Complications of Diabetes Rajeev Chawla
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Acute Complications of Diabetes1

 
Introduction
Acute complications of diabetes mellitus comprise diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar syndrome (HHS), and iatrogenic hypoglycemia. DKA and HHS result from absolute or relative insulin deficiency coupled with concomitant increase in counter-regulatory hormones. Iatrogenic hypoglycemia is often a result of overzealous glycemic control treatments. Although the incidences of these complications have been reducing due to increased awareness among patients and physicians, they tend to cause serious effects in patients, resulting in significant mortality and morbidity. A recurring and central theme in the management of diabetes and related complications is the need for implementing preventive strategies, which include routine monitoring and patient education. These aspects are even more important in avoiding iatrogenic hypoglycemia, where self-monitoring plays a crucial role. The following sections present a review of current literature on the acute metabolic complications of diabetes along with relevant guidelines and recommendations for their prevention and management.
 
Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome
 
Epidemiological Aspects
Available data indicate the incidence of DKA at 1 per 2,000 patients. Results of the Rhode Island Hospital Study from Fishbein et al. showed an estimated DKA incidence of 4.6 per 1000 diabetic patients per year with a greater incidence in younger age groups and women.1 DKA occurs mostly in patients with type 1 diabetes but is not uncommon among patients with type 2 diabetes.
The incidence of HHS is about 1 in 1,000 patients per year (Table 1-1).16 HHS is seen predominantly in patients with type 2 diabetes and may be the initial manifestation of diabetes in about 30—40% of patients.5
2
TABLE 1-1   Comparative Summary of Epidemiological Aspects in DKA and HHS
DKA
HHS
Incidence rate
4.6–8 episodes per 1,000
1 in 1,000 patients per year
Prevalence by age group
More common in children and women
More common in elderly
Prevalence by diabetes type
More common in type 1 diabetes
More common in type 2 diabetes
Mortality/Morbidity
< 5% (in experienced centres)
~11%
The prevalence of HHS is more in elderly patients.6 Mortality rates in patients with HHS remain high at about 11%.
 
Pathogenesis
The basic underlying mechanism for the pathogenesis of DKA and HHS involves a net reduction in circulating insulin levels coupled with a concomitant increase in counter-regulatory hormones like catecholamines, cortisol, glucagon, and growth hormone.7 Metabolic derangements, which ensue in these settings, lead to hyperglycemia, hyperosmolarity of the extracellular space, ketonemia, and metabolic acidosis. Hyper-glycemia results in reduced glucose utilization coupled with increased gluconeogenesis and glycogenolysis. Ketoacidosis results from increase in ketogenesis due to increased lipolysis and increased supply of free fatty acids for hepatic fatty acid oxidation. Figure 1-11,8,9 presents a schematic diagram of these pathogenic effects. Factors known to precipitate DKA and HHS include
  • poor treatment compliance,
  • vascular disease,
  • injury or infection,
  • medications such as corticosteroids,
  • thiazides,
  • sympathomimetic agents, and
  • second generation antipsychotics.Figure 1-11,8,9
 
