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Disorders of Water MetabolismDisorders of Water Metabolism
Diabetes Insipidus and HyponatremiaDiabetes Insipidus and Hyponatremia
Lewis S. Blevins, Jr., M.D.
A French woman had suffered from “a burning thirst” since birth.
At the age of three she consumed two buckets of water per day.
She ran away from home because of “the ill treatment this
disposition occasioned her to experience from her parents”.
When examined in Paris in 1791 she was in good health and
had given birth to ten children. She continued to drink great
quantities of water. The other patient was an English laborer
who after a long febrile disease developed thirst and polyuria at
the age of 31. Twenty-four years later he was still drinking
20–25 l per day but otherwise in perfect health. It is difficult to
doubt that both patients suffered from diabetes insipidus—
though less clear of which type.
First clear description of Diabetes Insipidus in 1792
Lindholm Pituitary 7: 33–38, 2004
Medical facts and observations. London. 1792;2:73–101
NeurohypophysisNeurohypophysis
AVP secreting neurons in SON and PVN
Osmo- and thirst receptors/centers in anterior
hypothalamus
Ascending pathways from ANS and brainstem
Terminal boutons in neurohypophysis
Relationship between Plasma Osmolarity and AVPRelationship between Plasma Osmolarity and AVP
© Astellas
Alterations in AVP secretionAlterations in AVP secretion
AVP ReceptorsAVP Receptors
Receptor
V1A
V1B
V2
Location
Vascular smooth
muscle, platelets
Anterior pituitary
Renal collecting duct
Effect
Vasoconstriction,
platelet aggregation
ACTH release
Free water absorption
AquaporinsAquaporins
Relationship between Urine Osmolarity andRelationship between Urine Osmolarity and
AVPAVP
© Astellas
AVP DynamicsAVP Dynamics
Diabetes InsipidusDiabetes Insipidus
PolyuriaPolyuria
• Passage of large quantities of dilute urine due to absence of
vasopressin or lack of its action
• Urine specific gravity usually <1.005
• Polyuria defined as 30 mL urine per kg body weight in 24h
• UOP >300 mL/h over 2-3 consecutive hrs in hospitalized
patient at-risk for DI is suggestive
• Broad DDx including DM, renal disease, solute load, excessive
intake of oral fluids, overzealous administration of IV fluids,
post surgery for Acromegaly, therapy with vaptans, etc.
Diabetes InsipidusDiabetes Insipidus
ThirstThirst
• Thirst is logarithmic
• Usually begins at a pOsm higher than the set point
for AVP secretion
• Defense against dehydration
• Serum sodium and pOsm usually “normal” and at
thirst set point if patient able to respond to thirst
• Concern in patients with:
o Adipsia
o Altered sensorium
o Restrained
PolydipsiaPolydipsia• Water intake due to a combination of factors
o Social
o Cultural
o Solute load
o Volume status
o Psychological
• Polydipsia in DI is a measure of the response to thirst due
to increased pOsm and volume depletion
• Patients often prefer iced water, take water everywhere,
always know where to get it…. “water dogs”
• Beware of those with Psychogenic Polydipsia who can
nearly mimic DI
Neurogenic Diabetes InsipidusNeurogenic Diabetes Insipidus
CausesCauses
• Transsphenoidal surgery 5-30% depending on many factors
• ACA aneurysms/bleeds
• Suprasellar lesions
o Craniopharyngioma
o Pilocytic astrocytoma
• Infiltrative disorders
o Langerhans Cell Histiocytosis
o Sarcoidosis
• Inflammatory disorders
• Metastases
• Head trauma
• Heritable disorders
• Nephrogenic causes
Diabetes InsipidusDiabetes Insipidus
Suspicion and DiagnosisSuspicion and Diagnosis
• Intake and Output relative to body weight
• Urine specific gravity
• Serum or urine glucose if Ur spgr is not low
• Serum sodium
• Clinical history and imaging characteristics
• Observation
• Trial of therapy
• Water deprivation test
Diabetes InsipidusDiabetes Insipidus
Acute ManagementAcute Management
• Encourage PO intake to drink to thirst
• Use GI tract access via tube if possible
• IVF ½ NS or D5W at 150-200 mL/hr for a few liters if
needed
• AVP sc 3-5 U q4-6 hrs PRN
• Intranasal dDAVP 10 mcg PRN
• sc dDAVP 0.5-2 mcg PRN
• Re-dose when needed
Diabetes InsipidusDiabetes Insipidus
Chronic ManagementChronic Management
• Intranasal dDAVP 10-20 mcg qd-bid PRN
• dDAVP 0.05-0.2 mg PO qD-tid PRN
• Drink to thirst
• Awareness of I/O, body weight
• Subsequent dosing based on demonstrated need at
least once per week
• Avoidance of situations that lead to water intoxication
• Periodic withholding of therapy as DI sometimes
improves
• Water Rx for those with adipsic hypernatremia
• Careful control of rate of rise in patients with
hyponatremia
HyponatremiaHyponatremia
one of many algorithmsone of many algorithms
Hyponatremia in Pituitary PatientsHyponatremia in Pituitary Patients
• Preoperative
o Cortisol deficiency
o Hypothyroidism
o SIADH
• rarely seen due to pituitary tumors
• Not uncommon in hypothalamic tumors
• Immediate Postoperative
o SIADH
• Delayed Postoperative
o dDAVP excess
o Other causes (medications, etc.)
