The ‘stress response’ is a systemic reaction to an injury that encompasses
hormonal and metabolic changes leading to haematological, immunological
and endocrine effects (Table 1-2)(16). The response collectively leads to
substrate mobilisation, muscle protein loss, sodium and water retention, and
suppression of anabolic hormone secretion. The typical extent of this stress
response has been found to be proportional to the severity of the surgical
Afferent nerve input from the area of injury initiates the stress response by
leading to the activation of both the hypothalamic-pituitary axis and the
sympathetic nervous system (17). An interaction between the endocrine and
inflammatory response is then characterised by a cascade of events
involving the release of catabolic hormones (e.g. catecholamines, pituitary
hormones) and suppression of anabolic hormones (e.g. insulin) (Table 1-3).
In addition, there is a prevalence of pro-inflammatory cytokines followed by
an influx of inflammatory cytokines.
Following tissue injury, the ‘acute phase response’ is activated and mediated
mainly by pro-inflammatory cytokines interleukin (IL)-1 and IL-6 (Table
1-4). These proteins act as inflammatory mediators, anti-proteinases,
scavengers and aid in tissue repair. The response is modulated by an
interaction between the immune system and the neuroendocrine system via
other components of the stress response (e.g. glucagon, cortisol, adrenaline).
The ensuing combination of catecholamine release and hyper-inflammation
followed by immunosuppression can contribute to a state of insulin resistance
Normal metabolism is governed by an interaction between anabolic and
catabolic hormones. Any major injury such as surgery can disturb the
normal metabolic homeostasis and lead to insulin resistance (16). Insulin
resistance can be defined as a condition whereby a normal concentration of
insulin produces a subnormal biological response (19). A number of studies
have demonstrated a significant association between the patient’s insulin
sensitivity on POD 1 with LOS and complications (18). In fact, it is one of
three independent factors along with scale of surgery and blood loss
accounting for 70% of the variation in LOS (18). As a consequence of the
developing insulin resistance, the normal mechanisms that regulate glucose
production and homeostasis are less effective, in turn contributing to
Hyperglycaemia is also a consequence of increased glucose production from
glycogenolysis and gluconeogenesis as a result of the metabolic response to
stress. This can be further enhanced by iatrogenic effects via perioperative
administration of glucose infusions and blood products. It is well established
that hyperglycaemia, particularly >12mmol/L can have adverse effects by impairing wound healing, increasing infection rates and causing ischaemic
damage to the nervous system and myocardium (20).
In regard to protein metabolism, it is characterised by an initial inhibition of
protein anabolism, followed by enhanced catabolism. Protein catabolism is
stimulated by increased cortisol and cytokines leading to a net loss of
functional and structural body protein (21). Loss of lean tissue can lead to a
delay in wound healing, compromised immune function and diminished
muscle strength, in turn impeding mobilisation and recovery (22). This
response is particularly enhanced in those that have insulin resistance (22).
The overall stress response is important in patients with altered metabolic
and inflammatory states such as; elderly, diabetics, and patients with cancer.
These patients can be exposed to a greater stress response and develop a
profound catabolic state as a result of poor reserve, in turn leading to greater
morbidity and delayed recovery (23).
Studies have suggested that if the stress response is left untreated, it can lead
to increased morbidity and mortality (16). In recent years, research has
focused on methods to minimise the surgical stress response and thereby
improve patient outcomes. To this end, the concept of enhanced recovery
after surgery (ERAS) has been developed. Compared with traditional
perioperative care, the ERAS programme represents a fundamental shift in
the process of care, by encompassing multiple elements that aim to reduce the
stress response to the injury caused by the operation, maintain homeostasis
and expedite return to baseline.