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Anesth Analg 1999;89:1188
© 1999 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

The Inflammatory Response to Pediatric Cardiac Surgery: Correlation of Granulocyte Adhesion Molecule Expression with Postoperative Oxygenation

Helen E. Gilliland, FRCA*, Marilyn A. Armstrong, PhD{dagger}, and Terence J. McMurray, MD*

*Department of Clinical Anaesthesia, Royal Victoria Hospital; and {dagger}Department of Microbiology and Immunobiology, Queen’s University Belfast, Belfast, Ireland

Address correspondence and reprint requests to Helen Gilliland, FRCA, Royal Victoria Hospital, Grosvenor Road, Belfast, BT12 6BA, Ireland.


   Introduction
Top
 Introduction
Methods
 Results
 Discussion
 References
 
Despite advances in our understanding of the inflammatory response to cardiac surgery, few investigators have been able to correlate mediators of this response with clinical variables (1,2). Children undergoing surgery for congenital heart disease suffer from more postoperative complications than adults (3). This study was designed to test the hypothesis that inflammatory mediators correlate with, or can help to predict, postoperative oxygenation in children undergoing cardiac surgery.


   Methods
Top
 Introduction
 Methods
Results
 Discussion
 References
 
After ethical approval, we studied 10 children (age <12 yr) undergoing surgery for congenital heart disease. Very young patients (<3 mo) with immature immune systems were excluded.

Anesthesia was induced with IV ketamine (3 mg/kg) or inhaled halothane (0%–3%). After the induction, patients received 25 µg/kg fentanyl IV. Maintenance was with 0.5% isoflurane in oxygen/air plus incremental fentanyl to a total dose of 50 µg/kg. During cardiopulmonary bypass (CPB), flow was maintained at 2.4 L · m-2 · min-1, reduced to 1.8 L · m-2 · min-1 if temperature was <28°C. A hollow-fiber, membrane oxygenator was used, and patients were cooled between 23° and 31°C.

Three leukocyte (L) adhesion molecules, L selectin, CD18, and CD11b were measured, as were systemic and lung levels of three cytokines: the neutrophil chemotactic factor interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and the antiinflammatory cytokine interleukin-10 (IL-10).

Arterial samples for adhesion molecule analysis were taken after the induction of anesthesia (Time 0), 10 min after fentanyl (Time 1), at the institution of CPB (Time 2), 10 min after aortic cross-clamp release (Time 3), and 2 h post-CPB (Time 4). Arterial and bronchoalveolar lavage (BAL) samples for cytokines were taken at Times 0, 1, 3, and 4.

BAL samples were obtained by advancing a fine suction catheter into the trachea until resistance was felt. One mg/kg of normal saline was then instilled, and after two breaths, BAL fluid was aspirated into a sputum trap. Direct microscopy of each sample confirmed that fluid instilled had reached the alveoli.

All samples were processed within 10 min of collection to minimize ex vivo stimulation. Samples for adhesion molecule expression were stained with fluorescent dye before cell lysis and analyzed using flow cytometry (4). Samples for cytokine analysis were centrifuged and stored at -70°C before enzyme-linked immunoassay (R&D Quantikine, Abingdon, Oxon, UK).

The ratio of the arterial partial pressure of oxygen to the fractional inspired oxygen concentration (PaO2/FIO2) was recorded 2 h after CPB.

Previous studies suggest that adhesion molecule data are normally distributed (4,5). In contrast, cytokine production may be genetically determined (6,7). Parametric tests were therefore applied to adhesion molecule data and nonparametric tests to cytokine data. Spearman and Pearson analyses were used to test for correlation between inflammatory mediators and perioperative events.


   Results
Top
 Introduction
 Methods
 Results
Discussion
 References
 
Demographic data are shown in Table 1. Results for cyanotic and noncyanotic children did not differ significantly and are presented together.


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  		Table 1. Demographic Data
 
Adhesion molecule expression was recorded as mean channel fluorescence. The mean channel fluorescence of L selectin did not change significantly during the study.

Granulocyte, but not monocyte or lymphocyte, CD18 expression was significantly higher than baseline 10 min after release of the aortic cross-clamp (Fig. 1). Both granulocyte and monocyte CD11b expression rose after cross-clamp release (P < 0.001, P < 0.05, respectively). In all cases, increased expression was transient (Fig. 1).