Hyponatremia due to dDAVP excessHyponatremia due to dDAVP excess
• Prevention is essential
• Check labs!!!
• Must control rate of rise of sodium
• Small dose of AVP or dDAVP often administered as
soon as aquaresis begins due to waning drug effect
• Be quick to lift fluid restriction!!!!
Disorders of water metabolisn
Hyponatremia after Pituitary SurgeryHyponatremia after Pituitary Surgery
• 32 of 1045 patients (3%) had preoperative
hyponatremia
• 41% of these were symptomatic
• Postoperative hyponatremia after 165 operations
(16%)
• Mean was 4 days after surgery with range of 0-28
days
• Preoperative hypopituitarism was the only
independent predictor of a likelihood to develop
hyponatremia
HyponatremiaHyponatremia
• Disorders or processes that cause hyponatremia are
dynamic:
o Initiation
o Maintenance
o Recovery
• It is critical to ascertain where the patient might be
in their course as one initiates and measures a
response to management
HyponatremiaHyponatremia
Symptoms and SignsSymptoms and Signs
Feature
Nausea/Vomiting
Delerium/Confusion
Weakness
Lethargy
Myalgia/Cramps
Dizziness
Hiccups
Dysarthria
%
71
50
50
50
21
21
14
14
Illowsky et al. Medicine 72:359-373,1993.
Headache!!
Severe HyponatremiaSevere Hyponatremia
168 patients Na+ <115 mEq/L168 patients Na+ <115 mEq/L
Nzerue et al J Natl Med Assoc 95:335-343,2003.
HyponatremiaHyponatremia
Verbalis TEM 3:1-7,1992.
Hyponatremia
Outcomes of Correction
Osmotic DemyelinationOsmotic Demyelination
Central Pontine Myelinolysis
Central Demyelination Syndrome
Central DemyelinationCentral Demyelination
• Demyelination injury to oligodendrocytes
• Disruption of blood brain barrier may play a
role
• Accumulation of microglials cells
• Release of pro-inflammatory cytokines
• Destruction of myelin
• Animal studies suggest minocycline and
lovastatin may be protective
Clinical Features of Osmotic DemyelinationClinical Features of Osmotic Demyelination
Feature
Mutism/Dysarthria
Lethargy/Obtundation
Behavioral changes
Confusion
Movement difficulty
Muscle contractions
Dysphagia
%
71
57
29
21
21
7
7
Spasticity, rigidity, Babinski reflex, hyperreflexia, impaired gag reflex,
fasciculations, nonreactive or dilated pupils, snout, grasp or rooting
reflexes,impaired gait, ataxia,cognitive deficits.
Illowsky et al. Medicine 72:359-373,1993.
Reducing risks of myelinolysisReducing risks of myelinolysis
• Limit correction of chronic hyponatremia to 10 to 12
mmol/L in 24 hours and to 18 mmol/L in 48 hours.
• When other recognized risk factors for myelinolysis
are present (menstruant women, hypokalemia, liver
disease, poor nutritional state, alcoholism, burns),
correction should not exceed 10 mEq/L/24h.
• In acute hyponatremia a more rapid initial
correction rate, roughly 1-2 mEq/L, is acceptable.
HyponatremiaHyponatremia
Common SenseCommon Sense
• Acute treatment should be interrupted once
any of 3 end points is reached:
o the patient’s symptoms are abolished;
o a safe serum [Na] level (>120 mEq/L) is achieved;
o a total magnitude of correction of 18 mEq/L is
achieved.
