CENTRAL DIABETES INSIPIDUS:

“A Potential Neurosurgical Complication”

Sanam ShoreyPgy5 Endocrinology

OBJECTIVES1) Case Report2) Differential of Polyuria3) ADH: Production, Action,Regulation4) Causes of Central DI5) Triphasic Presentation6) Diagnosis 7) Treatment 8) Back to Case

Case PresentationHistory

40 yr old male, R-handed, mennonite farmer, father of 6 Presented with 2 wk history of decreased vision in his right

eye PMHX: bilateral inguinal hernia repair Med’ns: None No smoking or drinking No family hx of brain tumors, no symptoms of hormonal

deficiency or excess prior to presentation. No hx of polyuria or polydipsia

No c/o of headaches, weakness, sensory changes, changes in gait etc.

Examination NAD, thin male bp 140/80, pulse 78 and afebrile Alert and oriented X 3 R nasal hemianopsia, with Visual acuity

20/80 right eye and 20/20 left eye, Both pupils full and reactive and symmetric.

Power 5/5, cerebellar and gait normal. No pronator drift, normal reflexes

Investigations

MRI/MRA: large right 2.6 by 2.8 cm aneurysm likely in the paraclinoid or opthalmic segment of the right internal carotid artery with compression of the right optic nerve.

Aneurysm large enough to cause mass effect on right optic nerve right nasal hemifield defect > 1% per yr chance of hemorrhage.

Investigations Con’t No preop blood work for hormonal deficiency Preop Na= 139 Preoperative steroids and IV fluids administered

JULY 15Th R craniotomy and clipping of the giant opthalmic

segment aneurysm

Had 4 clips put in place.

Pituitary was clamped

Post-Op Decadron 4mg Po BID , then tapering dose Inputs and Outputs measured hourly Daily Urine osmolality, urine lytes , serum lytes and

serum osmolality

Post-Op Values POD

#2

#3

#5

#9

#10

#12

#14

Na

142

138

128

135

140

138

141

Serum Osm

312

290

274

291

298

291

292

Urine Osm

92

860

896

222

208

248

287

Other Blood Work TSH: 0.511, FT4 9.0, Ft3 2.7 started on

0.075 mg L-T4

Tapered hydrocortisone to 20mg in AM and 10mg in PM

Testosterone normal, LH and FSH low normal

Disposition Discharged and told to monitor his urine output: If increase

noted during the day or night, told to contact us to adjust his DDAVP dose. (10ug bid NS)

Told to keep up with fluids if a problem. If had headaches, confusion, weakness, should go to the

emergency department Serum lytes, serum osm and urine osmolality q wkly X 4wks Follow-up within a month. Serum free T4 and testosterone repeated before next

appointment Serum cortisol after missing pm dose hydrocortisone in

future

Definition : Polyuria Def’n: arbitrarily defined as U/O > 3L /day

Must be differentiated from the more common complaints of frequency or nocturia which are not associated with an increase in total urine output

Ddx nocturia: drinking before sleeping, diuretics before sleeping, prostatic enlargement in men > 50 yrs

If cannot explain new onset nocturia in the absence of the above factors is often an important clue to presence of central or nephrogenic DI

Major Polyuric Syndromes

A) Primary Disorders of Water Intake1) Psychogenic polydipsia2) Hypothalamic disease3) Drug induced polydipsia

B) Primary Disorders of Water Output 1) Nephrogenic DI a) congenital b) acquired: several chronic renal diseases,

(obstructive uropathy, unilateral RAS,), hypokalemia, chronic hypercalcemia, drug induced (lithium, demeclocycline)

2) Central DI 3) Transient DI of pregnancy: placental vasopressinases

C) Primary Disorders of Renal absorption of solutes (osmotic diuresis)

1) Glucose: DM 2) Salts, esp NACL, diuretics, including mannitol

Vasopressin Production

ACTIONS

Effect on V2 Receptors

7) As the collecting ducts transverse the renal medulla, the urine passes regions of ever increasing osmolality, up to 1200mosm/Kg of water at the tip of the papilla.

8) In the presence of ADH, collecting duct fluid equilibrates with the hyperosmotic environment, and urine osmolality approaches that of medullary interstitial fluid.

Thus, maximal ADH effect results in low urine flow, and urine osmolality may approximate 1200mosm/kg

with ADH deficiency, urine flow may be as high as 15-20cc/min and urine osmolality is less than 100 mosm/kg

Common agents affecting ADH V2R action Calcium and lithium inhibit the adenylate cyclase response to vasopressin

Lithium also interferes with a subsequent biochemical action, as does potassium deficiency

Demeclocycline inhibits adenylate cyclase stimulation and also inhibits the cyclic AMP-dependent protein kinase.

