Membrane versus bubble oxygenator for cardiac operations

J

THORAC CARDIOVASC SURG

80:111-122, 1980

Membrane versus bubble oxygenator for cardiac operations A prospective randomized study The advantages of membrane oxygenators over bubble oxygenators for cardiopulmonary bypass during clinical cardiac operations are controversial. A prospective randomized double-blind experimental design was utilized in 64 adult patients undergoing elective cardiac operations with either the Travenol microporous polyprolyene membrane oxygenator or the Bentley Q-IOO bubble oxygenator. Sixteen patients in each group underwent coronary artery bypass grafting (CABG) and 16 underwent valvular or other types of operation. The two oxygenator groups were comparable in terms of patient characteristics and perioperative management. Both oxygenators functioned acceptably for an average duration of 115 minutes. Higher relative platelet counts (percent of control) were observed immediately after bypass in CABG patients in whom the membrane oxygenator was used. Otherwise, no significant differences were noted in objectively assessed results between the two oxygenators in regards to bleeding. pulmonary, renal, cardiac, and neurologic function. duration of lCU stay. and postoperative hospital stay. Thus no significant advantages in terms of clinical results could be detected with this type of membrane oxygenator versus another type of bubble oxygenator for elective cardiac operations in adults.

Eugene A. Hessel II, M.D., Douglas D. Johnson, M.D., Tom D. Ivey, M.D., and Donald W. Miller, Jr., M.D., Seattle, Wash.

Membrane oxygenators have numerous theoretical advantages over bubble oxygenators for extracorporeal circulation. Although various potentially beneficial biologic differences have been observed between membrane and bubble oxygenators in cardiac operations, the clinical importance of these differences is still unresolved. Some investigators have observed less bleeding and better pulmonary and mental function with membrane oxygenators, but these observations are flawed by the use of historical or nonrandomized controls. From the Division of Cardiothoracic Surgery, Department of Surgery, University of Washington School of Medicine, Seattle, Wash. This work was supported in part by a Grant-in-Aid from Travenol Laboratories, Inc., Morton Grove, Ill. A portion of this work was presented at the Twenty-eighth Annual Scientific Session of the American College of Cardiology, March IS, 1979, Miami Beach, Aa. Received for publication Nov. 26, 1979. Accepted for publication Jan. 10, 1980. Address for reprints: Eugene A. Hessel II, M.D., Division of Cardio-Thoracic Surgery, Department of Surgery, RF-25, University of Washington School of Medicine, Seattle, Wash. 98195.

This study, employing a prospective randomized double-blind experimental design, was carried out to answer the question of whether there are any detectable clinical differences in the outcome of patients undergoing cardiac procedures with one type of membrane oxygenator versus another type of bubble oxygenator. Methods

Adult patients scheduled for elective cardiac operation for acquired heart disease were invited to participate in the study. Patients were not included if they had a neurologic abnormality, had undergone prior cardiac procedures, required the use of an intra-aortic balloon pump, or if only a single coronary artery bypass graft was planned. Patients who agreed to participate were classified into one of four categories according to the expected procedure: (1) coronary artery bypass grafting (CABG); (2) aortic valve operation; (3) mitral valve operation; (4) miscellaneous-left ventricular aneurysmectomyplus CABG, multiple valve procedures, or aortic valve operation plus CABG. The patients in each group were then randomly assigned to have either a bubble oxygenator or membrane oxygenator utilized.

0022-5223/801070111+12$01.2010 © 1980 The C. V. Mosby Co.

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Hessel et al.

Surgery

Table I. Operative procedure No. of patients Procedure ALL CABG xl x2 x3 x4 Avg. No. of grafts OTHER AVR Mitral valve procedure Commissurotomy MVR MVR + TA Miscellaneous AVR + CABG AVR + MVR LVA + CABG

Bubble oxygenator

I

Membrane oxygenator

32

32

16

16

0 8 8 0 2.5 ± 0.5

I 5 7 3 2.8 ± 0.9

16

16

6

6

5

5

2 2 I

p* NS NS

NS NS NS NS NS

I

4 0 5

2 2 I

NS 5

2 2

NS NS

I

Legend: CABG. Coronary artery bypass graft. AYR. Aortic valve replacement. MVR. Mitral valve replacement. TA. Tricuspid annuloplasty. LVA. Left ventricular aneurysmectomy.

*NS implies p > 0.05

The investigators responsible for postoperative evaluation (E. A. H. or D. D. J.) were not aware of the oxygenator assigned. The following factors were analyzed to determine the comparability of the membrane and bubble oxygenator groups: age, sex, weight, body surface area, functional class, left ventricular end-diastolic pressure, left ventricular ejection fraction, cardiac output, extent of coronary artery disease, type of operation, number of bypass grafts, duration of bypass, blood given prior to bypass, priming fluids, amount of morphine administered intraoperatively, amount of cardiotomy suction, surgeon, and anesthesiologist. For the bubble oxygenator, the Bentley-Temptrol adult oxygenator with its integral heat exchanger (Model Q-loo)* was used, with a single arterial pump. For the membrane oxygenator, the Travenol Adult TMO total bypass membrane oxygenator (Model 5M1430)t was used. This device contains 2.25 m 2 of microporous polypropylene membrane with plastic screen blood spacers. The Travenol disposable heat exchanger (Model 5M0338)t in the venous position, the Travenol collapsible-reservoir pump set (Model M51460),t and two pumps (venous and arterial) were utilized with the membrane oxygenator.

