quantitative approach in dysnatremias

Quantitative Approach in Dysnatremias- a complementary tool for the busy intensivist -

13th November 2015

Assigning a context

Define the determinants(“independent” variables) of plasma water sodium

Define the physiological basis of sodium-related transport(e.g. Layton’s math-models of urine

concentrating mechanism, mammalian transporters, Gibbs-Donnan equilibrium,

intercompartmental dynamics-Hahn’s fluid distribution kinetics)

Describe the generation of dysnatremias in terms of plasma water sodium determinants

Classification, etiology and pathophysiology of dysnatremias

Incidence, short and long-term prognosis of dysnatremias

Clinical/pathological frame and implications of dysnatremias

Diagnosis (differential) of dysnatremias (e.g. the never ending debate about CSW(Maesaka’s

RSW) vs SIADH – Stern’s salt “wanting” syndromes)

Describe cell-volume related physiology and its clinical implications

Build a quantitative-based framework to treat/prevent dysnatremias

Devise new monitoring frameworks(e.g. trending the urinary uric fractional excretion

according to Maesaka’s algorithm to better delineate between SIADH-RSW)

Narrowing the context to hyponatremia

Define the rules, pitfalls, risk factors inherent to hyponatremia correction

Describe classical ill-derived equations to prevent/amend overcorrection and/or

perform/guide correction

Provide a quantitative, physiologically – derived, still perfectible equation(“master equation”or maybe just “intractable abracadabra” J Appl Physiol 101: 692–694, 2006) for understanding

plasma water sodium determinants

Describe the shortcomings of equation-based ways to manage hyponatremias

Describe a case naturally resembling a beaker - meant to be the ideal patient to be dealt with

when using an equation-based management

Provide a solution whereby at least severely hyponatremic patients at high risk of

overcorrection-related complications might benefit from being artificially, temporarily

transformed into human beakers

You just cannot escape this anymore

Diagnosis, Evaluation, and Treatment of Hyponatremia: Expert Panel Recommendations-2013 Joseph G. Verbalis, Steven R. Goldsmith, Arthur Greenberg, Cynthia Korzelius, Robert W. Schrier, Richard H. Sterns, Christopher J. Thompson. The American Journal of Medicine (2013) 126, S1-S42

Clinical practice guideline on diagnosis and treatment of hyponatraemia – 2014Goce Spasovski, Raymond Vanholder, Bruno Allolio, Djillali Annane, Steve Ball, Daniel Bichet, Guy Decaux, Wiebke Fenske, Ewout Hoorn, Carole Ichai, Michael Joannidis, Alain Soupart, Robert Zietse, Maria Haller, Sabine van der Veer, Wim Van Biesen and Evi Nagler on behalf of the Hyponatraemia Guideline Development Group. European Journal of Endocrinology (2014) 170, G1–G47; Intensive Care Med. 2014 Mar;40(3):320-31; Nephrol Dial Transplant. 2014 Apr;29 Suppl 2:i1-i39

most common disorder of electrolytes occurring in 15%-30% of acutely or chronically hospitalized patients – Madias et al; Am J Med. 2006; 119:S30-S35

severe hyponatremia(serum [Naþ] <125 mmol/L) more than doubled the risk of in-hospital mortality (RR 2.10; P <.001) in an ICU with a overall mortality rate of 37.7% - Bennani et al; Rev Med Interne. 2003;24:224-229

Dissenting results as to whether chronic hyponatremia is just a marker of the underlying disease severity or is itself a risk factor - Chawla, Sterns et al; Clin J Am Soc Nephrol. 2011 May;6(5):960-5

Overall, chronic hyponatremia, not in the least inconsequential, indirectly is proven to be a cause of increased morbidity and mortality - Kinsella et al; Clin J Am Soc Nephrol. 2010;5:275-280

Classification according to biochemical and clinical severity

In terms of overall severity and therapeutic management, the clinical picture will override the biochemical one

Defining target /aim and limit concepts Always aiming for the smallest increase needed to

effect a clinical improvement Low treshold for searching other explanations in

view of the low specificity of hyponatremiaassociated symptoms

Focus on defining acute versus chronic given the risks related to brain volume autoregulation

Low treshold for positing chronic instead of acute with less than severe symptoms

