Thoughts and ProgressIt is the goal of this section to publish material that provides information regarding specific issues, aspects of artificial organapplication, approach, philosophy, suggestions, and/or thoughts for the future.
Perfusate Lactate Dehydrogenase Leveland Intrarenal Resistance Could Not BeAdequate Markers of Perfusion Quality
During Isolated Kidney Perfusion
*Berta Herrera, *Gustavo Eisenberg,*M. Mar Desco, *Oliver Holberndt,
†Alberto Rabano, *Manuela Castilla,*Pedro Garcıa-Barreno, and *Juan F. Del Canizo,
*Unidad de Medicina y Cirugıa Experimental,Hospital General Universitario Gregorio Maranon;
† and Laboratorio de Apoyo a la Investigacion,Fundacion Hospital Alcorcon, Alcorcon,
Madrid, Spain
Abstract: The main goal of this work was to study theinfluence of perfusion pressure and flow waveform duringkidney perfusion, and the relationship between renal vas-cular resistance (RVR) and lactate dehydrogenase (LDH)concentration in the perfusate. Simultaneous constantpressure kidney perfusions were performed with eitherpulsatile or continuous flow at either 30 or 80 mm Hg ofconstant perfusion pressure. Mean flow, pressure, andRVR were displayed online during perfusion. Perfusatesamples for LDH, creatine phosphatase kinase (CPK), andalkaline phosphatase (AP) determinations were taken. Atthe end of the perfusion, 2 ml of Evans blue was injectedinto the circuit to obtain images of perfusate distribution,and the kidneys were weighed. Also, hematoxylin/eosinestudies were performed, showing more Bowman’s spaceand tubular dilation in kidneys perfused with high pres-sure. We did not find differences in RVR between kidneysperfused at 30 and 80 mm Hg; nevertheless, perfusate dis-tribution was better in the 80 mm Hg perfusions. We didnot find any correlation between enzyme release and RVRin kidneys perfused with different mean pressures. Thesefindings suggest that vascular resistance and LDH concen-tration cannot be independently considered as adequatemarkers of perfusate distribution. Key Words: Renalpreservation—Machine perfusion—Perfusion pressure—Kidney perfusion.
Cold storage preservation after an initial flush hasbeen the most widely used method for renal preser-vation (1), but non-heart-beating donors are acquir-ing increasing importance, and preservation by ma-chine perfusion is thought to be advantageous indamaged kidneys (2). For machine preservation, 2different flow waveforms, pulsatile flow (3) and con-tinuous flow (4), can be used, and also different so-lutions may be chosen (5). Different perfusion pres-sures were described when using constant pressuretechnique. It has been proposed that high flow andpressures could be harmful for renal microcircula-tion (6), even though there are some studies usinghigh pressure during kidney perfusions (7). The es-timation of organ damage during perfusion is essen-tial to know the graft viability, and lactate dehydro-genase (LDH) concentration in the perfusate is oneof the most widely used markers of tissue damage(8).
The aim of this study was to compare 2 differentpressure conditions (30 versus 80 mm Hg) and 2 dif-ferent flow waveforms (pulsatile versus continuous).This work reports a model for organ preservationwhich provides online information of flow, pressure,and renal vascular resistance (RVR). In addition,this study raises doubts about the utilization of meanvascular resistance during perfusion and LDH con-centration into the perfusate as optimal parametersfor perfusion quality as well as for viability status.
Materials and methodsTwenty-four kidneys were harvested from 35 to 50
kg Maryland minipigs (9). Anesthesia was inducedand then maintained with Pancuronium and Fenta-nyl (4 mg each) every 30 min. After median laparot-omy, heparin was administered intravenously andkidneys were exposed, resected, and weighed. Therenal artery was cannulated and immediately con-nected to the perfusion circuit. All surgical proce-dures were performed according to internationalrules for animal handling (European Agreement onHuman Care and Use of Laboratory Animals March18, 1986).
The perfusion circuit used is a modification of onepreviously described (10). The modification allows
Received October 1999; revised April 2000.Address correspondence and reprint requests to Dr. Juan F. del
Canizo, Unidad de Medicina y Cirugıa Experimental, HospitalGeneral Universitario Gregorio Maranon, Dr. Esquerdo 46,E-28007 Madrid, Spain.
simultaneous perfusion of 2 kidneys, 1 with continu-ous flow and the other with pulsatile flow at either 30or 80 mm Hg of constant perfusion pressure. Maxi-mal systolic pressure was limited to 120 mm Hg. Thissystem allows online visualization of mean flow,pressure, and RVR.
The 24 kidneys were assigned randomly to 4groups. Group 1 consisted of 6 kidneys perfused witha pulsatile flow at 30 mm Hg. Group 2 consisted of 6kidneys perfused with a continuous flow at 30 mmHg. Group 3 included 6 kidneys perfused with a pul-satile flow at 80 mm Hg. Group 4 consisted of 6kidneys perfused with continuous flow at 80 mm Hg.
RVR was calculated dividing the mean pressureby the measured flow. In some cases, at the end ofthe perfusion, 2 ml of Evans blue was injected intothe circuit. The kidney then was weighed, sectioned,and photographed. In other groups, hematoxylin/eosine studies of renal cortex were performed. Allperfusions were performed at 4°C, and 400 ml ofBelzer solution (11) was used as perfusate during 120min. Perfusate samples were taken at 5, 30, 60, and120 min for LDH, creatine phosphatase kinase(CPK), and alkaline phosphatase (AP), Na+, and K+
determinations. Statistical analysis was performed byusing SPSS Version 8.0 software (SPSS/PC Inc., Chi-cago, IL, U.S.A.). A General Factorial Analysis testwas done in order to show any significant difference.Data are reported as mean ± SEM at a significancelevel of p < 0.05.
ResultsRVR decreased during perfusion in all groups.
There was no difference between perfusions per-formed at 30 mm Hg and 80 mm Hg in terms of RVR(mean resistance of 0.82 ± 0.1 and 0.83 ± 0.09 mm Hgmin/ml, respectively). There was a statistically sig-nificant interaction between 2 factors: perfusionpressure and the pump used. Mean RVR during per-
fusion comparing both flow patterns seemed to bedifferent depending on the perfusion pressure. The80 mm Hg perfusions (mean flow of 118.3 ± 8.48ml/min/100 g) showed a higher vascular resistancewhen using continuous flow (Fig. 1b) while 30 mmHg perfusions (mean flow of 47.3 ± 3.91 ml/min/100g) showed a higher resistance when using pulsatileflow (Fig. 1a) (p < 0.05). Independently of the pumpused, LDH concentration increased along the perfu-sion. Mean LDH concentration in the perfusate washigher in kidneys perfused at 80 mm Hg than at alower pressure (115.78 ± 8.6 and 53.40 ± 5.4 U/L,respectively, p < 0.05) (Fig. 1c). No significant dif-ference was found between pulsatile and continuousflows in terms of LDH, AP, or CPK release into theperfusate. Mean AP (18.13 ± 4.07 U/L versus 2.66 ±2.13 U/L, p < 0.05) (Fig. 1d) and CPK (23.12 ± 2.10U/L versus 13.64 ± 1.56 U/L) (Fig. 1e) concentra-tions were higher at 80 mm Hg compared with the 30mm Hg perfusions. Kidneys perfused at 80 mm Hgshowed a mean weight increase of 28.8 ± 3.2 g whilekidneys perfused at 30 mm Hg did not gain weight.
Kidneys perfused at 80 mm Hg showed a largerarea dyed than kidneys perfused at 30 mm Hg. In thelatter, the area perfused usually was limited to therenal cortex (Fig. 2, upper panels). Hematoxylin/eosine studies showed more Bowman’s space andtubular dilation in kidneys perfused with high pres-sure (Fig. 2, lower panels). No differences werefound between pulsatile and continuous perfusions.
DiscussionWhile there was no difference in mean RVR be-
tween 30 and 80 mm Hg perfusions (consideringpressure as isolated factor), we observed a differentresponse of these groups depending on the type offlow used. Group 1 (pulsatile, 30 mm Hg) showedhigher resistance than continuous perfusions (Group2). On the other hand, continuous perfusions showed
FIG. 1. Shown are the mean RVR(mm Hg/ml/min) at t = 5, 30, 60,and 120 min in 30 mm Hg (a) and80 mm Hg (b) perfusions and thefinal concentrations into the per-fusate of LDH (c), AP (d), andCPK (e).
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higher resistance when the mean perfusion pressurewas set at 80 mm Hg (Groups 3 and 4). Therefore,we suggest that pulsatile perfusion shows lower re-sistance than continuous perfusion when mean flowis high enough.
In a previous study (10), constant pressure (40 mmHg) kidney perfusions using EuroCollins as the per-fusate showed a similar resistance behavior to the 80mm Hg perfusions presented in this study. Whileperfusate composition could account for these dif-ferences, further research is necessary to find themechanisms involved.
Low RVR usually was thought to be a marker forperfusion quality (12). Nevertheless, we observedthat 2 kidneys with the same intrarenal resistance didnot necessarily have the same perfusate distribution.There was no difference in RVR between kidneysperfused at 30 and 80 mm Hg even though perfusatedistribution was not the same in both groups. Mostlikely, the perfusate easily finds a vascular path topass through, not necessarily covering the whole kid-ney vascular tree. Therefore, low RVR alone shouldnot be considered as a marker of perfusion quality ifthe flow perfusate is not sufficient.
We did not find any correlation between enzymerelease and RVR in kidneys perfused with differentmean pressures. In addition, kidneys that showedmore tissue perfused also released more LDH, AP,and CPK into the perfusate. Again, it is questionablethat the high LDH concentration in the perfusate isnot only a sign of cellular damage (or of an inad-equately flushed kidney), but also the result of alarger volume of renal tissue perfused. This idea issupported by other studies in which differences inLDH concentration in the perfusate do not correlatewith ischemic damage (13). The kidneys perfused ata high pressure showed weight increases. In mostcases, this was related to interstitial and glomerularedema, but these kidneys were more homogeneouslyperfused.
