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Anesthesia & Analgesia:
doi: 10.1213/ANE.0b013e3182554337
Critical Care, Trauma, and Resuscitation: Brief Report

Systemic Inflammatory Response Does Not Correlate with Acute Lung Injury Associated with Mechanical Ventilation Strategies in Normal Lungs

Hong, Caron M. MD, MSc*; Xu, Da-Zhong MD, PhD; Lu, Qi MD; Cheng, Yunhui PhD*; Pisarenko, Vadim MD; Doucet, Danielle MD; Brown, Margaret MSN; Zhang, Chunxiang MD, PhD*; Deitch, Edwin A. MD; Delphin, Ellise MD, MPH*

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Author Information

From the Departments of *Anesthesiology and Surgery, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey.

Supported by the Department of Anesthesiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the IARS annual meeting, 2011.

Caron M. Hong, MD, MSc, is currently affiliated with the Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD. Ellise Delphin, MD, MPH, is currently affiliated with the Department of Anesthesiology, Albert Einstein School of Medicine of Yeshiva University, Bronx, NY.

Reprints will not be available from the authors.

Address correspondence to Caron M. Hong, MD, MSc, Department of Anesthesiology, University of Maryland, 22 S. Greene St., S11C, Baltimore, MD 21201. Address e-mail to chong@anes.umm.edu.

Accepted March 2, 2012

Published ahead of print May 14, 2012

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Abstract

BACKGROUND: Mechanical ventilation (MV) can lead to ventilator-induced lung injury secondary to trauma and associated increases in pulmonary inflammatory cytokines. There is controversy regarding the associated systemic inflammatory response. In this report, we demonstrate the effects of MV on systemic inflammation.

METHODS: This report is part of a previously published study (Hong et al. Anesth Analg 2010;110:1652–60). Female pigs were randomized into 3 groups. Group H-VT/3 was ventilated with a tidal volume (VT) of 15 mL/kg predicted body weight (PBW)/positive end-expiratory pressure (PEEP) of 3 cm H2O; group L-VT/3 with a VT of 6 mL/kg PBW/PEEP of 3 cm H2O; and group L-VT/10 with a VT of 6 mL/kg PBW/PEEP of 10 cm H2O, for 8 hours. Each group had 6 subjects (n = 6). Prelung and postlung sera were analyzed for inflammatory markers. Hemodynamics, airway mechanics, and arterial blood gases were monitored.

RESULTS: There were no significant differences in systemic cytokines among groups. There were similar trends of serum inflammatory markers in all subjects. This is in contrast to findings previously published demonstrating increases in inflammatory mediators in bronchoalveolar lavage.

CONCLUSION: Systemic inflammatory markers did not correlate with lung injury associated with MV.

Mechanical ventilation (MV) is a medical method that has affected every subpopulation of the community. The significance of MV as a lifesaving measure and its essential role in surgical procedures is obvious. Yet, the overall effects of MV on normal, noninjured lungs and its contribution to outcome are still an area of debate.

Ventilator-induced lung injury has been described secondary to ventilation with high volume and pressure as well as low volume secondary to cyclic opening and closure of peripheral airways.1,2 Ex vivo and in vivo animal models ventilated with physiologic tidal volumes (VTS) were associated with functional alterations, histologic injury, and release of pulmonary proinflammatory cytokines.3,4 Rodent studies have demonstrated increases in cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 with very large (40 mL/kg) VTs and long durations of MV.36 These inflammatory cytokines detected within the pulmonary parenchyma or bronchoalveolar lavage (BAL) did not correlate with a similar increase in systemic inflammation or were not investigated in these studies. Human prospective studies comparing MV strategies have had inconsistent results.714 Although there is growing human research demonstrating increases in pulmonary inflammatory cytokines in response to particular types of MV, there are still differing opinions on the effects of MV on the systemic inflammatory response and whether these 2 entities correlate.

The ability to provide MV that will not injure and may protect normal lungs during major surgical procedures may improve postoperative outcomes and decrease morbidity and mortality. We previously published an in vivo animal study that compared conventional high and low VT ventilation strategies with different positive end-expiratory pressure (PEEP) values and their effect on inflammation in noninjured lungs.15 This brief report demonstrates an important finding during that study that demonstrated no systemic inflammatory correlation with a BAL inflammatory response for different MV strategies.

