When Hypoglycemia Causes Hypothermia in Diabetic Patients

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Hypothermia is a symptom of severe hypoglycemia, which can of course be life-threatening.

Annette, a 47-year-old African-American female with Type 1 diabetes mellitus, was admitted to the hospital with a foot infection that was progressive despite therapy with intravenous vancomycin.

Annette had a long-standing history of type 1 diabetes. She had developed significant peripheral neuropathy and had previous diabetic foot infections, which had led to partial amputations of both feet. Her diabetes was controlled with insulin glargine (Lantus), as well as a prandial insulin aspart (NovoLog) sliding scale. Her medical history was also remarkable for a remote history of seizures, for which she took no medication.

Overnight Personality Change

Radiographs of Annette’s foot revealed osteomyelitis of the calcaneus. Her antibiotic regimen was expanded to include piperacillin-tazobactam, and she underwent surgical debridement on the fourth day of the admission.

The next morning, Annette was found to be noticeably less responsive relative to baseline. She also exhibited slurred speech and was very argumentative in her interactions with staff. In addition, she was diaphoretic and cool to touch.

Temperature Dropping Fast

Annette had received multiple doses of hydromorphone in the preceding 12 hours, and initially, a narcotic overdose was suspected. However, her vital signs revealed significant hypothermia of 93.5°F (axillary), with otherwise unremarkable vital signs (heart rate 90 beats/minute, blood pressure 140/66 mmHg, respirations 14/minute, with pulse oximetry of 94% on room air). Her temperature was also taken via rectal thermometer, which yielded a reading of 95.6°F.

Interestingly, just two hours earlier, her oral temperature had been recorded as 98.7°F.

One Missed Meal

This confusing clinical picture was quickly clarified when a point-of-care glucose reading registered at 47 mg/dl (reference range 70 – 110 mg/dl). A 50 ml bolus of 50% dextrose was given immediately, and over the next two hours her mental status returned to baseline and her core temperature (when taken orally) normalized to 97.6°F.

It was discovered later that she had received her morning dose of insulin aspart, but had not eaten her breakfast. The remainder of her hospital stay was uneventful, and she was discharged two days later in stable condition to complete her intravenous antibiotics at a skilled nursing facility.

Downside of Exogenous Insulin

The number of Americans living with diabetes has more than tripled over the past 30 years, and by 2014, 29.1 million Americans had been diagnosed with the disease.1,2 Patients with Type 1 diabetes are entirely insulin-deficient due to a loss of insulin-producing pancreatic beta cells, usually as a result of autoimmune destruction of these cells.

For Type 1 diabetics, the standard method for lowering glucose is to inject exogenous insulin into the body. While Type 1 diabetics are a minority of the overall diabetic population, comprising only 5% of all diabetic patients, they are at the greatest risk of hypoglycemia because of their total dependence on exogenous insulin, which lowers the serum glucose regardless of its current level. In 2011, there were approximately 282,000 emergency room visits of adults ages 18 years or older with hypoglycemia as the primary diagnosis and diabetes as a secondary diagnosis.2

Dangers of Hypoglycemia

Hypoglycemia places any patient at risk for serious systemic complications. The lower limit of normal fasting glucose levels is generally regarded as 70 mg/dL (3.9 mmol/L). Symptoms of hypoglycemia will often appear at levels around 50 mg/dL to 55 mg/dL, although this is variable based on an individual’s physiologic profile.

Hypoglycemia can progress quickly if left untreated, and can include extremely varied, and often unpleasant, physical and psychological symptoms (see list below3):

  • Shakiness
  • Nervousness or anxiety
  • Sweating, chills and clamminess
  •  Irritability or impatience
  • Confusion, including delirium
  • Rapid or fast heartbeat
  • Lightheadedness or dizziness
  • Hunger and nausea
  • Sleepiness
  • Blurred or impaired vision
  • Tingling or numbness in the lips or tongue
  • Headaches
  • Weakness or fatigue
  • Anger, stubbornness, or sadness
  • Lack of coordination
  • Nightmares or crying out during sleep
  • Seizures
  • Unconsciousness

It is important that diabetic patients learn to recognize these symptoms as signs of severe hypoglycemia, and to take action immediately if they begin experiencing them. If left uncorrected, severe hypoglycemia can lead to loss of consciousness, coma, and even death.

Enter Hypothermia

Hypothermia is a symptom of severe hypoglycemia believed to manifest in response to severely depressed levels of glucose in the central nervous system (neuroglycopenia). It serves as a mechanism by which the body preserves energy during times of extreme energy storage depletion.4 Decreased body temperature (i.e., hypothermia) reduces oxidative stress and decreases the body’s energy requirements. For this reason, therapeutic hypothermia is integrated into the care of some patients with ischemic heart disease or stroke.5,6

Hypoglycemia causes heat loss through peripheral vasodilation and sweating, a paradox of rapid heat loss occurring during a time of increased energy expenditure and heat production.7 Additionally, shivering is inhibited when serum glucose levels fall in the range of 30 mg/dL to 45 mg/dL. Core temperature remains constant while shivering, but drops significantly when shivering ceases.

In cases of hypoglycemic hypothermia, shivering re-appears within 40 seconds of the administration of intravenous glucose.7 This physiology may help support the lack of shivering during hypoglycemic hypothermia, as decreased glucose demand in peripheral tissues would leave more glucose available for use by the brain and other critical areas of the body.

