Frank was saying to All .........
FA>To any how may help,
FA>I'm taking an E.M.T. Intermediate class and the new state guide lines
FA>are out and they include something that the instructor has not seen
FA>before it is worth extra credit for me if I can find out something abou
FA>Hyperosmolar Hyperglycemia Non-Ketotic Coma (HHNK) I really need to fin
FA>out the Pathophysiology of this.  I also need Preciptating factors,
FA>Sighs and symptoms, and management.  But any help on this topic would b
FA>greatly appreciated.  Thank you in advance.
Frank,
The following should help....
Non-ketotic hyperosmolar coma is characterized by extremes of hyperglycemia 
and dehydration in
the absence of significant ketoacidosis. The term is actually a misnomer, as 
many patients in a
hyperosmolar state due to decompensated diabetes are not comatose. For 
historical reasons, the
term "non-ketotic hyperosmolar coma" (NHC) will be continue to be used with 
the caveat that the
term implies a diabetic in a hyperglycemic, hyperosmolar state with a mental 
status ranging from
mild drowsiness to deep coma. As our understanding of the pathophysiologic 
processes has
improved, emphasis has shifted from rapid rehydration in conjunction with 
large doses of insulin to
a more cautious, gradual approach. The key to successful management involves 
avoiding rapid
fluid shifts which possibly contribute to cerebral edema, pulmonary edema, 
and other
complications as well as treating any precipitating causes for the illness.
Pathophysiology
There are several theories to explain why some patients with decompensated 
diabetes develop
NHC, and others go into a state of ketoacidosis. Not one study purporting to 
reveal the
pathogenesis of NHC has been met with widespread agreement. At least three 
possible
mechanisms are considered to play a role: 1) free fatty acid and counter 
regulatory hormone levels
are lower in nhc; 2) pancreatic insulin secretion is higher in nhc so that 
lipolysis is prevented; 3) the
hyperosmolar state inhibits lipolysis[1, 2].
Regardless of the precise mechanism, in all patients the pathogenesis is the 
same: hyperglycemia
leading to osmotic diuresis in the setting of inadequate water intake, with 
subsequent hypotonic
fluid losses, severe hypertonicity, and profound volume depletion. 
There are numerous factors that may predispose to the development of a 
hyperosmolar state in the
diabetic patient. Infections (particularly pneumonia and pyelonephritis), 
steroid use,
cerebrovascular accident, myocardial infarction, and noncompliance are the 
most common
triggers[3]. 
Clinical Features
The hallmark of NHC is dehydration. It would be very difficult for a patient 
to develop NHC had
they access to an adequate supply of water and the ability to drink. 
Occasionally, patients present
with a remarkably high serum glucose value yet their mentation is normal. 
Such patients have
avoided dehydration either by keeping up with their fluid losses with oral 
intake, or else renal
insufficiency prevented excessive excretion of fluid. It takes time for 
patients to develop the
dehydrated state, an average of 9-12 days. As the onset of the condition can 
be insidious, the
pathologic processes may proceed unchecked until the patient is brought to 
medical attention. In
contrast, the patient with DKA usually has dramatic findings within 3 days 
of onset of the
decompensation due to the dynamic process of ketoacidosis. Siperstein points 
out that DKA and
NHC are at polar ends of a continuous spectrum of diabetic decompensation, 
and patients in a
state of NHC often will have a mild ketosis present. [4] 
Patients with NHC who are alert enough to give a history will usually 
complain of nausea,
weakness, intense thirst, and polyuria. Family members may note behavior 
disturbances, seizures,
obtundation, or other neurologic complaints. There may be complaints 
referable to the underlying
illness. Special attention should be paid to the possibility of gram 
negative pneumonia and
urosepsis. See Table 1 for a complete list of factors associated with 
NHC[1-3] 
Vital sign measurements in NHC will usually reveal a mild tachycardia, with 
normal or low blood
pressure. Temperature will be normal or low; it will not be elevated simply 
as a result of
hyperosmolarity. An elevated temperature should cause significant concern 
over the possibility of
infection. Physical findings will include signs of severe dehydration. The 
appearance of the tongue
is a good indicator as to the degree of water loss. Various nonspecific 
neurologic findings often
include Babinski reflexes, hypo or hyperreflexia, nystagmus, and urinary 
retention [6].
