Diabetic Ketoacidosis. Myths based therapy

DKA mythology

Sergei Shushunov, MD

MYTH:

A popular belief or tradition that has grown up around

something or someoneMerriam-Webster dictionary

A traditional or legendary story, usually concerning some

being or hero or event, with or without a determinable

basis of fact or a natural explanation, especially one that

is concerned with deities or demigods and explains some

practice, rite, or phenomenon of nature.Dictionary.com

A sacred narrationWikipedia.com

Patients with DKA have at least 10% dehydration


Rehydration should be started with isotonic saline solution



Effective serum osmolarity is a good estimate of total serum osmolarity




Measured serum sodium should be converted to adjusted serum sodium using a correction factor.





Hyponatremia should not be corrected if the serum sodium value adjusted forthe degree of hyperglycemia is within normal range




Measured serum sodium should be converted to adjusted serum sodium usinga correction factor.

Do not correct hyponatremia if the serum sodium value adjusted forthe degree of hyperglycemia is within normal range

Insulin should be administered at a low dose of 0.1U/kg/h.







Serum glucose should be allowed to decrease by 50 to 100 mg% per hour




Measured serum sodium should be converted to adjusted serum sodium usinga correction factor.



Serum glucose should decrease by 50 to 100 mg% per hour

5% to 10% dextrose should be added once the serum glucose concentration falls to approximately 250 mg%

A 16-year-old male diabetic, who had been on insulin for five years, started to vomit

two days before admission. …precipitated by an infection of the upper respiratory tract.

He was drowsy but rational; …marked dehydration and air hunger. B.P. 120/70, blood

sugar 546 mg./lO0 ml., HCO3 9.5 mEq/l. He had heavy glycosuria and ketonuria.

Treatment consisted of 250 units of insulin and 4.5 litres of the hypotonic saline

lactate, followed by 1.5 litres of the potassium-containing solution. During the first

seven hours he passed nearly 2 litres of urine. He remained drowsy but otherwise

seemed better.

Eight hours after admission he suddenly became unconscious and was found to have

large unequal pupils, hypotonic limbs, and bilateral extensor plantar responses. At this

time his blood sugar was 200 mg./ 100 ml., Na 150 mEq/l, K 3.9 mEq/l. Cl 110 mEq/l,

HCO3 22 mEq/1, and urea 46 mg./100 ml. Soon after, a very marked increase in the

urinary output was noted. This was found to be at the rate of 16 ml./min., with a

specific gravity of 1003. The intense polyuria responded to "pitressin ". He did not

regain consciousness; his respiration failed and the B.P. fell. He survived a further six

days in a respirator, having continuous noradrenaline infusion. At necropsy the brain

showed widespread necrosis of the hypothalamus and mid-brain.

FitzGerald MG, O'Sullivan DJ, Malins JM. Fatal

Diabetic Ketosis. Br Med J. 1961;1(5221):247–50.

First article published in 1936


Incidence in 1960’s 2 to 19%



Related to treatment of DKA




Asymptomatic vs. symptomaticUp to 90% of children with DKA may have asymptomatic CE





CE is a form of organ failure, therefore term “asymptomatic” CE is as

meaningful as “asymptomatic” cardiac, respiratory or renal failure.






meaningful as “asymptomatic” respiratory, renal or cardiac failure

Incidence in children and young adults 0.5-1%; unchanged

for the past 25 years






meaningful as “asymptomatic” respiratory or cardiac failure

Incidence in children and young adults 0.5-1%; unchanged

for the past 25 years

Mortality 25%; Disability 40%

Rosenbloom AL. Intracerebral crises during treatment of

diabetic ketoacidosis. Diabetes Care. 1990; 13:22-33.

Rosenbloom AL. Intracerebral crises during treatment of

diabetic ketoacidosis. Diabetes Care. 1990; 13:22-33.

Arieff AI, Kleeman CR. Studies on mechanisms of cerebral edema

in diabetic comas. Effects of hyperglycemia and rapid lowering of

plasma glucose in normal rabbits. J Clin Invest. 1973;52(3):571-83.

Hyperglycemia of 4 hr duration achieved by IV infusion of

50% glucose

Serum osmolarity = CSF osmolarity = Brain osmolarity

Increases in the concentration of Na, K, Cl, glucose, sorbitol,

lactate, urea, myoinositol, and amino acids accounted for only

about half of this increase.

The unidentified solute was designated “idiogenic osmoles”.

Administration of insulin to rapidly decrease plasma glucose

concentration to normal level produced gross CE.

