Your SlideShare is downloading. ×
0
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Disorder of sodium imbalance
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×
Saving this for later? Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime – even offline.
Text the download link to your phone
Standard text messaging rates apply

Disorder of sodium imbalance

2,193

Published on

Published in: Health & Medicine, Technology
0 Comments
6 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
2,193
On Slideshare
0
From Embeds
0
Number of Embeds
4
Actions
Shares
0
Downloads
156
Comments
0
Likes
6
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. Case discussionand topic reviewPresenter Dr. Pradip KatwalModerator Dr. Thomas JohnDept of internal medicineBPKIHS DHARAN,NEPAL
  • 2. • 67 yrs female• Presenting complains- fever- 4 days vomiting-4 days loose stool-4 days ( for 2 days) Past h/o- no significant illness
  • 3. Case summary• Elderly lady without significant pass illness presented to emergency with h/o low grade fever without chills and rigors, multiple episodes of non-projectile vomiting associated with nausea and watery stool not containing blood or mucus for initial two day and has not passed stool since then. She also complains of weakness and was unable to sit from the supine position.• No headache, no seizures, no abdominal pain• H/o of treatment in local hospital for two days before presentation.
  • 4. At Presentation CHEST- b/l symmetrical and equal air entry B/l normal vesicular breath sounds• Gcs-14/15 no crepts• Pulse-113 beats/min CVS - apical impulse 5th ics• B.P-80/40 mmhg medial to MCL (supine) S1 S2 M(-) P/A- Soft non tender• Afebrile no organomegaly• Rr-18 breath/min Bowel sound-sluggish• JVP-not visible CNS-GCS 14/15 higher mental function cranial nerve- normal• Pallor(+) motor- dehydration(+) Power 3/5 skin turgor decreased proximal musle of b/l limbs Rest-WNL sensory-intact no nuchal rigidity
  • 5. PROVISIONAL DIAGNOSIS• ACUTE INFECTIVE GASTROENTERITIS IN PRESENTED IN HYPOVOLUMIC SHOCK
  • 6. Initial managementInj. Normal saline 1 liter iv bolusThen Inj.NS 5OO ml iv 6 hourlyInj.5%dextrose 500 ml 8 hourlyInj. Ciprofloxacin 200 mg iv BDInj. Metronidazole 500 mg iv TDSInj Pantoprazole 40mg iv OD
  • 7. INVESTIGATIONS• HB-12.2 • SUGAR-84 • UREA-41• TLC-14600/MM3 • CREATININE-0.8• DLC-N70,L30 • NA-118• PT-179000/mm3 • K-2.5 • ABG-• URINE RE/ME-WNL • PH-7.288• STOOL RE/ME- • HCO3-14.6 SENT TO CENTRAL • PCO2-28.4 • LACTATE-1.0 LAB
  • 8. DIAGNOSIS• ACUTE INFECTIVE GASTROENTERITIS IN HYPOVOLUMIC SHOCK WITH DYSELECTROLYTEMIA -HYPOKALEMIA -HYPOOSMOLAR HYPOVOLUMIC HYPONATREMIA -METABOLIC ACIDOSIS -PARALYTIC ILEUS
  • 9. ManagementInj. Normal saline 1 liter iv bolusThen Inj.NS 5OO ml iv 6 hourly with 30meq KCl in each pintInj.5%dextrose 500 ml 8 hourlyInj. Ciprofloxacin 200 mg iv BDInj. Metronidazole 500 mg iv TDSInj Pantoprazole 40mg iv OD Inj 3%NS 100 ml TDS
  • 10. DAY 3 OF ADMISSION• Subjective- Multiple • Sugar-108 episodes of vomiting • Urea-13• Bowel sounds-sluggish • Creatinine-1.0• Proximal muscle weakness • Na-121 • K-2.5• PULSE-98 • Stool re/me-WNL• B.P.-90/60 mmhg• Afebrile• 16 breath/min• Urine output-400ml
  • 11. DISORDERS OFSODIUM BALANCE
  • 12. HYPONATREMIA• Hyponatremia is defined as a plasma [Na+] < 135 mEq/L
  • 13. Hyponatremia• Physiology of Serum sodium concentration regulation: 1. Renin-angiotensin-aldosterone system 2.Stimulation of thirst 3.Renal handling of filtered sodium 4.Secretion of ADH
  • 14. Hyponatremia• Epidemiology: ocw.jhsph.edu ▫ Frequency  Hyponatremia is the most common electrolyte disorder  Occurring in 22% of hospitalized patients.