Judicious use of 3% SalineJudicious use of 3% Saline
• Hyponatremic patients with significant neurological
symptoms, such as seizures, severe altered mental
status, or coma
• The high likelihood of cerebral edema outweighs
the risk of possible demyelination.
• Target rate of correction is 1.5 to 2 mEq/L per hour
with 3% hypertonic saline for the first 3 to 4 hours, or
more briefly, if symptoms improve or the sodium
level exceeds 120 mEq/L.
3% Saline3% Saline
An Alternative ApproachAn Alternative Approach
• Rate in mL/h is the desired rate of rise in Na+
in mEq/L/h per kg body weight
• Furosemide 20 mg iv
• For a 70 kg patient with desired correction
rate of 1.5 mEq/L 3% saline infusion rate
would be 105 mL/h.
Fluid restrictionFluid restriction
?
Vasopressin Receptor AntagonistsVasopressin Receptor Antagonists
Drug Route Receptor Effective Doses
Conivaptan IV/Oral V1/V2 20-40 mg/d
Tolvaptan Oral V2 15-60 mg/d
Adapted from N Engl J Med 2007; 356:2064-2072.
Disorders of water metabolisn
Vaprisol at UCSFVaprisol at UCSF
• Na+ 125 mEq/L at baseline
• Na+ 134 mEq/L at 24h
• 5 patients required a second dose
• 2 patients required more than 2 doses
• I/O 1.4L negative first day of Rx
• Eight patient had sellar lesions and 6 were post TSA
o Sodium levels 124 →132→134 mEq/L at baseline, 12h and
24h
o 6 mEq/L achieved in 10 hrs
o No recurrent hyponatremia
Disorders of water metabolisn
Conivaptan IVConivaptan IV
Verbalis et al Clin Endocrinol epub 8-10% experience rapid correction
Conivaptan IVConivaptan IV
Verbalis et al Clin Endocrinol epub
Schrier RW et al. N Engl J Med 2006;355:2099-2112.
Tolvaptan in the Management of Hyponatremia
Water is a marvelous life sustaining and yet simple molecule
that must be offered tremendous respect for it can be a very
dangerous thing in many different ways.

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Disorders of water metabolisn

  • 1. Disorders of Water MetabolismDisorders of Water Metabolism Diabetes Insipidus and HyponatremiaDiabetes Insipidus and Hyponatremia Lewis S. Blevins, Jr., M.D.
  • 2. A French woman had suffered from “a burning thirst” since birth. At the age of three she consumed two buckets of water per day. She ran away from home because of “the ill treatment this disposition occasioned her to experience from her parents”. When examined in Paris in 1791 she was in good health and had given birth to ten children. She continued to drink great quantities of water. The other patient was an English laborer who after a long febrile disease developed thirst and polyuria at the age of 31. Twenty-four years later he was still drinking 20–25 l per day but otherwise in perfect health. It is difficult to doubt that both patients suffered from diabetes insipidus— though less clear of which type. First clear description of Diabetes Insipidus in 1792 Lindholm Pituitary 7: 33–38, 2004 Medical facts and observations. London. 1792;2:73–101
  • 3. NeurohypophysisNeurohypophysis AVP secreting neurons in SON and PVN Osmo- and thirst receptors/centers in anterior hypothalamus Ascending pathways from ANS and brainstem Terminal boutons in neurohypophysis
  • 4. Relationship between Plasma Osmolarity and AVPRelationship between Plasma Osmolarity and AVP © Astellas
  • 5. Alterations in AVP secretionAlterations in AVP secretion
  • 6. AVP ReceptorsAVP Receptors Receptor V1A V1B V2 Location Vascular smooth muscle, platelets Anterior pituitary Renal collecting duct Effect Vasoconstriction, platelet aggregation ACTH release Free water absorption
  • 8. Relationship between Urine Osmolarity andRelationship between Urine Osmolarity and AVPAVP © Astellas
  • 10. Diabetes InsipidusDiabetes Insipidus PolyuriaPolyuria • Passage of large quantities of dilute urine due to absence of vasopressin or lack of its action • Urine specific gravity usually <1.005 • Polyuria defined as 30 mL urine per kg body weight in 24h • UOP >300 mL/h over 2-3 consecutive hrs in hospitalized patient at-risk for DI is suggestive • Broad DDx including DM, renal disease, solute load, excessive intake of oral fluids, overzealous administration of IV fluids, post surgery for Acromegaly, therapy with vaptans, etc.