Clinical Features of DKA and HHS
Clinically, there may be a significant overlap between DKA and HHS. Altered sensorium is one of the most common and prominent features of HHS. Furthermore, patients with HHS commonly present with fever due to an underlying infection, and signs of acidosis such as Kussmaul respiration and acetone breath are usually absent (Table 1-2).8
Metabolic complications of DKA and HHS include hyperglycemia, ketonemia, metabolic acidosis, and hyperosmolar states.
3
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FIGURE 1-1: Schematic representation of pathogenesis of DKA and HHS.
4
TABLE 1-2   Clinical Features of DKA and HHS
DKA
HHS
• Polydipsia
• Polyuria
• Polyphagia
• Weakness
• Dehydration
• Weight loss
• Nausea
• Vomiting
• Abdominal pain
• Poor skin turgor
• Kussmaul respiration
• Tachycardia
• Depressed sensorium may be present
• Frank/orthostatic hypotension
• Odor of acetone in the breath
• Shock
• Coma
• Altered sensorium
• Polyuria/oliguria
• Dehydration
• Orthostatic hypotension
• Tachycardia
• Fever
• Seizures
• Focal neurological symptoms such as
  • Choreoathetosis
  • Ballismus
  • Dysphagia
  • Segmental myoclonus
  • Hemiparesis
  • Hemianopia
  • Central hyperpyrexia
  • Nystagmus
  • Visual hallucinations
  • Acute quadriplegia
A consensus statement from American Diabetes Association recommends a panel of laboratory investigations to evaluate these altered metabolic states.8 The diagnostic criteria for DKA and HHS as per this consensus statement are presented in tables 1-3 & 1-4. The consensus statement also prescribes electrocardiogram, chest X-ray, and urine, sputum, or blood cultures (Box 1-1).8 It is important to differentiate DKA from other forms of ketoacidosis. Differential diagnosis of DKA must include alcoholic ketoacidosis, and previous history of drug abuse and metformin use. Accumulation of ketoacids in DKA results in an increased anion gap metabolic acidosis, which can also be due to lactic acidosis, chronic renal failure, and salicylate use. Altered sensorium, a hallmark of HHS, may sometimes be present in patients with profound hypoglycemia.
 
Management
Treatment of DKA and HHS involves management of hyperglycemia, dehydration, and electrolyte imbalance. Intensive patient monitoring is extremely important.
5
Management of DKA and HHS is largely similar, but few important differential considerations and subtleties warrant clinical attention and are summarized in table 1-5.8
 
Preventive Strategies
Many cases of DKA and HHS are prevent-able by better access to medical care, proper education, and effective communication with a health care provider during an inter- current illness. Discontinuation of treatments or poor compliance may be a precipitating factor of DKA and HHS. Patient education strategies are crucial to prevent the incidences of these conditions which exert a significant health care and economic burden.8
 
Fluid Therapy
The protocol for management of fluid imbalance is summarized in figure 1-2. In patients with DKA, the cumulative fluid deficit is between 3—12 liters, and fluid loss continues with persisting glycosuria. In adults, about 1—2 liters of normal saline must be administered in the first three hours, followed by a slower infusion of half-normal saline. In children, normal saline solution (20 mL/kg) is administered over the first hour, following which the fluid rate is adjusted to achieve a urine output of 1 to 2 mL/kg/hr.
TABLE 1-3   Diagnostic Criteria for DKA and HHS
Investigations
DKA
HHS
Mild
Moderate
Severe
Plasma glucose (mg/dL)
> 250
> 250
> 250
> 600
Arterial pH
7.25 to 7.30
7.00 to < 7.25
< 7.00
> 7.30
Serum bicarbonate (mEq/L)
15 to 18
10 to < 15
< 10
> 15
Urine ketonea
Positive
Positive
Positive
Small
Serum ketonea
Positive
Positive
Positive
Small
Effective serum osmolality (mOsm/kg)b
Variable
Variable
Variable
> 320
Anion gapc
> 10
> 12
> 12
< 12
Alteration in sensorial or mental obtundation
Alert
Alert/drowsy
Stupor/coma
Stupor/coma
a Nitroprusside reaction method;b Calculation: 2 [measured Na (mEq/L)] + glucose (mg/dL)/18;c Calculation: (Na+)-(CI- + HCO3-) (mEq/L).
6
TABLE 1-4   Total Body Deficits in DKA and HHS
Typical deficits
DKA
HHS
Total water (L)
6
9
Water (mL/kg body weight)
100
100—200
Sodium (mEq/kg)
7—10
5—13
Chloride (mEq/kg)
3—5
5—15
Potassium (mEq/kg)
3—5
4—6
Phosphate (mmol/kg)
5—7
3—7
Magnesium (mEq/kg)
1—2
1—2
Calcium (mEq/kg)
1—2
1—2
In patients with HHS, fluid replacement goals must be to replace one-half of the fluid deficits in the first 12 hours and the remaining in the next 12—24 hours.5,8,9 There is general agreement that initial replacement should be with isotonic crystalloid (e.g., 0.9% sodium chloride). In adult patients, 0.9% sodium chloride is administered at the rate of 15—20 mL/kg per hour (average of 1—1.5 L), during the first hour.10 In children and adolescents, there may be a risk of cerebral edema associated with fluid resuscitation. Therefore, the rate of administration of 0.9% sodium chloride should be less than that in adults, and should not exceed 50 mL/kg over the first 4 hours of therapy. In children, fluid replacements must be calculated over 48 hours as compared to 24 hours in adults.11 In general, fluid replacement rates must carefully incorporate suggestions such as age, cardiac status, and degree of dehydration along with coexisting conditions like ischemic heart disease and renal impairment.11,12
 
