Ugly Twins: Combined HHS + DKA

Insulin Ratio When Treating Hyperkalemia

A 13 year-old castrated male domestic shorthaired cat (2.72 kg) was presented to the veterinary teaching hospital emergency department for worsening lethargy and weakness. He had been recently diagnosed with diabetes mellitus and started on PZI insulin at 1 unit twice a day.  Historically, the cat was diagnosed with ocular histoplasmosis that was in remission on fluconazole treatment. 

The physical examination showed severe dehydration, obtunded mentation, hypothermia and low body condition score. The point-of-care bloodwork revealed the following findings:

  • Blood glucose 700 mg/dl
  • Creatinine 2.23 mg/dl (RR, 0.6-2)
  • BUN 41 mg/dl (RR, 10-30) 

Venous blood gas and electrolytes

  • pH 7.093
  • pvCO2 24.3 (RR 29.8-40.8)
  • HCO3 7.5
  • BEecf -22.5
  • Na 159 mmol/l (RR, 146-153)
  • K 3.81 mmol/l (RR, 3.9-4.4)
  • Cl 114.3 mmol/l (RR, 110-115)
  • Calculated osmolality = 2xNa + BUN/2.8 + glucose/18 = 371 mosm/l

A urinalysis showed high concentration of ketones (3+; nitroprusside reaction). 

Based on the initial diagnostics, a combination of diabetic ketoacidosis, hyperglycemic hyperosmolar syndrome and unusual concurrent hypernatremia were suspected.  

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar syndrome (HHS) are two common types of diabetic crises in cats and dogs. Both conditions result from relative or complete lack of insulin. Osmotic diuresis, GI losses, and decreased water intake contribute to progressive dehydration, hypovolemia, and a reduction in the GFR. Severe hyperglycemia can occur only in the presence of reduced GFR, because there is no maximum rate of glucose loss via the kidney. That is, all glucose that enters the kidney in excess of the renal threshold will be excreted in the urine. Reduction in the GFR leads to the glucose elimination failure resulting in severe hyperglycemia and hyperosmolar state (Owen et al., Diabetes. 1981; Kandel et al., Can Med Assoc J. 1983).

A hyperglycemic hyperosmolar state usually leads to hypertonic hyponatremia or eunatremia due to the extracellular shifting of free water from the intracellular space. Although mild hypernatremia could be present in patients who also exhibit as severely dehydrated DKA, the severe degree of hypernatremia is rarely presented. 

In a clinical human survey (MacIsaac et al., Intern Med J 2002), a combined diagnosis of DKA and HHS (DKA-HHS) was noted in 30% of adults with DKA and/or HHS subjects with diabetes. According to the diagnostic criteria for the DKA-HHS definition, such as pH ≤7.30, HCO3 ≤15 mmol/L and serum osmolarity ≥330 mOsm/L, our cat could also be diagnosed as DKA-HHS. However, our case was different from typical DKA-HHS or DKA/HHS cases due to the presence of hypernatremia, which rarely occurs in patients with severe hyperglycemia.

The criteria for diagnosis of HHS in veterinary medicine include a serum glucose concentration  >600 mg/dl, absence of urine ketones, and serum osmolality greater than 350 mOsm/kg. There are no accepted criteria for combined DKA-HHS syndrome in veterinary medicine. 

There are only few case reports in human medical journals presenting DKA combined with severe hyperosmolar hypernatremic states, and, to my knowledge, there are no case reports described similar presentation in veterinary journals. In a human case report (Kim et al, BMJ 2014), the patient (a 13 yo boy with diabetes mellitus) had played school soccer games for 3 days before admission. He consumed a high volume of sports drinks and cola daily to quench his thirst. These drinks usually contain large amounts of sugar, high sodium and have high carbonate content, which were believed to contribute to the development of combined DKA/HHS in this patient. 

Venous Blood Gas Interpretation 

Let’s take a look at this cat’s blood gas and analyze the major acid-base and electrolyte abnormalities using traditional and semi-quantitative approaches. 

  • pH 7.093
  • pvCO2 24.3 (RR 29.8-40.8)
  • HCO3 7.5
  • BEecf -22.5
  • Na 159 mmol/l (RR, 146-153)
  • K 3.81 mmol/l (RR, 3.9-4.4)
  • Cl 114.3 mmol/l (RR, 110-115)
  • Albumin = 3.8 (2.5-3.9)
  • Phosphorus = 3.2 (RR, 3.1-7.5)
  • Lactate = 2.5 (RR, <2.5)

Traditional Approach

1. pH = 7.093 –  acidemia

2. Low pCO2 and low HCO3 are consistent with a primary metabolic acidosis

3. Calculation of compensation for primary metabolic acidosis: 

  • predicted pCO2 = 35 – 0.7 x (22 – 7.5) = 25 
  • measured pCO2 =24.3

Since both predicted and measured pCO2 are close to each other, the respiratory compensation is adequate. 

