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Osmotic Demyelination Syndrome

Emily Horn, MD Critical Care Fellow

University of New Mexico Hospital

Case Presentation

50F presents to ER w/ weakness and frequent falls;

hematemesis x2

EtOHism since age 15 w/ significant increase in intake of

exclusively hard liquor (1 pint vodka daily) x8 months

PMH/PSH: Chr HCV, EtOHism

No home meds; NKDA

SHx: 1 pint vodka daily, 1 ppd, no IVDU

FHx: EtOHism

Physical Exam

VS: 36.4 109 102/61 95/60 18 96% 2L

Gen: NAD, A&O x2 after receiving Librium

CV: tachycardic, reg rhythm

Chest: CTAB

Abd: mild diffuse tenderness, ascites

Labs

11.1

31

8.6 169 Coags normal

Lactate 4.8

118

3.1

79

22

8

1.06

146

Tot bili 2.6

AP 111

AST 164

ALT 73

Serum Sodium Course

Time

8/30 @ 1301 2L NS, 2L LR

8/30 @ 2040

8/31 @ 0335

8/31 @ 1532

9/1 @ 1718 (2L NS that AM)

Serum Sodium

118

126 (+8 in <8 hrs)

131

134 (+16 in 24 hrs)

144 (+26 in 48 hrs)

Hospital Course

8/30: admitted from ER to MICU

9/1: transferred to Medicine

MRI for reported dysarthria PTA – unable to complete 2/2 motion artifact

CT 9/2 neg acute; nonspecific mod diffuse brain volume loss, greater than expected for age

9/6: transferred to MICU for resp failure 2/2 suspected aspiration event; intubated

9/7: extubated

9/8: re-intubated for tachypnea/hypoxia

9/9: agitated – Precedex started w/ Fentanyl prn

9/10: unresponsive – Precedex D/Ced

9/13: CT w/ symmetric decreased attenuation involving pons, lateral aspects of caudate heads, and thalami

Hospital Course

9/14: MRI w/ symmetric increased T2 prolongation involving the

central pons and bilateral thalami, lentiform nuclei, and external

capsules

Hospital Course

9/16: comfort care

9/17: pt death

Hyponatremia

Occurs in 15-20% of hospital admissions; independent risk factor for mortality

Present in the setting of a wide variety of conditions

Managed by clinicians with a wide variety of backgrounds

Diverse institution- and specialty-based approaches to treatment

Few well-designed, prospective studies

Limited evidence-based approaches, especially when duration unknown

Unpredictable treatment response, especially in profound hyponatremia

Spasovski et al. Clinical practice guideline on diagnosis and treatment of hyponatremia. Nephrol Dial Transplant 2014 Apr;29 Suppl 2:i1-i39.

Geoghegan et al. Sodium correction practice and clinical outcomes in profound hyponatremia. Mayo Clin Proc 2015;90(10):1348-55.

Central Pontine Myelinolysis

Osmotic Demyelination Syndrome

Definitions

CPM (central pontine myelinolysis) – solitary, symmetric,

demyelinating focus in the central pons

EPM (extrapontine myelinolyses) – symmetrically arranged

lesions of similar histology in other areas: thalamus,

globus pallidus, putamen, lateral geniculate body,

cerebellar white matter

UptoDate. Osmotic demyelination syndrome and overly rapid correction of hyponatremia.

Pathogenesis: hyponatremia

Difference in osmolality between brain and plasma extracellular to intracellular movement of water brain edema

Adaptive mechanism

Reduction in intracellular osmotically active particles (mostly potassium and organic solutes) in an attempt to restore brain volume

Process takes 24-48 hrs

Spasovski et al. Clinical practice guideline on diagnosis and treatment of hyponatremia. Nephrol Dial Transplant 2014 Apr;29 Suppl 2:i1-i39.

