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Systemic response to surgery
BASIC SKILLS
Conference3 (Box 1). SIRS is diagnosed if two or more of the criteria in Box 1 are met. This article discusses the elements of the surgical stress response and the different ways of modulating these elements to ensure optimal outcomes for the surgical patient.
Systemic response to surgery Jessica de Bois Dominic Moor
The endocrine pathway
Geeta Aggarwal
In response to direct tissue injury, there is a surge in afferent stimuli via the somatic and autonomic pathways from the affected area. These stimuli activate both the sympathetic nervous system and the hypothalamus, leading to a variety of hormones being released from the pituitary. High volumes of stress hormones are released during this response, principally adrenaline and cortisol, but levels of other hormones such as glucagon, growth hormone, antidiuretic hormone (ADH) and aldosterone are also increased.
Abstract The direct traumatic injury of surgery initiates a chain of physiological events via the endocrine, metabolic, cardiovascular and immune systems. The unregulated stress response can lead to systemic inflammatory response syndrome (SIRS), but if the response was totally obliterated then this would predispose to infection and failure of the recovery process. To an extent this response is protective. This article outlines the components of the interlinked endocrine, metabolic, immune and haemodynamic responses and discusses the ways in which the various components of the response can be modified in order to optimize postoperative recovery and to reduce complications. The role of vitamin supplementation and the controversial element of glucocorticoids is also discussed.
The sympatho-adrenal response Increased catecholamine release: activation of the sympathetic autonomic nervous system leads to release norepinephrine and epinephrine from the adrenal medulla and local release of norepinephrine from the presynaptic nerve terminals, causing hypertension and tachycardia.
Keywords SIRS; stress response; systemic response The sympatho-renal response Activation of the renin-angiotensin-aldosterone axis: this is a key component of the surgical stress response in terms of sodium retention. Renin is released from the kidneys in response to sympathetic activation, initiating the conversion of angiotensin I to angiotensin II, which in turn stimulates aldosterone release from the adrenal cortex. This results in an increase in sodium reabsorption in the distal convoluted tubules and an increase in vascular tone.
Introduction The systemic response to surgery refers to a series of interlinked physiological changes that occur in response to a surgical insult. These are a mixture of immune, endocrine, metabolic and haemodynamic responses and many of these overlap. Cuthbertson classically identified the response as a distinctly biphasic ‘ebb’ and ‘flow’ process.1 A period of reduced metabolic activity lasting for 2e3 days (ebb phase) may be seen initially, followed by a more prolonged catabolic and hyper-metabolic phase (flow phase) lasting over a week depending on the recovery process. Current evidence suggests that the two phases defined by Cuthbertson are, in reality, less clearly defined and the traditional model does not take into account the prevalence of reconditioning in frail, elderly patients presenting for surgery.2 Similar physiological changes may also occur as a result of other injuries, for example, non-penetrating trauma, burns or infection. Whether the response is to surgery or any other insult, the term systemic inflammatory response syndrome (SIRS) may be used. SIRS was first defined in 1992 at the American College of Chest Physicians/Society of Critical Care Medicine Consensus
The hypothalamicepituitaryeadrenal axis Increased adrenocorticotropic hormone (ACTH) and cortisol: ACTH is the principal hormone released by the anterior pituitary in response to surgical stress. ACTH stimulates secretion of glucocorticoid from the adrenal cortex. In turn, the adrenal cortex exhibits an exaggerated response to ACTH and there is a supra-normal release of cortisol. In addition to the initially raised cortisol levels, significant blunting of the normal negative feedback mechanisms leading to continuing raised cortisol production also occurs. This has significant implications on the metabolism of carbohydrate, fat and protein; an overall effect to increase blood glucose levels as well as a potent anti- inflammatory effect. Increased growth hormone (GH) GH is released from the anterior pituitary in proportion to the degree of tissue injury. The principal effect of this is to increase glycogenolysis within the liver, increasing blood glucose. There is also a marked increase in insulin resistance.
Jessica de Bois MBBS BSc is a Registrar in Anaesthesia at the Royal Surrey County Hospital, Guildford, UK. Conflicts of interest: none declared. Dominic Moor MBBS BSc FRCA FFICM is a Consultant in Anaesthesia at Basingstoke and North Hampshire Hospital, Basingstoke, UK. Conflicts of interest: none declared.
Increased ADH release ADH is released from the posterior pituitary gland and stimulates the insertion of aquaporins into the walls of the renal collecting ducts. This permits the reabsorption of free water down its
Geeta Aggarwal MBBS MRCP FRCA is a Consultant Anaesthetist at the Royal Surrey County Hospital, Guildford, UK. Conflict of interest: none declared.
