Download Cardioprotective Effects of Acute Normovolemic

Cardioprotective Effects of Acute
Normovolemic Hemodilution in Patients
Undergoing Coronary Artery Bypass
Surgery*
Marc Licker, MD; Christoph Ellenberger, MD; Jorge Sierra, MD;
Afksendiyos Kalangos, MD; John Diaper, RN; and Denis Morel, MD
Study objectives: We hypothesized that lowering blood viscosity with acute normovolemic
hemodilution (ANH) would confer additional cardioprotection in patients undergoing coronary
artery bypass surgery (CABG) with aortic cross-clamping.
Design: In a prospective, randomized controlled trial, we studied the efficacy of ANH in
anesthetized patients prior to cardiopulmonary bypass for the prevention of myocardial injuries.
Setting: Cardiac surgical center in a university hospital.
Patients and methods: Patients scheduled to undergo elective CABG entered the study protocol
and were randomly allocated to one of two groups: ANH (n ⴝ 43 patients) or standard care
management (n ⴝ 41 patients). In the ANH group, the whole-blood/colloid exchange was aimed
to achieve a hematocrit value of 28%. All patients were managed with standard myocardial
preservation techniques including cold-blood cardioplegia and anesthetic preconditioning. The
outcome measures included the release of myocardial enzymes (plasma troponin I and creatinine
phosphokinase), perioperative hemodynamic changes, need for pharmacologic cardiovascular
support, and cardiac complications.
Results: In the hemodilution group, the postoperative release of troponin I (mean peak plasma
concentration, 1.4 ng/mL; 95% confidence interval, 1.0 to 1.8) and myocardial fraction of creatine
kinase (mean, 29 U/L; 95% confidence interval, 23 to 35) were significantly lower than in the
control group (mean, 3.8 ng/mL; 95% confidence interval, 3.2 to 4.5; and 71 U/L; 95% confidence
interval, 53 to 89). Requirement for inotropic support was significantly lower in the protocol
patients (7 of 41 patients vs 15 of 39 patients), and fewer patients presented with either atrial
fibrillation, atrioventricular conduction blockade, or combined disorders (12 of 41 patients vs 26
of 39 patients, p < 0.05).
Conclusions: In addition to conventional myocardial preservation techniques, preoperative ANH
achieved further cardiac protection in patients undergoing on-pump myocardial revascularization.
(CHEST 2005; 128:838 – 847)
Key words: cardiac surgery; cardiopulmonary bypass; coronary artery disease; hemodilution; troponin; myocardial ischemia
Abbreviations: ANH ⫽ acute normovolemic hemodilution; CABG ⫽ coronary artery bypass surgery; CPB ⫽ cardiopulmonary bypass
n the Western world, coronary artery bypass
I surgery
(CABG) is one of the most frequently
performed major operations and is highly effective in
improving life expectancy and quality of life in
patients with coronary artery disease.1 Although the
number of surgical procedures will continue to
decline along with the advances in interventional
cardiology, the proportion of higher-risk patients
requiring complex surgical procedures will likely
continue to increase in the near future.2 Moreover,
in spite of improvements in surgical, anesthetic, and
perfusion techniques, a wide spectrum of perioper-
*From the Department of Anesthesiology, Pharmacology and
Surgical Intensive Care (Drs. Licker, Ellenberger, and Morel,
and Mr. Diaper) and the Clinic of Cardiovascular Surgery (Drs.
Dierra and Kalangos), University Hospital of Geneva, Geneva,
Switzerland.
The study was supported by institutional department funds.
Manuscript received October 25, 2004; revision accepted February 14, 2005.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Marc Licker, MD, Department of Anesthesiology, Pharmacology, and Surgical Intensive Care, Hopital Universitaire, rue Micheli-Ducrest, CH-1211 Genève 14, Switzerland; e-mail: [email protected]
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Clinical Investigations
ative ischemic myocardial injuries still result in significant cardiac morbidity complications including
contractile dysfunction, myocardial infarction, and
low output syndrome requiring prolonged intensive
care.3,4
Over the last 2 decades, the potential benefits of
avoiding homologous blood transfusion and optimizing oxygen delivery in vital organs have led to a
renewed interest for acute normovolemic hemodilution (ANH) in major surgery.5 With this technique,
the adequacy of tissue oxygenation and organ function is maintained by compensatory increases in
cardiac output, improved blood flow distribution,
and higher oxygen extraction ratios.5–7 In the myocardium, hemodilution-induced lowering of blood
viscosity is thought to facilitate blood flow through
stenotic and collateral vessels, thereby counteracting
the reduced blood oxygen-carrying capacity.8 To
date, although ischemic cardiac dysfunction has not
been detected during moderate normovolemic hemodilution (reduction of hemoglobin concentrations
to 90 g/L or hematocrit levels of 28%) even in
anesthetized patients with coronary artery disease,9,10 clinical outcome benefits (or adverse events)
have not been thoroughly investigated in high-risk
patients for myocardial ischemia.
In this study, we hypothesized that ANH afforded
cardioprotective effects in patients undergoing
CABG. Indeed, improved rheologic blood flow conditions might restore an optimal balance between
flow and metabolic demand within the myocardium
before the obligatory period of ischemia associated
with aortic cross-clamping. Therefore, we designed a
randomized controlled trial in patients undergoing
elective on-pump coronary revascularization procedures and evaluated the protective potential of moderate hemodilution vs standard management. Myocardial injuries were assessed postoperatively by
determination of the release of myocardial enzymes
(troponin I and creatine kinase), ECG changes, and
the need for pharmacologic interventions.