All other components of the extracorporeal circuit were identical for both groups, including Tygon tubing and polycarbonate connectors, Sams deluxe roller pumps adjusted to be barely nonocclusive, and a cardiotomy reservoir employing a 110 1J. filter (Model Q-120).* No arterial microfilter was utilized. Bank blood passed through a standard 170 1J. filter. The prime volume of both circuits was approximately 2,200 ml, consisting of mannitol 20%, 5 mIlkg, lactated Ringer's solution, up to 20 ml/kg, and heparinized and recalcified CPD modified whole blood to keep the expected hematocrit value on bypass greater than 25%. No bicarbonate was added. The patients were premedicated with morphine sulfate and diazepam. Anesthesia was induced by morphine sulfate, 0.5 mg/kg, and diazepam, 0.33 mg/kg, followed by pancuronium. Anesthesia was maintained with nitrous oxide, oxygen, and halothane. After induction of anesthesia each patient received 500 mg of Solu-Medrol. Anticoagulation prior to bypass was induced with 300 U/kg of heparin and was supplemented with 150 Ulkg each hour. After bypass this was neutralized with protamine sulfate, 2 mg/IOO U of total heparin, and checked by recalcification times. During cardiopulmonary bypass, arterial flow rates of 2.4 L'min/rn", mean arterial pressures between 60 and 80 mm Hg, arterial P0 2 between 80 and 150 torr, and arterial P0 2 between 20 and 44 torr were maintained. With the bubble oxygenator, an initial ratio of gas (100% oxygen) to blood flow of 2: 1 was utilized, and with the membrane oxygenator, an initial shim pressure of 200 torr and a gas (100% oxygen) flow rate of 5 Llmin were utilized. Gas flow and shim pressure were subsequently adjusted on the basis of arterial blood gases. Volume in the extracorporeal circuit was maintained with lactated Ringer's solution or whole blood (to keep the hematocrit level greater than 25%). After the first hour of bypass a mannitol drip (20%) was instituted at 3 mIlmin. No other diuretics were administered. The left ventricle was vented through the right superior pulmonary vein. Systemic hypothermia to 30°C (rectal) was used during the procedure, and cold potassium cardioplegic solution was used during periods of ischemic cardiac arrest. Various laboratory parameters were measured during and after operation, including platelet counts, plasma free hemoglobin, quantitative serum creatine phosphokinase (CK-MB) isoenzyme levels, serum glutamic oxaloacetic transaminase (SGOT), and alveolar-arterial P0 2 differences (A-aDo2 ) . The time required to set up

*Bentley Laboratories, Inc .• Irvine, Calif. tTravenol Laboratories. Inc.• Morton Grove. Ill.

*Bentley Laboratories. Inc.• Irvine. Calif.

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Table II. Preoperative and operative characteristics Bubble oxygenator (No.) Age (yr) Weight (kg) Body surface area (m 2 ) Functional Class (NYHA) Cardiac index (Lzrnin/rns) Ejection fraction (%) No. of diseased coronary vessels (CABG pts. only) Morphine sulfate, premed. (mg) Morphine sulfate, induction (mg) Prime volume (ml) Blood in prime (ml) Duration of bypass (min) Cardiotomy suction (ml/min) Average arterial pressure during bypass (mm Hg) Average arterial flow during bypass (Lzrnin/ms)

I

(32) (32) (32) (31) (20) (26) (15) (32) (29) (32) (32) (32) (32) (30) (31)

Membrane oxygenator

Mean ± 1 SD

(No.)

55.3 75.0 1.86 3.0 2.5 64.2 2.8 11.1 34.9 2,181 353 III 112 62.3 2.23

(32) (32) (32) (32) (25) (27) (16) (28) (31) (31) (31) (31) (32) (30) (31)

± ± ± ± ±

± ± ± ± ± ± ±

± ± ±

13.1 14.0 0.20 0.6 0.8 18.2 0.4 3.3 8.6 172 331 29 155 12.0 0.25

I

Mean ± 1 SD 57.5 75.5 1.90 3.1 2.9 60.1 2.5

11.3 33.0 2,266 419 121 158 61.2 2.35

± 8.6 ± 12.4 ± 0.19 ± 0.7 ± 1.1 ± 13.9 ± 0.7 ± 3.8 ± 9.0 ± 107 ± 344 ± 42 ± 156 ± 14.5 ± 0.20

P NS NS NS NS NS NS NS NS NS NS NS NS NS NS 0.05

Legend: NYHA, New York Heart Association. CABO, Coronary artery bypass graft.

Table III. Oxygenator function and course of bypass Bubble oxygenator

II

Mean ± 1 SD (No.) or [No. of values] or (occurrences) Time to set up and prime (min) Heat exchanger efficiency Rate of cooling (OC/min) Rate of warming (OC/min) Arterial P0 2 < 60 torr (No. of values) Arterial Pco, > 50 torr (No. of values) Minimal hematocrit (%) Pump fluid balance* (ml) Nitroprusside given during bypass (No. of pts.) Average SVR on bypass (dynes' sec' cm") Urine output during bypass (ml) Weight gaint (kg) Weight gainr (kg) SGOT (18 hr postop.) (lUlL)

Membrane oxygenator (No.) or [No. of values]

I

Mean ± 1 SD or (occurrences)

p

(32)

21.0 ± 8.0

(31)

28.0 ± 8.0

<0.001

(32) (31)

[121]

0.38±0.18 0.14 ± 0.04 (12)

0.34 ± 0.17 0.16 ± 0.06 (3)

[121] (30) (32) (32) (31) (32) (27) (31) (31)

25.6 ± 1.8 1,768 ± 992 (21) 1,092 ± 292 877 ± 387 1.9 ± 1.4 0.8 ± 1.8 42.4 ± 42.2

(31) (32) (121) (121) (29) (31) (31) (30) (31) (20) (27) (31)

NS NS <0.05 NS <0.02 NS NS NS NS NS NS NS

(0)

(3)

27.0 ± 2.6 1,706 ± 763

(22) 994 915 2.2 l.l 49.3

± ± ± ± ±

291 505 1.9 1.8 68.3

Legend: SVR, Systemic vascularresistance. SOOT, Serum glutamic oxaloacetic transaminase.

