Low Prime Volume

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INTRODUCTIONA significant advance in coronary artery

revascularization was reported by Favarolo1 in 1968.

Further improvements in operative techniques and

devices have continued since then. The influence of

cardiopulmonary bypass (CPB) has been reported

in several articles.24 After undergoing CPB, some

patients exhibit various homeostasis dysfunctions

(involving respiratory function, renal function and

the clotting system) that have been described aspost-perfusion syndrome. To reduce the deleterious

effects of CPB, various improvements have been

made.58 Utilizing these improvements, we devised a less

invasive CPB (low prime volume closed CPB; LPVP).

In this article, we demonstrate the decreased

invasiveness and improved efficacy of LPVP using

molecular biological techniques.

PATIENTS AND METHODSAfter approval by the institutional review board,

we studied 14 patients undergoing isolated

coronary artery bypass grafting (CABG). Patients

were randomized into two groups prospectively:

patients undergoing LPVP, Group L (8 cases),

and those with normal prime volume CPB,

Group N (6 cases).

The exclusion criteria were as follows: emergentand urgent cases, renal dysfunction cases

(serum creatinine > 1.5 mgdL1), low ejection

fraction cases (EF < 35%), single bypass cases,

on-pump beating-heart CABG cases, patients with

severe chronic obstructive pulmonary disease or

uncontrolled asthma, preoperative use of steroids

and previous heart surgery.

ORIGINAL CONTRIBUTION

Demonstration and Operative Influence ofLow Prime Volume Closed Pump

Hideaki Takai, MD, Kiyoyuki Eishi, MD, Shiro Yamachika, MD,

Shiro Hazama, MD, Tsuneo Ariyoshi, MD, Katsuo Nishi, MD

Department of Cardiovascular Surgery

Nagasaki University School of Medicine

Nagasaki, Japan

For reprint information contact:

Hideaki Takai, MD Tel: 81 95 849 7307 Fax: 81 95 849 7311 Email: [email protected]

Department of Cardiovascular Surgery, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.

2005, VOL. 13, NO. 1 65 ASIAN CARDIOVASCULAR & THORACIC ANNALS

ABSTRACTVarious improvements have been made in cardiopulmonary bypass (CPB) in the

past few decades. We designed a new type of CPB to reduce the secretion of

systemic inflammatory markers. We used a low prime volume pump (LPVP),

completely closed CPB circuit and examined coagulant factors and inflammatory

cytokines. In this study, we demonstrate the efficacy of LPVP using molecularbiological data. Fourteen patients were randomized prospectively into two groups:

Group L patients underwent LPVP (n = 8) and Group N patients underwent

normal prime volume CPB (n = 6). We measured thrombin-antithrombin III

complex (TAT), complement factor (C3a), and interleukin (IL)-10 levels at

four time points. TAT (66.1 15.1 ngmL1), C3a (1895 282 ngmL1) and

IL-10 (486 114 pgmL1) levels in Group N were significantly higher

than in Group L (TAT, 19.5 4.4 ngmL1; IL-10, 105 24.6 pgmL1;

C3a, 1349 369 ngmL1) immediately following CPB. LPVP demonstrated a

lower systemic inflammatory response compared to normal prime volume CPB,

as assessed using a molecular biological approach.

(Asian Cardiovasc Thorac Ann 2005;13:659)


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ASIAN CARDIOVASCULAR & THORACIC ANNALS 66 2005, VOL. 13, NO. 1

Demonstration and Operative Influence of LPVP Takai

The characteristics of the two types of CPB are showed

in Table 1. A CAPIOX EBS (Terumo Co., Tokyo, Japan)

with a heparin-coated circuit was used in the LPVP circuit.

A needle vent was placed in the aortic root and connected

to the vent circuit and the cardioplegic solution circuit.

A removable soft reservoir bag (500 mL capacity) was

fixed in the middle of the blood removal circuit and the

vent circuit, and was primed with Ringers lactate solutionwithout blood (Figure 1). The priming solution

(total volume 590 mL) was drained through the

circuit (Figure 1), before starting CPB. The soft reservoir

collected the blood that remained in the circuit after CPB,

which was subsequently used for autologous transfusion.

Suction was provided using the cell saver (Medtronic Inc.,

Blood Management Business Electromedics, Parker,

CO, USA). The cell saver was set up independently

and not connected to the LPVP circuit. Each patient

was administered an initial pre-bypass bolus dose

of heparin (100 IUkg1). During CPB, activated

clotting time (ACT) was maintained at 250300 sec.

Protamine sulfate was administered at a rate of 100

IUkg1 in LPVP. Myocardial protection was provided

by intermittent antegrade injection of warm blood

cardioplegia, according to the protocol of Calafiore et al9

in which cardioplegia flows into every anastomosis.