Correcting Electrolyte Imbalance and Acidosis
Sodium deficit is corrected by normal saline. Potassium is replenished by adding 20—40 mEq potassium chloride to 1 liter of fluid. Magnesium deficit is corrected by adding 1—2 g of magnesium sulphate to the first 2 liters of fluid (Figure 1-3).8 No specific evidence-based advantages are seen with phosphate replenishment, and overzealous phosphate use may result in severe hypocalcemia.8
TABLE 1-5   Key Features in the Management of DKA and HHS
DKA
HHS
Insulin treatment
Immediate insulin therapy is extremely crucial for reversal of DKA and must be initiated at the earliest8
Immediate insulin therapy may not be required at all with appropriate fluid therapy. Fluid replacement is the foremost priority in the management of HHS therapy9
Electrolyte imbalance
Potassium loss is lesser in DKA as compared to HHS; however, potassium replenishment is needed in patients with DKA
Acute hypokalemia is the most serious immediate risk to patient with HHS, and monitoring and replacement of potassium are critical9
7
Acidosis is corrected by adding 44—88 mEq/L of bicarbonate to the first liter of IV fluids (Figure 1-4).8
 
Management of Hyperglycemia
Prompt insulin therapy is crucial to reverse DKA. Short-acting insulin is administered as IV infusion at an infusion rate of 5—10 U/hr mixed with IV fluids.11 The infusion is continued until re-initiation of normal insulin regimen. In children, glucose levels must be reduced with caution to avoid cerebral edema due to rapid decrease in plasma osmolarity.
Insulin plays a secondary role in the management of HHS, and immediate insulin therapy may not be required at all with appropriate fluid therapy.13 The patient can be started on low-dose insulin therapy once the patient is hemodynamically stable with adequate renal perfusion. Additionally, insulin administration should be delayed if the serum potassium is lesser than 3.3 mEq/L. The recommended dose of insulin in HHS is 0.1 U/kg per hour of regular insulin by continuous intravenous infusion.10
Overzealous treatment with insulin could lead to hypoglycemia in both DKA and HHS.2 The goal is to decrease glucose to not less than 300 mg/dL.9 Once the serum concentration of glucose reaches 300 mg/dL or less, dextrose should be added to the intravenous fluids, and the insulin infusion rate must be modified suitably (Figure 1-5).8
 
Hypoglycemia
Hypoglycemia in diabetes leads to severe debilitating microvascular and macrovascular complications. The results of Diabetes Control and Complications Trial (DCCT) led to wide-spread adoption of intense glycemic control measures for the management of diabetes. A number of clinical studies have demonstrated an association between intense glycemic control and iatrogenic hypoglycemia in type 1 and type 2 diabetes.14,15 The incidence is greater in type 1 diabetes as compared to type 2 diabetes.16 Thus, hypoglycemia presents a clinical barrier against the beneficial effects of tight glycemic control. Optimization of these two factors has become an important and integral part of diabetes management.
8
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FIGURE 1-2: Fluid therapy for management of adult patient with fluid and sodium imbalance in DKA or in HHS.
 