In conclusion, we believe that RVR alone is not anadequate marker of perfusate distribution. Ad-equate perfusate flow, pressure conditions, and flowwaveform seem to be essential for machine preser-vation, and it seems necessary to find the ideal per-fusion parameters as well as accurate markers of or-gan viability in order to find a balance betweenvascular damage and distribution of the perfusate.Consequently, a junction of low vascular resistanceand a high flow level of around 100 ml/min/100 gtissue is a good hemodynamic marker for renal per-fusion.
Acknowledgments: All reagents were obtained fromSigma-Aldrich Co. Biochemical analysis of enzymes wasperformed at the Servicio de Bioquimica, Hospital Gen-eral Universitario Gregorio Maranon. This research waspartially supported by Grant FIS 96/0561 from Fondo deInvestigaciones Sanitarias.
References
1. Collins GM, Bravo-Shugarman M, Terasaki PI. Kidney pres-ervation for transportation. Initial perfusion and 30 hours’ icestorage. Lancet 1969;2:1219–22.
2. Daemen JH, de Vries B, Oomen AP, DeMeester J, KootstraG. Effect of machine perfusion preservation on delayed graftfunction in non-heart-beating donor kidneys—early results.Transpl Int 1997;10:317–22.
3. Polyak M, Boykin J, Arrington B, Stubenbord WT, Kinkha-bwala M. Pulsatile preservation characteristics predict earlygraft function in extended criteria donor kidneys. TransplantProc 1997;29:3582–3.
5. Muhlbacher F, Langer F, Mittermayer C. Preservation solu-tions for transplantation. Transplant Proc 1999;31:2069–70.
6. Yland MJ, Nakayama Y, Abe Y, Rapaport FT. Organ pres-ervation by a new pulsatile perfusion method and apparatus.Transplant Proc 1995;27:1879–82.
7. Hansen TN, D’Alessandro A, Southard JH. Reduced renalvascular injury following warm ischemia and preservation byhypothermic machine perfusion. Transplant Proc 1997;29:3577–9.
FIG. 2. Shown are Evans blue stained images (upper panels)and hematoxylin/eosine staining of renal cortex (lower panels) ofkidneys perfused at 80 mm Hg (left) and 30 mm Hg (right).
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8. Kohn M, Ross H. Lactate dehydrogenase output of the ex-cised kidney as an index of acute ischemic renal damage.Transplantation 1971;11:461–4.
9. Sachs DH, Leight G, Cone J, Schwarz S, Stuart L, RosenbergS. Transplantation in miniature swine: I. Fixation of the ma-jor histocompatibility complex. Transplantation 1976;22:559–67.
10. del Canizo JF, Tejedor A, Lledo E, Radvan J, Desco M, DulinE, Holberndt O, Hernandez C, Garcia-Barreno P. Isolatedkidney controlled perfusion with true physiological pulsatilewaveform. Artif Organs 1998;22:279–84.
11. Hoffmann RM, Stratta RJ, D’Alessandro AM, Sollinger HW,Kalayoglu M, Pirsch JD, Southard JH, Belzer FO. Combinedcold storage-perfusion preservation with a new synthetic per-fusate. Transplantation 1989;47:32–7.
12. Polyak MM, Arrington BO, Stubenbord WT, Kapur S,Kinkhabwala M. Prostaglandin E1 influences pulsatile pres-ervation characteristics and early graft function in expandedcriteria donor kidneys. J Surg Res 1999;85:17–25.
13. Daemen JW, Oomen AP, Janssen MA, van de Schoot L, vanKreel BK, Heineman E, Kootstra G. Glutathione S-trans-ferase as predictor of functional outcome in transplantation ofmachine-preserved non-heart-beating donor kidneys. Trans-plantation 1997;63:89–93.
Combination of Inhaled Nitric OxideTherapy and Inverse Ratio Ventilation in
Patients with Sepsis-Associated AcuteRespiratory Distress Syndrome
Kohji Matsuda, and Takeshi Motoyama, Division ofIntensive and Critical Care Medicine, KumamotoUniversity School of Medicine, Kumamoto, Japan
Abstract: Inverse ratio ventilation (IRV) is a ventilatorytechnique that uses an inspiratory to expiratory ratio (I:E)greater than 1:1. We studied the effects of mechanical ven-tilation with an I:E of 1:3, 1:1, and 2:1 on arterial oxygen-ation in 10 patients with sepsis-associated acute respiratorydistress syndrome (ARDS). At each I:E, patients received0 and 4 ppm of inhaled nitric oxide (INO) in random orderfor 30 min. Respiratory and cardiovascular parameterswere measured. Of the 10 patients studied, 7 responded toIRV and 3 did not. An increase in the I:E and the additionof INO significantly improved arterial oxygenation in theresponders (p < 0.0001 and p < 0.006, respectively). Thecombination of an increase in the I:E and INO had anadditive effect on arterial oxygenation. The combineduse of IRV and INO is a more effective method of avoid-ing hypoxemia than either INO or IRV alone. KeyWords: Nitric oxide—Acute respiratory distress syn-drome—Mechanical ventilation—Inverse ratio ventila-tion—Sepsis.
Acute respiratory distress syndrome (ARDS) is asevere manifestation of acute lung injury (1). Sepsisis a prominent cause of ARDS (2). Despite recentadvances in respiratory care, the mortality rate ofpatients with sepsis-associated ARDS remains highat about 60 to 70% (2,3).
Nitric oxide (NO)is a potent endogenous vasodi-lator. The addition of NO to inspired gas was shownto reduce pulmonary arterial pressure without caus-ing systemic hypotension and to improve arterialoxygenation by improved ventilation/perfusionmatching in patients with ARDS (4). However, thisfavorable effect on arterial oxygenation has not beenobserved in all patients with ARDS (3). A methodthat increases the efficacy of inhaled nitric oxide(INO) in these patients would be desirable.
Inverse ratio ventilation (IRV) is a ventilatorytechnique that uses an inspiratory to expiratory ratio(I:E) greater than 1:1 (5). In IRV, intentional end-expiratory gas trapping due to the short expiratorytime occurs. This prevents complete alveolar empty-ing and leads to intrinsic positive end-expiratorypressure (PEEP), thereby recruiting collapsed al-veoli (5).
In patients with ARDS, arterial oxygenation de-pends on the distribution of ventilation perfusion re-lationships at the alveolar level (4). To improve ven-tilation/perfusion matching by INO in patients withARDS, INO must reach the alveolus where gas ex-change is performed, and INO must dilate con-stricted pulmonary arteries and veins (6). We hy-pothesized that IRV with INO would improvearterial oxygenation because alveolar recruitmentcaused by IRV increases INO delivery to its site ofaction. However, to our knowledge, there is no in-formation about the combination of these 2 thera-peutic approaches in ARDS. To test this hypothesis,we studied the combined effects of an increase in theI:E and the INO in patients with sepsis-associatedARDS.
Materials and methods
PatientsThis study was approved by the institutional re-
view board of Kumamoto University Hospital, andwritten informed consent was obtained from the pa-tients’ families. Ten mechanically ventilated patients(aged >16 years) with ARDS due to sepsis werestudied. None of the patients had preexisting chronicrespiratory disease or left ventricular failure. Under-lying conditions resulting in sepsis and ARDS weremajor surgery in 8 patients, diabetes mellitus in 1patient, and leukemia in 1 patient. The source ofsepsis was documented in all patients except for Pa-
Received November 1999; revised April 2000.Address correspondence and reprint requests to Dr. Kazufumi
Okamoto, Division of Intensive and Critical Care Medicine, Ku-mamoto University School of Medicine, 1-1-1 Honjo, Kumamoto860-8556, Japan. E-mail: [email protected]
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tient 10, who had endotoxemia following a pulmo-nary lobectomy (Table 1).
The diagnosis of sepsis was made by the criteria ofthe American College of Chest Physicians and theSociety of Critical Care Medicine Consensus Con-ference (7), requiring a systemic inflammatory re-sponse to infection manifested by 2 or more of thefollowing conditions: temperature greater than 38°Cor less than 36°C, heart rate greater than 90 bpm,respiratory rate greater than 20 breaths/min orPaCO2 less than 32 mm Hg, white blood cell countmore than 12,000 cells/mm3, and less than 4,000 cells/mm3 or more than 10% immature forms.
ARDS was diagnosed according to the American-European Consensus Conference (1), requiringacute onset, bilateral infiltrates, severe hypoxemia(ratio of arterial oxygen tension to the fraction ofinspired oxygen [PaO2:FiO2] less than 200 despite ap-plied PEEP [PEEP set by a ventilator]) and a pul-monary artery wedge pressure (PAWP) less than 18mm Hg.
The severity of ARDS was expressed as a lunginjury score (8). Criteria for the definition of organsystem failure were based on information from thesepsis-related organ failure assessment scoring sys-tem of the working group of the European Society ofIntensive Care Medicine (9). Hemodynamic failurewas defined as a requirement for dopamine (>5 mg/kg/min), epinephrine, or norepinephrine to maintainan adequate systemic blood pressure in the absenceof hypovolemia. Liver failure was defined as a totalbilirubin greater than or equal to 6 mg/dl. Renal
failure was defined as a serum creatinine greaterthan or equal to 3.5 mg/dl or a urine output less than500 ml/day. Coagulopathy was defined as a plateletcount less than 50,000/mm3. To estimate the severityof disease in each patient, the acute physiology andchronic health evaluation (APACHE) II score ac-cording to Knaus et al. (10) was assessed for eachpatient.
