Addressing the Global Burden of Trauma in Major Surgery

Abstract

Despite a technically perfect procedure, surgical stress can determine the success or failure of an operation. Surgical trauma is often referred to as the "neglected step-child" of global health in terms of patient numbers, mortality, morbidity, and costs. A staggering 234 million major surgeries are performed every year, and depending upon country and institution, up to 4% of patients will die before leaving hospital, up to 15% will have serious post-operative morbidity, and 5-15% will be readmitted within 30 days. These percentages equate to around 1000 deaths and 4000 major complications every hour, and it has been estimated that 50% may be preventable. New frontline drugs are urgently required to make major surgery safer for the patient and more predictable for the surgeon. We review the basic physiology of the stress response from neuroendocrine to genomic systems, and discuss the paucity of clinical data supporting the use of statins, beta-adrenergic blockers and calcium-channel blockers. Since cardiac-related complications are the most common, particularly in the elderly, a key strategy would be to improve ventricular-arterial coupling to safeguard the endothelium and maintain tissue oxygenation. Reduced O2 supply is associated with glycocalyx shedding, decreased endothelial barrier function, fluid leakage, inflammation, and coagulopathy. A healthy endothelium may prevent these "secondary hit" complications, including possibly immunosuppression. Thus, the four pillars of whole body resynchronization during surgical trauma, and targets for new therapies, are: (1) the CNS, (2) the heart, (3) arterial supply and venous return functions, and (4) the endothelium. This is termed the Central-Cardio-Vascular-Endothelium (CCVE) coupling hypothesis. Since similar sterile injury cascades exist in critical illness, accidental trauma, hemorrhage, cardiac arrest, infection and burns, new drugs that improve CCVE coupling may find wide utility in civilian and military medicine.

Keywords: coagulopathy; endothelium; inflammation; injury; perioperative; sepsis; surgery; trauma.

Figure 1

Anatomy of the Surgical Stress Response. Surgical stress triggers a wide and varied response at multiple levels depending on the type and duration of surgery, anesthesia and the patient’s age, gender and prior health status. The early drivers of the stress response are sterile local injury, afferent nerve cell firing, activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis, Nucleus Tractus Solitarus (NTS), endothelial dysfunction and inflammation. Damage signals (also termed danger-associated molecular patterns or DAMPs and alarmins, e.g., heat shock proteins, adenosine, HMGB-1) are generated from tissue injury and detected by resident and non-resident immune cells. The key pro-inflammatory cytokines are IL-1, IL-6, and TnF-alpha and a complex interactions with complement. The primary goal of the acute immune response is wound healing and to prevent pathogen invasion. It is a restorative process that involves four phases: coagulation, inflammation, proliferation, and remodeling. Each phase of repair is predominately mediated by immune cells, cytokines, chemokines, transcription, and post-translational pathways (Tables 1 and 2). However, during major trauma, the early repair process can be overexpressed and lead to further injury, if not held in check. Peripheral nerve injury and pain induce afferent mediators and neurotransmitters to the spinal cord and central nervous system (CNS) and produce stress hormones, which exacerbate the stress response during major surgery.

Figure 2

Schematic of the HPA axis and the Stress Response to Surgery. Different anesthetics have different effects on the HPA axis and immune system (see Effects of Anesthesia on the Surgical Stress Response). During surgical stress, activation of the HPA axis is controlled by a relatively small number of neurons located in the paraventricular nucleus (PVN) of the hypothalamus. These neurons release neural factors, such as corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) into the hypophyseal portal circulation, which stimulates the anterior pituitary gland to release ACTH into the blood and activates the adrenal gland to release the stress hormones, catecholamines, and cortisol. Under normal exposure to stress, the HPA axis is held in check via multiple negative feedback mechanisms. However, during major surgery, trauma, infection or burns, imbalances occur and the action of stress hormones are potentiated by cytokines IL-1beta, IL-6 and TNF-alpha, prostaglandin-2 (PGE-2), and nitric oxide (NO), which predispose the body to further injury from ischemia, inflammation, and coagulopathy. Older surgical patients appear to be more vulnerable to surgical stress because their hypothalamus and pituitary are less sensitive to negative feedback from both cortisol and ACTH (–9). The medullary Nucleus Tractus Solitarus (NTS) is also influenced by the stress response as it receives sensory neural inputs from the arterial baroreceptors, integrates this information with the hypothalamus, and other parts of the brain, and regulates the sympathetic and parasysmpathetic outflows to the body (, –72).

Figure 3

Effect of Major Surgery on the Blood Brain Barrier and Neuroinflammation. The blood brain barrier (BBB) is the body’s natural “firewall” to protect against unwanted incoming agents entering the CNS from the general circulation. During major stress and trauma, the BBB is particularly vulnerable to attack from inflammatory cells and cytokines (156). A breach can lead to neuroinflammation and activation of microglial cells, the brain’s resident macrophages, which may lead to further injury and cognitive dysfunction. The three most common types of cognitive dysfunction are delirium, postoperative cognitive dysfunction (POCD) and dementia (168). Delirium is normally defined as a transient loss of mental attention and orientation in the hours after surgery; dementia is a series of syndromes associated with global deterioration of cognitive ability lasting months to years; and POCD is the deterioration in performance (156, 169). POCD is a more subtle condition and longer lasting than delirium and can include post-traumatic stress disorder after an ICU stay (156). Stroke is another leading cause of severe, long-term cognitive disability after major surgery and occurs in around 2% of patients (167, 170), and 20% of these occur within the first two postoperative days (171).

Figure 4

A broad schematic of the Central-CardioVascular-Endothelium (CCVE) “uncoupling” hypothesis that may be responsible for the high mortality and morbidity after major surgery. Loss of whole body homeostatic control during surgical trauma may be leveled at: (1) the CNS, (2) the heart, (3) the vascular tree, and (4) the endothelium. There is an urgent need to develop a pharmacological therapy that supports a high flow (maintained cardiac output), hypotensive, vasodilatory state with endothelial protection and tissue oxygenation (287). If central and local control of cardiac output and ventricular-arterial coupling are improved, endothelial and micro-vascular function will be improved and tissue O₂ delivery will be maintained. An uncoupling is reflected in increased stress hormones, sympathetic discharge, loss of baroreceptor sensitivity, and loss of heart rate variability (229, 230). Impaired sympathetic control and a loss of heart rate variability are two of the strongest predictors of death in critically ill patients (188), and promote a pro-inflammatory state with higher IL-1, IL-6, TnF-alpha, and CRP levels, and coagulopathy. A new whole body therapy is required to bolster the patient’s defense against the trauma of surgery and prevent “secondary hit” complications from ischemic and inflammatory cascades, coagulopathy, multiple organ failure, and immunosuppression.