SURGERY xxx:xxx
1
Ó 2020 Published by Elsevier Ltd.
Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004
BASIC SKILLS
insulin resistance which further compounds the hyperglycaemic effect. This not only affects wound healing but also has an impact on fluid homoeostasis and recovery.
Systemic inflammatory response syndrome (SIRS)
SIRS is confirmed by the presence of two or more of the following features: C C C C
Salt and water retention Fluid retention, reduced urine output and accumulation of extracellular fluid are commonly seen after surgery. This is due to the up-regulation of the renin-angiotensin-aldosterone axis in combination with the increased release of ADH.
Heart rate: >90 beats per min Body temperature: <36oC or >38oC Respiratory rate: >20 breaths per min White cell count <4 109 cells/litre or >12 109 cells/litre
The immune response The immune response is complex and multifactorial but involves the release of a series of both pro-inflammatory and antiinflammatory cytokines. In addition, a cell-mediated response occurs. The severity of the immune response is proportional to the extent of trauma but also depends on other factors such as nutritional status, co-existing infection or the background disease requiring surgery (e.g. cancer).
Box 1
concentration gradient back into the renal medulla and reducing urine output. Insulin and glucagon Reduced insulin secretion and insulin resistance: Insulin is the key anabolic hormone. Protein catabolism and lipolysis are inhibited by insulin. The sympathetic nervous system exerts an effect on the pancreas via a2-adrenergic receptors which cause an early reduction in insulin secretion. At a later stage there is a delayed reduction in sensitivity of target cells to insulin, further reducing its effectiveness and leading to relatively unopposed catabolism.
Cell-mediated response Trauma activates both the innate and adaptive immune systems. Initially, the surgical insult leads a cascade of responses including activation of the complement system and recruitment of granulocytes to the site of injury. Later on, natural killer (NK) cells, neutrophils and monocytes all undergo a degree of suppression. In addition, there is a relative increase in T-helper 2 lymphocytes (Th2) which are considered to be anti-inflammatory compared to T-helper 1 (Th1) cells that are essentially proinflammatory. Th1 cells fight intracellular pathogens and target cancer cells in the circulation, whereas Th2 cells are primarily involved in targeting extracellular pathogens.5 In addition to surgical trauma, malnutrition also increases the expression of Th2 cells. This, coupled with the activation of the hypothalamic epituitary axis, increases the expression of Th2 cells. Th2 cells result in an increase of myeloid-derived suppressor cells, which impair lymphocyte function by decreasing arginine production.
Increased glucagon release: Sympathetic activation of the pancreas results in increased glucagon levels. Although glucagon does stimulate lipolysis, gluconeogenesis, and hepatic glycogenolysis it has not been found to be a major player in the development of postoperative hyperglycaemia.4 Other hormonal responses Although most exert a negligible effect on the overall function in the context of the stress response there are elevated levels of prolactin and reduced levels of testosterone, thyroxine (T4), and tri-iodothyronine (T3) returning to normal after several days.
Pro-inflammatory response This inflammatory response is designed to target pathogens, reduce tissue damage and start the healing process. There is a massive production of pro-inflammatory cytokines including interleukin (IL)-1, IL-6 and tumour necrosis factor-a (TNF-a). If postoperative complications occur or there is prolonged infection, the pro-inflammatory response can lead to multiple organ failure (MOF) in some patients.5 Further acute phase proteins such as procalcitonin (PCT) and C-reactive protein (CRP) are also released.5
The metabolic effects (Figure 1) The net result of the endocrine responses that have been discussed can be viewed of in terms of several metabolic entities, as follows. Catabolism and substrate mobilization In the immediate postoperative period, an initial period of low metabolic activity may be seen. However, following this, the overwhelming response to major surgery is the development of a hypermetabolic and catabolic state. Mobilization and production of glucose substrate occurs from glycogen stores in the liver and from proteolysis and lipolysis of skeletal muscle and fat reserves, respectively.
The anti-inflammatory response After surgery there are also increased numbers of the antiinflammatory agents such as IL-4, IL-10 and transforming growth factor-b (TGF-b). These can reduce the severity and duration of SIRS but if this element is unregulated, it can predispose to immunodeficiency and sepsis.5
Hyperglycaemia and insulin resistance In response to the supra-normal levels of cortisol, glucagon and GH, there is increased catabolism to provide substrate for cortisol-regulated gluconeogenesis in the liver. The glycogenolysis leads to elevated blood glucose levels. GH also induces an
SURGERY xxx:xxx
The haemodynamic response The sympatho-adrenal response leads to increases release of catecholamines and resulting hypertension and tachycardia, and
2
Ó 2020 Published by Elsevier Ltd.
Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004
BASIC SKILLS
catabolic state.7 In addition, with a reduced stress response comes a faster recovery time and improves both morbidity and short and long term mortality.8 The principal components of the ERAS pathway with the mechanism in which they exert their effects are listed below. Preoperative Pre-hydration and reduced fasting: Reduced fasting times and carbohydrate loading preoperatively both reduces the amount of fluid (and associated sodium) given intraoperatively and reduces postoperative insulin resistance with associated catabolism. Prehabilitation: Optimization of pre-existing comorbidities will help minimize the effect of the surgical stress response. There is an increasing amount of research into this area. A comprehensive preoperative prehabilitation programme, which includes medicines optimization, nutritional support, psychological support and physiotherapy, has shown a reduction in length of stay and postoperative complications.9e11 Intraoperative Reduction in duration and magnitude of surgery: The amount of tissue manipulation and damage as well as the duration of surgery are proportional to the resulting stress response. It follows that minimally invasive surgery, including robotic surgery, and a short operating time both independently have an impact.8 Appropriate use of regional anaesthesia and analgesia: These techniques can dramatically reduce the autonomic and somatic stimulation that the brain receives from the site of tissue injury, and thereby reduce the degree of the response. In addition, the use of systemic opiates reduces the secretion of ACTH and GH, reducing the glycaemic response to surgery; however, systemic opiates have also been shown to influence rates of tumour recurrence in cancer patients.12
Figure 1
salt and water retention contributes to an increase in intravascular volume initially. The glycocalyx is a glycoprotein and proteoglycans layer between the blood and endothelium. In health this has a critical role in the regulation of both vascular tone and vascular permeability and is likely to have a significant effect on the way in which the body handles intravascular fluid. This structure is very fragile and may be damaged by excessive administration of perioperative fluids. In fluid overload TNF-a and atrial natriuretic peptide (ANP) are released in response to atrial stretch, and secondary mast cell-mediated cytokines trigger glycocalyx breakdown. This results in capillary leak and wind-up of the inflammatory process at a microvascular level as well as loss of vascular tone and goes some way to explaining hypotension seen in SIRS.6
Haemodynamic optimization: Monitoring the amount of fluid delivered perioperatively in order to maintain a euvolaemic state has been shown to play an important role. The measurement of euvolaemia is still the subject of great debate but it has been shown to reduce complications.13 Avoiding blood transfusion: While perioperative blood transfusions can be life-saving, they can cause significant alterations to the anti-inflammatory/pro-inflammatory balance in the patient. Blood transfusion can cause transfusion-related immune modulation (TRIM) where there is depression of the immune system; in particular, inhibition of IL-2 production and a suppression of cytotoxic cell activity14 Postoperative Early mobilization: Apart from the wider benefits of early mobilization, there is evidence to suggest that this reduces insulin resistance and subsequent hyperglycaemia.
Management An unregulated surgical stress response, at its worst, can lead to SIRS and MOF in the form of acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and cognitive dysfunction, amongst others. There is evidence that enhanced recovery after surgery (ERAS) programmes reduce the component parts of the surgical stress response; principally insulin resistance and the resulting
SURGERY xxx:xxx
Blood glucose control: Strict attention needs to be paid to management of blood glucose levels and, where necessary, supplementary insulin may play a role in minimizing the stress response.
3
Ó 2020 Published by Elsevier Ltd.
Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004
BASIC SKILLS
multi-system phenomenon involving complex interplay between the endocrine, immune and metabolic systems. This combined effect has potential to develop into multi-organ failure as a result of unregulated inflammation and capillary leakage and shock. ERAS pathways have been shown to reduce the systemic response to surgery and reduce specific aspects of the endocrine and immunological response to surgery leading to reduced length of stay and better patient outcomes. A
Nutrition: Minimizing preoperative nutritional deficit and encouraging patients to recommence balanced nutritional intake as soon as is practical helps to match the metabolic demands from the body. Modulation of enteral feed by adding arginine and omega-3 fatty acids can blunt the immune-mediated changes seen after surgery.15 Glucocorticoids: The ADRENAL trial showed that the administration of up to 200 mg of hydrocortisone per day to septic shock patients offered some cardiopuImonary benefit.2 Whether this work is transferable to the perioperative patient remains unclear. What is known is that timing, clinical context and individualizing treatments is key, and further research is required to give such high doses of steroids in perioperative patients.
