits. In this setting BK release is thought to beinfluenced by factors such as plasma dilution (as oc-curs during blood priming of the extracorporeal cir-cuit) and pH of dialysate and rinsing solutions (5).Indeed, recent work has suggested that alkaline rins-ing solutions are effective in preventing hypersensi-tivity reactions during chronic hemodialysis (6).

The clinical significance of early BK release incritically ill patients requiring hemodialysis supporthas been approached indirectly in a previous studythat examined the effects of PAN and polysulphone(PS) dialysis membranes on hemodynamic responseduring the initiation of CRRT (7). Although hypo-tension was more likely to occur with use of a PANmembrane, a significant reduction in blood pressurewas seen frequently in both groups. This suggestedthat factors other than BK release influence hemo-dynamic response. We have sought to identify thesefactors in a prospective study of criticaly ill patientscommencing CRRT in the intensive care unit (ICU).

Patients and methodsAll patients requiring continuous renal support in

our ICU were considered eligible for the study, butanalyses were performed only in patients for whomthere was an opportunity to prepare a BK inhibitorcocktail (aprotonin 10,000 KIU/ml, soya bean tryp-sin inhibitor 800 �g/ml, polybrene 4 mg/ml, phenan-throline 10 mg/ml, EDTA 20 mg/ml) immediately

Received August 2000; revised March 2001.Address correspondence and reprint requests to Dr. J. Stoves,

Department of Renal Medicine, St. James’s University Hospital,Beckett Street, Leeds LS9 7TF, United Kingdom.

Artificial Organs25(12):1009–1021, Blackwell Science, Inc.© 2001 International Society for Artificial Organs

1009

prior to the initiation of CRRT. Patients were en-rolled between March 1998 and June 1999. A singlestudy was performed in each case.

During the initial phase of the study (13 patients),the continuous venovenous hemodialysis systemused consisted of a single Gambro (Lund, Sweden)blood pump, 2 mechanically linked dialysate pumps,and a single IMED pump (IVAC, Abingdon, U.K.)to control ultrafiltration rate (8). This was subse-quently replaced by a venovenous hemodiafiltrationsystem (HYGEIA, Kimal, Middlesex, U.K., 34 pa-tients). Monosol S (Baxter, Norfolk, U.K.) with lac-tate buffer was used as dialysate, except in cases ofhyperlactatemia where bicarbonate dialysate (Hae-mosol, Ivex, Belfast, U.K.) was appropriate (9). Anextracorporeal blood flow of 150 ml/min was pre-scribed in all cases.

Patients were randomized to either polyacryloni-trile (PAN [AN69]; Hospal, Meyzieu, France, sur-face area 0.9 m2, Kuf 26 ml/h/mm Hg, blood-sidepriming volume 69 ml) or polysulphone (PS [F40];Fresenius, St. Wendel, Germany, surface area 0.7 m2,Kuf 20 ml/h/mm Hg, blood-side priming volume 44ml) filters. Individual patients were dialyzed usingthe same type of filter throughout their continuoustreatment. The dialyzers were rinsed with 2 L of hep-arinized saline (1,000 IU/L) prior to use.

In all cases, the extracorporeal circuit (total vol-ume approximately 150 ml) was allowed to fill withblood prior to connecting the return line to the di-alysis access (dual lumen catheter), a process thatlasted no longer than 3 min. Blood pressure wasmonitored continuously using an arterial line. Bloodsamples (0.9 ml) were taken from this line at t0 (asthe blood pump was switched on) and then from thereturn line of the extracorporeal circuit (proximal tothe substitution fluid connection) at 3 min intervalsfor a period of 12 min (t3, t6, t9, and t12). The dial-ysate and ultrafiltration pumps were not started untilall samples had been collected. Samples were trans-ferred to ice-cooled tubes containing 100 �l of in-hibitor cocktail. In cases where anticoagulation withprostacyclin rather than heparin was indicated, theprostacyclin infusion was withheld until monitoringhad been completed. Changes to the rate of admin-istration of intravenous fluids and inotropic agentswere not made unless clinically indicated. Bloodsamples were centrifuged at 1,500 rpm for 5 min at4°C (Mistral 3000I, Sanyo Gallenkamp, Leicester,U.K.). Separated plasma (200 �l) was added to 800�l of ice-cold ethanol and then allowed to stand for15 min at 4°C before centrifugation at 2,500 rpm for5 min. The supernatant was collected and evapo-rated to dryness under a stream of air. The dried

residue was redissolved in 500 �l 66% acetone/waterand washed with 1 ml of petroleum ether. The su-pernatant (ether) was discarded after 5 min at 20°C,and the residual layer (acetone) was again evapo-rated to dryness. This was rehydrated with 200 �l ofassay buffer prior to analysis (10). A competitiveBK-ELISA was performed in triplicate using a highsensitivity enzyme immunoassay (EIA) kit (EIAH-7051, Peninsula Laboratories Europe, St. Helens,U.K.). The interassay reproducibility of the methodwas evaluated routinely at concentrations of 130 and500 pg/ml. The coefficients of variation were 12.4and 19.3%, respectively.

The following patient variables were recorded;age; gender; clinical diagnosis; acute physiology, age,and chronic health evaluation (APACHE) II scoreat admission to ICU; arterial pH prior to treatment;dialysate buffer (bicarbonate, lactate); time since ad-mission to ICU; number of previous dialysis sessions;preconnection inotrope requirements; and bloodmeasurements including albumin, calcium, lactate,bicarbonate, and C-reactive protein (CRP).

Statistical analysis involved tests of correlation forcontinuous variables and Mann-Whitney tests forgrouped data. A p value of <0.05 was taken to rep-resent statistical significance.

TABLE 1. Patient demographics (n = 47)

Age (years) (median + interquartile range) 62 (49–69)Gender

Male 31Female 16

Primary diagnosis (n)Sepsis 16Postsurgical 10Postliver transplant 7Acute hepatic failure 5Trauma 3Others 6

APACHE II score on admission to ICU(median + interquartile range)

29 (24–35)

APACHE: Acute physiology, age, and chronic health evalua-tion, ICU: intensive care unit.

TABLE 2. Data recorded at the start of CRRT (n = 47)

MAP0 (mm Hg) (mean ± SD) 84 ± 14Inotropes (%) 46Membrane type (n)

PAN 22PS 25

Lactate buffer (%) 94Arterial pH (mean ± SD) 7.33 ± 0.12Arterial bicarbonate (mmol/L) (mean ± SD) 19.6 ± 4.5CRP (mg/L) (mean ± SD) 159 ± 91Plasma albumin (g/L) (mean ± SD) 25 ± 6.8Plasma calcium (mmol/L) (mean ± SD) 2.35 ± 0.17

CRRT: continuous renal replacement therapy, MAP: mean ar-terial pressure, PAN: polyacrylonitrile, PS: polysulfone, CRP: C-reactive protein.

