| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 1999;67:978-985
© 1999 The Society of Thoracic Surgeons
a Departments of Surgery and Cardiovascular Perfusion, SUNY Health Science Center, Syracuse and Cortland, New York, USA
Accepted for publication September 5, 1998.
Address reprint requests to: Dr Nieman, Department of Surgery, SUNY Health Science Center, 750 E. Adams Street, Syracuse, NY 13210;
e-mail: niemang{at}vax.cs.hscsyr.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterial and methodsProtocolResultsCommentsReferences |
|---|
Methods. Pigs were anesthetized, placed on a ventilator, instrumented for measurements of hemodynamic function, and separated into five groups: (1) Control (n = 4)—surgery only, (2) CPB (n = 4)—placed on femoral-femoral hypothermic (28°C) bypass for 1 h, (3) LPS (n = 6)—underwent sham CPB followed by infusion of low dose endotoxin [E. colilipopolysaccharide (LPS-1 µg/kg)], (4) Heparin + protamine + LPS (HP + LPS, n = 4)—were heparinized without CPB for 1 h, following which protamine and LPS were infused and (5) CPB + LPS (n = 8)—subjected to both CPB and LPS.
Results. Only CPB + LPS resulted in acute respiratory distress typical of PPS as indicated by a significant decrease in PaO2 and increase in intrapulmonary shunt fraction (p< 0.05). CPB + LPS significantly increased tissue density and the number of sequestered monocytes and PMNs (p < 0.05) above all other groups. Alveolar macrophages (AM) increased equally in all groups receiving LPS.
Conclusions. CPB primes the inflammatory system causing pulmonary PMN sequestration without lung injury. Exposure to an otherwise benign dose of endotoxin results in activation of the sequestered PMNs causing PPS. This study confirms that PPS can be caused by multiple minor insults.Key words: Cardiopulmonary bypass, ARDS, endotoxin, sepsis, post-pump syndrome
|
Introduction |
|---|
|
TopAbstractIntroductionMaterial and methodsProtocolResultsCommentsReferences |
|---|
The etiology of post-pump syndrome is not well understood. Post-pump syndrome may be caused by a single, massive insult such as protracted bypass time [1], although clinically it is more likely caused by multiple, relatively minor, sequential insults. In our proposed paradigm CPB initiates the systemic inflammatory response syndrome (SIRS) that constitutes the first insult. This response is most likely caused by contact between blood and the artificial surfaces of the perfusion circuit [3–7]. A subsequent insult (eg hypoxia, ischemia, endotoxemia) that, by itself, would not be of clinical significance results in an overwhelming inflammatory response leading to vascular injury, ARDS, and MOF. This study tests the hypothesis that post-pump syndrome can be caused by sequential minor insults.
The mechanism believed responsible for multiple insult ARDS is a priming of polymorphonuclear leukocytes (PMN) causing them to sequester in the lung without lung injury. Priming is defined as the enhancement or amplification of a PMN response to a given stimulus following prior exposure to a different agonist [8]. If a second insult occurs, the primed PMNs are activated and release large amounts of toxic oxygen metabolites and proteases causing tissue injury that eventually precipitates ARDS [9–16]. We hypothesize that post-pump syndrome can also occur by the same mechanism with CPB acting as the primary or initial insult.
To test this hypothesis we measured pathophysiologic changes in cardiovascular and respiratory function in pigs exposed to either one hour of CPB or a low dose endotoxin (1 µg/kg). The two insults were then combined (CPB followed by endotoxin infusion) in a third group of animals and pathophysiologic changes were compared to those elicited by each insult individually. The inactivation of heparin with protamine results in the formation of a heparin-protamine complex that can cause an inflammatory reaction. Because heparin-protamine complexes, not CPB, may be the initial insult, we exposed a separate group of pigs to a similar small dose of endotoxin after receiving heparin and protamine without CPB.
|
Material and methods |
|---|
|
TopAbstractIntroductionMaterial and methodsProtocolResultsCommentsReferences |
|---|
|
Peak airway pressure (Paw) was measured from a side port 2 cm from the proximal end of the tracheal tube. Static pulmonary compliance (Cstat) was measured by disconnecting the ventilator and injecting twice the calculated tidal volume (VT = Wt. kg*12) into the lung with a Collins 1 liter syringe. Plateau airway pressure was recorded and used to calculate Cstat (injected volume/plateau pressure, mL/mm Hg). The lung was sighed every 30 minutes. A cystotomy was performed through a midline incision and a Foley catheter and temperature probe were placed into the bladder. Base excess (BE) below normal limits (-3 mEq/L) was corrected with intravenous sodium bicarbonate and adjustments made in tidal volume and ventilatory rate to maintain PaCO2 within normal range (40–45 mm Hg). Heating pads and warmed IV fluids were utilized to maintain a core temperature between 34° and 38°C.