  • 15. Clinical features• Symptoms primarily neurological ▫ Nausea ▫ Vomiting ▫ Headache ▫ Seizure ▫ Coma
  • 16. Hyponatremia• Types ▫ Hypovolemic hyponatremia ▫ Euvolemic hyponatremia ▫ Hypervolemic hyponatremia ▫ Low solute intake and hyponatremia ▫ Pseudohyponatremia
  • 17. Osmolality• Calculated Plasma Osmolality: P osm = 2 (Na) + glucose/18 + BUN/2.8 Normal = 290 (275-290 mM)• Measured osmolality (MO) ▫ Osmolality measured by osmometer. ▫ works on the method of depression of freezing point.• Urine Osmolality:  Normal: 400-500 mM ▫ Maximal dilution 50-100 mM ▫ Maximal concentration 900-1200 mM
  • 18. Hyponatremia Serum OSM LOW NORMAL HIGH Marked Hypotonic hyperlipidemia Hyperglycemiahyponatremia Hyperproteinemia Mannitol
  • 19. PseudohyponatremiaPseudohyponatremia is laboratory error due to high content of plasma proteins and lipidsExpansion of nonaqueous portion of the plasma sampleErrant report of a low ECF [Na+]
  • 20. Hyponatremia Serum OSM LOW NORMAL HIGH Marked Hypotonic hyperlipidemia Hyperglycemiahyponatremia Hyperproteinemia Mannitol
  • 21. Hyperosmolar hyponatremia Osmotically active solute other than sodium accumulates in the ECF, drawing water into the ECF and diluting the Na+ content.  Glucose  Glycine100 MG/DL RISE IN FALL IN PLASMA [NA+] MannitolPLASMA GLUCOSE OF 1.6 TO 2.4 MEQ/L Sorbitol
  • 22. Hyponatremia Serum OSM LOW NORMAL HIGH Marked Hypotonic hyperlipidemia Hyperglycemiahyponatremia Hyperproteinemia Mannitol
  • 23. RESET OSMOSTATSet point for plasma osmolality is reduced.ADH and thirst responses maintain osmolalityat this lower level. This phenomenon occurs in almost allpregnant women
  • 24. PSYCHOGENIC POLYDIPSIAUrine cannot be diluted to an osmolality lessthan ~50 mosm/l A small amount of solute is required in eventhe most dilute urine.
  • 25. Assessment of volume status hypovolemia Euvolemia hypervolemiaU na >20 Una <20 RENAL LOSSES Diuretic excess EXTRA RENAL LOSSES Mineralocorticoid deficiency Vomiting Salt losing deficiency DIARRHOEA Ketonuria THIRD SPACING Osmotic diuresis BURNS,PANCREATITIS,TRAUMA Cerebral salt wasting syndrome
  • 26. HYPOVOLEMIC HYPONATREMIADevelops as sodium and free water are lost and/or replaced by inappropriately hypotonic fluids
  • 27. Assessment of volume statushypovolemia Euvolemia hypervolemia Acute or chronic renal U Na >20 failure NEPHROTIC SYNDROME U Na<20 CIRRHOSIS Cardiac failure
  • 28. Assessment of volume statushypovolemia Euvolemia hypervolemia U Na >20 Glucocorticoid deficiency Hypothyroidism Stress Drugs Syndrome of inappropriate ADH secretion
  • 29. WHAT is inappropriate about SIADH? Despite the absence of osmotic or volume-related stimuliNonphysiologic release of vasopressin from the posterior pituitary or an ectopic source
  • 30. Cerebral salt-wasting  Hyponatremia in cns disease particularly in patients with subarachnoid hemorrhage Characterized by hyponatremia & extracellular fluid depletion due to inappropriate sodium wasting in the urine
  • 31. Cerebral Salt Wasting• Cerebral disease (particularly SAH)• Mimics SIADH with hyponatremia except primary defect is salt wasting not water retention.• Treatment is NS to correct ECFv contraction
  • 32. SIADH CSWUrine Output decreased polyureaSerum Na low lowUrine Na high highSerum osm low lowUrine osm high highCVP high low
