Review
Evidence-based management of hyperglycemic emergencies in diabetes mellitus

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Abstract

The hyperglycemic emergencies, diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are potentially fatal complications of uncontrolled diabetes mellitus. The incidence of DKA and the economic burden of its treatment continue to rise, but its associated mortality rate which was uniformly high has diminished remarkably over the years. This Improvement in outcome is largely due to better understanding of the pathogenesis of hyperglycemic emergencies and the application of evidence-based guidelines in the treatment of patients. In this article, we present a critical review of the evidence behind the recommendations that have resulted in the improved prognosis of patients with hyperglycemic crises. A succinct discussion of the pathophysiology and important etiological factors in DKA and HHS are provided as a prerequisite for understanding the rationale for the effective therapeutic maneuvers employed in these acute severe metabolic conditions. The evidence for the role of preventive measures in DKA and HHS is also discussed. The unanswered questions and future research needs are also highlighted.

Section snippets

Background

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are acute severe metabolic complications of uncontrolled diabetes mellitus. The estimated annual incidence rate of DKA is 13.6 and 14.9 per 1000 type 1 diabetic patients in the UK [1] and Sweden [2] respectively. In the USA, the incidence varies with age from 4 to 8 in all age groups to 13.4 per 1000 patients in subjects younger than 30 years [3], [4]. Hospital admission for DKA has increased by 30% over the last decade in

Etiology

Mortality in patients with DKA is frequently related to the underlying etiological precipitant rather than the metabolic sequelae of hyperglycemia or ketoacidosis [15]. Therefore, a diligent search for a precipitating illness should be undertaken in every hyperglycemic emergency. Omission or inadequate dosing of insulin and infection are the most common precipitants of DKA or HHS [12], [16]. Other causes include pancreatitis, silent myocardial infarction and cerebrovascular accident. Drugs

Literature search strategy

We conducted a literature search through PubMed using “hyperglycemic crises” and “diabetic ketoacidosis” as search terms. Original articles, consensus statements or guidelines and reviews published in English were selected for review. The grading of evidence is based on the system used by the International Diabetes Federation (Appendix A).

Clinical questions

  • 1.

    What is optimal fluid therapy in patients with hyperglycemic crises?

  • 2.

    What is the most efficacious route and dose of insulin in the treatment of patients with DKA and HHS?

  • 3.

    After recovery from DKA, can some patients with type 2 diabetes be managed with oral drugs?

  • 4.

    What is the role of electrolyte repletion in DKA and HHS?

  • 5.

    Is there any role for anti-coagulation in hyperglycemic emergencies?

  • 6.

    Is there any role for preventive measures in hyperglycemic emergencies?

A basic knowledge of the pathogenesis of

Pathogenesis

DKA is characterized by (1) reduced net effective action of circulating insulin due to decreased insulin secretion and/or insulin resistance, (2) elevation in level of counter-regulatory hormones such as glucagon, growth hormone, cortisol, and catecholamines, which give rise to (3) hyperglycemia from accelerated gluconeogenesis, glycogenolysis, impaired peripheral glucose utilization [12], [15], [16] and exaggerated lipolysis with consequent elevation in free fatty acid concentration. Increased

What is optimal fluid therapy in patients with DKA?

Rehydration corrects the volume deficit in DKA and HHS, the reversal of which is essential for adequate tissue perfusion and ultimate resolution of the associated metabolic abnormalities. Prospective studies in patients with severe DKA have demonstrated that fluid repletion alone, results in significant improvement in hyperglycemia, reduction in the level of counter-regulatory hormones and amelioration of peripheral insulin resistance [27], [32]. Thus adequate rehydration produces optimal

What is the most efficacious route and dose of insulin in the treatment of patients with DKA?

Important studies about three decades ago established low or physiologic dose regular insulin therapy as the cornerstone for the management of hyperglycemic emergencies [38], [39]. In a prospective randomized controlled trial, Kitabchi and colleagues investigated the effect of low-dose vs high-dose insulin therapy in 48 patients with DKA [39], [40]. In this study, the biochemical profiles were similar in the two arms before randomization; both groups showed no significant difference in the rate

After recovery from DKA, can some patients with type 2 diabetes be managed with oral drugs?