The cardiopulmonary bypass circuit included Cobe oxygenators (Cobe Duo flat plate membrane) (Cobe Inc, Arvada, CO), tubing pack, and arterial filter (40 µm). A Sarns roller pump was used. The pump prime solution consisted of lactated Ringers (3M, Ann Arbor, MI) (1500 mL), mannitol (5 gm), sodium bicarbonate (35meq), and porcine lung heparin (300 Units/kg). Surgical cutdowns facilitated placement of an arterial cannula (USCI 14F arterial catheter) in the right femoral artery, and the venous cannula (Medtronic percutaneous femoral arterial catheter) (Medtronic Inc, Eden Prairie, MN) in the right femoral vein (18F), advanced into the right atrium.
|
Protocol |
|---|
|
TopAbstractIntroductionMaterial and methodsProtocolResultsCommentsReferences |
|---|
CPB
Animals were heparinized and placed on CPB for 1 hour, taken off CPB and given protamine, infused with Sham LPS and monitored for 3 hours (n = 4).
LPS
Animals were subjected to 1 hour of Sham CPB followed by LPS infusion and monitored for 3 hours. No heparin or protamine were given (n = 6).
HP + LPS
Animals were heparinized and subjected to 1 hour of Sham CPB followed by protamine and LPS infusion and monitored for 3 hrs (n = 4). Treatment with heparin and protamine was a part of the bypass protocol which had the potential of acting itself also as inflammatory stimulus; thus, the HP + LPS group served to rule out this possibility.
CPB + LPS
Animals were heparinized and placed on CPB for 1 hour, taken off CPB and given protamine, followed by infusion of LPS and monitored for 3 hours (n = 8).
Experimental scheme
Following instrumentation, a 20-minute period was allowed for the stabilization of hemodynamic and blood gas parameters, at which point data were recorded as baseline values. Before heparin administration, a blood sample was drawn and baseline activated clotting time (ACT) measured with a Hemochron 401 whole blood coagulation instrument (International Technidyne Corp, Edison, NJ). All vascular and airway pressures, CO, arterial and mixed venous blood gas samples, oxygen content, oxygen saturation, Hgb, and urine output measurements were recorded at Baseline and every 30 minutes for the duration of the experiment (Fig 1). Preliminary experiments in our laboratory using a porcine model of endotoxin induced ARDS demonstrated that arterial PCO2 increased sufficiently to cause lethal respiratory acidosis. Therefore we adjusted our protocol such that the respiratory rate would be increased to maintain arterial CO2 below 50 mm Hg with the upper limit of respiratory adjustments being 40 breaths/min. This respiratory rate adjustment was used in this protocol. Because respiratory rate could be adjusted throughout the study, depending on arterial CO2, we assessed ventilatory status by calculating the ventilatory efficiency index (VEI) rather than simply expressing ventilatory status by arterial CO2 [17]. Lactated Ringers solution (25 mL/kg/h) was initiated and cardiac output (CO) was measured every 15 minutes following the start of LPS/sham LPS.
Cardiopulmonary bypass
It is our hypothesis that the initial insult in this model is caused by blood contact with the perfusion circuits that are currently used clinically. Thus, we selected to place the animals on femoral-femoral bypass rather than full bypass, which decreased the change that the surgical intervention contributed to the initial insult. All animals placed on CPB were heparinized (300 U/kg). After verification of adequate anticoagulation (ACT > 480 seconds) CPB was initiated at a flow rate of 120 mL/kg. Mean arterial blood pressure was maintained (30–60 mm Hg) by adjusting blood flow rate. Oxygen and air flow to the oxygenator were titrated to obtain good blood gases (pH: 7.4; PCO2-40 mm Hg; PO2: > 150 and < 300 mm Hg). During CPB the integrated warming coils in the blood reservoir were used to decrease body temperature to 28°C over a period of 10 to 15 minutes. The animals were cooled to simulate clinical CPB. Body temperature was returned to normal over 20 minutes before terminating CPB.