MeasurementsEach patient had an indwelling arterial catheter
for monitoring arterial pressure and blood gases. Apulmonary arterial catheter (P7110-EH, Abbot Lab.,North Chicago, IL, U.S.A.) was inserted for moni-toring pulmonary artery pressures and mixed venousblood gases. A bedside monitor (Sirecust 1281, Sie-mens Medical Electronics, Danvers, MA, U.S.A.)was used to measure heart rate, mean arterial pres-sure (MAP), mean pulmonary artery pressure (meanPAP), PAWP, central venous pressure (CVP), andcore temperature. The cardiac output (CO) wasmeasured by a CO computer (Oxymetrix 3 SaO2/CO-computer, Abbot) after 10 ml injections of 5%dextrose in water at room temperature. The CO wascalculated as an average of 3 thermodilution mea-surements at random points during the respiratorycycle. Hemoglobin (Hb), arterial (SaO2), and pulmo-nary artery oxygen saturation (SvO2), pH, and bloodgas tensions (PaO2, PaCO2, PvO2, and PvCO2) weremeasured with a pH-blood gas analyzer (Ciba Corn-ing 860, Chiron Diagnostics Co., Medfield, MA,U.S.A.). The blood gas analyzer was calibrated prior
TABLE 1. Clinical characteristics of patients with sepsis-associated ARDS
Patient no. Age/sex Underlying disease Source of sepsis LIS P/FARDS daysbefore study Other OF A II
ARDS: acute respiratory distress syndrome, LIS: lung injury score, P/F: PaO2/FiO2 ratio before NO inhalation, A II: APACHE II score,OF: organ failure, H: hemodynamic failure, L: liver failure, R: renal failure, C: coagulopathy, M: male, F: female.
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to each determination. The cardiac index (CI), sys-temic and pulmonary vascular resistance indices(SVRI) (PVRI), arterial and pulmonary arterial oxy-gen content (CaO2) (CvO2), and oxygen delivery in-dex (DO2) were calculated according to standard for-mulas: SVRI 4 (MAP − CVP)/CI × 80; PVRI 4(mean PAP − PAWP)/CI × 80; CaO2 4 Hb × 1.39 ×(SaO2/100) + PaO2 × 0.0031; CvO2 4 Hb × 1.39 ×(SvO2/100) + PvO2 × 0.0031; and DO2 4 CI × CaO2 ×10. Venous admixture (Qv/Qt) was calculated usingthe following formula: Qv/Qt 4 (Cc8O2 − CaO2)/(Cc8O2 − CvO2), where Cc8O2 is the pulmonary cap-illary oxygen content, estimated from the alveolargas equation assuming a respiratory quotient (RQ)of 0.8. The mean Hb of the blood taken simulta-neously was used for the calculation of CaO2 and CvO2.
The actual FiO2 in the inspiratory limb of the ven-tilator was measured by an in-line oxygen analyzer(TED200, Teledyne Electronic Devices, City of In-dustry, CA, U.S.A.). Changes in oxygenation wereassessed by direct measurements of PaO2 and FiO2.Then, the PaO2/FiO2 and alveolar-arterial oxygenpressure difference (A − aDO2) (calculated by as-suming a barometric pressure of 760 mm Hg and anRQ of 0.8) was compared. Respiratory frequency,tidal volume, inspiratory plateau airway pressure(Pplat) and mean airway pressure (mean Paw), totalPEEP (applied PEEP + intrinsic PEEP), and expi-ratory minute ventilation (MV) were monitored by aPatient Data Management System (FS-2100, FukudaElectronics, Tokyo, Japan) connected to the ventila-tor. Peripheral arterial oxygen saturation (SpO2) wasmonitored by a pulse oximeter attached to the bed-side monitor.
Administration of NONO was obtained from Taiyo Sanso Co. (Osaka,
Japan) as a mixture of approximately 800 ppm ofpure nitrogen. The concentration of nitrogen dioxide(NO2) was less than 4 ppm in this stock tank. NOand NO2 concentrations in the tank were certified bythe supplier. To maintain a constant INO concentra-tion, NO was administered with the NO delivery sys-tem of a Servo 900C ventilator (Siemens Elema,Lund, Sweden) using the low-pressure inlet (11),which premixes NO before it enters the ventilator.The concentrations of NO and NO2 in the inspira-tory limb were verified by a chemiluminescenceanalyzer (Model 42, Thermo Environmental Instru-ments, Franklin, MA, U.S.A.). Before measurements,the chemiluminescence analyzer was calibrated at 0and 16.11 ppm of NO. The methemoglobin concen-tration was measured during the study (Ciba Corn-ing 860, Chiron Diagnostics).
ProtocolAll patients were studied in a stable condition.
They were sedated and paralyzed with fentanyl, mid-azolam, and vecuronium. Patients’ lungs were venti-lated using time-cycled pressure-controlled ventila-tion (PCV) with the following ventilatory settings(control settings): FiO2 4 1.0, I:E 4 1:3 (33% inspi-ratory time, 0% pause time), respiratory frequency4 20 to 35 breaths/min, inspiratory pressure controllevel 4 15 to 25 cm H2O, and applied PEEP 4 6 to10 cm H2O. Peak airway pressure was limited to lessthan 40 cm H2O, permitting hypercarbia if necessary.These ventilator settings remained unalteredthroughout the study except for the I:E. The stan-dard medical treatment (for example, antibiotics andvasoactive drugs) also were not changed during thestudy.
Several studies suggested that mechanical ventila-tion with a high plateau pressure or a high PEEP wasrequired to achieve aeration of the lungs after pre-vious collapse whereas aeration of the lungs could bemaintained after this with lower levels of airwaypressures (12). These findings imply that if IRV hadbeen used first, the improvements might have per-sisted into the subsequent study intervals. To avoidthe aftereffects of IRV on the alveolar recruitment,the changes in I:E were not applied randomly to thepatients in the present study. Patients were sequen-tially exposed to increasing I:E from 1:3, 1:1, and to2:1, and exposure to INO (0 or 4 ppm) was randomlyassigned at each I:E for 30 min. Respiratory andcardiovascular parameters were measured after eachtest.
Statistical analysisAll values are expressed as the mean ± SD. A two-
factor repeated measure analysis of variance wasperformed to test for interaction between changesI:E and INO. A p value <0.05 was considered sig-nificant in this analysis. For internal comparisonsamong the 6 groups (3 I:E levels with or withoutINO), a one-factor repeated measure analysis ofvariance was performed. Multiple two-tailed paired ttests with Bonferroni correction were performed aspost hoc analyses. To keep the significance levels at0.05 in these multiple paired t tests, p values <0.0033(0.05/15) were judged to be statistically significant ineach t test.
ResultsTable 1 summarizes patient characteristics. All
were enrolled within 9 days after the onset of ARDS.The lung injury score was $2.7 in each case. Exceptfor Patient 3, all were receiving vasoactive drugs:dopamine <5 mg/kg/min in Patients 4 and 7, dopa-
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mine 5 to 10 mg/kg/min with or without dobutaminein Patients 1, 2, 5, 9, and 10, and dopamine greaterthan 10 mg/kg/min with or without noradrenaline inPatients 6 and 8. The APACHE II score was $22 ineach case. The mean mortality risk estimated by theAPACHE II score on the study day was 56 ± 12%while the final mortality rate was 60%.
Table 2 shows the overall effects of changes in I:Eand INO on respiratory and cardiovascular param-eters. There were statistically significant changes inMV (p < 0.0001), mean Paw (p < 0.0001), and totalPEEP (p < 0.0001) during the changes in the I:E. TheMV tended to increase during an I:E of 1:1 and de-creased during an I:E of 2:1. The mean Paw and totalPEEP increased significantly when the I:E was in-creased. There were statistically significant improve-ments in the mean values of PaO2/FiO2 (p < 0.0001),A-aDO2 (p < 0.0001), and Qv/Qt (p < 0.0001) whenthe I:E was increased. The improvements in arterialoxygenation were significant when an increased I:Eof 1:1 and INO were combined. The mean value ofPaO2/FiO2 during the combined use of an I:E of 1:1and INO was approximately twice as high as thecontrols (I:E of 1:3 without INO). The mean value ofPaO2/FiO2 during an I:E of 2:1 and INO was approxi-mately about 2.5 times as high as the controls. Themean PaCO2 value tended to decrease during an I:E
of 1:1, and the decrease in PaCO2 was associated witha tendency to increase in pH. The mean PAP andPVRI increased significantly when the I:E was in-creased. Although the mean values of MAP, SVRI,CI, and DO2 did not change significantly, decreasesin MAP, CI, and DO2 of more than 20% were ob-served during an I:E of 2:1 with INO in 2 patients(Patients 4 and 10). There were no statistically sig-nificant effects of INO on PaCO2, mean PAP, andPVRI.
Figure 1 shows individual changes in PaO2/FiO2
when the I:E was increased and when INO wasadded. Of the 10 patients studied, 7 showed a clini-cally meaningful increase of PaO2/FiO2 of $20 mmHg from baseline during an I:E of 2:1 without INO(responders) while 3 did not (nonresponders). Theresponders showed a marked increase in PaO2/FiO2
during the combined use of an I:E of 2:1 and INOwhile the nonresponders did not.
Figure 2 shows the mean effects of INO on PaO2/FiO2 and mean PAP under an increase in the I:Efrom 1:3 to 1:1 and 2:1 in 3 nonresponders and 7responders. The combination of an increase in theI:E and INO significantly improved arterial oxygen-ation in the responders while it did not in the non-responders. The combination of an increase in theI:E and INO had an additive effect on arterial oxy-
TABLE 2. Effects of inhaled NO and inverse ratio ventilation on the respiratory and cardiovascular parameters inpatients with sepsis-associated ARDS
I:E 4 1:3 I:E 4 1:1 I:E 4 2:1 ANOVA (p)
NO 0 ppm NO 4 ppm NO 0 ppm NO 4 ppm NO 0 ppm NO 4 ppm NO I:E
a Significant differences between NO 0 and 4 ppm at each I:E.b Significant differences from I:E 1:3 without NO.c Significant differences from I:E 1:3 with NO.d Significant differences from I:E 1:1 without NO.e Significant differences from I:E 1:1 with NO.f p < 0.05 (one-factor repeated measure analysis of variance).Values are mean ± SD. NO: nitric oxide, ARDS: acute respiratory distress syndrome, I:E: inspiratory to expiratory ratio, MV: expiratory
genation. There were no significant changes in meanPAP by the addition of INO in both nonrespondersand responders.