Materials and Methods
Selection of Patients and Sample Size
After approval by the local Ethics Committee, written informed consent was obtained from all patients scheduled for
elective CABG and thought to meet the eligibility criteria.
Inclusion criteria were as follows: a screening hemoglobin concentration ⬎ 120 g/L in men or 110 g/L in women; stable angina
(classes I and II of the Canadian Cardiology Society); left
ventricular ejection fraction ⬎ 30%; and absence of significant
coexistent diseases, namely, valvular disease, recent myocardial
infarct (⬍ 6 weeks), significant carotid stenosis (⬎ 70%) or recent
stroke (⬍ 3 weeks), renal insufficiency (estimated creatinine
clearance ⬍ 20 mL/min), chronic respiratory disease (arterial
www.chestjournal.org
oxygen pressure ⬎ 7 kPa on room air), liver insufficiency (aspartate transaminase or alanine transaminase two or more times the
upper range), and uncontrolled hypertension or diabetes mellitus.
Samples sizes were calculated for a two-sided significance level
of ␣ ⫽ 0.05 and a power of 1⫺␤ ⫽ 0.8 to detect a difference of
0.5 ␮g/L in troponin I concentrations between the two groups. In
a preliminary assessment including cardiac surgical patients, the
SD of postoperative troponin I measurements was 0.8; thus, the
number of subjects required was 38 per group.
Randomization and Masking
Eligible patients were randomized to one of the two groups:
the ANH group and the standard care group. The allocations
were generated from random-number tables by an independent
observer and concealed in sealed envelopes. Although intraoperative masking was not possible in the ICU, the attending
physicians and nurses were blinded to the treatment group.
Trial Protocol
Anesthesia and Surgical Procedure: On the morning of surgery,
the patients were premedicated (morphine, 0.1 mg/kg; midazolam, 7.5 mg) and received their usual cardiac drug regimen,
except aspirin, diuretics, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers, which were withdrawn
at least 24 h before surgery. In the operating theater, cannulae
were inserted in a peripheral vein, a radial artery, and the right
jugular vein. Standard monitoring included pulse oximetry, leads
II and V5 of the ECG for heart rate and automated ST-segment
trend analysis, continuous measurements of mean arterial and
central venous pressures, nasopharyngeal temperature, end-tidal
capnography, bispectral analysis of the EEG (BIS A-2000 XP;
Aspect Medical Systems; De Meern, the Netherlands), as well as
transesophageal echocardiography (Philips Sonos 5500; Philips
Medical Systems; Andover, MA).
A balanced anesthetic technique included sufentanyl (bolus of
0.5 to 0.9 ␮g/kg followed by 0.4 to 0.8 ␮g/kg/h), midazolam (bolus
of 0.05 to 0.1 mg/kg followed by 0.1 mg/kg/h), pancuronium (0.1
mg/kg) and inhaled isoflurane (0.5 to 1% in the prebypass
period), which was administered to enhance cardiac protection
before aortic clamping (anesthetic preconditioning). In the two
groups, a similar depth of anesthesia was obtained by targeting
bispectral EEG values between 40 and 60 arbitrary units.
ANH: In the ANH group, after anesthesia induction, blood was
withdrawn (60 to 80 mL/min) from a central vein by gravity into
citrate-phosphate-dextrose collection bags that were placed on a
rocking platform of a precision scale. In parallel, poly(0 –2hydroxy-ethyl)amidon (hydroxyethyl starch; HAES-Steril; KabiFresenius; Stans, Switzerland) [mean molecular weight, 200,000;
50% substitution degree; C2/C6 ratio ⫽ 5] was infused through a
16-gauge peripheral catheter on the opposite arm, to a ratio of
1.15:1 to the donated blood.11 The blood volume to be removed
was calculated according to a standard formula to reach a
hematocrit of 28%.12 The whole-blood/colloid exchange procedure lasted 20 min (range, 15 to 25 min), and it could be
interrupted if there were signs of myocardial ischemia and/or
unresponsive hypotension. The autologous blood was labeled and
reinfused intraoperatively when the transfusion criteria were
met.
Perioperative Standardized Interventions: In the two groups,
additional blood saving methods were used: aprotinin (2 million
kallikrein inhibitory units before surgical incision, 2 million units
in the bypass circuit with a continuous infusion of 200,000 UI/h)
and a cell saver device to retrieve blood shed from the surgical
field and from the bypass circuit at the end of surgery. Using
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839
transesophageal echocardiography, systematic evaluation of cardiac function, chamber size, and valves were repeatedly performed before and after cardiopulmonary bypass (CPB) according to the guidelines of the American Society of
Echocardiography and the Society of Cardiovascular Anesthesiologists.13
Strategies for CPB and myocardial preservation were uniform
among the three participating surgeons. After full heparinization
(300 IU/kg), CPB including a membrane oxygenator and a circuit
primed with a 2-L normal saline solution was instituted using
nonpulsatile flow (2.2 to 2.5 L/min/m2) and mild hypothermia
(32° to 34°C). An ␣-stat control for acid-base management was
applied, and mean arterial pressure was targeted between 50 and
70 mm Hg with pharmacologic manipulation as necessary. Myocardial protection was achieved with anterograde hyperkalemic
blood cardioplegia (4°C, 20 mEq potassium) repeated every 30
min and single aortic clamping for all distal anastomosis. Before
aortic unclamping, warm-blood cardioplegia was administered
and IV nitroglycerine was started (2 mg/h). Hemofiltration was
not performed during CPB.