Laboratory evaluation
Various parameters have been used to invoke the diagnosis of NHC, expecially 
since the
distinction between NHC and DKA has become blurred. Depending on which 
author you read,
the serum osmolarity should be anywhere from 320mOsm/l[7] to 350mOsm/l[6]. 
Most feel the
serum bicarbonate should be above 15mEq/L, the arterial pH above 7.2 or 7.3, 
and the glucose
above 600[2, 4, 8].
When considering the serum osmolarity, it is only particles that have an 
effect accross cell
membranes that are relevant. Sodium and glucose are effective osmolar 
particles as they do not
move freely across cell membranes. On the other hand, urea does not exert an 
osmolar effect as it
moves freely across the cell membrane. What we are most interested in, 
therefore, is the effective
osmolarity, otherwise known as the tonicity of the solution[9]. The 
effective osmolarity should be
calculated by the equation:
(2 x sodium) + Glucose/18 = Effective osmolarity (tonicity)
Note that the usual calculation of BUN/2.8 is excluded as urea does not 
contribute an osmolar
force. By the same token, measured osmolarity can confuse the picture, 
because determination of
the measured osmolarity includes urea particles in the analysis. A measured 
osmolarity may be
useful for other purposes, i.e. if an ingestion of methanol or ethylene 
glycol is suspected. 
These calculations become important when one is faced with a patient in a 
coma that is ascribed to
NHC. Note that if the effective osmolarity is less than 330 or 340, it is 
highly unlikely that the
coma is due to hyperosmolarity, and other causes of coma should be sought 
aggressively. 
Appropriate laboratory determinations would include electrolytes, BUN, 
creatinine, and glucose.
Anion gap should be calculated by the equation 
Na - (Cl + HCO3) normal range = 8 -16
An elevated anion gap with rare exceptions indicates a metabolic acidosis. 
Lactate levels and
serum ketones may be useful in determining the etiology when significant 
acidosis is present. 
Other lab values of interest would be an arterial blood gas, serum 
phosphate, liver function tests,
and PT/PTT in extremely ill patients. The CBC frequently reveals 
leukocytosis which may be
nonspecific. However, increased band count correlates with infection more 
consistently than the
overall white cell count. Urinalysis for infection and ketones should be 
documented. One should
have a low threshold for obtaining blood cultures and CSF for analysis. 
Electrocardiogram and
chest x-ray are important basic modalities in the work-up, and a CT of the 
brain should be
obtained if the possibility of intracranial pathology exists.
Management
The cornerstones of therapy in NHC are rehydration and electrolyte 
supplementation, along with
treating the underlying etiology for the decompensation. Administering 
insulin is not a crucial aspect
of management, because as a patient's volume status improves, there will be 
more native insulin
delivered to distal insulin receptors[10]. Until the 1980's it was common 
for patients to receive
boluses of 100 units of regular insulin at a time. A retrospective study in 
1983 found that a uniform
regimen of low dose insulin reduced the incidence of complications[3] . It 
is generally
recommended that once rehydration is well under way, patients should receive 
0.1 to 0.2 units/kg
regular insulin IV bolus, followed by the same dose per hour in an insulin 
infusion. If the insulin is
given prior to starting volume resuscitation, there may be intravascular 
collapse as glucose and
water moves into cells and out of the intravascular space. In situations 
where an insulin drip is
impractical, it may be administered as an hourly IM dose after the initial 
intravenous dose.
However, the IM route should be avoided in hypotensive patients due to 
erratic absorption. The
goal should be to lower the serum glucose no faster than 80-100mg/dl/hr. 
Faster rates may
precipitate hypotension and undesirable fluid and electrolye shifts. There 
is controversy regarding
the serum level at which supplemental D5W should be started. Arieff (1986) 
reported on 5
patients with NHC who suffered devastating consequences from cerebral edema, 
which he felt
was due to rapid lowering of the serum glucose to levels below 250mg/dl[8]. 
