Ugly Twins: Combined HHS + DKA (a Feline Case Study)

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 was 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 = 38.9 mmol/L
• Creatinine 2.23 mg/dl = 197 umol/L (RI, 0.6-2 mg/dl or 53-176 umol/L)
• BUN 41 mg/dl = 14.6 mmol/L (RI, 10-30 mg/dl or 3.5-10.7 mmol/L) 

• pH = 7.093 (RI, 7.27-7.4)
• pvCO2 = 24.3 (RI, 29.8-40.8)
• HCO3 = 7.5 (RI, 18-23.2)
• BEecf = -22.5 mmol/L (RI, 0 to -6)
• Na = 159 mmol/l (RI, 146-153)
• K = 3.81 mmol/l (RI, 3.9-4.4)
• Cl = 114.3 mmol/l (RI, 110-115)
• Anion Gap = (159 + 3.81) – (114.3 + 7.5) = 41 (RI, 13-27)
• Calculated osmolality = 2xNa + BUN/2.8 + glucose/18 = 371 mOsm/kg
• Albumin = 3.8 g/dl (RI, 2.5-3.9 g/dl)
• Phosphorus = 3.2 mg/dl (RI, 3.1-7.5)
• Lactate = 2.5 mmol/l (RI, <2.5)

A urinalysis showed high concentration of ketones (3+; nitroprusside test) and ketonemia of 3.9 mmol/L. 

Based on the initial diagnostics (osmolality >350 mOsm/kg + BG > 600 mg/dL + high anion gap metabolic acidosis with ketonemia of >3 mmol/L), a combination of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) were diagnosed.  

DKA and 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 (>600 mg/dl) 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).

In a clinical human survey (MacIsaac et al., Intern Med J 2002), a combined diagnosis of DKA and HHS (DKA-HHS, also known as hyperosmolar DKA, H-DKA) was noted in 30% of adults with DKA and/or HHS subjects with diabetes mellitus. HHS-DKA carries a poor prognosis in people and the prognosis is suspected to be similar in dogs and cats. To the other’s knowledge, there is only one veterinary report of dogs that may have had HHS-DKA (Trotman et al. JVECC 2013). In this paper, dogs with HHS had a similar outcome to dogs with hyperosmolar DKA (=HHS-DKA). However, the strict criteria that define HHS, DKA, and HHS-DKA in people were not applied to all dogs in this study. 

There are only few case reports in human medical journals presenting DKA combined with severe hypernatremic states. In a human case report (Kim et al, BMJ 2014), the patient (a 13-year-old 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 quick look at the cat’s blood gas and analyze the major acid-base and electrolyte abnormalities using traditional and semi-quantitative approaches. 

• pH = 7.093 (RI, 7.27-7.4)
• pvCO2 = 24.3 (RI, 29.8-40.8)
• HCO3 = 7.5 (RI, 18-23.2)
• BEecf = -22.5 mmol/L (RI, 0 to -6)
• Na = 159 mmol/l (RI, 146-153)
• K = 3.81 mmol/l (RI, 3.9-4.4)
• Cl = 114.3 mmol/l (RI, 110-115)
• Anion Gap = (159 + 3.81) – (114.3 + 7.5) = 41 (RI, 13-27)
• Calculated osmolality = 2xNa + BUN/2.8 + glucose/18 = 371 mOsm/kg
• Albumin = 3.8 g/dl (RI, 2.5-3.9 g/dl)
• Phosphorus = 3.2 mg/dl (RI, 3.1-7.5)
• Lactate = 2.5 mmol/l (RI, <2.5)
• Serum ketones = 3.9 mmol/l (RI, <0.5)

Traditional Approach

1. pH = 7.093 –  acidemia

2. Low pCO2 and low HCO3 are consistent with a primary metabolic acidosis (since low pCO2 [hypocapnia] cannot cause acidemia)

3. Calculation of compensation for primary metabolic acidosis: unable to perform in a feline patient

4. Calculation of anion gap = (Na + K) – (HCO3 + Cl) = 41  (significantly elevated, reference interval in cats = 13-27) 

5. Delta Delta Ratio (can be calculated only in patients with high anion gap metabolic acidosis): Δ/Δ = ΔAG : ΔHCO3 = (41-20) : (21-7.5) = 21 : 13.5 = 1.55

Interpretation of ΔAG/ΔHCO3:

• <1: mixed normal and high anion gap metabolic acidosis (HAGMA + NAGMA)
• 1.0-2.0: Purely HAGMA (consistent with our feline case here)
• >2.0: HAGMA with pre-existing metabolic alkalosis

• The delta/delta ratio is the ratio of Δ anion gap and Δ bicarbonate (ΔAG/ΔHCO3), and it is used to detect coexisting acid-base disorders in patients with high anion gap metabolic acidosis (also known as HAGMA or AGMA). 
• The theory behind the delta ratio is that from a purely chemistry point of view the AG and bicarbonate should change together, mole for mole, in opposite directions because a mole of unmeasured anion (i.e. acid) should be buffered by a mole of bicarbonate. However, bicarbonate is not the only buffer system in the extracellular compartment.
• This calculation is not well-described in veterinary textbooks or papers, and therefore, ACVECC residents don’t need to calculate it on their actual examination.
• Use the ΔAG/ΔHCO3 ratio as one piece of evidence among many in making your final diagnosis of a mixed disorder. Be aware of its limitations. 

