Systemic stress response and hyperglycemia after abdominal surgery in rat and man

Surgical trauma results in a complex neuroendocrine and metabolic response known as the systemic stress response, which is initiated by neuronal and humoral signals from the site of the injury. These signals converge at central sites and result in the activation of the hypothalamicpituitary-adrenal (HPA) axis, the sympathetic nervous system and an inflammatory response. The systemic stress response is crucial for survival and results in metabolic changes in order to provide fuel and retain fluids until the damage is healed. An exaggerated and prolonged stress response however, results in depletion of energy stores with deleterious consequences on wound healing and convalescence.

The implementation of new anesthesiological treatments regimes, such as epidural anesthesia and fluid restriction necessitates the administration of vasopressors such as noradrenaline in order to maintain adequate tissue perfusion. Peri-operative insulin therapy has also been recently introduced aiming to reduce postoperative morbidity. However, insulin can act as a metabolic stressor and the effect of this pluri-potent hormone in different surgical populations needs to be further explored.

The general aim of this thesis work was to investigate the systemic stress response and hyperglycemia after abdominal surgery in rat and man.

For this purpose, studies were performed in experimental models as well as after major abdominal surgery in humans. We investigated whether preoperative suppression of the HPA-axis by corticotropin releasing factor antagonism or suppression of the inflammatory response by the administration of glucocorticoids affects the stress response and glucose metabolism after intestinal resection in the rat. Furthermore, the effect of glucocorticoids in a concentration similar to that after surgical trauma in the rat on the metabolic and hormonal stress response was investigated. We used a new experimental model including intestinal resection and compensated blood loss, aiming to reflect major abdominal surgery in man. In humans, the metabolic and hormonal responses after major gastrointestinal surgery were characterized and related to the intra- and post-operative clinical course in order to identify changes of special importance for outcome.

Corticotropin releasing factor antagonism decreased postoperative hyperglycemia and hypercorticosteronemia without affecting insulin transduction or glucose uptake in skeletal muscle. Preoperative administration of glucocorticoids attenuated the postoperative stress response by reducing plasma concentrations of interleukin-6 and catecholamines. Plasma glucocorticoids administered in concentrations similar to levels observed after intestinal resection did not cause hyperglycemia in the rat. Compensated blood loss and intestinal resection potentiated the hormonal response and induced persistent volume-dependent hyperglycemia which was independent on changes in plasma corticosterone and, in the early postoperative phase, mean arterial blood pressure and catecholamine levels. During pancreatic surgery in humans, we observed hyperglycemia, increased lipolysis and high levels of exogenous noradrenaline. Intraoperative lipolysis and plasma concentrations of interleukin-6 were correlated to the incidence of postoperative complications and length of hospital stay.

In conclusion, our results showed that inhibition of the stress response s efferent pathways results in compensatory mechanisms in order to maintain the glucocorticoid response and hyperglycemia after surgery. New anesthesiological and surgical techniques attenuated the postoperative stress response in humans. However, marked metabolic changes induced by infusions of vasopressors were observed during surgery.

List of scientific papers

I. Hager P, Hagman B, Wikström AC, Strömmer L (2004). CRF-receptor 1 blockade attenuates acute posttraumatic hyperglycemia in rats. J Surg Res. 119(1): 72-9.
https://pubmed.ncbi.nlm.nih.gov/15126085

II. Hager P, Permert J, Wikström AC, Herrington MK, Östenson CG, Strömmer L (2008). Preoperative glucocorticoid administration attenuates the systemic stress response and hyperglycemia after surgical trauma in the rat. [Submitted]

III. Hager P, Permert J, Strömmer L (2008). An experimental model of intestinal resection and compensated nonhypotensive blood loss. Journal of Surgical Research. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/19201422

IV. Hager P, Permert J, Östenson CG, Hållström L, Strömmer L (2008). Systemic stress response during and after major gastrointestinal surgery. [Submitted]