Continuous Pulmonary Perfusion DuringCardiopulmonary Bypass Prevents Lung Injury inInfantsTakaaki Suzuki, MD, Toyoki Fukuda, MD, Tsutomu Ito, MD, Yoshito Inoue, MD,Yasunori Cho, MD, and Ichiro Kashima, MDDivision of Cardiovascular Surgery, Tokyo Metropolitan Children’s Hospital, Tokyo, Japan

Background. Lung injury after cardiopulmonary by-pass is a serious complication for infants with congenitalheart disease and pulmonary hypertension. Excessiveneutrophil sequestration in the lung occurring after re-establishment of pulmonary circulation implies that in-teraction between neutrophils and pulmonary endothe-lium is the major cause of lung injury.

Methods. Thirty infants with either ventricular septaldefect or atrioventricular septal defect and with pulmo-nary hypertension were enrolled in this study. We per-formed continuous pulmonary perfusion during totalcardiopulmonary bypass on 16 patients (perfused group)and conventional cardiopulmonary bypass on 14 patients(control group). PaO2/FiO2 and neutrophil counts wereassessed from immediately before surgery to 24 hoursafter termination of cardiopulmonary bypass.

Results. PaO2/FiO2 was higher in the perfused groupthan in the control group, and the difference was signif-icant throughout the study period. Neutrophil countsdecreased below prebypass values in both groups at 30minutes after aortic unclamping, and the difference wassignificant in the control group but was not in theperfused group. Duration of postoperative ventilatorysupport was significantly less in the perfused group.

Conclusions. Our study demonstrates that arrested pul-monary circulation during cardiopulmonary bypass isthe major risk factor of lung injury and that continuouspulmonary perfusion is effective in preventing lunginjury.

(Ann Thorac Surg 2000;69:602–6)© 2000 by The Society of Thoracic Surgeons

Although technical refinements of cardiopulmonarybypass (CPB) have progressively improved the re-

sults of cardiac surgery, postoperative lung dysfunctionremains as a serious complication that could lead to alife-threatening problem, particularly for infants withcongenital heart disease and pulmonary hypertension[1]. Previous reports have demonstrated that direct con-tact of blood with the synthetic surface of the CPB circuitinduces systemic inflammatory response [2] and progres-sive accumulation of neutrophils in the pulmonary cir-culatory system [3], which are presently known to resultin tissue injury mediated by neutrophil-endotheliuminteraction and oxygen-derived free radicals [4, 5]. Inaddition, ischemic insult and reperfusion are known toinduce the lung to be damaged. Because neutrophilsequestration usually occurs in the lung during CPB,particularly when the pulmonary circulation is reestab-lished after an arrest [6–8], it is highly probable thatcontinued pulmonary circulation throughout the periodof CPB will minimize ischemic insult and prevent lunginjury. With these considerations in mind, we performedcontinuous pulmonary perfusion during total CPB andassessed its efficacy against the lung injury.

Patients and Methods

PatientsThirty infants with either ventricular septal defect (VSD)or atrioventricular septal defect (AVSD) and with pulmo-nary hypertension were enrolled in this study. Pulmo-nary hypertension was defined as pulmonary-to-systemic arterial systolic pressure ratio of greater than 0.5(Pp/Ps . 0.5). The ages of the patients at the definitivesurgical repair were limited to less than 1 year, so as tomake their perioperative conditions uniform. Hence,their ages ranged from 1 to 11 months (mean 5.8 6 0.5months). There were 26 patients with VSD and 4 patientswith complete form of AVSD. The patients were allocatedto the perfused (n 5 16) and the control (n 5 14) groupsat random before operation. The perfused group under-went continuous pulmonary perfusion during total CPB,whereas the control group underwent conventional CPBwithout corresponding pulmonary perfusion. Their dataare depicted in Table 1. This study was approved by theEthics Committee of Tokyo Metropolitan Children’s Hos-pital, and informed consent was obtained from all par-ents of the patients.