Greatly limiting the aim for acute hyponatremia-4 to 6 mmol/l/first 6h

Setting a common aim of 4-6mmol/l /24h for acute and chronic states but with a different time-scale

Setting a limit at 8-10mmol/l/24h Describe high risk ODS patients Describe management for preventing ODS

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six a day makes sense for safety; so six in six hours for severe sx’s and stop Sterns RH, Hix JK, Silver S. Treating profound hyponatremia: a strategy for controlled correction. Am J Kidney Dis. 2010;56:774-779

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Adrogue HJ, Madias NE. The challenge of hyponatremia. J Am SocNephrol. 2012

Arampatzis S, Frauchiger B, Fiedler GM, et al. Characteristics,symptoms, and outcome of severe dysnatremias present on hospitaladmission. Am J Med. 2012



SENSITIVITY

INCREASED

ODS

Hypokalemia#Hyperkalemia

Alcoholism

Malnutrition

Contextual SIADH

Hypoxemia

Low solutes(e.g.beerpotomania)#urea

Corticoid deficiency-after substitution

Hypothyroidism-after substitution

Serum sodium<105mmol/l

Advanced liver disease

acute water diuresis(EFWC) is most often responsible for overcorrectionMohmand et al,Clin J Am Soc Nephrol 2: 1110–1117, 2007

Reasons behind large positive EFWC- contextual SIADH or non-osmotic induced ADH secretion-

Undiagnosed hypovolemia is the most common feature of overcorrectors

Unpredictable time-dependent stimulation due to thiazide, SSRI

Stress,pain, exercise - related but in this case without consequences due to the acute nature

Hypothiroidism induced ADH-secretion(indirectly-low EABV) Glucorticoid deficiency induced ADH suppression failure

sAntidepressants SSRIs Tricyclic MAOI Venlafaxine Anticonvulsants Carbamazepine Sodium valproateLamotrigineAntipsychoticsPhenothiazidesButyrophenonesAnticancer drugsVinca alkaloidsPlatinum compoundsIfosfamideMelphalanCyclophosphamideMethotrexatePentostatinAntidiabetic drugsChlorpropamideTolbutamineMiscellaneousOpiatesMDMA (XTC)LevamisoleInterferonNSAIDsClofibrateNicotineAmiodaroneProton pump inhibitorsVasopressin analoguesDesmopressinOxytocinTerlipressinVasopressin

Urea as a protector and therapeutic strategy

- lessons from the elasmobranchs -

Sharks are osmoconformers

Have a low adaptability to outer osmolarity variation but still much higher than predicted (high urea, high K)

Urea has been proven to be a true antioxidant - Novel cardiac protective e€ffects of urea: from shark to rat, Wang et al, Br. J. Pharmac., 1999

Urea is known to act as a cryoprotector in amphibians - Cryoprotection by urea in terrestrially hibernating frog, Constazo, J Exp Biol 2005; Urea loading enhances freezing survival and postfreeze recovery in a terrestrially hibernating frog, Constazo J Exp Biol 2008

400mOsm

1000mOsm/kg

Na280 m0sm

K7-14 m0sm

Urea as a protector and therapeutic strategy- icu beginnings -

EFWC = Vu × (𝟏 −𝑼𝑵𝑨 + 𝑼𝑲

𝑷𝑵𝑨

))

Vu = 𝒔𝒐𝒍𝒖𝒕𝒆 𝒆𝒙𝒄𝒓𝒆𝒕𝒊𝒐𝒏

𝑼𝒐𝒔𝒎

Decaux, Soupart; Nephrol Dial Transplant (2007) 22: 1856–1863

Decaux, Soupart, Critical Care 2010 Decaux, Soupart; Nephron. 1993;63(4):468-70 Decaux, Musch; Clin J Am Soc Nephrol 3: 1175–

1184, 2008. Soupart, Decaux; Clin J Am Soc Nephrol 7: 742–

747, 2012 Reeth, Decaux; Clinical Science (1989) 77,35 1-

355 Soupart, Decaux; Nephrol Dial Transplant (2007)

22: 1856–1863 Decaux, J.L.Vincent; Annals of Intensive Care

2012 Decaux, Soupart, Kidney International (2015) 87,

323–331; Urea minimizes brain complications following rapid correction of chronic hyponatremia compared with vasopressin antagonist or hypertonic saline

‘Only a pathetic oaf would suggest anything so ludicrous. Putting back into the body the final waste product of protein metabolism could only be deleterious!’1950 (from Rocque, Neurosurgery 2012; 70: 1049–1054)

Urea as a protector and therapeutic strategy- context-sensitive osmolar effectiveness -

σ=0.5

σ=0.5

Sterns et al,Kidney International (2015) 87, 268–270

A tribute to the forerunners of urea treatment

1892Friedrich W., Magy.orv.Arch.1:400-415,1892

Manucher J. Javid, MD.