However,
Rosenbloom (1990) found no correlation in rate of correction of 
hyperglycemia or tonicity of
administered fluids and the development of cerebral edema in his review of 
69 patients with
DKA[11]. Arieff advocates administering D5W with insulin once the serum 
glucose reaches
300mg/dl, and not allowing the serum glucose to drop below 250- 300mg/dl for 
the first 24 hours
of treatment. Further studies need to be performed before a definitive 
conclusion can be drawn.
It is the hyperosmolar state that is the most dangerous aspect of NHC. The 
average deficit of total
body water is 20-25% of the total body water, or 8-12 liters. Attention must 
be paid to electrolyte
supplementation early on due to large total body deficits. This is 
especially true for potassium. As
glucose is driven into cells, so will be potassium, which may lead to 
precipitous hypokalemia and
cardiac arrhythmias. Hypokalemia is usually accompanied by hypomagnesemia, 
and early
supplementation of magnesium should be considered. Serum magnesium levels 
may be obtained,
but unfortunately these levels frequently do not accurately reflect total 
body magnesium stores.
How quickly should euvolemia be restored, and with what type of fluid? In 
one retrospective
review, the initial infusion rate was one to two liters per hour for the 
first two hours, followed by
one liter per hour for the next two hours, followed by decreases as dictated 
by clinical response
[3]. The authors of this study felt that the rapid rehydration helped to 
avoid thromboembolic
complications. Siperstein argues for 3.5-5 liters in the first five hours, 
followed by a rate of
250-500cc/hour[4]. 
Others suggest an approach that is more conservative, with a goal of 
replacing half the fluid deficit
in the first 12 hours, and half in the second 12 to 24 hours [1,6,8]. If 
there is a significant
component of ketoacidosis, a more modest rate of resuscitation may be 
indicated. This is based on
a prospective trial in which patients with DKA were randomized: group 1 
received one liter normal
saline per hour for four hours followed by 500cc/hr for four hours; group 2 
received fluid at half
this rate. Group 2 had a better outcome, with more rapid normalization of 
the serum
bicarbonate[12]. 
A few authors have recommended colloid in the setting of severe dehydration 
with hypotension. In
clinical practice, however, normal saline is more often chosen in the 
presence of hypotension.
Cerebral edema, a dreaded complication of diabetic decompensation, was once 
thought simply to
be due to too rapid a rate of fluid resuscitation. This was not confirmed by 
a recent retrospective
study[11]. The etiology of cerebral edema in the DKA- hyperosmolar state is 
not known. One
theory invokes particles known as "idiogenic osmoles" which are formed in 
the brain in the
presence of severe hypertonicity and serve to prevent complete intracellular 
dehydration . The
topic is quite controversial and complex; a detailed analysis is beyond the 
scope of this chapter. 
Cerebral edema often occurs at a time when the patient appears to be 
improving in response to
therapy, but it also has occurred prior to initiation of therapy. Rosenbloom 
conducted a thorough
retrospective search for treatment variables contributing to cerebral edema. 
Among the variables
he examined included rate of correction of serum glucose, sodium, and 
potassium; amount of
insulin used; and bicarbonate use. He was unable to show any correlation 
with these variables and
the occurrence of cerebral edema. Rosenbloom recommended vigilance for signs 
of cerebral
edema: headache, change in mental status, vomiting, especially after a 
period where the patient had
shown substantial clinical improvement. Rapid intervention should consist of 
mannitol 1-2g/kg
intravenously and hyperventilation to an arterial pCO2 of 25-30 mm Hg for 
intubated patients. 
Rehydrating the hyperosmolar diabetic should be approached thoughtfully, 
with management
individualized for every patient. The elderly patient should probably 
receive no more than 500cc to
one liter over the first hour, with a rate of 250-500cc/hour over subsequent 
hours. The younger
patient, however, may tolerate a more aggressive treatment regimen. 
A relatively safe approach would be to restore one half the fluid deficit in 
the first eight to twelve
hours, and the second half within thirty six to seventy two hours. The urine 
of the patient with NHC
is hypotonic, with a consistency similiar to that of half normal saine with 
40 mEq KCL per liter.