  • 33. Treatment• Distinction between CSW & SIADH is critically important since the two disorders are managed differently ▫ fluid restriction, the usual first-line therapy for SIADH, may increase the risk of cerebral infarction among patients who actually have CSW ▫ Volume repletion with isotonic saline is the recommended therapy in CSW, since it will suppress the release of ADH, thereby permitting excretion of the excess water and correction of the hyponatremia
  • 34. Diagnostic Testing for classification Plasma osmolality Urine osmolality Urine sodium concentration Diagnosis of underlying cause  CT head, EKG, CXR if symptomatic  CT scan  Urea ,Creatinine  Serum potassium levels  Uric acid  TFT
  • 35. Treatment of Hyponatremia• Issues to be addressed  Asyptomatic vs. Symptomatic  Acute (within 48 hours) vs. Chronic (>48 hours)  Volume status  Monitoring response to intervention
  • 36. calculations• Calculation: Total Body Water (TBW) ▫ Men  TBW = 0.6 x (kilograms Lean Body Mass) ▫ Women  TBW = 0.5 x (kilograms Lean Body Mass)• Calculations based on Total Body Water (TBW) ▫ Total Body Water Excess (Hyponatremia)  Normal TBW = TBW x (Serum Sodium / 140)  Excess TBW = TBW - Normal TBW ▫ Free Water Deficit (Hypernatremia)  FWD = TBW x (Serum Sodium - 140) / 140• Calculations: Total Body Sodium Deficit ▫ Sodium deficit = TBW x (140 - Serum Sodium)
  • 37. EXAMPLEA 70 years old women is having seizure,her serum sodium is 100 Meq/l.her body wt is 60 kg. INITIAL GOAL- Increase the sodium concentation to 116 meq or symptoms resolution ESTIMATE TOTAL BODY WATER O.45 * 60=27 ESTIMATE CHANGE IN SERUM SODIUM (USING one liter of 3% hypertonic saline) (531-110)/(27+1)=14.39SYMPTOMATIC PATIENT SO RATE IS 1 MEQ/L/HR FOR NEXT THREE HOUR For 14.39 meq change - lt. of hypertonic saline 1 lt. For 3 meq change –lt.of hypertonic saline used is (1/14.39)*3 Rate of administration for 3 hours 208/3=69.33 ml/hr
  • 38. Rx Hyponatremia• When do you need to treat quickly? ▫ Acute (<24h) ▫ severe (< 120 meq/L) ▫ Symptomatic hyponatremia (seizures, coma, etc.)• “Quickly” by: ▫ 3% NS, 1-2 mEq/L/h until:  Till Symptoms stops  3-4h elapsed and/or Serum Na has reached 120 mEq/L• Then SLOW down correction to 0.5 mEq/L/h with 0.9% NS or simply fluid restriction.• Aim for overall 24h correction to be < 10-12 mEq/L/d to prevent myelinolysis
  • 39. Treatment Hyponatremia• Act slowly (correct < 0.5 mEq/L/h, 10-12 mEq/L/d) ▫ Symptomatic/Acute: rapid Rx has resolved symptoms and brought serum Na up to 120 mEq/L ▫ Asymptomatic, mild, chronic hyponatremia ▫ Want to prevent myelinolysis  Increased risk: Women, alcoholics, malnourished• ECFv contracted  Bolus NS until BP, HR, JVP stable  Then correct slowly with 0.9% NS or salt tablets
  • 40. SIADHTreatment• Fluid Restriction• Oral Salt, Hi-protein diet or Urea(30 g/d• Lasix 20 mg po od-bid• Demeclocycline 300-600 mg bid)• Lithium
  • 41. • Tolvaptan• Most appropriate for significant and persistant SIADH not responding to furesomide, salt tablets and water restriction
  • 42. • WATER RESTRICTION.• The amount of fluid restriction necessary depends on the extent of water elimination. ▫ If (Urine Na + Urine K)/Serum Na < 0.5, restrict to 1 L/d. ▫ If (Urine Na + Urine K)/Serum Na is 0.5 to 1.0, restrict to 500 mL/d. ▫ If (Urine Na + Urine K)/Serum Na is >1, the patient has a negative renal free water clearance and is actively reabsorbing water.