4. Calculation of anion gap = (Na + K) – (HCO3 + Cl) = 41.3  (significantly elevated) 

5. Delta Anion Gap (can be calculated only in patients with metabolic acidosis)

DISCLAIMER: this is not validated in dogs and cats; it is taken from human medicine. 

ΔAG = Measured AG – Normal AG = 41.3 – 21 = 20.3

  • shows how much of HCO3 was titrated by organic acids
  • ΔAG + measured HCO3 should result in normal HCO3 value; if it is not the case, there is an additional acid-base disorder

ΔAG + measured HCO3 = 20.3 + 7.5 = 27.8 mmol/l – this value is slightly above the upper range of normal for bicarbonate, therefore this cat may have 2 metabolic acid-base disorders: severe elevated anion gap metabolic acidosis (AGMA) and mild metabolic alkalosis that is hidden by the AGMA.  

6. Conclusion: severe anion gap metabolic acidosis (AGMA), mild metabolic alkalosis and adequate respiratory compensation. 

Semi-quantitative Approach

  1. A free water effect (Na+) = 0.22 x (Na measured – Na mid-normal) = 0.22 x (159 – 149.5) = +2
  • Water = acid
  • Hyponatremia -> dilutional acidosis (-)
  • Hypernatremia -> contraction alkalosis (+)

2. Chloride effect = mid-normal Cl – corrected Cl =  112.5 – 107 = +5.5

Corrected Cl = Cl measured x Na mid-normal/Na measured = 114 x (149.5/159) = 107

  • Cl- and HCO3 are reciprocally linked
  • Hyperchloremia leads to acidosis
  • Hypochloremia leads to alkalosis

3. Albumin effect = 3.7 x (mid-normal alb – measured alb) = 3.7 x (3.2 – 3.8) = -2.2

  • Albumin
  • Hyperalbuminemia -> acidosis
  • Hypoalbuminemia -> alkalosis

4. Lactate effect = -1 x measured lactate = -1 x 2.5 = -2.5

5. Phosphate effect = 0.58 x (mid-normal PO4 – measured PO4) = 0.58 x (4.3 – 3.2) = +0.7

  • Phosphorous = acid
  • Hyperphosphatemia -> acidosis
  1. Sum of all effects = 2 + 5.5 – 2.2 – 2.5 +0.7 = +3.5
  2. Unmeasured anions = Difference between measured BE and these effects = -22.5 – 3.5 = -26, i.e. there is 26 mmol/l of unmeasured organic acids that contribute to metabolic acidosis (ketone bodies in this case). 
  3. Conclusion: severe metabolic acidosis caused by unmeasured anions (ketoacidosis) and SID alkalosis (due to contraction alkalosis and hypochloremia).


All patients with hypernatremia may be divided into 3 groups based on their volume status: hypervolemic, euvolemic and hypovolemic. Hypervolemic hypernatremia usually occurs secondary to salt ingestion, however other causes such as hyperaldosteronism may also exist. Excessive sodium ingestion will lead to elevation of serum sodium followed by an increase in water content in the extracellular space resulting in hypervolemia. 

Euvolemic hypernatremia may occur secondary to free water losses or inadequate water consumption. Since only free water is being lost, the intravascular volume is being preserved and the animal remains euvolemic. Typical example of euvolemic hypernatremia include animals without access to free water or animals that are losing water from panting, fever or diabetes insipidus in combination with inadequate water consumption. 

Finally, hypovolemic hypernatremia occurs in animals that are losing both free water and sodium, but the loss of free water is more significant. Since the serum sodium is determined by the ratio of sodium to free water, this may lead to hypernatremia in combination with hypovolemia. The fluid losses may occur via 3rd spacing or renal and GI systems. Our cat likely had a combination of severe osmotic diuresis, inability to concentrate urine due to chronic kidney disease that was exacerbated by inadequate water consumption secondary to depressed mentation. 

Interestingly enough a “sickness behavior” syndrome was described in some critically ill patients (humans and animals) leading to lack of water consumption that may worsen hypernatremia. “Sickness behavior” is a condition in animals in which systemic infection/inflammation or critical illness leads to a highly regulated set of responses such as fever, anorexia, adipsia, inactivity, and cachexia. The neuroimmune communication may involve the interaction of cytokines with peripheral nerves. In rat models, lipopolysaccharide is used to induce adipsia as part of sickness behavior (Hübschle T et al. Am J Physiol Regul Integr Comp Physiol. 2006; Damm et al., Neuropharmacology 2013).

Treatment Approach

Goals of therapy for patients with HHS and DKA include correcting hypovolemia if present, replacing the fluid deficit, slowly reducing serum glucose levels, addressing electrolyte abnormalities, and treating concurrent disease. 