1925Crawford, Arch Intern Med (Chic).

1925;36(4):530541

Heart failure-diuretic

The 1950’sManucher and Settlage

See review - Neurosurgery 70:1049–1054, 2012

ICP management

1960s-1970s

1980-Guy Decaux, Alain Soupart

Belgium, Erasme

hNa+

management

Know the cause, the subtype(e.g.pseudohyponatremia, hyperosmolar hypertonic hyponatremia, RSW vs SIADH) or the probable course after having begun correction(underlying hypovolemia )

Frequently monitoring(plasma as well as urine Na, K; urine flow, total balance; even hourly basis) with a limited possibilty for now to have a quasicontinuous urinary flow and electrolyte monitoring(K.I.N.G. system, Italy-Milan, P.Caironi)

Judicious use of equation based-forecasting(Adrogue-Madias, Barsoum-Levine, EFWC-approach or the tonic balance approach, sodium deficit formula)

Targeting normal-high potassium(4.5-5.5 mmol/l)

Use urea in selected cases(e.g. euvolemic hyponatremia-SIADH)

Avoid vaptans for chronic hyponatremia management

Prompt counteraction of overcorrection(D5W, half normal saline, oral water input, desmopressin) +/- CS

Classical approach to minimize the risk of

overcorrection

Soichi Oya et al,Neurology November 27, 2001 vol. 57 no. 10 1931

Equation-driven correction of hNa+

𝑵𝒂𝒅𝒆𝒇 = (𝑵𝒂𝒂𝒄𝒕−𝑵𝒂𝒊𝒅𝒆𝒂𝒍) × 𝑻𝑩𝑾

𝑵𝒂𝟐= 𝑽𝒐𝒍𝒊𝒏𝒇×(𝑵𝒂𝒊𝒏𝒇+𝑲𝒊𝒏𝒇) + 𝑻𝑩𝑾×𝑵𝒂𝟏

𝑻𝑩𝑾+𝑽𝒐𝒍𝒊𝒏𝒇

𝑵𝒂𝟐= 𝑽𝒐𝒍𝒊𝒏𝒑𝒖𝒕× 𝑵𝒂𝒊𝒏𝒑𝒖𝒕+𝑲𝒊𝒏𝒑𝒖𝒕 −𝑽𝒐𝒍𝒐𝒖𝒕× 𝑵𝒂𝒐𝒖𝒕+𝑲𝒐𝒖𝒕 + 𝑻𝑩𝑾×𝑵𝒂𝟏

𝑻𝑩𝑾+∆𝑽𝒐𝒍

𝑵𝒂𝟐 =𝑵𝒂𝟏 × 𝑻𝑩𝑾

𝑻𝑩𝑾− 𝑬𝑭𝑾𝑪

Halperin’s tonicity balance – reply to EFWC approach. Undistinguishable from BL.

Sodium deficit formula

Adrogue-Madias

Barsoum-Levine

Electrolyte free water formula

EFWC = Vu × (𝟏 −𝑼𝑵𝑨+

𝑼𝑲

𝑷𝑵𝑨

)

Simplicity should have been the ultimate sophistication

+

Na1 = 𝑵𝒂𝒆+𝑲𝒆

𝑻𝑩𝑾𝟏

Na2 = 𝑵𝒂𝒆+𝑲𝒆+∆(𝑵𝒂+𝑲)

𝑻𝑩𝑾𝟏+∆𝑻𝑩𝑾

Na2 = (𝑵𝒂𝟏×𝑻𝑩𝑾𝟏)+∆(𝑵𝒂+𝑲)

𝑻𝑩𝑾𝟏+∆𝑻𝑩𝑾

The orange equations are all derived from the blue one The blue equation is itself a marked oversymplification of

another one which we’ll deal with later(Edelman-derived by Nguyen and Kurtz)

Orange SDF psupp. that ∆TBW=0 – TBWsensibility is actually high

and does not suit as a model for 99.9% of all path. states

Orange AM does not take into account anything but the

infusate. If output is large, then it would be futile to use it.