ANESTHESIA. Anesthetic management consisted of con-trolled mechanical ventilation and intravenous infusionof fentanyl and incremental doses of pancuronium bro-mide as required for neuromuscular blockade.

Accepted for publication July 27, 1999.

Address reprint requests to Dr Suzuki, Division of Cardiovascular Sur-gery, Tokyo Metropolitan Children’s Hospital, 1-3-1 Umezono, Kiyose-shi, Tokyo, 204-8567 Japan; e-mail: suzuki@chp.kiyose.tokyo.jp.

© 2000 by The Society of Thoracic Surgeons 0003-4975/00/$20.00Published by Elsevier Science Inc PII S0003-4975(99)01332-6

CARDIOPULMONARY BYPASS. The CPB circuit consisted of aroller pump (Stockert Instrument GMBH, Munich, Ger-many) and a membrane oxygenator (VPCML; COBELaboratories, Inc, Denver, CO; Capiox SX-10; TermoCorporation, Shizuoka, Japan). The circuit was primedwith lactated Ringer’s solution, albumin, mannitol, andleukocyte-depleted whole blood to achieve and maintainthe hematocrit value greater than 20%. Depletion of theleukocyte was achieved by leukocyte removal filter (Se-pacell; Asahi Medical Co, Ltd, Tokyo, Japan). Anticoag-ulation was accomplished by intravenous administrationof heparin sulfate (300 IU/kg), which was neutralizedwith protamine sulfate at the end of the operation.During CPB, nonpulsatile flow was maintained at 150mL/kg/min. All patients were cooled with the perfusateto a moderate hypothermic state ranging from 28°C to30°C. Cardiac arrest was accomplished by aortic cross-clamp and infusion of high-potassium (20 mEq/L) bloodcardioplegia (20 mL/kg) into the aortic root. The samesolution was repeatedly infused in 60-minute intervals(10 mL/kg) during aortic cross-clamp and immediatelybefore unclamping. Blood gas management during CPBwas directed toward maintenance of pH at 7.35 to 7.40and arterial carbon dioxide tension (PaCO2) at 35 to40 mm Hg. Arterial oxygen tension (PaO2) was main-tained higher than 150 mm Hg. Blood gas managementwas conducted according to the principle of alpha-statmanagement, where temperature correction of the mea-sured pH and PaCO2 were not performed.

During total CPB, the perfused group underwent con-tinuous pulmonary perfusion with the oxygenated bloodat the flow rate of 30 mL/kg/min. The perfusate wasinfused into the pulmonary arterial trunk through an18-gauge pediatric cardioplegia cannula (DLP, Inc,Grand Rapids, MI) and was drained away from the leftatrium through a vent circuit to secure a bloodless field.The continuous pulmonary perfusion was continued un-til unclamping of the aorta. By contrast, the pulmonaryartery was not perfused in the control group, so that theforwarded pulmonary blood flow was arrested duringtotal CPB. The mechanical ventilation was arrested in

both groups with positive endexpiratory pressure at 5 cmH2O.

LUNG FUNCTION. Arterial blood gas analysis was performedwith the samples obtained from the peripheral systemicartery (Blood Gas System 288; Ciba Corning, Medfield,MA). The ratio of arterial oxygen tension to inspiredoxygen fraction (PaO2/FiO2 ratio) was used as the param-eter of the pulmonary function and was measured beforethe operation and at 3, 6, 12, and 24 hours after thetermination of CPB. All patients were kept sedated withcontinuous intravenous infusion of morphine sulfate andwere ventilated mechanically for at least 24 hours aftertermination of CPB.

LEUKOCYTE COUNTING. Blood samples were obtained fromthe peripheral systemic artery as well as blood gasanalysis, and the neutrophils were counted before theoperation, at 30 minutes after removal of the aorticcross-clamp, and immediately after termination of CPB.Measurements were made by Coulter counter (SE-9000;Sysmex Corporation, Kobe, Japan) and the values werecorrected for the hematocrit values at the respectivesampling points.