Most authors recommend normal saline for initial intravenous fluid choice 
until the blood pressure
is normalized, followed by half normal saline. If the patient's serum sodium 
is elevated at the outset,
it would preferable to use half normal saline as the the initial choice of 
fluid, provided shock is not
present. As soon as the blood sugar has dropped to below 300, the patient 
should be given
dextrose in the intravenous fluids to avoid hypoglycemia. Dropping the 
glucose level rapidly to
below 250mg/dl was found to be a predisposing factor for cerebral edema, 
according to one of
the original studies of NHC[13]. It should be noted that not all 
investigators agree with this
conclusion, however.
Once the patient has started producing urine, potassium should be added to 
the intravenous
solution if the measured potassium is 5 meq/l or less. The serum potassium 
should be checked
every one to two hours for the first few hours.
There has been considerable controversy regarding the use of phosphate in 
DKA and NHC.
Fisher (1983) conducted a randomized controlled trial of phosphate in 30 DKA 
patients. There
was no difference in recovery indices such as mental alertness and hours to 
reach a glucose of
250mg/dl. The group receiving phosphate exhibited significantly lower plasma 
ionized calcium
values. Fisher concluded that phosphate therapy may accelerate regeneration 
of erythrocyte
2,3-DPG but it had no demonstrable influence on tissue oxygenation or 
clinical response to low
dose insulin therapy of DKA. Furthermore, the exaggeration of hypocalcemia 
seen in phosphate-
treated patients may be reason for caution in the use of such therapy. 
Bohannon noted in a case
report (1989) that since rapid shifts of phosphorus can occur among body 
compartments, and
severe hypophosphatemia is potentially life-threatening, phosphate levels 
should be frequently
monitored during therapy for hyperglycemia and intervention should be 
undertaken if phosphate
levels fall below 0.5 mmol/L. Phosphate may be given as K2PO4, each 
milliliter of K2PO4
contains 4.4 mEq potassium and 3mmol phospate. The K2PO4 should be diluted 
and
administered slowly via an intravenous drip. The danger of inducing ectopic 
calcifications, severe
hypocalcemia, and tetany should be considered whenever phosphate is 
given[14-16].
Magnesium may be of benefit as well for the malnourished appearing patient 
who does not have
renal failure, and several authors recommend empiric magnesium therapy in 
addition to
multivitamins for patients with DKA or NHC. Magnesium may be given in the 
form of magnesium
sulfate, 2 grams added to a liter of intravenous fluids.
Seizures are not uncommon with NHC, and deserve special consideration. 
Phenytoin should be
avoided as not only is it ineffective in this setting, it also inhibits 
release of endogenous insulin[6].
Correcting the hyperosmolar state, and using benzodiazepines and 
phenobarbital for recurrent
seizures represents the correct management when NHC is present. 
Complications
Once rehydration is well underway along with insulin and electrolyte 
repletion, the clinician must
remain vigilant for complications of the illness. Warning signs for cerebral 
edema include severe
headache, worsening level of consciousness, and non- specific neurologic 
findings. Although
cerebral edema is more of a concern in DKA, it can occur in patients 
presenting with NHC.
Measures to reverse elevated intracranial pressure should be undertaken when 
clinically indicated.
A new complaint of shortness of breath would bring up the concern of ARDS, 
CHF, pulmonary
emboli, or myocardial infarction. Aspiration pneumonia may occur due to the 
obtunded state.
Pancreatitis may both precipitate and complicate the hyperosmolar state. 
Hypokalemia may occur
due to undertreatment with potassium, and hypoglycemia due to excessive 
insulin. Patients with
NHC are in a hypercoagulable state due to the increased osmolarity, and are 
at risk for arterial or
venous thrombosis. Intravenous heparin should probably be avoided as 
patients with DKA-NHC
often develop gastrointestinal bleeding. Subcutanous heparin may be helpful, 
although it has never
been studied prospectively. Finally, an underlying trigger of diabetic 
decompensation may become
apparent at any point in the patient management, so complacence must be 
avoided.
