Appendix

Definition of low cardiac output syndrome

Low cardiac output syndrome (LCOS) was diagnosed if the patient required an intraaortic balloon pump (IABP) in the operating room (to be weaned from cardiopulmonary
bypass, CPB) or in the intensive care unit because of hemodynamic compromise. LCOS
was also diagnosed if the patient required inotropic medication (either dopamine,
dobutamine, milrinone, or epinephrine) to maintain systolic blood pressure greater than
90 mm Hg and cardiac output greater than 2.2 L/min/m2 for at least 30 minutes in the
intensive care unit, after optimizing preload and afterload and correction of all electrolyte
and blood gas abnormalities. Patients who required a renal dose of dopamine (3 g/kg)
were not considered to have LCOS. Patients who received vasoconstricting medications
to increase peripheral vascular resistance in the presence of normal or high cardiac
outputs (2.5 L/min/m2) were not considered to have LCOS as well.

Cardioplegia Technique
In both groups the heart was arrested with an induction dose of 12 to 15 mL/kg of cold
(4C), hyperkalemic (potassium concentration of 27 mEq/L) cardioplegia. The surgeon
attempted to adequately perfuse the arrested heart with blood following each
anastomosis. A maintenance dose of cold (4C ) antegrade cardioplegia was delivered
following each distal and proximal anastomosis (or every 15 min) at a dose of 5-7 mL/kg
(with a potassium concentration of 15 mEq/L). The systemic temperature was allowed to
drift down until the last distal anastomosis when rewarming was instituted slowly. Distal
and proximal anastomoses were constructed during a single cross clamp period. If the

systemic potassium level increased during the procedure, the amount of potassium was
progressively lowered, particularly during rewarming, provided that the heart remained
arrested. In the 8:1 group the reduction in potassium was accomplished by removing the
crystalloid infusion tubing from the pump housing and delivering undiluted pump blood
for the last part of the procedure. In the microplegia group the potassium concentrations
was slowly decreased during the rewarming phase with careful attention to the
maintenance of cardiac arrest, with the goal to achieve normal systemic potassium levels
when the cross clamp was removed. If the systemic potassium levels were elevated in
either group, then insulin was given and the heart was perfused with undiluted pump
blood. A dose of intravenous furosemide was usually given if the potassium was > 6
meq/L. A terminal dose of warm (37C) antegrade cardioplegia (a hot shot) was
delivered following the last anastomosis before the release of cross clamp (at a dose of 57 mL/kg) and a potassium concentration of 15mEq/L or lower (if the systemic potassium
concentration was elevated) to maintain cardiac arrest. We always attempted to reduce
the amount of crystalloid infused with the blood cardioplegia. In the 1990s we converted
from 4:1 to 8:1 blood cardioplegia and in 2004 we switched to microplegia exclusively.
This investigation attempted to determine whether our attempts at reducing the
crystalloid volume resulted in any clinical benefit to the patients.
The crystalloid solution employed for the cardioplegia was based on Ringer's Lactate
with the following concentrations: sodium =130 mmol/L; chloride =109 mmol/L; lactate
= 28 mmol/L; pottassium = 4 mmol/L; calcium = 1.5 mmol/L. The sodium concentration
and the osmolality of the final formulation for both types of cardioplegia (microplegia
and 8:1 blood) were dependent on the extent of hemodilution on bypass. No attempt was

made to modify either the sodium concentration or the osmolality in either group. The 8:1
group received an additional 400 ml of crystalloid for each case, however, the total
amount of potassium chloride, magnesium sulphate and dextrose were not different
between the two groups. The microplegia system maintained the same amount of
potassium and magnesium as was delivered with the 8:1 blood cardioplegia. However,
the amount of sodium chloride (NaCl) delivered to the heart was lower in the microplegia
group.

