Glucose is a vital source of energy for mammalian cells throughout the body. The process of glycolysis breaks down glucose molecules, to enable incorporation into the Krebs cycle with the result being ATP production. Oral intake of carbohydrates offers the ongoing provision of glucose; however, glucose can also be derived from non-carbohydrate carbon substrate source metabolism (lactate, glycerol, certain amino acids), through the process of gluconeogenesis. Lastly, glucose is stored in the body as a multi-branched polysaccharide (glycogen), which can undergo glycogenolysis back to its original form, to provide a readily available source of cellular energy.
Insulin is a hormone released from the pancreas to facilitate the uptake of glucose into cells via glucose transporters, precipitate glycolysis, and enable storage of protein and fat within the body. Glucagon works in opposition to insulin, promoting glycogenolysis, gluconeogenesis, and catabolizing proteins and fats.
Blood glucose concentrations can be transiently increased in systemic disease due to glucose production in excess of clearance or utilization. It is also well documented that high levels of epinephrine, norepinephrine, cortisol and pro-inflammatory cytokines (all of which can be seen in acute illness or traumatic injury) can impact carbohydrate metabolism in multiple ways, including the development of insulin resistance, increased hepatic glucose production and glycogenolysis, impaired peripheral glucose use, and relative insulin deficiency. There is suspected to be synergistic action between glucagon, cortisol and epinephrine. Additionally, critical illness can result in impairment of glucose transporters, leading to reduced insulin-mediated glucose uptake into cells. Lastly, exogenous medications used in treatment may possess the undesired side effect of worsening glucose homeostasis. If this hyperglycemic state is prolonged, there can be several deleterious consequences. Osmotic diuresis leads to dehydration, hypovolemia, decreased glomerular filtration rate and subsequent worsening of hyperglycemia due to reduced solute excretion. Impaired leukocyte function with reduced phagocytosis and bacterial killing has been reported, in addition to impaired complement activity, and mitochondrial injury through increased reactive oxygen species generation. Ultimately, such immunomodulation leads to increased risk of infection, impaired wound healing, multiple organ failure, prolonged hospital stay and death.
The phenomenon of stress hyperglycemia has been reported in 38–50% of non-diabetic human adults presenting to the emergency room (ER), with specific higher risk critically ill populations identified, such as post-operative cardiac patients, and ICU patients with sepsis or respiratory failure. Hyperglycemia has a reported period prevalence of 43% in non-diabetic canine patients presenting to a veterinary ER, and 16% in a canine intensive care population. Similarly, the presence of a transient stress hyperglycemia, resolving with treatment of underlying disease without insulin therapy, was found to occur in 3.2% of cats presenting to one veterinary facility and hyperglycemia associated with non-diabetic illness was reported in at least 69% of cats on initial arrival to another veterinary hospital.
Although there remains question as to whether hyperglycemia is simply reflective of disease severity, there is increasing evidence in both the veterinary and human literature that this condition is independently associated with mortality. A heterogeneous human medical and surgical ICU population was evaluated showing both mean and maximum glucose values were significantly higher in non-survivors than in survivors, with a linear increase in mortality risk as glucose concentration increased. A review of critically ill non-diabetic trauma patients noted those with hyperglycemia had longer length of hospitalization, increased infection rate and a 2.2 times greater risk of mortality. Finally, a study in a large number of general surgery patients reported a strong association between perioperative hyperglycemia and the development of post-surgical pneumonia, decreased wound healing, systemic blood infection, acute renal failure, and urinary tract infection. In veterinary medicine, elevated blood glucose concentrations have been shown to have an association with severity of head trauma in dogs, though this finding was not predictive of outcome. Other studies have shown increased mortality in hyperglycemic emergency room patients when compared to those with normoglycemia and, in dogs with congestive heart failure the mean plasma glucose concentration was significantly higher in non-survivors compared to survivors and was above reference values. Lastly, in a group of septic dogs and cats where post-surgical blood glucose concentration was compared, there was a 50% mortality (4/8) in patients with a glucose value >8.3 mmol/L (>150 mg/dL) but only a 14% mortality (1/7) in the animals where the blood glucose concentration was <8.3 mmol/L (<150 mg/dL).