"(Prime volume + fluids added) - residual volume. tlmmediately after operationversus morning of operation. tlmmediately after operation versus t day before operation.

and prime the extracorporeal circuits, arterial blood gases during bypass, and heat exchanger efficiency were noted. The amount of postoperative bleeding and blood replacement, urinary function, duration of endotracheal intubation, and time spent in the intensive care unit (K'U) and in the hospital were recorded. Mental function was evaluated by determining the time of awakening. and by administering a neurologic examination, which included a 6 point orientation score (1 point each for person, place, day-of-week, day-of-

month, month, year), and a 14 point objective Mental Function Test, preoperatively and each day postoperatively for 5 days. The Mental Function Test was modified from Katz and associates! and has been previously used by us. 2, 3 The patients were asked to state the year, month, their birth date, and their surgeon's name (1 point each); to count backward from 20 to 10 (to 16, 1 point; to 13, 2 points; to 10, 3 points); to repeat a series of three, four, five, and six digits backwards (1 point for three digits, up to 4 points for six digits); and then to

The Journal of Thorac ic and Cardiovascular Surgery

Hessel et al ,

I I4

400 Pa0

Mean

SEM

0--0 Bubble

300

2

~

c; --a Membfane

mmHg

200

P
100

~

o

::1

PaC02 mmHg

2~ Z

~-~:~~ :_- - ~.

o- ••.••. •• ....

p . 0001

7.60 pH units

P <: O.OOl

PH

7.50 7.40

P ~ O OO I

P < OOOI

• P < OOl

••.0----_. -'--0." P <0.05

P ~ 0 . 02

<,

• ••••

o

P < O.OO l

~

NS I

on By pass

Lowest ~ Flow orShim

Start Warming

Mid Warming

Fig. 1. Cour se of arterial blood gases during cardiopulmonary bypass. See text for discussion . BE , Base excess.

recall three items mentioned at the beginning of the test, such as a flower, paper, or glass (1 point for each recalled item) . Thus a perfect score would be 14. Sixty-four patients entered the study ; 32 were randomized to the membrane oxygenator group and 32 to the bubble oxygenator group (ALL patients). CABG was done on 16 patients in each group (CABG patients), and other procedures (aortic valve, mitral valve, and miscellaneous procedures) were done in the remaining 16 patients in each group (OTHER patients). The tabular data are expressed as the mean ± I standard deviation and graphic data as the mean ± standard error of the mean . Observed differences between the oxygenators in ALL patients and in CABG and OTHER subgroups were tested by means of the Student 's t test for unpaired data or the chi square with the Yate s correction where appropriate . Statistical significance was described only when p < 0 .05 utilizing tables for two tails. This study was approved by the Human Subjects Review Committee of the Universit y of Washington, and each patient gave a written informed consent. Results Comparability of groups. The types of operations performed are summarized in Table I and were similar in the two groups. The preoperative, operative, and anesthetic features

are compared in Table II, which shows that the two oxygenator groups are comparable when ALL patients are compared. Compared with OTHER patients, the CABG patients were younger (53.5 versus 59 .3 years, p < 0.05), weighed more (81.7 versus 69.9 kg, P < 0.001) , had a larger body surface area (1.97 versus 1.80 m Z , p < 0.001) , had a higher cardiac index (3.2 versus 2.4, p < 0.01) , received less blood in the prime (243 versus 526 ml, p < 0 .001) , and had less cardiotomy suction (66 versus 205 mllmin, p < 0.001) . However, there was no statistical difference in these parameters between the membrane and the bubble oxygenator CABG patients and the membrane and the bubble oxygenator OTHER patients . Function of the oxygenators and course of bypass (Fig. 1 and Table III). The membrane oxygenator required slightly more time (7 minutes) to set up and prime and was somewhat more complicated to operate but presented no significant difficulties to the perfusionists . Both oxygenators functioned satisfactorily . The rates of cooling and warming were comparable . The course of arterial blood gases during bypass are depicted in Fig. I: The arterial Po-s were lower in the bubble oxygenator group, due both to an effort to minimize the gas-blood flow ratio with the bubble oxygenator and to the oxygen transfer efficiency of the membrane oxygenator. Arterial Pee-s of 50 to 58 torr were encountered on three occasions with the membrane oxygenator and presumably could have been corrected by increasing the oxygen flow had it been deemed necessary. The differences in pH (Fig. I) are due entirely to differences in arterial Pcoj , The minimal hematocrit value on bypass (Table III) was slightly lower with the bubble oxygenator. The mean arterial pressure was similar in the two groups, as was the use of vasoactive drugs during bypass . The mean flow was slightly higher in the membrane oxygenator group (2.35 versus 2.23 L'rnin/rn", p < 0 .05), but the average calculated systemic vascular resistence during bypass was similar in the two groups . Neither group developed a significant base deficit during bypass or postoperatively, and the base excess in the two groups was comparable at all times. Only one patient in each group required bicarbonate therapy . Urine output during bypas s was comparable in the two groups , and the patients in both groups gained a comparable amount of weight during the procedure . The postoperative serum SGOT level , thought by some to reflect the degree of organ injury during bypass , was not significantly different between the two groups . Hematologic effects and bleeding (Table IV). The degree of hemolysis, as assessed by plasma free hemoglobin immediately at the end of bypass and 18

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Table IV. Hematologic effects and blood loss and replacement Bubble oxygenator Mean ± I SD or (occurrences)

(No.)

Mean ± I SD or (occurrences)

p

(31) (26) (32)

44 ± 30 9 ± 17 (10)

(30) (20) (32)

42 ± 28 4 ± 7 (6)

NS NS NS

(32) (32) (28)

223 ± 65 160 ± 46 130 ± 40

(31) (31) (25)

213 ± 52 170 ± 43 128 ± 45

NS NS NS

(32) (28) (32)

72.8 ± 14.8 60.0 ± 17.8 (2)

(31) (25) (31)

81.9 ± 19.5 62.2 ± 17.7 (3)

<0.05 NS NS

(30) (30) (30)

375 ± 210 599 ± 485 21 ± 7

(27) (27) (26)

352 ± 233 544 ± 367 18 ± 6

NS NS NS

811 403 844 930 4.9

NS NS NS NS NS

(No.) Plasma free hemoglobin (mg/Ioo ml) Immediately after bypass 18 hr postop. Gross hemoglobinuria (No. of pts.) Absolute platelet count (X 103 /rnm") Control End of bypass 18 hr postop. Relative platelet count (% control) End of bypass 18 hr postop. Reoperation for bleeding (No. of pts.) Chest tube drainage in ICU" (rnl) First 8 hr Total Chest tube removed (hr postop.) Blood given after bypass" (ml) In OR First 8 hr in ICU Total OR and ICU Total blood administered" (ml) Predischarge hematocrit (%)

Membrane oxygenator

(30) (30) (30) (30) (20)

I

1,250 610 2,093 2,869 38.9

± ± ± ± ±

935 366 1,133 1,165 4.4

(27) (27) (27) (27) (18)

1,676 562 2,395 2,991 39.8

± ± ± ± ±

Legend: leU, Intensive care unit. OR. Operating room.

