Download Pulmonary Injury After Cardiopulmonary Bypass

direction is expected to have a major impact on
our future practice.
Song Wan, MD, PhD
Anthony P. C. Yim, DM, FCCP
Shatin, Hong Kong, China
Dr. Yim is Chief, Division of Cardiothoracic Surgery, The
Chinese University of Hong Kong, Prince of Wales Hospital. Dr
Wan is a cardiac surgeon at the Prince of Wales Hospital.
Correspondence to: Anthony P. C. Yim, DM, FCCP, Chief,
Division of Cardiothoracic Surgery, The Chinese University of
Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China;
e-mail: [email protected]
References
1 Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA guidelines for coronary artery bypass graft surgery: a report of the
American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee to Revise the
1991 Guidelines for Coronary Artery Bypass Graft Surgery).
J Am Coll Cardiol 1999; 34:1262–1347
2 Wan S, LeClerc JL, Vincent JL. Inflammatory response to
cardiopulmonary bypass: mechanisms involved and possible
therapeutic strategies. Chest 1997; 112:676 – 692
3 Anderson RE, Li TQ, Hindmarsh T, et al. Increased extracellular brain water after coronary artery bypass grafting is
avoided by off-pump surgery. J Cardiothorac Vasc Anesth
1999; 13:698 –702
4 Selnes OA, Goldsborough MA, Borowicz LM Jr, et al.
Determinants of cognitive change after coronary artery bypass surgery: a multifactorial problem. Ann Thorac Surg
1999; 67:1669 –1676
5 Wolman RL, Nussmeier NA, Aggarwal A, et al. Cerebral
injury after cardiac surgery: identification of a group at
extraordinary risk. Stroke 1999; 30:514 –522
6 Hogue CW Jr, Murphy SF, Schechtman KB, et al. Risk
factors for early or delayed stroke after cardiac surgery.
Circulation 1999; 100:642– 647
7 Kilminster S, Treasure T, McMillan T, et al. Neuropsychological change and S-100 protein release in 130 unselected
patients undergoing cardiac surgery. Stroke 1999; 30:1869 –
1874
8 Anderson RE, Hansson LO, Vaage J. Release of S-100 during
coronary artery bypass grafting is reduced by off-pump
surgery. Ann Thorac Surg 1999; 67:1721–1725
9 Lloyd CT, Ascione R, Underwood MJ, et al. Serum S-100
protein release and neuropsychologic outcome during coronary revascularization on the beating heart: a prospective
randomized study. J Thorac Cardiovasc Surg 2000; 119:148 –
154
10 Westaby S, Saatvedt K, White S, et al. Is there a relationship
between serum S-100 protein and neuropsychologic dysfunction after cardiopulmonary bypass? J Thorac Cardiovasc Surg
2000; 119:132–137
11 Taggart DP, Browne SM, Halligan PW, et al. Is cardiopulmonary bypass still the cause of cognitive dysfunction after
cardiac operations? J Thorac Cardiovasc Surg 1999; 118:414 –
420
12 Cartier R, Brann S, Dagenais F, et al. Systematic off-pump
coronary artery revascularization in multivessel disease: experience of three hundred cases. J Thorac Cardiovasc Surg
2000; 119:221–229
Pulmonary Injury After
Cardiopulmonary Bypass
t has been known since the early experience with
I cardiac
surgery using cardiopulmonary bypass that
significant pulmonary injury may follow these operations and can cause significant mortality and morbidity. The pulmonary injury, colloquially referred to
as “pump lung,” was recognized early on to be a
problem of increased microvascular permeability,
since the pulmonary edema and hypoxemia with
increased alveolar-arterial oxygen gradient occurred
in the presence of relatively low directly measured
left atrial pressure, a value that was then rarely
available to the clinician except early after cardiac
surgery. It has since become clear that the clinical
features and pathophysiology of pulmonary injury
associated with cardiopulmonary bypass is nearly
identical to ARDS associated with other etiologies.