After achieving a rectal temperature ⱖ 35.5°C, weaning from
CPB was guided by echocardiographic assessment and standard
hemodynamic measurements. The pump flow was gradually
reduced while the heart was progressively filled in order to
optimize the preload-recruitable stroke volume and to reach a
mean arterial pressure ⱖ 65 mm Hg (Table 1). Optimal cardiac
filling was judged by achieving a maximal left ventricular diameter in the short-axis view of 2.5 to 2.8 cm/m2. The heart was
electrically paced if it failed to maintain a heart rate ⱖ 70
beats/min because of atrioventricular conduction blockade or
bradyarrhythmia. Phenylephrine (50 to 100 ␮g, repeated boli)
was administered to maintain mean arterial pressure ⱖ 65 mm
Hg after optimizing cardiac preload and contractility parameters.
Inotropes were not routinely administered during weaning from
CPB. Dobutamine was initiated (starting at 3 ␮g/kg/min) in the
presence of mean arterial pressure ⬍ 65 mm Hg and persistent,
new, or worsening cardiac systolic dysfunction (left ventricular
fractional area ⬍ 30%); norepinephrine infusion was added to
this regimen if mean arterial pressure remained ⬍ 65 mm Hg
despite satisfactory cardiac filling parameter (vasoplegia syndrome).
At the end of CPB, protamine was administered to neutralize
circulating heparin; the residual bypass circuit volume and shed
blood processed by the cell salvage machine were retransfused to
the patient. The threshold for blood transfusion was a hematocrit
value ⬍ 18% during CPB and ⬍ 25% after CPB, or higher values
(26 to 30%) when accompanied by hemodynamic instability
and/or ECG signs of myocardial ischemia. In the ANH group, the
whole autologous blood volume was retransfused during CPB or
shortly after weaning from CPB.
Clinical, Hemodynamic, and Biochemical Measurements: Myocardial tissue ischemic injury—the main study end point—was
quantified by the release of cardiac biomarkers. Venous blood
samples were sequentially collected (before surgery [baseline], at
1 to 3 h, 18 to 24 h, 40 to 48 h, and 72 h after surgery) for
measurements of troponin I (Access Immunoassay System; Beckman Instruments; Fullerton, CA), creatinine kinase and myocardial fraction of creatinine kinase (optical standard technique).
Sensitivity for troponin I determination was 0.09 ng/mL.
Hemodynamic measurements and calculation of the ratepressure-product were obtained at the following times: (1) 5 min
after anesthesia induction (baseline), (2) 5 min after the end of
ANH or 30 min after anesthesia induction, (3) 5 min after
sternotomy, (4) after weaning from CPB, and (5) during skin
closure. All patients underwent a 12-lead ECG before surgery, at
arrival in ICU, and then daily after surgery; transmural myocardial infarction was defined by the presence of new Q-waves (at
least 0.04 ms and a reduction in R-waves of ⬎ 25% in at least two
leads).
Data regarding perioperative fluid management, homologous
transfusion, and pharmacologic intervention were recorded intraoperatively and for the first 24 h after surgery. All patients
were followed up until hospital discharge to detect adverse
events. In-hospital mortality rate, hemodynamic changes, need
for pharmacologic cardiac support, and the incidence of cardiovascular complications (new Q wave on ECG, atrial fibrillation,
conduction blockade requiring electrical stimulation, stroke)
were considered as secondary study end points.
Statistical Analysis
All data were analyzed using statistical software (version 9.0 for
Windows; SPPS; Chicago, IL). Values were expressed as mean
(⫾ SD or 95% confidence interval), median (interquartile range,
25 to 75%), or percentage as appropriate. Dichotomous variables
were compared by the x2 statistic or Fisher Exact Test, and
quantitative variables were compared with unpaired Student t
test. Cardiac markers and hemodynamic data were compared
with repeated-measures analysis of variance, having the group
(ANH vs control) as a between-factor and time as a within-factor.
Statistical significance was attributed to p ]ltequ] 0.05.
Results
Four patients who consented to take part were
excluded because myocardial revascularization was
performed without CPB (Fig 1). Data were obtained
in 80 patients (39 in the ANH group and 41 in the
control group).
Baseline Characteristics and Operative Data
The preoperative characteristics of the two groups
were similar with regards to age, gender, body mass
Table 1—Hemodynamic Management and End Points During Weaning From CPB*
Hemodynamics
End Points
Heart rate ⬍ 70 beats/min
EDD ⬍ 2.5–2.8 cm/m2 and MAP ⬍ 65 mm Hg
EDD ⱖ 2.5–2.8 cm/m2 and MAP ⬍ 65 mm Hg
EDD ⱖ 2.5–2.8 cm/m2, MAP ⬍ 65 mm Hg and
systolic LV dysfunction
Electrical cardiac pacing (A, V, or AV)
Fluid challenge (100-mL increments)
Phenylephrine (50–100 ␮g repeated boli, up to 50 ␮g)
1, dobutamine infusion (starting at 3 ␮g/kg/min); 2, norepinephrine
infusion (if dobutamine ⬎ 8 ␮g/kg/min)
*A ⫽ atrial; V ⫽ ventricular; AV ⫽ atrioventricular; EDD ⫽ end-diastolic diameter; LV ⫽ left ventricle; MAP ⫽ mean arterial pressure.
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Clinical Investigations
Figure 1. Flow of the participants through the trial.
index, concomitant morbidity, left ventricular ejection fraction, and use of medications (Table 2). Also,
the number of grafted coronary arteries as well as the
durations of aortic cross-clamping, CPB, and surgery
were comparable (Table 2).
Hemodynamics, Fluid Balance, and Hemoglobin
Results
Following blood withdrawal and isovolemic compensation with colloids, hematocrit decreased from
Table 2—Preoperative Characteristics and Operative Data of Patients Undergoing Myocardial Revascularization
With CPB*
Characteristics
ANH (n ⫽ 41)
Control (n ⫽ 39)
p Value
Age, yr
BSA, m2
Male/female gender, No.