Pathogenesis: demyelination

Correction of hypoNa movement of water out of brain

Rapid fall in brain volume demyelination

Osmotic shrinkage of endothelial cells opening of BBB entry

of complement and other cytotoxic plasma components

Loss of cell water + movement of Na and K back into cells initial

increase in cell cation concentration before repletion of organic

osmolytes (myoinositol, glutamate, glutamine) direct astrocyte

injury apoptosis disruption in function of myelin-producing

oligodendrocytes, release of cytokines, and activation of microglia

Sterns et al. Brain volume regulation in response to hypo-osmolality and its correction. Am J Med

2006;119(7Suppl1):S12.

Gankam-Kengne et al. Astrocytes are an early target in osmotic demyelination syndrome. J Am Soc

Nephrol 2011 Oct;22(10):1834-45.

Pathogenesis: demyelination

Demyelination primarily occurs in areas of the brain that

are slowest in re-accumulating osmotically active

substances after rapid correction of hypoNa

Yeates et al. Salt and water: a simple approach to hyponatremia. CMAJ 2004;170(3):365.

Risk Factors

Serum Na at presentation

Majority < 105 mEq/L

Vast majority < 120 mEq/L

Duration of hypoNa

Present for at least 2-3 days (time required for cerebral adaptation)

Assume significant duration unless history c/w acute water intoxication

Sterns et al. Neurologic sequelae after treatment of severe hyponatremia: a multicenter

perspective. J Am Soc Nephrol 1994;4(8):1522.

Risk Factors

Rapid rate of correction

Rate of correction over 24-hr period a more important determinant than maximum rate in any given hour

Greatest risk for irreversible and disabling brain injury

Raised by > 20 mEq/L in 24 hrs OR

Corrected to > 140 mEq/L

Occasional pts develop ODS even when corrected by 9-12 mEq/L/day

Target a rate of correction < 9 mEq/L in any 24-hr period

Verbalis et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med 2007;120(11 Suppl 1):S1.

Risk Factors

Underlying malnutrition

EtOHism

Liver transplantation

Simultaneous hypoxia or sepsis

Geoghegan et al. Sodium correction practice and clinical outcomes in profound

hyponatremia. Mayo Clin Proc 2015 Oct;90(10):1348-55.

Risk Factors

Rare in ESRD treated w/ HD

Rise in serum osmolality w/ increase in Na counterbalanced by fall in serum osmolality w/ removal of urea

Azotemia enhances brain reuptake of organic osmolytes, minimizing cellular shrinking

Oo et al. Does uremia protect against the demyelination associated with correction of hyponatremia during hemodialysis? A case report and literature review. Semin Dial 2003;16(1):68.

Mechanisms of Overly Rapid Correction

Following therapy specifically directed at raising the sodium concentration

Auto-correction

Following cessation of a reversible stimulus to ADH release rapid excretion of excess free water

Requires normal kidney function


Mechanisms of Overly Rapid Correction:

Auto-correction

Administration of NS in true volume depletion: restoration of euvolemia rapidly suppresses ADH release, allowing excretion of excess water

Administration of glucocorticoids in adrenal insufficiency

Discontinuation of thiazides (interfere w/ urinary dilution)

Discontinuation of drugs causing SIADH

Spontaneous resolution of a transient cause of SIADH

Treatment with a vasopressin receptor antagonist


Epidemiology

Non-optimal correction of profound hyponatremia is common

Infrequently associated with serious morbidity

Retrospective review (5 yrs, 1 ICU): 412 pts w/ Na <120

211 (51.2%) w/ optimal correction at 24 hrs

87 (21.1%) under-corrected

114 (27.9%) over-corrected

One case of ODS

Geoghegan et al. Sodium correction practice and clinical outcomes in profound hyponatremia. Mayo Clin Proc 2015 Oct;90(10):1348-55.