"Excludes patients reoperated upon for bleeding and the one patienton intra-aortic balloon pumping.

hours postoperatively, and the incidence of gross hemoglobinuria were comparable in the two oxygenator groups. The platelet count fell significantly (p < 0.001) during bypass and fell even further (p < 0.01) during the first 18 hours postoperatively in both groups, but the absolute platelet counts were comparable at all times in the two oxygenator groups. However, the relative platelet count (percent of control) was higher in the membrane oxygenator group than in the bubble oxygenator group (81.9% versus 72.8%, p < 0.05) immediately after bypass, but not when measured 18 hours postoperatively. This difference was seen only in the CABG patients and not in the OTHER patients. A comparable number of patients in each group required reoperation for excessive postoperative bleeding. No significant differences were noted between the two oxygenator groups in amount of blood lost or blood given or in the discharge hematocrit value (Table IV). The OTHER patients lost more blood and more frequently required reoperation for bleeding than did CABG patients, but to an equal degree in both oxygenator groups. Renal function (Table V). The urine output after bypass and during the first 18 hours postoperatively

was similar between both oxygenator groups. No patient required dialysis postoperatively. The maximum blood urea nitrogen (BUN) and the number of patients with a BUN above 30 postoperatively were greater in the membrane oxygenator group, but this difference was not statistically significant. CABG patients voided more urine in the first 18 hours postoperatively than did OTHER patients, but no differences were noted between oxygenators within these two categories of patients. Pulmonary function (Table V). The mean duration of postoperative endotracheal intubation, number of patients requiring intubation for more than 24 hours, and number of patients requiring positive end-expiratory pressure (PEEP) were similar in the two groups. The mean A-aDo2s at various times postoperatively are shown in Fig. 2 and demonstrate no differences between the two groups. Although patients undergoing OTHER procedures required longer intubation (25.0 versus 12.6 hrs, p < 0.01), had a higher mean A-aDo2 , and were the only ones who required PEEP, still no differences were noted between the two oxygenator groups within these operative categories. Cardiac effects (Table V). Only one patient in the bubble oxygenator group and two in the membrane

The Journal of Thoracic and Cardiovascular Surgery

1 16 Hessel et al.

Table V. Renal, pulmonary, and cardiac function Bubble oxygenator (No.)

Renal Urine output (ml) After bypass in OR First 18 hr in ICU Maximum postop. BUN (mg/lOO ml) BUN> 30 mg/lOO ml (No. of pts.) Pulmonary Duration of endotracheal intubation (hr postop.) Intubated> 24 hr (No. of pts.) Required PEEP (No. of pts.) Cardiac Perioperative acute MI' (No. of pts.) Peak CK-MB (lUlL) CK-MB > 50 lUlL (No. of pts.) Cardiovascular complicationst (total No.) Nitroprusside required postop. (No. of pts.)

(31) (32) (32) (32)

I

Membrane oxygenator

Mean ± I SD or (occurrences)

(No.)

662 ± 466 1,779 ± 819 22.0 ± 7.5 (4)

(31) (29) (30) (30)

591 ± 467 1,885 ± 708 27.9 ± 13.9 (9)

NS NS NS NS

(31) (31) (31)

20.0 ± 18.8 (3) (2)

NS NS NS

(32) (32) (32)

17.7 ± 17.5 (3)

(32) (32) (32) (32) (32)

(0) 26.3 ± 25.9 (2) (20) (22)

(I)

(31) (30) (31) (31) (31)

r

Mean ± I SD or (occurrences)

(I)

27.7 ± 25.4 (4) (17)

(20)

p

NS NS NS NS NS

Legend: OR, Operating room. leU, Intensive care unit. BUN, Blood urea nitrogen. PEEP, Positive end-expiratory pressure. MI, Myocardial infarction. 'New Q waves on electrocardiogram (see text for results with expanded criteria). tHypolension or arrhythmias.

oxygenator group (X 2 = 0.29, P > 0.20) experienced a perioperative infarct as detected by either the development of new Q waves andlor a CK-MB enzyme level above 50 lUlL associated with a positive technetium pyrophosphate scan. The average peak serum CK-MB enzyme level postoperatively and the number of patients with CK-MB levels above 50 lUlL were similar in both oxygenator groups. Likewise, the number of patients requiring vasopressors, nitroprusside for hypertension, or experiencing ventricular premature beats or atrial arrhythmias postoperatively were similar in the two oxygenator groups. Neurologic and mental function (Table VI). Only one patient was found to have a localizing neurologic abnormality postoperatively-a patient in the bubble oxygenator group who had a left-sided hemiplegia and aphasia following an aortic valve replacement. There was no significant difference in the average time of awakening between the two oxygenator groups, nor was there any significant difference in the mean postoperative orientation score or the mean postoperative Mental Function Test score between the two groups. The results of serial testing of mental function for the first 5 days postoperatively are shown in Fig. 3. A statistically significantly higher mean score was observed in the bubble oxygenator patients than in the membrane oxygenator patients on postoperative day 2, but at all other times the results were similar. A similar pattern was noted with serial testing of orientation

score. Patients undergoing OTHER operations had low.er mean postoperative orientation scores (5.2 versus 5.7, p < 0.01) and mental function test scores (10.3 versus 12.1, P < 0.001) than those undergoing CABG, but no significant differences were noted within these operative subgroups between the two oxygenators. Overall results (Table VI). There were one early death and one late death, both in the membrane oxygenator group. One patient had severe triple-vessel coronary artery disease with poor distal vessels and a depressed left ventricular ejection fraction; he could not be weaned from cardiopulmonary bypass. Another patient, a 65-year-old man with end-stage aortic and mitral insufficiency, died 2 months postoperatively of multisystem failure. Neither of these deaths was thought to be related to the oxygenator used. The average stay in the ICU and average postoperative hospital stay were nearly identical in the two oxygenator groups. The ICU and postoperative hospital stay were shorter in CABG patients than in OTHER patients (1.4 and 6.4 days versus 2.7 and 9.3 days, respectively, p < 0.05), but no differences were noted between the two oxygenators within these subgroups.