Medical history
Diabetes mellitus
Hypercholesterolemia
Hypertension
Prior myocardial infarction
Left ventricular ejection fraction, %
Medications
␤-Blockers
Nitrates
Angiotensin-converting enzyme inhibitors/angiotensin II blockers
Calcium blockers
Diuretics
Statins
Aspirine taken ⱕ 72 h preoperatively
Cross-clamp time, min
CPB time, min
Surgical time, min
Grafted coronary arteries, No. (range)
67 (63–70)
27 (26–28)
33/8
65 (62–68)
28 (24–30)
33/6
0.7
0.6
0.9
12 (29)
31 (76)
33 (80)
17 (41)
54 (51–57)
9 (23)
32 (82)
30 (77)
15 (38)
55 (51–59)
0.7
0.7
0.9
0.9
0.8
38 (93)
18 (41)
21 (51)
10 (24)
7 (17)
22 (54)
8 (20)
78 (63–93)
114 (101–127)
269 (251–287)
3 (1–5)
37 (95)
17 (44)
16 (41)
7 (18)
5 (13)
20 (51)
8 (21)
87 (70–104)
122 (111–133)
281 (263–300)
3 (1–4)
0.9
0.8
0.9
0.7
0.8
0.9
0.9
0.44
0.35
0.41
1
*Data are presented as mean (95% confidence interval) or No. (%) of patients unless otherwise indicated.
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841
41 ⫾ 2 to 28 ⫾ 1% (p ⬍ 0.001) and was accompanied by a significant increase in central venous
pressure and a decrease in heart rate and ratepressure product compared with baseline values
(Table 3). No patients exhibited signs of myocardial
ischemia as judged by the analysis of automated
ST-segment and left ventricular wall motion monitoring.
Before CPB, hematocrit levels, heart rate, and
rate-pressure-product remained significantly lower
in the ANH group compared with the control group
(Table 3). After weaning from CPB and at the end of
surgery, hemodynamic data and hematocrit levels
did not differ between the two groups.
Intraoperatively, the total volume of colloids was
slightly but significantly higher in the ANH group
compared with the control group. However, cumulative fluid balance and allogenic blood transfusion
requirements were comparable in the two groups
over the 24-h perioperative period (Table 4). In the
ANH group, the autologous blood was reinfused
during CPB in all the patients as the transfusion
trigger was reached.
Primary Outcomes
In the two groups, troponin I concentrations were
below the detection limit before CPB and increased
significantly after arrival in the ICU. At 18 to 24 h, 40
to 48 h, and 72 h after aortic unclamping, myocardial
release of troponin was significantly lower in the
ANH group than in the control group (Table 5).
Values for creatine kinase and myocardial fraction of
creatine kinase were also comparable at the beginning of surgery and increased significantly after
arrival in ICU in both groups. Compared with the
control group, the release of the myocardial fraction
of creatine kinase in the ANH group was significantly
lower at arrival in ICU and 18 to 24 h after aortic
unclamping (Table 5).
Secondary Outcomes
All patients survived, and one patient in each
group met the ECG criteria for perioperative myocardial infarct. The groups were similar with respect
to length of stay in the ICU and in the hospital, as
well as the occurrence of noncardiac complications
(Table 6). However, of 41 patients in the ANH
group, 7 patients were administered dobutamine,
compared with 15 patients in the control group (odds
ratio, 0.35; confidence interval, 0.12 to 0.98;
p ⫽ 0.04), and the total amount of dobutamine was
significantly lower in the ANH group than in the
control group. The combined incidence of arrhythmia and conduction disorders requiring transient
cardiac pacing was also significantly lower in the
ANH group, compared with the control group.
Plasma troponin I concentrations (18 to 24 h after
the end of CPB) were significantly higher in subgroups of patients receiving dobutamine infusion
compared with those not requiring inotropic support
(4.5 ⫾ 3.1 ng/mL vs 2.2 ⫾ 1.9 ng/mL in the control
group, and 3.1 ⫾ 2.3 ng/mL vs 0.7 ⫾ 0.4 ng/mL in
the ANH group, respectively).
Table 3—Intraoperative Time Course of Hemoglobin and Hemodynamic Variables*
Variables
Hematocrit, %
Control group
ANH group
Baseline 1
After Hemodilution
or Baseline 2
Sternotomy
10 min After
Starting CPB
After Weaning
From CPB
End of Surgery
27 (24–29)‡
20 (18–22)†‡
25 (23–27)‡
24 (22–26)‡
27 (25–29)‡
27 (24–30)‡
81 (77–85)‡
78 (74–82)‡
81 (78–84)‡
79 (75–83)‡
73 (70–76)
74 (71–77)
78 (74–82)
79 (75–84)
40 (38–42)
41 (39–43)
39 (37–43)
28 (27–29)†‡
39 (37–43)
27 (26–9.3)†‡
Heart rate, beats/min
Control group
67 (64–70)
ANH group
65 (61–69)
64 (61–77)
54 (51–57)†‡
65 (61–69)
55 (52–58)†‡
Mean arterial pressure, mm Hg
Control group
80 (76–84)
ANH group
77 (74–80)
78 (74–82)
74 (71–77)
87 (84–90)
85 (81–89)
Rate-pressure product, mm Hg/beats/min
Control group 6,849 (6,102–7,496) 6,304 (5,960–6,640)
ANH group
6,502 (6,140–6,904) 5,522 (5,290–5,755)†‡
Central venous pressure, mm Hg
Control group
11.4 (10.3–12.5)
ANH group
11.8 (10.9–12.7)
11.6 (10.7–12.5)
13.9 (13.1–14.7)†‡
7,373 (6,895–7,851)
6,353 (5,812–6,894)†
12.0 (11.1–12.9)
13.1 (12.1–14.1)
65 (52–68)‡
64 (61–67)‡
8,263 (7,475–9,055)
7,746 (7,311–8,181)
8,204 (7,667–8,741)
8,160 (7,427–8,893)
14.4 (13.4–15.4)‡
14.6 (13.4–15.8)‡
14.6 (13.6–15.6)‡
14.9 (13.7–15.1)‡
*Data are presented as mean (95% confidence interval).