Clinical Manifestations

Typically delayed for 2-6 days after overly rapid correction

Symptoms often irreversible or partially reversible

Dysarthria, dysphagia, parapesis/quadriparesis, behavioral

disturbances, lethargy, confusion, disorientation, obtundation, coma

Seizures less common

“Locked in” syndrome

Sterns et al. Neurologic sequelae after treatment of severe hyponatremia: a multicenter

perspective. J Am Soc Nephrol 1994;4(8):1522.

Detection

MRI >>> CT

Even MRI may not become positive for 4 wks after onset,

especially if diffusion-weighed imaging not used

Karp et al. Pontine and extrapontine myelinolysis: a neurologic disorder following rapid

correction of hyponatremia. Medicine (Baltimore). 1993;72(6):359.

Prevention

Re-lowering Na if Overly Rapid

Correction Has Occurred

May reverse BBB breakdown and prevent the infiltration of microglia

More effective than glucocorticoid administration

Recommended if:

Initial Na < 120 mEq/L AND

Present at least 2 days (or unknown duration) AND

Rate of correction has exceeded the maximum recommended goals (< 9 mEq/L in 24 hrs and < 18 mEq/L in 48 hrs)

Gankam et al. Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats. Kidney Int 2009;76(6):614.


Re-lowering Na if Overly Rapid

Correction Has Occurred

D5W 6 mL/kg IBW over 2 hrs, repeated until at goal

1 mEq/L per hour

Net rate of correction < 9 mEq/L over 24 hrs

E.g. serum Na 115 127 in 16 hrs, target 124 over next 8 hrs

Measure serum Na after each infusion

Desmopressin 2 mcg IV/SQ q6h

Once at goal

D/C D5W

Continue desmopressin to prevent Na from rising again due to excretion of dilute urine

Gankam et al. Re-induction of hyponatremia after rapid overcorrection of hyponatremia reduces mortality in rats. Kidney Int 2009;76(6):614.


Slowing Rate of Correction

Trajectory of correction is too rapid, but has not yet

exceeded the maximum recommended rate of correction

Exceptions

Pts who cannot be relied upon to curtail water intake

Pts w/ hyperacute hyponatremia developing over a few hours 2/2

marked increase in water intake (low risk for ODS)


Slowing Rate of Correction

Desmopressin 2 mcg IV/SQ q6-8h

+/- hypertonic saline @ 10-30 mL/hr to produce rise in serum Na at a

desired rate

Continued until serum Na 125-130

OR

Desmopressin 2 mcg IV/SQ x1, repeated if serum Na rising too quickly

or urine output has increased dramatically

Sterns et al. Overcorrection of hyponatremia is a medical emergency. Kidney Int

2009;76(6):587.

Desmopressin

Administration after a 24-hr limit of 12 mEq/L had been reached or exceeded (n = 6)

Correction prevented from exceeding the 48-hr limit of 18 mEq/L in 5 pts

All 6 received D5W concurrently

Administration in anticipation of over-correction (n = 14)

Correction prevented from exceeding 24- or 48-hr limit in all 14 pts

5 pts received D5W concurrently

Proves feasibility, but not better outcomes, than watchful waiting

Perianayagam et al. DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia. Clin J Am Soc Nephrol 2008;3(2):331.

Management

Re-lowering Serum Na to Treat ODS

Same regimens recommended to re-lower serum Na after overly rapid correction

Initiate ASAP after onset of sx attributed to ODS

No evidence of benefit if begun >24 hrs after onset

Re-lower to a level just below the maximal target value at 48 hrs (< 18 mEq/L above the initial serum Na)

48-hr goal chosen because pts w/ ODS typically present 2-6 days after overly rapid correction

Based on case reports

Soupart et al. Therapeutic relowering of the serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol 1999;51(6):383.

Oya et al. Reinduction of hyponatremia to treat central pontine myelinolysis. Neurology 2001;57(10):1931.

