Exposure of the host to diverse noxious stimuli results in a stereotypic and coordinated response, referred to by Hans Selye as the “general adaption syndrome” (or stress response) which serves to restore homeostasis and enhance survival [1]. The stress response is mediated primarily by the hypothalamic-pituitary-adrenal (HPA) axis as well as the sympathoadrenal system (SAS). Activation of the HPA axis results in increased secretion from the paraventricular nucleus of the hypothalamus of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) (see Fig. 13.1) [2]. CRH stimulates the production of ACTH by the anterior pituitary, causing the zona fasciculata of the adrenal cortex to produce more glucocorticoids (cortisol in humans) [3]. Activation of the SAS results in the secretion of epinephrine and norepinephrine from the adrenal medulla and sympathetic nerves and to an increased production of inflammatory cytokines such as interleukin-6 (IL-6) [2].

In general, there is a graded response to the degree of stress. Cortisol and catecholamine levels correlate with illness severity, the type of surgery, the severity of injury, the Glasgow Coma Scale and the APACHE score [3]. Adrenal cortisol output increases up to tenfold with severe stress (~300 mg hydrocortisone/day) [3]. In patients with shock, plasma concentrations of epinephrine increase 50-fold and norepinephrine levels increase tenfold [4]. The adrenal medulla is the major source of these released catecholamines [4]. Adrenalectomy eliminates the epinephrine response and blunts the norepinephrine response to hemorrhagic shock [4].

The increase in serum cortisol during stress protects the organism against developing post-traumatic stress disorder (PTSD) [5]. The fight and flight response is essential for survival and is present in the most primitive of species. Furthermore, within species the degree of activation of the HPA axis has evolved to match the degree of stress to which the organism is exposed [6] (see Fig. 13.2). Dysfunction of the stress response is illustrated in Fig. 13.3.

Modulators of the stress response

Chronic stress syndrome is characterized by: (see also Chap. 8)

The neuroendocrine response to stress is characterized by excessive gluconeogenesis, glycogenolysis and insulin resistance. Stress hyperglycemia, however, appears predominantly by increased hepatic output of glucose (gluconeogenesis) rather than impaired tissue glucose extraction. Cortisol increases blood glucose concentration through the activation of key enzymes involved in hepatic gluconeogenesis and inhibition of glucose uptake in peripheral tissues such as the skeletal muscles [13]. Both epinephrine and norepinephrine stimulate hepatic gluconeogenesis and glycogenolysis; norepinephrine has the added effect of increasing the supply of glycerol to the liver via lipolysis. Stress hyperglycemia and insulin resistance are evolutionarily preserved responses which allows the host to survive during periods of severe stress [14]. Insects, worms and all verterbrates including fish develop stress hyperglycemia when exposed to stress [14, 15].

Glucose is largely utilized by tissues that are non-insulin dependent, and these include the central and peripheral nervous system, bone marrow, white and red blood cells and the reticuloendothelial system [16]. Cellular glucose uptake is mediated by plasma membrane glucose transporters (GLUT) which facilitate the movement of glucose down a concentration gradient across the non-polar lipid cell membrane [16]. Insulin increases GLUT4 mediated glucose transport in adipose tissue and skeletal muscle by increasing translocation of GLUT4 from intracellular stores to the cell membrane [16]. Thermal injury and sepsis have been demonstrated to increase expression of GLUT-1 mRNA and protein levels in the brain and macrophages [17, 18]. Concomitantly, stress and the inflammatory response result in decreased translocation of GLUT-4 to the cell membrane. It is likely that pro-inflammatory mediators particularly TNF-α and IL-1 are responsible for the reciprocal effects on the surface expression of these glucose transporters. During infection, the upregulation of GLUT1 and downregulation of GLUT-4 may play a role in redistributing glucose away from peripheral tissues towards immune cells and the nervous system.

