Credits:Albert H. O-Yurvati, Steven Rodriguez,
Glen Bell,Damon Kennedy, Robert T. Mallet
of Surgery and Integrative Physiology, University of North Texas Health Science Center,3500 Camp Bowie Boulevard,Fort Worth,Texas 76107-2699, USA.
Address for correspondence : Albert H. O-Yurvati DO, FACOS, FICS, FAHA,Department of Surgery,University of North Texas Health Science Center,3500 Camp Bowie Boulevard,Fort Worth,Texas 76107-2699 USA.
Atrial fibrillation remains the leading postoperative complication following cardiopulmonary
bypass. A randomized trial was undertaken to evaluate the effectiveness of leukocyte
filtration and aprotinin, applied separately and in combination, on the
incidence of post-operative atrial fibrillation. A secondary component of the
study was the impact of these adjunct interventions on post-surgical renal and
total of 1,220 patients undergoing primary isolated coronary artery bypass
grafting were randomly assigned to one of four treatment groups. The control
group (305 patients) received standard cardiopulmonary bypass with moderately
hypothermic (34ºC) cardioplegic arrest. In the filtration group (310 patients)
leukocyte reducing filters were incorporated into the bypass circuit
and deployed strategically. The aprotinin group (285
patients) received full Hammersmith dose aprotinin. The combination therapy
group (320 patients) received both aprotinin and leukocyte filtration.
incidences of atrial fibrillation were 25% in the control group, 16% in the filtration
group, 19% in the aprotinin group and 10% in the combination therapy group (P <
0.001). Renal dysfunction was detected in 3% of the control group, 2% of the filtration
group, 8% of the aprotinin group, and 5% of the combination group (P < 0.005).
Neurological dysfunction occurred in 2% of the control group, 2% of the filtration
group, 1% of the aprotinin group, and 2% of the combination group (P = n.s.).
therapy with aprotinin and leukocyte filtration markedly reduced atrial
fibrillation post-cardiopulmonary bypass, and was more effective than the
individual treatments. Aprotinin treatment increased the incidence of renal
dysfunction, and the addition of leukocyte filtration partially mitigated this
detrimental effect of aprotinin. Thus, strategic
leukocyte filtration augments aprotinin’s anti-arrhythmic effects while
suppressing its nephrotoxic sequelae.
aprotinin, atrial fibrillation, cardiopulmonary bypass, encephalopathy,
leukofiltration, renal failure
Atrial fibrillation ranks among the most frequent and potentially
deleterious complications associated with cardiopulmonary bypass. This
arrhythmia has been reported in up to 50% of cases, and its incidence remains high
despite advances in surgical and anesthetic techniques. The arrhythmia occurs approximately 48-72 hours after
surgery and can be manifested by persistent
tachycardia, hypotension, and in many cases cardiac failure and cerebrovascular
events. Different strategies have been
advocated to prevent atrial fibrillation. Pharmacological agents such as
anti-arrhythmics have been used in some studies with variable results.Another approach is the use of leukocyte filters, as there seems to be a connection between atrial
fibrillation and inflammation.[6,7]
Indeed, systemic inflammation can elicit atrial fibrillation by activating the
complement system and stimulating release of activated cytokines.[8,9]
To minimize the
incidence of atrial fibrillation, we advocate therapy combining a pharmacological
strategy, in which the serine protease inhibitor aprotinin is included in the
cardioplegia, with a mechanical approach involving the placement at multiple
positions within the bypass circuit of filters to selectively remove activated
leukocytes.[10,11] In a recent,
randomized trial, this type of combination therapy produced a marked, 67%
decrease in atrial fibrillation.
In addition to atrial fibrillation, renal and neurological dysfunction rank among the leading comorbidities of cardiopulmonary bypass surgery. Cardiopulmonary bypass causes numerous complex and interactive deleterious effects to the
kidney, including inflammatory injury to the organ inflicted by activated neutrophils. Cardiopulmonary bypass also may induce neurological encephalopathy; however, the precise mechanisms
of encephalopathy are poorly understood, and its
reported incidence is variable, criteria-dependent and subject to clinical
study was undertaken to evaluate pharmacological (aprotinin) and mechanical
(leukocyte filtration) anti-inflammatory measures, applied singly or in
combination during cardiopulmonary bypass, as strategies to minimize the
occurrence of atrial fibrillation, renal dysfunction and neurological
impairment following coronary artery bypass grafting (CABG) on cardiopulmonary
This study was approved by the Institutional Review Board at
the University of North Texas Health Science Center, and included two of the
major teaching hospitals associated with the Science The study was constructed as a randomized comparative trial and was designated the Leukocyte-Aprotinin Atrial Fibrillation Study (LAAFS).Only patients undergoing primary CABG were included; all patients undergoing re-do or adjunct procedures, including valve repair/replacement, were excluded. Echocardiograms were performed on all patients to measure pre-operative ejection fraction.