Supportive Therapy

Some pts recover function after prolonged periods of severe

neurologic impairment

Intubation/mech ventilation often required 2/2 aspiration and

resp failure

Recovery from seemingly hopeless neurologic deficits can occur

Supportive tx should be continued 6-8 wks before concluding

irreversibility

Sterns et al. Osmotic demyelination syndrome following correction of hyponatremia. NEJM.

1986;314(24):1535.

Supportive Therapy

Observational study (n = 44; follow-up data in 34) w/ observation period of 3 wks to 44 mos

Complete recovery: 11

Independent w/ some deficits: 11

Dependent on personal help or assistive devices: 10

Death: 2

Outcome independent of severity of neurologic deficits, degree of hypoNa, extent of initial pontine lesion, or persistence of lesion on MRI

Previous mortality nearly 100% w/in 3 months

Menger et al. Outcome of central pontine and extrapontine myelinolysis. J Neurol 1999;246-700-705.

Plasmapheresis

5 case reports w/ improvement (n = 4) or resolution (n = 1) of

neurologic symptoms

Theory: reduction of high molecular myelinotoxic substances, which

were released in response to osmotic stress to cause irreversible

demyelination

Possible benefit difficult to interpret since some pts experience short-

lived, self-limiting episodes of neurologic impairment

Bibl et al. Treatment of central pontine myelinolysis with therapeutic plasmapheresis. Lancet

1999;353(9159):1155.

Grimaldi et al. Plasmapharesis improves the outcome of central pontine myelinolysis. J Neurol

2005;252(6):734.

Saner et al. Treatment of central pontine myelinolysis with plasmapheresis and immunoglobulins in

liver transplant patient. Transpl Int 2008;21(4):390.

IVIG

Case reports

48 year-old man w/ alcoholism: unable to sit unaided, unable to

ambulate mild dysarthria and ataxia

40 year-old man w/ alcoholism: “locked in” syndrome requiring

mechanical ventilation ambulatory with support

IVIG 0.4 g/kg/day x5 days

May represent acceleration of spontaneous recovery

Thirunavukarasu et al. Response to IV immunoglobulin in a case of osmotic demyelination syndrome.

BMJ Case Reports 2015 Nov 25;doi:10.1136/bcr-2015-212985.

Finsterer et al. Immunoglobulins are effective in pontine myelinolysis. Clin Neuropharmacol

2000;23:110-13.

Minocycline (rat studies)

Crosses BBB and inhibits microglial activation and

production of cytokines

Neuroprotective effects in experimental models of other

demyelinating disorders

No human data

Suzuki et al. Minocycline prevents osmotic demyelination syndrome by inhibiting the

activation of microglia. J Am Soc Nephrol 2010 21(12):2090.

Gankam-Kengne et al. Minocycline protects against neurologic complications of rapid

correction of hyponatremia. J Am Soc Nephrol 2010 21(12):2099.

Take-Home Points

Target rate of correction < 9 mEq/L in any 24-hr period

Risk strongly correlates with chronicity of hypoNa

ODS sx typically delayed; MRI findings may be even further delayed

Re-lowering if overly rapid correction

If initial Na < 120 for more than 2 days, and rate has exceeded goal

D5W and Desmopressin

Slowing rate of correction

Desmopressin +/- hypertonic saline

Treatment of ODS

Same as re-lowering if overly rapid correction

No benefit if initiated >24 hrs after symptom onset

Question #1

Which of the following is FALSE regarding correction of hyponatremia?

A. Treatment should continue until serum sodium is in the range of 125-130 mEq/L

B. Treatment does not need to be initiated in cases of hyperacute hyponatremia

C. The goal for the net rate of correction should be <12 mEq/L over 24 hours

D. Will not likely improve outcome if initiated more than 24 hours after the onset of ODS

Question #2

What is the strongest risk factor for the development of ODS?

A. Rate of correction

B. Duration of hyponatremia

C. Presence of renal failure

D. Initial serum sodium level

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