LETTER TO Effect of Simvastatin on Physiological and Biological Outcomes in Patients Undergoing Esophagectomy: A Randomized Placebocontrolled Trial To the Editor: he study by Shyamsundar et al1 that presented an anti-inflammatory effect and modification of systemic endothelial cell function with 80-mg Simvastatin in patients undergoing esophagectomy should include a statement to emphasize that effective tissue healing is dependent upon inflammation. The pleiotropic effects of statins have been recognized for over a decade2 with both in vitro and in vivo studies demonstrating modification of inflammation, angiogenesis, and cell signalling. On the basis of these effects, it is likely that clinical applications beyond lipid lowering will be identified for this class of drug in years to come.3 As described in the study, suppressing inflammation with the goal of limiting postoperative complications is of clear benefit to patients undergoing major surgery such as esophagectomy. Our concerns surround the potential adverse consequences of excessive suppression of inflammation and angiogenesis; 2 fundamental physiological drivers of functional tissue healing. Inflammation is not an intrinsically negative process. It is widely accepted that effective wound healing and return to normal tissue homeostasis relies on the inflammatory response as part of the innate immune response. Insufficient or inadequate inflammation will result in failure of the healing tissue to vascularize, impaired tissue regeneration, and increased risk of infection. We must therefore take care when manipulating inflammation that any intended suppression does not shift the balance of the inflammatory response toward nonhealing, chronic inflammation or a recurrent wound.4,5 As tissue repair is driven by inflammation and angiogenesis, it is reasonable to hypothesize that interventions, which may suppress one or both of those processes, could plausibly lead to failure of tissue repair. Consequences of impaired tissue healing may include leakage of gastrointestinal
T
Disclosure: The authors declare no conflicts of interest. Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0003-4932/14/26105-0821 DOI: 10.1097/SLA.0000000000000669
THE
EDITOR
anastomoses and impaired healing of abdominal wounds. The study by Shyamsundar et al does state that no unexpected adverse effects occurred in either group; however, there is no report of postoperative outcomes; specifically, it would be interesting to report anastomotic leak. We are not invalidating or criticizing the research; this is a fascinating study, with findings to support further potential uses of statins beyond their current applications. The authors have also chosen a condition with significant associated morbidity and mortality, for which they should be commended. It would, however, also be noteworthy to find out whether the authors consented patients for increased risk of problems related to impaired tissue healing including anastomotic leak and impaired wound healing. It would also be interesting to establish whether future studies will investigate a dose-dependent relationship between systemic statin dose and inflammation, which we believe is required in such studies to ensure that balance of inflammation remains suitably efficacious to support tissue regeneration.
Christopher L. F. Battersby, MBChB, BSc The UK Centre for Tissue Engineering The Institute of Ageing and Chronic Disease University of Liverpool Liverpool, UK Royal Liverpool and Broadgreen University Hospitals Trust Liverpool, UK Nicholas Bryan, PhD, BSc John A. Hunt, PhD, DSc, BSc The UK Centre for Tissue Engineering The Institute of Ageing and Chronic Disease University of Liverpool Liverpool, UK [email protected]
REFERENCES 1. Shyamsundar M, McAuley DF, Shields MO, et al. Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebo-controlled trial. Ann Surg. 2014;259:26–31. 2. Werner N, Nickenig G, Laufs U. Pleiotropic effects of HMG-CoA reductase inhibitors. Basic Res Cardiol. 2002;97:105–116. 3. Davignon J, Leiter LA. Ongoing clinical trials of the pleiotropic effects of statins. Vascul Health Risk Manage. 2005;1:29–40. 4. Duaby DA, Franz MG. Acute wound healing: the biology of acute wound failure. Surg Clin N Am. 2003;83:463–481. 5. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83:835–870.