Surgical preparation and cardiopulmonary bypass procedure
All patients were intravenously pre-medicated with 0.7 mg/kg
of ranitidine, 2-4 mg/kg of glycopyrrolate, 0.7 mg/kg of diphenhydramine, and 20-40
mg/kg of midazolam. Monitoring catheters were placed in all patients including a radial arterial catheter, a central venous jugular introducer with a continuous cardiac output pulmonary artery catheter (Abbott Laboratories, Abbott Park, IL), and one or two large
bore peripheral intravenous cannulae. General anesthesia was induced by 1-2
mg/kg of propofol, 0.7-2.0 mg/kg of sufentanil, and 0.1 mg/kg of vercuronium. After endotracheal intubation, anesthesia was maintained with sevoflurane on supplemental O2.
Additional narcotic and relaxants were administered to maintain sedation
throughout the surgery.
Patients were systemically heparinized to effect an ACT of >
700 s and were given protamine sulfate to restore clotting after separation from
bypass. All patients had direct ascending aorta and right atrial cannulation
and were maintained on moderately hypothermic (34 C) cardiopulmonary bypass. Cold blood-crystalloid potassium based cardioplegia (4 vol. blood:1 vol. crystalloid solution) was administered to produce cardiac arrest. Initial induction of cardiac arrest
was accomplished by administering 500 ml cardioplegia antegrade via the aortic
root, followed by retrograde infusion of an additional 500 ml via the coronary
sinus at a pressure of 45 mmHg. Supplemental cardioplegia was administered
through the vein grafts at a pressure of 14 mmHg, for 2 min per infusion, after
completion of each distal anastomosis.
From January 2004 -
March 2006, a total of 1,220 patients undergoing isolated coronary artery
revascularization were enrolled and assigned by a sealed envelope approach to one of the four treatment groups described below. There were no statistically significant differences between the groups regarding demographics, co-morbid conditions, pre-operative laboratory data,durations of cardiopulmonary bypass and cross clamp, or number of grafts
completed (Table 1).
(n = 305): Standard cardiopulmonary bypass was
instituted as described above and cold potassium based cardioplegia was
utilized for arrest.
Leukocyte filtration group(n = 310): These patients received standard cardioplegia as in the control group; in addition, leukocyte depleting filters were incorporated into the bypass circuit, including a Pall LGB and a
BC1B filter (Pall Biomedical Products, East Hills, NY, USA). The circuit prime
and configuration are described in a previous report.
These patients were strategically leukodepleted by use of filtration instituted
30 min before crossclamp release, and all arterial, cardioplegia and cell saver
blood was leukocyte filtered.
Aprotinin group (n = 285): This group received standard
cardiopulmonary bypass with cold potassium based cardioplegia, and a standard
extracorporeal circuit was employed. In addition, full Hammersmith, regimen A
dosing of aprotinin (Bayer Pharmaceuticals,West Haven,CT, USA) was utilized. After a test dose the
pump was primed with 200 ml of aprotinin-fortified priming solution, then
aprotinin solution was infused at 50 ml/h.
Combination group(n = 320): This group received the combination
of aprotinin and total leukocyte filtration.
Evaluation of brain, renal and electrocardiographic function
All subjects had pre-operative echocardiography and carotid
duplex scanning. Patients exhibiting post-operative encephalopathy,defined as post-operative confusion, agitation or delirium within 24 h after bypass, or frank stroke were evaluated by a neurologist and underwent cerebral CT scanning. Post-operative renal function was categorized by peak post-surgical serum creatinine concentration according to National Kidney Foundation guidelines [normal: creatinine < 1.6 mg/dl; renal
dysfunction: creatinine 1.6-2.5 mg/dl; acute renal failure: creatinine > 2.5
patients exhibiting renal dysfunction or frank renal failure were evaluated by
a nephrologist, who determined the need for hemodialysis. All patients had
continuous ECG monitoring throughout the hospital stay. Arrhythmias were detected
by Hewlett-Packard 78220 arrhythmia monitoring system
(Hewlett-Packard, Palo Alto CA, USA) and validated by the cardiology
Values for continuous variables, e.g. ejection
fraction or serum creatinine, are expressed as mean ± standard deviation. Between-group
comparisons of these variables were accomplished by single-factor analyses of
variance (ANOVA), with treatment as the factor. None
of these ANOVAs revealed statistically significant differences, so post-hoc
tests to identify specific differences were not employed. Incidences of
discrete events among the treatment groups were compared by chi-square tests. Yates correction for continuity was applied to
chi-square comparisons of two groups. P values
< 0.05 were taken to indicate statistically significant treatment effects.
