hyponatremia in the icu: morbidity, mortality and...

Hyponatremia in the ICU: Morbidity,Mortality and Therapy

Mitchell H. Rosner, MD

Division of Nephrology

Prevalence of dysnatremias at initialpresentation to a health care provider

0.49

28.2

1.430.060.17

21

0.53 0.010.03

7.2

0.72 0.010

5

10

15

20

25

30

Na < 116 Na < 135 Na > 145 Na > 165

Pre

va

len

ce

(%

)

Acute hospital careAmbulatory hospital care

Community care

Hawkins. Clin Chim Acta 337:169-172, 2003

(data from 303,577 samples on 120,137 patients available for analysis)

Hyponatremia is an independent risk factorfor in-hospital mortality

Serum [Na +] >130 mEq/L

Serum [Na +] <130 mEq/L Serum [Na +]

120-129 mEq/L

Serum [Na +] <120 mEq/L

0

5

10

15

20

25

Mo

rta

lity

(%

)

Study of 4,123 patients ≥65 years old admitted to a community hospital3.5% had a serum [Na+] <130 mEq/L at admissionIn this study, hyponatremia was found to be a predictor of in-hospital

mortality (RR=2.0)

RR=relative risk.

Terzian C et al. J Gen Intern Med.9:89-91, 1994

Most recently…

Prospective cohort study of 98,411 adultshospitalized between 2000-2003

Assessed mortality in-hospital and at 1 and 5 years

Prevalence of serum Na+ < 135 meq/L was 14.5%

Those with hyponatremia: older (67 v. 63.1 yrs) andmore comorbid conditions

Waikar et al. Am J Med 2009; 122: 857

Odds-Ratio of Death inHyponatremia

1.091.291.331.241.251 (ref)

1.031.781.531.351.381 (ref)

1.461.672.011.371.471 (ref)

Serum sodium values (meq/L)

135-144 < 135 130-134 125-129 120-124 < 120

In-hospitalmortality

1 yearmortality

5 yearmortality

Adapted from: Waikar et al. Am J Med 2009; 122: 857

Resolution of hyponatremia

In this study, more than one serum sodium level was available on52,468 patients.

Allowed investigators to look into the effects of resolution v. non-resolution of hyponatremia on mortality:

38.5%40.8%

18.5%23.5%

3.9%6.2%

Persistent (n = 4254) Resolved (n = 3794)

In-hospitalmortality

1 yearmortality

5 yearmortality

Impact on length of stay and otheroutcomes

2 recent studies:

LOS is increased from 1 to 2 days in patients withhyponatremia

Patients with hyponatremia had between 12-58%increased risk of requiring an ICU stay (higher riskassociated with lower initial sodium level)

Total cost per admission increased from $1300 to $3500(higher costs associated with lower sodium levels)

Callahan et al. Hosp Pract 2009; 121

Zilberberg et al. BMC Pulm Med 2008; 8:16

Does treatment matter?Prospective review of lab and chart data over 6 months in a

large teaching hospital

104 patients with serum [Na+] <125 mEq/L identified

Only 28 (26%) had plasma osmolality measured, 29 (27%)urine osmolality, 11 (10%) urinary sodium, 8 (8%)

33% had “significant” management errors

-Fluid restriction and IV saline, fluid restriction inhypovolemia, hypotonic fluids in SIADH

27% mortality rate (28 of 104 patients)– 20% mortality in patients managed appropriately– 41% mortality in patients with management errors

Huda et al. Postgrad Med J. 82:216-219, 2006

Therapy of Hyponatremia

Two Key Questions

How much correction is enough to improveoutcomes?

How much correction is too much?

Clinical Hyponatremia– Acute (<48 hrs): Cerebral edema, seizures, death due to herniation especially in young

women and children

– Chronic (>48 hrs): Adaptations minimize brain cell swelling, but reversibly alterneurologic function:

• Nausea and vomiting

• Confusion & personality changes

• Gait disturbances

• Seizures with very low serum sodium values

Acute Hyponatremia:Water Intoxication

Clinical symptoms first described in 1920’s andreproduced in experimental animals

Rowntree LG. Pharmacol Exp Ther 1926:29:135

First case of fatal cerebral edema from tap water byproctoclysis reported in 1935

Helwig FC. JAMA 1935:104:1569

Normal study Fatal hyponatremia

Acute Hyponatremia

Clinical Hyponatremia:Rapid Correction

Rapid Correction

Acute hyponatremia: Generally well tolerated

Chronic hyponatremia (>48 hrs): Delayed onset ofneurological deterioration associated with pontine andextrapontine demyelination

Central Pontine Myelinolysis

New disease of unknownetiology was found in fourpatients in Boston CityHospital and first reportedin 1959. Dozens of casereports soon followedprompting a search for anetiology.Eventually an associationwith hyponatremia wasmade.