Discussion Membrane oxygenators have the advantage of eliminating the blood-gas interface, which is thought to be an important source of blood trauma during extracorporeal oxygenation. Some in vitro and animal studies

Volume 80

Membrane versus bub ble oxygen ators

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July. 1980

14

ALL

300

ALL

12

NS

C, 100

:r

E

E

Mean :: SEM

o

CABG

; 300

is

NS

0 ..1.-- - - - - - - - - - - - - - - '


2

10

NS

...... Bubb le

G - -O{] Membrane

200

o

a. 100

~

o

NS

NS

til

~

c: '0

NS

0-'-- - - - - - - - - - - - - - - - - ' T

300

OTHER

~

CIJ

«> 200

NS

NS

P < 0.02

00

en u;Ql

13

c

II

0c

9

.~

::>

NS

NS

NS

NS

NS

NS

NS

NS

P <0.05

NS

u.

<0

"--c:
Mean

:l:

SEM

- - - - - -- - - - 0--0 Bubble

cr- -a

OTHER

13

NS

NS

CABG

:::E

--~2.~

100

NS

8

.e oZ CIJ l-

N

«

u;-

Membrane

11

9 o..l-----

-

-r--

Im m ed PO

-

-

..,-- --

2 hr PO

r -----,,....J

1 day PO

2 days PO

7

of

NS

,

NS

,

P

0.05

,

NS

,

NS

NS

I

i

P04

POS

Fig. 2. Course of alveolar-arterial P0 2 differences in the postoperative period. Results in alI patients (CABG and OTHER operations) are depicted in the top panel , results in patients undergoing CABG only are depicted in the middle panel . and results in patients undergoing OTHER operations (aortic valve, mitral valve, and miscelIaneous procedures) are depicted in the bottom panel . No statistical differences are observed.

Fig. 3. Course of Mental Function Test scores during the first 5 days postoperatively in ALL patients (top panel), patients undergoing CABG only (middle panel) , and in patients undergoing OTHER operations (bottom pane l) . See text for description of Mental Function Test.

have indicated that membrane oxygenators are associated with less protein denaturation , 4 less fat embolization, " less release of toxic sub stance s into the blood," less hemolysis," less platelet loss and damage.v 9 less pulmonary damage, 10 and fewer cerebral , cardiac, and respiratory complications 1I than are bubble oxygenators . However , other animal studies have failed to confirm the superiority of membrane oxygenators over other type s of ox ygenators. 12. 13 Althou gh membrane oxygenators are well-s uited for prolonged extracorporeal oxygenation , their value in cardiac operations is debated ' < 15. In vitro and animal studies of simple extracorporeal circulation , and even clinical extracorporeal ox ygenation may not be applicable to clinical cardiac operations because of species differences , use of cardiotomy suction, effect of other interventions on the heart , and different anesthetic and postoperative management. Furthermore, many membrane oxygenators have the disadvantage of being more expens ive and more complicated to set up and run. It is therefore important to determine if the ir use makes any

clinically significant difference in cardiac operations. The results from previous studie s comparing membrane with other types of oxygenators in the clinical setting of cardiac operations have been conflicting, and they are somewhat difficult to interpret because , for the most part , these studies have not employed concurrent, randomly selected controls . Also , many studies have not used objective parameters to evaluate outcome , or the y have failed to anal yze the statistica l significance of their result s. Our study has attempted to rect ify these deficiencies. Although the absolute platelet counts after bypass we re not different between the two ox ygenator groups in our study, the relative platelet count (percent of control) was higher in the membrane ox ygenator group. Further anal ysis found thi s difference to be limited to those undergoing CABO alone . Th is ma y be related to the difference in the amount of cardiotomy suction used in patients undergoing CABO as compared to OTHER operation s (65 versus 205 mllmin , p < 0.001 ). The increased amount of cardiotomy suction, which is as-

Preop

POl

P02

P03

D ay

The Journal of

I I 8 Hessel et al.

Thoracic and Cardiovascular Surgery

Table VI. Neurologic function and overall outcome Membrane oxygenator

Bubble oxygenator

Neurologic Time of awakening* (hr) Neurologic abnormality (No. of pts.) Mean postop. orientation scoret (points) Mean postop. mental function test scoret (points) Overall Mean stay in ICU* (days) Mean postop. hospital stay§ (days) Deaths (No. of pts.)

(No.)

Mean ± 1 SD or (occurrences)

p

5.6 ± 0.7 11.6±1.9

(30) (31) (26) (27)

1.9 ± 1.4 (0) 5.2 ± 1.0 10.8 ± 2.2

NS NS NS NS

2.1 ± 1.3 7.8 ± 4.6 (0)

(30) (16) (32)

2.0 ± 1.1 7.7 ± 3.4 (2)

NS NS NS

(No.)

Mean ± 1 SD or (occurrences)

(27)

1.5 ± 1.2

(32) (25) (26)

(I)

(32) (22) (32)

Legend: leu. Intensive care unit. *Excludes patients not given morphine sulfate. tExciudes patients who were intubated >36 hr, or who were reoperated upon for bleeding, or who were aphasic.

*Excludes two patients who died. §Excludes patients transferred to Veterans Administration hospital.

sociated with an increased degree of thrombocytopenia during bypass.!" may have overshadowed the inherent differences between oxygenators in the OTHER operation groups. Some studies have observed less thrombocytopenia with membrane oxygenators, 17-20 whereas others have failed to demonstrate any significant difference. 2 1- 25 Except for this difference in relative platelet count early after bypass, we were unable to detect any significant difference between results with the membrane and bubble oxygenators, regardless of the type of operation performed. Likewise, in the only other reported prospectively randomized, double-blind clinical study comparing membrane with nonmembrane oxygenators, Chopra and associates" found no major differences between the General Electric-Peirce membrane oxygenator and a bubble oxygenator. Their study comprised 20 patients, 10 patients in each group, undergoing CABG during a long period of cardiopulmonary bypass (average time about 4 t.4 hours in each group). WilIiams;" Hicks.t" and their co-workers, in less rigidly controlled studies (alternate or matched patients), found no differences in coagulation factors, bleeding, renal or pulmonary function, or clinical outcome with the use of a Travenol membrane oxygenator employing microporous Teflon membranes compared with a Harvey bubble-film hybrid oxygenator" or a Bentley Q-100 oxygenator. 23 The latter study was confined to patients undergoing CABG. We observed no difference in pulmonary function as manifested by the duration of intubation, A-aDo 2 , or need for prolonged intubation or PEEP postoperatively. Williams '25 and Hicks '23 groups found that