CPB was terminated after 1 hour. Thirty minutes into CPB isoproterenol (1 mg/kg) was given IV. Because the pig was not on full bypass support, isoproterenol facilitated effective ejection volume to eliminate cardiac distension and prevent ischemia. Isoproterenol was titrated to off to maintain systemic arterial pressure within 10% of baseline values (
20 minutes). Five minutes before discontinuation of CPB calcium chloride (500 mg) and magnesium sulfide (1 gm) were given. Within 30 minutes animals were returned to a baseline status as follows: (1) the blood in the oxygenator was transfused into the animal and (2) heparin was reversed with protamine (1.3 mg/100 Units heparin). The time point when ACT returned to normal range was defined as off CPB (Fig 1) and all pressures and blood chemistries were then measured.
Endotoxin infusion
From t = 90 to 150 minutes (Fig 2), pigs receiving LPS were infused with 1 µg/kg of E. Coli lipopolysaccharide-LPS (SIGMA 111:B4) mixed in 500 ml of saline and delivered via a Flo-Guard 8000 volumetric infusion pump (Travenol Inc, Deerfield, IL). A dose of 100 µg/kg is necessary to cause ARDS in pigs not subjected to CPB [18]. Pigs not receiving LPS were infused with 500 ml Saline. All pigs were infused with lactated Ringer’s solution (25 mL/kg/h). Cardiac output was measured every 15 minutes following endotoxin or sham endotoxin infusion and maintained at 1 standard deviation from baseline CO by bolus infusion of 6% dextran 70 in saline (18).
|
 |
 |
 |
 |
 |
P = the difference between peak and end expiratory pressure (mm Hg) and Rf = respiratory frequency. The VEI is described in units analogous to compliance and was calculated assuming that the rate of total CO2 production was constant at 5 ml/kg/min, and PAO2 = PaCO2. The index allowed comparison of respiratory status among animals whose ventilator pressures, frequency, and PaCO2 vary (17). The right ventricular ejection fraction was measured (Baxter, Explorer) and the stroke volume index (SVI mL/m2/beat) was calculated. At necropsy representative lung samples were dissected free of nonparenchymal tissue, placed in a dish and weighed, and dried in an oven (65°C) until completely dry. Lung water was expressed as a wet to dry weight ratio (W/D).
Histometric evaluation
In the first four animals of each treatment condition the right cardiac lobe was excised at the end of the experiment and its hilar airway cannulated. Glutaraldehyde fixative (2.5%, phosphate-buffered) was slowly instilled through the cannula until air was no longer displaced from the airway; then, the lung was immersed in glutaraldehyde and additional fixative was infused with a syringe while pressure was monitored with a mercury manometer. When the pressure of the fixative stabilized at 25 mm Hg the cannula was clamped and the tissue was stored at 25 mm Hg airway pressure in glutaraldehyde, at room temperature for at least 24 hours.
Each lung specimen was studied according to a stratified and random sampling method that assured the unbiased coverage of parenchymal structures lacking a homogeneous distribution. One tissue block from the fixed lobe of each animal was randomly chosen and processed for routine paraffin sections. The blocks were sectioned grossly until the entire profile of the tissue entered the plane of the section, usually constituting a rectangle of approximately 15 mm x 20 mm. At that point, ten serial sections made at 7 µm were individually mounted on numbered slides. Then, either even or odd numbered slides (random choice) were stained with hematoxylin and eosin. In this manner, five equidistant sections were studied in each animal. A sampling probe consisting of a vertical line traversing the height of the slide was established for each of the serial sections, as follows: The sampling probe in the first section was drawn close to the left edge of the tissue, the probe on the last was drawn close to the right edge, and the remaining three were drawn at equidistant locations.