Indeed, the lung injury is only a part of a systemic
inflammatory response syndrome (SIRS) that is
probably activated to a variable degree in all patients
undergoing cardiopulmonary bypass1 and perhaps
even those undergoing major operations without
bypass.2
The SIRS after bypass as well as the pulmonary
injury that is a major part of this syndrome has been
the subject of recent comprehensive reviews in
CHEST and other journals.1– 4 The clinical features
of this syndrome include pulmonary injury with
increased pulmonary vascular resistance; increased
alveolar-arterial oxygen gradient with a pulmonary
edema pattern shown on chest radiography; as well
as decreased peripheral vascular resistance, with
increased cardiac output, tachycardia, fever, and a
tendency for hemoconcentration. The transient neurologic dysfunction variably observed after bypass
has also been in part attributed to the inflammatory
response it elicits.5 Most patients have this syndrome
resolve in the first 24 h after bypass and have no
serious consequences. When patient weights are
followed accurately, patients are typically 3 to 8%
over their preoperative dry weight on the first postoperative day. Early correction of this state of fluid
retention, caused in large part by the inflammatory
response after bypass, is important to achieving early
recovery after operation and, in particular, in preventing significant delayed pulmonary complications.
Unfortunately, a few patients will have a lessbenign course. The incidence of more significant
pulmonary injury after cardiopulmonary bypass has
varied considerably and clearly depends on one’s
definition and threshold for this diagnosis. The reported incidence of ARDS has varied from about 0.5
to 1.7%,3 but the incidence of a lesser degree of early
2
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Editorials
postoperative pulmonary dysfunction, defined as a
Pao2/fraction of inspired oxygen ratio of ⱕ 150
mm Hg and chest radiography consistent with pulmonary edema on arrival in the ICU, was 12% in a
study by Rady et al6 from the Cleveland Clinic. In
the small group of patients in whom ARDS occurs,
the mortality has been reported to be in the 40 to
60% range or higher, with many of these being due
to progression to multiorgan failure.3
The pathophysiology of the SIRS and, in particular, the pulmonary injury associated with it has been
studied extensively both in laboratory models and
clinical studies. Clearly, what separates procedures
utilizing cardiopulmonary bypass from other situations in which similar injury may occur is the extensive exposure of blood to the foreign surfaces, and
abnormal conditions that result during cardiopulmonary bypass.7 Organ injury from ischemia and reperfusion and particularly gut mucosal injury from
occult splanchnic ischemia leading to endotoxin release may also contribute to the problem.8 All of
these cause activation of complement, and release of
thromboxane and pro-inflammatory cytokines, particularly interleukin (IL)-6 and IL-8 and tumor
necrosis factor (TNF)-␣.1 Inflammatory cells, particularly leukocytes, are activated and in turn become
sequestered in various organs (particularly the lungs)
and cause an inflammatory response and tissue
injury. In this issue of CHEST (see page 31), Massoudy et al studied the role of the lung itself in the
release of the proinflammatory cytokines, IL-6, IL-8,
and TNF-␣. By measuring levels in the right atrial as
well as the right superior pulmonary vein blood, they
showed a significant percent increase in the levels of
IL-6 and IL-8, but not TNF-␣, on the pulmonary
venous side. They also showed that there was a
decrease in the counts of activated leukocytes across
the lung consistent with sequestration and presumably from adherence of these inflammatory cells to
the pulmonary vascular endothelium. They did not
correlate these variables with pulmonary function
measured early postoperatively, which may have
added clinical relevance to this study.