THOUGHTS AND PROGRESS1010

Artif Organs, Vol. 25, No. 12, 2001

ResultsA total of 47 patients requiring continuous

therapy were studied. The demography of these pa-tients is shown in Table 1. Data recorded prior to theintroduction of continuous therapy are summarizedin Table 2. No patients were receiving ACE inhibitormedication.

For the study group as a whole, the mean arterialpressure at time zero (MAP 0) was 83.3 ± 14.3 mmHg. The median maximal reduction in MAP was 11.5(7–20) mm Hg, occurring between 4 and 8 min afterpatient connection to the extracorporeal circuit. Me-dian MAP reduction was 9 (6–15) mm Hg with PANmembranes versus 14 (5–19) mm Hg with PS (notsignificant [NS]).

There was a significant, positive correlation be-tween reduction in MAP and BK concentrations at 3(BK3, r � 0.58, p < 0.01) and 6 (BK6, r � 0.67, p <0.001) min after patient connection with PAN butnot with PS. BK6 values for PAN and PS are plotted

on a logarithmic scale in Fig. 1. A greater reductionin blood pressure was seen in patients who were notreceiving inotropic support (Mann-Whitney test, p <0.01). None of the other variables that were consid-ered showed a statistically significant correlationwith hemodynamic response (Table 3). We foundthat peak BK concentrations were significantlyhigher with hemodiafiltration treatment comparedto hemodialysis (125 [76–320] versus 68 [0–-119], p <0.01) but BK0 concentrations were also higher inpatients receiving hemodiafiltration (p < 0.05).These apparent differences may be attributable tothe relatively small size of the hemodialysis groupalthough similar observations have been reported byother workers (11).

BK response was most marked when CRRT wasperformed using PAN membranes, but BK release

TABLE 3. Whole group analysis of recorded variables according to reduction in MAP

VariableCorrelation

(r) (p)Mann-Whitney

test (p)

Bradykinin (BK3) PAN only 0.58 (Spearman) <0.01Bradykinin (BK6) PAN only 0.67 (Spearman) <0.001Bradykinin (BK3) PS only −0.19 (Spearman) NSBradykinin (BK6) PS only −0.01 (Spearman) NSAge 0.06 NSAPACHE II 0.15 NSArterial pH −0.20 NSTime since ICU admission −0.20 NSTime since initiation of CRRT −0.26 NSNo. of previous CRRT sessions −0.14 NSCRP 0.08 NSAlbumin 0.10 NSCalcium −0.05 NSInotropes <0.01Membrane (PAN versus PS) NSGender NS

MAP: mean arterial pressure, PAN: polyacrylonitrile, PS: polysulfone, APACHE: acute physiology,age, and chronic health evaluation, ICU: intensive care unit, CRRT: continuous renal replacementtherapy, CRP: C-reactive protein.

FIG. 1. The graph shows BK concentration at 6 min (BK6) andMAP reduction (whole group).

FIG. 2. Shown are BK profiles for individual patients (PAN mem-branes, P1–P22).

THOUGHTS AND PROGRESS 1011


varied considerably in magnitude between individu-als (Fig. 2). The median BK concentrations at 3 and6 minutes for the PAN and PS groups were not sig-nificantly different (e.g.. a median BK6 of 94 [33–310] with PAN compared to 60 [30–120] pg/ml withPS). However, peak BK measurements in excess of1,000 pg/ml were only seen with PAN (Table 4). Themedian reduction of MAP in this subgroup was 26(17–31) mm Hg. This was not statistically significantin view of the small number of patients. Four of the6 patients were not receiving inotropes compared to16 out of the other 41 study patients (p � NS).

One of the patients with marked BK release hadprimary nonfunction of a cadaveric renal transplant(MAP reduction 13 mm Hg). There were 3 otherpatients with chronic renal failure in the study popu-lation (2 PAN and 1 PS) in whom MAP reductionsof 5, 14, and 18 mm Hg were seen with peak BKconcentrations of less than 200 pg/ml.

Data from the PAN and PS groups were analyzedseparately to assess the relationship of different vari-ables to BK release. Positive (serum albumin: PAN p< 0.01, PS p � 0.02) and negative (CRP: PAN p <0.05) correlations with BK release were apparent(Table 5).

DiscussionThe intention of this study was to investigate in

critically ill patients the link between hemodynamicchanges at the start of CRRT and clinical variablesincluding BK release. Our interest in the latter phe-nomenon stems from previous reports concerningthe vasoactive properties of BK and its release in thechronic hemodialysis setting (4,5,7). A positive andsignificant correlation between reduction of bloodpressure and plasma BK at 3 and 6 min after patientconnection to an extracorporeal dialysis circuit wasfound with PAN membranes (r � 0.58, p < 0.001[BK3] and r � 0.67, p < 0.01 [BK6]) but not with PS.The nadir of blood pressure occurred between 4 and8 min after initial patient connection (consistent withour previously reported work), suggesting that thevolume effect of blood priming the extracorporealcircuit (completed within 3 min) contributed little tothe overall response. As with previous studies, majorBK release (>1,000 pg/ml) was seen only with use ofa PAN membrane and was associated with a greaterreduction in MAP.

The degree of correlation between reduction ofMAP and plasma BK with PAN is convincing, butthe importance of other clinical factors is apparentfrom the finding that MAP reduction was not signifi-cantly different between the PAN and PS groups.There was a tendency for patients who did not re-quire inotropes to have a more substantial reductionin blood pressure (An understanding of the mecha-nism by which inotropes exert a protective effect,other than through alteration of cardiac output andvascular tone, was beyond the scope of this study.). Itseems probable that hypotension was mediated bythe release of other (unmeasured) vasoactive pep-tides, especially in cases where a PS dialysis mem-brane was used.

TABLE 4. Bradykinin response according to diagnosticgrouping (PAN membranes)

Diagnosticcategory

Patients withpeak bradykinin>1,000 pg/ml (n)

Patients withpeak bradykinin<1,000 pg/ml (n)

Liver transplant 1 2Acute liver failure 1 2Postsurgical 4Sepsis 2 4Trauma 2Other 2 2

PAN: polyacrylonitrile.

TABLE 5. Correlation of recorded variables with bradykinin response

Variable

Bradykinin at 3 min(BK3) PAN only

Bradykinin at 6 min(BK6) PAN only

r p r p

Age −0.22 NS −0.08 NSAPACHE II −0.17 NS −0.01 NSCRP −0.48 <0.05 −0.37 NSAlbumin 0.62 <0.01 0.50 0.02Calcium −0.23 NS −0.02 NSpH 0.01 NS −0.20 NSTime since ICU admission −0.04 NS −0.14 NSTime since initiation of CRRT 0.01 NS −0.12 NSNo. of previous CRRT sessions −0.10 NS −0.21 NSMann Whitney

Inotropes NS NSGender NS NS

PAN: polyacrylontrile, APACHE: acute physiology, age, and chronic health evaluation, C-reactiveprotein, ICU: intensive care unit, CRRT: continuous renal replacement therapy.