Annals of Surgery Volume 262, Number 6, December 2015
Reply: e read with interest the comment by Battersby et al regarding our study looking at the anti-inflammatory and cellular effects of simvastatin in patients undergoing esophagectomy.1 They expressed their valid concern about the impact of the anti-inflammatory effect of simvastatin on wound healing. Inflammation is an essential and complex process involving the interaction of various cells and mediators and is integral to wound healing and host defense. Mediators of inflammation such as interleukin-62 and proteases such as matrix metalloproteinase-9 (MMP-9)3 have been shown to be involved in this healing process. Excessive suppression of inflammation can be deleterious to wound healing4 but this has not been conclusively proven in human studies.5 This obviously leads to concerns about using an anti-inflammatory therapy in surgical patients, which depends on wound healing. Although inflammation per se is essential, it is unmitigated inflammation, which is injurious and indeed can result in clinical conditions such as acute lung injury (ALI). Statins have anti-inflammatory properties but the attraction of statins is likely to be that they do not ablate the inflammatory response but restrain it. This is well demonstrated in our study of simvastatin in reducing the inflammatory response to inhaled lipopolysaccharide6 in healthy human volunteers at a dose of 80 mg. The inflammatory cascade is appropriately activated but to a lesser degree and it is therefore tempting to postulate that statins might redress the inflammatory–anti-inflammatory balance. Statins have been shown to reduce postoperative morbidity such as postoperative myocardial infarction and atrial fibrillation.7 A meta-analysis, which studied the effect of adding a statin before surgery, did not show an increased reoperation rate,8 which is reassuring as it is plausible to suggest that a significant impairment of wound repair would be reflected in a higher reoperation rate. There is also evidence of the beneficial effect of statins in wound healing in patients with venous ulceration with a higher proportion of healing and at a faster rate9 and more specifically in relation to our study,1 there was one instance of anastomotic leak in the placebo group whereas none in the simvastatin group. Indeed the incidence of ALI, cardiac, respiratory, and other complications in the placebo group were higher, but this study was not powered for clinical outcomes. Statin use is ubiquitous and has been shown to have a significantly favorable
W
Disclosure: The authors declare no conflicts of interest. DOI: 10.1097/SLA.0000000000000670
www.annalsofsurgery.com | e95
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Annals of Surgery Volume 262, Number 6, December 2015
Letter to the Editor
effect on perioperative morbidity with no obvious evidence to date to suggest that they impair wound repair, whereas it should be acknowledged that there might be a dosedependent difference in effects.10 In the absence of any clear signal toward any adverse impact on wound healing with a strong evidence of a protective effect, consenting for a theoretical risk will cause anxiety11 for the patients and may impede medical advance.
Murali Shyamsundar, PhD Daniel F. McAuley, MD Cecilia M. O’Kane, PhD Centre for Infection and Immunity School of Medicine Dentistry and Biomedical Sciences Queen’s University of Belfast Belfast, UK [email protected]
e96 | www.annalsofsurgery.com
REFERENCES 1. Shyamsundar M, McAuley DF, Shields MO, et al. Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebocontrolled trial. Ann Surg. 2014;259:26– 31. 2. Gallucci RM, Simeonova PP, Matheson JM, et al. Impaired cutaneous wound healing in interleukin6-deficient and immunosuppressed mice. FASEB J. 2000;14:2525–2531. 3. O’Kane CM, McKeown SW, Perkins GD, et al. Salbutamol up-regulates matrix metalloproteinase-9 in the alveolar space in the acute respiratory distress syndrome. Crit Care Med. 2009;37:2242–2249. 4. Aszodi A, Ponsky JL. Effects of corticosteroid on the healing bowel anastomosis. Am Surg. 1984;50:546–548. 5. Wang AS, Armstrong EJ, Armstrong AW. Corticosteroids and wound healing: clinical considerations in the perioperative period. Am J Surg. 2013; 206:410–417. 6. Shyamsundar M, McKeown ST, O’Kane CM, et al. Simvastatin decreases lipopolysaccharide-induced
ß
pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med. 2009;179:1107–1114. 7. Chopra V, Wesorick DH, Sussman JB, et al. Effect of perioperative statins on death, myocardial infarction, atrial fibrillation, and length of stay: a systematic review and meta-analysis. Arch Surg. 2012;147:181–189. 8. Guay J, Ochroch EA. Effects of adding statins before surgery on mortality and major morbidity: a meta-analysis. J Cardiothorac Vasc Anesth. 2014; 28:255–266. 9. Evangelista MT, Casintahan MF, Villafuerte LL. Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebocontrolled trial. Br J Dermatol. 2014;170:1151– 1157. 10. Medina RJ, O’Neill CL, Devine AB, et al. The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies. PLoS One. 2008;3: e2584. 11. Uzbeck M, Quinn C, Saleem I, et al. Randomised controlled trial of the effect of standard and detailed risk disclosure prior to bronchoscopy on peri-procedure anxiety and satisfaction. Thorax. 2009;64:224– 227.