The dilution of 66:1 for the microplegia was based on the highest concentration of
potassium chloride and magnesium sulfate commercially available. These constituents
totaled 1.5 mL of crystalloid for each 100 mL of blood; producing a ratio of 66.6:1
blood-to- crystalloid. This was the least dilution that we could achieve. The concentration
of potassium in the cardioplegia was adjusted during the procedure to both maintain
cardiac arrest and limit elevation of the systemic potassium concentration. When lower
concentrations of potassium in the cardioplegia were desired, the volume of potassiummagnesium additive was reduced accordingly, so that with low-concentration potassium
infusions, the ratio of blood:crystalloid would have been proportionally greater. Other
dilutions have been used by other investigators who developed "minicardioplegia".
Menasch and colleagues7,8 used a dilution of 15:1 (blood-to-crystalloid) and Machiraju
and associates9 used a ratio of 30:1. The volume of crystalloid in the 4:1 blood
cardioplegia is 250mL per L of blood, for 8:1 cardioplegia it is 125 mL of crystalloid per
L of blood and for microplegia it is 15mL per L of blood. Therefore, the volume of
crystalloid in the standard blood cardioplegia (8:1 or 4:1) is about 8 to 16 fold higher than

in microplegia. The composition of 8:1 cardioplegia compared to microplegia is detailed

in Appendix Table 1.

Propensity score matching

The multivariable logistic regression was run to compute propensity scores for the two
groups [microplegia (cases) and 8:1 cardioplegia (controls)] based on the following
covariates: age, gender, diabetes, hypertension, hyperlipidemia, angina, preoperative
myocardial infarction, preoperative cardiogenic shock, congestive heart failure,
preoperative left ventricular grade (by left ventricular ejection fraction [LVEF]: grade 1,
LVEF 60%; grade 2, LVEF 40%-59%; grade 3, LVEF 20%-39%; grade 4, LVEF
<20%) , left main disease, triple vessel disease, preoperative stroke, preoperative renal
failure, peripheral vascular disease, chronic obstructive pulmonary disease, preoperative
hemoglobin level , reoperative CABG, smoking, previous percutaneous coronary
interventions, urgency of surgery, body surface area (BSA) and method of cardioplegic
protection. Identity of the surgeon was not a predictor of mortality or LCOS. By using
these covariates, a propensity score was calculated for each patient. Each patient who had
microplegia was matched to one patient who had standard blood cardioplegia with the
closest propensity score. With this technique, 1,980 comparable patient pairs were
identified for the propensity analysis (74% of cases were matched). Figure 1 depicts the
distribution of propensity scores for both groups before and after matching.
The Greedy 5 to 1 Digit Match means that the cases (microplegia) were first matched to
controls (8:1 cardioplegia) on five digits of the propensity score. For those that did not
match, cases were then matched to controls on 4 digits of the propensity score. This

continued down to a single-digit match on the propensity score for those that remained
unmatched. Seventy four percent of cases were matched with this technique.11

Anaesthetics and operative management

Fast-track anesthesia with fentanyl (10-20 g/kg), midazolam (0.1 mg/kg), pancuronium
(0.15-0.20 mg/kg), isoflurane (0.5%-1.5%), and propofol (0.5-4 mg/kg/hr) was
employed.12 An antifibrinolytic agent tranexamic acid (50-100 mg/kg) was given
prophylactically to each patient undergoing cardiopulmonary bypass (CPB). Cardiac
output was measured with a thermodilution catheter placed percutaneously via the
internal jugular vein into the pulmonary artery.

Intravenous heparin was used for anticoagulation and the activated clotting time was
maintained at greater than 480 seconds. The CPB circuit was primed with 1.8 L of
lactated Ringer's solution and 50 mL of 20% mannitol, albumin (25%) or synthetic
colloids (Pentaspan; Bristol-Myers Squibb Canada Inc, Montreal, Quebec, Canada). After
median sternotomy and heparinization, CBP was established with a single two-stage right
atrial cannula and an ascending aortic cannula. Pump flow rates were kept between 2.0
and 2.5 L/min per square meter, and mean arterial pressures between 50 and 60 mm Hg.
In elderly patients or in patients with carotid artery stenoses, the mean arterial pressure
was maintained at higher than 70 mm Hg in an attempt to improve cerebral perfusion.
Under mild systemic hypothermia (34 C), cardiac arrest was induced and maintained
using intermittent hyperkalemic cold blood cardioplegia. Proximal and distal

anastomoses were constructed during a single crossclamp period. A left internal thoracic
artery graft was used in 90% of patients.