STATISTICAL ANALYSIS. Statistical analysis was performedwith StatView software (Abacus Concepts, Inc, Berkeley,CA). Data were expressed as mean plus or minus stan-dard error of the mean. An unpaired t test was used todetermine differences between the groups. One-way re-peated-measures analysis of variance (ANOVA) followedby the multiple comparison method was used to detectdifferences among the sampling points within eachgroup. Two-way repeated-measures ANOVA was usedto determine differences between the groups over time ofthe study. A p value less than 0.05 was consideredstatistically significant.

Results

There were no significant differences between groupswith respect to age, body weight, duration of CPB,duration of the aortic cross-clamp, preoperative pulmo-nary-to-systemic arterial systolic pressure ratio, pulmo-nary-to-systemic flow ratio, and pulmonary-to-systemicvascular resistance ratio (Table 1). Pulmonary-to-systemic arterial systolic pressure ratio at the terminationof CPB revealed no significant difference between thegroups (0.35 6 0.03 vs 0.33 6 0.02, p 5 0.5083).

LUNG FUNCTION. In both groups, the PaO2/FiO2 ratio de-creased gradually during the period from 3 to 12 hoursafter termination of CPB and showed the nadir at 12hours. Then, the values increased by 24 hours andapproached near to the prebypass value in the perfusedgroup, but stayed less than that in the control group (Fig1). At each measuring point, the PaO2/FiO2 ratio of theperfused group was significantly higher than that of thecontrol group. Namely, the mean values of the perfusedvs the control group at 3, 6, 12 and 24 hours after the

Table 1. Characteristics of Patients in Perfused and ControlGroups

CharacteristicPerfused Group

(n 5 16)Control Group

(n 5 14)p

Value

Age (months) 5.9 6 0.6 5.6 6 0.8 0.726Body weight (kg) 4.6 6 0.2 4.5 6 0.3 0.821Pp/Ps 0.81 6 0.04 0.79 6 0.04 0.774Qp/Qs 3.48 6 0.28 3.78 6 0.26 0.440Rp/Rs 0.17 6 0.02 0.17 6 0.02 0.932Duration of CPB (min) 125.4 6 7.9 131.9 6 7.3 0.559Duration of AoX (min) 60.1 6 5.9 66.2 6 5.5 0.460

Data are mean 6 standard error of the mean.

AoX 5 aortic cross-clamp; CPB 5 cardiopulmonary bypass; Pp/Ps 5 pulmonary-to-systemic arterial systolic pressure ratio; Qp/Qs 5pulmonary-to-systemic flow ratio; Rp/Rs 5 pulmonary-to-systemicvascular resistance ratio.

603Ann Thorac Surg SUZUKI ET AL2000;69:602–6 CONTINUOUS PULMONARY PERFUSION DURING CPB

termination of CPB were: 384.4 6 24.9 vs 281.2 631.9 mm Hg ( p 5 0.0155), 347.8 6 30.1 vs 217.5 628.6 mm Hg ( p 5 0.0043), 295.3 6 17.4 vs 165.8 616.2 mm Hg ( p , 0.0001), and 336.1 6 21.1 vs 257.1 626.2 mm Hg ( p 5 0.0248), respectively (Fig 1). Whencompared with the prebypass value, the postbypassvalues of the control group were significantly lessthroughout the postbypass period, namely at 3 hours( p 5 0.0053), 6 hours ( p , 0.0001), 12 hours ( p ,0.0001), and 24 hours ( p 5 0.0007). By contrast, only 12hours after the termination of CPB was the value signif-icantly lower than prebypass value in the perfused group( p 5 0.0083) (Fig 1). Moreover, the trend of the PaO2/FiO2 ratio revealed a significant difference between thegroups by two-way repeated-measures ANOVA ( p 50.0031).