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
T
Disclosure: The authors declare no conflicts of interest. Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0003-4932/14/26105-0821 DOI: 10.1097/SLA.0000000000000669
THE
EDITOR
anastomoses and impaired healing of abdominal wounds. The study by Shyamsundar et al does state that no unexpected adverse effects occurred in either group; however, there is no report of postoperative outcomes; specifically, it would be interesting to report anastomotic leak. We are not invalidating or criticizing the research; this is a fascinating study, with findings to support further potential uses of statins beyond their current applications. The authors have also chosen a condition with significant associated morbidity and mortality, for which they should be commended. It would, however, also be noteworthy to find out whether the authors consented patients for increased risk of problems related to impaired tissue healing including anastomotic leak and impaired wound healing. It would also be interesting to establish whether future studies will investigate a dose-dependent relationship between systemic statin dose and inflammation, which we believe is required in such studies to ensure that balance of inflammation remains suitably efficacious to support tissue regeneration.
Christopher L. F. Battersby, MBChB, BSc The UK Centre for Tissue Engineering The Institute of Ageing and Chronic Disease University of Liverpool Liverpool, UK Royal Liverpool and Broadgreen University Hospitals Trust Liverpool, UK Nicholas Bryan, PhD, BSc John A. Hunt, PhD, DSc, BSc The UK Centre for Tissue Engineering The Institute of Ageing and Chronic Disease University of Liverpool Liverpool, UK [email protected]
REFERENCES 1. Shyamsundar M, McAuley DF, Shields MO, et al. Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebo-controlled trial. Ann Surg. 2014;259:26–31. 2. Werner N, Nickenig G, Laufs U. Pleiotropic effects of HMG-CoA reductase inhibitors. Basic Res Cardiol. 2002;97:105–116. 3. Davignon J, Leiter LA. Ongoing clinical trials of the pleiotropic effects of statins. Vascul Health Risk Manage. 2005;1:29–40. 4. Duaby DA, Franz MG. Acute wound healing: the biology of acute wound failure. Surg Clin N Am. 2003;83:463–481. 5. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev. 2003;83:835–870.
Annals of Surgery Volume 262, Number 6, December 2015
Reply: e read with interest the comment by Battersby et al regarding our study looking at the anti-inflammatory and cellular effects of simvastatin in patients undergoing esophagectomy.1 They expressed their valid concern about the impact of the anti-inflammatory effect of simvastatin on wound healing. Inflammation is an essential and complex process involving the interaction of various cells and mediators and is integral to wound healing and host defense. Mediators of inflammation such as interleukin-62 and proteases such as matrix metalloproteinase-9 (MMP-9)3 have been shown to be involved in this healing process. Excessive suppression of inflammation can be deleterious to wound healing4 but this has not been conclusively proven in human studies.5 This obviously leads to concerns about using an anti-inflammatory therapy in surgical patients, which depends on wound healing. Although inflammation per se is essential, it is unmitigated inflammation, which is injurious and indeed can result in clinical conditions such as acute lung injury (ALI). Statins have anti-inflammatory properties but the attraction of statins is likely to be that they do not ablate the inflammatory response but restrain it. This is well demonstrated in our study of simvastatin in reducing the inflammatory response to inhaled lipopolysaccharide6 in healthy human volunteers at a dose of 80 mg. The inflammatory cascade is appropriately activated but to a lesser degree and it is therefore tempting to postulate that statins might redress the inflammatory–anti-inflammatory balance. Statins