Humans are simply trillions of cells packaged in various organs and structures that define our physical and functional makeup. To maintain life, these cells require the energy stored in complex molecules such as ATP (Adenosine Triphosphate) that are created in each cell from the fuel we provide them.
Fuel is anything that stores potential energy (think gasoline), so most of the stuff we eat and absorb can be converted to energy: carbohydrates, protein and fats.
Carbohydrates include simple sugars like glucose, galactose and fructose; and complex sugars such as starches that must be digested into simple sugars to be absorbed. These simple sugars, primarily glucose, are the preferred cellular fuel for energy production. Fats and proteins have other primary functions but can be converted to cellular energy when necessary; and in prolonged starvation, the effects on body fat and muscle protein are obvious.
Once glucose is absorbed or produced by the body, insulin is the key to getting it into the cells. The one fortunate exception is brain cells which can import glucose without insulin. Glucagon is the counter hormone to the insulin hormone and as with many hormone systems in the body, one hormone provides opposing effects to another hormone to maintain a balanced function.
So, what happens if there are inadequate insulin levels or ineffective insulin due to cellular resistance? The transport of glucose into the cells decreases, serum glucose levels increase, urine output increases attempting to flush out the excess glucose; and glucagon along with other anti-insulin substances are released in larger than normal amounts.
Glucagon is the most significant anti-insulin actor in this scenario and causes the release of glucose from stored glycogen in the liver and muscles, increases production of new glucose using the amino acids from protein breakdown and increases release of free fatty acids (FFA) from fat stores1.
The FFAs are converted to ketones in the liver and can be used as a fuel source by the cells in moderate amounts. In the face of a low insulin effect, the glucagon response is abnormally increased and adds to the already elevated glucose levels and causes the production of excessive amounts of ketones resulting in acidosis.
You now recognize we have just described diabetic ketoacidosis, a condition that’s increasing in the US population1:
- Diabetes: hyperglycemia due to inadequate circulating levels of insulin or insulin resistance
- Keto: increased ketone (keto-acid) production from increased FFAs from excessive glucagon levels
- Acidosis: increased circulating keto-acids with abnormal decrease in body pH (normal blood pH 7.35-7.45; acidosis is anything less than 7.35 and the lower the number the worse the acidosis)
Although a common cause of DKA is unrecognized, new-onset diabetes or a non-compliant diabetic patient, other conditions can trigger the process such as heart attacks, pregnancy, stroke, and substance abuse, however the number one cause is infection1.
The stress from these events may trigger the release of other anti-insulin substances such as the catecholamines epinephrine and nor-epinephrine which cause the circulating glucose to increase. These reactions are normally welcome in times of stress but in DKA it just adds to the hyperglycemia and the resultant problems.
Now, take away the increase in ketone production and make the hyperglycemia worse and you have a hyperosmolar, hyperglycemic state (HHS) and not DKA. This occurs simply because the HHS patient has just enough effective insulin to suppress over production of ketones but not enough to prevent the hyper-hyperglycemia that defines HHS where the blood sugar climbs to 600 mg/dl or higher2. This problem is also called hyperosmolar nonketotic state (HNS) and in the past the favored term was hyperosmolar, hyperglycemic, non-ketotic condition or coma (HHNC) because they often experience an altered mental status.
Osmolarity is the measure of the concentration of the molecules in a liquid. In HHS the abnormal number of circulating glucose molecules increases the osmolarity of the blood plasma as does the excessive water loss through the kidneys as they try to decrease the hyperglycemia by excreting sugar and water in the urine. This increased urine production is called osmotic diuresis and occurs when large amounts of non-absorbable molecules are delivered to the kidneys and require excessive amounts of water for their excretion in the urine. Osmotic diuresis occurs with hyperglycemia or when a medication such as mannitol is administered intravenously. More molecules and less water equal a more concentrated plasma or hyperosmolarity. This problem is more severe in HHS than DKA due to the higher level of circulating glucose. In either condition the dehydration is further worsened by the frequent inability of these patients to maintain adequate fluid intake.
- Hyperosmolar: extreme concentration from too many glucose molecules, too much water loss, and too little water replacement
- Hyperglycemic: minimum of 600 mg/dl and often higher
- State: or condition with potential for severe dehydration and altered mental status
To recognize these conditions in the field get liberal in checking blood sugars on any sick patient. This is a reasonable approach due to the increasing incidence of diabetes in the US and thus the potential for you to discover your ill patient has undiagnosed diabetes. The DKA patient may have an increased respiratory rate due to the acidosis and maybe a fruity breath from exhaled acetone, one of the keto-acids produced in DKA. Both HHS and DKA patients may be dehydrated but the degree of dehydration is likely worse with the HHS patient as noted above. The HHS patient will generally be older than the patient with DKA. In any diabetic patient with the complaint of nausea, vomiting and/or abdominal pain suspect DKA. The acidosis may cause these gastrointestinal symptoms or they may be the result of the underlying problem that initiated the DKA3.
Treatment is supportive. If you are IV capable, begin rehydration and sodium repletion with normal saline at 15 to 20 milliliters per kilogram per hour1 or skip the calculation and run it in at one liter per hour3. Patients with signs of shock will require more aggressive fluid therapy initially. Actively seek an underlying condition and if possible initiate treatment, for example a myocardial infarction inducing DKA.
Both insulin dependent diabetics (Type 1) and non-insulin dependent diabetics (Type 2) can develop DKA or HHS however HHS is most common in older patients with Type 2 diabetes4. Both were universally fatal before the development of insulin therapy. Modern death rates are two to 5 percent for DKA and around 15 percent for HHS. Interestingly the cause of death is most often due to the disease process that initiated the DKA or HHS in the first place. The key to successful outcomes is the aggressive treatment of DKA or HHS induced dehydration and disordered electrolytes and the initiation of insulin therapy to shut down the undesirable effects of the anti-insulins. Ultimately, the cause and cure for DKA and HHS is the degree of insulin activity.
References
1. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic Crisis in Adult Patient with Diabetes. Diabetes Care. 2009;32(7):1335-1343.
2. Stoner, GD. Hyperosmolar Hyperglycemic State. Am Fam Physician. 2005 May 1;71(9):1723-1730.
3. Umpierrez G, Freire, AX. Abdominal Pain in Patients with Hyperglycemic Crisis. Journal of Critical Care. 2002 March;17(1):63-67.
4. Umbierrez GE, Murphy MB, Kitabchi AE. Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Syndrome. Diabetes Spectrum. 2002 January;15(1):28-36.