Chlorpropramide increases AVP-induced activation of adenylate cyclase.

AVP also stimulates PgE2 which inturn acts as a feedback inhibitor of adenylate cyclase activation

Also ADH stimulates release of clotting factor VIII and VWF from vascular endothelium through V2 receptors. Physiological significance of this action unknown.

Hypothalamic Osmoreceptors Situated in the anterior hypothalamus

1) High serum osmolality (threshold: 280-290mosm/kg)

2) efflux of water from the cells

3) osmoreceptors shrink

4) signals ADH secretion

Baroreceptors Pts with ECF volume depletion (ie

vomiting, cirrhosis or CHF) may secrete ADH even in the presence of low plasma osmolality.

1) Carotid baroreceptors:

are pressure receptors but act as volume receptors indirectly: MABP= CO X SVR

i) fall in CO due to volume depletion

ii) Changes in the rate of parasympathetic afferent discharge from these neurons

iii) affect rate of ADH secretion by the cells of the paraventricular nuclei (via the medulla) The supraoptic nuclei do not appear to be involved in this volume sensitive response

Baroreceptors (cont’d)2) Atrial receptors

act similarly: moderate reduction in filling pressure does not stimulate ADH release unless there is a concomitant decline in systemic blood pressure

NOTES:

Sensitivity of these receptors are less than osmoreceptors:

ie <1% drop serum osmolality causes ADH release via osmoreceptors but need substantial drops in volume that cause significant change in bp before you get ADH release

Also RAAS with volume depletion get increase in Ang II which stimulates ADH and thirst.

Non-Osmotic Stimuli not related to osmolality or volume balance

1) Nausea: most potent: potentially lead to a 500 fold rise in ADH levels (unknown mechanism)

2) Pain, Post op: get lots of ADH, if lots of free water given in this setting, water retention, severe hyponatremia, and potentially irreversible neurological damage may ensue.

Non-Osmotic Stimuli3) Pregnancy: lowers the osmoregulatory threshold for ADH release and

thirst. As a result there is a downward resetting of the osmostat leads to a fall in the normal plasma sodium concentration by about 5meq/L This change, which is rapidly reversed after delivery, may be mediated by increased release of hcg.

4) Cortisol inhibitory effect secretion CRF and ADH from the paraventricular nuclei.

Adrenal insufficiency rise in ADH contributes LOW NA

Polyuria Post Neurosurgery Most common cases

1) excretion of excess fluid administered during surgery (stress induces ADH and pt receiving fluid preop)

2) osmotic diuresis resulting from treatment aimed at minimizing cerebral edema with mannitol (which causes hyperglycemia)

3)Stress of surgery may also induce insulin resistance and may exacerbate DM (or steroid induced hyperglycemia) producing an osmotic diuresis

Central DI post Neurosurgery Can be induced by injury to the hypothalamus,

the hypothalamic tract and posterior pituitary.

The incidence of CDI in pts varies with the extent of injury, ranging from 10-20% after removal of an adenoma limited to the sella to as high as 60-80% after removal of very large tumors.

Majority of DI is transient gradually resolving over 2-5 days

Prevalence of permanent CDI is consistent in the literature ranging from zero to 1.2%

Central DI post Neurosurgery

Very early onset polyuria often associated with major hypothalmic damage and increased mortality

Least frequent but most important to recognize is the triple response which usually results in permanent CDI.

Patterns of Postoperative Polyuria

Study of 1571 pts underwent TSS for pituitary adenomas of all types

30% had microadenomas, 70% macroadenomas.

Hensen, J, Henig, A et al. Prevalence, predictors and patterns of postoperative polyuria and hyponatremia in the immediate course after TSS for pituitary adenomas Clin Endocrinol (Oxf) 1999; 50:431

Results (Cont’d) After 3 months, only 0.9% or pts were still

receiving ADH. Decreased to 0.25% after 1 yr.

Risk analysis showed pts with Cushing’s disease had a fourfold higher risk for polyuria than pts with Acromegaly and a 2-8 fold increase risk of post-op hyponatremia.

Younger age, male sex, and intrasellar expansion were associated with a higher risk of hypotonic polyuria but not considered clinically relevant

Triphasic Presentation

Sequelae: Pituitary Stalk Damage Magnicellular neurons are unique, after the axons are

sectioned, the neurons survive and there is outgrowth of the dendrites and regeneration of the new axons.

Create neurosecretory processes in the CSF of the third ventricle as well as in the perivascular region of the external zone of the median eminence

However this is generally not sufficient to restore ADH secretion

Long term follow up of pts: possible return of sufficient vasopressin function that the patient no longer has symptomatic DI.