  • 11. Diabetes InsipidusDiabetes Insipidus ThirstThirst • Thirst is logarithmic • Usually begins at a pOsm higher than the set point for AVP secretion • Defense against dehydration • Serum sodium and pOsm usually “normal” and at thirst set point if patient able to respond to thirst • Concern in patients with: o Adipsia o Altered sensorium o Restrained
  • 12. PolydipsiaPolydipsia• Water intake due to a combination of factors o Social o Cultural o Solute load o Volume status o Psychological • Polydipsia in DI is a measure of the response to thirst due to increased pOsm and volume depletion • Patients often prefer iced water, take water everywhere, always know where to get it…. “water dogs” • Beware of those with Psychogenic Polydipsia who can nearly mimic DI
  • 13. Neurogenic Diabetes InsipidusNeurogenic Diabetes Insipidus CausesCauses • Transsphenoidal surgery 5-30% depending on many factors • ACA aneurysms/bleeds • Suprasellar lesions o Craniopharyngioma o Pilocytic astrocytoma • Infiltrative disorders o Langerhans Cell Histiocytosis o Sarcoidosis • Inflammatory disorders • Metastases • Head trauma • Heritable disorders • Nephrogenic causes
  • 14. Diabetes InsipidusDiabetes Insipidus Suspicion and DiagnosisSuspicion and Diagnosis • Intake and Output relative to body weight • Urine specific gravity • Serum or urine glucose if Ur spgr is not low • Serum sodium • Clinical history and imaging characteristics • Observation • Trial of therapy • Water deprivation test
  • 15. Diabetes InsipidusDiabetes Insipidus Acute ManagementAcute Management • Encourage PO intake to drink to thirst • Use GI tract access via tube if possible • IVF ½ NS or D5W at 150-200 mL/hr for a few liters if needed • AVP sc 3-5 U q4-6 hrs PRN • Intranasal dDAVP 10 mcg PRN • sc dDAVP 0.5-2 mcg PRN • Re-dose when needed
  • 16. Diabetes InsipidusDiabetes Insipidus Chronic ManagementChronic Management • Intranasal dDAVP 10-20 mcg qd-bid PRN • dDAVP 0.05-0.2 mg PO qD-tid PRN • Drink to thirst • Awareness of I/O, body weight • Subsequent dosing based on demonstrated need at least once per week • Avoidance of situations that lead to water intoxication • Periodic withholding of therapy as DI sometimes improves • Water Rx for those with adipsic hypernatremia • Careful control of rate of rise in patients with hyponatremia
  • 17. HyponatremiaHyponatremia one of many algorithmsone of many algorithms
  • 18. Hyponatremia in Pituitary PatientsHyponatremia in Pituitary Patients • Preoperative o Cortisol deficiency o Hypothyroidism o SIADH • rarely seen due to pituitary tumors • Not uncommon in hypothalamic tumors • Immediate Postoperative o SIADH • Delayed Postoperative o dDAVP excess o Other causes (medications, etc.)
  • 19. Hyponatremia due to dDAVP excessHyponatremia due to dDAVP excess • Prevention is essential • Check labs!!! • Must control rate of rise of sodium • Small dose of AVP or dDAVP often administered as soon as aquaresis begins due to waning drug effect • Be quick to lift fluid restriction!!!!
  • 21. Hyponatremia after Pituitary SurgeryHyponatremia after Pituitary Surgery • 32 of 1045 patients (3%) had preoperative hyponatremia • 41% of these were symptomatic • Postoperative hyponatremia after 165 operations (16%) • Mean was 4 days after surgery with range of 0-28 days • Preoperative hypopituitarism was the only independent predictor of a likelihood to develop hyponatremia
  • 22. HyponatremiaHyponatremia • Disorders or processes that cause hyponatremia are dynamic: o Initiation o Maintenance o Recovery • It is critical to ascertain where the patient might be in their course as one initiates and measures a response to management
  • 23. HyponatremiaHyponatremia Symptoms and SignsSymptoms and Signs Feature Nausea/Vomiting Delerium/Confusion Weakness Lethargy Myalgia/Cramps Dizziness Hiccups Dysarthria % 71 50 50 50 21 21 14 14 Illowsky et al. Medicine 72:359-373,1993. Headache!!
  • 24. Severe HyponatremiaSevere Hyponatremia 168 patients Na+ <115 mEq/L168 patients Na+ <115 mEq/L Nzerue et al J Natl Med Assoc 95:335-343,2003.