Ayus JC, Armstrong DL, Arieff AI. Effects of hypernatremia in the central nervous

system and its therapy in rats and rabbits Journal of Physiology;1999:492(1)243-55

Hypernatremic rabbits (serum Na 170-190 mEq/L) treated

with 1/2 NS IV to normalize plasma Na over 4-24 h

intervals.

Therapy resulted in significant brain edema.

Arieff AI, Kleeman CR. Cerebral edema in diabetic comas. II. Effects of hyperosmolality,

hyperglycemia and insulin in diabetic rabbits. J Clin Endocrinol Metab. 1974; 38:1057-67.

N-acetylaspartate - ?

Glycerophosphorylcholine – high energy phosphate

Phosphocreatine – high energy phosphate

Glutamine – precursor of glutamic acid

Myoinositol - elevated levels are associated with gliosis and demyelination

Betaine – elevated levels in hepatic encephalopathy; produces ataxia, lethargy and coma

Glutamic acid – neurotransmitter

Taurine – neurotransmitter


Fluid resuscitation!

Mucus membranes - dry secondary to hyperosmolar state


Capillary refill – could be prolonged due to ketones induced vasoconstriction



Tachycardia - can result from acidosis.




Blood pressure - often normal and sometimes elevated





Urine output – usually high due to osmotic diuresis






Hypernatremia – rarely develops due to urinary loss of sodium secondary to

osmotic diuresis and ketonuria.

Mucus membranes - dry secondary to hyperosmolarstate





Hypernatremia – rarely develops due to urinary loss of sodium secondary to


BUN - may fail to increase when a poor appetite leads to a low protein load.

Mucus membranes - dry secondary to hyperosmolarstate





Hypernatremia – rarely develops because sodium is lost as a result of


BUN - may fail to increase when a poor appetite leads to a low protein load.

Weight loss - can be aggravated by lipolysis and decreased food intake.

No correlation with the degree of ketoacidosis

Misleading physical examination with overestimation of

the degree in dehydration in the majority of patients

Sottosanti M, Morrison GC, Singh RN, Sharma AP, Fraser DD, Alawi K, Seabrook JA, Kornecki A. Dehydration in children with diabetic

ketoacidosis: a prospective study. Arch Dis Child. 2012;97(2):96-100.

75% had dehydration 8.3% and less

Ugale J, Mata A, Meert KL, Sarnaik AP. A measured degree of dehydration in children and adolescents with type 1 diabetic ketoacidosis.

Pediatr Crit Care Med. 2011 Jun 9. Epub

Median degree of dehydration is 5.2%Severe dehydration in 5% of patients

Fagan MJ, Avner J, Khine H. Initial fluid resuscitation for patients with diabetic ketoacidosis: how dry are they? Clin Pediatr (Phila).

2008;47(9):851-5

Majority had 4-8% dehydration

Koves IH, Neutze J, Donath S, Lee W, Werther GA, Barnett P, Cameron FJ. The accuracy of clinical assessment of dehydration during

diabetic ketoacidosis in childhood. Diabetes Care. 2004;27(10):2485-7

Mean degree of dehydration 8.7%

What Fluid resuscitation?

Rehydration should be started with isotonic saline

solution

It depends on the patient’s serum osmolarity

Effective serum osmolarity is a good estimate of

factors influencing water shift between the serum and

cerebral cells in patients with DKA

mMol/L = (2 × Na+ mEq/L) + glucose mg%/18 + (2 × K+ mEq/L).

mMol/L = (2 × Na+ mEq/L) + glucose mg%/18.

mMol/L = (2 × Na+ mEq/L).

The exclusion of potassium from some of the equations is

justified by the fact that changes of serum potassium level in

humans occur within a very narrow range, which precludes

significant changes of serum osmolarity due to changes in

serum potassium concentration.

The exclusion of urea is based on the notion that urea moves

freely across cellular membranes of almost all organs, and for

this reason, does not have a significant contribution to water

movement across biological membranes.

CR Kleeman , H davson, E. Levin. Urea transport in the

central nervous system. Am. J. Physiol. 1962;203(4):

739-47

Despite its apparent distribution throughout total body

water…, urea causes marked reduction in intraocular and

CSF pressure…

…(urea) transport kinetics with respect to CSF and central

neural tissues differ considerably from non-neural tissuesCR Kleeman , H davson, E. Levin. Urea transport in the

Central nervous system. Am. J. Physiol. 1962;203(4): 739-47

TSO mMol/L = (2 × Na ) + glucose mg%/18 + BUN/2.8.