the duration of ventilatory support after heart procedures did not vary irrespective of whether a membrane or bubble oxygenator was used, and Hicks and associates 23 found no difference in the postoperative arterial P0 2 values between the two oxygenators. Wright and co-workers,"? however, claimed that patients undergoing cardiac operations with the membrane oxygenator had better pulmonary function postoperatively, but they provided no supportive data for this conclusion in their nonrandomized study. Byrick and Noble'" evaluated the effect of membrane versus bubble oxygenators on pulmonary physiology in patients undergoing CABG, but they did not state their method of selecting controls. They observed a statistically significant rise in pulmonary vascular resistance immediately postoperatively and an increase in lung water on the first and second postoperative days in patients in whom the bubble oxygenator was used. However, the mean absolute value for lung water was higher in the membrane group at all times, and pulmonary vascular resistance was similar in both groups after the immediate postoperative determination. Furthermore, there was no significant difference in the shunt fraction (Qs/Qt) between the two groups (which did not change in either group). There was a significant rise in physiological dead space (VO/VT) on the first postoperative morning in the membrane group but no such change in the bubble group. Thus their data do not seem to demonstrate a clear-cut physiological advantage of the membrane oxygenator in regard to pulmonary function. We observed no difference in the incidence of serious postoperative bleeding, measured blood loss postoperatively, or blood requirements at any time after

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July. 1980

bypass, and the discharge hematocrit value was not different between the two oxygenator groups. Wright." McKenzie,18 and their colleagues observed less postoperative bleeding with the use of membrane oxygenators, but these studies are flawed by the lack of statistical analyses and a nonrandomized experimental design. Liddicoat and associates;" using historical bubble oxygenator controls, observed less postoperative bleeding following the use of a membrane oxygenator when duration of bypass was less than 90 minutes but no difference for longer periods of cardiopulmonary bypass. In contrast, several other groups'": 23. 25. 28 observed no difference in postoperative bleeding or blood given between membrane and bubble oxygenators used in alternate patients. Friedenberg and associates" studied blood coagulation and platelet function in alternate patients operated upon with membrane or bubble oxygenators. No differences were observed between the two oxygenators except for better collagen-induced aggregation after bubble oxygenation and better adenosine diphosphate-induced aggregation after membrane oxygenation. Several other groups": 23. 25. 27 have also failed to find differences in coagulation after membrane versus other types of oxygenation. Other reports regarding platelet function have been conflicting. Wright.t" Solis,24 and co-workers reported less severe impairment of in vitro platelet function with the membrane oxygenator, whereas Siderys' group'" observed no difference in bleeding time or clot retraction with membrane oxygenators. We observed no differences in degree of hemolysis between oxygenators. This may be due partially to our employment of a low gas-blood flow ratio with the bubble oxygenator and careful management of the use of cardiotomy suction. Several groups of investigators have likewise observed no difference in degree of hemolysis between membrane and bubble oxygenators,22. 25. 29 whereas other groups have noted less hemolysis following the use of membrane oxygenators.18-21, 23 Of particular note, postoperative neurologic and mental function was no better in patients undergoing cardiopulmonary bypass with the membrane as compared with the bubble oxygenator in our study. Conversely, Wright and associates" reported that cerebral function was clinically better in patients undergoing cardiopulmonary bypass with a membrane oxygenator, but these investigators provided no objective documentation for this conclusion in their nonrandomized study. Carlson and associates": 31 observed less deterioration of mental function, assessed by the Bender-Gestalt visual-motor test, in patients following membrane

compared with bubble oxygenation in a prospective randomized controlled study. However, our application of the chi square test to their data indicates that the differences they observed were not statistically significant. Furthermore, using the Wechsler Intelligence Test, these same investigators'": 31 observed no difference between the two oxygenator groups. Chopra and colleagues" applied a large battery of tests for neuropsychological function and performed electroencephalograms, as well, in their prospectively randomized comparison of membrane and bubble oxygenators; they found no differences between the two groups. Thus we have been unable to find any report that shows a statistically significant, objectively assessed difference in mental function following the use of membrane compared with bubble oxygenators. Therefore, neither our results nor those reported in the literature provide any convincing evidence of the superiority of membrane oxygenators over other types of oxygenators for clinical cardiopulmonary bypass in conventional cardiac operations in the adult. This does not refute the theory that they are superior oxygenators, particularly in regard to blood trauma, but we have been unable to demonstrate any clinical advantages with their use in cardiac operations. There are several possible explanations for this outcome. First, our tests may be too crude and insensitive to detect clinical differences, but no better tests are currently available. Second, because of the relatively small sample size, those differences which exist may have failed to reach levels of statistical significance, or, by chance, we missed significant differences. The differences that we did observe, however, tended to favor the bubble oxygenator, and thus larger sample sizes would not likely have shown superiority of the membrane oxygenator. Furthermore, the similar results of other studies just reviewed tend to support our observations. Third, the results reported in this study indicate that the practice of cardiopulmonary bypass with bubble oxygenators has been made less traumatic by (1) use of low gas-blood flow ratios ( < 2: 1), the importance of which has been emphasized by others 14. 25. 32. 33; (2) maintenance of physiological arterial blood gases!" 34 and arterial pressures and flow; (3) use of nonblood prime; (4) minimal use of cardiotomy suction; and (5) a generally improved quality of anesthetic and perioperative care. The lack of operative deaths (0/32) and short average ICU and hospital stay after operation observed in our bubble oxygenator group emphasize the need to use concurrent controls for the study of any potentially better treatment modality.

The Journal of

1 20 Hessel et al.