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  		Figure 1. Expression of leukocyte adhesion molecules measured as mean channel fluorescence (MCF): A, leukocyte selectin. B, CD18. C, CD11b. *P < 0.05, ***P < 0.001 compared with Time 0 (repeated measures analysis of variance).

 
Plasma levels of cytokines increased by the end of the study (P < 0.001). MCP-1 rose earliest, being significantly elevated 10 min after release of the cross-clamp (P < 0.05). BAL cytokine levels did not change. BAL MCP-1 and IL-10 levels were always much lower than those in plasma, whereas IL-8 levels were more than 20 times those in plasma (Table 2).


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  		Table 2. Cytokine Levels (pg/mL) of Pediatric Patients Undergoing Cardiopulmonary Bypass
 
PaO2/FIO2 ratios ranged from 168 to 442 mm Hg. All patients were tracheally extubated within 48 h of surgery. No relationship between cytokines or monocyte adhesion molecules and postoperative PaO2/FIO2 ratios could be established. In contrast, granulocyte CD18 and CD11b at cross-clamp removal showed a negative correlation with postoperative oxygenation (P < 0.02, P < 0.0007, respectively) (Fig. 2).



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  		Figure 2. Pearson correlation between integrin expression 10 min after release of the aortic cross clamp and PaO2/FIO2 ratio 2 h after cardiopulmonary bypass. P < 0.02, r = -0.7259 for CD18. P < 0.0007, r = -0.8854 for CD11b.

 
There was no correlation between inflammatory mediators or postoperative oxygenation and intraoperative events such as hypothermia, duration of CPB, or aortic cross-clamping.


   Discussion
Top
 Introduction
 Methods
 Results
 Discussion
References
 
Pulmonary dysfunction in the first few hours after surgery has been attributed to endothelial injury, a process in which leukocyte-endothelial interactions may play a pathogenic role (8,9). Leukocytes adhere to endothelium in three stages (10). First, selectins mediate leukocyte rolling. Second, chemotactic cytokines (chemokines) activate leukocyte integrins. Finally, activated integrins mediate firm adhesion by binding to the endothelial surface. Our study investigated all three stages.

L selectin is shed upon activation (11). Shedding of neutrophil L selectin has been reported during both simulated CPB and pediatric cardiac surgery (12,13) but did not occur in our study. This discrepancy may relate to the fact that cell separation techniques upregulate adhesion molecules (14,15). Staining blood before separation minimized such artefactual upregulation.

Although systemic levels of the chemokines IL-8 and MCP-1 increased during our study, their BAL levels did not change significantly. Despite this and the dilution inherent in lavage fluid, BAL IL-8 levels were consistently higher than systemic, a finding which points to the lung as an important source of this neutrophil-chemotactic cytokine.

Neither plasma nor BAL chemokine levels correlated with postoperative oxygenation. This supports authors who found no link between plasma IL-8 and respiratory dysfunction (16) but contradicts those who suggest using BAL IL-8 levels to predict the development of severe lung injury (17).

The two integrin molecules studied here, CD11b and CD18, belong to a group whose members share the CD18 component, bound to CD11a, -b, or -c. Expression of CD18, therefore, reflects changes across the group, whereas expression of CD11b gives information about the CD11b/CD18 heterodimer. Upregulation of integrins has been demonstrated during adult cardiac surgery (5) and, inconsistently, during pediatric cardiac surgery (13). Our study confirmed consistent, short-lived integrin activation and generated two additional findings: that CD11b upregulation was more marked than that of CD18 and that different cells were affected to different degrees. Granulocytes showed the greatest change, followed by monocytes, whereas lymphocyte integrin expression did not change at all. These results show that cardiac surgery preferentially affects expression of the CD11b/CD18 heterodimer on the granulocyte population.

Granulocyte integrin expression appeared to predict postoperative oxygenation, regardless of initial diagnosis. It is important to note, however, that postoperative PaO2/FIO2 ratio may have been influenced by residual shunt as well as lung injury. The exact stimulus for adhesion molecule upregulation remains unclear, as perioperative factors showed no correlation with this process. Perhaps upregulation of granulocyte integrins reflects the combined effect of many coexisting proinflammatory stimuli.