TSO mMol/L = (2 × Na) + glucose /18 + (2 × K) + BUN /2.8.

TSO mMol/L = (1.84 × Na) + glucose/18 + (1.84 × K) + BUN /2.8 +

(1.15 x Ca) + (1.17 x Mg)

Freezing point is a gold standard method to measure TSO

Measured SO – calculated TSO = osmolar gap

Normal osmolar gap is around 10.

The major unmeasured osmoles in DKA are: lactic acid, acetocetic

acid, beta-hydroxybutyric acid, acetone

Serum level of ketone bodies in patients with DKA can be well over

20 mMol/L

Osmolar gap in patients DKA is usually 30-40 mMol/L

The presence of an osmotic gradient between the serum and brain

caused by ketone bodies, lactic acid and urea makes the application

of the concept of ESO or calculated TSO in patients with DKA

misleading.

The use of either ESO, or calculated TSO as a clinical aid in

decision making in treating DKA is better to be avoided.

Only measured SO can provide accurate information about the

changes in osmotic forces taking place during treatment of DKA.

Measured serum sodium in patients with DKA should

be converted to adjusted serum sodium using a

correction factor.

Patients with DKA often have hyponatremia

Decrease in measured serum sodium concentration due to

high serum glucose concentration causing water shift from

intracellular to extracellular space

Adjusted Na = serum Na x CF x (serum glucose – 100) / 100

where CF is:

1.35 - calculated using mathematical model

1.6 - calculated using mathematical model (1973)

2.4 - measured in healthy volunteers (1999)

1.5 - measured in patients undergoing hemodialysis (2010)

Question: Which correction factor is more accurate?

A. 1.35 - calculated

B . 1.6 - calculated

C. 2.4 - measured

D. 1.5 - measured

Serum and urinary Na concentration changes in patients

with DKA

2 days duration

Conclusion: hyponatremia in DKA was caused by sodium

loss with urine

Measured CF value is more accurate in healthy volunteers

with acutely induced hyperglycemia of brief duration when

applied to healthy volunteers or when it is measured in

patients with renal failure on dialysis and applied to the

patients with renal failure

Nether factor can be accurate in patient with hyperglycemia

of long duration (DKA) and healthy kidneys.

Answer:

A. 1.35 - calculated

B . 1.6 - calculated

C. 2.4 - measured

D. 1.5 - measured

E. None of the above

Dilutional hyponatremia is physiologically improbable in the

settings of DKA. The practice of calculating adjusted serum Na

according to the degree of hyperglycemia is based on inappropriate

data.

Osmotic tension of serum is represented by measured (actual) rather

than adjusted (calculated) Na concentration.

If calculating serum Na is not utilized in clinical decision making, it

becomes a useless exercise.

Using adjusted serum Na in clinical decision making may interfere

with selecting crystalloid solutions with higher Na content, that

would allow serum Na to increase in a controlled manner during

treatment of DKA.

Do not correct hyponatremia if the serum sodium

value adjusted for the degree of hyperglycemia is

within normal range

Allow serum glucose to decrease by

50 to 100 mg/%

600

500

400

300

200

100

600

400

200

0 2 4 6 8 10 12 14 16 18 20 22 24

Recommended rate of decrease of serum glucose

50%/hr 100 mg%/h

600

500

400

300

200

600

400

200

0 2 4 6 8 10 12 14 16 18 20 22 24

Recommended rate of decrease of serum glucose

50%/hr 100 mg%/h

600

344 340 336 332 328 324 320 316 312 308 304 300

0 2 4 6 8 10 12 14 16 18 20 22 24

Osmolarity

50 mg% of glucose = 2.7 mOsm

1 mMol = 18 mg%

2 mMol = 36 mg%

600

500

400

300

200

100

344 340 336 332 328 324 320 316 312 308 304 300

0 2 4 6 8 10 12 14 16 18 20 22 24

Recommended rates of decrease of serum glucose and

serum osmolarity

Glucose Osmolarity

600

500

400

300

200

100

344 330 320 310 305 300 300 300 300 300 300 300

0 2 4 6 8 10 12 14 16 18 20 22 24

Actual rates of decrease serum osmolarity when serum

glucose decreases at 50 mg%/h

Glucose Osmolarity

600

555

510470

425

380

335

290

245

200

155

100

344 340 336 332 328 324 320 316 312 308 304 300

0 2 4 6 8 10 12 14 16 18 20 22 24

Ideal rate of decrease of serum glucose to match

recommended rate of decrease of serum osmolarity

Glucose Osmolarity

600

500

400

300

200

100 100 100 100 100 100 100

344 340 336 332 328 324 320 316 312 308 304 300

130 133 136 139 142 145 148 145 142 139 139 139

0 2 4 6 8 10 12 14 16 18 20 22 24

“Ideal” changes of serum glucose, Na and osmolarity

Glucose Osmolarity Na

Insulin should be administered at a low dose of

0.1U/kg/h.