Methemoglobin levels did not rise above 1.5% inany patient. We did not observe any side effects ofINO therapy, that is, a high NO2 level, increasedbleeding time, or hypoxemia after discontinuation ofINO.
DiscussionThis study showed that IRV (an I:E of 2:1) with
INO was a more effective method of improving ar-
terial oxygenation than either IRV or INO alone.The combined effect of an increase in the I:E andINO on arterial oxygenation was additive.
Sepsis is the most common clinical disorder asso-ciated with the development of ARDS (2). AlthoughINO is not a curative therapy for sepsis-associatedARDS, it has been used to improve arterial oxygen-ation and provide time for the lungs to recover fromacute injury. However, this favorable effect on arte-rial oxygenation has not been observed in all pa-tients with ARDS (3). Krafft et al. (3) studied theeffects of 18 and/or 36 ppm INO on 25 septic shock
FIG. 1. Shown are individualchanges in PaO2/FiO2 inducedby an increase in the I:E from1:3 to 1:1 and 2:1 with or with-out INO at a concentration of 4ppm. Seven patients showed amarked improvement in arte-rial oxygenation during an I:Eof 2:1 (IRV) without INO (re-sponders) and 3 patients didnot (nonresponders).
FIG. 2. The mean effects of INOon PaO2/FiO2 and mean PAP un-der an increase in the I:E from1:3 to 1:1 and 2:1 in 3 nonre-sponders and 7 responders areshown. Values are mean ± SD(ANOVA: two-factor repeatedmeasure analysis of variance,NS: not significant.) a, signifi-cant differences between INO 0and 4 ppm at each I:E level; b,significant differences from I:E1:3 without INO; c, significantdifferences from I:E 1:1 withoutINO; d, significant differencesfrom I:E 1:3 with INO; e, signifi-cant differences from I:E 1:1with INO.
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patients with ARDS. They showed that INO im-proved arterial oxygenation and/or pulmonary hy-pertension in only 40% of patients.
IRV is a mode of ventilation that extends the in-spiratory time percentage of the respiratory cycle(5). Although it has not been firmly established thatIRV is better than conventional mechanical ventila-tion in ventilating patients with ARDS (5), IRV isused to limit or decrease the peak airway pressures.Pressure-controlled IRV, used in this study, is morewidely utilized than volume-cycled IRV in patientswith ARDS (5,13).
There was a wide variation in the magnitude of theindividual responses of PaO2 to the combined use ofIRV and INO. Associations were described betweenlevel of the baseline pulmonary vascular resistance(6), level of the baseline PaO2/FiO2 (14), and use ofphenylephrine (15) and the effect of INO on arterialoxygenation. We could not determine which factorswere associated with responsiveness to INO. In ad-dition, we could not find any significant changes inmean PAP by the addition of INO in both nonre-sponders and responders. However, patients who re-sponded to IRV had a good response to the com-bined use of IRV and INO. Patients who did notrespond to IRV had a poor response to the com-bined use of IRV and INO. These findings imply thatrecruitment of collapsed alveoli by an increase in theI:E is necessary to produce a beneficial effect of INOon arterial oxygenation. Putensen et al. (16) studiedthe effect of continuous positive airway pressurewith INO in mongrel dogs with oleic acid-inducedlung injury. They showed that INO did not improvearterial oxygenation unless PEEP was added. Thisfinding is consistent with our results and also impliesthat recruitment of collapsed alveoli is a prerequisitefor improving arterial oxygenation by INO.
To recruit collapsed alveoli in patients withARDS, the American-European Consensus Confer-ence on ARDS recommended to increase mean air-way pressure by adding PEEP or IRV (17). How-ever, there is no consensus whether an increase inmean airway pressure is best made by adding PEEPor IRV (17). As shown in previous studies on IRV(18), an increase in the I:E was associated with anincrease in mean Paw and total PEEP. Arterial oxy-genation is related to mean Paw and/or total PEEP(5). Mean Paw alters mean alveolar pressure and,thus, may promote alveolar recruitment (5). TotalPEEP also may prevent collapse of unstable airwaysand alveoli during expiration independent of meanPaw (5).
The effects of acute hypercarbia on pulmonary
and systemic circulation were evaluated extensively(19). Acute hypercarbia causes pulmonary vasocon-striction and pulmonary hypertension (19). All pa-tients were ventilated in accordance with the prin-ciples of permissive hypercarbia (20). Thus, 8patients were hypercarbic before the study (exceptPatients 3 and 9). In addition, in accordance withprevious studies (5,13,18), MV decreased because ofa decrease in tidal volume during IRV, and the de-crease in MV led to an increase in PaCO2. However,we did not find statistically significant changes inPaCO2 and PVRI after INO administration. Oka-moto et al. (14) found that the magnitude of thedecrease in PaCO2 during INO was remarkable inpatients with high baseline PaCO2 values. Puybassetet al. (19) showed that INO reversed the increase inpulmonary vascular resistance induced by acute hy-percarbia.
IRV is associated with several problems (5,13).IRV usually requires heavy sedation, relaxation, orboth to prevent patient-ventilator asynchrony. In ad-dition, the increase in mean Paw and PEEP duringIRV may be associated with pulmonary barotraumaand a decrease in CO (5,13). Although we did notfind significant changes in the mean values of MAP,CI, and DO2, there were decreases in MAP, CI, andDO2 of more than 20% in 2 patients. Therefore, therelative advantages of the combined use of IRV andINO should be balanced against the potential sideeffects.
The main limitation of this study is its short-termnature. IRV was administered for a 30 min period, atthe end of which measurements were done. Marcyand Marini (5) suggested that the effect of IRV onthe recruitment of collapsed alveoli was time depen-dent and that the maximal benefit took several hoursto achieve. This may be why 3 patients did not re-spond to IRV. Further study is needed to determinethe long-term combined effects of IRV and INO oncardiopulmonary parameters.
In conclusion, the combined use of IRV and INOis a more effective method of improving arterial oxy-genation than either IRV or INO alone. This com-bination of IRV and INO has the potential to rescuea hypoxemic patient.
Acknowledgments: This study was supported by Grants-in-Aid for Scientific Research Nos. 07457360 and09470333, Ministry of Education, Science and Culture, Ja-pan.
References
1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hud-son L, Lamy M, Legall JR, Morris A, Spragg R. The Ameri-can-European Consensus Conference on ARDS. Definitions,
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mechanisms, relevant outcomes, and clinical trial coordina-tion. Am J Respir Crit Care Med 1994;149:818–24.
2. Hudson LD, Milberg JA, Anardi D, Maunder RJ. Clinicalrisks for development of the acute respiratory distress syn-drome. Am J Respir Crit Care Med 1995;151:293–301.
3. Krafft P, Fridrich P, Fitzgerald RD, Koc D, Steltzer H. Ef-fectiveness of nitric oxide inhalation in septic ARDS. Chest1996;109:486–93.
4. Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM.Inhaled nitric oxide for the adult respiratory distress syn-drome. N Engl J Med 1993;328:399–405.
5. Marcy TW, Marini JJ. Inverse ratio ventilation in ARDS.Rationale and implementation. Chest 1991;100:494–504.
6. Puybasset L, Rouby JJ, Mourgeon E, Cluzel P, Souhil Z, Law-Koune JD, Stewart T, Devilliers C, Lu Q, Roche S, Kalfon P,Vicaut E, Viars P. Factors influencing cardiopulmonary ef-fects of inhaled nitric oxide in acute respiratory failure. Am JRespir Crit Care Med 1995;152:318–28.
7. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM,Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsisand organ failure and guidelines for the use of innovativetherapies in sepsis. Chest 1992;101:1644–55.
8. Murray JF, Matthay MA, Luce JM, Flick MR. An expandeddefinition of the adult respiratory distress syndrome. Am RevRespir Dis 1988;138:720–3.
9. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A,Bruining H, Reinhart CK, Suter PM, Thijs LG, for the Work-ing Group on Sepsis-Related Problems of the European So-ciety of Intensive Care Medicine. The SOFA (Sepsis-RelatedOrgan Failure Assessment) score to describe organ dysfunc-tion/failure. Intensive Care Med 1996;22:707–10.
10. Knaus WA, Draper EA, Wagner DP, Zimmerman JE.APACHE II: a severity of disease classification system. CritCare Med 1985;13:818–29.
11. Sato T, Okamoto K, Kukita I, Kikuta K, Hamaguchi M, Shi-ihara K, Shibata Y. Nitrogen dioxide production in a nitricoxide inhalation system using the Servo 900C ventilator. ActaPaediatr Jap 1997;39:172–5.
12. Sjostrand UH, Lichtwarck-Aschoff M, Nielsen JB, Mark-strom A, Larsson A, Svensson BA, Wegenius GA, NordgrenKA. Different ventilatory approaches to keep the lung open.Intensive Care Med 1995;21:310–8.
13. Slutsky AS. Mechanical ventilation. Chest 1993;104:1833–59.14. Okamoto K, Hamaguchi M, Kukita I, Kikuta K, Sato T. Ef-
ficacy of inhaled nitric oxide in children with ARDS. Chest1998;114:827–33.
15. Doering EB, Hanson CW, Reily DJ, Marshall C, MarshallBE. Improvement in oxygenation by phenylephrine and nitricoxide in patients with adult respiratory distress syndrome.Anesthesiology 1997;87:18–25.
16. Putensen C, Rasanen J, Lopez FA, Downs JB. Continuouspositive airway pressure modulates effect of inhaled nitricoxide on the ventilation-perfusion distributions in canine lunginjury. Chest 1994;106:1563–9.