Diagnostic Approach to DI1) HX

2) PE

3) DIAGNOSTIC TESTS

Results of Diagnostic Studies In Various Types of Polyuria

Central Diabetes Insipidus

Partial CDI

Nephrogenic Diabetes Insipidus

Psychogenic Polydipsia

Random Plasma Osmolality

↑

↑

↑

↓

Random urine Osmolality

↓

↓

↓

↓

Water Restriction Test Done under close supervision since PP will go to

great length to find water and pts with DI will get dehydrated quickly.

Serum OSm is less than 295mosm/Kg

Allow no fluids for 12-18hrs

Measure body weight, Urine volume and osmolality q 1h and plasma sodium and osmolality every 2 hrs.

Principles: Water Restriction Test

1) Raising the plasma Osmolality leads to a progressive elevation in ADH release and therefore urine Osm should increase in normals.

2) Once the plasma Osm reaches 295 to 300 mosmol/kg (normal 275-290 mosmol/kg) the effect of endogenous ADH on the kidney is maximal. At this pt administrating ADH will not further elevate the urine Osm unless the endogenous ADH is impaired ( ie pt has central DI)

WRT: HOW IS IT DONE?

Done under close supervision since PP will go to great length to find water and pts with DI will get dehydrated quickly.

Serum OSm is less than 295mosm/Kg

Allow no fluids for 12-18hrs

Measure body weight, Urine volume and osmolality q 1h and plasma sodium and osmolality every 2 hrs.

WRT: WHEN TO STOP?

1) Urine Osm reaches a clearly normal value ( >600 mosmol/kg) (normal 275-290), indicating both ADH release and effect is normal.

2) Urine Osm is stable on two or three successive measurements despite a rise in plasma Osm. Ie not increased more than 30mOsm/Kg for three consecutive hours.

3) Plasma Osm exceeds 295-300 mosm/kg At plasma osm of 295 –300mosm/kg, endogenous ADH levels

should be 2-5pg/ml, and the kidney should respond with maximal urinary concentration

4) body wt falls > 3% since serious problems may occur.

Norm

CDI

Partial CDI

Nephrogenic DI

Psychogenic Polydipsia

Urine Osmolality during water deprivation

> 800

< 200

Slight increase (>300-800)

Slight increase but still < 200

Rise to > 500

Urine Osmolality following IV vasopressin

300-800

300-800

↑ still < 300

No response since endogenous release is intact

Plasma Vasopressin levels (after WRT pg/ml)

> 2

undetectable

<1.5

5

< 5 No change

Special Caveats -similar to pCDI UOsm dilute after water restrict Hx helpful

Maximum conc’n ability frequently impaired, resulting in a maximum Uosm 500-600 osm/kg Due to 1) partial wash out of the medullary interstitial gradient 2) Downregulation ADH

Two Sources of Error

1) partial central DI ADH receptor upregulation may be hyperresponsive to the submaximal rise in ADH induced by water restriction

therefore they may be polyuric at the normal posm 280-290 (low ADH levels)

then have a maximally concentrated urine at a posm above 290 mosm/kg when ADH levels are somewhat higher.

In this effect exogenous ADH will be without effect, resulting in a pattern suggestive of primary polydipsia.

In this case history important where abrupt onset favors Partial CDI and hx of psychiatric illness favors primary polydipsia

Errors Con’t2) Gestational DI:

polyuria results from the release of vasopressinases from the placenta

pt will be resistant to aqueous Vasopressin (suggesting NDI) but will respond to DDAVP which is resistant to vasopressinases.

Aquaporin-2 Excretion Future test to measure the urinary excretion of aquaporin-2, the

collecting tubule channel which normally fuses with the luminal membrane of the collecting tubule cells under the influence of ADH.

Two reports:

1) uaq02 excretion was several fold higher in normal persons compared to those with central DI while drinking water ad lib and after infusion of hypertonic saline (Saito T, Ishikawa S Et al JCEM 1997;82:1823)

2) Uaq02 excretion increased substantially and to a similar extent after the administration of ADH in normal subjects and those with central DI: there was no increase however in 4 pts with hereditary NDI (Kanno K, Sasaki S et al. NEJM 1995;332:1540)

Problem: measurement of this is expensive and not currently available

Treatment of CDI Goal: decrease thirst and polyuria to an

acceptable level and to allow pt to maintain a normal lifestyle

Most pts with CDI have intact thirst and can keep up with fluids.