Epidemiological Aspects
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group reported a significantly high incidence of hypoglycemia (requiring any assistance) in patients receiving intense glycemic treatment as compared to those on standard treatment (16.2% vs 5.1%, p < 0.001).14 Numerous other studies have reported similar findings. In regular clinical settings, asymptomatic and moderate hypoglycemic episodes have a low probability of detection in the absence of routine glucose monitoring.
9
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FIGURE 1-3: Protocol for correcting electrolyte imbalance.
zoom view
FIGURE 1-4: Management of acidosis.
Estimates indicate that patients on intense glycemic control may suffer at least one episode of severe hypoglycemia every year. It has been estimated that 2—4% of deaths of people with T1DM are caused by hypoglycemia.1721 As a barrier to effective glycemic control and with a serious potential to impair psychological and social well-being, iatrogenic hypoglycemia is associated with serious medical and economic burden.
 
Risk Factors and Pathogenesis
The pathogenesis of iatrogenic hypoglycemia results from the interplay of insulin excess and blunting of key physiological and behavioral defenses (Figure 1-6).22
10
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FIGURE 1-5: Management of glucose imbalance.
Conventionally, relative or absolute insulin excess is the sole risk determinant for iatrogenic hypoglycemia, during glycemic control.
11
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FIGURE 1-6: Pathogenic processes in iatrogenic hypoglycemia.
However, the results of DCCT trial indicated that these risk factors account only for a minority of episodes of severe iatrogenic hypoglycemia (Box 1-2).23,24
 
Management
Management of iatrogenic hypoglycemia includes two components: treatment of hypoglycemia and risk minimization optimized to adequate glycemic control. The Global Partnership for Effective Diabetes Management provides practical recommendations to help improve the care of patients with type 1 and type 2 diabetes.15 These recommendations are summarized in box 1-3.15 In essence, the recommendations seek to blunt iatrogenic hypoglycemia through improved patient awareness and patient education programs along with stringent patient monitoring. Patient education programs must include the following aspects:25,26
12
  • Symptoms of hypoglycemia.
  • Physiologic factors that come into play: knowledge of the inter-relationship of physical activity, diet, and insulin.
  • The duration and action of the medications they are on.
  • Prevention and treatment of hypoglycemia episodes.
  • Frequent self-monitoring of blood glucose levels.
  • Importance of adhering to treatment regimens.
  • Need to document hypoglycemic episodes and to contact doctor in case of frequent/unexpected episodes.
13
 
Treatment
Most mild or moderate episodes of hypoglycemia can be self-treated relatively easily by ingesting fast-acting carbohydrates such as glucose tablets, glucose gels, or food (juices, soft drinks, or a meal). The suggested amount of carbohydrate to be ingested is about 15 g. However, when the symptoms are severe parenteral glucose may be required. One to three ampoules of 50% dextrose in water (D50W) should be adminis-tered intravenously.
In case of alcohol abuse, thiamine is also given. In infants and younger children, 10% dextrose water should be given, as D50W can lead to venous sclerosis, resulting in rebound hypoglycemia. About 1—2 mg of glucagon can be administered either intra-muscularly or subcutaneously, in cases where I.V. access cannot be rapidly obtained.27
One milligram of glucagon raises the blood glucose levels similar to 1 ampoule of D50W, with the onset of action being 10—20 minutes, and peak response 30—60 minutes. Other treatment strategies include adjustment of insulin/oral hypoglycemic agents. Regimen adjustments include use of insulin analogues and bedtime treatments.28
 
Conclusion
The acute metabolic complications of diabetes are a major health care burden, which can be avoided by prudent and optimal use of glycemic control measures. Various economic considerations and clinical opinions emphasize a need for preventive strategies. Improved patient education and measures to redirect health care resources towards better access to care and educational initiatives can produce sustainably better outcomes for patients with diabetes.
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