†p ⬍ 0.05 between groups.
‡p ⬍ 0.05 compared with baseline 1.
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Clinical Investigations
Table 4 —Intraoperative and Postoperative Fluid Balance and Allogenic Blood Transfusion*
ANH (n ⫽ 41)
Variables
Intraoperative fluid balance, mL
Cristalloids
Colloids
Urine output
Postoperative fluid balance (first 24 h), mL
Cristalloids plus colloids
Urine output
Chest tube drainage, mL/24 h
Patients receiving RBC concentrates (intra- and postoperatively)
No. of patients
Mean (SD) of units per patient
Patients receiving fresh frozen plasma (intra- and postoperatively)
No. of patients
Mean (SD) of units per patient
Control (n ⫽ 39)
p Value
3,753 (3,427–4,079)
1,370 (1,270–1,470)
942 (735–1,149)
3,580 (3,116–4,044)
974 (850–1,098)
739 (554–924)
0.5
0.04
0.14
2,864 (2,448–3,280)
2,074 (1,808–2,340)
623 (515–731)
3,444 (2,991–3,847)
1,732 (1,452–2,006)
567 (430–704)
0.07
0.08
0.5
17
0.9 (1.3)
14
1.0 (1.4)
0.8
0.7
3
0.3 (1.1)
4
0.3 (1.3)
0.9
0.9
*Data are presented as mean (95% confidence interval) unless otherwise indicated.
Discussion
The results of this investigation demonstrate that
moderate ANH prior to on-pump CABG confers
additional myocardial protection beyond that provided by blood cardioplegia and anesthetic preconditioning, as expressed by lower release of biomarkers of myocardial injury, lesser requirements for
inotropic support, as well as fewer patients presenting with arrhythmia’s or conduction disorders after
weaning from CPB.
Perioperative Myocardial Injury
After CABG, the variable incidence of myocardial
infarcts (from 1 to 29%) has been attributed to
nonuniform definitions and different baseline patient characteristics.1,14 In addition, postoperative
sternal pain makes clinical symptoms unreliable, and
ECG-derived diagnosis of myocardial infarct cannot
be satisfied in the presence of transient conduction
block, arrhythmias, and ventricular hypertrophy.15–17
To detect myocardial injury, we adopted measurements of troponin I and restrictive ECG criteria, ie,
the occurrence of new Q waves. As shown by
radionuclide techniques using single-photon emission CT imaging, plasma release of cardiac biomarkers parallels the extent of myocardial damage in the
transmural or subendocardial areas regardless of its
mechanisms.18 Importantly, most episodes of perioperative myocardial necrosis are clinically silent,
unaccompanied by Q-wave evolution and result in
plasma release of troponin, which carries both shortterm and long-term prognostic significance for inhospital mortality and later complications.19 –21 The
Table 5—Perioperative Biological Markers of Cellular Injury*
After Weaning From CPB, h
Variables
Troponin I, ng/mL
Control group
ANH group
1–3
Before Surgery
0.04 (0.04–0.06)
0.04 (0.03–0.05)
Creatinine phosphokinase, U/L
Control group
82 (76–88)
ANH group
85 (77–93)
1.64 (1.25–2.03)‡
0.63 (0.51–0.75)†‡
740 (514–966)‡
469 (350–588)‡
18–24
3.87 (3.15–4.59)‡
1.43 (1.02–1.84)†‡
40–48
3.16 (2.30–4.02)‡
1.13 (0.84–1.42)†‡
1,284 (928–1,640)‡
603 (497–705)†‡
1,120 (775–1,465)‡
490 (449–541)†‡
Myocardial fraction of creatinine phosphokinase, U/L
Control group
13 (10–16)
35 (28–42)
ANH group
10 (7–13)
28 (24–32)
71 (53–89)‡
29 (23–35)†‡
62 (40–84)‡
21 (16–26)†
C-reactive protein, ng/dL
Control group
ANH group
72 (48–96)†
66 (46–86)†
⬍5
⬍5
72
2.31 (1.63–2.97)‡
0.81 (0.58–1.02)†‡
787 (592–982)‡
380 (272–428)†‡
38 (25–51)‡
15 (12–18)
78 (52–94)‡
71 (56–86)‡
*Data are presented as mean (95% confidence interval).
†p ⬍ 0.05 between groups.
‡p ⬍ 0.05 compared with baseline (before surgery).