If not treated and can’t keep up with fluids: hypernatremic: encephalopathy with obtundation, coma and seizures by brain shrinkage. A decreased volume of brain in the skull may lead to SAH and intracerebral bleeding.

DI after Hypothalamic or Pituitary Surgery Surgeon often knows how severely the posterior pituitary or

stalk has been injured

Sometimes duration of DI is transient, and may prefer to treat only with fluid replacement parenterally or orally (if pt is alert and able to respond to thirst)

Treatment = Desmopressin 0.5-2 ug sc, im, or iv. Iv preferred since there is no question about absorption. U/O is reduced in 1-2 hrs and the duration of effect is 6-24 hrs.

Because DI may be transient and some pts experience the triphasic pattern, it is desirable to allow polyuria to return before administrating subsequent doses of desmopressin.

Desmopressin Initial aim therapy to reduce nocturia, therefore

provide adequate sleep, after this is achieved one aims to control diuresis during the day.

Previously used IM Vasopressin: problem occasional development of Antivasopressin antibodies with a subsequent increase in urine output that now appeared to be ADH-resistant

IM vasopressin now replaced by desmopressin: a 2 aa substitute synthetic structural analogue of the human hormone arginine vasopressin: ADH that has potent antidiuretic but no vasopressor activity.

Forms of DDAVP

Supplied Dosage/day Titration Equivalence Injection

Ampules 1ml=4ug

1-4 ug

1

Nasal Spray Rhinyle Solution

2ml or 5ml spray= 10ug 2.5 ml 250ug with rhinyle tube

Upto 40ug Onset 1hr Peak 1-5hr Duration 6-16hr

Nocturia Then daytime titration

10

Tablets

0.1 or 0.2 mg

0.1-0.8mg three divided doses onset 1hr duration 7-9hrs

Initial dose 0.05mg bedtime then daytime titration

100

Risk of Hyponatremia HOW??

Once Desmopressin given, the pt has a non-suppressible ADH activity and may be unable to excrete ingested water normally

HOW AVOIDED??

Give the minimum dose that is required to control the polyuria

Tell Pt to drink fluids only when thirsty

Other side effects:

headache, nausea, rhinitis, epistaxis, HTN, flushing, pain at injection sites, nasal congestion, abdominal cramps

1) Chlorpropramide: Acts by promoting the renal response to ADH or

Desmopressin. How? Enhanced sodium chloride reabsorption in the

thick ascending limb (increases medullary hypertonicity) or by augmented collecting tubule permeability to water.

Usual dose 125-250mg, once or twice a day. SIADH Higher doses may create hypoglycemia

2) Carbamazepine And 3)Clofibrate

Carbamazepine (antiepileptic) dose of 100-300mg twice daily and Clofibrate (anti-hyperlipidemic) dose of 500mg every 6 hrs

Carb: enhances renal response to ADH

Clofibrate: may increase ADH release

4) Thiazides + 5)NSAIDs Act independent of ADH

These drugs can be used with other agents in central DI and generally constitute the only effective therapy in ADH-resistant Nephrogenic DI.

Thiazide and low sodium diet mild volume depletion increase in proximal sodium and water reabsorption diminishes water delivery to the ADH-sensitive sites in the collecting tubules reducing the urine output.

1-1.5 kg wt loss can reduce the u/o by more than 50% form 10L/day to below 3.5L/day in one study with pts with nephrogenic DI

Dose: 25mg once or twice a day of HCTZ

Also raises blood sugar to counteract effect of Chlorpropramide.

NSAIDs Increases concentrating ability, by inhibiting

prostaglandins (note PG normally antagonize action of ADH)

If pts given a submaximal dose of ADH, the ensuing rise in urine osmolality can be increased by more than 200mosm/Kg if the pt pretreated with a NSAID

Net effect = 25-50% reduction in urine output

Not all NSAIDS equally effective ie: some good response with indomethacin, other little benefit with ibuprofen.

IV FLUIDS Most can replace water losses orally via

stimulation of thirst

But those unable to do so require IV therapy with D5W

Problem: IV administration of dextrose and water at a rate exceeding 1000ml/hr can result in delivery of glucose at a rate exceed endogenous metabolic capacity: osmotic diuresis

Such diuresis is ADH resistant but the administration of insulin to correct hyperglycemia will restore ADH sensitivity.

Patient Update 3 months later: drinking fluids despite not feeling thirsty,

peeing copious amounts of urine and decided to increase number of sprays per day from 3 to 4.

Na= 128 SOsm: 258 Uosm: 819

Told to cut back on drinking (drink only when thirsty) and cut back to two sprays/day

Na=138, serum osm and urine osm normal

Doing well clinically, follow-up March with interim blood work.