Laureno R, Karp BI. Ann Intern Med 1997; 126(1): 57-62

Osmotic DemyelinationSyndrome

Images from Hart. N Engl J Med. 1995;333:1259.

Question #1

How much correction of hyponatremia is “enough”to prevent complications in severe acutehyponatremia?

Consensus Conference on Treatment of AcuteHyponatremia in Marathon Runners

Recommended Therapy:

In the field: 3% saline 100 ml over 10 minutes,repeated x 2 if needed

In hospital: 3% saline 100 ml or 1 ml/kg bolusfollowed by 100 ml/hr or 1-2 ml/kg/hr

Hew-Butler, Clin J Sport Med 2008;18:111-121

Therapeutic hypernatremia forcerebral edema

30 ml bolus of 23.4% saline (equivalent to 238 ml3% saline)

Δ Serum Na = 5 mEq/L

Reversed clinical signs of brain herniation in mostcases

Decreased intracranial pressure by 40%

Koenig, MA. Neurology 70: 1023–1029, 2008

Hypertonic Saline for Seizures, Coma orCerebral Edema: Data @ ≤ 4 hours

Sterns, Semin Nephrol 29:282-299

Hypertonic Saline for Seizures, Coma orCerebral Edema: Data @ ≤ 4 hours

Sterns, Semin Nephrol 29:282-299

4 to 6mEq/L

IncreaseAppearsTo Be

“Enough”

Therapy of HyponatremicEmergencies- Summary

Goal: 4 to 6 mEq/L increase in serum sodiumconcentration

2 ml/kg bolus of 3% saline for severe symptoms(repeated if necessary) or

1 to 2 ml/kg infusion of 3% saline for 2 to 3 hours

Question #2

How much correction of hyponatremia is “enough”to cause complications in severe chronichyponatremia?

How much is too much?

How Much is Too Much?

CPM by Autopsy (Fatal cases)

Norenberg1 20 mEq/L in 3 daysAyus 2 25 mEq/L in 2 days

Non-fatal cases

Author Δ Na/day Δ Na/2 daysSterns1,2,3 12 mEq/L 18 mEq/LElllis4 10 mEq/L Karp5 10 mEq/L 21 mEq/L

1. N Engl J Med 1986; 314:15352. Ann Internal Med 1987; 107:6563. JASN 1994;4:15224. QJM 1995; 88:9055. Medicine 1993; 72:359

Serum Na ≤ 105 mEq/LRate of Correction and Outcome

0 10 20 30

Rapid

Slow

Rapid

Slow

Uncomplicated Transient SequelaePermanent Sequelae

{{

Chronic Cases

Acute Cases

Data from SternsJASN 1994;4:1522 Number of Patients

Serum Na ≤ 105 mEq/LRate of Correction and Outcome

0 10 20 30

Rapid

Slow

Rapid

Slow

Uncomplicated Transient SequelaePermanent Sequelae

{{

Chronic Cases

Acute Cases

Data from SternsJASN 1994;4:1522 Number of Patients

“Rapid”:>12/day>18/48h

Treatment of ChronicHyponatremia

• Limits are not goals

• Target therapy to stay well clear of limits– 6 to 8 mEq/L daily

• Use special care in patients at high risk for osmoticdemyelination:

– Chronic hyponatremia

– Alcoholism

– Malnutrition

– Liver disease

– Burns

– Hypokalemia– Serum Na ≤ 105 mEq/L

Avoiding Inadvertent RapidCorrection

Reversibly impaired water excretion– Volume depletion– DDAVP– Hypocortisolism– Thiazide diuretics– SSRI’s– Nausea & alcohol withdrawalIn these cases, the stimulus for impaired water excretion is

corrected quickly, and a rapid water diuresis then ensues.

Maximally dilute urine increases the serum sodium concentration by > 2mEq/L/hr

Continued vigilance with frequent measurements of the serum sodiumconcentration and attention to urine output is essential in all patientswith very low serum sodium concentrations

Equations- serious pitfalls

Δ SNa after 1 liter of infusate =

Infusate Na – Serum NaTotal Body Water + 1

Assumes all of the infusate is retained; does not consider urinelosses of electrolyte or water

Must be vigilant to watch for water diuresis which will lead to muchmore rapid correction than predicted

Adrogue. N Engl J Med 2000:342:1581-9

3% Saline for Serum Na <120 mEq/L

Total Body Water + 1 ΔΔ Serum [Na] with 1 L infusate =

Infusate [Na] – [Na]