LEUKOCYTE COUNTING. The behavior of the neutrophilcounts during CPB was biphasic in both groups, wherethe values of the perfused group remained higher thanthose of the control group, but without statistical signif-icance by two-way repeated-measures ANOVA ( p 50.2666) (Fig 2). The neutrophil counts at 30 minutes afterremoval of the aortic cross-clamp were lower than theprebypass values in both groups. The difference wassignificant in the control group ( p 5 0.0192) but was notin the perfused group. By contrast, the values at thetermination of CPB increased in both groups to the extentthat they exceeded the prebypass values. The incrementwas significant in the perfused group ( p 5 0.0164) andwas not in the control group (Fig 2). As for comparisonbetween the groups, the neutrophil counts at 30 minutesafter unclamping were higher in the perfused group thanin the control group but without statistical significance(3,095.2 6 355.5 vs 2,205.2 6 261.1 cells/mm3, p 5 0.098).Likewise, the neutrophil counts at the termination of CPBwere higher in the perfused group than in the controlgroup but without statistical significance (5,030.6 6 640.7vs 3,974.7 6 517.9 cells/mm3, p 5 0.1247) (Fig 2).

PERIOPERATIVE REQUIREMENT OF VENTILATORY SUPPORT AND MOR-

TALITY. Duration of the mechanical ventilatory supportwas significantly less in the perfused group (67.2 6 13.8hours) than in control group (183.8 6 56.5 hours) ( p 50.049). There was one hospital death in the control groupbut none in the perfused group. The only death occurredin a 3-month-old female infant with VSD and Down’ssyndrome whose postoperative dysfunction of the lungwas severe enough to require an extracorporeal mem-brane oxygenation (ECMO) support at postoperative day5. Although she weaned from ECMO, she succumbed tothe recurred pulmonary dysfunction and multiple organfailure.

Comment

Despite the extensive investigations in relevance to CPB,postoperative dysfunction of the lung remains as a life-threatening problem, particularly among infants withcongenital heart diseases revealing high pulmonaryblood flow and pressure [1]. Previous studies have dem-onstrated that exposure of blood to the synthetic surfaceof the CPB circuit activates the complements, therebyprovoking a systemic inflammatory response [2], andCPB elevates the values of the circulating inflammatorycytokines [9, 10], which exerts activating stimuli on theendothelial cells. The activated endothelial cells promotewidespread expression of a variety of adhesion mole-cules, which play crucial roles in adhesion of the com-plement-activated neutrophils to the endothelial cell sur-face and also in the subsequent neutrophil migration intothe extravascular space [11–13]. Once bound to the en-dothelium, the activated neutrophils release cytotoxicprotease and oxygen-derived free radicals, which areresponsible for the end-organ damage [4, 5]. According tothis evidence, the neutrophil-mediated damaging effecthas been considered the major contributing factor to lunginjury seen after CPB.

Fig 1. Postoperative trends of PaO2/FiO2 ratio in the perfused (n 516) and control (n 5 14) groups. Data are presented as mean 6SEM. †p , 0.01 when compared with prebypass value within eachgroup for both groups; *p , 0.05, perfused group vs control group;**p , 0.01, perfused group vs control group.

Fig 2. Neutrophil counts before, during, and at the end of CPB. Val-ues are corrected for hematocrit. Data are presented as mean 6SEM. †p , 0.05 when compared with prebypass value within eachgroup.