17. Artigas A, Bernard GR, Carlet J, Dreyfuss D, Gattinoni L,Hudson L, Lamy M, Marini JJ, Matthay MA, Pinsky MR,Spragg R, Suter PM. The American-European consensus con-ference on ARDS, part 2. Ventilatory, pharmacologic, sup-portive therapy, study design strategies, and issues related torecovery and remodeling. Intensive Care Med 1998;24:378–98.
18. Poelaert JI, Vogelaers DP, Colardyn FA. Evaluation of thehemodynamic and respiratory effects of inverse ratio ventila-tion with a right ventricular ejection fraction catheter. Chest1991;99:1444–50.
19. Puybasset L, Stewart T, Rouby JJ, Cluzel P, Mourgeon E,Belin MF, Arthaud M, Landault C, Viars P. Inhaled nitricoxide reverses the increase in pulmonary vascular resistanceinduced by permissive hypercapnia in patients with acute re-spiratory distress syndrome. Anesthesiology 1994;80:1254–67.
20. Hickling KG, Henderson SJ, Jackson R. Low mortality asso-ciated with low volume pressure limited ventilation with per-
missive hypercapnia in severe adult respiratory distress syn-drome. Intensive Care Med 1990;16:372–7.
Comparative Analysis of Alpha-stat andpH-stat Strategies with a Membrane
Oxygenator During Deep HypothermicCirculatory Arrest in Young Pigs
Won Gon Kim, Cheong Lim, Hyun Jong Moon, andYong Jin Kim, Department of Thoracic andCardiovascular Surgery and Heart ResearchInstitute, BK 21 Human Life Sciences, SeoulNational University College of Medicine and
Clinical Research Institute, Seoul NationalUniversity Hospital, Seoul, Korea
Abstract: Using young pigs, this study compared the strat-egies of alpha-stat and pH-stat during deep hypothermiccirculatory arrest (DHCA) for the cooling time of brainsduring the induction of hypothermia and rewarming timewith cardiopulmonary bypass (CPB); the cerebral perfu-sion rate and metabolism rate, and the ratio of these 2rates; and the extent of the cerebral edema developmentafter circulatory arrest. Fourteen young pigs were assignedto 1 of 2 strategies of gas management. Cerebral bloodflow was measured with a cerebral venous outflow tech-nique. With CPB, core cooling was initiated and continueduntil the nasopharyngeal temperature fell below 20°C. Theflow rate was set at 2,500 ml/min. Once the temperaturereached below 20°C, the animals were subjected to DHCAfor 40 min. During the cooling period, the acid-base bal-ance was maintained using either alpha-stat or pH-statstrategy. After DHCA, the body was rewarmed to thenormal body temperature. The animals then were sacri-ficed, and we measured the brain water content. The ce-rebral perfusion and metabolism rates were measured be-fore the onset of CPB, before cooling, before DHCA, 15min after rewarming, and upon the completion of rewarm-ing. The cooling time was significantly shorter with alpha-stat than with pH-stat strategy while no significant differ-ences were observed in the rewarming time betweengroups. Also, no significant differences were found in ce-rebral blood flow volume, metabolic rate, or flow/metabolic rate ratio between groups. In each group, thecerebral blood flow volume, metabolic rate, and flow/metabolic rate ratio showed significant differences in bodytemperature. Brain water content showed no significantdifferences between the 2 groups. In summary, this studyfound no significant differences between alpha-stat andpH-stat strategies, except in the cooling time. The coolingtime was rather shorter with the alpha-stat than with thepH-stat strategy. Key Words: Deep hypothermic circu-
Received January 2000; revised April 2000.Address correspondence and reprint requests to Dr. Won Gon
Kim, Department of Thoracic and Cardiovascular Surgery, SeoulNational University Hospital, Seoul National University Collegeof Medicine, Yongon-Dong 28, Chongno-Gu, Seoul 110-744, Ko-rea. E-mail: [email protected]
Deep hypothermia and circulatory arrest are dra-matic applications demonstrating the protective ef-fects of hypothermia in cardiac surgery. However,the human body is unable to maintain normal physi-ology when exposed to such induced hypothermia,and the maintenance of bodily functions under sucha condition, especially that of acid-base balance, re-mains controversial (1–8). Particularly, controllingthe acid-base balance during a circulatory arrest un-der deep hypothermia strongly influences the func-tion of the central nervous system and thus is animportant risk factor for the development of adverseneuropsychiatric complications (9–13). Theoretical-ly, the advantages of the poikilotherm mechanism ofacid-base balance control, alpha-stat, are the pos-sible maintenance of intracellular neutral electrome-chanical states during hypothermia and the close re-semblance of coupling pattern of brain perfusion toits metabolic activity to that in the normal tempera-ture state. On the other hand, the advantages of thehibernator mechanism of acid-base balance control,pH-stat, are in stabilizing cerebral hemodynamicsand maintaining balanced cerebral perfusion thusproviding uniform cooling during hypothermia. ThepH-stat approach, however, carries the risk of devel-oping thromboembolism or cerebral edema. Thus,this study aims to compare alpha-stat with pH-statstrategy for the time required to cool brains duringthe induction of hypothermia and to rewarm withcardiopulmonary bypass; cerebral perfusion rate,brain metabolism rate, and their coupling ratio; andthe extent of cerebral edema development after car-diopulmonary bypass (CPB) in an experimentalmodel of hypothermic circulatory arrest in juvenilepigs.
Materials and methodsFor this study, juvenile pigs of both sexes weighing
25 to 30 kg were used. The 2 test subject groups ofalpha-stat and pH-stat consisted of 7 pigs each. Foranesthesia, 0.03 mg/kg of atropine was used as a pre-medication, and 15 to 20 mg/kg of ketamine and 15to 20 mg/kg of thiopental sodium were used as in-ducing agents. Intratracheal intubation was followedby ventilation with a volume-cycled ventilator. Formaintenance anesthesia, 0.5 to 1.0% halothane andsupplemental oxygen were used. Muscle relaxationwas maintained with a continuous infusion of Pan-curonium (0.25 mg/kg/h).
A cannula was inserted into the superior sagittal
sinus to measure the volume of cerebral blood flowand to take blood sampling of the cerebral vein (14–16). Before the onset of CPB, an incision was madeon the scalp followed by the removal of the perios-teum and bone overlying the sagittal sinus. To mini-mize extracranial blood input into the superior sag-ittal sinus, a 3 cm circular excision was made fromthe outer cortical layer and spongiosa area surround-ing the exposed region. Thereafter, a 24 Fr catheterwas inserted (Fig. 1). A Forgarty catheter then wasinserted into the sagittal sinus and inflated to pre-vent the inferior leakage whenever the sagittal sinusoutflow was measured. The weight of the braindrained by the catheter was presumed to average43% of the total brain weight although the study wasdone in dogs (17). The heart was revealed by a me-dian sternotomy, after which 300 IU/kg of heparinwas administered. Ascending-aortic and right-atrialcannulas were then inserted through purse-string su-tures with 5-0 prolene sutures. A pediatric mem-brane oxygenator (Univox-IC, Bentley Laborato-ries. Inc., Baxter Healthcare Corporation, Irvine,CA, U.S.A.) and a roller pump (American OpticalCorporation, Greenwich, CT, U.S.A.) were used.For priming solution, 500 ml of Pentaspan, 160 ml ofmannitol, and 700 ml of Hartman’s solution weregiven along with 54 mg of sodium bicarbonate. Thetotal priming volume given was 1,360 ml, and hemat-ocrit was adjusted between 18 and 20%. The perfu-sion rate was maintained at 2,500 ml/min. During thefirst 10 to 15 min after the onset of CPB, a normo-thermic perfusion was maintained while basic testswere performed. Perfusion cooling then was carriedout until the body temperature was decreased to20°C as measured in the nasopharynx. When the
FIG. 1. The schematic drawing shows the superior sagittal sinusoutflow measurement (superior sagittal sinus [1], Fogarty cath-eter [2], and sampling catheter [3] ).
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body temperature fell to 20°C, the circulation wasstopped for 40 min. After the arrest period, the bodywas rewarmed to normal body temperature. Duringthe cooling and rewarming period, the acid-base bal-ance was maintained according to either the alpha-stat or the pH-stat strategy (Tables 1 and 2). Theanimals then were sacrificed, and their brains wereremoved and examined for edema. The brains alsowere microscopically analyzed for signs of cerebralthromboembolism.
The cerebral perfusion and metabolism rates weremeasured before the onset of CPB, before perfusioncooling, before circulatory arrest, 15 min after re-warming, upon the completion of rewarming, and 1 hafter rewarming. The cerebral metabolism rate wascalculated according to the following equation: meta-bolic rate = cerebral blood flow × (arterial blood oxy-gen content − sagittal sinus blood oxygen content)/100. Arterial blood gas analyses were regularlycarried out as needed. Body temperature was mea-sured from the nasopharynx and the rectum. Theextent of cerebral edema was calculated by subtract-ing the dry weight of the brain from its wet weightand then dividing this value by the wet weight. Thedry weight of the brain was measured after subject-ing the brain to 72 h of dehydration at 60°C in adryer machine.
The measurements obtained from the 2 groups
were compared with the Wilcoxon rank sum testwhile the variations with each group were analyzedwith repeated measures ANOVA. A p value lessthan 0.05 was considered statistically significant.