A problem with this study that the authors have
recognized is that during cardiopulmonary bypass,
after release of the aortic cross-clamp and resumption of cardiac mechanical activity, the amount of
blood flow through the lungs by way of the pulmonary arterial circulation is highly variable (5 to 20%
of normal as stated in their article) and is dependent
on the effectiveness of venous drainage from the
right heart. Indeed, if venous drainage is highly
effective and the right heart is nearly completely
decompressed on full cardiopulmonary bypass, the
majority of pulmonary blood flow could still be
coming from the bronchial circulation. The authors
stated they have measured simultaneously drawn
blood from the right atrium and radial artery and
have determined there were no differences in the
same inflammatory variables, indicating no detectable activation across the cardiopulmonary bypass
circuit. If bronchial arterial and right atrial blood
levels are indeed not different, this would validate
their qualitative conclusion that the lungs are the site
of inflammatory mediator release, but leave us without the ability to quantitate this without knowing
pulmonary blood flow.
Another factor the authors recognized that may
have affected their results is their routine use of
aprotinin, which has been shown to decrease the
inflammatory response to bypass by decreasing complement activation as well as decreasing neutrophil
expression of several adhesion molecules, including
CD11b.1,9 Since aprotinin is reserved for use in
cardiac reoperations in most centers, the authors
may have underestimated the potential extent of
neutrophil activation and sequestration within the
lungs in most patients having bypass, since aprotinin
is not routinely used.
The data from their study do support the idea that
the lung is the site of proinflammatory cytokine
production in the period between the release of the
aortic cross-clamp and discontinuation of cardiopulmonary bypass. During this early period of reperfusion after release of the aortic cross-clamp, the lungs,
like the heart, may be involved in an ischemia/
reperfusion injury pattern. This may be the major
inciting factor that causes release from the lung of
inflammatory mediators as measured in the pulmonary venous blood and mirror the efflux of similar
mediators from the heart that occurs early after
cardiac reperfusion.1 It is unfortunate, however, that
they did not extend their measurements to the
period early after discontinuation of cardiopulmonary bypass, particularly when protamine is being
administered. Protamine and the heparin protamine
complex have been shown to activate complement by
the classical pathway and to cause leukosequestration in the lungs.1
Although there have been numerous studies investigating interventions to blunt the inflammatory response
and decrease lung injury after bypass, we are still far
from having an immediately available intervention that
will eliminate this problem. The list of such interventions that have been variably effective in decreasing the
inappropriate inflammatory response has included the
use of heparin-coated bypass circuits; leukocyte filtration; ultrafiltration early after bypass; and various pharmacologic agents, including aprotinin, steroids, direct
inhibitors of inflammatory mediators, metalloproteinase inhibitors, and, most recently, nitroprusside.1,3,4,9 –11
With the incidence of hard end points such as clear
CHEST / 119 / 1 / JANUARY, 2001
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ARDS or death being so low with current techniques,
well-planned randomized clinical trials will have to
either be very large, perhaps prohibitively large, to
show efficacy using a new intervention. If we are to
make progress in eliminating this problem, it may have
to be accepted that softer end points, such as inflammatory mediator levels coupled with postoperative
clinical variables such as alveolar-arterial oxygen gradient, pulmonary and peripheral vascular resistance, and
degree of fluid retention, be used to determine efficacy. The variable morbidity from the inflammatory
response to bypass has been a major motivation for the
increasing trend to perform coronary artery bypass
grafting without bypass. This disadvantage of bypass
would be considerably less compelling and our outcomes further improved for operations using cardiopulmonary bypass, were we to have an effective, preventive regimen to eliminate the SIRS and pulmonary
injury that is associated with it.
Vincent R. Conti, MD, FCCP
Galveston, TX
Dr. Conti is Professor and Chief, Division of Cardiothoracic
Surgery, Department of Surgery, The University of Texas Medical Branch.