  • 43. Osmotic Demyelination Syndrome due to Rapid correctionNeurologic Features  flaccid paralysis  Dysarthria  dysphagia.Diagnosis  suspected clinically  can be confirmed by neuroimaging .Treatment  No effective therapy  aggressive plasmapheresis
  • 44. Osmotic Demyelination Syndrome chronic hyponatremia  most susceptible to ODS Administration of hypertonic saline  sudden osmotic shrinkage of brain cells. Risk factors ▫ prior cerebral anoxic injury, ▫ hypokalemia, ▫ Malnutrition ▫ chronic alcoholism.• Prognosis ▫ 50% mortality
  • 45. Hypernatremia(Na+ > 145 mEq)
  • 46. Introduction• Caused by a relative deficit of water in relation to sodium which can result from- Iatrogenic sodium loading Net water loss
  • 47. Causes of HypernatremiaNet water lossPure water loss •Unreplaced insensible losses (dermal and respiratory) • 10ml/kg per day •Exercise •Fever •heat exposure •mechamical ventilation
  • 48. Central diabetes insipidus•Post-traumatic TumorsCystsHistiocytosisTuberculosisSarcoidosis Idiopathic Aneurysms, meningitis, encephalitis
  • 49. Nephrogenic diabetes insipidus• Congenital• Mutation• ▫ X-linked V2 receptors ▫ aquaporin 2 water channel ▫ Aquaporin one channel
  • 50. • Acquired Renal disease (e.g. medullary cystic disease) Hypercalcemia Hypokalemia Drugs (lithium, demeclocycline, foscarnet, methoxyflurane, amphotericin B, vasopressin V2- receptor antagonists)
  • 51. • Adipsic diabetes insipidus • Central defect in osmoreceptor function • Both AVP secretion and thirst• Gestational diabetes insipidus • Late pregnancy • Placental protenease have vasopressinase activity
  • 52. Causes of Hypernatremia (cont’d) Hypotonic fluid loss • Renal causes Loop diuretics Osmotic diuresis (glucose, urea, mannitol) Post-obstructive diuresis Intrinsic renal disease
  • 53. Hypotonic Fluid Loss (cont’d) • Gastrointestinal Vomiting Nasogastric drainage Enterocutaneous fistula Diarrhea Use of osmotic cathartic agents (e.g.,lactulose) • Cutaneous Burns Excessive sweating
  • 54. Causes of Hypernatremia (cont’d)Hypertonic sodium gain Cushing’s syndrome Primary hyperaldosteronism Hypertonic sodium bicarbonate infusion Ingestion of sodium chloride Ingestion of sea water Sodium chloride-rich emetics Hypertonic dialysis
  • 55. Clinical Manifestations• CNS dysfunction ▫ Depend on large or rapid increases in serum Na+ concentration (acute and chronic) ▫ Few symptoms until Na+ > 160 ▫ Affects extremes of ages ▫ Altered mental status ▫ seizures • confusion • coma • Subarachnoid hemorrhages • Rabdomyoslsis
  • 56. Diagnostic approach• Presence of thrist?• Polyuria?• Source of extra-renal loss• Deatiled neurological examination• Extracellular fluid volume Assesment
  • 57. ECF VOLUMEINCREASED NOT INCREASED ADMINISTRATION ?MINIMUM VOLUME OF MAXIMALLY OF HYPERTONIC CONCENTRATED NACL OR NACO3 URINE
  • 58. MINIMUM VOLUME OF MAXIMALLY CONCENTRATED URINE Insensible water loss URINE OSMOLE no Gastrointestinal water loss EXCERTION RATE<750Remote renal water loss mosoml/day yes Renal response to Diuretic no Osmotic diuresis desmopressin Unire osmolality Urine increase osmolality unchanged Central diabetes insipidus Nephrogenic diabetes insipidus
  • 59. DIAGNOSIS FOR HYPERNATREMIA• Renal response to hypernatremia is small volume of concentrated (urine osmolality > 800 mOsm/L) urine. can occur from urine osmolality <300 A suggests complete mOsm forms of CDI and NDI Urine osmolality between Partial forms of DI as well 300 and 800 mosm/L as osmotic diuresis. The two can be differentiated by quantifying the daily solute excretion (estimated by the urine osmolality × urine volume in 24 hours).  A daily solute excretion > 900 mOsm defines an osmotic diuresis.
  • 60. DIAGNOSIS FOR HYPERNATREMIARESPONSE TO to hypernatremia is a small volume of concentratedThe appropriate renal response DDAVP(urine osmolality > 800 mOsm/L) urine. Submaximal urine osmolality (<800 mOsm/L) suggests a defect in renal waterComplete forms of CDI and NDI can be distinguishedconservation. byadministering the vasopressin analog dDAVP (10 mcgintranasally) after careful mOsm in the setting of hypernatremia suggests A urine osmolality <300 water restriction. complete forms of CDI and NDI. Urine osmolality between 300 and 800 mOsm/L can occur from partialThe urine as well as osmotic diuresis. forms of DI osmolality should increase by at least 50% incomplete CDI and does not change in NDI. The diagnosis issometimes difficult when partial defectsdaily solute excretion (estimated by The two can be differentiated by quantifying the are present. the urine osmolality × urine volume in 24 hours). A daily solute excretion > 900 mOsm defines an osmotic diuresis.