00

11

22

33

44

00 11 22 33 44 55Ratio of Actual Rise in Sodium to the Expected Rise

Fre

quen

cy

Mohmand et al, CJASN 2:1110-1117, 2007




00

11

22

33

44


Fre

quen

cy


Less Than

Expected




00

11

22

33

44


Fre

quen

cy


More than expected

Lower Serum Na=Higher Riskof Overcorrection

––55

00

55

1010

1515

2020

105105 110110 115115 120120 125125 130130 135135

Serum Sodium Before Infusion (mEq/L)

Ris

e in

Ser

um

in

48 H

ou

rs (

mE

q/L

))


95

100

105

110

115

120

0 12 24 36 48 60 72

Ser

um S

odiu

m (

mm

ol/l )

Hours

DDAVP 2 mcg q 6hrs3% NaCl

3% NaClD5W

Urine Osmolality (mOsm/kg)

600 80 700 700 700 700

Reversing Overcorrection

Sterns, R. Kidney Int August, 2009

Re-Induction of HyponatremiaPrevents Myelinolysis

1/1612/12Deaths Day 10

1/1612/12Sx’s Day 5

14 ± 1 mmol/l29 ± mmol/lΔSNa at 24 hrs

29 ± 1 mmol/l--ΔSNa at 12 hrs

104 ± 2 mmol/l108 ± 2 mmol/lSNa Pre-Rx

Rapid CorrectionPlus Re-Lowering

Rapid Correction

Gankam Kengne, F. Kidney International 2009;76:614-621

Vasopressin ReceptorVasopressin ReceptorAntagonistsAntagonists

AVP-Receptor SubtypesAVP-Receptor Subtypes

ReceptorSubtype Site of Action Pharmacologic Effects

V1A

Vascular smoothmuscle

Platelets

Lymphocytes andmonocytes

Hepatocytes

Vasoconstriction

Platelet aggregation

Coagulation factorrelease

Glycogenolysis

V1B Anterior pituitaryACTH and β-endorphinrelease

V2Renal collecting ductcells

Free water absorption

ACTH=adrenocorticotropic hormoneAdapted from Lee CR et al. Am Heart J. 2003;146:9-18.

Verbalis JG. J Mol Endocrinol. 2002;29:1-9.

NonpeptideNonpeptide AVP Receptor AVP ReceptorAntagonistsAntagonists

Tolvaptan Lixivaptan Satavaptan Conivaptan

Receptor V2 V2 V2 V1a/V2

Route ofadministration Oral Oral Oral IV

Urine volume ↑ ↑ ↑ ↑

Urineosmolality

↓ ↓ ↓ ↓

Na+ excretion/24 h

↔

↔ for lowdose

↑ for highdose

↔ ↔

Reprinted with permission from Verbalis JG et al. Am J Med. 2007;120:S1-S21.

Serum Sodium by VisitSerum Sodium by VisitSevere Severe HyponatremiaHyponatremia Group Group

120

125

130

135

140

Seru

m N

a (m

Eq/L

)

120

125

130

135

140

Seru

m N

a (m

Eq/L

)

Baseli

neDay

1

8-hr Day

2Day

3Day

4

Week 1

Week 2

Week 3

Day 30

7 Day

Follow-U

p

p<0.0001

p<0.0001

PlaceboTolvaptan

SALT-1

SALT-2

Schrier RW et al. SALTInvestigators. N Eng J Med.2006;355:2099-2112.

SIADH Responded Better to TolvaptanSIADH Responded Better to TolvaptanThan CHF and CirrhosisThan CHF and Cirrhosis

Mean increase of the serum sodium between baselineand day 30 in cirrhosis, CHF, and SIADH

0

1

2

3

4

5

6

7

8

Cirrhosis CHF SIADH

Del

ta in

crea

se in

ser

umso

dium

( mEq

/L)

control

tolvaptan

*

*

*

* P<0.05

ConivaptanConivaptan in in EuvolemicEuvolemic HyponatremicHyponatremic Patients PatientsChange From Baseline in Serum [Na+]Change From Baseline in Serum [Na+]

Time (hr)

0 96

Cha

nge

in S

erum

[Na+ ]

(mEq

/L)

–2

4

6

8

10

2

0

8 16 24 32 40 48 56 64 72 80 88

Conivaptan 40 mg/dPlacebo

Mean (SE) change from baseline in serum [Na+] with intravenous conivaptan

Verbalis JG. J Mol Endocrinol. 2002;29:1-9.

Treatment of HyponatremiaSummary

Acute hyponatremia:– Prompt correction may avoid morbidity and mortality from

cerebral edema

– Adequate correction: 4 to 6 mmol/l

Chronic symptomatic hyponatremia:– Limited correction avoids iatrogenic neurologic injury: <10

mmol/l/24 hrs; <18 mmol/l/48 hr; <20 mmol/l/72 hrs

hyponatremia in the icu: morbidity, mortality and...

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