THOUGHTS AND PROGRESS1012


Why did BK activation occur in only a minority ofpatients who were dialyzed with a PAN membrane?First, intraindividual variability of BK response to adefined stimulus is well recognized even in stablepatients (11). Second, BK production may be dimin-ished in some patients as a consequence of preestab-lished immune activation, which would depend onthe severity, type, and duration of illness as well ason premorbid factors. We found significant positive(albumin) and negative (CRP) correlations of cer-tain variables with peak BK measurements thatwould not contradict this hypothesis. Other reasonsfor interindividual variability might include patientmetabolic heterogeneity (affecting the rate of BKgeneration and degradation), variation in the mem-brane adsorptive capacity for BK, differences in pro-tein binding of BK, and the known variability ofsampling and measurement (11).

In summary, blood pressure reduction at the startof CRRT in critically ill patients can be associatedwith an acute surge in circulating BK, apparentlystimulated by blood contact with a PAN membrane.However, the similarity of circulatory response withPAN and PS suggests an importance for other fac-tors. In this study, hemodynamic instability wasmore likely in patients with a less severe inflamma-tory/septic illness. Further studies are necessary tomeasure other vasoactive peptides (such as nitric ox-ide), which may give further insight into these earlyhemodynamic responses. The utility of nitric oxide–binding dithiocarbamate compounds in preventingintradialytic hypotension is currently being exam-ined (12). On this evidence, blockade of the kal-likrein system would not be expected to eliminatethe early hypotension of CRRT.

Acknowledgments: We are indebted to the YorkshireKidney Research Fund for their sponsorship of the study.We also thank Mrs. D. Crellin for her valuable contribu-tion to the laboratory measurement of bradykinin concen-trations.

References1. Davenport A, Will EJ, Davison AM. Efffective renal replace-

ment therapy inpatients with combined acute renal and ful-minant hepatic failure. Kidney Int 1993;43(Suppl.):S245–51.

2. McCann R, Wasserman F, Haberland G. The kallikrein-kininsystem in the acutely-ill: (A) changes in plasma kininogen inacutely-ill patients. (B) the efficacy of pulmonary clearance ofbradykinin. Adv Exp Med Biol 1983;156(Pt. B):1019–35.

3. Martinez-Brotons F, Oncins JR, Mestres J, Amargos V, Rey-naldo C. Plasma kallikreinkinin system in patients with un-complicated sepsis and septic shock. Thromb Haemost 1987;58:709–13.

4. Schulman G, Hakim R, Arias R, Silverberg M, Kaplan AP,Arbeit L. Bradykinin generation by dialysis membranes: Pos-sible role in anaphylactoid reactions. J Am Soc Nephrol 1993;3:1563–9.

5. Renaux JL, Thomas M, Crost T, Loughrieb N, Vantard G.Activation of the kallikrein-kinin system in haemodialysis:

Role of membrane electronegativity, blood dilution and pH.Kidney Int 1999;55:1097–1103.

6. Amore A, Guarnieri G, Atti M, Schena FP, Coppo R. Use ofalkaline rinsing solution to prevent hypersensitivity reactionsduring hemodialysis: Data from a multicentre retrospectiveanalysis. J Nephrol 1999;12:383–9.

7. Jones CH, Goutcher E, Newstead CG, Will EJ, Dean SG,Davison AM. Hemodynamics and survival of patients withacute renal failure treated by continuous dialysis with twosynthetic membranes. Artif Organs 1998;22:638–43.

8. Dyson EH, Johnston P, Prabhu P, Goutcher E, Davison AM,Will EJ. Volumetric control of continuous haemodialysis inmultiorgan failure. Artif Organs 1991;15:439–42.

9. Hilton PJ, Taylor J, Forni LG, Treacher DF. Bicarbonate-based haemofiltration in the management of acute renal fail-ure with lactic acidosis. Q J Med 1998;91:279–83.

10. Verresen L, Fink E, Lemke H-D, Vanrenterghem Y. Brady-kinin is a mediator of anaphylactoid reactions during haemo-dialysis with AN69 membranes. Kidney Int 1994;45:1497–1503.

11. Van der Niepen P, Sennesael JJ, Verbeelen DL. Kinin kinet-ics during different dialysis protocols with AN69 dialyser inACEI-treated patients. Nephrol Dial Transplant 1995;10:1689–95.

12. Orida NK, Lai CS. Nitric oxide and the renal patient. DialTransplant 2000;29:174–86.

Errors Involved in the Application of anImperfect Peritoneal Volume Marker

*Andrzej Werynski, *Jacek Waniewski,†Maria Marciniak, ‡Daniel Baczynski, and

‡Zofia Wankowicz *Institute of Biocybernetics andBiomedical Engineering; †Military Institute of

Hygiene and Epidemiology; and ‡Department ofNephrology, Postgraduate Military Medical Center,

Warsaw, Poland

Abstract: Peritoneal volume markers have been used innumerous studies on fluid transport in peritoneal dialysis.The basic assumption used was that the macromolecularmarker was stable and that the free fraction of a label(usually radiolabel) was negligibly small. In this study arepresented theoretical investigations on the errors involvedin application of an imperfect volume marker containingfree fraction of a label. These investigations were used inassessing the errors in calculation of peritoneal volumetime course, V, and fluid absorption rate (estimated byvolume marker clearance, kE) using data from 20 clinicaldwell studies with 1.36% Dianeal dialysis solution and ra-dioiodinated human serum albumin as a volume marker. Ithas been shown that with an in vitro measured 125I freefraction of 2.72%, the error of kE estimation was 11%.However, the maximal error in estimation of V was only0.2%. In conclusion, the performed analysis implies thatcalculation of the peritoneal volume time course duringthe dwell (with correction for the volume marker elimina-tion) is very reliable, and the existence of a free fractionof a volume marker label results in a negligibly smallerror. However, even small free fraction of the label re-sults in a significant overestimation of the fluid absorptionrate. Key Words: Kinetic modeling—Peritoneal dialy-sis—Volume marker—Fluid transport—Peritoneal vol-ume.

ERRORS IN PERITONEAL VOLUME CALCULATION 1013


It has been shown that implementation of a vol-ume marker can serve 2 purposes: estimation of fluidabsorption rate and estimation of a peritoneal vol-ume with correction for a volume marker (clear-ance) kE (1,2).

In these estimations it has been assumed that thevolume marker is stable. However, even the moststable labeled macromolecules such as iodinated al-bumin exhibit small free fraction of a radioisotope(iodine). Another experimental volume marker,technetium labeled albumin (99mTc-HSA), hasshown about 20% breakdown in glucose-based peri-toneal dialysis solution as well as in alternative so-lutions (3).

The purpose of this study was to investigate theo-retically the effect of an imperfect volume marker onthe accuracy of estimation of fluid absorption rateand peritoneal volume.