Ten sampling areas were designated 1 mm apart along each sampling probe, thus establishing 50 unbiased sampling areas in each animal (N = 200 per treatment condition) before microscopic observation. Each sampling area was located blindly using the x-y vernier scales of the microscope stage, and then observed with a 100x oil-immersion objective using a high-resolution video camera. The field of view was defined by a square grid consisting of 64 intersections that covered an area of 6,400 um2 at the focal plane. Areas featuring bronchi, interlobular connective tissue, or muscular blood vessels were discarded by advancing the stage 0.5 mm along the sampling probe; thus, quantifications were limited to alveolar parenchyma. Tissue density was estimated for each sampling area as the percentage of intersection points falling over tissue structures (as opposed to points corresponding to air spaces). Cell counts were made in all focal planes following a counting rule designed to avoid overestimation of the number of objects per unit area [19]. The cells were tallied according to three categories: (1) PMN within tissue, (2) mononuclear cells within tissue, and (3) alveolar macrophages (AM). An increase in any of these parameters is indicative of lung pathology. Edema is self explanatory, leukocyte recruitment indicates inflammation, and decreased alveolar size suggests reduced alveolar compliance and atelectasis. Tissue density does not quantify the contribution of each parameter to total change in tissue density.
Statistics
Statistical significance between groups was determined using a one way analysis of variance; significance between parameters within the same group was determined with a repeat analysis of variance using the Instat statistical package. Whenever the F ratio indicated significance, a Newman-Keul’s test was used to identify the individual differences. A significant difference was assumed if the probability of the null hypothesis was less than 5%.
Tissue density estimates and cell counts were compared within each treatment condition using analysis of variance, and differences between treatment conditions were studied with t-tests, using the Minitab statistical package. Significance was established at the 0.05 level.
Animals were euthanized with an overdose of pentobarbital (90 mg/kg IV) 3 hours following the start of the endotoxin infusion. The experiments described in this study were performed in adherence with the National Institutes of Health guidelines for the use of experimental animals in research. The protocol was approved by the Committee for the Humane Use of Animals (CHUA) at the SUNY Health Science Center, Syracuse, NY.
|
Results |
|---|
|
TopAbstractIntroductionMaterial and methodsProtocolResultsCommentsReferences |
|---|
|
|
Arterial pressure (Psys) was significantly greater (p < 0.05) at the end of the study in the control (75 ± 3.1 vs 115 ± 6.3 mm Hg) and LPS (71 ± 3.8 vs 109 ± 8.4 mm Hg) groups as compared to Baseline values. No significant change in Psys from Baseline values were measured in any other group. LPS caused a significant (p < 0.05) increase in Ppa in all exposed groups (LPS: 14.8 ± 1.4 vs 32.4 ± 4.4; CPB + LPS: 15.0 ± 1.3 vs 34.1 ± 3.2; HP + LPS:15.2 ± 1.5 vs 32.5 ± 2.3 mm Hg) at the end of the study. Pulmonary artery wedge pressure (Ppaw) demonstrated only minor changes in all groups. A slight fall in CO as compared to baseline values was seen in all groups. Stroke volume index (SVI) fell slightly over time in all groups except the control. SVI fell the most in both groups that were placed on CPB (CPB: 31 ± 7.6 vs 18.3 ± 4.3; CPB + LPS: 48.2 ± 4.5 vs 26.1 ± 3.7, mL/m2/beat).
Arterial pH did not change over time since acidemia was corrected with appropriate administration of HCO3, adjustments in respiratory rate, or both. Methods to correct the acidemia were employed most often in the CPB + LPS group. SvO2 was significantly different (p < 0.05) at the end of the study in both groups subjected to CPB (CPB: 77.7 ± 1.7 vs 48.7 ± 6.7; CPB + LPS: 76.7 ± 1.9 vs 49.4 ± 2.9%). Oxygen delivery (DO2) trended downward in all groups and was significantly different from baseline at the end of the experiment in the CPB + LPS.
Insults that did not result in lung dysfunction (CPB, LPS, HP + LPS) did cause a significant increase in both tissue density and leukocyte sequestration (Table 1) as compared to the control group. CPB + LPS caused a further increase in tissue density and leukocyte sequestration (Table 1) and these increases were associated with severe lung dysfunction.
|
|
Comments |
|---|
|
TopAbstractIntroductionMaterial and methodsProtocolResultsCommentsReferences |
|---|
The most likely mechanism of sequential injury post-pump syndrome is a priming and subsequent activation of PMNs. Primed PMNs selectively sequester in the lung [8–16], but do not cause lung injury unless they are activated [9, 10, 15]. Our groups, which did not cause lung dysfunction (LPS, CPB, HP + LPS), did cause pulmonary PMN recruitment. This is consistent with PMN priming with subsequent sequestration in the lung seen in animal models of sequential insult ARDS [9–16]. Activation of the PMNs primed by CPB with low dose LPS caused a significant loss of lung function that was associated with an increase in tissue density. Again this is consistent with the etiology seen in animal models of sequential insult ARDS [9, 10]. Together these data suggest that sequential insult post-pump syndrome is caused by a priming and activation of PMNs.