Orange BL seems identical to the blue one. Indeed it is if you

discard e.g. metabolic water. Output refers to urine, drains,

vomiting etc. whilst input refers to iv, oral.

The numerator Nae+Ke stands for total exchangeable sodium

and potassium which by definition (1958) is the sum of total

osmotically active as well as inactive sodium and potassium.

This sheds doubt on the blue equation(and therefore on all the

other) as Na(osm. active) cannot be the result of smth inactive.

Orange EFWC psupp. that the kidney is the single most

important determinant of Nap. What if there is no urine output?

Tzamaloukas et al, J Am Heart Assoc. 2013. Lindner et al, Nephrol Dial Transplant (2008) 23: 3501–3508 Nguyen, Kurtz, Clin Exp Nephrol (2004) 8:12–16 Nguyen, Kurtz, Clin Exp Nephrol (2005) 9:1–4 Barsoum, Levine, Nephrol Dial Transplant (2002) 17:1176-1180 Adrogue, Madias, J Am Soc Nephrol 23: 1140–1148, 2012 Halperin et al, Crit Care Clin 18 (2002) 249 – 272 Halperin et al, ICM Volume 27, Issue5/May 2001

Understanding Nae+Ke- 1958 -

Understanding Nae+Ke- 1958 -

98 patients were studied with “maximum heterogeneity in clinical andmetabolic status to to assure that any correlations between body compositionand serum electrolyte concentrations would have general validity”

Isotope administration Na34 and K42

D2O administration

Regression equations obtained by least squares method

Equilibrium time is never straightforward-main issue

Edelman’s results- 1958 -

Nap is a reflection of the ratio between the sum of monovalent cations (Na and K) and TBW – the slope is ~1

The y-intercept (Na for a ratio=0) “probably is a measure of the quantity of osmoticallyinactive exchangeable sodium and potassium per unit of body water.”

Edelman revisitedNguyen, Kurtz

What do the slope and the y-intercept stand for in termsof physiological significance?

Comprehensivemathematical description offactors determining Nap

Appreciation of the fact thatthe slope as well as the y-intercept might be variablein certain disease states

Multiple equations derivedto serve particular issues e.g.definition of an isonatricurine

Still perfectible in terms of mathematical manipulation of physiological parameters

Disease states might be characterized by activation of inactive pools or vice versa(resistant Na-HTN) # Nguyen et al. J Appl Physiol102: 445–447, 2007.

While there is still uncertainty regarding the 95% conf.interval of the slope andy-intercept, the Nguyen&Kurtz formula “is worth one’s salt” (J Appl Physiol100: 1105–1106, 2006;) as it highlights all Na-determinants.

Ring, Troels, J ApplPhysiol 101: 692–

694, 2006INTRACTABLE

ABRACADABRADenmark, Aalborg

Dorrington, J ApplPhysiol 104: 569,

2008 PROOF or SPOOF

UK, Oxford

www.soapoperadigest.com

“The truth is in the spoof”

Napw = 𝑮

𝜣×

𝑵𝒂𝒆+𝑲𝒆

𝑻𝑩𝑾-𝑮

𝜣×

𝑵𝒂 𝟎𝒔𝒎 𝒊𝒏𝒂𝒄𝒕𝒊𝒗𝒆+𝑲 𝒐𝒔𝒎 𝒊𝒏𝒂𝒄𝒕𝒊𝒗𝒆

𝑻𝑩𝑾−

𝑶𝒔𝒎𝑰𝑪𝑭+𝑶𝒔𝒎𝑬𝑪𝑭

𝑻𝑩𝑾+𝑲𝒑𝒘 +

𝑶𝒔𝒎𝒐𝒍𝒑𝒘𝑽𝒑𝒘

Napw = 𝟏. 𝟏𝟏 ×𝑵𝒂𝒆+𝑲𝒆

𝑻𝑩𝑾- 25.6

Edelman revisitedNguyen, Kurtz

“The truth is in the spoof”