REFERENCES 1 Cuthbertson DP. Post-shock metabolic response. Lancet 1942; 239: 433e7. 2 Manou-Stathopoulou V, Korbononits M, Auckland G. Redefining the perioperative stress response: a narrative review. Br J Anaesth 2019; 123: 570e83. 3 Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus conference committee. American College of chest physicians/Society of critical Care medicine. Chest 1992; 101: 1644e55. 4 Desborough JP, Hall GM. Endocrine response to surgery. Anaesth Rev 1993; 10: 131e48. 5 Dabrowska AM, Slotwinski R. The immune response to surgery and infection. Cent Eur J Immunol 2014; 39: 532e7. 6 Alphonsus CS, Rodseth RN. The endothelial glycocalyx: a review of the vascular barrier. Anaesthesia 2014; 69: 777e84. 7 Carli F. Physiologic considerations of Enhanced Recovery after Surgery (ERAS) programs: implications of the stress response. Can J Anaesth 2015; 62: 110e9. 8 Scott MJ, Miller TE. Pathophysiology of major surgery and the role of enhanced recovery pathways and the anaesthesiologist to improve outcomes. Anaesthesiol Clin 2015; 33: 79e91. 9 Santa Mina D, Clarke H, Ritvo P, et al. Effect of total body prehabilitation on postoperative outcomes: a systematic review and meta-analysis. Physiotherapy 2014; 100: 196e207. 10 Banugo P, Amouko D. Prehabilitation. Br J Anaesth Educ 2017; 17: 401e5. 11 Boden I, Skinner EH, Browning L, et al. Preoperative physiotherapy for the prevention of respiratory complications after upper abdominal surgery: pragmatic, double blinded, multicentre randomised controlled trial. BMJ 2018; 360: j5916. 12 Kaye AD, Patel N, Bueno FR, et al. Effect of opiates, anaesthetic techniques, and other perioperative factors on surgical cancer patients. Ochsner J 2014; 14: 216e28. 13 Grocott MPW, Dushianthan A, Hamilton MA, et al. Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery: a Cochrane Systematic Review. Br J Anaesth 2013; 111: 535e48. 14 Kirkley S. Proposed mechanisms of transfusion-induced immunomodulation. Clin Diagn Lab Immunol 1999; 6: 652e7. 15 Marik PE, Flemmer M. Immunonutrition in the surgical patient. Minerva Anestesiol 2012; 78: 336e42. 16 Roxburgh CS, McMillan DC. Cancer and systemic inflammation: treat the tumour and treat the host. Br J Canc 2014; 110: 1409e12.
Modulation in specific circumstances Cancer surgery Modulating the surgical stress response in cancer surgery has a major role in morbidity and mortality. Progressive loss of weight and other cancer-associated symptoms may be manifestations of a chronic systemic inflammatory response. Measurements of a raised inflammatory response have been found to be associated with a poorer outcome independent of the stage of the tumour. In particular, the, acute phase proteins such as CRP and albumin have a prognostic value.16 The use of anti-inflammatory agents such as corticosteroids, non-steroidal anti-inflammatory drugs and statins may have a use in modifying this chronic insult to improve outcomes.16 Allogenic blood transfusion has been shown to promote tumour recurrence in most surgical procedures but especially in colorectal surgery.17 Cardiac surgery During cardiac surgery involving cardiopulmonary bypass (CPB), it is common for a surgical stress response to occur in patients as a result of surgical trauma, ischaemic/reperfusion injury and activation of blood components from the CPB circuit. This can have a range of effects, from a mild response, development of ARDS and even death. Efforts to modulate the immune stress response include the use of leucocyte-depleting filters, the use of off-pump techniques, and the use of nitric oxide or corticosteroids. No single intervention demonstrated a difference but multiple approaches may be better.18 In addition, the postoperative cognitive dysfunction (POCD) seen after cardiac surgery has also been shown to be as a result of the surgical inflammatory response as well as the cardio- pulmonary bypass circuit. The blooddbrain barrier changes, allowing exposure of the neurons to inflammatory cells. Systemic inflammation and possible regional hypoperfusion all increase the risk of POCD.19
Summary The concept of the surgical stress response and our understanding of it continues to evolve but it remains a very complex
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4
Ó 2020 Published by Elsevier Ltd.
Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004
BASIC SKILLS
review of the evidence base. J Extra Corpor Technol 2014; 46: 197e211. 19 Martucci G, Lo Re V, Arcadipane A. Neurological injuries and extracorporeal membrane oxygenation: the challenge of the new ECMO era. J Extra Corpor Technol 2014; 46: 15e22.
17 Cata JP, Wang H, Gottumukkala V, et al. Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions. Br J Anaesth 2013; 110: 690e701. 18 Landis RC, Brown JR, Fitzgerald D, et al. Attenuating the systemic inflammatory response to adult cardiopulmonary bypass: a critical
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5
Ó 2020 Published by Elsevier Ltd.
Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004
Conference3 (Box 1). SIRS is diagnosed if two or more of the criteria in Box 1 are met. This article discusses the elements of the surgical stress response and the different ways of modulating these elements to ensure optimal outcomes for the surgical patient.
Systemic response to surgery Jessica de Bois Dominic Moor
The endocrine pathway
Geeta Aggarwal
In response to direct tissue injury, there is a surge in afferent stimuli via the somatic and autonomic pathways from the affected area. These stimuli activate both the sympathetic nervous system and the hypothalamus, leading to a variety of hormones being released from the pituitary. High volumes of stress hormones are released during this response, principally adrenaline and cortisol, but levels of other hormones such as glucagon, growth hormone, antidiuretic hormone (ADH) and aldosterone are also increased.
Abstract The direct traumatic injury of surgery initiates a chain of physiological events via the endocrine, metabolic, cardiovascular and immune systems. The unregulated stress response can lead to systemic inflammatory response syndrome (SIRS), but if the response was totally obliterated then this would predispose to infection and failure of the recovery process. To an extent this response is protective. This article outlines the components of the interlinked endocrine, metabolic, immune and haemodynamic responses and discusses the ways in which the various components of the response can be modified in order to optimize postoperative recovery and to reduce complications. The role of vitamin supplementation and the controversial element of glucocorticoids is also discussed.
The sympatho-adrenal response Increased catecholamine release: activation of the sympathetic autonomic nervous system leads to release norepinephrine and epinephrine from the adrenal medulla and local release of norepinephrine from the presynaptic nerve terminals, causing hypertension and tachycardia.
Keywords SIRS; stress response; systemic response The sympatho-renal response Activation of the renin-angiotensin-aldosterone axis: this is a key component of the surgical stress response in terms of sodium retention. Renin is released from the kidneys in response to sympathetic activation, initiating the conversion of angiotensin I to angiotensin II, which in turn stimulates aldosterone release from the adrenal cortex. This results in an increase in sodium reabsorption in the distal convoluted tubules and an increase in vascular tone.
Introduction The systemic response to surgery refers to a series of interlinked physiological changes that occur in response to a surgical insult. These are a mixture of immune, endocrine, metabolic and haemodynamic responses and many of these overlap. Cuthbertson classically identified the response as a distinctly biphasic ‘ebb’ and ‘flow’ process.1 A period of reduced metabolic activity lasting for 2e3 days (ebb phase) may be seen initially, followed by a more prolonged catabolic and hyper-metabolic phase (flow phase) lasting over a week depending on the recovery process. Current evidence suggests that the two phases defined by Cuthbertson are, in reality, less clearly defined and the traditional model does not take into account the prevalence of reconditioning in frail, elderly patients presenting for surgery.2 Similar physiological changes may also occur as a result of other injuries, for example, non-penetrating trauma, burns or infection. Whether the response is to surgery or any other insult, the term systemic inflammatory response syndrome (SIRS) may be used. SIRS was first defined in 1992 at the American College of Chest Physicians/Society of Critical Care Medicine Consensus
The hypothalamicepituitaryeadrenal axis Increased adrenocorticotropic hormone (ACTH) and cortisol: ACTH is the principal hormone released by the anterior pituitary in response to surgical stress. ACTH stimulates secretion of glucocorticoid from the adrenal cortex. In turn, the adrenal cortex exhibits an exaggerated response to ACTH and there is a supra-normal release of cortisol. In addition to the initially raised cortisol levels, significant blunting of the normal negative feedback mechanisms leading to continuing raised cortisol production also occurs. This has significant implications on the metabolism of carbohydrate, fat and protein; an overall effect to increase blood glucose levels as well as a potent anti- inflammatory effect. Increased growth hormone (GH) GH is released from the anterior pituitary in proportion to the degree of tissue injury. The principal effect of this is to increase glycogenolysis within the liver, increasing blood glucose. There is also a marked increase in insulin resistance.
Jessica de Bois MBBS BSc is a Registrar in Anaesthesia at the Royal Surrey County Hospital, Guildford, UK. Conflicts of interest: none declared. Dominic Moor MBBS BSc FRCA FFICM is a Consultant in Anaesthesia at Basingstoke and North Hampshire Hospital, Basingstoke, UK. Conflicts of interest: none declared.
Increased ADH release ADH is released from the posterior pituitary gland and stimulates the insertion of aquaporins into the walls of the renal collecting ducts. This permits the reabsorption of free water down its
Geeta Aggarwal MBBS MRCP FRCA is a Consultant Anaesthetist at the Royal Surrey County Hospital, Guildford, UK. Conflict of interest: none declared.