Animal models have defined the mechanism of sequential insult ARDS as a priming and activation of PMNs; priming induces PMNs to sequester in the lung and should an activating insult follow, the PMNs release oxygen radicals and proteases resulting in lung injury [8–16]. Anderson and colleagues [9] demonstrated that PMN-mediated lung injury is dependent upon both priming and activation of PMNs. Injection of sublethal amounts of endotoxin in rats resulted in PMN sequestration in the pulmonary vasculature but did not cause lung injury. Thus, endotoxin had primed PMNs causing them to accumulate in the lung but did not activate them and lung injury did not occur. However, if the noninjurious PMN activator (FNLP) was injected into the rats shortly following endotoxin significant lung damage occurred. If FNLP was injected 12 hours after endotoxin, when PMNs were no longer primed and sequestered in the pulmonary vasculature, no lung damage occurred. Worthen and coleagues [10] also demonstrated that small amounts of LPS resulted in pulmonary PMN sequestration without lung injury. Addition of either FNLP or the biologically relevant fragments of complement, C5, with LPS caused a significant endothelial injury. It has also been demonstrated that sequential infusion of inflammatory cytokines can have an additive pathologic effect on lung function. Injection of a small dose of IL-1 into a rabbit produced no adverse effects; likewise, a small dose of TNF had no adverse effects. However, severe lung injury occurred if the two were combined [11].
In the most widely studied model of sequential insult ARDS, gut ischemia serves as the initial insult and causes pulmonary PMN sequestration without lung injury [12, 13]. In this model the superior mesenteric artery of rats is clamped for 45 minutes. PMNs were primed in the gut during the ischemic period and upon reperfusion were released and sequestered in the lung [12, 13]. However, lung injury did not occur unless a small dose of LPS was infused during the time that PMNs were sequestered in the lung. It was concluded that gut ischemia (initial insult) primed PMNs that were released into the systemic circulation during reperfusion. PMNs subsequently sequestered in the pulmonary vascular bed and did little damage unless activated by a second insult. It was further demonstrated that platelet-activating factor (PAF) was the mediator of PMN priming. Phospholipase A2 is activated during gut ischemia and catalyzes the formation of lysophospholipids, which remodels to yield PAF [12, 13]. These experiments established that numerous insults can prime or activate PMNs leading to the development of ARDS and strongly suggest that priming and activation of PMNs are the likely etiology in the development of sequential insult ARDS.
The etiology of post-pump syndrome is consistent with the development of sequential insult ARDS, the only difference being that of the priming insult (i.e. CPB vs trauma). It is well established that CPB primes PMNs causing them to sequester in the lung and other organs [20]. Tennenberg and colleagues [20] demonstrated that both complement and PMNs were activated in patients undergoing CPB without damage to the pulmonary epithelium. In a similar study Lundblad and colleagues [21] measured PMN activation, manifest as increases in plasma levels of endothelin-1, lactoferrin, and myeloperoxidase, in patients following CPB without any clinical side effects. This suggests that CPB primes PMNs but does not cause lung injury (initial insult), which is consistent with data from this experiment. Thus, CPB primes PMNs but a second stimulus (hemorrhage, endotoxin, etc) is necessary to activate PMNs and cause tissue injury. We believe that this sequence of events is critical in the cascade leading to vascular endothelial injury and post-pump syndrome.
Unlike PMNs and monocytes, which increased moderately in response to a insults that did not cause lung dysfunction (LPS, CPB, and HP + LPS), AMs increased equally in all groups exposed to endotoxin (LPS, HP, CPB + LPS) regardless if exposed to one or two insults. This could be explained by the amount and type of cytokines that are being secreted in the pulmonary parenchyma. The chemoattractive force on PMNs and monocytes of various cytokines differs greatly. For example, IL-8 and epithelial cell-derived neutrophil activator-78 (ENA-78) are powerful chemoattractants for PMNs whereas monocyte chemotactic peptide-1 (MCP-1) and macrophage inflammatory peptide-1
(MIP-1) strongly attract monocytes [22]. An increased number of PMNs in the bronchoalveolar lavage fluid of ARDS patients is associated with a poor prognosis whereas increased numbers of monocytes and AMs correlate with an improved outcome [22]. However, monocytes and AMs contain a large array of cytokines, both pro and anti-inflammatory, such that the mediators that these cells secrete, rather than just the number of cells, determines the physiologic effect. Thus, it is difficult to draw conclusion on the pathologic significance of increased monocytes and AMs from a histometric assessment alone.