KINETIC MODEL OF AN IMPERFECTVOLUME MARKER TRANSPORT

The volume marker is a high molecular weightsubstance (usually albumin) bound (labeled) with alow molecular easily detectable compound-label(fluorescent dye or radioisotope). The solution of avolume marker purchased from the manufacturercontains, however, a small fraction (less than 5%)of a free label. A good marker should exhibit astable binding with a label. The bound breaks down,however slowly, producing a free label. It seems rea-sonable to assume that the breakage is a stochasticprocess with the rate proportional (coefficient ofproportionality �) to the mass of the bound label.With this assumption, the mass balance equations fora bound label, of concentration CZ, as well as for afree label, of concentration CF, in the peritoneal cav-ity are as follows:

d�VCZ�

dt= −kZCZ − �VCZ (1a)

d�VCF�

dt= −kFCF + �VCZ (1b)

where V is a peritoneal volume variable in time andkZ and kF are elimination coefficients (clearances) ofbound and free label, respectively. The high molecu-lar weight volume marker is removed from the peri-toneal cavity by a fluid absorption (diffusive trans-port is negligible), and the clearance of a bound label,

kZ, can be used as an estimation of fluid absorptionrate.

If concentration of a bound label could be mea-sured, then only Eq. 1a should be considered. How-ever, in practice the measured quantity is activity(radioactivity in the case of radiolabel) that is pro-portional to the total concentration of a label, C �CZ + CF.

The mass balance equation for the total amount ofa label is a sum of Eqs. 1a and 1b:

d�VC�

dt= −kZCZ − kFCF (2)

EVALUATION OF THE FLUID ABSORPTIONRATE, QA, ESTIMATED BY kZ

Putting CZ � C − CF and integrating Eq. 2 for thedialysis duration time T, one gets

kZ =V�0�C�0� − V�T�C�T�

�0

TC dt

− �kF − kZ��0

TCF dt

�0

TC dt

(3)The value calculated using measured data, usuallyused as an estimation of QA with assumption of aperfect marker (C � CZ), is kE (1,2):

kE =V�0�C�0� − V�T�C�T�

�0

TC dt

(4)

Using Eq. 4 in Eq. 3, one can express kZ as

kZ =1

�0

TCZdt

�kE �0

TC dt − kF �0

TCF dtF�

(5)From Eq. 5, it follows that if C = CZ (CF � 0), kZ

= kE.

ESTIMATION OF THE PERITONEALVOLUME, V

Integrating Eq. 2 for a particular dialysis time t,putting CZ = C − CF, and using Eqs. 3 and 4, one gets

V�t� =V�0�C�0�

C�t�− kE

�0

tC d�

C�t�−

kF − kZ

C�t�

��0

tCF d� −

�0

TCF dt

�0

TC dt

�0

tC d�� (6)

For a perfect volume marker, C � CZ (CF � 0), theterm containing kZ and kF in Eq. 6 is equal to zero.Equation 6 represents an expression for calculationof peritoneal volume, V, in which the first 2 terms onthe right hand are used in case of a perfect volume

Received May 2000; revised April 2001.Address correspondence and reprint requests to Dr. Andrzej

Werynski, Institute of Biocybernetics and Biomedical Engi-neering PAS, ul. Ks. Trojdena 4, 02-109 Warsaw, Poland. E-mail:[email protected]

A. WERYNSKI ET AL.1014


marker. The term containing kZ and kF, which isequal to zero at the beginning and at the end of thedwell, should be applied for correction involved inthe use of an imperfect volume marker.

SIMPLIFIED ANALYSIS OF ERRORSINVOLVED IN ESTIMATION OF

PERITONEAL VOLUME, V, AND VOLUMEMARKER ELIMINATION RATE

COEFFICIENT, kE

During preparation of a labeled macromolecularsubstance, some of the label remains free (usuallyless than 5%). Also, during storage and during ex-periments, there is a cleavage of a label from themacromolecules. The rate of a cleavage is describedin Eqs. 1a and 1b by a term �VCZ. In the following,the cleavage during experiments is regarded as neg-ligible (� ≅ 0), and only the impact of a free label inthe infused dialysis fluid on the estimation of V andkE is considered. This assumption is supported bythe fact that a commonly used volume marker, ra-dioiodinated serum albumin (RISA), is stable inphysiological fluids (4). Furthermore, in our own ex-periments, we did not detect any cleavage of iodinefrom RISA. To further simplify the analysis, it isassumed that d(VCF)/dt ≅ VdCF/dt and d(VCZ)/dt ≅VdCZ/dt where V is the average peritoneal volumeduring the dwell. These simplifications are justifiedby rather small changes of peritoneal volume duringdialysis. With these assumptions, the solutions ofEqs. 1a and 1b yield

CF = CF�0�e−kF

Vt, CZ = CZ�0�e−

kZ

Vt

denoting

e−

kF

VT

= A e−

kF

Vt= �

e−

kZ

VT

= B e−

kZ

Vt= �

from Eq. 5

kZ =kE

1 +CF�0�

CZ�0��1 −kE

kF� 1 − A

1 − B

(7)

and from Eq. 6

V�t� =V�0�C�0�

C�t�− V1 − V2 (8)

where

V1 = kEV

1kF

CF�0�

CZ�0��1 − �� +

1kZ

�1 − ��

CF�0�

CZ�0�� + �

(9a)

V1 can also be calculated and denoted as V1ex, as it isusually done, directly using measurements of the to-tal concentration (radioactivity) of the label (SeeEq. 6.).

V1ex = kE

�0

tC dt

C�t�(9b)

V2 =kF − kZ

C�t� ��0

tCF d� −

�0

TCF dt

�0

TC dt

�0

tC d��

= V��1 − B� − ��1 − A� + B − A

�1 − A

kF+

CZ�0�

CF�0�

1 − B

kZ��CF�0�

CZ�0�� + ��

� 1kF

−1

kZ� (10)

CLINICAL AND EXPERIMENTAL STUDIES

Twenty dwell studies, 1 study in each patient, wereperformed at the Department of Nephrology, Post-graduate Military Medical Center, Warsaw, Poland.Overnight dialysate (Dianeal PD1, 1.36% of glucose,Baxter) was drained in the morning. Then a standard4 h dwell with fresh fluid (Dianeal PD1, 1.36% ofglucose, Baxter, Budapest, Hungary) was per-formed. The bag with dialysis fluid was prewarmedto 37°C and prepared with a priming dose of 0.2 g ofhuman serum albumin to minimize the adhesion oflabeled albumin to the surface of the plastic material.Subsequently, flush before fill was performed. Thenradioisotopically labeled albumin (RISA) wasadded, and the fluid after vigorous shaking of thebag was infused to the peritoneal cavity. The infusedvolume was calculated from the total weight of thebag with fluid and the empty bag. Dialysate samples(15 ml) were taken through the stopcock at 3, 15, 30,90, 180, and 240 min after the complete infusion ofthe dialysis fluid. Prior to each sampling, 15 ml of thedialysate was flushed back and forth 10 timesthrough the stopcock. Additionally, the patient wasmoving before sampling to mix the dialysate in theperitoneal cavity. In the dialysate sample, radioac-tivity and solute concentration were measured.Blood samples (10 ml) were drawn at 0, 120, and 240min for measurement of radioactivity and soluteconcentration. After 240 min, the dialysate wasdrained, and the volume recorded (in the way men-tioned above). The peritoneal cavity was then rinsedfor 5 min with 2 L of fresh 1.36% glucose dialysisfluid (without RISA) to provide data for calculationof the residual volume at 240 min.