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843
Table 6 —Pharmacologic Cardiac Support and Perioperative Complications
Variables
Cardiac drugs
Dobutamine
No. of patients
Median dose (interquartile range), mg
Norepinephrine
No. of patients
Median dose (interquartile range), mg
Cardiac complications, No. of patients
New Q wave on ECG
Conduction block
Atrial fibrillation
Noncardiac complication, No. of patients
Postoperative ventilation ⬎ 24 h
Reoperation for bleeding
Stroke or transient cerebral ischemia
Renal dysfunction (creatinine ⬎ 120% of baseline)
ICU stay, median d (range)
Hospital stay, median d (range)
ANH (n ⫽ 41)
7
71 (20–255)*
Control (n ⫽ 39)
15
112 (34–425)
4
0.8 (0.4–2.1)
12*
1
8
10
4
0.7 (0.3–2.1)
26
1
12
17
1
1
2
3
2 (1–5)
12 (10–15)
2
1
2
3
2 (1–7)
13 (10–16)
p Value
0.04
⬍ 0.01
0.9
0.28
⬍ 0.01
0.9
0.36
0.11
0.9
0.9
0.6
0.7
1.0
1.0
*p ⬍ 0.05 between groups.
most recent consensus guidelines22 from the American Heart Association/American College of Cardiology and European Society of Cardiology have incorporated troponin (I or T) as the myocardial
biomarkers of choice, not only in medical patients
with suspected acute coronary syndrome but also
following cardiac surgery. A large range of troponin
I cut-off levels (3 to 9 ng/mL, depending on the
immunoassay) has been reported for diagnosing
early graft failure and transmural myocardial
infarct.22,23
In the two groups, postoperative elevation of
troponin and myocardial fraction of creatine kinase
was the biological expression of myocardial cellular
damage consequent to prolonged aortic clamping
time with ischemia-reperfusion phenomenon, possible coronary microembolization, and direct myocardial trauma by surgical manipulations.24 Neither
patient required reoperation nor mechanical assistance for ventricular failure, the incidence of Q-wave
myocardial infarct was low (2.5%), and plasma troponin I levels were in the low-to-intermediate range,
excluding early vascular graft failure or coronary
occlusion. Such a favorable cardiac outcome reflected the low preoperative risk profile of our
surgical population (eg, stable coronary disease, preserved left ventricular function, without associated
valve disease) and the successful application of myocardial preservation techniques including blood cardioplegia and anesthetic preconditioning with isoflurane.25 The postoperative release of cardiac
biochemical markers has been shown to correlate
with the amount of infarcted myocardium as determined by contrast-enhanced MRI; accordingly, peak
troponin I levels in the low-to-intermediate range (1
to 9 ng/mL) would correspond to myonecrosis involving 0.5 to 17 g of left ventricle mass (or 1.2 to
10% of ventricular volume).26
Patients requiring temporary inotropic support to
maintain hemodynamic stability after weaning from
CPB also presented the highest blood levels of
troponin I, regardless of the treatment group. In
clinical and experimental studies, correlations have
been demonstrated between the duration of global
myocardial ischemia, the extent of necrosis/apoptosis, and the severity of ventricular dysfunction following reperfusion.27,28 Likewise, higher 30-day
mortality rate after cardiac surgery has been associated with the use of inotropic agents, a surrogate of
unstable hemodynamics and impaired ventricular
function.29 Taken together, these results suggest that
both global myocardial stunning (reversible) and
necrosis (irreversible) are responsible for the transient decline in cardiac contractility that has been
shown to correlate with the duration of cardioplegic
arrest.
ANH
In addition to the use of antifibrinolytics and
intraoperative cell saving, preoperative hemodilution
failed to provide any blood-sparing effects. Consistent with these data, a recent meta-analysis30 including 42 trials demonstrated that the risk of allogenic
transfusion was similar among hemodiluted patients,
those managed with another conservation method,
and those receiving standard care.
The safety of the hemodilution procedure was
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Clinical Investigations
ascertained by maintaining circulatory normovolemia and by close monitoring of cardiovascular
parameters with ECG and echocardiography. Presumably, general anesthesia and chronic ␤-blockade
decreased the metabolic needs (approximately 20 to
30%) and prevented the sympathetic-mediated inotropic and chronotropic response in our patients.31
Occasional reports of myocardial ischemia have been
attributed to extremely low hemoglobin levels, concomitant hypovolemia, reflex tachycardia in awake
volunteers, and/or increased postoperative metabolic
needs.32–34
In preliminary studies, we demonstrated that lowering blood viscosity at similar levels of hemodilution
induced a predominant preload-dependent increase
in stroke volume (⫹ 28%) owing to enhanced venous
return and mobilization of a fraction of the unstressed splanchnic volume, whereas left ventricular
contractility and afterload were unaffected.35 As a
result, the decreased blood oxygen carrying capacity
was partially offset by the increased cardiac output
with systemic oxygen delivery remaining above the
critical anaerobic threshold.
In this study, the improved intraoperative myocardial preservation in the hemodiluted patients was
clearly demonstrated by the lower postoperative
release of myocardial biomarkers, the reduced need
for inotropic support, and the lower incidence of
combined arrhythmia and conduction disorders,
compared with patients receiving standard care.
Except for prebypass and intrabypass hematocrit
levels, the two groups were comparable in terms of
baseline characteristics as well as perioperative hemodynamics and medical management. Such hemodilution-induced cardioprotection might be related to optimization of the myocardial balance in
oxygen demand/delivery before aortic cross-clamping.
Indeed, an approximate 12% reduction in myocardial oxygen consumption was expected according to
the decline of the rate-pressure product, a sensitive
index of cardiac metabolic requirements. The increased cardiac filling pressure following hemodilution was associated with a baroreflex-mediated lowering of heart rate that would also contribute to
facilitate coronary blood flow and enhance ventricular relaxation due to prolonged diastolic time.