SURGERY xxx:xxx
1
Ó 2020 Published by Elsevier Ltd.
Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004
BASIC SKILLS
insulin resistance which further compounds the hyperglycaemic effect. This not only affects wound healing but also has an impact on fluid homoeostasis and recovery.
Systemic inflammatory response syndrome (SIRS)
SIRS is confirmed by the presence of two or more of the following features: C C C C
Salt and water retention Fluid retention, reduced urine output and accumulation of extracellular fluid are commonly seen after surgery. This is due to the up-regulation of the renin-angiotensin-aldosterone axis in combination with the increased release of ADH.
Heart rate: >90 beats per min Body temperature: <36oC or >38oC Respiratory rate: >20 breaths per min White cell count <4 109 cells/litre or >12 109 cells/litre
The immune response The immune response is complex and multifactorial but involves the release of a series of both pro-inflammatory and antiinflammatory cytokines. In addition, a cell-mediated response occurs. The severity of the immune response is proportional to the extent of trauma but also depends on other factors such as nutritional status, co-existing infection or the background disease requiring surgery (e.g. cancer).
Box 1
concentration gradient back into the renal medulla and reducing urine output. Insulin and glucagon Reduced insulin secretion and insulin resistance: Insulin is the key anabolic hormone. Protein catabolism and lipolysis are inhibited by insulin. The sympathetic nervous system exerts an effect on the pancreas via a2-adrenergic receptors which cause an early reduction in insulin secretion. At a later stage there is a delayed reduction in sensitivity of target cells to insulin, further reducing its effectiveness and leading to relatively unopposed catabolism.
Cell-mediated response Trauma activates both the innate and adaptive immune systems. Initially, the surgical insult leads a cascade of responses including activation of the complement system and recruitment of granulocytes to the site of injury. Later on, natural killer (NK) cells, neutrophils and monocytes all undergo a degree of suppression. In addition, there is a relative increase in T-helper 2 lymphocytes (Th2) which are considered to be anti-inflammatory compared to T-helper 1 (Th1) cells that are essentially proinflammatory. Th1 cells fight intracellular pathogens and target cancer cells in the circulation, whereas Th2 cells are primarily involved in targeting extracellular pathogens.5 In addition to surgical trauma, malnutrition also increases the expression of Th2 cells. This, coupled with the activation of the hypothalamic epituitary axis, increases the expression of Th2 cells. Th2 cells result in an increase of myeloid-derived suppressor cells, which impair lymphocyte function by decreasing arginine production.
Increased glucagon release: Sympathetic activation of the pancreas results in increased glucagon levels. Although glucagon does stimulate lipolysis, gluconeogenesis, and hepatic glycogenolysis it has not been found to be a major player in the development of postoperative hyperglycaemia.4 Other hormonal responses Although most exert a negligible effect on the overall function in the context of the stress response there are elevated levels of prolactin and reduced levels of testosterone, thyroxine (T4), and tri-iodothyronine (T3) returning to normal after several days.
Pro-inflammatory response This inflammatory response is designed to target pathogens, reduce tissue damage and start the healing process. There is a massive production of pro-inflammatory cytokines including interleukin (IL)-1, IL-6 and tumour necrosis factor-a (TNF-a). If postoperative complications occur or there is prolonged infection, the pro-inflammatory response can lead to multiple organ failure (MOF) in some patients.5 Further acute phase proteins such as procalcitonin (PCT) and C-reactive protein (CRP) are also released.5
The metabolic effects (Figure 1) The net result of the endocrine responses that have been discussed can be viewed of in terms of several metabolic entities, as follows. Catabolism and substrate mobilization In the immediate postoperative period, an initial period of low metabolic activity may be seen. However, following this, the overwhelming response to major surgery is the development of a hypermetabolic and catabolic state. Mobilization and production of glucose substrate occurs from glycogen stores in the liver and from proteolysis and lipolysis of skeletal muscle and fat reserves, respectively.
The anti-inflammatory response After surgery there are also increased numbers of the antiinflammatory agents such as IL-4, IL-10 and transforming growth factor-b (TGF-b). These can reduce the severity and duration of SIRS but if this element is unregulated, it can predispose to immunodeficiency and sepsis.5
Hyperglycaemia and insulin resistance In response to the supra-normal levels of cortisol, glucagon and GH, there is increased catabolism to provide substrate for cortisol-regulated gluconeogenesis in the liver. The glycogenolysis leads to elevated blood glucose levels. GH also induces an
SURGERY xxx:xxx
The haemodynamic response The sympatho-adrenal response leads to increases release of catecholamines and resulting hypertension and tachycardia, and
2
Ó 2020 Published by Elsevier Ltd.
Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004
BASIC SKILLS
catabolic state.7 In addition, with a reduced stress response comes a faster recovery time and improves both morbidity and short and long term mortality.8 The principal components of the ERAS pathway with the mechanism in which they exert their effects are listed below. Preoperative Pre-hydration and reduced fasting: Reduced fasting times and carbohydrate loading preoperatively both reduces the amount of fluid (and associated sodium) given intraoperatively and reduces postoperative insulin resistance with associated catabolism. Prehabilitation: Optimization of pre-existing comorbidities will help minimize the effect of the surgical stress response. There is an increasing amount of research into this area. A comprehensive preoperative prehabilitation programme, which includes medicines optimization, nutritional support, psychological support and physiotherapy, has shown a reduction in length of stay and postoperative complications.9e11 Intraoperative Reduction in duration and magnitude of surgery: The amount of tissue manipulation and damage as well as the duration of surgery are proportional to the resulting stress response. It follows that minimally invasive surgery, including robotic surgery, and a short operating time both independently have an impact.8 Appropriate use of regional anaesthesia and analgesia: These techniques can dramatically reduce the autonomic and somatic stimulation that the brain receives from the site of tissue injury, and thereby reduce the degree of the response. In addition, the use of systemic opiates reduces the secretion of ACTH and GH, reducing the glycaemic response to surgery; however, systemic opiates have also been shown to influence rates of tumour recurrence in cancer patients.12
Figure 1
salt and water retention contributes to an increase in intravascular volume initially. The glycocalyx is a glycoprotein and proteoglycans layer between the blood and endothelium. In health this has a critical role in the regulation of both vascular tone and vascular permeability and is likely to have a significant effect on the way in which the body handles intravascular fluid. This structure is very fragile and may be damaged by excessive administration of perioperative fluids. In fluid overload TNF-a and atrial natriuretic peptide (ANP) are released in response to atrial stretch, and secondary mast cell-mediated cytokines trigger glycocalyx breakdown. This results in capillary leak and wind-up of the inflammatory process at a microvascular level as well as loss of vascular tone and goes some way to explaining hypotension seen in SIRS.6
Haemodynamic optimization: Monitoring the amount of fluid delivered perioperatively in order to maintain a euvolaemic state has been shown to play an important role. The measurement of euvolaemia is still the subject of great debate but it has been shown to reduce complications.13 Avoiding blood transfusion: While perioperative blood transfusions can be life-saving, they can cause significant alterations to the anti-inflammatory/pro-inflammatory balance in the patient. Blood transfusion can cause transfusion-related immune modulation (TRIM) where there is depression of the immune system; in particular, inhibition of IL-2 production and a suppression of cytotoxic cell activity14 Postoperative Early mobilization: Apart from the wider benefits of early mobilization, there is evidence to suggest that this reduces insulin resistance and subsequent hyperglycaemia.
Management An unregulated surgical stress response, at its worst, can lead to SIRS and MOF in the form of acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and cognitive dysfunction, amongst others. There is evidence that enhanced recovery after surgery (ERAS) programmes reduce the component parts of the surgical stress response; principally insulin resistance and the resulting
SURGERY xxx:xxx
Blood glucose control: Strict attention needs to be paid to management of blood glucose levels and, where necessary, supplementary insulin may play a role in minimizing the stress response.
3
Ó 2020 Published by Elsevier Ltd.
Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004
BASIC SKILLS
multi-system phenomenon involving complex interplay between the endocrine, immune and metabolic systems. This combined effect has potential to develop into multi-organ failure as a result of unregulated inflammation and capillary leakage and shock. ERAS pathways have been shown to reduce the systemic response to surgery and reduce specific aspects of the endocrine and immunological response to surgery leading to reduced length of stay and better patient outcomes. A
Nutrition: Minimizing preoperative nutritional deficit and encouraging patients to recommence balanced nutritional intake as soon as is practical helps to match the metabolic demands from the body. Modulation of enteral feed by adding arginine and omega-3 fatty acids can blunt the immune-mediated changes seen after surgery.15 Glucocorticoids: The ADRENAL trial showed that the administration of up to 200 mg of hydrocortisone per day to septic shock patients offered some cardiopuImonary benefit.2 Whether this work is transferable to the perioperative patient remains unclear. What is known is that timing, clinical context and individualizing treatments is key, and further research is required to give such high doses of steroids in perioperative patients.