Diffusive mass transport coefficients for glucoseand creatinine were estimated using the modified



Babb-Randerson-Farrell model as described previ-ously (5) using the computer program PERTRAN(Baxter Novum, Karolinska Institutet, Stockholm,Sweden) available at internet address http://www.ibib.waw.pl/ ˜peritome. The model describes the netchange of the solute amount in dialysate over thetime increment due to combined transport of thesolute by diffusion and convection between bloodand dialysate and by peritoneal absorption.

The free fraction of iodine was measured at 5, 120,and 180 min in an in vitro experiment in dilution 1:10in fresh 1.36% Dianeal solution. The iodine freefraction was stable, and its mean radioactivity valuewas 2.72 ± 0.18% (mean ± SD) of the total.

Evaluation of the stability of 125I-HSA complex(RISA) was done by means of paper radiochroma-tography in the following way. One half microliter ofincubated solution was placed on Whatman 1 paperstrips. After drying, chromatograms were developedin a water solution of 17% formic acid with 3 g/Lsodium thiosulfate. Next, chromatograms were driedagain, cut, and their radioactivity was counted (Clini-gamma LKB-Wallac, Turku, Finland). In this condi-tion radiofrequency (rf) of 125I-HSA complex was0.2, and rf of free ion of 125I was 0.7. On the basis ofthese measurements of radioactivity, the percentageof each fraction in the study solution was estimated.

EVALUATION OF AN ERROR IN THEESTIMATION OF PERITONEAL VOLUME

AND FLUID ABSORPTION RATE INDWELLS WITH 1.36% GLUCOSE

SOLUTION (DIANEAL)

The molecular weight (MW) of 125I is betweenthat of creatinine and glucose. Using data from thisstudy, the diffusive mass transport coefficient be-tween the peritoneal cavity and blood, kBD, wasfound for glucose (MW � 180) to be 8.05 ± 2.95ml/min (mean ± SD) and for creatinine (MW � 113)12.80 ± 6.39 ml/min. The value for kF for iodine (MW� 125) was chosen to be 10 ml/min.

The experimental value of kE calculated using thedwells data and Eq. 4 was 1.6 ± 0.5 ml/min. Thisvalue was used in Eq. 7. Because the average freefraction of iodine was about 2.7%, CF(0)/CZ(0) waschosen to be 0.027/0.973. With these values and V �2384 ml (Table 1) and using Eq. 7 in the iterativefashion, kZ was found to be 1.44 ml/min. It meansthat kE overestimates RISA clearance, kZ, by about11%. If the free fraction of 125I would rise to 5%, thisoverestimation would be more than 20%. This analy-sis shows the reliable determination of RISA clear-ance estimated by kE, which serves as a measure of

fluid absorption rate QA, requires that the free frac-tion of iodine should be rather small. High kE couldindicate either increased fluid absorption rate in aparticular patient or high free fraction of 125I.

The assumed time courses of CF and CZ could notbe verified experimentally because we measuredonly total radioactivity, C � CF + CZ. It can beshown however that the double exponential functiondescribing the theoretical course of normalized C,Cnth � Cth(t)/Cth(0)

Cnth = A exp�−kZ

Vt� + B exp�−

kF

Vt�

can be fitted to the averaged experimental course ofnormalized C, Cn � C(t)/C(0) between 3 and 240min in such a way that, choosing A � 0.876 and B �0.024, for every measurement time Cnth lay within 1standard deviation of the corresponding value of Cn.It means that B/A � 0.0274, and it does not practi-cally differ from that used in calculations �a �CF(0)/CZ(0) � 0.0277.

Peritoneal volumes V were calculated using ex-perimental data from dwells as

V�t� =V�0�C�0�

C�t�− V1ex

where V1ex was determined using Eq. 9b in which thetime integral of total concentration was evaluatedusing the trapezoidal rule and experimental data. Itmeans it was assumed that there was no free fractionof 125I.

In Table 1 are shown values of peritoneal volumesV for particular time of the dwell as well as a cor-rection pertaining to the elimination of a volumemarker, V1, as well as a correction pertaining to theexistence of a free fraction of 125I, V2. V1 was calcu-lated using Eq. 9a and V2 using Eq. 10 with kE, kF,

TABLE 1. Peritoneal volume calculated usingexperimental data from clinical dwells, V (mean ± SD),

correction for volume marker elimination determinedusing Eq. 9b and experimental data, V1ex (mean ± SD),

correction for volume marker eliminationdetermined using Eq. 9a, V1, and correction for free

fraction of 125I, V2

Time(min)

V(ml)

V1ex

(ml)V1

(ml)V2

(ml)

0 2,147 ± 52 – 0 03 2,384 ± 157 – 4.8 0.2

15 2,401 ± 133 19.4 ± 0.2 24.1 1.030 2,414 ± 135 44.0 ± 0.5 48.5 1.960 2,430 ± 144 94.1 ± 1.6 98.0 3.190 2,430 ± 131 145.0 ± 2.2 148.5 3.1

120 2,416 ± 132 196.1 ± 3.2 200.0 3.9180 2,354 ± 145 296.6 ± 4.9 306.0 2.8240 2,289 ± 159 398.7 ± 7.6 416.0 0

Time averaged V, V � 2,384 ml.



kZ, �, �, A, B, and CF(0)/CZ(0) as specified above. Itis of interest to note that V1, denoted as V1ex, canalso be calculated using measured values of radioac-tivity, C(t) using Eq. 9b. V1 only slightly overesti-mates V1ex (except at 15 min) for every time point.This observation may serve as a justification of as-sumptions used in the construction of free andbound label kinetic models at least for investigateddwells. From data shown in this table, it can be in-ferred that correction pertaining to the eliminationof a volume marker should be taken into account incalculation of V as it is usually done. However, verysmall values of V2 make this correction unnecessary.With a maximum value of V2 at 120 min of 3.9 mland mean V at 120 min being 2,416 ml (Table 1), theerror resulting in this omission is about 0.2%. This isthe largest among errors calculated for every timepoint. In fact, calculation showed that even with 20%of a free fraction of 125I the maximum value of V2

would be 27 ml.In Fig. 1 the time course of peritoneal volume V

and uncorrected volume Vnc are shown. Vnc, calcu-lated as Vnc � V(0)C(0)/C(t), represents peritonealvolume evaluation in which correction for volumemarker elimination was omitted. Vnc substantiallyoverestimates V indicating the necessity of correc-tion for volume marker clearance. In Fig. 1 it is alsoshown that the mean value of V, V, lies within 1standard deviation of V for every time point, whichdemonstrates that the simplification in using V in-stead of V in the description of time courses of CF

and CZ should not result in substantial error.Another way of showing the impact of free frac-

tion of the label on kZ, V1, and V2 is application ofthe so-called sensitivity analysis. In the vicinity of theassumed ratio CF(0)/CZ(0) denoted �a, one canevaluate relative (percentage) change of kZ, and V2