6. Final Acid-Base Status Interpretation using the Traditional Approach: Severe high anion gap metabolic acidosis (HAGMA) caused by ketonemia +/- uremia.

Semi-quantitative Approach

If you want to geek out and perform a non-traditional acid-base analysis, bear with me. Otherwise, skip ahead to the Hypernatremia section below.

1. A free water effect (Na+) = 0.22 x (Na [measured] – Na [mid-normal]) = 0.22 x (159 – 149.5) = +2

• Water = acid, in this feline case there is a net loss of water evident by hypernatremia, therefore the free water effect is alkalotic (i.e. +2)
• Hyponatremia -> dilutional acidosis (-)
• Hypernatremia -> contraction alkalosis (+)

2. Chloride effect = Cl [mid-normal] – Cl [corrected] =  112.5 – 107 = +5.5 (alkalotic effect)

Cl [corrected] = Cl [measured] x Na [mid-normal]/Na [measured] = 114 x (149.5/159) = 107

• Cl- and HCO3 are reciprocally linked; when chloride goes down, HCO3 goes up and vice versa
• Chloride has an acidotic effect since it reduces HCO3, therefore the following is true:
• Hyperchloremia leads to acidosis
• Hypochloremia leads to alkalosis
• In our case, the corrected [i.e. true chloride] is low, therefore this led to an alkalotic effect of +5.5.

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

• Albumin is an acid, therefore the following is true:
• Hyperalbuminemia -> acidosis
• Hypoalbuminemia -> alkalosis
• In our case, the albumin is relatively elevated (above mid-normal value), therefore it has an acidotic effect of -2.2.

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

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

• Phosphorous is considered an acidifying compound, therefore:
• Hyperphosphatemia -> acidosis
• Our cat’s phosphate is below mid-normal, which leads to mild alkalotic effect of +0.7.

1. Sum of all effects = 2 + 5.5 – 2.2 – 2.5 +0.7 = +3.5
2. Unmeasured anions = Difference between measured base excess (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 and uremic toxins 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 3^rd 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).

General 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 plasma osmolality, glucose and sodium too rapidly (check out the VETEMCRIT HHS treatment guidelines here). 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 (e.g. 5-10 ml/kg IV with reassessment of all perfusion parameters after each bolus).

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) * 0.6 * (measured Na / desired sodium – 1) = 2.72 kg * 0.6 * (159/153 – 1) = 64 ml
• Dehydration deficit (ml) = BW (kg) * % dehydration (as decimal) * 1000 (ml/L) = 2.72 * 0.07 * 1000 = 190 ml

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 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, 0.45% saline was selected as a source of free water. 

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 with the fluid rate of 5 ml/hr (64:12 ~5.3 ml/hr). However, NaCL 0.45% is not a pure source of free water since it contains sodium chloride. Therefore, to provide 5 ml/hr of free water via NaCl 0.45% supplementation, the fluid rate should be doubled to a total of 10 ml/hr.

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. Since our cat is severely acidemic, balanced replacement crystalloid solutions such as Normosol-R with Na=140 mEq/l or LRS with Na=130 mEq/L may be appropriate. In patients with isolated HHS (no DKA), whose blood pH is greater than 7.3, the use of NaCl 0.9% is appropriate as well.

The calculated dehydration deficit was 190 ml (see equation above). If we correct this deficit over 12 hours + maintenance rate, the total fluid rate will equal ~22 ml/hr in addition to the free water deficit correction rate of 10 ml/hr (if NaCl 0.45% is used).

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 (q4h in the first 24 hours) 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 (by ~ 3-8 mOsm/hr). Most commonly cited rate of safe serum glucose reduction is <50-75 mg/dl/hr. One should consider correcting hypovolemia and severe dehydration first prior to initiating insulin therapy in order to prevent the rapid reduction of serum glucose and serum osmolality as a result. If, despite your fluid therapy, there is no to minimal reduction in serum glucose concentration, IV or IM insulin should be initiated and titrated according to the patient’s needs (see HHS guidlines here). 

References

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.