REFERENCES 1 Cuthbertson DP. Post-shock metabolic response. Lancet 1942; 239: 433e7. 2 Manou-Stathopoulou V, Korbononits M, Auckland G. Redefining the perioperative stress response: a narrative review. Br J Anaesth 2019; 123: 570e83. 3 Bone RC, Balk RA, Cerra FB, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus conference committee. American College of chest physicians/Society of critical Care medicine. Chest 1992; 101: 1644e55. 4 Desborough JP, Hall GM. Endocrine response to surgery. Anaesth Rev 1993; 10: 131e48. 5 Dabrowska AM, Slotwinski R. The immune response to surgery and infection. Cent Eur J Immunol 2014; 39: 532e7. 6 Alphonsus CS, Rodseth RN. The endothelial glycocalyx: a review of the vascular barrier. Anaesthesia 2014; 69: 777e84. 7 Carli F. Physiologic considerations of Enhanced Recovery after Surgery (ERAS) programs: implications of the stress response. Can J Anaesth 2015; 62: 110e9. 8 Scott MJ, Miller TE. Pathophysiology of major surgery and the role of enhanced recovery pathways and the anaesthesiologist to improve outcomes. Anaesthesiol Clin 2015; 33: 79e91. 9 Santa Mina D, Clarke H, Ritvo P, et al. Effect of total body prehabilitation on postoperative outcomes: a systematic review and meta-analysis. Physiotherapy 2014; 100: 196e207. 10 Banugo P, Amouko D. Prehabilitation. Br J Anaesth Educ 2017; 17: 401e5. 11 Boden I, Skinner EH, Browning L, et al. Preoperative physiotherapy for the prevention of respiratory complications after upper abdominal surgery: pragmatic, double blinded, multicentre randomised controlled trial. BMJ 2018; 360: j5916. 12 Kaye AD, Patel N, Bueno FR, et al. Effect of opiates, anaesthetic techniques, and other perioperative factors on surgical cancer patients. Ochsner J 2014; 14: 216e28. 13 Grocott MPW, Dushianthan A, Hamilton MA, et al. Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery: a Cochrane Systematic Review. Br J Anaesth 2013; 111: 535e48. 14 Kirkley S. Proposed mechanisms of transfusion-induced immunomodulation. Clin Diagn Lab Immunol 1999; 6: 652e7. 15 Marik PE, Flemmer M. Immunonutrition in the surgical patient. Minerva Anestesiol 2012; 78: 336e42. 16 Roxburgh CS, McMillan DC. Cancer and systemic inflammation: treat the tumour and treat the host. Br J Canc 2014; 110: 1409e12.
Modulation in specific circumstances Cancer surgery Modulating the surgical stress response in cancer surgery has a major role in morbidity and mortality. Progressive loss of weight and other cancer-associated symptoms may be manifestations of a chronic systemic inflammatory response. Measurements of a raised inflammatory response have been found to be associated with a poorer outcome independent of the stage of the tumour. In particular, the, acute phase proteins such as CRP and albumin have a prognostic value.16 The use of anti-inflammatory agents such as corticosteroids, non-steroidal anti-inflammatory drugs and statins may have a use in modifying this chronic insult to improve outcomes.16 Allogenic blood transfusion has been shown to promote tumour recurrence in most surgical procedures but especially in colorectal surgery.17 Cardiac surgery During cardiac surgery involving cardiopulmonary bypass (CPB), it is common for a surgical stress response to occur in patients as a result of surgical trauma, ischaemic/reperfusion injury and activation of blood components from the CPB circuit. This can have a range of effects, from a mild response, development of ARDS and even death. Efforts to modulate the immune stress response include the use of leucocyte-depleting filters, the use of off-pump techniques, and the use of nitric oxide or corticosteroids. No single intervention demonstrated a difference but multiple approaches may be better.18 In addition, the postoperative cognitive dysfunction (POCD) seen after cardiac surgery has also been shown to be as a result of the surgical inflammatory response as well as the cardio- pulmonary bypass circuit. The blooddbrain barrier changes, allowing exposure of the neurons to inflammatory cells. Systemic inflammation and possible regional hypoperfusion all increase the risk of POCD.19
Summary The concept of the surgical stress response and our understanding of it continues to evolve but it remains a very complex
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Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004
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review of the evidence base. J Extra Corpor Technol 2014; 46: 197e211. 19 Martucci G, Lo Re V, Arcadipane A. Neurological injuries and extracorporeal membrane oxygenation: the challenge of the new ECMO era. J Extra Corpor Technol 2014; 46: 15e22.
17 Cata JP, Wang H, Gottumukkala V, et al. Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions. Br J Anaesth 2013; 110: 690e701. 18 Landis RC, Brown JR, Fitzgerald D, et al. Attenuating the systemic inflammatory response to adult cardiopulmonary bypass: a critical
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Please cite this article as: de Bois J et al., Systemic response to surgery, Surgery, https://doi.org/10.1016/j.mpsur.2020.01.004