We believe that CPB, like other forms of trauma, stimulates the inflammatory system predisposing the patient to the development of post-pump syndrome if subjected to a second insult. The diffuse inflammatory reaction following CPB involves activation of both plasma (complement, coagulation, kallikrein-kinin, and fibrinolytic systems) and cellular (macrophages, monocytes, lymphocytes neutrophils, and endothelial cells) defense systems. Proinflammatory mediators released by the cellular elements include cytokines (TNF, IL-1, IL-8, etc) [4], lipid metabolites (leukotrienes, prostaglandin, PAF) [23, 24], proteases (elastase, collagenase) [3], toxic oxygen products (superoxide, H2O2, etc.) [25], adhesion proteins (selectins, ICAMs, CD11/18) [3, 24], and complement [4]. Activation of the coagulation and fibrinolytic cascades also occurs [26]. During CPB, PMNs are primed by C5a, kallikrein, PAF, leukotriene B4, or direct contact with the perfusion circuit synthetic surfaces [26]. Hirthler and colleagues demonstrated a biphasic generalized systemic inflammatory response to prolonged bypass with the initial phase due to increased plasma levels of inflammatory mediators such as complement, interleukin 1(IL-1), and tumor necrosis factor (TNF) and the second due to endotoxin [25]. They hypothesized that the renal, cardiac, and pulmonary dysfunction associated with CPB was caused by a classic sepsis syndrome.
Further support that a whole body inflammatory response is the mechanism responsible for the development of post-pump syndrome arises from studies in which components of the inflammatory mechanism are inhibited [23, 24, 27, 28]. Lung injury was reduced following CPB by blocking the formation of PAF [24] or thromboxane [23]. Jansen and colleagues [27] demonstrated that CPB caused a PMN inflammatory response evidenced by increases in TNF, IL-1, and tissue plasminogen activator (t-PA) activity that was associated with hemodynamic instability. Treatment with dexamethasone significantly inhibited the formation of the above inflammatory mediators and restored hemodynamic stability. PMNs activated by CPB upregulate the membrane protein CD11/CD18, which plays an important role in the adhesion and sequestration of neutrophils in the pulmonary vasculature [29]. Gillinov et al [28] showed that blocking upregulation of CD11/CD18 during CPB reduced neutrophil sequestration and subsequent lung injury. Inhibition of complement activation during CPB with soluble human complement receptor type 1 (sCR1) was associated with a significant reduction in the severity of lung injury [29]. Thus, CPB activates both plasma and cellular defense systems, and blocking these individual components prevents lung injury associated with post-pump syndrome in animal models.
The most likely mechanism of PMN priming during CPB is contact of blood with the foreign surfaces of the perfusion circuit. Simulated CPB, in which blood was circulated through a standard perfusion circuit at 3 L/min for 2 hours, caused generation of complement, adhesion molecules, cytokines, and activated PMNs [3]. Numerous studies have tested heparin-coated CPB circuits and found that the coated circuits reduced serum concentrations of cytokines [4], myeloperoxidase [5, 6], complement [6], and endothelin-1[5] with subsequent reduction in PMN activation [5, 6], and lung injury [7].
A second possibility for PMN priming is from the gut. Splanchnic hypoperfusion may cause PAF release by a mechanism similar to that found during gut ischemia in the sequential insult ARDS models [30]. Circulating PAF is increased by 350% after CPB and is a powerful PMN priming agent [24]. Decreased splanchnic perfusion during CPB may disrupt the mucosal barrier allowing endotoxin to enter the plasma [30]. Endotoxin has been shown to be elevated following CPB and is associated with PMN priming. Jansen and colleagues showed that endotoxin concentrations significantly increased immediately after the start of CPB and a second increase was measured following release of the aortic cross-clamp [31]. In a similar study Rocke and colleagues determined that routine CPB resulted in endotoxemia with the peak LPS level reached during the period of myocardial and pulmonary reperfusion [32]. The source of endotoxin is unknown but may originate from pulmonary infection or necrosis, catheter colonization, urinary tract infection, or bacterial translocation from the intestinal tract. Regardless of the mechanism, this study confirms that CPB causes PMNs sequestration in the lung.