Table 1 summarizes the
demographic characteristics of the four treatment groups. Age, gender, and body
mass were typical for patients requiring CABG. Occurrences of comorbidities,
including diabetes mellitus and hypertension, were also as expected. There
were no statistically significant differences among the treatment groups for
any of these characteristics. Moreover, operative cardiopulmonary bypass and
cross clamp times, and number of grafts did not differ among the groups.
Atrial fibrillation (Figure 1) occurred in 76 (25%) of the 305 control patients,
49 (16%) of the 310 leukocyte filtered patients, 55 (19%) of the 285 aprotinin
patients and 32 (10%) of the 320 combined treatment patients (P < 0.001).
Leukofiltration (P < 0.01) and the leukofiltration:aprotinin combination (P
< 0.001) lowered incidence of atrial fibrillation vs. control. The
combination treatment also decreased atrial fibrillation incidence vs.
aprotinin (P < 0.005) and leukofiltration (P < 0.05) alone.
Figure 1 Impact of aprotinin and leukocyte filtration, applied separately and in combination, on incidence of atrial fibrillation after cardiopulmonary bypass surgery.
line-height:200%'>The combination group and, especially, the aprotinin group
had higher incidences of renal insufficiency (Figure 2A)
and renal failure requiring hemodialysis (Figure 2B). Renal
insufficiency occurred in 9 (3%) of control patients, 6 (2%) of leukocyte
filtration patients, 22 (8%) of the aprotinin group, and 16 (5%) of the
combination group (P < 0.005). Acute renal failure requiring hemodialysis (Figure 2B) was observed in 1 control patient, 3 leukocyte
filtered patients, 11 aprotinin patients and 6 combined therapy patients (P <
0.01). Aprotinin increased incidences of renal insufficiency (P < 0.02) and
acute renal failure (P < 0.01) vs. the respective control rates.
These detrimental effects of aprotinin were partially, albeit not significantly
(P ~ 0.10) mitigated by additional leukocyte filtration.
Figure 2 Incidence of post-surgical renal insufficiency (panel A) and acute renal failure requiring hemodialysis (panel B).
Encephalopathy (Figure 3) was documented in 6 (2%) of the control patients,
6 (2%) of the leukocyte filtered patients, 3 (1%) of the aprotinin patients and
6 (2%) of the combined therapy patients (P = n.s.). Acute cerebral vascular
events evidenced by focal neurological signs and CT findings were not detected
in the leukocyte filtered and aprotinin groups. Three (1%) of the control
patients and one (0.3%) combined treatment patient had neurologically
Figure 3 Incidence of encephalopathy post-cardiopulmonary bypass.
Atrial fibrillation remains a very common complication post
cardiopulmonary bypass with a reported incidence of 25-60%.[1,20] Peak incidence of the arrhythmia occurs between 48-72
post bypass.[21 ] In a retrospective review of
off-pump CABG patients, Edgerton et al.
reported an atrial fibrillation incidence between 10.6 and 18.5%, with the
lower atrial fibrillation rate occurring in patients who were extubated immediately
in the operating room.
Previously we reported incidence of atrial fibrillation in
patients undergoing isolated elective CABG. We
also observed a tendency of atrial fibrillation to occur within 48-72 hours after
surgery. This non-blinded, randomized study enrolled 120 patients (55 control,
65 treatment), with the treatment arm receiving strategic total leukocyte
filtration and full Hammersmith dose of aprotinin. The atrial fibrillation
rate was lowered from 27% in the control group to 7.6% in the aprotinin group,
a reduction of 72%. A follow-up study compared
rates of atrial fibrillation in on-pump vs. off-pump procedures. In that study the incidence of atrial fibrillation in
the on-pump leukocyte filtered-aprotinin group was 7.8% compared to 23.3% in
the non-treatment group. In the off-pump cohort of 90 patients, atrial
fibrillation rate was 17.8%.[12 ]
The current LAFFS trial also demonstrated a reduction in
atrial fibrillation by the combination of aprotinin and leukocyte filtration. Atrial
fibrillation occurred in 10% of the combination treatment group, as compared to
25% in the control group. The combined application of aprotinin and leukocyte
filtration appears to produce a synergistic anti-inflammatory effect in the
clinical setting, by impacting both complimentary and distinct pathways of the
inflammatory cascade. Indeed, Lamm et al  reported
a strong correlation between elevated post-operative white blood cell counts
and atrial fibrillation. In their study of 253 patients, consisting of both
primary CABG and valve cases, the atrial fibrillation rate was 39.1%. Collectively, these results are concordant with the
concept that reduction in activated neutrophils either by mechanical
(filtration) or pharmacologic (aprotinin) means, could directly impact the
development of atrial fibrillation post cardiopulmonary bypass.
