CENTRAL DIABETES INSIPIDUS:

1

• CENTRAL DIABETES INSIPIDUS
• A Potential Neurosurgical Complication
• Sanam Shorey
• Pgy5 Endocrinology

2
OBJECTIVES

• Case Report
• Differential of Polyuria
• ADH Production, Action,Regulation
• 4) Causes of Central DI
• 5) Triphasic Presentation
• 6) Diagnosis
• 7) Treatment
• 8) Back to Case

3
Case Presentation

• History
• 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
• Medns 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.

4
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

5
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
  gt 1 per yr chance of hemorrhage.

6
Investigations Cont

• 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

7
Post-Op

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

8
Post-Op Values
9
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

10
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

11
Definition Polyuria

• Defn arbitrarily defined as U/O gt 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 gt
  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

12
Major Polyuric Syndromes

• Primary Disorders of Water Intake
• Psychogenic polydipsia
• Hypothalamic disease
• Drug induced polydipsia
• 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
• Primary Disorders of Renal absorption of solutes
  (osmotic diuresis)
• 1) Glucose DM
• 2) Salts, esp NACL, diuretics, including
  mannitol

13
Vasopressin Production
14
ACTIONS
15
(No Transcript)
16
Effect on V2 Receptors

• 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.
• 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

17
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.

18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
(No Transcript)
22
Hypothalamic Osmoreceptors

• Situated in the anterior hypothalamus
• High serum osmolality (threshold 280-290mosm/kg)
• efflux of water from the cells
• osmoreceptors shrink
• signals ADH secretion

23
Baroreceptors

• Pts with ECF volume depletion (ie vomiting,
  cirrhosis or CHF) may secrete ADH even in the
  presence of low plasma osmolality.
• 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

24
Baroreceptors (contd)

• 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 lt1 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.

25
Non-Osmotic Stimuli

• not related to osmolality or volume balance
• Nausea most potent potentially lead to a 500
  fold rise in ADH levels (unknown mechanism)
• 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.

26
Non-Osmotic Stimuli

• 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

27
(No Transcript)
28
Polyuria Post Neurosurgery

• Most common cases
• 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

29
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

30
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.

31
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 50431

32
(No Transcript)
33
Results (Contd)

• After 3 months, only 0.9 or pts were still
  receiving ADH. Decreased to 0.25 after 1 yr.
• Risk analysis showed pts with Cushings 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

34
Triphasic Presentation
35
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.

36
Diagnostic Approach to DI

• 1) HX
• 2) PE
• 3) DIAGNOSTIC TESTS

37
Results of Diagnostic Studies In Various Types of
Polyuria
38
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.

39
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)

40
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.

41
WRT WHEN TO STOP?

• 1) Urine Osm reaches a clearly normal value
  ( gt600 mosmol/kg) (normal 275-290), indicating
  both ADH release and effect is normal.
• 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.
• 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
• body wt falls gt 3 since serious problems may
  occur.

42
(No Transcript)
43
(No Transcript)
44
Two Sources of Error

• 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

45
Errors Cont

• 2) 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.

46
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
• 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
  1997821823)
• 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 19953321540)
  
• Problem measurement of this is expensive and not
  currently available

47
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 cant 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.

48
(No Transcript)
49
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.

50
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.

51
Forms of DDAVP
52
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

53
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

54
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

55
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.

56
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.

57
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.

58
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
• Na138, serum osm and urine osm normal
• Doing well clinically, follow-up March with
  interim blood work.