Napw = 𝑮

𝜣×


𝑻𝑩𝑾-𝑮

𝜣×


𝑻𝑩𝑾−


𝑻𝑩𝑾+ 𝑲𝒑𝒘 +


Napw = 𝟏. 𝟏𝟏 ×𝑵𝒂𝒆+𝑲𝒆

𝑻𝑩𝑾- 25.6

G=correction factor as dictated by Gibbs-Donnan equilibrium (1.04)

Θ=average osmotic coeffiecient

of osmotic salts(0.93)

Nae, Ke=total exchangeable

cations(osm. Active + inactive)

Osm = osmoles non Na, non K

Pw=plasma water

ICF=intracellular fluid

ECF=extracellular fluid

(PW+ISF)

Nap = 𝟏. 𝟎𝟑 ×𝑵𝒂𝒆+𝑲𝒆

𝑻𝑩𝑾- 23.8Plasma has 93% water

𝑮

𝜣


𝑻𝑩𝑾


𝑻𝑩𝑾


𝑻𝑩𝑾

𝑲𝒑𝒘


Increase

Increase

Decrease

Increase

Decrease

decrease

With all parameters leftunchanged except for𝑵𝒂 𝟎𝒔𝒎 𝒊𝒏𝒂𝒄𝒕𝒊𝒗𝒆+𝑲 𝒐𝒔𝒎 𝒊𝒏𝒂𝒄𝒕𝒊𝒗𝒆

𝑻𝑩𝑾,

increasing this one willtranslate into cationinactivation and thereby aplasma sodium decrease

OsmECF + OsmICF (Ca2+,Mg2+ ,organic cations, glucose etc)=OsmISF + OsmPW + OsmICF OsmPW

will oppose the other two butmass balance will eventuallyfavor a direct proportionality :

Napw versus𝑶𝒔𝒎 𝑰𝑪𝑭+𝑶𝒔𝒎 𝑬𝑪𝑭

𝑻𝑩𝑾

Unforseen theoretical implications

Defining the role of albumin infusion in cirrhosis-associated hyponatremiaNguyen, Am J Physiol Gastrointest Liver Physiol307: G229–G232, 2014

“we have demonstrated for the first time thatchanges in the [Alb] can directly lead to changes inthe [Na] due to the effect of Gibbs-Donnanequilibrium. Our findings demonstrated that, foreach 1 g/dl increase in the plasma [Alb], plasma [Na]is expected to increase by 1 mmol/l due to the Gibbs-Donnan effect”

Unforseen clinical implications

“Fluid overconsumption or retention of a moderate fluid overload is the‘easiest’ way to induce EAH. Loss of the electrolytes sodium and potassiumcan be significant over time and in hot weather, and should be considered inpost-event rehydration. The most effective treatment of hyponatraemiaassociated to exercise would be to induce excretion of EFW”

More than eleven equations

Nguyen et al, Kidney International, Vol. 68 (2005), pp. 1982–1993

just keep in mind that people cannot be beakers1

Numerators as well as denominators- how to assess them both simultaneously -

+100mmol NaCl1M

cation challenge test

Assess carefully any other ∆V and

∆E over the next 10-15 minutes

Adrogue and Madias, J Am Soc Nephrol 23: 1140–1148, 2012

Draw blood test, measure Nap1

Draw blood test, measure Nap2

Solve the 2 unknowns

Solve for (Nae+Ke) and TBW1

Use the values for further predictionsjust keep in mind that people cannot be beakers2

HOW MUCH?

Nap2 = 𝟏. 𝟎𝟑 ×𝑵𝒂𝒆+𝑲𝒆+𝟏𝟎𝟎

𝑻𝑩𝑾𝟐+𝟎.𝟏- 23.8

Nap1 = 𝟏. 𝟎𝟑 ×𝑵𝒂𝒆+𝑲𝒆

𝑻𝑩𝑾𝟏

- 23.8

Do they work?