A fourth reason why the membrane oxygenator might not have proved superior may have been that the duration of bypass was not long enough. However, virtually all runs in our study were longer than I hour and nearly one half exceeded 2 hours. Furthermore, Chopra and associates" could demonstrate no advantages with the membrane oxygenator in a series in which cardiopulmonary bypass exceeded 4 hours in each case! A fifth possible reason for the failure of the membrane oxygenator to produce superior results during cardiac operations is that other factors may playa dominant role in the outcome of patients undergoing such operations which overshadow the influence of the type of oxygenator used. These might include the preoperative condition of the patient, such as cardiac and nutritional status and pulmonary and cerebral function. Dubin and associates" have suggested that preoperative cardiac and cerebral function may be the most important determinants of postoperative mental and psychological function. Furthermore, the impact of the use of cardiotomy suction, which is an invariable component of cardiac operations, and which imposes a direct bloodgas interface, may be so great that it negates the advantages of the membrane oxygenator. Others have demonstrated, for example, that cardiotomy suction is the major source of microemboli and a major determinant of thrombocytopenia and hemolysis during cardiopulmonary bypass.:": 19, 24 Some might attribute our negative results to the omission of microfilters. However, in a previous prospective randomized controlled study, we" were unable to demonstrate any differences in bleeding or pulmonary or neurologic function with or without a Dacron wool cardiotomy filter, and other Investigatorss"?" were unable to demonstrate any advantages with use of screen-type arterial filters. Therefore, we do not use microfilters routinely. Furthermore, Chopra and associates," in a previously described controlled study of membrane versus bubble oxygenators, did use a cardiotomy microfilter, and they suggested that the microfilter might have obscured any potential differences between the two oxygenators. It is conceivable that some other membrane oxygenator system might prove superior to bubble oxygenation. The membrane oxygenator employed in our study utilized a microporous-type membrane which may not be comparable to a true membrane, such as silicone rubber, although it is more efficient. It also has a plastic separator within the bloodstream and requires the use of two pumps, Elimination of these constraints conceivably could change the outcome. This study did confirm the results of several other

Thoracic and Cardiovascular Surgery

groupsf" 25. 27. :19-41 with a similar but not identical Travenol membrane oxygenator system, i.e., that this system takes only a trivial amount of extra time to set up and prime (7 minutes), is safe and relatively easy to use, and is a highly efficient gas exchanger. Our study represents the first clinical report of use of the polyproylene microporous membranes with the TMO (previous reports were with models employing the microporous Teflon membranes), and we experienced no serious problems with carbon dioxide control. Arterial carbon dioxide can be lowered by raising oxygen flow rate through the membrane, a nicety which we did not find necessary to use. This study also underscores the fact that there are significant differences in the preoperative characteristics (e.g., age, cardiac index), course of bypass (e.g., amount of cardiac suction and urine output), and outcome (e.g., degree of thrombocytopenia, bleeding, pulmonary function, mental function, and durations of ICU stay and in hospital stay) between patients undergoing isolated CABO and those undergoing OTHER cardiac operations. This emphasizes, again, the need to have similar stratification of these two groups of patients when conducting a study designed to compare different methods of cardiopulmonary support.

Addendum Since submission of this manuscript, Clark and associates THORAC CARDIOVASC SURG 78:655-666, 1979) have reported a prospective study of cardiopulmonary bypass in man which revealed notable advantages with membrane oxygenators for perfusions lasting more than 2 hours. Therefore, we have analyzed our results in the 12 bubble oxygenator patients and the 14 membrane oxygenatorpatients whose perfusion lasted between 2 and 3 hours (average 142 minutes). The two oxygenator groups had a similar composition in terms of operations performed and duration of bypass. Although relative platelet counts were higher at 18 hours postoperatively as well as immediately postoperatively in the membrane oxygenator group, there were still no differences in blood loss or replacement between the two oxygenator groups. No other significant differences were observed in the course of bypass, postoperative course, or outcome of patients between the two oxygenator groups with regards to systemic vascularresistance and fluid balance during bypass, renal, pulmonary, and neurologic function postoperatively, duration of stay in leu or hospital, or any of the other parameters listed in our paper.

(J

We thank the cardiopulmonary perfusionists, Gary Tarter, Roland Alberto, and Raymond Johnson, for invaluable contributions to this study; the cardiac anesthesiologists and nurses at the University Hospital for their cooperation; and Jeanne Morrison, Kathie Long, and Donna Stirton for preparation of the manuscript.

Volume 80 Number 1 July, 1980

REFERENCES Katz NM, Agle DP, DePalma RG, et al: Delirium in surgical patients under intensive care. Utility of mental status examination. Arch Surg 104:310-313, 1972 2 Hessel EA, Dillard DH, Winterscheid LC, et al: Microfiltration during open heart surgery. Circulation 51, 52:Suppl 2:199, 1975 3 Mossing KA: Post cardiotomy delirium and microfiltration. Masters of Arts Thesis, University of Washington School of Nursing, 1975 4 Lee WH, Krumhaar D, Kerry G, et al: Comparison of the effects of membrane and non-membrane oxygenators on the biochemistry and biophysical characteristics of blood. Surg Forum 12:200-202, 1961 5 Owens G, Adams JE, Scott HW: Emboli fat as a measure of adequacy of various oxygenators. J Appl Physiol 15:999-1,000, 1960 6 Dobell ARC, Mitri M, Galva R, et al: Biologic evaluation of blood after prolonged recirculation through films and membrane oxygenators. Ann Surg 161:617-622, 1965 7 Peirce E, Corrigan JJ, Kent BB, et al: Comparative trauma to blood in the disc oxygenator and membrane lung. TransAm Soc Artif Intern Organs 15:1-6, 1969 8 deLeval M, Hill JD, Mielke CH Jr, Macur MF, Gerbode F: Blood platelets and extracorporeal circulation. Kinetic studies on dogs on cardiopulmonary bypass. J THORAC CARDIOVASC SURG 69:144-151, 1975 9 Ward BD, Berry GL: Comparative platelet function during prolonged extracorporeal bubble and membrane oxygenation. Am SECT Proc pp. 6-9, 1975 10 Hill DG, de Lanerolle P, Kosek JC, et al: The pulmonary pathophysiology of membrane and bubble oxygenators. Trans Am Soc Artif Intern Organs 21:165-170, 1975 11 Subramanian VA, Berger RL: Comparative evaluation of a new disposable rotating membrane oxygenator with bubble oxygenator. Ann Thorac Surg 21:48-54, 1976 12 Dutton RC, Edmunds LH Jr, Hutchinson JC, Roe BB: Platelet aggregate emboli produced in patients during cardiopulmonary bypass with membrane and bubble oxygenators and blood filters. J THORAC CARDIOVASC SURG 67:258-265, 1974 13 Rhodes EL, Kirsh MM, Howatt W, O'Rourke PT, Straker J, Sloan H: A comparison of pulmonary function in puppies undergoing total cardiopulmonary bypass with bubble or membrane oxygenators. J THORAC CARDIOVASC SURG 68:658-663, 1974 14 Kayser KL: Blood gas interface oxygenators versus membrane oxygenators. Ann Thorac Surg 17:459-463, 1974 15 Peirce EC: Is the blood-gas interface of clinical importance? Ann Thorac Surg 17:526-528, 1974 16 Edmunds LH Jr, Saxena NC, Hillyer P, et al: Relationship between platelet count and cardiotomy suction return. Ann Thorac Surg 25:306-310, 1978 17 Goulon M, Gajdos P, Raphel JC, et al: Traitment de I'insuffisance respiratoire aigue refractaire par oxygenateur a membrane. Guerison de deux malades. Nouv Presse Med 3:1795-1800, 1974