  • 61. Lab measurements• Serum and urine osmolality• Urine electrolytes• Water deprivation test• Response to DDAVP
  • 62. ManagementA two-pronged approach:• Addressing the underlying cause: stopping GI loss, controlling pyrexia, hyperglycemia, correcting hypercalcemia or feeding preparation, moderating lithium induced polyuria• Correcting the prevailing hypertonicity: rate of correction depends on duration of hypernatremia to avoid cerebral edema
  • 63. Correction of Hypernatremia• Hypernatremia that developed over a period of hours (accidental loading) ▫ Rapid correction improves prognosis without cerebral edema ▫ Accumulated electrolytes in brain rapidly extruded ▫ Reducing Na+ by 1 mmol/L/hr appropriate
  • 64. Rate of Correction (Cont’d)• Hypernatremia of prolonged or unknown duration ▫ A slow pace of correction prudent ▫ Full dissipation of brain solutes occurs over several days ▫ Maximum rate 0.5 mmol/L/hr to prevent cerebral edema ▫ A targeted fall in na+ of 10 mmol/L/24 hr
  • 65. Goal of Treatment• Reduce serum sodium concentration to 145 mmol/L• Make allowance for ongoing obligatory or incidental losses of hypotonic fluids that will aggravate the hypernatremia• In patients with seizures prompt anticonvulsant therapy and adequate ventilation
  • 66. Administration of Fluids • Preferred route: oral or feeding tube • IV fluids if oral not feasible • Except in cases of frank circulatory compromise, isotonic saline is unsuitable • Only hypotonic fluids are appropriate-pure water, 5% dextrose, 0.2 % saline, 0.45% saline- the more hypotonic the infusate, the lower the infusion rate required
  • 67. ▫ CORRECTION OF HYPERNATREMIA IS ACCOMPLISHED BY CALCULATING FREE WATER DEFICIT BY THE EQUATION:• The change in [Na+] from the administration of fluids can be estimated as follows:• Δ[Na+] = {[Na+i] + [K+i] - [Na+s]} ÷ {TBW + 1}
  • 68. WATER DEFICIT Ongoing water losses:- (kg) byI. TBW is estimated by multiplying lean weight Management of hypernatremia 0.5 in men (rather than 0.6) and 0.4 in women. Insensible loss- CALCULATE ELECTROLYTE FREE WATER CLEARANCE • Water deficit + ongoing water loss +insensibleII.Free water deficit = ml/kg - 140)/140} × (TBW) 1o {([Na] per day loss C H2O= V(1-UNa+Uk)/PNa • Correct the water deficit over 48 to 72 hours • Avoid correction of plasma Na by >10 mM/day
  • 69. Diabetes insipidus is best treated by removing the underlying causeI. CENTRAL DIABETES INSIPIDUS Administration of dDAVP, a vasopressin analog.II. NEPROGENIC DIABETES INSIPIDUS. A low-Na+ diet combined with thiazide diuretics will decrease polyuria through inducing mild volume depletion. Decreasing protein intake will further decrease urine output by minimizing the solute load that must be excreted.
  • 70. HOSPITAL COURSE• PATIENT IMPROVED DURING HER COURSE OF STAY IN HOSPITAL BUT HAD PERSITANT HYPOKALEMIA AND WEAKNESS OF PROXIMAL MUSCLE DESPITE POTASSIUM SUPPLEMENT. D5 D6 D7 SODIUM 130 140 145 POTASSIUM 3.1 3.1 3.8 UREA 49 10 CREATININ 1 O.7 E
  • 71. • DUE TO PERSISTEN HYPOKALEMIA SERUM MAGNESIUM LEVELS WAS EVALUATED CALCIUM MAGNESIUM DAY 7 6.9 O.41 DAY 8
  • 72. Mechanism of Hypokalemia inMagnesium Deficiency
  • 73. DAY 8 ADMISSION• SHE IMPROVED GRRADUALLY• NO DIFFICULTING IN LIFTING HER HEAD• NO DIFFICULTY IN WALKINGPATIENT WAS DISCHARGED ON DAY 9.
  • 74. •Thank you
  • 75. Refrences• HarrisonsPrinciples.of.Internal.Medicine.18th.E dition• Raoof Manual of critical care• Washington Manual® of Medical Therapeutics, The, 34rd Edition.• HYPONATREMIA REVIEW ARTICLE, Adrogué HJ, Wesson DE. The New England Journal of Medicine 2004:205-84

×