ResultsThe cooling time was considered to be the time
taken for the nasopharynx temperature to reach20°C after CPB cooling was started. The rewarmingtime was considered to be the time taken for thenasopharynx temperature to reach 38°C after the on-set of rewarming. The cooling time for the alpha-statgroup was 16.57 ± 5.13 min, which was significantlyshorter than that of the pH-stat group, 22.83 ± 2.14min (p < 0.05). However, no significant differencewas observed in the rewarming time, which was 40.0± 5.07 min for the alpha-stat group and 46.5 ± 6.32min for the pH-stat group. While the values of thecerebral metabolic rate and cerebral perfusion as es-timated from the sagittal sinus outflow measurementwere higher in the pH-stat group than those in thealpha-stat group, the values were not statistically sig-nificant (Fig. 2). The perfusion-to-metabolic-rate ra-tios also showed no statistically significant differ-ence. However, a significant change was observed inthe cerebral perfusion and metabolic rate withineach group over the course of the experiment. Par-ticularly at 20°C, the brain metabolic rate fell more
TABLE 2. Gas amounts administered in alpha-stat and pH-stat acid-base managements
Cooling Rewarming
Temp (°C) O2 L/min FiO2 CO2 Temp (°C) O2 L/min FiO2 CO2
than the cerebral perfusion, so that the perfusion-to-metabolic-rate recorded was greater than 1. No sig-nificant difference was observed between groups inbrain water content (78.4 ± 5.56% for pH-stat, 81.93± 3.70% for alpha-stat). No signs of cerebral embo-lism were observed microscopically.
DiscussionDespite theoretical advantages and disadvantages
of alpha-stat and pH-stat, current studies revealedno significant difference between these 2 acid-basemanagement systems in terms of postoperative neu-ropsychiatric complications after CPB under moder-ate hypothermia (13). However, extrapolating theresults obtained using either of these systems undermoderate hypothermia directly into pediatric pa-tients under profound hypothermia is not reasonableand led us to compare alpha-stat and pH-stat underprofound hypothermia in young pigs. Until now,only limited experimental data were available onwhich of these 2 gas management systems would givebetter protection for brain metabolism, and no stud-ies compared the alpha-stat and pH-stat under pro-found hypothermia in the human body. However,there is a general consensus that a difference doesexist between the 2 mechanisms since values of thepH and Paco2 balance deviate far from their normalvalues. The results of this experiment showed no dif-ference between alpha-stat and pH-stat in the cere-bral metabolic rate at 20°C. While the cerebral per-fusion rate decreased along with the rate ofmetabolism at low temperatures, the cerebral bloodvessels remained responsive to PaCO2. Thus, the rela-tive hypercarbia under pH-stat allowed the dilata-
tion of cerebral vessels and a better perfusion ratethan under alpha-stat. While not statistically signifi-cant, a higher cerebral blood flow volume appearedto have been maintained in the pH-stat test groupthan in the alpha-stat test group. In an alert healthyanimal, brain perfusion and metabolism are deter-mined by regional metabolic demands. Such cerebralcoupling plays an important role in cerebral homeo-stasis. Under hypothermia, cerebral blood flow fallsproportionately, but brain metabolic rate falls expo-nentially. The perfusion-to-metabolic-rate ratio thusincreases with a fall in temperature. This experimentalso revealed the highest perfusion-to-metabolic-rate ratio at 20°C. However, there was no significantdifference in the perfusion-to-metabolic-rate ratiosbetween the 2 groups. The cerebral water content,used as a measure of edema, also showed no differ-ence. We did not observe any evidence of thrombo-embolism in the brain specimens of the groups. Aspreviously described, pH-stat has the theoretical ad-vantage of better cooling through luxuriant cerebralperfusion, which led us to anticipate that the pH-statwould show shorter cooling and rewarming timescompared to alpha-stat. However, alpha-stat showedthe statistically faster cooling time. While not statis-tically significant, alpha-stat also showed the ten-dency for a faster rewarming time. One possible ex-planation for these results is that more uniformcooling provided theoretically by pH-stat does notnecessarily mean fast cooling. Another possibility isthat the nasopharyngeal temperature measurement,which acts as a monitor to measure cerebral tem-perature, does not adequately reflect the global tem-perature of the brain in the pig. Further work with
FIG. 2. Shown are cerebral flow (A), metabolism (B), and cerebral blood flow/metabolism (C) before the onset of cardiopulmonary by-pass (#1), before cooling (#2), before deep hypothermic circulatory arrest (#3), 15 min after rewarming (#4), and on completion ofrewarming (#5).
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direct temperature measurement at multiple sites inthe brain of the animal may be needed to clarify thelatter problem although a small difference of coolingtime to induce deep hypothermic circulatory arrest isnot considered to offer a practical problem in clinicalsituations.
References
1. White FN. A comparative physiological approach to hypo-thermia. J Thorac Cardiovasc Surg 1981;82:821–31.
2. Malan A, Wilson TL, Reeves RB. Intracellular pH in cold-blooded vertebrates as a function of body temperature. RespirPhysiol 1976;28:29–47.
3. Swan H. The importance of acid-base management for car-diac and cerebral preservation during open-heart operations.Surg Gyn Obstet 1984;158:391–414.
4. Dickinson D, Sambrooks J. Intellectual performance in chil-dren after circulatory arrest with profound hypothermia ininfancy. Arch Dis Child 1979;54:1–6.
5. Jonas RA, Wernovsky G, Ware J. The Boston circulatoryarrest study: perioperative neurologic outcome after the arte-rial switch operation. Circulation 1992;86(Suppl 1):360A.
6. Grote CL, Shanahan PT, Salmon P, Meyer RG, Barrett C,Lansing A. Cognitive outcome after cardiac operations. JThorac Cardiovasc Surg 1992;104:1405–9.
7. Ferry PC. Neurologic sequelae of open-heart surgery inchildren. An irritating question. Am J Dis Child 1990;144:369–73.
8. Wright J, Hicks R. Deep hypothermic arrest. Observation onlater development in children. J Thorac Cardiovasc Surg 1979;86:466–8.
9. Nattie EE. The alpha-stat hypothesis in respiratory controland acid-base balance. J Appl Physiol 1990;69:1201–7.
10. Treasure T, Naftel DC, Conger KA, Garcia JH, Kirklin JW,Blackstone EH. The effect of hypothermic circulatory arresttime on cerebral function, morphology, and biochemistry. Anexperimental study. J Thorac Cardiovasc Surg 1983;86:761–70.
11. Watanabe T, Miura M, Inui K, Minowa T, Shimanuki T, Nish-imura K, Washio M. Blood and brain tissue gaseous strategyfor profoundly hypothermic total circulatory arrest. J ThoracCardiovasc Surg 1991;102:497–504.
12. Lundar T, Lindegaard KF, Froysaker T, Grip A, Bergman M,Am-Holen E, Nornes H. Cerebral carbon dioxide reactivityduring nonpulsatile cardiopulmonary bypass. Ann ThoracSurg 1986;41:525–30.
13. Hindman BJ. Cerebral physiology of hypothermia and hypo-thermic acid-base management during cardiopulmonary by-pass. Cardiol Young 1993;3:273–80.
14. Upton R, Grant C, Ludbrook G. An ultrasonic Doppler ve-nous outflow method for the continuous measurement of ce-rebral blood flow in conscious sheep. J Cereb Blood FlowMetab 1994;14:680–8.
15. Takeshita H, Michenfelder JD, Theye R. The effects of mor-phine and N-allylnormorphine on canine cerebral metabolismand circulation. Anesthesiology 1972;37:605–12.
16. Stange K, Lagerkranser M, Sollevi A. Effect of adenosine-induced hypotension on the cerebral autoregulation in theanesthetized pig. Acta Anesthesiol Scand 1989;33:450–7.
17. Michenfelder JD, Messick JM Jr, Theye RA. Simultaneouscerebral blood flow measured by direct and indirect methods.J Surg Res 1968;8:475–81.
Experimental Use of a CompactCentrifugal Pump and MembraneOxygenator as a Cardiopulmonary
Tsuyoshi Itoh, Department of Thoracic andCardiovascular Surgery, Saga Medical School,
Saga, Japan
Abstract: Compactness and high performance are themost important requirements for a cardiopulmonary sup-port system. The Nikkiso (HPM-15) centrifugal pump isthe smallest (priming volume; 25 ml, impeller diameter; 50mm) in clinically available centrifugal pumps. The KurarayMenox (AL-2000) membrane oxygenator, made ofdouble-layer polyolefin hollow fiber, has a minimum prim-ing volume (80 ml) and a low pressure loss (65 mm Hg at2.0 L/min of blood flow) compared with other oxygen-ators. The aim of this study was to evaluate the perfor-mance of the most compact cardiopulmonary support sys-tem (total priming volume: 125 ml) in animal experiments.The cardiopulmonary bypass was constructed in a caninemodel with the Nikkiso pump and Menox oxygenator incomparison with a conventional cardiopulmonary supportsystem. The partial cardiopulmonary bypass was per-formed for 4 h to evaluate the gas exchange ability, bloodtrauma, serum leakage, hemodynamics, and blood coagu-lative parameters. The postoperative plasma free hemo-globin level of the compact cardiopulmonary system was29.5 ± 10.21 mg/dl (mean ± SD), which was lower than thatof the conventional cardiopulmonary system, 48.75 ± 27.39mg/dl (mean ± SD). This compact cardiopulmonary systemprovided the advantage in terms of reduction of the prim-ing volume and less blood damage. These results suggestedthe possibility of miniaturization for the cardiopulmonarybypass support system in open-heart surgery in the nearfuture. Key Words: Compact cardiopulmonary sys-tem—Centrifugal pump—Membrane oxygenator—Hemolysis—Coagulation parameters.
In open-heart surgery, a majority of cardiopulmo-nary bypass (CPB) systems still utilize bulky rollerpumps. The continuous invasion of the CPB to thepatient is related to the CPB time, flow rate, totalinternal surface area, pressure gradient of the circuit,and biocompatibility of the material (1).
Currently, a compact atraumatic centrifugal pumpand membrane oxygenator are available for clinicaluse (2,3). The combination of these 2 devices is ex-
Received January 2000; revised June 2000.Address correspondence and reprint requests to Dr. Etsuro
Suenaga, Department of Thoracic and Cardiovascular Surgery5-1-1, Nabeshima, Saga 849, Japan.
