Modified Ultrafiltration Reduces Elaboration of Alveolar Proinflammatory Cytokines in Response to Cardiopulmonary Bypass in Neonatal Piglets
B. Z. Atkins1, C. M. Fitzpatrick2, D. S. Danielson3, P. Dixon4, W. G. Wolfe*1, A. J. Carpenter2. 1Duke University, Durham, NC, 2University of Texas Health Science Center-San Antonio, San Antonio, TX, 3Northwestern University, Chicago, IL, 459th Clinical Research Squadron, San Antonio, TX,
Background: Cardiopulmonary bypass (CPB) invokes an inflammatory response with the greatest effect upon the lungs. In similar models, elevated alveolar cytokines have been associated with adverse outcomes. Modified ultrafiltration (MUF) may elicit favorable clinical effects post-CPB by reducing the elaboration of various pro-inflammatory mediators including cytokines. This study evaluated the effect of MUF on indices of pulmonary function and systemic and alveolar cytokines in a neonatal piglet model of CPB.
Methods: Using locally-approved protocols, 24 neonatal piglets underwent instrumentation for CPB via median sternotomy prior to undergoing hypothermic CPB for 2 hours, followed by rewarming and weaning from CPB. MUF subjects (n=12) underwent hemoconcentration with a polyarylethersulfone hemoconcentrator (COBE HC 700 Midi COBE Cardiovascular Arvada, CO) post-CPB to goal hematocrit (35%-40%) and were monitored for 4 hours after CPB. Controls (n=12) were monitored post-CPB for 4 hours. Indices of pulmonary mechanics [dynamic compliance, mean airway resistance], sera for inflammatory mediators, and broncho-alveolar lavage (BAL) specimens for proinflammatory cytokines were obtained at baseline, following CPB, and at the end of study (EOS). Upon study completion, animals were euthanized, and lungs were excised for wet-to-dry lung weight ratio determination. Data were analyzed using student’s t-test within groups and ANOVA between groups.
Results: Pulmonary compliance was decreased after CPB and mean airway resistance was increased after CPB to similar degrees in both groups. In addition, wet-to-dry lung weight ratios were not different among control and MUF subjects. Similarly, systemic cytokine levels were not different between groups at any timepoint (Table 1). However, BAL concentrations of IL-6 and IL-8 were significantly elevated at EOS compared with post-CPB among control subjects (Table 2, p < 0.04). In contrast, BAL concentrations of IL-6 and IL-8 were unchanged among MUF subjects at EOS compared with post-CPB, indicating attenuation of inflammatory processes. IL-6 levels were significantly less among MUF subjects at EOS compared with controls at EOS (Table 2, p=0.05).
Conclusions: This CPB model induces inflammation as indicated by altered pulmonary mechanics and elevated systemic and alveolar cytokine concentrations. Although MUF did not appear to affect systemic cytokine levels, MUF reduced concentrations of pulmonary-derived proinflammatory cytokines, providing further evidence that MUF improves pulmonary endothelial-based processes and attenuates inflammatory processes within the lung. These observations may help to explain well-documented clinical benefits of MUF after CPB in infants and neonates. Further studies will seek to define a unifying mechanism by which these processes occur.
| Baseline | Post-CPB | EOS | ||
| IL-6 | ||||
| Control | 14+/-30 | 140 +/- 200 | 1800 +/- 1000 | |
| MUF | 70 +/- 90 | 30 +/- 40 | 1400 +/- 2000 | |
| IL-8 | ||||
| Control | 25 +/- 60 | 12 +/- 40 | 1100 +/- 1400 | |
| MUF | 80 +/- 90 | 20 +/- 40 | 1100 +/- 2000 | |
| TNF-alpha | ||||
| Control | 140 +/- 200 | 800 +/- 700 | 850 +/- 600 | |
| MUF | 37 +/- 50 | 1140 +/- 1000 | 1140 +/- 600 |
| Baseline | Post-CPB | EOS | ||
| IL-6 | ||||
| Control | 32.3 +/- 60 | 180 +/- 300 | 1000 +/- 1000 | |
| MUF | 23.8 +/- 40 | 253 +/- 500 | 394 +/- 300 | |
| IL-8 | ||||
| Control | 1160 +/- 1500 | 2400 +/- 2000 | 3700 +/- 2000 | |
| MUF | 900 +/- 1200 | 3060 +/- 2700 | 3090 +/- 2300 |
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