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METHODS

This study is part of a previously published study that was approved by the New Jersey Medical School Animal Care and Use Committee.15

Female pigs (n = 18) were randomized into 3 groups. Group H-VT/3 (n = 6) was ventilated with a VT of 15 mL/kg predicted body weight (PBW)/PEEP of 3 cm H2O; group L-VT/3 (n = 6) with a VT of 6 mL/kg PBW/PEEP of 3 cm H2O; and group L-VT/10 (n = 6) with a VT of 6 mL/kg PBW/PEEP of 10 cm H2O, for 8 hours. For this report, prelung and postlung sera were analyzed for inflammatory markers. Hemodynamics, airway mechanics, and arterial blood gases were monitored.

See previously published study for detailed methods.15

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RESULTS

We assayed cytokines TNF-α, IL-1β, IL-6, IL-8, IL-10, and IL-12 in prelung and postlung blood via a pulmonary artery catheter and aortic catheter. No significant differences in any cytokines were demonstrated within or between any group prelung and postlung (Fig. 1). However, all groups demonstrated similar trends of TNF-α, IL-1β, IL-6, and IL-12 (Fig. 1). There were no significant levels of IL-8 and IL-10 in serum prelung or postlung in any group regardless of findings of exponentially increased IL-8 found in BAL. All 3 groups demonstrated a peak of TNF-α at hour 3 of MV. IL-1β and IL-6 gradually increased over the 8 hours of MV. IL-12 gradually decreased through the 8 hours of MV (Fig. 1).

Figure 1
Figure 1
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DISCUSSION

Our previously published study15 was designed to evaluate the effects of 3 different ventilator strategies on the pulmonary and systemic inflammatory response in anesthetized animals with noninjured lungs. We have evidence that although ventilation with low VT/high PEEP is associated with increased levels of pulmonary inflammatory mediators, high and low VT MV strategies are associated with similar systemic inflammatory mediator trends (Fig. 1). Systemic correlation, regardless of the pulmonary findings, are inconsistent among many studies.46,1012,14,16

This observation was removed from the original published article15 during peer review because of increasing complexity and length as well as overall concept of the article, but remains an unexplained and pertinent observation. The results provide evidence that different ventilation strategies affect the systemic inflammatory process similarly in noninjured lungs irrespective of the pulmonary inflammatory response over 8 hours. The effects that different MV strategies may have on outcome in this population are still uncertain.

Some human studies have demonstrated a correlation between pulmonary and systemic inflammatory mediators and MV. Michelet et al.10 demonstrated a decrease in systemic inflammatory response (IL-1β, IL-6, and IL-8) with low VT MV in esophagectomy patients. Zupancich et al.11 also demonstrated decreased systemic inflammatory mediators with low VT/PEEP ventilation during cardiac surgery. In contrast, we found no differences in systemic inflammatory mediators with different ventilation strategies. Other human studies support this finding and have found no differences among varying MV strategies.79,12

One can postulate that time may have a role in the correlation between systemic and pulmonary inflammatory response to MV. There have been a few human studies that have investigated MV in patients without acute lung injury (ALI) in the intensive care unit (ICU). These data are also inconsistent. Determann et al.13 demonstrated decreases in IL-6 with low VT ventilation strategies in ICU patients without ALI. However, the question remains whether the systemic inflammatory response to MV is a major factor in outcome in human subjects. There may be a “lag time” between pulmonary inflammation secondary to MV and the systemic inflammatory response. It would be worthwhile to investigate the role of MV and its effects on pulmonary and systemic inflammation on outcome and determine whether there are differences in common postoperative complications such as wound infections, fevers, and pneumonia.

Although this study revealed pertinent systemic inflammatory findings regarding different ventilation strategies in normal lungs, there were limitations. The study limited the number of subjects to 6 per group and was performed in young swine. The effects of MV in normal young swine lungs may be different than adult human lungs ventilated similarly. Blood samples (prelung and postlung) were taken only during the 8-hour period of MV. There was no postsurvival blood sample analysis. It would be valuable to perform survival studies.