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pected to be superior to the conventional CPB sys-tem. In this experiment, a compact atraumatic CPBcircuit, with only 125 ml of priming volume, was con-structed with the Nikkiso centrifugal pump (HPM-15, Nikkiso Co., Ltd., Tokyo, Japan) and the Menoxmembrane oxygenator (Dainippon Ink & Chemicals,Inc., Tokyo, Japan) using canines. This study evalu-ated the benefit of the compact circuit and the pos-sibility of miniaturization of the CPB system (4).
Material and methods
Compact cardiopulmonary systemFive healthy canines (20 kg) were anesthetized
with intravenous thiopental (25 mg/kg). With theanimal under anesthesia, endotracheal intubationwas performed, and ventilation was maintained by arespirator with room air. The right femoral arterywas exposed and cannulated for arterial pressuremonitor and blood sampling. A thoracotomy wasperformed through the bilateral fifth intercostalspace. After intravenous administration of heparinin a dose of 1 mg/kg, an arterial cannula (Sarns 5.2mm metal tip, 3M Health Care, Borken, Germany)was inserted into the ascending aorta, and a venouscannula (28 Fr, Research Medical Inc.) was insertedinto the right atrium.
The partial CPB was performed for 4 h to evaluatethe gas exchange ability, blood trauma, serum leak-age, hemodynamics, and coagulative parameters.Blood sampling was done preoperatively, at 60, 120,and 240 min after the beginning of CPB, and at 60min after the end of CPB.
Conventional CPB systemThe compact CPB system was compared with the
conventional CPB system. The conventional CPBsystem was established in 5 healthy canines (20 kg)in the same technique and with the same cannula.The system consists of the Pemco roller pump(Pemco, Inc., Cleveland, Ohio, U.S.A.) and Meraexcellan (HPO-15HF) oxygenator (Senko MedicalInstrument Mfg., Tokyo, Japan). Its priming volumewas 750 ml. The partial CPB was performed for 4 h,and blood sampling was done.
ResultsThe partial CPB was performed for 4 h with the
compact CPB system and the conventional system.The blood sampling data were analyzed in regard toblood trauma, blood coagulation parameters, andgas exchange ability.
Blood traumaFigure 1 shows the change of plasma free hemo-
globin values. The plasma free hemoglobin value at
pre-CPB was almost the same in 2 groups. AfterCPB was initiated, plasma free hemoglobin valuesincreased gradually. At 120 min after CPB was be-gun, the plasma free hemoglobin level of the con-ventional system was 37.54 ± 11.90 mg/dl (mean ±SD), which was higher than the compact system(19.50 ± 7.51 [mean ± SD]). The postoperativeplasma free hemoglobin level of the compact systemwas 29.5 ± 10.21 mg/dl (mean ± SD), which waslower than that of the conventional system (48.75 ±27.3 9 mg/dl [mean ± SD]).
Blood coagulationThrombin-antithrombin III complex (TAT) in-
creased linearly after the initiation of CPB; the maxi-mum value of the 2 groups was almost the same after4 h of pumping. However, at 60 min after CPBstarted, the TAT level of the conventional systemwas 23.50 ± 6.88 ng/ml, which was higher than thecompact system (7.25 ± 5.62 ng/ml) (Fig. 2A). Fi-brinogen tended to decrease as CPB time increasedin contrast to TAT. Its minimal level of compactCPB was 49.7 mg/dl at 4 h of pumping (Fig. 2B).
Gas exchange abilityOxygen of 100% saturation was provided to the
cardiopulmonary system at a rate of 2 L/min. The gasflow rate/blood flow rate ratio was 1.0. An excellentgas exchange ability was obtained during the partialCPB in both groups.
DiscussionIt has been over 40 years since the cardiopulmo-
nary support system was invented for cardiac sur-gery. However, it is still a bulky system with a largepriming volume of the blood circuit. Clinically, thisprovokes several disadvantages for the patient.
This study proved that the compact system causedless blood trauma and less activation of blood coagu-
FIG. 1. The graph shows changes of plasma free Hb with theconventional versus the compact CPB (CPB: cardiopulmonarybypass).
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lation parameters, and is more beneficial comparedwith the conventional system. Plasma free hemoglo-bin data of the compact CPB system varied similarlyas clinical cases. However, the maximum value wasstatistically lower than that of the conventional sys-tem. TAT increased linearly after the initiation ofCPB; in other words, thrombin was produced duringCPB (5,6). The compact CPB system maintained theactivation of thrombin production to a minimumcompared with the conventional system.
These results revealed that benefits of the com-pact system were due to several reasons, such as thepump, oxygenator, and minimal priming volume ofthis system. First, the Nikkiso (HPM-15) centrifugalpump is the smallest of the clinically available cen-trifugal pumps. To reduce the thrombus formation,especially around the V-ring, 6 small holes are incor-porated in the impeller (7). In vitro tests comfirmedthat the Nikkiso centrifugal pump indicated theminimal hemolysis effect compared with other clini-cally available centrifugal pumps. Second, the Kura-ray Menox (EL-2000) membrane oxygenator ismade of a double-layer polyolefin hollow fiber. Theefficient disposition of the hollow fibers does notallow any channeling of blood and brings about ahigh gas exchange ability. This solid membrane isefficient in preventing liquid leakage even under theextraordinarily high pressure caused by the high ro-tational speed of centrifugal pump. Its priming vol-ume is 80 ml and causes a 65 mm Hg pressure loss at2.0 L/min of blood flow.
This compact CPB system has only 125 ml ofblood circuit. The minimal priming volume is equalto the minimal blood contact surface area of circuit,and for this reason, reactions between the blood andsurface of the circuit were able to keep a minimumlevel during the experiment.
ConclusionsThis compact CPB system provided the advantage
in terms of reducing the priming volume and blooddamage. These results suggest that the possibility ofminiaturization exists for the CPB system in open-heart surgery in the near future.
References
1. Sasako Y, Nakatani T, Akagi H, Matsuki O, Miura R, YaudaK. New compact integrated cardiopulmonary bypass unit forpercutaneous cardiopulmonary support. In: Akutsu T, Koy-anagi H, eds. Heart Replacement. Artificial Heart 4. Tokyo:Springer-Verlag, 1993:217–20.
2. Ninomiya J, Shoji T, Tanaka S, Ikeshita M, Ochi M, Yamau-chi S, Yajima T, Yamauchi H, Sugimoto T, Aizawa T. Clinicalevaluation of a new type of centrifugal pump. Artif Organs1994;18:702–5.
3. Tatsumi E, Taenaka Y, Nakatani T, Akagi H, Sekii H, YaguraA, Sasaki E, Goto M, Nakamura H, Takano H. A VAD andnovel high performance compact oxygenator for long-termECMO with local anticoagulation. ASAIO Trans 1990;36:M480–3.
4. Fukui Y, Kawamura T, Higami T, Funakubo A, Sakuma I.Development of an all-in-one percutaneous cardiopulmonarybypass support system. Artif Organs 1993;17:313–7.
5. Oba J, Shinya N, Matsui Y, Goda T, Sakuma M, Yasuda K.The alternation of coagulation and fibrinosis after open-heartsurgery under cardiopulmonary bypass. Jpn J Artif Organs1994;23:243–6.
FIG. 2. Changes of TAT with theconventional versus the compactCPB are shown (A). Changes offibrinogen with the conventionalversus the compact CPB systemare shown (B) (TAT: thrombin-antithrombin complex, CPB: car-diopulmonary bypass).
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6. Nakajima H. A clinical study on hemostatic fluctuation duringand after cardiopulmonary bypass using hemostatic molecularmarkers. Jpn J Thorac Surg 1995;40:1992–7.
7. Sasaki T, Jikuya T, Aizawa T, Shiono M, Sakuma I, TakataniS. A compact centrifugal pump for cardiopulmonary bypass.Artif Organs 1992;16:592–8.
Development of an AffordableDiaphragmatic Pump for
Chunxiu Ye, and Zhengxiang Luo, Department ofCardiovascular Surgery and LVAD Laboratory,Guangdong Provincial Cardiovascular Institute,
Guangzhou, People’s Republic of China
Abstract: A new diaphragmatic pump (L-Y pump) and itsdrive unit were developed in our institute. The pump hasa priming volume of 80 ml. The pump housing is 72 mm indiameter and 42 mm in height. Its total weight is 139 g. Toassess and confirm the function and controllability of thispump, comparative studies of cardiopulmonary bypass(CPB) with L-Y pump (group A) and conventional rollerpump (Group B) were performed using dogs. Both pumpsprovided pump flow of 90 to 100 ml/kg/min. The hemody-namics of both groups were stable and within the normalrange. No leakage or thrombus formation was observed inthe L-Y pump. All biochemistry data showed no signifi-cant differences between the 2 groups. This data demon-strated low plasma-free hemoglobin levels in the L-Ypump group; after 120 min of CPB, mean plasma freehemoglobin levels were 48.7 ± 8.6 mg/dl in the roller pumpgroup and 21.4 ± 7.1 mg/dl in the L-Y pump group, andminimal hemolysis was indicated. In conclusion, this L-Ypump and its controller system might be useful for CPB interms of its low hemolysis and good pump quality. Thispump demonstrated easy manipulation, good controllabil-ity, and provided a sufficient pulsatile flow. This pump issuitable not only for CPB, but also as a long-term circula-tory support system. Key Words: New diaphragmaticpump—Cardiopulmonary bypass—Hemolysis—Plasmafree hemoglobin.
Cardiovascular operations involving cardiopulmo-nary bypass (CPB) using the roller pump have beenroutinely performed around the world. However, the
roller pump takes a longer time to set up, uses muchmore tubing, and needs a great deal of space in theoperating room. To solve these problems, varioustypes of centrifugal pumps recently were developedand used clinically (1–3). The major problems asso-ciated with using centrifugal pumps are bloodtrauma, thrombus formation, and leakage of bloodinto the actuator chamber (4). We developed a dia-phragmatic pump (L-Y pump) intended as a CPBpump. We report here on the function, controllabil-ity, hemodynamics, and changes of myocardial en-zyme, hematology, and hemolysis during CPB usingthe L-Y pump in an in vivo experiment.