(�kZ/kZ and �V2/V2) as

�kZ

kZ× 100 ≅

dkZ

d� �a

×��

kZ× 100%

�V2

V2× 100 ≅

dV2

d� �a

×��

V2× 100%

where dkZ/d�|�aand dV2/d�|�a

represents deriva-tives of kZ and V2 with respect to � determined forassumed �a, respectively. �� is the difference be-tween �a and a new value of �. The derivativesobtained using Eqs. 7 and 10 are expressed by ratherlengthy formulas. Besides, the value of dV2/d� de-pends also on time. The formulas are therefore notreported in this study. The complicated formula fordV1/d� is obtained as a result of evaluation of de-rivative using Eq. 9a. The sensitivity analysis of V1 inreference to � is however unnecessary because V1

can be calculated directly using Eq. 9b, thus avoidingany errors involved in assumption of free label ki-netics. The values of derivatives calculated for �a �0.0277 are as follows:

dkZ

d� �a

= −6.0 ml�min,dV2

d� �a

= 141 ml at 120 min.Thus, for kZ = 1.44 ml/min and V2 � 3.9 ml at 120min of the dwell, which is the maximum V2 value, seeTable 1:

�kZ

kZ× 100 ≅ −416 × ��%;

�V2

V2× 100

= 3615 × ��%

With � changing from the assumed value of 0.0277(2.7% of a free label) to 0.053 (5% of a free label),kZ decreases by 10% (which in fact represents thecorresponding increase of an apparent volumemarker clearance, kE), and V2 increases by 90%.

FIG. 1. The peritoneal volume, V (squares), timecourse was determined as V(0)C(0)/C(t) − V1ex,where V1ex was calculated using Eq. 9b. Vnc (tri-angles), calculated as Vnc = V(0)C(0)/C(t), repre-sents peritoneal volume evaluation in which cor-rection for volume marker elimination wasomitted. The dashed line represents V, the meanvalue of V. For every measurement time point Vand Vnc are presented as mean ± SD (n = 20).



Sensitivity analysis confirmed that kE and V2 arehighly sensitive to the increase of a free fraction of alabel. However, because even the maximum V2 valueat 120 min of the dwell is very small as compared tothe peritoneal volume V (Table 1), a 90% increase ofV2 results in a still negligible error in estimation of V.

Sensitivity analysis was also performed in respectto changes in free label clearance, kF. The deriva-tives of kZ and V2 in respect to kF, calculated forassumed kFa � 10 ml/min, are

dkZ

dkF kFa

= 0.01,dV2

dkF kFa

= 7.9 min at 120 min

The small values of these derivatives show rathersmall sensitivity of V2 and very small sensitivity ofkZ, to change in kF. Thus, even a big error in esti-mation of kF would not influence substantially cal-culated values of bound label clearance, kZ, and peri-toneal volume V.

In summary, the performed analysis has indicatedthat calculation of the peritoneal volume time courseduring the dwell with correction taken for volumemarker elimination is very reliable, and the existenceof a free fraction of a volume marker label results ina negligibly small error. However, even a small freefraction of the label results in significant overestima-tion of volume marker clearance.

Acknowledgment: This study was supported by Grant1151/POV/97/112 from the State Committee for ScientificResearch, Poland.References

1. Lindholm B, Werynski A, Bergstrom J. Fluid transport inperitoneal dialysis. Int J Artif Organs 1990;13:352–8.

2. Waniewski J, Heimburger O, Park MS, Werynski A, Lind-holm B. Methods for estimation of peritoneal dialysate vol-ume and reabsorption rate using macromolecular markers.Perit Dial Int 1994;14:8–16.

3. Marciniak M, Wankowicz Z, Baczynski D. Influence of thevolume ration of the 99mTc-HSA complex to dialysis fluid onthe stability during in vitro incubation (in Polish). ProblemyMedycyny Nuklearnej 1998;12(24):201–7.

4. Harbert JC, Eckelman WC, Neumann RD. Nuclear medicine:Diagnosis and Therapy. New York: Thieme Medical, 1996:779–80.

5. Waniewski J, Werynski A, Heimburger O, Lindholm B.Simple membrane models for peritoneal dialysis: Evaluationof diffusive and convective solute transport. ASAIO Trans1992;38:788–96.

NOMENCLATUREV peritoneal volume (ml)V1ex peritoneal volume correction factor for volume

marker elimination determined using experi-mental data (ml)

V1 peritoneal volume correction factor for volumemarker elimination evaluated using assumedkinetic models of free and bound labels (ml)

V2 peritoneal volume correction factor for free la-bel fraction (ml)

kE volume marker clearance (ml/min)kF clearance of a free label (ml/min)kZ clearance of a bound label (ml/min)QA fluid absorption rate (ml/min)C total concentration (radioactivity) of a label in

dialysate (cpm/sample volume)CF concentration of free label in dialysateCZ concentration of bound label in dialysate� coefficient of cleavage of compound-label com-

plex� ratio of initial concentrations of free to bound

label, CF(0)/CZ(0), in dialysate�a assumed value of �

Hemodynamic Exercise Response inCalves with an Implantable Biventricular

Centrifugal Blood Pump

*†Jorg Linneweber, †Kenji Nonaka, †TamakiTakano, †Shinji Kawahito, †Sebastian

Schulte-Eistrup, †Tadashi Motomura, †SeijiIchikawa, †Minoru Mikami, †Shelly Stevens,

‡Heinrich Schima, ‡Ernst Wolner, and †YukihikoNose, *Department of Cardiovascular Surgery,

University Hospital Charité, Humboldt University,Berlin, Germany; †Michael E. DeBakey

Department of Surgery, Baylor College ofMedicine, Houston, Texas, U.S.A.; and

‡Department of Surgery, University of Vienna,Vienna, Austria

Abstract: An implantable biventricular assist device(BVAD) has been developed at Baylor College of Medi-cine using 2 centrifugal blood pumps. The aim of this studywas to investigate the exercise-reflex response during non-pulsatile biventricular assistance and to evaluate to whichdegree the autoregulation of the system would accommo-date the changed hemodynamic situation during physicalexercise. The Baylor Gyro PI 710 BVAD has been im-planted into 2 calves (strain half-Dexter) in a biventricularbypass fashion with native heart remaining. Allowing a 10day convalescence, 2 animals were subjected to incremen-tal exercise tests. The speed of the treadmill was increasedat zero slope from 0.7 mph to 1.5 mph with increments of0.2 mph every 3 min. During the exercise the pump flowswere maintained at a fixed rate (6.93 ± 0.01 L/min for theleft ventricular assist device and 5.36 ± 1.44 L/min for theright ventricular assist device). Hemodynamic parametersand pump performance were recorded continuously. Thecardiac output (CO) and heart rate (HR) increased signifi-cantly during the exercise. CO increased from 11.1 ± 0.3 to

Received January 2001; revised April 2001.Address correspondence and reprint requests to Dr. Jörg Linne

Weber, Department of Cardiovascular Surgery, University Hos-pital Charité, Humboldt University, Schumannstrasse 21, 10177Berlin, Germany.