A CAPIOX-SX (HP) (Terumo Co., Tokyo, Japan)with a heparin-coated circuit was used in the normal

prime volume open CPB circuit. This type of CPB

was primed with 1.5 liters of 6% hydroxyethylated

starch (10 mLkg1) and Ringers lactate solution

without blood. A Sarns 9000 roller pump

(Terumo Cardiovascular Systems, Ann Arbor, MI,

USA) was used. Myocardial protection was provided

by intermittent, antegrade injection of cold (4C)

cardioplegic solution (St. Thomas solution). Each

patient was administered an initial pre-bypass

bolus dose of heparin (150 IUkg1). ACT was

Table 1. Characteristics of CPB

LPVP Normal Prime Volume CPB

Pump Centrifugal Roller

Oxygenator Membranous Membranous

Suction Yes No

Venous reservoir Soft reservoir Hard shell cardiotomy reservoirPriming volume (mL) 590 1500

Circuit Completely closed circuit Open circuit

Figure 1. Schema of the improved CPB circuit.

Right Atrium Asc. Aortic

Venting

Aortic Root

Calafiore Solution

Reservoir Bag

Pump & Oxygenator

A


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Takai Demonstration and Operative Influence of LPVP


kept > 400 sec during CPB. Protamine sulfate was

administered at a rate of 150 IUkg1 in the standard

prime volume open CPB.

All samples were measured for thrombin-antithrombin III

complex (TAT), complement factor (C3a), and interleukin

(IL)-10 levels prior to the initiation of CPB

(the beginning of operation; T1), just after the end of

CPB (the end of total anastomosis; T2), 4 hours after the

end of CPB (total anastomosis; T3), and 24 hours afterthe end of CPB ( total anastomosis; T4).

All samples were stored at 80C until analysis by

enzyme-linked immunosorbent assay: IL-10 (CytoscreenUS

hIL-10 Ultra Sensitive; Biosource International, Camarillo,

CA, USA), TAT (Enzygnost TAT micro; Dade Behring,

Liederbach, Germany), or radioimmunoassay C3a

(Human Complement C3a des Arg (125I) assay system;

Amersham, Buckinghamshire, UK). The limits of

sensitivity were 0.5 pgmL1 (IL-10), 20 ngmL1 (C3a),

and 0.5 ngmL1 (TAT).

All values are expressed as the mean standard

deviation (SD). The non-repeated analysis of

variance (ANOVA) and Mann-Whitney U-test were

used for intragroup comparisons. All computations

were performed using SPSS statistical software

packages version 11.0 (SPSS Inc., Chicago, IL, USA).

Ap-value < 0.05 was considered statistically significant.

RESULTS

The progress of all patients was uneventful during the perioperative and postoperative course. Preoperative

values between the 2 groups were not statistically

different (Table 2).

The value of intraoperative minimum hematocrit (Hct)

in Group L was significantly higher than that

in Group N ( p < 0.05). The preoperative Hct

percent ratio and the intraoperative minimum Hct

value (% R-Hct) were determined as an index of

hemodilution. The value of % R-Hct in Group N

was lower (67.2%) than in Group L (76.3%). Blood

Table 2. Preoperative Data

Group L Group N p-Value

Age (years) 66 7.3 68 7.3 NS

Body weight (kg) 65 7.6 58.3 6.9 NS

Height (m) 1.60 0.15 1.57 0.07 NS

BSA (m2) 1.69 0.11 1.54 0.21 NSBMI 25.7 2.6 24.1 2.1 NS

Anastomosis 3.3 1.1 2.8 0.69 NS

Operation time (min) 288 59 297 61 NS

CPB time (min) 122 48 121 25 NS

Clamp time (min) 80 38 76 21 NS

EF (%) 67 15 71 12 NS

NS = no statistically significant difference between groups; BSA = body surface area; BMI = body mass index;

EF = ejection fraction.

Table 3. Intra- and Postoperative Data

Group L Group N p-Value

Preoperative Hct (%) 40.1 4.7 38.1 2.9 NS

Minimum Hct (%) 30.5 5.2 25.6 2.1 0.0028

% R-Hct (%) 76.3 4.9 67.2 2.5 0.0065

Blood transfusion (U) 1.1 1.8 3.0 3.4 NS

Blood loss over 24 hours (ml) 348 152 685 434 NS

Ventilation time (hours) 5.9 2.1 6.5 3.9 NS

Max CK-MB 22.8 11.3 21.7 20.6 NS

NS = no statistically significant difference between groups; Hct = hematocrit;

CK-MB = creatine kinase-myocardial band.


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ASIAN CARDIOVASCULAR & THORACIC ANNALS 68 2005, VOL. 13, NO. 1

Demonstration and Operative Influence of LPVP Takai

transfusion was usually performed after weaning

off CPB for Hct > 20%. The number of packed

red blood cells was greater in Group N than that

in Group L. Postoperative blood loss over 24 hours

was less in Group L (348 51 mL) than that in

Group N (685 34 mL), however this was not

significantly different.