Materials and methods
DeviceWe developed the L-Y pump at Guangdong Pro-
vincial Cardiovascular Institute, China. It is a pulsa-tile pneumatic ventricular assist device. The pumphousing is 72 mm in diameter and 42 mm in height.Its total weight is 139 g, and the priming volume is80 ml. The ventricle is made of polyurethanewith a double-layer inner displacement mem-brane and is pneumatically driven. The mechanicalvalves (St. Vincent’s valve, Guangzhou Pacific Bio-medical Products Ltd., China) are incorporatedseamlessly, and the ventricle is totally transparent toallow visual control of filling and emptying and ob-servation of any air during installment of the systemor clot formation during prolonged pumping. Thedesign of the ventricle was optimized by the de-mands of fluid dynamics (Fig. 1). Three L-Y pumpspassed a durability test of over 200 days with noabnormalities.
The drive unit (Fig. 2) can be operated by externalpower, pressure, and vacuum sources. It generatesup to 300 mm Hg positive pressure and to −300 mmHg negative pressure at rates up to 180 bpm. It canbe used in a fixed rate, and the pump systole can beadjusted to different systolic time percentage. Thedrive unit is operated by a monitor displaying theoperational status of the pump.
Experimental study for cardiopulmonary bypassA total of 18 dogs were used in the experiment.
Ten dogs (22.3 ± 2.9 kg body weight), Group A, weresupported by the L-Y pump. In the experimentalgroup, the CPB circuit consisted of 1 L-Y pump, adrive system, a Terumo Capiox SX membrane oxy-genator which was put on the inflow side of thepump, a cardiotomy reservoir, and suction lines. An-other 8 dogs (23.3 ± 3.7 kg body weight), Group B,
Received January 2000; revised March 2000.Address correspondence and reprint requests to Dr. Xuejun
Xiao, Department of Cardiovascular Surgery and LVAD Labo-ratory, Guangdong Provincial Cardiovascular Institute, 96 Dong-chuan Road, Guangzhou 510100, People’s Republic of China.
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using conventional roller pumps for CPB were com-pared.
The dog was placed on the operating table in asupine position. A central venous pressure (CVP)and an arterial pressure line were inserted into thefemoral vein and artery, respectively. A median ster-notomy was performed.
Heparin at 3 mg/kg of body weight was adminis-
tered by bolus injection. The activated clotting time(ACT) was maintained at 480 to 600 s during CPB.An arterial cannula (20 Fr) was inserted into theascending aorta, and 28 Fr venous cannulas wereinserted into the superior and inferior vena cavae,respectively, from the right atrium. After connectionof each cannula, the CPB circuit was primed withcrystalloid solution, and CPB was initiated. Whenhypothermia (30°C) was routinely induced with corecooling on the bypass for periods of 5 to 10 min, 2tourniquets were placed around both vena cavae andtightened, aortic cross-clamping, and cold crystalloidcardioplegic protection. The aortic cross-clampingtime was 2 h, and CPB time was 2.5 h. The drivepositive pressure was 150 to 300 mm Hg, the nega-tive pressure −50 to −200 mm Hg, the frequency 60to 90/min, and the systolic time percentage 30%to 40%. Bypass flow was kept at 90 to 120ml?kg−1?min−1. The flow was assessed by an electro-magnetic blood flowmeter (MFV-2100, Nihon Ko-hden Co., Tokyo, Japan). From the beginning of theoperation, CVP, arterial pressure, heart rate, urineoutput, and fluid intake were recorded continuously.Blood gas analysis, hematology (red and white bloodcells, hemoglobin, hematocrit [Ht], and platelets),aspartate translocase (AST), lactic dehydrogenase(LDH), creatine phosphokinase isoenzyme (CK-MB), and plasma free hemoglobin were examinedbefore CPB and 30 min, 1 h, and 2 h after CPB. TheL-Y pump was examined macroscopically and mi-croscopically after CPB.
Comparison between the groups was analyzed us-ing the Student’s t test for unpaired data. All resultswere expressed as mean ± SD, and a p value lessthan 0.05 was considered statistically significant.
ResultsIn all 18 dogs, CPB was successfully maintained
during the 2.5 h period without any difficulties, andweaning from CPB was possible. In Group A, thepulsatile flow maintained stable hemodynamics dur-ing CPB. After aortic cross-clamping release, allhearts returned sinus rhythm spontaneously except1, which incurred ventricular fibrillation and con-verted to sinus rhythm after using lidocaine. InGroup B, 7 hearts returned to sinus rhythm afteraortic cross-clamping release; 1 needed defibrilla-tion. All dogs regained consciousness. After CPB,the L-Y pump demonstrated the smooth surface ofthe pump without thrombus formation, leakage, ormechanical abnormality.
During pumping, the pump flow of the L-Y pumpwas 2.4 ± 0.4 L/min while that of the roller pump was2.2 ± 0.6 L/min. There was no significant difference
FIG. 1. Shown is the diaphragmatic pump (L-Y pump).
FIG. 2. The drive unit of the L-Y pump is shown.
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between groups. Before and after the CPB, bothgroups showed similar values in hemodynamics,heart rate, and rectal temperature. During pumping,Group A demonstrated a higher mean aortic pres-sure and a CVP than did Group B (Table l).
After the CPB, Ht was reduced to 60% to 70% ofpreoperative values, demonstrating no significantdifference between groups. Platelets were consumedto around 30% to 40% of the initial values during 2h of CPB in both groups. There were no significantdifferences between groups. The AST, LDH, andCK-MB showed no significant differences in eithergroup. The plasma free hemoglobin levels of GroupA were lower than that of Group B, 21.4 ± 7.1 mg/dland 48.7 ± 8.6 mg/dl, respectively; there were signifi-cant differences between these values (p < 0.05). Af-ter CPB, all L-Y pumps were examined macroscopi-cally and microscopically. There was no thrombusformation, leakage, or mechanical abnormality.
using the roller pump have been routinely per-formed around the world, we selected the rollerpump as a standard against which to compare theL-Y pump. According to the results of the pumpingconditions and hemodynamic changes, both pumpsprovided flows that were satisfactory to maintain thesystemic circulation during CPB. There were almostno differences in the hemodynamic changes betweenthe 2 pumps, which demonstrated normal values.
From our data demonstrating lower plasma freehemoglobin levels in the L-Y pump group, after 120min of CPB, mean plasma free hemoglobin levelswere 48.7 ± 8.6 mg/dl in the roller pump group and21.4 ± 7.1 mg/dl in the L-Y pump group; minimalhemolysis was indicated. When CPB time was ex-tended, this L-Y pump was significantly effective inrestricting hemolysis compared with the roller pumpgroup. In both groups, Ht was decreased after the
initiation of CPB because the circulating blood wasdiluted by the crystalloid solution, which was initiallyprimed into the CPB circuit. The platelets weregradually decreased during pumping because of con-sumption.
The L-Y pump is a pulsatile pump that can createsufficient pulsatile flow during CPB with both car-diac arrest and the beating heart of the reperfusionperiod. Pulsatile flow increases oxygen consumptioncompared with nonpulsatile flow. The increased oxy-gen consumption during pulsatile flow was inter-preted as beneficial, especially because most studiesshowed decreased lactic acid production as well. Areduction in peripheral vascular resistance and thebeneficial effects on several organ systems also weredocumented during pulsatile perfusion (5–7). In thisexperiment, the mean aortic pressure and CVP dur-ing pumping were significantly higher in Group Athan in Group B.
In conclusion, the L-Y pump and its controllersystem might be useful for CPB in terms of its lowhemolysis and good pump quality. This pump dem-onstrated easy manipulation, good controllability,and provided a sufficient pulsatile flow. The L-Ypump is suitable not only for CPB, but also as along-term circulatory support system.
Acknowledgments: This study was partly supported byspecial coordination funds of the Science and TechnologyCommittee and Ministry of Health of the People’s Repub-lic of China (1996–2000).
References
1. Taguchi S, Yozu R, Mori A, Aizawa T, Kawada S. A minia-turized centrifugal pump for assist circulation. Artif Organs1994;18:664–8.
2. Iatridis E, Chan T. An evaluation of vortex, centrifugal, androller pump systems. In: Schima H, Wiselthaler G, Thoma H,Wolner E, eds. Proceedings of the International Workshop onRotary Blood Pumps, 1991:124–31.
3. Orime Y, Takatani S, Sasaki T, Aizawa T, Ohara Y, Naito K,Glueck J, Noon GP, Nose Y, DeBakey ME. Cardiopulmo-
m-AoP: mean aortic pressure, m-CVP: mean central venous pressure, HR: heart rate, bpm: beats perminute, RT: rectal temperature, NS: not significant.
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nary bypass with Nikkiso and BioMedicus centrifugal pumps.Artif Organs 1994;18:11–6.
4. Sasaki T, Jikuya T, Aizawa T, Shiono M, Sakuma I, TakataniS, Glueck J, Noon GP, Nose Y, DeBakey ME. A compactcentrifugal pump for cardiopulmonary bypass. Artif Organs1992;16:592–8.
5. Ninomiya J, Shoji T, Tanaka S, Ikeshita M, Ochi M, YanauchiS, Yajima T, Yamauchi H, Sugimoto T, Aizawa T. Clinical
evaluation of a new type of centrifugal pump. Artif Organs1994;18:702–5.
6. Dunn J, Kirsh MM, Harness J, Carrol M, Straket J, Sloan H.Hemodynamic, metabolic, and hematologic effects of pulsa-tile cardiopulmonary bypass. J Thorac Cardiovasc Surg 1974;68:138–47.
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