Owing to the reduced blood viscosity, oxygen
delivery within underperfused myocardial areas
might be improved before aortic cross-clamping and
global cardiac ischemia. Physical concepts and experimental data lend support for increased tissue blood
flow distribution following moderate hemodilution
as a result of increased collateral blood flow, higher
density of functional capillaries, increased Fahraeus
effects, and shear-dependent vasodilatation.7,36,37
www.chestjournal.org
Limitations
First, monitoring of ECG changes was not continued postoperatively to detect transient myocardial
ischemia or ischemia-reperfusion phenomenon. Although Holter monitors have a high specificity (88 to
92%) to detect ischemia, sensitivity is low (37 to
50%).38 Moreover, changes in acid-base balance and
electrolytes, surgical wound and draping, hypothermia, as well as arrhythmia and left ventricular hypertrophy may all interfere with interpretation of ECG
changes and explain the high variability in the reported incidence of perioperative myocardial ischemia.
Second, an increase in central venous pressure
following hemodilution could be related to excess
fluid administration or to enhanced venous blood
return from the peripheral “slow flow/low shear rate”
compartment. However, hypervolemic hemodilution
was unlikely since the amount of blood withdrawn
was precisely measured and compensated by infusing colloid in a 1/1.15 ratio, which took into account
the extravasation of fluids into the interstitial space.11
Third, our trial involved low-risk patients undergoing elective CABG, and the study was not sufficiently powered to detect overall differences in
mortality, major cardiac complications, and ICU or
hospital resources. In previous reports, a nonsignificant trend toward fewer serious adverse events has
been observed in patients undergoing ANH (death
or myocardial infarct: 2.6% vs 4.0% in ANH vs
non-ANH groups, respectively).30 Accordingly, a
large number of patients would be required (⬎ 600
patients in each group) to detect significant reduction in major clinical events; in contrast, smaller
studies using surrogate biological end points such as
cardiac troponin are suitable to detect clinically
“silent” myocardial injuries, which carries long-term
prognostic values.
Finally, although intraoperative masking was not
possible, the ICU staffs were blinded to allocation to
group, perioperative medical care was standardized,
and similar clinical and physiologic end points were
achieved in the two groups. Preoperative cardiac
condition and intraoperative surgical treatment were
also comparable, although nonsignificant shorter duration of aortic cross-clamping (⬍ 10%) was noted in
the ANH group. As no protocol violations occurred,
we can assume that the reduction in postoperative
myocardial release of troponin was related to preoperative ANH.
Conclusions
Preventing myocardial damage during cardiac surgery contributes to better postoperative recovery.
CHEST / 128 / 2 / AUGUST, 2005
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845
Along with standard blood cardioplegia and anesthetic preconditioning, acute preoperative hemodilution attenuates the deleterious effects of aortic
cross-clamping and improves myocardial recovery in
patients undergoing CABG. The optimal value of
hematocrit levels before CPB remains unknown.
Further studies are warranted to confirm these
preliminary results, to investigate the mechanisms of
hemodilution-related cardioprotection, and to test
the efficacy of this simple procedure in higher-risk
patients with poor ventricular function and those
requiring complex cardiac surgery.
References
1 Mack MJ, Brown PP, Kugelmass AD, et al. Current status
and outcomes of coronary revascularization 1999 to 2002:
148,396 surgical and percutaneous procedures. Ann Thorac
Surg 2004; 77:761–766
2 Ulrich MR, Brock DM, Ziskind, AA. Analysis of trends in
coronary artery bypass grafting and percutaneous coronary
intervention rates in Washington State from 1987 to 2001.
Am J Cardiol 2003; 92:836 – 839
3 Nalysnyk L, Fahrbach K, Reynolds MW, et al. Adverse events
in coronary artery bypass graft (CABG) trials: a systematic
review and analysis. Heart 2003; 89:767–772
4 Bolling SF, Olszanski DA, Childs KF, et al. Stunning, preconditioning, and functional recovery after global myocardial
ischemia. Ann Thorac Surg 1994; 58:822– 827
5 Kreimeier U, Messmer K. Hemodilution in clinical surgery:
state of the art. World J Surg 1996; 20:1208 –1217
6 Mirhashemi S, Ertefai S, Messmer K, et al. Model analysis of
the enhancement of tissue oxygenation by hemodilution due
to increased microvascular flow velocity. Microvasc Res 1987;
34:290 –301
7 Hudetz AG, Wood JD, Biswal BB, et al. Effect of hemodilution on RBC velocity, supply rate, and hematocrit in the
cerebral capillary network. J Appl Physiol 1999; 87:505–509
8 Pries AR, Secomb TW. Rheology of the microcirculation.
Clin Hemorheol Microcirc 2003; 29:143–148
9 Spahn DR, Schmid ER, Seifert B, et al. Hemodilution
tolerance in patients with coronary artery disease who are
receiving chronic ␤-adrenergic blocker therapy. Anesth Analg
1996; 82:687– 694
10 Herregods L, Foubert L, Moerman A, et al. Comparative
study of limited intentional normovolaemic haemodilution in
patients with left main coronary artery stenosis. Anesthesia
1995; 50:950 –953
11 Rehm M, Orth VH, Kreimeier U, et al. Changes in blood
volume during acute normovolemic hemodilution with 5%
albumin or 6% hydroxyethylstarch and intraoperative retransfusion. Anaesthesist 2001; 50:569 –579
12 Gross JB. Estimating allowable blood loss: corrected for
dilution. Anesthesiology 1983; 58:277–280
13 Shanewise JS, Cheung AT, Aronson S, et al. ASE/SCA
guidelines for performing a comprehensive intraoperative
multiplane transesophageal echocardiography examination:
recommendations of the American Society of Echocardiography Council for Intraoperative Echocardiography and the
Society of Cardiovascular Anesthesiologists Task Force for
Certification in Perioperative Transesophageal Echocardiography. J Am Soc Echocardiogr 1999; 12:884 –900
14 Smith RC, Leung JM, Mangano DT. Postoperative myocardial ischemia in patients undergoing coronary artery bypass
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
graft surgery. S.P.I. Research Group. Anesthesiology 1991;
74:464 – 473
Benoit MO, Paris M, Silleran J, et al. Cardiac troponin I: Its
contribution to the diagnosis of perioperative myocardial
infarction and various complications of cardiac surgery. Crit
Care Med 2001; 29:1880 –1886
Sharp SD, Mason JW. Comparison of ST depression recorded
by Holter monitors and 12-lead ECGs during coronary
angiography and exercise testing. J Electrocardiol 1992; 25:
323–331
Tupper-Carey DA, Newman DJ, Price CP, et al. How silent
is perioperative myocardial ischemia? A hemodynamic, electrocardiographic, and biochemical study in patients undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc
Anesth 2000; 14:144 –150
Ingkanisorn WP, Rhoads KL, Aletras AH, et al. Gadolinium
delayed enhancement cardiovascular magnetic resonance
correlates with clinical measures of myocardial infarction.