604 SUZUKI ET AL Ann Thorac SurgCONTINUOUS PULMONARY PERFUSION DURING CPB 2000;69:602–6

In addition to the CPB-derived inflammatory response,ischemic insult and reperfusion are known to inducelung function to be damaged. Previous reports havedemonstrated that reperfusion after an ischemic insultaccelerates structural and functional abnormalities of theendothelial cells with an ensuing result of progressiveorgan injury, in which activated neutrophils play thecrucial role as well [14–18]. During total CPB, the lung isperfused solely by the bronchial arterial system, so thatthe lung is exposed and at risk for the development ofischemic insult. An experimental study demonstratedthat the regional blood flow and tissue adenosinetriphosphate (ATP) in the lung decreased to 11% and 50%of the prebypass values, respectively, during total CPB.By contrast, during partial CPB, the regional blood flowdecreased only to 41% of the prebypass value, and tissueATP remained unchanged [19]. Other studies clarifiedthe fact that lesser deprivation of pulmonary arterialblood flow during CPB provoked much less severe lunginjury [20, 21]. Furthermore, neutrophil accumulation orextensive neutrophil sequestration in the lung is knownto occur commonly when the pulmonary circulation isreestablished during CPB [6–8].

Based on this evidence, our study was conducted withthe assumption that restored pulmonary arterial bloodflow during total CPB may prevent the pulmonary isch-emia and subsequent lung injury. In fact, a recent exper-imental study has revealed that low-flow lung perfusionduring total CPB demonstrated better preservation oftissue ATP stores and arterial oxygen tension in the pigletmodel [22]. In our study, the fact that the perfused groupshowed well-preserved PaO2/FiO2 ratios and signifi-cantly less duration of ventilatory support in the earlypostoperative period suggests that continuous pulmo-nary perfusion during total CPB is an effective means topreventing the lung injury. As for the neutrophil count-ing analysis, our study provided evidence that the neu-trophil sequestration in the lung is less severe in theperfused group. Neutrophils are sequestered accordingto intravascular pathologies such as neutrophil pluggingin the alveolar capillaries and sticking to the pulmonaryarterioles and venules, which were thought to be causedby mechanical hindrance and neutrophil-endothelial in-teraction mediated by adhesion molecules [23–25]. Ourresults imply that continuous pulmonary perfusion dur-ing total CPB minimized ischemic insult and inhibitedneutrophil sequestration by minimizing mechanical hin-drance and neutrophil-endothelial interaction in pulmo-nary microvessels. This study also suggests that isch-emia-reperfusion injury is an augmenting factor of thelung injury. With respect to depletion of the neutrophils,as our study failed to disclose the difference of neutrophilcounts between the right and left atrium, our results didnot necessarily ascribe depletion of the neutrophils to thesequestration into the lung. However, previous studiesclearly demonstrated neutrophil sequestration in thelung after reperfusion of the lung [3, 21]. In this context,the neutrophil depletion, which occurred in the systemiccirculation after unclamping of the aorta, may imply thatthe neutrophils are sequestered mostly to the lung.

Normally, the bronchial blood flow is given a share ofnearly 8% to 10% of the systemic blood flow. A recentstudy has shown that the pulmonary dysfunction andultrastructural derangement of the lung tissue after CPBwere less severe among the patients whose bronchialblood flow exceeded 25% of the systemic blood flow [26].Another experimental work has also shown that thepulmonary blood flow of 35 mL/kg/min obviated the lunginjury [22]. Although these studies failed to clarify theoptimal flow rate of the bronchial arterial system duringCPB, it is likely that more than normal bronchial bloodflow is the prerequisite for protection of the lung duringCPB. The flow rate of 30 mL/kg/min, which was em-ployed in our study, constituted 20% of the total bypassflow and presumably amounted to 30% of the systemicblood flow. Because no experimental work has beenperformed in relevance to the physiologic pulmonaryflow rate during total CPB, further investigative work isrequired to determine the optimal flow rate for thecontinuous pulmonary perfusion.

In conclusion, our results suggest that ischemia-reperfusion injury can be the augmenting factor of lunginjury for infants with congenital heart disease andpulmonary hypertension, and that continuous pulmo-nary perfusion during total CPB is an effective means topreventing the lung injury that is derived from CPB.

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