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Ann Thorac Surg 2003;76:654-655
© 2003 The Society of Thoracic Surgeons

Correspondence

Time course of proinflammatory and anti-inflammatory responses after cardiac operation: monocyte HLA-DR expression

Y. John Gu, MD, PhDa, Willem van Oeveren, PhDa

a Department of Cardiothoracic Surgery, Thorax Center, University Hospital Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands

e-mail: y.j.gu{at}med.rug.nl

To the Editor:

We read with interest the recent article by Franke and co-workers [1] on the postoperative proinflammatory and anti-inflammatory responses after cardiac operation with cardiopulmonary bypass (CPB). On the basis of their findings of several proinflammatory and anti-inflammatory cytokines, they described a postoperative biphasic immune response. However, two major limitations of their study are the use of isolated cell cultures and the lack of clinical relevance.

In fact, there are clinically relevant monocyte membrane markers discussed in the literature that directly indicate the status of the body host defense known as the anti-inflammatory profile [2–5]. One of these markers is the histocompatibility leukocyte antigen-DR (HLA-DR), the levels of which can be determined by flow cytometry. It is known that on activation, monocytes release different sorts of proinflammatory and anti-inflammatory cytokines, as shown in the work of Franke and colleagues [1]. After activation, however, the defense ability of monocytes is impaired as these cells express fewer surface HLA-DR receptors. Expression of HLA-DR on monocytes is thus considered an ideal marker for monitoring the status of a patient’s anti-inflammatory profile, especially that of a patient at risk.

We recently studied a group of high-risk cardiac surgical patients who had compromised preoperative renal function as indicated by elevated serum creatinine levels. Monocyte HLA-DR expression was determined by a whole-blood cytometric assay using a fluorescence-activated cell sorter. Blood samples were taken before, during, and after operation until postoperative day 7. We found that anesthesia and surgical trauma before CPB caused a marked reduction in monocyte HLA-DR expression (Fig 1). Within the first 30 minutes of CPB, only a slight drop in HLA-DR expression was observed, whereas it had dropped significantly by the end of CPB. After operation, monocyte HLA-DR expression remained low during the first 2 hours in the intensive care unit, and this low level persisted on postoperative day 1. The lowest level of HLA-DR expression on monocytes was observed on postoperative day 2. By postoperative day 7, it had partially recovered, though, was still much lower than the preoperative baseline.



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  		Fig 1. Monocyte histocompatibility leukocyte antigen-DR (HLA-DR) expression in 12 patients undergoing cardiac operation with cardiopulmonary bypass. Each box indicates the upper and lower quartiles, and the line within each box is the median. The upper and lower error bars indicate the 90th and 10th percentiles, respectively. The percentages indicate the average drop in HLA-DR fluorescence intensity compared with baseline before operation. # = p < 0.01 compared with previous time point by paired t test; ** = p < 0.01 compared with baseline by paired t tests. (CPB = cardiopulmonary bypass; ICU = intensive care unit; Op = operation; POD = postoperative day.)

 
Severe postoperative complications occurred only in the 2 patients with the lowest monocyte HLA-DR expression on the first and second postoperative days (thus 2 consecutive days of monocyte depression). On postoperative day 5, wound infection developed in 1 and adult respiratory distress syndrome, in the other. Both patients eventually recovered after extensive intensive care. The clinical impact of our preliminary observation is in line with the strategy of Kox and co-workers [3]. According to them, a low monocyte HLA-DR expression of less than 30% for 2 consecutive days is a therapeutic target for treating patients with the so-called compensatory anti-inflammatory response syndrome. It was reported that in patients with sepsis, persistent monocyte inactivation for more than 2 days correlates with a mortality rate of 58% and inactivation for more than 5 days, with a mortality rate of 88%. It is not known whether this applies to cardiac surgical patients who have developed postoperative septic complications.

According to the study of Franke and associates [1], cardiac operation with CPB stimulates the release of proinflammatory and anti-inflammatory cytokines from different cellular sources at different times. Our data further specify that after contributing to both proinflammatory and anti-inflammatory responses by releasing different cytokines in the early postoperative phase, monocytes can become exhausted and lose their host defense ability in the second postoperative phase. Once monocytes have lost their defense function, as appeared in our patients with continuously depressed monocyte HLA-DR expression, the consequences can be serious. Postoperative organ dysfunction and infection can develop as a result of a fragile host defense.

References

  1. Franke A., Lante W., Fackeldey V., et al. Proinflammatory and antiinflammatory cytokines after cardiac operation: different cellular sources at different times. Ann Thorac Surg 2002;74:363-371.[Abstract/Free Full Text]
  2. Rinder C.S., Mathew J.P., Rinder H.M., Tracey J.B., Davis E., Smith B.R. Lymphocyte and monocyte changes during cardiopulmonary bypass: effects of aging and gender. J Lab Clin Med 1997;129:592-602.[Medline]
  3. Kox W.J., Bone R.C., Krausch D., et al. Interferon gamma-Ib in the treatment of compensatory anti-inflammatory response syndrome. A new approach: proof of principle. Arch Intern Med 1997;157:389-393.[Abstract/Free Full Text]
  4. Muller Kobold A.C., Tulleken J.E., Zijlstra J.G., et al. Leukocyte activation in sepsis; correlations with disease state and mortality. Intensive Care Med 2000;26:883-892.[Medline]
  5. Tepaske R., Velthuis H., Oudemans-van Straaten H.M., et al. Effect of preoperative oral immune-enhancing nutritional supplement on patients at high risk of infection after cardiac surgery: a randomised placebo-controlled trial. Lancet 2001;358:696-701.[Medline]



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A. Franke, W. Lante, L. G. Zoeller, E. Kurig, C. Weinhold, and A. Markewitz
Delayed recovery of human leukocyte antigen-DR expression after cardiac surgery with early non-lethal postoperative complications: only an epiphenomenon?
Interactive CardioVascular and Thoracic Surgery, April 1, 2008; 7(2): 207 - 211.
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