While on CPB, red blood cell concentrates (leukoreduced allogeneic or autologous) were
transfused to maintain the hematocrit concentration at more than 17%. Pericardial blood
was salvaged into the cardiotomy suction reservoir and then reinfused via the CPB circuit
as long as patients were anticoagulated. After separation from CPB, heparin was
neutralized with protamine sulphate, 1 mg per 100 U of heparin, to achieve an activated
clotting time within 10% of baseline. After CPB, red blood cell concentrates were
transfused to maintain the hematocrit at more than 21% in stable patients and more than
27% in bleeding or unstable patients.
Insulin was not added to either cardioplegic regime and blood sugar management was
standarized. Patients with a blood sugar greater than 20 mmol/L in the first 4
postoperative hours were given a 5- to 10 IU intravenous bolus of Humulin R. In cases of
insulin-dependent diabetes or persistent hyperglycemia, an intravenous insulin drip was
administered until the patient reverted to the usual preoperative insulin regimen.

LCOS was also diagnosed if the patient required inotropic medication (either dopamine,
dobutamine, milrinone, or epinephrine) to maintain systolic blood pressure greater than
90 mm Hg and cardiac output at greater than 2.2 L/min1/ m2 for at least 30 minutes in
the intensive care unit, after optimizing preload and afterload as well as correction of all
electrolyte and blood gas abnormalities [25]. The use of inotropic agents in the operating
room but not the ICU was not included in the definition unless the previously mentioned

criteria were met in the ICU. Patients who required a renal dose of dopamine (3 g/kg)
were not considered to have LCOS. As well, patients who received vasoconstricting
medications to increase peripheral vascular resistance in presence of normal or high
cardiac output (2.5 L min1 m2) were not considered to have LCOS. In patients who
received an IABP before surgical intervention, LCOS was determined if they required
postoperative inotropic support in addition to IABP to maintain systolic blood pressure
greater than 90 mm Hg and cardiac output greater than 2.2 L/min1/ m2 for at least 30
minutes in the intensive care unit. IABP was inserted in the operating room or the
intensive care unit only in the patients who could not be adequately rescued with
additional reperfusion on bypass and/or inotropic support.

Appendix Table 1. Composition of 8:1 blood cardioplegia and microplegia (N= 3960)
Component

8:1 cardioplegia

Microplegia

No. of patients

1980

1980

Blood-to-crystalloid ratio

8:1

66:1

Magnesium sulphate (mEq/L)

Induction dose

27

27

Maintenance dose

15

15

Dextrose 10% (mL)

50

50

Mean Hemoglobin (g/dL)

7.5 2.3

9.2 2.6

Temperature (C)

Volume of crystalloid per L of

125 mL/L

15mL/L

437 88 mL

45 32 mL

3.6 0.4 L

3.4 0.5 L

Potassium chloride (mEq/L)

cardioplegia
Volume of crystalloid delivered (mL)
mean SD
Volume of cardioplegia delivered (L)
mean SD

Appendix Table 2. Demographics and baseline clinical profile (unmatched groups)

Variable

8:1 cardioplegia

Microplegia

P value

No. of patients

5058

2630

Age (y) mean SD

63.4 10

64.3 10.2

<.001

BSA

1.92 0.21

1.92 0.23

.20

Female (%)

21.3

22.2

.34

Diabetes mellitus (%)

29.8

37.8

<.001

Hypertension (%)

56.4

77.7

<.001

Hyperlipidemia (%)

70

93

<.001

None/stable

34.4

45.2

<.001

Crescendo/ ACS

64.6

54.8

<.001

Preoperative MI (%)

21.7

23.2

.14

Cardiogenic shock (%)

1.3

.28

Congestive heart failure (%)

9.4

10.5

.12

40%

79.1

83.3

<.001

< 40%

20.9

16.7

Left main disease (%)

18.2

33.1

<.001

Triple-vessel disease (%)

75.8

83.7

<.001

Preoperative stroke (%)

8.3

9.1

0.24

Preoperative renal failure

0.8

1.5

.006

Angina (%)

LVEF (%)

Peripheral vascular disease (%)

13.7

18.9

<.001

COPD (%)

4.7

4.6

.93

Preoperative haemoglobin (mg/dl)

133.6 15.4

135.2 16.2

<.001

Reoperative CABG (%)

2.7

.006

Previous PCI stents

8.2

9.7

.03

Elective

46.9

51.1

<0.001

Same day hospitalization

44.1

39.2

Urgent

7.7

8.3

Emergency

1.3

1.3

Urgency of surgery (%)

ACS, acute coronary syndrome; BSA, body surface area; MI, myocardial infarction;
CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; COPD,
chronic obstructive pulmonary disease.

10