TAT concentrations reached peak values at

T2 (Group N, 66.1 3.7 ngmL 1; Group L,

19.5 13.1 ngmL1) and decreased gradually

thereafter. There were no significant differences

between the two groups except at T2.

C3a concentrations were similar between the

two groups. The value of C3a in Group L at T2

(1349 1106 ngmL1) was lower than that of Group N

(1895 630 ngmL1).

A significant increase in IL-10 concentrations was

observed in Group N (486 255 pgmL1) at T2.

However, only a small increase was observed in Group L

(105 65.1 ngmL) at T2.

DISCUSSIONSeveral studies examining less invasive procedures forCPB have been reported.1012 Two noteworthy methods of

LPVP are commonly performed: one utilizes a completely

closed CPB with a reservoir bag, the other utilizes a low

priming volume and low volume cardioplegia. LPVP is

similar to the MECC system reported by Fromes et al12.

However, there is one distinct difference between LPVP

and the MECC system: LPVP is achieved with a reservoir

bag and vent circuit. By installing this soft reservoir

and connecting a vent circuit during CPB we are able

to drain the blood into the soft reservoir and reserve it.

Therefore, it is possible to freely control both the size

of the heart and the visual field of the target bypass

area more effectively.

The advantages of high Hct during CPB have been

reported.5,13,14 Hemodilution was avoided by reducing the

priming volume in the CPB circuit and by maintaining

a low priming volume during cardioplegia. This results

in blood conservation and a reduction in blood surface

area contact. LPVP was effective at maintaining a high

Hct compared to normal prime volume CPB.

The levels of TAT were examined as an indicator of

coagulant activity. There were statistically significantdifferences in TAT at T2. As shown in Table 4, the

transition of TAT in Group L was more stable than in

Group N. It would appear that the system of coagulation

activity was very stable during the perioperative period

in Group L.

The damaging effects of CPB, related in part to

complement activation by foreign surfaces, have

been reported.2 Similarly, CABG is associated with

a systemic inflammatory response which has been

attributed to human cytokine response.15 IL-10 plays an

anti-inflammatory role by suppressing T-cell activity.16

A significant increase in the values of C3a and IL-10 at

T2 in Group N was demonstrated, as opposed to only a

slight increase in Group L. Therefore, LPVP elicited a

reduced inflammatory response in comparison with that

of normal prime volume open CPB.

The most significant challenge encountered with LPVP

is air elimination. The future safe clinical use of LPVP

will depend on the incorporation of a device, such

as an arterial filter, in the venous line to remove air.

If such a device that can remove air efficiently was

Table 4. Values of TAT (ngmL1), IL-10 (ngmL1), and C3a (ngmL1)

T1 T2 T3 T4

TAT

Group N 8.52 4.19 66.1 33.7* 16.9 4.9 15.7 7.3

Group L 18.5 14.9 19.5 13.1 17.5 6.3 12.8 4.39

IL-10Group N 4.56 1.04 486 255* 79.2 46.5 18.5 11.3

Group L 2.70 1.69 105 65.1 29.9 15.1 9.06 6.43

C3a

Group N 290 148 1895 630* 301 128 140 47

Group L 279 104 1349 1106 417 146 295 226

All values are expressed as mean standard deviation.

*Significant difference between the two groups.

Significant difference in T2 vs T1, T3 and T4.


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Takai Demonstration and Operative Influence of LPVP


available, it might be possible to perform aortic valve

replacement using LPVP. This study was designed to be

a small-scale pilot study to evaluate a possible positive

effect of LPVP. LPVP should be further investigated in

a larger cohort.

In conclusion, the value of Hct was maintained higher

in LPVP than with normal prime volume CPB. This

study showed that the transitions of TAT in LPVP were

more stable than those found in normal prime volume

CPB. The inflammatory reaction in LPVP, as evidenced

by C3a and IL-10, was preferable to that demonstrated

with normal prime volume CPB. We believe that LPVP,

as a new device for on-pump CABG, is less invasive

than normal prime volume CPB.

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segmental coronary artery occlusion: operative technique.

Ann Thorac Surg 1968;5:3349.2. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW,

Chenoweth DE, Pacifico AD. Complement and the damaging

effects of cardiopulmonary bypass. J Thorac Cardiovasc

Surg 1983;86:84557.

3. Butler J, Rocker GM, Westaby S. Inflammatory response to

cardiopulmonary bypass. Ann Thorac Surg 1993;55:5529.

4. Wan S, Izzat MB, Lee TW, Wan IY, Tang NL, Yim AP. Avoiding

cardiopulmonary bypass in multivessel CABG reduces cytokine

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