have been shown to reduce postoperative morbidity such as postoperative myocardial infarction and atrial fibrillation.7 A meta-analysis, which studied the effect of adding a statin before surgery, did not show an increased reoperation rate,8 which is reassuring as it is plausible to suggest that a significant impairment of wound repair would be reflected in a higher reoperation rate. There is also evidence of the beneficial effect of statins in wound healing in patients with venous ulceration with a higher proportion of healing and at a faster rate9 and more specifically in relation to our study,1 there was one instance of anastomotic leak in the placebo group whereas none in the simvastatin group. Indeed the incidence of ALI, cardiac, respiratory, and other complications in the placebo group were higher, but this study was not powered for clinical outcomes. Statin use is ubiquitous and has been shown to have a significantly favorable
W
Disclosure: The authors declare no conflicts of interest. DOI: 10.1097/SLA.0000000000000670
www.annalsofsurgery.com | e95
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Annals of Surgery Volume 262, Number 6, December 2015
Letter to the Editor
effect on perioperative morbidity with no obvious evidence to date to suggest that they impair wound repair, whereas it should be acknowledged that there might be a dosedependent difference in effects.10 In the absence of any clear signal toward any adverse impact on wound healing with a strong evidence of a protective effect, consenting for a theoretical risk will cause anxiety11 for the patients and may impede medical advance.
Murali Shyamsundar, PhD Daniel F. McAuley, MD Cecilia M. O’Kane, PhD Centre for Infection and Immunity School of Medicine Dentistry and Biomedical Sciences Queen’s University of Belfast Belfast, UK [email protected]
e96 | www.annalsofsurgery.com
REFERENCES 1. Shyamsundar M, McAuley DF, Shields MO, et al. Effect of simvastatin on physiological and biological outcomes in patients undergoing esophagectomy: a randomized placebocontrolled trial. Ann Surg. 2014;259:26– 31. 2. Gallucci RM, Simeonova PP, Matheson JM, et al. Impaired cutaneous wound healing in interleukin6-deficient and immunosuppressed mice. FASEB J. 2000;14:2525–2531. 3. O’Kane CM, McKeown SW, Perkins GD, et al. Salbutamol up-regulates matrix metalloproteinase-9 in the alveolar space in the acute respiratory distress syndrome. Crit Care Med. 2009;37:2242–2249. 4. Aszodi A, Ponsky JL. Effects of corticosteroid on the healing bowel anastomosis. Am Surg. 1984;50:546–548. 5. Wang AS, Armstrong EJ, Armstrong AW. Corticosteroids and wound healing: clinical considerations in the perioperative period. Am J Surg. 2013; 206:410–417. 6. Shyamsundar M, McKeown ST, O’Kane CM, et al. Simvastatin decreases lipopolysaccharide-induced
ß
pulmonary inflammation in healthy volunteers. Am J Respir Crit Care Med. 2009;179:1107–1114. 7. Chopra V, Wesorick DH, Sussman JB, et al. Effect of perioperative statins on death, myocardial infarction, atrial fibrillation, and length of stay: a systematic review and meta-analysis. Arch Surg. 2012;147:181–189. 8. Guay J, Ochroch EA. Effects of adding statins before surgery on mortality and major morbidity: a meta-analysis. J Cardiothorac Vasc Anesth. 2014; 28:255–266. 9. Evangelista MT, Casintahan MF, Villafuerte LL. Simvastatin as a novel therapeutic agent for venous ulcers: a randomized, double-blind, placebocontrolled trial. Br J Dermatol. 2014;170:1151– 1157. 10. Medina RJ, O’Neill CL, Devine AB, et al. The pleiotropic effects of simvastatin on retinal microvascular endothelium has important implications for ischaemic retinopathies. PLoS One. 2008;3: e2584. 11. Uzbeck M, Quinn C, Saleem I, et al. Randomised controlled trial of the effect of standard and detailed risk disclosure prior to bronchoscopy on peri-procedure anxiety and satisfaction. Thorax. 2009;64:224– 227.
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