In summary we have established that post-pump syndrome can be caused by multiple sequential insults. These data establish that CPB causes pulmonary PMN sequestration without lung injury. A subsequent exposure to an otherwise benign insult activates primed and sequestered PMNs to cause vascular injury, which leads to post-pump syndrome. We speculate that if the inflammatory effects of CPB can be reduced, the incidence of post-pump syndrome will be diminished.
|
References |
|---|
|
TopAbstractIntroductionMaterial and methodsProtocolResultsCommentsReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  E. M. Carvalho, E. A Gabriel, and T. A Salerno Pulmonary Protection During Cardiac Surgery: Systematic Literature Review Asian Cardiovasc Thorac Ann, December 1, 2008; 16(6): 503 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Novitzky, A L. Shroyer, J. F Collins, G. O McDonald, J. Lucke, B. Hattler, E. Kozora, D. D Bradham, J. Baltz, F. L Grover, et al. A study design to assess the safety and efficacy of on-pump versus off-pump coronary bypass grafting: the ROOBY trial Clinical Trials, February 1, 2007; 4(1): 81 - 91. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Wakayama, I. Fukuda, Y. Suzuki, and N. Kondo Neutrophil Elastase Inhibitor, Sivelestat, Attenuates Acute Lung Injury After Cardiopulmonary Bypass in the Rabbit Endotoxemia Model Ann. Thorac. Surg., January 1, 2007; 83(1): 153 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kotani, Y. Kotake, H. Morisaki, J. Takeda, H. Shimizu, T. Ueda, and A. Ishizaka Activation of a Neutrophil-Derived Inflammatory Response in the Airways During Cardiopulmonary Bypass Anesth. Analg., December 1, 2006; 103(6): 1394 - 1399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Fan, Y. Liu, Q. Wang, C. Yu, B. Wei, and Y. Ruan Lung Perfusion With Clarithromycin Ameliorates Lung Function After Cardiopulmonary Bypass. Ann. Thorac. Surg., March 1, 2006; 81(3): 896 - 901. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lemma, A. Mangini, A. Redaelli, and F. Acocella Do cardiac stabilizers really stabilize? Experimental quantitative analysis of mechanical stabilization Interactive CardioVascular and Thoracic Surgery, June 1, 2005; 4(3): 222 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Raja The 'dark side' of cardiopulmonary bypass Eur. J. Cardiothorac. Surg., May 1, 2004; 25(5): 906 - 906. [Full Text] [PDF]
|
|
|
|
 |
|
 M Tang, Y J Gu, W J Wang, Y P Xu, and C Z Chen Effect of cardiopulmonary bypass on leukocyte activation: changes in membrane-bound elastase on neutrophils Perfusion, March 1, 2004; 19(2): 93 - 99. [Abstract] [PDF]
|
|
|
|
|
|
Z. K. Su, Y. Sun, Y. M. Yang, H. B. Zhang, and Z. W. Xu Lung Function After Deep Hypothermic Cardiopulmonary Bypass in Infants Asian Cardiovasc Thorac Ann, December 1, 2003; 11(4): 328 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Ngaage Off-pump coronary artery bypass grafting: the myth, the logic and the science Eur. J. Cardiothorac. Surg., October 1, 2003; 24(4): 557 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. J. Gu, P. Schoen, I. Tigchelaar, B. G. Loef, T. Ebels, A. J. Rankin, and W. van Oeveren Increased neutrophil priming and sensitization before commencing cardiopulmonary bypass in cardiac surgical patients Ann. Thorac. Surg., October 1, 2002; 74(4): 1173 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S.H. Ng, S. Wan, A. P.C. Yim, and A. A. Arifi Pulmonary Dysfunction After Cardiac Surgery* Chest, April 1, 2002; 121(4): 1269 - 1277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Carney, C. J. Lutz, A. L. Picone, L. A. Gatto, N. S. Ramamurthy, L. M. Golub, S. R. Simon, B. Searles, A. Paskanik, K. Snyder, et al. Matrix Metalloproteinase Inhibitor Prevents Acute Lung Injury After Cardiopulmonary Bypass Circulation, July 27, 1999; 100(4): 400 - 406. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
= p < 0.05 vs control, HP + LPS, and LPS groups.