A woman, aged 73 admitted with DKA. Drowsy but rational,

dehydrated, BP 160/70, HR 108, serum glucose 605. She received

100 u of insulin IV, then another 100 u. Following administration

of the second dose of insulin she developed urticaria. Subsequent

doses of insulin were given IM. Repeat serum glucose was 812,

and insulin dose was increased to 300 u, the third glucose level was

856 followed by 500 u of insulin. She received two more doses of

insulin 1000 u each for a total dose of 3000 u. Assuming the time

period was 24 hours, this amount of insulin was = 1.7 u/kg/hr

She survived to discharge

Nabarro JDN, Spencer AG, Lond MD, Lond GM, Stowers JM, Gamb MB,

Harvard MD. Treatment of diabetic ketosis. Lancet, 1952:May,6716-22

Randomized prospective study of low-dose insulin (0.1U/kg/h) vs. high-dose (1.0 U/kg/h) given by continuousintravenous infusion.

Plasma glucose decrease faster in the high-dose insulin group.

Hypoglycemia during the first 12 h of therapy - fewer in the low dose group.

The decrement of ketone bodies, cortisol, and glucagon was similar in both groups.

The rate of correction of acidosis was similar in both groups

Hypokalemia – fewer in the low dose group.

Burghen GA, Etteldorf JN, Fisher JN, Kitabchi AQ. Comparison of high-dose and low-dose insulin by continuous

intravenous infusion in the treatment of diabetic ketoacidosis in children. Diabetes Care. 1980;3(1):15-20.

33 patients, 2 - 4 U/h (0.028 – 0.057 U/kg/h assuming 70kg body mass)Hannah TJ, Stathers GM. Constant low-dose insulin infusion

in severe diabetes mellitus. Med J Aust.1976;1(1-2):11-3

114 patients with severe DKA, mean age 31, mean insulin dose

during ICU stay 0.026 U/kg/h (assuming 70 kg body mass). No

mortality and no complications.Wagner A, Risse A, Brill HL, Wienhausen-Wilke V, Rottmann M, Sondern K, Angelkort B. Therapy of severe

diabetic ketoacidosis. Zero-mortality under very-low-dose insulin application. Diabetes care. 1999;5:675-7

41 newly diagnosed with severe DKA, under 5 years, 0.05 U/kg/h Puttha R, Cooke D, Subbarayan A, Odeka E, Ariyawansa I, Bone M, Doughty I, Patel L, Amin R; Low dose

(0.05 units/kg/h) is comparable with standard dose (0.1 units/kg/h) intravenous insulin infusion for the initial treatment

of diabetic ketoacidosis in children with type 1 diabetes-an observational study. Pediatr Diabetes. 2010;11(1):12-7

What is considered to be low dose of insulin (0.1 U/kg/h) may not

be the lowest effective dose. This dose was designated as low by

default, since it was the lowest dose tested in a prospective

randomized trial (class I evidence).

“Ultra low” dose of insulin may often be as effective as the “low”

dose, but it has not been evaluated in a large prospective

randomized trial.

It would be prudent to use 0.05 U/kg/h as a starting dose and to

titrate it as needed for resolution of ketoacidosis with

simultaneous slow decline of serum glucose level.

Add 5% to 10% dextrose when the serum glucose

concentration falls to approximately 250 mg%

Recommendation: as high as 12.5%.


A hypothetical 5-year-old: weight 20 kg; double maintenance

(120 mL/kg/h); 10% or 12.5% dextrose




Sugar load with 12.5% projected over 24 h: 360 g (1440 kcal)

Sugar load with 10% projected over 24 h: 290 g (1160 kcal)






Energy requirement at the age of 5 is about 1600 kcal/24 h






Energy requirement at the age of 5 is about 1600 kcal/24 h

This patient would be forced to assimilate an exceptionally large

glucose load by receiving a non-physiologically high amount of insulin.

Edema is multifactorial


Mythology based therapy contribution to osmotic CE may

include:

Use of relatively hypotonic fluids



include:


Use of excessive amount of fluids



include:


Use of excessive amount of fluids

Use of excessive amount of insulin

Health & Medicine

Diabetic Ketoacidosis. Myths based therapy