For glucose to reach a cell with reduced blood flow (ischemia, sepsis), it must diffuse down a concentration gradient from the blood stream, across the interstitial space and into the cell. Glucose movement is dependent entirely on this concentration gradient, and for adequate delivery to occur across an increased distance, the concentration at the origin (blood) must be greater. Stress hyperglycemia results in a new glucose balance, allowing a higher blood ‘glucose diffusion gradient’ which maximizes cellular glucose uptake in the face of maldistributed microvascular flow [19]. In patients with infection and tissue injury the increased energy requirements of activated macrophages and neutrophils are regulated by enhanced cellular glucose uptake related to the increased glucose diffusion gradient and increased expression of glucose transporters [20, 21]. In addition, acute hyperglycemia may protect against cell death following ischemia by promoting anti-apoptotic pathways and favoring angiogenesis. These mechanisms ensure adequate glucose uptake by immune cells and neuronal tissue in the face of decreased microvascular flow. Indeed, two independent groups of investigators using microdialysis and brain pyruvate/lactate ratios demonstrated that attempts at blood glucose normalization in critically ill patients with brain injury were associated with a greater risk of critical reductions in brain glucose levels and brain energy crisis [22, 23]. Similarly, Duning and colleagues demonstrated that hypoglycemia worsened critical illness induced neurocognitive dysfunction [24]. Multiple studies have demonstrated that even moderate hypoglycemia is harmful and increases the mortality of critically ill patients [20, 21]. Iatrogenic normalization of blood glucose may impair immune and cerebral function at a time of crises. In summary, these data suggest that stress hyperglycemia provides a source of fuel for the immune system and brain at a time of stress and that attempts to interfere with this evolutionary conserved adaptive response is likely to be harmful [25].

The association between hyperglycemia and adverse clinical outcomes is complicated by the pre-existing diabetes. Observational data has demonstrated that the association between increasing blood glucose and mortality was much stronger among non-diabetic than among diabetic patients [26, 27]. Egi and colleagues demonstrated that in patients with a high HbA1c (>7 %) there was an inverse relationship between ICU glycemic control and mortality—higher blood glucose levels during ICU stay were associated with lower mortality [28]. Biological adjustment to preexisting hyperglycemia might explain this phenomenon. These observations generate the hypothesis that glucose levels that are considered safe and desirable in other patients might be undesirable in diabetic patients with chronic hyperglycemia. In diabetic patients whose glucose has been poorly controlled prior to ICU admission, rapid and substantial lowering of their blood glucose levels during their acute illness/surgery may worsen outcomes.

Chronic hyperglycemia in patients with diabetes is associated with a myriad of harmful complications. The adverse outcomes associated with chronic hyperglycemia are attributed to the pro-inflammatory, pro-thrombotic and pro-oxidant effects observed with increased glucose levels [29]. The duration and degree of hyperglycemia appears to be critical in determining whether hyperglycemia is protective or harmful. Acute hyperglycemia limits myocardial injury following hypoxia and ischemia [30, 31]. However, in experimental models chronic hyperglycemia is associated with an increased the rate of myocyte death and increased infarct size [31, 32]. These data suggest that acute hyperglycemia may be protective and may result in greater plasticity and cellular resistance to ischemic and hypoxic insults. It is possible that severe stress hyperglycemia (BG >220 mg/dL) may be harmful; this postulate however remains unproven. Furthermore, it is unclear at what threshold stress hyperglycemia may become disadvantageous.

It is widely believed that in critically ill patients when oxygen delivery fails to meet oxygen demand an oxygen debt with global tissue hypoxia ensues [58, 59]. This results in anaerobic metabolism and increased lactate production [58, 59]. An increased blood lactate concentration is therefore regarded as evidence of anaerobic metabolism and tissue hypoxia [58]. It follows from this reasoning that patients with an elevated blood lactate should be treated by increasing oxygen delivery. In 2004 Nguyen and colleagues reported that “lactate clearance”, defined as the percentage decrease in lactate from emergency department presentation to 6 h, was an independent predictor of mortality [58]. They concluded that “lactate clearance in the early hospital course may indicate a resolution of global tissue hypoxia and that this is associated with decreased mortality rates.” This study popularized the concept of “lactate clearance” and has led to a number of studies which have used “lactate clearance” as the major end-point of hemodynamic resuscitation in critically in patients with sepsis (see also Chap. 12) [60–62].

We believe that these arguments are flawed and that in most situations lactate is produced aerobically as part of the stress response—hence the term stress hyperlactemia. Based on this argument it would be illogical to attempt to increase oxygen delivery in patients with an increased lactate concentration in order to treat a non-existent oxygen debt. Indeed, such an approach may be harmful [63]. Furthermore, as indicated below, the condition known as “lactic acidosis” may be a myth that does not exist.