13.1 ± 0.4 L/min, and HR increased from 99 ± 7.1 to 114 ±2.8 bpm, respectively. Mean aortic pressure, central ve-nous pressure, and left arterial pressure did not changesignificantly. Also, no change was observed for the left andright pump flows. This totally implantable BVAD showedexcellent long-term performance without any mechanicalproblems. It is feasible to operate without impairment un-der physical activity. However, the natural heart domi-nated the hemodynamic response during exercise underBVAD support. The left and the right pump flows didnot increase spontaneously with exercise. We thereforeconclude that a servo CO control system is necessary toregulate pump flows even during moderate exercise. KeyWords: Biventricular assist device—Left ventricular assistdevice—Right ventricular assist device.

Current left ventricular assist devices (LVADs)have demonstrated admirable results. However, ap-proximately one-fourth of the patients who requireleft ventricular assisted circulation suffer from rightheart failure due to the illness of the patient and thenegative effect of LVAD support. Contrary to theexcellent results that LVADs have demonstrated, abiventricular assist device (BVAD) is rarely usedclinically. At the moment, there is no implantableBVAD system. This is primarily due to the problemthat all currently available pulsatile VADs are toolarge to be totally implanted in a biventricular by-pass fashion. Therefore, an implantable nonpulsatilebiventricular assist system has been developed atBaylor College of Medicine using 2 completely seal-less centrifugal blood pumps. Recently, the systemhas been successfully implanted into calves, and 2animals survived for more than 4 weeks (44 days and52 days, respectively). The primary goal of an im-plantable BVAD system is to allow the patient tomove freely without the boundary of a big stationarydriver and control unit. This objective requires thatthe system is functional under low to moderate ex-ercise.

The effect of biventricular nonpulsatile blood flowon the regulation of the circulation and vice versa,the effect of the changed circulation on the pumpperformance, is little known.

The aim of the study was to evaluate if the newlydeveloped system can operate safely and function-ally not only under static but also under dynamicconditions. Furthermore, the study was undertakento evaluate the cardiovascular exercise response dur-ing nonpulsatile biventricular perfusion.

Materials and methods

Pump systemThe implanted BVAD system consisted of two

Baylor PI 710 centrifugal pumps and has been de-scribed previously (1). In brief, the housing of thepump and the impeller is made of titanium alloy with

a 6-pole magnet incorporated inside the impeller.The shaft of the impeller is made of ceramic, andpolyethylene female bearings are embedded into thetop and bottom housing of the pump. The primingvolume of each pump is 25 ml.

Implantation of the pump systemAfter endotracheal intubation and general anes-

thesia, a left lateral thoracotomy was made. Bothpumps were placed subdiaphragmal in the preperi-toneal abdominal region. An 11 mm albumin coatedDacron graft (Bard Albumin coated DeBakey Vas-cular II, C.R. Bard, Inc., Billerica, MA, U.S.A.) wasanastomosed end-to-side to the descending aorta asan outlet graft for the LVAD pump. The other endof the graft was connected to the outlet port of thepump. A titanium tip was inserted through the apexinto the left ventricle, and a flexible inflow cannulaconnected the ventricle with the pump. Similarly, theright pump outflow graft was anastomosed end-to-side to the main pulmonary artery, and the right inletcannula was inserted into the right ventricle. All ani-mals in this study were treated in accordance withthe Principles of Laboratory Animal Care formu-lated by the National Society for Medical Researchand the Guide to the Care and Use of LaboratoryAnimals (National Academy of Sciences NIH Pub-lication No. 8023, revised 1978). An Institutional Re-view Board approved the experimental protocol.

Treadmill exercise studyEach of the 2 animals absolved 1 experiment with

incremental workload per day for 6 consecutivedays. The speed of the treadmill was increased atzero slope from 0.7 to 1.5 mph with 0.2 mph incre-ments every 3 min. After surgery and before exercise,the pump flow was maintained over 5 L/min for theLVAD. The right ventricular assist device (RVAD)flow was maintained at levels 10% lower than theleft pump flow. All pump controls were left fixedthroughout the exercise test. Hemodynamic param-eters were continuously recorded using a compu-terized monitoring system (Ponemah System, GouldInstrument Systems, Valley View, OH, U.S.A.).Ultrasonic flow probes were attached at the pumpoutflow grafts (Transonic Systems, Inc., Ithaca, NY,U.S.A.) to monitor the pump flows. Rotationalspeed (rpm) of the impellers and power consump-tion of the pumps were monitored and recorded us-ing the device’s data acquisition system. Arterialblood pressure, central venous pressure, and leftatrial pressure were measured using transducers con-nected to saline solution–purged catheters leading tothe appropriate anatomical sites. Heart rate (HR)was determined by measuring the main pulmonary



artery flow curve peak to peak intervals. Arterialand central venous blood gases were collected andanalyzed (pH/Blood Gas Analyzer IL 1306, Instru-mentation Laboratory, Lexington, MA, U.S.A.).Preexercise values were taken at rest when the ani-mal was standing on the treadmill. For statisticalanalyses the 2-tailed paired t-test was used. A p-value of <0.05 was considered to be statistically sig-nificant.

ResultsThe HR increased significantly during exercise

from 99 ± 7.1 to 114 ± 2.8 bpm (p < 0.05) (Fig. 1).Oxygen consumption increased significantly from463 to 653 ml/min (Fig. 1). Central venous partialpressure of CO2 as well as partial pressure of O2 andO2 saturation did not change compared to preexer-cise values and maintained at 44.5 ± 0.7 mm Hg, 35.1± 0.8 mm Hg, and 66.1 ± 1.9% respectively.

Aortic pressure maintained stable during the ex-ercise (Fig. 2). The cardiac output (CO) as measuredby main pulmonary artery blood flow increased sig-nificantly from 11.1 ± 0.3 to 13.1 ± 0.4 L/min at 1.5mph. In contrast, flows for the LVAD as well asRVAD did not change and maintained constant at6.9 ± 0.01 L/min for the left pump and 5.37 ± 1.44L/min for the right pump, respectively (Fig. 3).