In lieu of these limitations, the observation that the systemic inflammatory response does not correlate with ALI associated with MV in normal lungs may prove to be an important factor in the human clinical arena. Patients whose lungs are ventilated for prolonged periods of time, whether in the operating room or in the ICU, may have a delayed systemic inflammatory response and be more prone to postoperative and ICU complications such as wound infections, oliguria, fevers, pneumonia, bacteremia, and sepsis. Human clinical trials should be done to address the effect of MV on the systemic inflammatory response. It is important to assess the extent of the effect of MV on systemic and pulmonary inflammation and how this inflammation affects postoperative and ICU complications. These vital trials would give rise to the possibility of innovative therapeutic interventions, such as antiinflammatory drugs, as a treatment to reduce the risk of associated complications after prolonged MV in normal lung patients. Concurrently, studies should be done to assess patients with normal lungs in the ICU requiring prolonged MV and its association with the risk, not only for common postoperative complications, but for critical care complications such as bacteremia and sepsis, increased risk for respiratory failure, risk for tracheal extubation failures, and tracheostomy.

In conclusion, we demonstrated, in conjunction with our previously published study,15 that frequently used high VT and low VT ventilation strategies resulted in similar trends of systemic inflammatory responses not correlating with significant pulmonary inflammatory response and ALI. The overall systemic effect and possible implications of postoperative and long-term recovery and morbidity may or may not be different among the different ventilation strategies, triggering the necessity for human clinical trials. The frequently used conventional positive pressure ventilation may itself induce a specific systemic response that is similar regardless of type of strategy. The questions still left unanswered are whether the effects of MV on inflammation alters or affects the recovery period and which strategy of MV will “protect” normal human lungs. Large human clinical trials with outcome analysis are necessary to determine the best strategy for ventilation of noninjured lungs that may improve postoperative recuperation and morbidity.

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DISCLOSURES

Name: Caron M. Hong, MD, MSc.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Caron M. Hong has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Da-Zhong Xu, MD, PhD.

Contribution: This author helped conduct the study.

Attestation: Da-Zhong Xu has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Qi Lu, MD.

Contribution: This author helped conduct the study.

Attestation: Qi Lu has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Yunhui Cheng, PhD.

Contribution: This author helped analyze the data.

Attestation: Yunhui Cheng has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Vadim Pisarenko, MD.

Contribution: This author helped conduct the study.

Attestation: Vadim Pisarenko has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Danielle Doucet, MD.

Contribution: This author helped conduct the study.

Attestation: Danielle Doucet has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Margaret Brown, MSN.

Contribution: This author helped conduct the study.

Attestation: Margaret Brown has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Chunxiang Zhang, MD, PhD.

Contribution: This author helped analyze the data.

Attestation: Chunxiang Zhang has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Edwin A. Deitch, MD.

Contribution: This author helped conduct the study.

Attestation: Edwin A. Deitch has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Ellise Delphin, MD, MPH.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Ellise Delphin has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Steven L. Shafer, MD.

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REFERENCES

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10. Michelet P, D'Journo XB, Roch A, Doddoli C, Marin V, Papazian L, Decamps I, Bregeon F, Thomas P, Auffray JP. Protective ventilation influences systemic inflammation after esophagectomy. Anesthesiology 2006;105:911–9

11. Zupancich E, Paparella D, Turani F, Munch C, Rossi A, Massaccesi S, Renieri VM. Mechanical ventilation affects inflammatory mediators in patients undergoing cardiopulmonary bypass for cardiac surgery: a randomized clinical trial. J Thorac Cardiovasc Surg 2005;130:378–83

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13. Determann RM, Royakkers A, Wolthuis E, Vlaar AP, Choi G, Paulus F, Hofstra J, de Graff M, Korevaar JC, Schultz MJ. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care 2010;14:R1

14. Wrigge H, Uhlig U, Baumgarten G, Menzenbach J, Zinserling J, Ernst M, Dromann D, Welz A, Uhlig S, Putensen C. Mechanical ventilation strategies and inflammatory responses to cardiac surgery: a prospective randomized clinical trial. Intensive Care Med 2005;31:1379–87

15. Hong CM, Xu D, Lu Q, Cheng Y, Pisarenko V, Doucet D, Brown M, Aisner S, Zhang C, Deitch EA, Delphin E. Low tidal volume and high positive end-expiratory pressure mechanical ventilation results in increased inflammation and ventilator-associated lung injury in normal lungs. Anesth Analg 2010;110:1652–60

16. Vlahakis NE, Schroeder MA, Limper AH, Hubmayr RD. Stretch induces cytokine release by alveolar epithelial cells in vitro. Am J Physiol 1999;277:L167–73

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