1 Albert Einstein College of Medicine, New York, NY, USA
2 Icahn School of Medicine at Mount Sinai, New York, NY, USA
Background
The last decades have witnessed great changes in the definition of glycemic control in the ICU. In the 1990s, stringent glucose control was encouraged. However, later studies have reported the complications of hypoglycemia.
After the NICE‐SUGAR trial demonstrated increased mortality with intensive control, current guidelines recommend a more lenient approach with a target blood glucose level of approximately 140–180 mg/dL. The prevalence of diabetes in the USA has greatly increased to an astonishing 23.9% of the population, 40% of whom are still undiagnosed. The prevalence of diabetes in hospitalized patients appears to be as high as 25%. However, because inpatient diabetes studies are not routinely performed this number is likely underestimated. It is estimated that about 3160 dollars per patient are saved in health care costs as a result of decreased ICU length of stay, sepsis, renal failure, and even mechanical ventilation.
The causes of hyperglycemia in the ICU are complex and not limited to diabetes but are also caused by the impact of stress hormones such as cortisol including both stress‐induced or iatrogenic increases in steroid levels. Differentiation between the causes of hyperglycemia is challenging which is why the exact incidence of each is not yet known.
Pathogenesis
There is a substantial amount of evidence to suggest that stress‐induced hyperglycemia or hospital‐related hyperglycemia is an independent risk factor for increased morbidity and mortality when compared with hyperglycemia in diabetic patients.
Multiple factors contribute to hyperglycemia in the critically ill non‐diabetic patient such as stress hormones and inflammatory mediators causing insulin resistance and an increase in the rate of gluconeogenesis. Nonetheless, the question that remains unanswered is whether the resultant hyperglycemia is a direct cause of mortality or simply an indicator of the severity of illness.
The effects of hyperglycemia in the critically ill patient include leukocyte dysfunction, increased oxidative stress, and hypercoagulability and have also been associated with myocardial injury and increase in stroke size.
Recent evidence has suggested that stress‐induced hyperglycemia and hyperglycemia secondary to diabetes do not have the same mortality risk. Stress‐induced hyperglycemia is associated with worse outcome, including increased risk of infection and increased length of stay compared with diabetic hyperglycemia.
Risk factors for hyperglycemia
Diabetes mellitus.
Medications including exogenous glucocorticoids, vasopressors, lithium, and beta‐blockers.
Inflammatory conditions including sepsis.
Overfeeding, intravenous dextrose, commonly used parenteral nutrition.
Dialysis solutions, antibiotic solutions.
Insufficient insulin.
Volume depletion can cause hyperglycemia.
Bed rest.
Prevention of hyperglycemia
In order to potentially reduce the adverse effects of hyperglycemia, it has to be recognized early with the necessary management implemented immediately. However, other than early detection and management, there is no evidence of any means of preventing hyperglycemia prior to its occurrence.
Diagnosis
Differential diagnosis of hyperglycemia in the ICU
Hormonal disorders such as Cushing’s disease or acromegaly
Elevated cortisol/growth hormone, weight gain, Cushingoid features
Drug such as steroids, sympathomimetic drugs
History of medication use
Typical presentation
Critically ill patients with hyperglycemia present differently compared with otherwise healthy diabetic patients. In a critically ill patient, polyuria, polydipsia, and other common symptoms of hyperglycemia may not be present. Patients may present with acute kidney injury and decreased urine output. Due to the severity of illness, including delirium and mechanical ventilation, patients may not be able to communicate their symptoms. Moreover, given the acuity of glucose change, the physical exam may be equivocal and therefore routine blood tests are essential for diagnosis.
Clinical diagnosis
History
Symptoms depend on both glucose level and duration of hyperglycemia:
Neurologic: mental status changes, encephalopathy, seizures, chorea, and other involuntary movements.
Renal: polyuria, acute kidney injury.
Physical examination
Depending on the cause of hyperglycemia, some physical exam findings may be present. In stress‐induced hyperglycemia, however, arguably the commonest cause in the critically ill patient, the physical exam may not be very revealing.
Physical exam findings may include acanthosis nigricans in diabetes mellitus and Cushingoid features in Cushing’s disease.
Laboratory diagnosis
Blood gas analyzers are considered accurate, making them the ideal test in the critical care unit. Blood gas analysis requires arterial blood draws, and monitoring via an arterial line would be preferred to provide adequate glucose control. Despite being invasive, it is the consensus recommendation for glucose monitoring of severely ill patients.
Non‐invasive point‐of‐care (POC) glucose testing devices utilizing fingerstick or tiny amounts of blood obtained via an indwelling vascular line are the most widely used tests for hyperglycemia. These provide rapid results in critically ill patients where glucose fluctuations are unpredictable. POC testing, however, is inaccurate, sometimes differing by as much as 20% from reference values.
Continuous glucose monitoring systems of the glucose in the interstitial space every 10 seconds is a promising test providing an average glucose value every 5 minutes.
The glucose trend may be more useful than the absolute glucose value when using less accurate blood glucose monitors such as POC and continuous interstitial glucose monitors.
Stress‐related hyperglycemia in the ICU is acute and therefore would not usually cause an elevation in hemoglobin A1c, making this a method to potentially differentiate between stress‐induced hyperglycemia and long‐standing diabetes.