Drugs that Add to the Problem

To varying degrees, all diabetes medications have the ability to induce hypoglycemia. They work by various mechanisms in order to reduce the serum glucose levels in the body, as lowering blood sugar is strongly linked to reducing microvascular complications such as diabetic nephropathy, neuropathy and retinopathy.8

Overzealous use of antidiabetic medications, most commonly insulin or its secretagogues (e.g., sulfonylureas), is the most common cause of hypoglycemia. Therefore, diabetic patients whose therapy is directed towards tightly-controlled glucose levels need to be closely monitored for hypoglycemia.

Other drugs that may contribute to hypoglycemia include fluoroquinolones, pentamine, quinine, beta blockers, ACE inhibitors, and IGF-1.9 It has been suggested that some types of medications, such as beta blockers, selective serotonin reuptake inhibitors, and even insulin itself, may prevent the patient from experiencing any of the warning signs of hypoglycemia.10 This problem is termed “hypoglycemia unawareness”.11

At-Risk Patients

Some diabetic patients are more prone to eventually experiencing hypoglycemia, particularly those with liver disease, alcoholism, malnutrition, renal insufficiency, sepsis, or other endocrine disorders. Because the liver is essential for gluconeogenesis and glycogenolysis, hepatic dysfunction can impair these processes. Exogenous insulin is renally metabolized, so individuals with renal failure are at risk of delayed clearance of insulin and resulting hypoglycemia.

In addition, certain medical conditions, such as sepsis and malignancy, can dramatically increase the metabolic demands on the body, which in turn can deplete glucose stores and precipitate hypoglycemic episodes.

Other rare causes of hypoglycemia include neuroendocrine tumors or insulin autoimmunity.12 Patients with impaired cognitive function, dementia or psychiatric conditions can be susceptible if they are unaware of their symptoms or unable to express themselves.

Also important to note is that alcohol may also cause hypoglycemia by inhibiting gluconeogenesis, so patients presenting after an extended alcohol binge with little to no ingestion of food may display symptoms of hypoglycemia.13,14

In any of these scenarios, a simple finger stick or serum glucose test can confirm the diagnosis. Furthermore, it should be noted that the risks and potential consequences of hypoglycemia are very significant for patients who are trying to operate heavy machinery, work at a construction job, and or drive an automobile.4

What About Type 2 Diabetics?

Type 2 diabetes is far more common in America than Type 1, comprising 90% to 95% of cases. In Type 2 diabetes, the patient’s own body tissue slowly becomes resistant to the effects of insulin. Eventually, the pancreas stops producing insulin because it cannot continually meet the great demand for it caused by the tissue-resistance to insulin. Although most Type 2 diabetics do not need insulin early in their disease course, many of these patients will eventually require insulin as part of their therapeutic regimen.

Advanced Type 2 diabetics who are using insulin, taking multiple medications for reducing serum glucose, are elderly, or who have a co-existing critical illness are at high-risk for developing hypoglycemia.15,16

Implications for Practice

When faced with a lethargic or unresponsive patient, every bit of information might be useful in arriving at the correct diagnosis—which is crucial to guide timely and effective treatment. As we see with Annette’s case, the differential diagnosis for altered mental status can be broad. An awareness of the variable signs and symptoms of hypoglycemia allowed for prompt recognition of symptoms and quick initiation of treatment. Given the frequency and potentially life-threatening nature of hypoglycemia, it is essential that clinicians understand the manifestations of this disorder and maintain an index of suspicion when managing diabetic patients who are exhibiting strange symptoms.

References

1. Centers for Disease Control and Prevention. Number (In millions) of civilian, noninstitutionalized persons with diagnosed diabetes, United States, 1980-2014.  December 1, 2015.  http://www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm.

2. Centers for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Atlanta, GA: U.S. Department of Health and Human Services; 2014.

3. American Diabetes Association. Signs and symptoms of hypoglycemia (happen quickly).  July 1, 2015. http://www.diabetes.org/living-with-diabetes/treatment-and-care/blood-glucose-control/hypoglycemia-low-blood.html

4. Tran C, Gariana K, Herrmann FR, et al. Hypothermia is a frequent sign of severe hypoglycaemia in patients with diabetes. Diabetes Metab. 2012;38(4):370-372.

5. Arrich J, Holtzer M, Havel C, et al. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database Syst Rev. 2012;9:CD004128.

6. Freinkel N, Boyd ME, Harris E, et al. The hypothermia of hypoglycemia. N Engl J Med. 1972; 287: 841-845.

7. Gale EM, Bennett T, Green HJ, et al. Hypoglycaemia, hypothermia, and shivering in man. Clinical Science. 1981;61:463-469.

8. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.

9. Murad MF, Coto-Yglesias AT, Wang N, et al. Drug-induced hypoglycemia: a systematic review. J Clin Endocrinol Metab. 2008;94(3):741-45.

10. White, JR. The contribution of medications to hypoglycemia unawareness. Diabetes Spectr. 2007;20(2):77-80.

11. Ma RC, Kong AP. Drug-induced endocrine and metabolic disorders. Drug Saf. 2014;30(3): 215-245.

12. Iglesias P, Diez J. A clinical update on tumor-induced hypoglycemia. Eur J Endocrinol. 2014;170:R147-R157.

13. Marks V, Teale, JD. Drug-induced hypoglycemia. Endocrinol Metab Clin North Am. 1999;28(3):555-577.

14. Fitzgerald FT. Hypoglycemia and accidental hypothermia in an alcoholic population. West J Med. 1980;133(2):105-107.

15. Chelliah A, Burge MR. Hypoglycaemia in elderly patients with diabetes mellitus: causes and strategies for prevention. Drugs Aging. 2004;21(8):511-530.

16. Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: risk factors and outcomes. Crit Care Med. 2007; 35(10):2262-2267.

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