J Am Coll Cardiol 2004; 16:2253–2259
Svedjeholm R, Dahlin LG, Lundberg C, et al. Are electrocardiographic Q-wave criteria reliable for diagnosis of perioperative myocardial infarction after coronary surgery? Eur
J Cardiothorac Surg 1998; 13:655– 661
Fellahi JL, Gue X, Richomme X, et al. Short- and long-term
prognostic value of postoperative cardiac troponin I concentration in patients undergoing coronary artery bypass grafting.
Anesthesiology 2003; 99:270 –274
Bonnefoy E, Filley S, Kirkorian G, et al. Troponin I, troponin
T, or creatine kinase-MB to detect perioperative myocardial
damage after coronary artery bypass surgery. Chest 1998;
114:482– 486
Alpert JS, Thygesen K, Antman E, et al. Myocardial infarction
redefined: a consensus document of The Joint European
Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll
Cardiol 2000; 36:959 –969
Holmvang L, Jurlander B, Rasmussen C, et al. Use of
biochemical markers of infarction for diagnosing perioperative myocardial infarction and early graft occlusion after
coronary artery bypass surgery. Chest 2002; 121:103–111
Chang PP, Sussman MS, Conte JV, et al. Postoperative
ventricular function and cardiac enzymes after on-pump
versus off-pump CABG surgery. Am J Cardiol 2002; 89:1107–
1110
Nicolini F, Beghi C, Muscari C, et al. Myocardial protection
in adult cardiac surgery: current options and future challenges. Eur J Cardiothorac Surg 2003; 24:986 –993
Steuer J, Bjerner T, Duvernoy O, et al. Visualisation and
quantification of peri-operative myocardial infarction after
coronary artery bypass surgery with contrast-enhanced magnetic resonance imaging. Eur Heart J 2004; 25:1293–1299
Opie LH. The multifarious spectrum of ischemic left ventricular dysfunction: relevance of new ischemic syndromes. J Mol
Cell Cardiol 1996; 28:2403–2414
Wesselink RM, de Boer A, Morshuis WJ, et al. Cardiopulmonary-bypass time has important independent influence
on mortality and morbidity. Eur J Cardiothorac Surg 1997;
11:1141–1145
Muller M, Junger A, Brau M, et al. Incidence and risk
calculation of inotropic support in patients undergoing cardiac surgery with cardiopulmonary bypass using an automated
anesthesia record-keeping system. Br J Anaesth 2002; 89:
398 – 404
Segal JB, Blasco-Colmenares E, Norris EJ, et al. Preoperative
acute normovolemic hemodilution: a meta-analysis. Transfusion 2004; 44:632– 644
846
Downloaded From: http://journal.publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/22028/ on 05/03/2017
Clinical Investigations
31 Spahn DR, Seifert B, Pasch T, et al. Effects of chronic
␤-blockade on compensatory mechanisms during acute isovolaemic haemodilution in patients with coronary artery
disease. Br J Anaesth 1997; 78:381–385
32 Carvalho B, Ridler BM, Thompson JF, et al. Myocardial
ischaemia precipitated by acute normovolaemic haemodilution. Transfus Med 2003; 13:165–168
33 Hogue CW Jr., Goodnough LT, Monk TG. Perioperative
myocardial ischemic episodes are related to hematocrit level
in patients undergoing radical prostatectomy. Transfusion
1998; 38:924 –931
34 Leung JM, Weiskopf RB, Feiner J, et al. Electrocardiographic
ST-segment changes during acute, severe isovolemic hemodilution in humans. Anesthesiology 2000; 93:1004 –1010
www.chestjournal.org
35 Licker M, Sierra J, Tassaux D, et al. Continuous haemodynamic monitoring using transoesophageal Doppler during
acute normovolaemic haemodilution in patients with coronary artery disease. Anaesthesia 2004; 59:108 –115
36 Rakusan K, Cicutti N, Kolar F. Effect of anemia on cardiac
function, microvascular structure, and capillary hematocrit in
rat hearts. Am J Physiol Heart Circ Physiol 2001; 280:H1407–
H1414
37 Fan FC, Chen RY, Schuessler GB, et al. Effects of hematocrit
variations on regional hemodynamics and oxygen transport in
the dog. Am J Physiol 1980; 238:H522–H545
38 Bjerregaard P, El-Shafei A, Kotar SL, et al. ST segment
analysis by Holter Monitoring: methodological considerations. Ann Noninvasive Electrocardiol 2003; 8:200 –207
CHEST / 128 / 2 / AUGUST, 2005
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