DiscussionDuring exercise the primary task of the circulatory

system is to augment and maintain sufficient deliveryof metabolic substrates and oxygen. A complex in-teraction between the autonomic nervous system,muscle chemo- and mechanoreceptors, and vascularbaroreceptors is necessary to adapt the circulation tothe increased oxygen demand. To maintain homeo-stasis and to provide adenosine triphosphate andoxygen to the working muscle, the activated circula-tory system increases CO. Furthermore, constriction

of the splanchnic and renal vasculature improves theblood flow to the active muscle.

The degree of treadmill exercise used for thisstudy must be considered moderate in nature, butwas adequate to increase CO and oxygen consump-tion. At the onset of exercise, an 18% increase in COwas observed as indicated by the main pulmonaryartery blood flow. This augmentation of CO was dueto an increase in HR. It was remarkable to note thatthe increase in heart rate had no negative effect onthe pump performance during this dynamic condi-tion. The decreased ventricle filling time at a higherHR did not lead to the “suction phenomenon” fre-quently observed in rotary blood pumps (2).

The increase in CO, however, was not followed byan increase in LVAD or RVAD blood flow. Thisleads to the conclusion that the natural heart domi-nated the hemodynamic response during exercise.The previously described hypothesis of “spontane-ous increase in centrifugal pump flow during exer-

FIG. 1. The graph shows increase in heart rate (HR) and oxygenconsumption (VO2) during incremental exercise.

FIG. 2. The graph shows that systolic, diastolic, and mean aorticpressures (RR) as well as central venous (CVP) and left atrialpressures (LVP) did not change during exercise.

FIG. 3. Left and right pump flows and total cardiac output (pul-monary artery [PA] flow) during exercise (LVAD: left ventricularassist device, RVAD: right ventricular assist device).



cise” (3) could not be confirmed in this in vivomodel. Autonomic regulation of rotary blood pumpflow during exercise remains a controversial issue.While Akimoto et al. (3) found a significant increasein LVAD flow with increased HR, Shoor et al. (4)could only demonstrate a modest increase in pumpflow during exercise. Consistent with our findings,they observed that the centrifugal pump providedonly a fraction of the increase in CO, while the na-tive heart provided a much larger portion of the CO.BVAD exercise studies with fibrillating ventriclesperformed by Yozu et al. (5) did not show any in-crease of pump flow during exercise. The fact thatthe animals used in this study had no specific cardiacinjury and that their myocardial performance duringexercise might approach normal physiologic re-sponse obviously had significant implications for theinterpretation of these data.

The rise in HR shifts the ratio of systole and di-astole in favor of the systolic phase. This increase intotal systolic time per minute is believed to lead toincreased pump flow. The data of this study as wellas results from other groups (4) showed, however,that in the healthy beating heart model, the flowproduced in the ventricle is much more likely to beejected through the aortic and pulmonary valve thanthrough the pumps. This problem, however, be-comes secondary in the injured heart in which con-tractility and ejection through the valve is limited. Inthis case the ventricles act as a reservoir to fill thepumps. The insufficient ventricle is not able to pro-duce adequate pressure during systole. Therefore,the total pressure head will not or only moderatelyincrease during physical activity. Also, the severelydilated myocardium is chronotropically incompe-tent. Since the basic parameters that determinepump flow (pressure head and filling time) will notchange, it is questionable if a spontaneous increasein pump flow is possible during physical exercise.

At the onset of exercise, 2 fundamental errorsmust be corrected by the autonomic nervous system:a mismatch between blood flow and metabolism (aflow error) and a mismatch between CO and vascu-lar conductance (a blood pressure error). The lat-ter activates the baroreflex and raises blood pres-sure. While nonpulsatile blood pumps can easilycompensate the demand in higher blood flow, little isknown about the baroreflex during nonpulsatile per-fusion. Because of rapid muscle vasodilation at theonset of exercise, muscle vascular conductance risesmore rapidly than CO, causing blood pressure to fall(6,7). Accordingly, the baroreflex is thought to initi-ate the circulatory exercise response. Although

blood pressure falls initially in healthy individuals, itrises rapidly and exceeds the preexercise levels.However, in dogs without an arterial baroreflex (bysinoaortic denervation), blood pressure does not riseat the onset of exercise; rather it falls (8,9). Thesefindings have important implications on the bloodpressure regulation during nonpulsatile biventricularassistance. The drop in blood pressure at the onset ofexercise is corrected by central command that ad-justs CO and HR through vagal withdrawal (10).Again, however, this compensation is impossible forthe end-stage failing heart. Based on these observa-tions, we conclude that a servo CO control is neces-sary to regulate pump flows even during moderate tomild exercise.

ConclusionThe implantable Baylor PI 710 BVAD system is

able to support the failing heart not only understatic, but also under dynamic conditions. No suctionor deterioration of pump flows occurred duringphysical activity. Yet right and left pump flow main-tained constant and did not increase spontaneouslyduring exercise.

References

1. Nose Y, Nakata K, Yoshikawa M, Letsou GV, Fujisawa A,Wolner E, Schima H. Development of a totally implantablebiventricular bypass centrifugal blood pump system. AnnThorac Surg 1999;68:775–9.

2. Yuhki A, Hatoh E, Nogawa M, Miura M, Shimazaki Y, Taka-tani S. Detection of suction and regurgitation of the implant-able centrifugal pump based on the motor current waveformanalysis and its application to optimization of pump flow. Ar-tif Organs 1999;23:532–7.

3. Akimoto T, Yamazaki K, Litwak P, Litwak KN, Tagusari O,Mori T, Antaki JF, Kameneva MV, Watach MJ, Umezu M,Tomioka J, Kormos RL, Koyanagi H, Griffith BP. Rotaryblood pump flow spontaneously increases during exercise un-der constant pump speed: Results of a chronic study. ArtifOrgans 1999;23:797–801.

4. Shoor PM, Hammill FS, Griffith LD, Dilley RB, BernsteinEF. Hemodynamic responses to exercise in the unanesthe-tized calf with pulseless arterial flow. Trans Am Soc ArtifIntern Organs 1980;26:1–7.

5. Yozu R, Golding L, Yada I, Harasaki H, Takatani S, KawadaS, Nose Y. Do we really need pulse? Chronic nonpulsatile andpulsatile blood flow: From the exercise response viewpoints.Artif Organs 1994;18:638–42.

6. Ludbrook J. Reflex control of blood pressure during exercise.Ann Rev Physiol 1983;45:155–68.

7. Rowell LB. Human Circulation: Regulation During PhysicalStress. New York: Oxford University Press, 1986.

8. Ardell JL, Scher AM, Rowell LB. Effects of baroreceptordenervation on the cardiovascular response to dynamic exer-cise. In: Sleight P, ed. Arterial Baroreceptors and Hyperten-sion. Oxford: Oxford University Press, 1980:311–7.

9. Hales JR, Ludbrook J. Baroreflex participation in redistribu-tion of cardiac output at onset of exercise. J Appl Physiol1988;64:627–34.

10. Freyschuss U. Cardiovascular adjustment of somatomotor ac-tivation. Acta Physiol Scand 1970;342(Suppl 1):1–63.