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18 McKenzie N, Wall W, Robert A, et al: Blood-free open heart surgery. The blood sparing effect of an atraumatic circuit and a membrane oxygenator (abstr). Circulation 51,52:Suppl 2:73, 1975 19 Siderys H, Herod GT, Halbrook H, Pittman IN, Rubush JL, Kasebaker V, Berry GR Jr: A comparison of membrane and bubble oxygenation as used in cardiopulmonary bypass in patients. J THORAC CARDIOVASC SURG 69: 708-712, 1975 20 Wright JS, Fish GC, Torda TA, Stacey RB, Hicks RG: Some advantages of the membrane oxygenator for openheart surgery. J THORAC CARDIOVASC SURG 69:884-890, 1975 21 Chopra PS, Dufek JH, Kroncke GM, et al: Clinical comparison of the General Electric-Peirce membrane lung and bubble oxygenator for prolonged cardiopulmonary bypass. Surgery 74:874-879, 1973 22 Friedenberg WR, Myers WO, Plotka ED, et al: Platelet dysfunction associated with cardiopulmonary bypass. Ann Thorac Surg 25:298-305, 1978 23 Hicks GL, Zwart HHJ, DeWall RA: Membrane versus bubble oxygenators. A prospective study of 52 patients. Arch Surg 114: 1285-1287, 1979 24 Solis R, Kennedy PS, Beall AC, et al: Cardiopulmonary bypass. Microembolization and platelet aggregation. Circulation 52: 103-108, 1975 25 Williams DR, Tyers GFO, William EH, et al: Similarity of clinical and laboratory results obtained with microporous Teflon membrane oxygenator and bubble-film hybrid oxygenator. Ann Thorac Surg 25:30-35, 1978 26 Byrick RJ, Noble WH: Postperfusion lung syndrome. Comparison of Travenol bubble and membrane oxygenators. J THORAC CARDIOVASC SURG 76:685-693, 1978 27 Liddicoat JE, Becassy SM, Beall AC: Membrane versus bubble oxygenator. Clinical comparison. Ann Surg 181: 747-753, 1975 28 Parker JL, Hackett JE, Clark D, et al: Membrane versus bubble oxygenators. A clinical comparison of postoperative blood loss. Bull Texas Heart Inst 6:78-84, 1979 29 Ryhanen P, Herva E, Hollmen A, Nuutinen L, Pihlajaniemi R, Saarela E: Changes in peripheral blood leukocyte counts, lymphocyte subpopulations, and in vitro transformation after heart valve replacement. Effects of oxygenator type and postoperative parenteral nutrition. J THORAC CARDIOVASC SURG 77:259-266, 1979 30 Carlson G, Lande AJ, Ivey LA, et al: The Laude-Edwards membrane oxygenator for total cardiopulmonary support in 110 patients during heart surgery. Surgery 72:913-919, 1972 31 Carlson RG, Lande AJ, Landis B, Rogoz B, Baxter J, Patterson RH Jr, Stenzel K, Lillehei CW: The LandeEdwards membrane oxygenator during heart surgery. Oxygen transfer, microemboli counts, and BenderGestalt visual motor test scores. J THORAC CARDIOVASC SURG 66:894-905, 1973 32 Kessler J, Patterson RH: The production of microemboli by various blood oxygenators. Ann Thorac Surg 9:222228, 1970

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33 Simmons E, MaGuire C, Lichti E, Helvey W, Almond C: A comparison of the microparticles produced when two disposable-bag oxygenators and a disc oxygenator are used for cardiopulmonary bypass. J THoRAc CARDIOVASC SURG 63:613-621, 1972 34 Vervloet AFC, Edwards MJ, Edwards ML: Minimal apparent blood damage in Lande-Edwards membrane oxygenator at physiologic gas tensions. J THORAC CARDIOVASC SURG 60:774-780, 1970 35 Dubin WR, Field HL, Gastfriend DR: Postcardiotomy delirium. A critical review. J THORAC CARDIOVASC SURG 77:586-594, 1979 36 Arrants JE, Gadsden RH, Higgins MB, et al: Effects of extracorporeal circulation upon blood lipids. Ann Thorac Surg 15:230-242, 1973

37 Heimbecker R, Robert A, McKenzie FN: The extracorporeal pump filter. Saint or sinner. Ann Thorac Surg 21:55-58, 1976 38 Loop F: Data presented at conference on microfiltration, Pacific Medical Center, April 9, 1975 39 Beall AC, Solis RT, Kakvan M, et al: Clinical experience with the Teflon disposable membrane oxygenator. Ann Thorac Surg 21:144-150, 1976 40 Karlson KE, Murphy WR, Kakvan M, et al: Total cardiopulmonary bypass with a new microporous Teflon membrane oxygenator. Surgery 76:935-945, 1974 41 Murphy W, Trudell LA, Friedman LI, et al: Laboratory and clinical experience with a microporous membrane oxygenator. Trans Am Soc Artif Intern Organs 20:278285, 1974

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