Hyperglycemic crises in adult patients with diabetes: a consensus statement from the American Diabetes Association: response to Kitabchi et al.

D iabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are the two most serious acute metabolic complications of diabetes. Most patients with DKA have autoimmune type 1 diabetes; however, patients with type 2 diabetes are also at risk during the catabolic stress of acute illness such as trauma, surgery, or infection. Table 1 outlines the diagnostic criteria and electrolyte and fluid deficits for both disorders. The mortality rate in patients with DKA is 5% in experienced centers, whereas the mortality rate of patients with HHS still remains high at 11% (1–8). Death in these conditions is rarely due to the metabolic complications of hyperglycemia or ketoacidosis but rather relates to the underlying precipitating illness. The prognosis of both conditions is substantially worsened at the extremes of age and in the presence of coma and hypotension (7,9– 11) This consensus statement will outline precipitating factors and recommendations for the diagnosis, treatment, and prevention of DKA and HHS in adult subjects. It is based on a previous technical review and more recently published peerreviewed articles since 2001, which should be consulted for further information. PATHOGENESIS — Although the pathogenesis of DKA is better understood than that of HHS, the basic underlying mechanism for both disorders is a reduction in the net effective action of circulating insulin coupled with a concomitant elevation of counterregulatory hormones, such as glucagon, catecholamines, cortisol, and growth hormone (1,3,4,8–13). DKA and HHS can fall anywhere along the disease continuum of diabetic metabolic derangements. At one extreme, pure DKA without significant hyperosmolarity typically indicates the total or relative absence of insulin (seen in type 1 diabetes). At the other extreme, HHS without ketoacidosis typically occurs with lesser degrees of insulin deficiency, as seen in type 2 diabetes. However, in most circumstances, a mixed presentation occurs depending on the duration of symptoms, coexisting medical illnesses, or underlying precipitating cause. In one study (14), 123 DKA laboratory admission profiles were reviewed, and 37% demonstrated an elevated total osmolality. Hormonal alterations in DKA and HHS lead to increased gluconeogenesis and hepatic and renal glucose production and impaired glucose utilization in peripheral tissues, which results in hyperglycemia and hyperosmolality of the extracellular space (1,3,10–17). The combination of insulin deficiency and increased counterregulatory hormones in DKA also leads to the release of free fatty acids into the circulation from adipose tissue (lipolysis) and to unrestrained hepatic fatty acid oxidation to ketone bodies ( hydroxybutyrate ([ -OHB] and acetoacetate), with resulting ketonemia and metabolic acidosis (18). On the other hand, HHS may be caused by plasma insulin concentrations that are inadequate to facilitate glucose utilization by insulinsensitive tissues but adequate (as determined by residual C-peptide) to prevent lipolysis and subsequent ketogenesis (15). Both DKA and HHS are associated with glycosuria, leading to osmotic diuresis, with loss of water, sodium, potassium, and other electrolytes (6,15–17). The pathogenic pathways of DKA and HHS are depicted in Fig. 1. The diagnostic criteria and typical total deficits of water and electrolytes in DKA and HHS are summarized in Table 1. As can be seen, DKA and HHS differ in the magnitude of dehydration, ketosis, and acidosis. DKA is a proinflammatory state producing reactive oxygen species that are indicative of oxidative stress. A recent study (19) has shown elevated levels of proinflammatory cytokines and lipid peroxidation markers, as well as cardiovascular risk factors (plasminogen activator inhibitor-1) and C-reactive protein, which return to normal levels with insulin therapy and remission of hyperglycemia.