66 patients, 681 patient-days(194 hypernatraemic) Excellent output-input balance Day-per-day change in plasma sodium concentration Results are definitely not to be expanded to hyponatremic patients as per author’s conclusions

all four formulae were inaccurate in the clinical setting for different reasons although there is a good correlation between the predicted and actual changes for the whole group, the formulae were

unable to predict changes in the serum sodium level in the individual patient and thus are not without risk in practice the analysis of major pathophysiological mechanisms (extrarenal and renal losses of electrolyte-free water, volume

status, etc) that contributes to hypernatraemia was more important for therapy guidance than all the proposed formulae (see Halperin, Crit Care Clin 2002; 18:249–272)

just keep in mind that people cannot be beakers3

Some think they do

Some think they do

EFWC = Vu × (𝟏 −𝑼𝑵𝑨 + 𝑼𝑲

𝑷𝑵𝑨

))

↑EFWC

Are they really spoof or intractable abracadabra?

Napw = 𝑮

𝜣×


𝑻𝑩𝑾-𝑮

𝜣×


𝑻𝑩𝑾−


𝑻𝑩𝑾+ 𝑲𝒑𝒘 +



𝑻𝑩𝑾+𝑽𝒐𝒍𝒊𝒏𝒇𝑵𝒂𝟐=

𝑽𝒐𝒍𝒊𝒏𝒑𝒖𝒕× 𝑵𝒂𝒊𝒏𝒑𝒖𝒕+𝑲𝒊𝒏𝒑𝒖𝒕 −𝑽𝒐𝒍𝒐𝒖𝒕× 𝑵𝒂𝒐𝒖𝒕+𝑲𝒐𝒖𝒕 + 𝑻𝑩𝑾×𝑵𝒂𝟏𝑻𝑩𝑾+∆𝑽𝒐𝒍

acute water diuresis (EFWC) is most often responsible for overcorrectionMohmand et al, Clin J Am Soc Nephrol 2: 1110–1117, 2007

Spasovski et al, European Journal of Endocrinology (2014) 170, G1–G47Verbalis et al, The American Journal of Medicine (2013) 126, S1-S42

just keep in mind that people cannot be beakers

4



People actually can be turned into human beakers.

Sterns, Kidney International (2009) 76, 587 – 589

Kengne, Kidney International (2009) 76, 614–621

Predictable, constant UO and Uosm.

Overcorrection of hNa+ is a medical emergency- lessons learned from rats -

Human Beakers

Desmopressin 2-4mcg/6h


𝑻𝑩𝑾+𝑽𝒐𝒍𝒊𝒏𝒇

𝑵𝒂𝟐= 𝑽𝒐𝒍𝒊𝒏𝒑𝒖𝒕× 𝑵𝒂𝒊𝒏𝒑𝒖𝒕+𝑲𝒊𝒏𝒑𝒖𝒕 −𝑽𝒐𝒍𝒐𝒖𝒕× 𝑵𝒂𝒐𝒖𝒕+𝑲𝒐𝒖𝒕 + 𝑻𝑩𝑾×𝑵𝒂𝟏

𝑻𝑩𝑾+∆𝑽𝒐𝒍

Preemtively or as a rescue therapy

Rochester General Hospital, Professor Richard Sterns

Control UO and UOsm

Clin J Am Soc Nephrol 3: 331-336, 2008

Am J Kidney Dis. 61(4):571-578. 2013


Frequent monitoring of UO, Nap, urinary electrolytes Use of 3% and less often higher than that Use of desmopressin 1-4mcg/6-8h preemtively Treat overcorrection as a medical EMERGENCY Eventually use D5W or 0.45 saline Use the 6 rule as an aim and limit the increase to 8-10mmol/24h Have a low treshold to declare at risk of ODS Have a low treshold to search for other explanations related to supposedly hyponatremia-

symptoms especially in case of moderate-mild hNa (biochemically) Search for causes of “contextual SIADH” May use an equation based management as long as frequent monitoring and clinical

judgement + physiological reasoning are not curtailed Avoid using vaptans – unpredictable behavior Potassium will increase Nap as per Edelman equation – fatal case review see Berl et al,

American Journal of Kidney Diseases, Vol 55, No 4 (April), 2010: pp 742-748 In case of overcorrection you may use CS but primordial is reversing the Na increase

Controlled hyponatremia correction- Sterns’ management -

Sterns, Clin J Am Soc Nephrol 3: 331-336, 2008 Sterns, Kidney International (2009) 76, 587 – 589 Kengne, Kidney International (2009) 76, 614–621 Sterns, Am J Kidney Dis 56:774-779. 2010


People actually can be turned into human beakers.

quantitative approach in dysnatremias

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