In critically ill human patients, glycemic control has been associated with improved patient outcome such as reduced morbidity and mortality, and lower rates of wound infection. This typically involves the infusion of rapid acting insulin to target a desired blood glucose concentration range. The main risk of attempting tight glycemic control (defined as maintaining normoglycemia) in this manner is inducing a hypoglycemic crisis; the largest human trials have conflicting results regarding optimal target range and adverse events.
Tight glycemic control has not been properly evaluated in veterinary medicine. A rabbit model of traumatic burn injury found using insulin to maintain normoglycemia prevented many adverse effects of hyperglycemia. This is an area requiring further investigation before any recommendations can be made regarding the treatment of stress hyperglycemia in critically ill veterinary patients.
References
1. McDonnell ME, Umpierrez GE. Insulin therapy for the management of hyperglycemia in hospitalized patients. Endocrinol Metab Clin North Am. 2012;41(1):175–201.
2. McCowen KC, Malhotra A, Bistrian BR. Stress-induced hyperglycemia. Crit Care Clin. 2001;17(1):107–124.
3. Montori VMB, Bistrian BR, McMahon MM. Hyperglycemia in acutely ill patients. JAMA. 2002;228(17):2167–2169.
4. Robinson LE, van Soeren MH. Insulin resistance and hyperglycemia in critical illness: role of insulin in glycemic control. AACN Clini Issues. 2004;15(1):45–62.
5. Hagley SP, Hopper K, Epstein SE. Etiology and prognosis for dogs with abnormal blood glucose concentrations evaluated in an emergency room. J Vet Emerg Crit Care. 2020;30(5):567–573.
6. Torre DM, deLaforcade AM, Chan, DL. Incidence and clinical relevance of hyperglycemia in critically ill dogs. J Vet Intern Med. 2007;21(5):971–975.
7. Opitz M. Stress hyperglycemia in cats. Berl Munch Tierarztli Wochenschr. 1990;103(5):151–158.
8. Laluha P, Gerber, Laluhova, D Boretti FS, Reusch CE. Stresshyperglykämie bei kranken Katzen: Eine retrospektive Studie über 4 Jahre (Stress hyperglycemia in sick cats: a retrospective study over 4 years). Schweiz Arch Tierheilkd. 2004;146(8):375–383.
9. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc. 2003;78(12):1471–1478.
10. Sung J, Bochicchio GV, Joshi M, et al. Admission hyperglycemia is predictive of outcome in critically ill trauma patients. J Trauma. 2005;59(1):80–83.
11. Frisch A, Chandra P, Smiley D, et al. Prevalence and clinical outcome of hyperglycemia in the perioperative period in noncardiac surgery. Diabetes Care. 2010;33(8):1783–1788.
12. Syring RS, Otto CM, Drobatz, KJ. Hyperglycemia in dogs and cats with head trauma: 122 cases (1997–1999). J Am Vet Med Assoc. 2001;218(7):1124–1129.
13. Brady CA, Hughes D, Drobatz KJ. Association of hyponatremia and hyperglycemia with outcome in dogs with congestive heart failure. J Vet Emerg Crit Care. 2004;14(3):177–182.
14. Hardie EM, Rawlings CA, George JW. Plasma-glucose concentrations in dogs and cats before and after surgery: comparison of healthy animals and animals with sepsis. Am J Vet Res. 1985;46(8):1700–1704.
15. Van den Berghe G, Schetz M, Vlasselaers D, et al. Clinical review: intensive insulin therapy in critically ill patients: NICE-SUGAR or Leuven blood glucose target? J Clin Endocrinol Metab. 2009;94(9):3163–3170.
16. Weekers F, Giulietti AP, Michalaki M, et al. Metabolic, endocrine and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness. Endocrinology. 2003;144(12):5329–5338.