Potential pitfalls/common errors made regarding diagnosis of disease
The diagnosis of diabetes mellitus in the ICU is commonly missed given the incidence of hyperglycemia due to secondary causes. One study showed that 26% of diabetic patients were undiagnosed during their admission to the ICU. These patients had a higher likelihood of requiring an insulin infusion, higher average blood glucose, an increased percentage of hyperglycemia and hypoglycemia (i.e. higher glycemic variability), and increased mortality. These findings suggest that a high suspicion of diabetes in order to anticipate insulin requirement might be beneficial.
Due to glycemic variability in the critically ill patient, routine monitoring, sometimes continuous, is recommended. A patient who is normoglycemic on admission may not remain so throughout their ICU stay and may even require an insulin infusion at some point depending on the degree of hyperglycemia. Therefore routine glucose measurements are recommended during critical illness with strict guidelines on initiation of insulin therapy.
Treatment
Much controversy surrounds the idea of what constitutes ideal blood glucose targets in the critically ill patient. Multiple trials have yielded contradictory results. Initially, stringent glucose level control was advocated; however this recommendation was challenged because of the recognition that hyperglycemia was the body’s way of adapting to stress. In the early 2000s, the Leuven surgical trial concluded that intensive glucose control decreased mortality. Despite the faults of this trial, it created a movement for strict glucose goals of around 120 mg/dL.
However, the subsequent NICE‐SUGAR trial, targeting a glucose level less than 180 mg/dL, showed decreased mortality and less hypoglycemia compared with intensive glucose control. Despite the contradicting evidence, the consensus at this time is to target a glucose level of 140–180 mg/dL.
There is no universally accepted insulin regimen for glycemic control in critically ill patients. However, to avoid prolonged hypoglycemia, which may be harmful, insulin infusions and intermittent short‐acting insulin are typically used until the patient is stable enough to be transitioned to subcutaneous insulin.
No oral agents are used in the ICU for glucose control given the unpredictability of the metabolism in critically ill patients.
Depending on the glucose level, insulin can be given intravenously or subcutaneously. If there is a reading above 220 mg/dL or two consecutive readings above 180 mg/dL, the intravenous route is preferred. If the glucose reading is between 160 and 179 mg/dL, subcutaneous insulin is given. The options in subcutaneous insulin include short‐acting insulin, sliding scale insulin, NPH insulin, and long‐acting insulin.
Preferred route of insulin administration
Glucose level (mg/dL)
Route
160–179
Subcutaneous
180–219
Subcutaneous
>220
Intravenous
Two consecutive readings of >180
Intravenous
Monitoring of glucose level
When on intravenous insulin, glucose is checked every hour until it remains within goal for over 4 hours, after which it can be checked every 2 hours. If there is any change in clinical condition, insulin infusion rate, or nutritional support, switching back to hourly glucose checks is advised. When on subcutaneous insulin, glucose can be checked every 2–4 hours initially, then with meals and at bedtime once glucose is within target for over four readings.
Transitioning from intravenous to subcutaneous insulin
The last 24 hour insulin requirement is calculated by multiplying the requirement in the last 6 hours of insulin infusion, dividing by 6 and multiplying by 20; this will be the total insulin given in a day.
40% of the total daily units are given as long‐acting insulin and 60% are given as short‐acting insulin three times a day.
If giving NPH insulin, the total dose is divided by 4 and given every 6 hours.
If a patient is on less than 2 units of insulin per hour while on the drip, consider starting on short‐acting insulin.
Discontinue intravenous insulin 60 minutes after giving subcutaneous insulin.
Nutrition and insulin
For PO feeds, long‐acting insulin and short‐acting insulin are preferred.
For continuous feeds, consider NPH insulin.
If feeds are held, give basal insulin and hold rapid‐acting insulin.
If continuous feeds are held, hold NPH and long‐acting insulin and give short‐acting insulin or add D10 at previous rate of feeds.
Management of complications
The commonest complication of glucose control in the ICU is hypoglycemia which is defined as blood glucose less than 80 mg/dL. The association between mortality and glucose level is ‘J‐shaped’ meaning that there is increased mortality at both extremes making it important to avoid hypoglycemia.
Blood glucose 90–120: hold insulin infusion and repeat blood glucose in 1 hour.
Blood glucose 71–89: hold insulin infusion and repeat glucose in 30 minutes.
Blood glucose 51–70: give 12.5 g of 50% dextrose and repeat glucose in 15 minutes.
Blood glucose <50: give 25 g of 50% dextrose then confirm reading with arterial blood if possible and repeat glucose in 15 minutes.
There are clinical, animal, and in vitro studies which support a pathogenic role of acute hyperglycemia by causing immune system dysfunction, coagulation abnormalities, and increasing overall mortality.
Reading list
Finfer S, et al. Clinical review: consensus recommendations on measurement of blood glucose and reporting glycemic control in critically ill adults. Crit Care 2013; 17(3):229.
Markovitz LJ, et al. Description and evaluation of a glycemic management protocol for patients with diabetes undergoing heart surgery. Endocrine Pract 2002; 8(1):10–18.
Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation [NICE‐SUGAR] trial
Significantly higher 90 day mortality in intensive glucose control group compared with moderate glucose control
Clinical trial
Leuven Surgical Trial
Intensive glucose control significantly reduced ICU length of stay, hospital length of stay, duration of mechanical ventilation, and acute kidney failure