In the present study, the aprotinin group experienced
increased incidence of renal insufficiency and acute renal failure requiring
hemodialysis. Interestingly, the leukocyte-filtered group was observed to have
a slightly reduced incidence (2%) of renal insufficiency and acute renal
failure vs. respective control values, although these trends did not reach
statistical significance. Mangano et al.,
utilizing a propensity-adjusted, multivariate logistic regression analysis of
an observational study of 4,474 patients, found a 5.5% vs. 1.8% (P <
0.001) incidence of renal dysfunction in aprotinin-treated vs. untreated
patients, an apparent tripling of the risk of renal failure requiring dialysis. In contrast, the Bayer pharmaceutical aprotinin
package insert from a pooled data base of 2,003 aprotinin and 1,084 control
patients reported a 1% incidence of acute renal failure in the aprotinin
treatment arm and 0.6% in the placebo arm. A
meta-analysis by Sedrakyan et al. showed that the risk ratio of developing renal
failure from aprotinin was 1.01 (95% CI 0.55-1.83) vs. placebo. Sedrakyan
et al.’s analysis examined studies drawn from MEDLINE, EMBASE and
PHARMLINE from 1988-2001, and included data from 35 CABG trials.
Cardiopulmonary bypass has also been associated with a
spectrum of neurological impairments[14,15]
from transient encephalopathy to frank stroke (CVA).
In a retrospective analysis of 1,524 patients undergoing CABG, Frumento et
a reduced incidence of cerebral events in aprotinin-treated patients. The
study consisted of control, half-dose and full dose aprotinin groups. The
overall incidence of CVA was 16% in the control versus 0% in the full dose
aprotinin group; interestingly, the half-dose cohort had a CVA incidence of
22%. There were no acute strokes in either the
filtration or aprotinin group, and the incidence of encephalopathy did not
differ significantly among the groups.
A limitation to the LAFFS study may be a bias in patient
selection as only isolated primary CABG subjects were enrolled, as well as a
lack of risk-stratification. Nevertheless, the reduction in atrial
fibrillation with leukocyte filtration and or aprotinin is striking. In
comparison Gunaydin et al. also found a reduction in post-operative
atrial fibrillation in patients who had leukocyte filtration.
In their study patients were assigned to three distinct groups based on
Euroscore risk stratification: low risk Euroscore 0-2, medium risk Euroscore
3-5, high risk Euroscore 6+. These groups were further subdivided to conventional, non-filtered extracorporeal
circuit (control), phosphorylcholine inert surface coated circuit, or leukocyte
filtered. Leukocyte filtration lowered incidence of atrial fibrillation in the
medium and high Euroscore groups. The non-coated, non-filter group medium to
high risk Euroscore had a 13% incidence of atrial fibrillation versus the leukodepleted
medium to high risk Euroscore group, which had a 3% incidence of atrial
A second limitation of this trial is that other pre-existing
factors that could possibly affect the incidence of post-operative atrial
fibrillation, including hypertension, valve disease, hyperlipidemia,
pre-operative atrial fibrillation, medications or nutraceuticals, were not
recorded. However, the size and randomized design of the trial make it likely
that these factors were evenly distributed among the four groups and therefore
were not independent contributors to the different outcomes. In addition,
post-operative factors, including post-pericardiotomy syndrome and the use of
anti-inflammatory agents, were not documented.
Leukocyte filtration and aprotinin were both effective in
reducing the incidence of atrial fibrillation after cardiopulmonary bypass surgery
for coronary revascularization. The synergistic combination of both treatment
modalities was the most effective. However, aprotinin treatment was associated
with increased post-surgical incidence of renal insufficiency and acute renal
failure. The addition of leukocyte filtration lessened the incidence of renal
dysfunction in aprotinin-treated patients. There are two important components
to leukocyte filtration: leukocyte filters must be deployed strategically (30
minutes prior to cross-clamp release), and total leukocyte filtration must also
be employed. Further research is necessary to define the mechanisms and
pathophysiology involved in the generation of atrial fibrillation
post-cardiopulmonary bypass, and to develop newer molecular strategies to
address this major complication of cardiopulmonary bypass surgery. With the recent withdrawal of aprotinin from the U.S. market, implementation and
refinement of strategic leukocyte filtration, including the use of novel
absorptive materials and carbon-based nanotechnology, seem warranted.
Funding for this work was provided by research grant no.
02-18-522 from the Osteopathic Heritage Foundation.
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