Systemic IL-10 production has been demonstrated after cardiac surgery and may represent an attempt to limit inflammatory side effects (18,16). In our study, the increase in plasma IL-10 two hours after CPB was not associated with better postoperative oxygenation. As this was the final sample time, later antiinflammatory effects remain a possibility.

In conclusion, this preliminary study suggests that granulocyte activation may predict postoperative oxygenation in pediatric patients undergoing heart surgery. This is an interesting finding that deserves further investigation.


   Acknowledgments
 
This study was supported by a grant from the Northern Ireland Chest Heart and Stroke Association.


   References
Top
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Casey WF, Hauser GJ, Hannallah RS, et al. Circulating endotoxin and tumor necrosis factor during pediatric cardiac surgery. Care Med 1992;20:1090–6.
  2. Seghaye MC, Engelhardt W, Grabitz RG, et al. Multiple system organ failure after open heart surgery in infants and children. Cardiovasc Surg 1993;41:49–53.
  3. Moat NE, Shore DF, Evans TW. Organ dysfunction and cardiopulmonary bypass: the role of complement and complement regulatory proteins. Cardiothorac Surg 1993;7:563–73.
  4. McBride WT, Armstrong MA, Crockard AD, et al. Cytokine balance and immunosuppressive changes at cardiac surgery: contrasting response between patients and isolated CPB circuits. Br J Anaesth 1995;75:724–33.[Abstract/Free Full Text]
  5. Paugam C, Chollet-Martin S, Dehoux M, et al. Neutrophil expression of CD11b/CD18 and IL-8 secretion during normothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997;11:575–9.[Web of Science][Medline]
  6. Sandberg-Wollheim M, Ciusani E, Salmaggi A, Pociot F. An evaluation of tumor necrosis factor microsatellite alleles in genetic susceptibility to multiple sclerosis. Mult Scler 1995;1:181–5.[Medline]
  7. Westendorp RG, Langermans JA, Huizinga TW, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997;349:170–3.[Web of Science][Medline]
  8. Bando K, Pillai R, Cameron DE, et al. Leukocyte depletion ameliorates free radical-mediated lung injury after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:873–7.[Abstract]
  9. Johnson D, Thomson D, Mycyk T, et al. Depletion of neutrophils by filter during aortocoronary bypass surgery transiently improves postoperative cardiorespiratory status. Chest 1995;107:1253–9.[Abstract/Free Full Text]
  10. Butcher EC. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell 1991;67:1033–6.[Web of Science][Medline]
  11. Kishimoto TK, Jutila MA, Berg EL, Butcher EC. Neutrophil Mac-1 and MEL-14 adhesion proteins inversely regulated by chemotactic factors. Science 1989;245:1238–41.[Abstract/Free Full Text]
  12. Moat NE, Rebuck N, Shore DF, et al. Humoral and cellular activation in a simulated extracorporeal circuit. Surg 1993;56:1509–14.
  13. Finn A, Moat N, Rebuck N, et al. Changes in neutrophil CD11b/CD18 and L-selectin expression and release of interleukin 8 and elastase in paediatric cardiopulmonary bypass. Agents Actions 1993;38:C44–6.
  14. Stibenz D, Buhrer C. Down-regulation of L-selectin surface expression by various leukocyte isolation procedures. Scand J Immunol 1994;39:59–63.
  15. Youssef PP, Mantzioris BX, Roberts-Thomson PJ, et al. Effects of ex vivo manipulation on the expression of cell adhesion molecules on neutrophils. J Immunol Methods 1995;186:217–24.[Web of Science][Medline]
  16. Seghaye M, Duchateau J, Bruniaux J, et al. Interleukin-10 release related to cardiopulmonary bypass in infants undergoing cardiac operations. J Thorac Cardiovasc Surg 1996;111:545–53.[Abstract/Free Full Text]
  17. Donnelly SC, Strieter RM, Kunkel SL, et al. Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups. Lancet 1993;341:643–7.[Web of Science][Medline]
  18. McBride WT, Armstrong MA, Gilliland H, McMurray TJ. The balance of pro and anti-inflammatory cytokines in plasma and bronchoalveolar lavage (BAL) at paediatric cardiac surgery. Cytokine 1996;8:724–9.[Web of Science][Medline]
Accepted for publication July 21, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press