Summary
NHC is a life threatening illness that may be found in patients with no 
prior history of diabetes. It is
primarily seen in elderly female nursing home patients, but can occur in any 
age group, including
infants and children. Successful outcome depends on reversing the critical 
effects of
hyperosmolarity while avoiding hypokalemia, hypomagnesemia, hypoglycemia, 
and
thromboembolic phenomena. Expeditious diagnosis and management of underlying 
predisposing
factors is essential as well. Ultimately, the importance of educating 
patients and family members so
that the development of NHC is prevented cannot be overemphasized. 
References
1. Ellis, E.N., Concepts of fluid therapy in diabetic ketoacidosis and 
hyperosmolar hyperglycemic
nonketotic coma. Pediatr Clin North Am, 1990. 37(2): p. 313-21.
2. Kitabchi, A.E. and M.B. Murphy, Diabetic ketoacidosis and hyperosmolar 
hyperglycemic
nonketotic coma. Med Clin North Am, 1988. 72(6): p. 1545-63.
3. Carroll, P. and R. Matz, Uncontrolled Diabetes Mellitus in Adults: 
Experience in treating
diabetic ketoacidosis and hyperosmolar nonketotic coma with low-dose insulin 
and a uniform
treatment regimen. Diabetes Care, 1983. 6(6): p. 579-585.
4. Siperstein, M.D., Diabetic ketoacidosis and hyperosmolar coma. Endocrinol 
Metab Clin North
Am, 1992. 21(2): p. 415-32.
5. Arieff, A.I. and H.J. Carroll, Nonketotic hyperosmolar coma with 
hyperglycemia: clinical
features, pathophysiology, renal function, acid-base balance, 
plasma-cerebrospinal fluid equilibria
and the effects of therapy in 37 cases. Medicine, 1972. 51(2): p. 73-94.
6. Pope, D.W. and D. Dansky, Hyperosmolar hyperglycemic nonketotic coma. 
Emerg Med Clin
North Am, 1989. 7(4): p. 849-57.
7. Wachtel, T.J., et al., Hyperosmolarity and acidosis in diabetes mellitus: 
a three-year experience
in Rhode Island. J Gen Intern Med, 1991. 6(6): p. 495-502.
8. Arieff, A.I., Cerebral edema complicating nonketotic hyperosmolar coma. 
Miner Electrolyte
Metab, 1986. 12(5-6): p. 383-9.
9. Geheb, M.A., Clinical approach to the hyperosmolar patient. Crit Care 
Clin, 1987. 3(4): p.
797-815.
10. West, M.L., et al., Quantitative analysis of glucose loss during acute 
therapy for hyperglycemic
hyperosmolar syndrome. Diabetes Care, 1986. 9(5): p. 465-71.
11. Rosenbloom, A.L., Intracerebral Crises During Treatment of Diabetic 
Ketoacidosis. Diabetes
Care, 1990. 13(1): p. 22-33.
12. Adrogue, H.J., J. Barrero, and G. Eknoyan, Salutary effects of modest 
fluid replacement in the
treatment of adults with diabetic ketoacidosis. Use in patients without 
extreme volume deficit.
Jama, 1989. 262(15): p. 2108-13.
13. Arieff, A.I. and H.J. Carroll, Cerebral edema and depression of 
sensorium in nonketotic
hyperosmolar coma. Diabetes, 1974. 23(6): p. 525-31.
14. Fisher, J.N. and A.E. Kitabchi, A randomized study of phosphate therapy 
in the treatment of
diabetic ketoacidosis. J Clin Endocrinol Metab, 1983. 57(1): p. 177-80.
15. Bohannon, N.J., Large phosphate shifts with treatment for hyperglycemia. 
Arch Intern Med,
1989. 149(6): p. 1423-5.
16. Berger, W. and U. Keller, Treatment of diabetic ketoacidosis and 
non-ketotic hyperosmolar
diabetic coma. Baillieres Clin Endocrinol Metab, 1992. 6(1): p. 1-22.
That should help!! (Even included references for you!!)
Bob Morgan, EMT-P
Bob Morgan (AKA The DoodaMan!!)
doodaman@fast.net
... You must pay for your sins. (If you've paid disregard this notice.)
 * PW *
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