To prevent exacerbation of neurologic signs, it is important not to lower the serum glucose or sodium too rapidly. Hyperosmolality induces formation of osmotically active idiogenic osmoles in the brain. These idiogenic osmoles protect against cerebral dehydration by preventing movement of water from the brain into the hyperosmolar blood. Because idiogenic osmoles are eliminated slowly, rapid reduction of serum osmolality establishes an osmotic gradient across the blood-brain barrier, leading to cerebral edema and neurologic signs (Arieff et al., J Clin Invest. 1973).

Correction of hypovolemia: Since our cat had Na=159 mmol/l, the fluid with similar sodium content is ideal for rapid resuscitation. Normal saline has sodium of 154 mmol/l, which is very close to the patient’s serum sodium and safe enough for bolus therapy. 

Replacing the fluid deficit and correction of hypernatremia: A free water deficit and dehydration deficit should be calculated first. 

  • Free water deficit (L) = BW (kg) x 0.6 x (measured Na / desired sodium – 1) 
  • Dehydration deficit (ml) = BW (kg) × % dehydration (as decimal) × 1000 (ml/L)

The correction of the hypernatremia should not exceed 10-12 mmol/l reduction of serum sodium per 24 hours, therefore free water deficit volume should be replaced with this information in mind. 

Fluid choice for fluid and water deficit replacement

1. Free water deficit replacement can be performed with a fluid solution that is hypotonic compared to the patients plasma. The less is the tonicity of the fluid, the less volume will be required. The most common options include 5% dextrose solution, 0.45% saline, and fresh water administered via a feeding tube, however a solution with any sodium concentration may be made by mixing sterile water with hypertonic saline. Since our cat was severely hyperglycemic, 5% dextrose solution would be less than ideal as an initial fluid choice. Therefore, fresh water administration via NG tube, 0.45% saline or self-made fluid could be considered. 

The calculated free water deficit was 64 ml (see equation above). This volume administered IV would decrease serum sodium from 159 to 153 mmol/l. This can be achieved over 12 hours (6 mmol/l /12h serum sodium reduction). If we placed the NG tube, we would give 6 ml/hr of fresh water as a CRI with a recheck of serum sodium every 4-6 hours. 

2. Dehydration deficit replacement can be performed with replacement solutions. In hypernatremic patients, replacement solutions don’t have to resemble serum sodium content of plasma as closely as solutions that are used for rapid resuscitation as long as the serum sodium is being monitored frequently and rapid reduction in sodium is avoided. In our case, Normosol R with Na=140 mEq/l may be appropriate as a replacement solution. 

The calculated dehydration deficit was 272 ml (see equation above). If we correct this deficit over 24 hours, the fluid rate will be around 12 ml/hr in addition to the free water deficit replacement via an NG tube. 

It is important to remember that our cat has a profound hyperglycemia that will continue to cause osmotic diuresis and ongoing free water losses. Therefore, our initial calculations may underestimate the total fluid rate required to correct dehydration and hypernatremia. 

Frequent body weight and electrolyte measurements are commonly used to titrate fluid administration rate in order to tailor fluid therapy to an individual patient’s fluid requirements.

The correction of hyperglycemia in HHS patients also should be slow enough to avoid rapid reduction in serum osmolality. Most commonly cited rate of safe serum glucose reduction is <50-75 mg/dl/hr. You may consider correcting hypovolemia and severe dehydration first prior to initiating insulin therapy in order to prevent the rapid reduction of serum glucose. If, despite your fluid therapy, there is no reduction in serum glucose concentration, IV or IM insulin should be initiated and titrated according to the patient’s needs. 


  1. Selected developments in understanding of diabetic ketoacidosis. Kandel et al., Can Med Assoc J. 1983.
  2. Renal function and effects of partial rehydration during diabetic ketoacidosis. Owen et al., Diabetes. 1981.
  3. Influence of age on the presentation and outcome of acidotic and hyperosmolar diabetic emergencies. MacIsaac et al., Intern Med J 2002.
  4. Pyrexia, anorexia, adipsia, and depressed motor activity in rats during systemic inflammation induced by the Toll-like receptors-2 and-6 agonists MALP-2 and FSL-1. Hübschle T et al. Am J Physiol Regul Integr Comp Physiol. 2006
  5. The putative JAK-STAT inhibitor AG490 exacerbates LPS-fever, reduces sickness behavior, and alters the expression of pro- and anti-inflammatory genes in the rat brain. Damm et al., Neuropharmacology 2013.
  6. A rare diabetes ketoacidosis in combined severe hypernatremic hyperosmolarity in a new-onset Asian adolescent with type I diabetes. Kim et al, BMJ 2014.
  7. Studies on mechanisms of cerebral edema in diabetic comas. Effects of hyperglycemia and rapid lowering of plasma glucose in normal rabbits. Arieff et al., J Clin Invest. 1973.

Author: Igor Yankin

Igor is the creator of He is a clinical assistant professor of Veterinary Emergency and Critical Care Medicine at the Texas A&M University.

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