  • 27. Osmotic DemyelinationOsmotic Demyelination Central Pontine Myelinolysis Central Demyelination Syndrome
  • 28. Central DemyelinationCentral Demyelination • Demyelination injury to oligodendrocytes • Disruption of blood brain barrier may play a role • Accumulation of microglials cells • Release of pro-inflammatory cytokines • Destruction of myelin • Animal studies suggest minocycline and lovastatin may be protective
  • 29. Clinical Features of Osmotic DemyelinationClinical Features of Osmotic Demyelination Feature Mutism/Dysarthria Lethargy/Obtundation Behavioral changes Confusion Movement difficulty Muscle contractions Dysphagia % 71 57 29 21 21 7 7 Spasticity, rigidity, Babinski reflex, hyperreflexia, impaired gag reflex, fasciculations, nonreactive or dilated pupils, snout, grasp or rooting reflexes,impaired gait, ataxia,cognitive deficits. Illowsky et al. Medicine 72:359-373,1993.
  • 30. Reducing risks of myelinolysisReducing risks of myelinolysis • Limit correction of chronic hyponatremia to 10 to 12 mmol/L in 24 hours and to 18 mmol/L in 48 hours. • When other recognized risk factors for myelinolysis are present (menstruant women, hypokalemia, liver disease, poor nutritional state, alcoholism, burns), correction should not exceed 10 mEq/L/24h. • In acute hyponatremia a more rapid initial correction rate, roughly 1-2 mEq/L, is acceptable.
  • 31. HyponatremiaHyponatremia Common SenseCommon Sense • Acute treatment should be interrupted once any of 3 end points is reached: o the patient’s symptoms are abolished; o a safe serum [Na] level (>120 mEq/L) is achieved; o a total magnitude of correction of 18 mEq/L is achieved.
  • 32. Judicious use of 3% SalineJudicious use of 3% Saline • Hyponatremic patients with significant neurological symptoms, such as seizures, severe altered mental status, or coma • The high likelihood of cerebral edema outweighs the risk of possible demyelination. • Target rate of correction is 1.5 to 2 mEq/L per hour with 3% hypertonic saline for the first 3 to 4 hours, or more briefly, if symptoms improve or the sodium level exceeds 120 mEq/L.
  • 33. 3% Saline3% Saline An Alternative ApproachAn Alternative Approach • Rate in mL/h is the desired rate of rise in Na+ in mEq/L/h per kg body weight • Furosemide 20 mg iv • For a 70 kg patient with desired correction rate of 1.5 mEq/L 3% saline infusion rate would be 105 mL/h.
  • 35. Vasopressin Receptor AntagonistsVasopressin Receptor Antagonists Drug Route Receptor Effective Doses Conivaptan IV/Oral V1/V2 20-40 mg/d Tolvaptan Oral V2 15-60 mg/d Adapted from N Engl J Med 2007; 356:2064-2072.
  • 37. Vaprisol at UCSFVaprisol at UCSF • Na+ 125 mEq/L at baseline • Na+ 134 mEq/L at 24h • 5 patients required a second dose • 2 patients required more than 2 doses • I/O 1.4L negative first day of Rx • Eight patient had sellar lesions and 6 were post TSA o Sodium levels 124 →132→134 mEq/L at baseline, 12h and 24h o 6 mEq/L achieved in 10 hrs o No recurrent hyponatremia
  • 39. Conivaptan IVConivaptan IV Verbalis et al Clin Endocrinol epub 8-10% experience rapid correction
  • 40. Conivaptan IVConivaptan IV Verbalis et al Clin Endocrinol epub
  • 41. Schrier RW et al. N Engl J Med 2006;355:2099-2112. Tolvaptan in the Management of Hyponatremia
  • 42. Water is a marvelous life sustaining and yet simple molecule that must be offered tremendous respect for it can be a very dangerous thing in many different ways.

Editor's Notes

  1. Figure 3. Mean Serum Sodium Concentrations According to the Day of Patient Visit. Asterisks indicate P&amp;lt;0.001 for the comparison between tolvaptan and placebo. Daggers indicate P&amp;lt;0.01 for the comparison between tolvaptan and placebo. Tolvaptan was discontinued on day 30. Circles denote patients receiving tolvaptan, and squares denote patients receiving placebo. Horizontal lines indicate the lower limit of the normal range for the serum sodium concentration. Vertical lines indicate the end of the treatment period. HN denotes hyponatremia.