Correspondence to: Vincent R. Conti, MD, FCCP, The University
of Texas Medical Branch, 301 University Blvd, Galveston, TX
77555-0528; e-mail: [email protected]
References
1 Wan S, LeClerc JL, Vincent JL. Inflammatory response to
cardiopulmonary bypass: mechanisms involved and possible
therapeutic strategies. Chest 1997; 112:676 – 692
2 Gu YJ, Mariani MA, Boonstra PW, et al. Complement
activation in coronary artery bypass grafting patients without
cardiopulmonary bypass: the role of tissue injury by surgical
incision. Chest 1999; 116:892– 898
3 Asimakopoulos G, Smith PL, Ratnatunga CP, et al. Lung
injury and acute respiratory distress syndrome after cardiopulmonary bypass. Ann Thorac Surg 1999; 68:1107–1115
4 Edmunds LH Jr. Inflammatory response to cardiopulmonary
bypass. Ann Thorac Surg 1998; 66:S12–S16
5 Taylor KM. Central nervous system effects of cardiopulmonary bypass. Ann Thorac Surg 1998; 66:S20 –S24
6 Rady MY, Ryan T, Starr NJ. Early onset of acute pulmonary
dysfunction after cardiovascular surgery: risk factors and
clinical outcome. Crit Care Med 1997; 25:1831–1839
7 Chenoweth DE, Cooper SW, Hugli TE, et al. Complement
activation during cardiopulmonary bypass: evidence for generation of C3a and C5a anaphylatoxins. N Engl J Med 1981;
304:497–503
8 Ohri SK, Bjarnason I, Pathi V, et al. Cardiopulmonary bypass
impairs small intestinal transport and increases gut permeability. Ann Thorac Surg 1993; 55:1080 –1086
9 Alonso A, Whitten CW, Hill GE. Pump prime only aprotinin
inhibits cardiopulmonary bypass-induced neutrophil CD11b
up-regulation. Ann Thorac Surg 1999; 67:392–395
10 Carney DE, Lutz CJ, Picone AL, et al. Matrix metalloproteinase inhibitor prevents acute lung injury after cardiopulmonary bypass. Circulation 1999; 100:400 – 406
11 Massoudy P, Zahler S, Freyholdt T, et al. Sodium nitroprus-
side in patients with compromised left ventricular function
undergoing coronary bypass: reduction of cardiac proinflammatory substances. J Thorac Cardiovasc Surg 2000; 119:566 –574
Sleep Apnea
A Global Perspective
ecently, two well-designed studies by researchR ers
from the University of Wisconsin and the
1
Sleep Heart Health Study Group2 documented that
untreated obstructive sleep apnea (OSA) increases
the risk for hypertension in American adults. In both
studies, the risk for hypertension increased in a
dose-response association with the frequency of obstructive respiratory events during the night, independently of confounding factors such as age, gender, and weight. It is expected that these and other
studies evaluating large patient cohorts will determine whether this increased risk for hypertension
results in added morbidity and mortality from ischemic heart disease and other cardiovascular diseases.
It may well be that the increased risk of cardiovascular disease sequelae from OSA will warrant widespread efforts at early detection and treatment,
much as is the current clinical practice for hyperlipidemia.
Sleep apnea is typically characterized as a disease
of obese, middle-aged men.3,4 This stereotype is a
result of older studies completed in the United
States, Europe, and Australia that found that 60 to
90% of all OSA patients are obese,5 as defined by a
body mass index (BMI) of ⱖ 28 kg/m2. A landmark
study by Young et al6 determined that 2 to 4% of
Wisconsin factory workers had OSA, and that the
risk for OSA increased in close association with
measures of truncal obesity, such as neck size. The
study by Ip et al in this issue of CHEST (see page 62)
indicates that OSA may occur with a similar prevalence in a cohort of nonobese subjects, as the mean
BMI for this study cohort was only 23.9 kg/m2. Of
great importance is the fact that the study cohort was
784 Chinese office workers in Hong Kong.
There are a paucity of data characterizing the
epidemiology of OSA in populations other than
middle-aged or older white men, and few studies
have focused on young adults, women, or patients of
African or Asian descent. Recent investigations on
the epidemiology of ischemic heart disease indicate
that the clinical recognition and management of this
disease varies markedly in cohorts of women7 or of
nonwhite patients, compared with that of white
men.8 The scenario may be much the same for the
epidemiology of OSA.
4
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Editorials