The occurrence of DKA in patients with type 2 diabetes is becoming increasingly well recognized in different ethnic groups, especially in people of African and Hispanic descent [2], [5]. These patients with ketosis-prone type 2 diabetes develop acute impairment in insulin secretion resulting in profound insulinopenia. Recovery of β-cell function occurs with resolution of DKA [51], [52], [53], and discontinuation of insulin therapy has been reported in 76% of such patients with 40% of them

What is the role of electrolyte repletion therapy in DKA?

Hyperglycemic emergencies are associated with considerable loss of electrolytes (see Table 1), while some of these electrolytes (sodium, potassium and chloride) can be corrected quickly, others may take several days or weeks to normalize [9], [30], [54].

Is there any role for anti-coagulation in DKA?

It has been shown that hyperglycemic emergencies predispose to inflammatory and procoagulant states; this may account for the increased incidence of thrombotic events in DKA and HHS [28]. Thrombotic conditions such as disseminated intravascular coagulation contribute to the morbidity and mortality in hyperglycemic crises [63].

Treatment of HHS

Subjects with HHS may also exhibit some degree of ketosis, and may have other conditions that lead to acidosis such as respiratory and renal failure and lactic acidosis. Altered mentation and focal neurological deficit are more frequent in HHS than DKA due to severe hypertonicity (Table 1). Dehydration is usually more profound in HHS as a result of longer period of metabolic decompensation, intercurrent illness, poor fluid intake and in some patients concomitant diuretic therapy [64]. The

Is there any role for preventive measures in hyperglycemic emergencies?

Prospective clinical studies have identified omission or poor adherence to insulin therapy as the major precipitant of DKA in some populations. In a review of 56 consecutive cases of DKA in a large urban hospital, cessation of insulin therapy was reported as the etiological factor in two-thirds of the patients [67]. In another study of 167 episodes of DKA in an indigent population, noncompliance was identified as the major trigger of DKA in about 60% of the cases [68]. A prospective

Euglycemic ketoacidosis

The term euglycemic diabetic ketoacidosis was used by Munro et al. to describe 37 of 211 episodes of DKA in which the patients had blood glucose of 300 mg/dl or less with plasma bicarbonate level of 10 mequiv./l or less. Nearly all the subjects were young type 1 diabetic patients who had anorexia and vomiting but continued to take insulin [73]. Important etiologic factors in euglycemic DKA include starvation or low caloric intake, vomiting, pregnancy and depression [74]. In patients with

Other important considerations

The three ketone bodies produced in DKA are β-hydroxybutyric acid, acetoacetic acid and acetone; of these, β-hydroxybutyric acid is the more abundant ketoacid especially in severe DKA. Ketone bodies are usually measured in most laboratories with the nitroprusside method, which reacts with acetoacetate and acetone, the less predominant ketones in DKA. Therefore, some subjects with severe DKA may test falsely negative for ketone bodies by the nitroprusside method. Furthermore, β-hydroxybutyrate

Future research needs

Remarkable progress has been made in the management of subjects with hyperglycemic emergencies, especially DKA, however, there are still areas that require further investigation. The use of bicarbonate in patients with pH <6.9 is yet to be investigated. Prospective randomized studies would be required to demonstrate the effect of bicarbonate in this category of patients. The explanation for the absence of severe ketosis in HHS is still lacking; understanding this mechanism may give further

Conflict of interest

The authors declare that they have no conflict of interest.

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      Previously insulin-treated patients should resume their usual insulin dose, while insulin-naive patients should start with multiple daily injections for a daily insulin dose (basal + boluses) of 0.5–0.8 U/kg. Thrombosis DKA is proinflammatory and it stimulates blood coagulation, raising the risk of thrombosis [14,141,142], so prophylactic heparin may be beneficial (Level of evidence 4). Cerebral edema may complicate DKA in children, accounting for 70–80% of DKA mortality.

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