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Channel Your Enthusiasm

Channel Your Enthusiasm

A chapter by chapter recap of Burton Rose’s classic, The Clinical Physiology of Acid Base and Electrolyte Disorders, a kidney physiology book for nephrologists, fellows, residents and medical students.

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  • S1 · E34
    August 16 · 1 hr 37 min

    Chapter Twenty-Three: Hypoosmolal States–Hyponatremia

    Roger’s Hydrogen to pH table References December 19, 2023 Joel had a patient with severe hypothyroidism and hyponatremia- case report Mel reviewed the endocrine factors that can contribute to hyponatremia in this report (from the 2020 ASN quiz and questionnaire): Pattern Recognition versus Pathogenesis - PMC and amy shared this too: Impact of etiology, age and gender on onset and severity of hyponatremia in patients with hypopituitarism: retrospective analysis in a specialised endocrine unit JC mentioned reports of sodium loss from biliary sodium as a cause of hyponatremia: Severe Persistent Hyponatremia: A Rare Presentation of Biliary Fluid Loss - PMC , Hyponatremia after Choledochostomy and T Tube Drainage but here’s a reference that did measure biliary sodium concentration in children and found the concentration in bile was similar to plasma (which can lead to significant sodium losses! But not hyponatremia unless replete with dilute fluids ;) 10.1001/archpedi.1986.02140200045024 Here’s a set of articles by Tom Berl on hyponatremia- the first on solute intake and the second in setting of CKD (enjoy! These are really great!): Impact of solute intake on urine flow and water excretion (this figure is brilliant!) and Dysnatremias in Patients With Kidney Disease - PMC Especially enjoy Figure 6! (and check out notes from chapter 9 that review reduced ability to maximally dilute the urine in older individuals- plus here’s a few more great references on the aging kidney: THE AGING KIDNEY: PHYSIOLOGICAL CHANGES - PMC, Urine Concentrating and Diluting Ability During Aging - PMC , Aging and physiological changes of the kidneys including changes in glomerular filtration rate We quickly referred to the Everest trial of tolvaptan in CHF and Anna shared the reference. Roger mentioned the weight gain that occurs in hyponatremia and marathon running: this study in the NEJM showed that the risk of hyponatremia was greatest in those with longer race times, more weight gain: https://www.nejm.org/doi/10.1056/NEJMoa043901 Amy’s VOG on Gastric Secretions Dr. Boyer: https://medicine.yale.edu/profile/james-boyer/ Dr. Boyer’s review on his original work on bile salts: https://pmc.ncbi.nlm.nih.gov/articles/PMC4091928/ Gastric secretions From 1961! https://pubmed.ncbi.nlm.nih.gov/13714620/ From 1959! https://physoc.onlinelibrary.wiley.com/doi/abs/10.1113/expphysiol.1960.sp001428 Secretions (2 book in PDF form) Basic Concepts of Fluid and Electrolyte Therapy (see page 14) https://www.researchgate.net/publication/369203977_BASIC_CONCEPTS_OF_FLUID_AND_ELECTROLYTE_THERAPY_2nd_Edition Basic Facts of Body Water and Ions (see page 96) https://link.springer.com/book/10.1007/978-3-662-38375-9 Chapter 23: Hypoosmolar States — Hyponatremia PATHOPHYSIOLOGY Plasma Sodium and Plasma Osmolality Plasma sodium is the main determinant of plasma osmolality. Hyponatremia = Na <135 mEq/L, which usually reflects hypoosmolality. Why this matters: Low plasma osmolality causes water to move into cells. This cellular overhydration produces the symptoms of hyponatremia, particularly in the brain. The Basic Mechanism of Hyponatremia Two questions provide a useful framework: How do patients develop hyponatremia? Why do they remain hyponatremic? Generation of Hyponatremia Either solute loss (Na or K) or water retention can produce hyponatremia. However, most fluid losses are approximately isoosmotic to plasma. Isoosmotic fluid loss by itself is neutral with respect to plasma sodium. It becomes a problem when the lost fluid is replaced with hypoosmotic fluid. Thus, hyponatremia is usually fundamentally a disorder of water gain relative to solute. Hypoosmolality generally cannot develop without water intake. Perpetuation of Hyponatremia The normal response to falling plasma osmolality is suppression of ADH. Reduced ADH → dilute urine and increased water excretion. ADH secretion progressively falls as plasma osmolality falls. ADH secretion essentially ceases when: Plasma osmolality falls below approximately 275 mOsm/kg, or Serum Na approaches 135 mEq/L. Figure 23-1 appears closer to 280 mOsm/kg. With maximal ADH suppression: Urine osmolality falls to approximately 40–100 mOsm/kg H₂O. Specific gravity falls to approximately 1.001–1.003. The kidney can potentially excrete >10 L/day of dilute urine. Because the normal kidney can clear enormous quantities of free water, some defect in renal water excretion is generally required for hyponatremia to persist. Major exception: primary polydipsia, where water intake overwhelms otherwise intact renal water excretion. Requirements for Free-Water Excretion Free-water excretion depends on two processes: Generation of dilute tubular fluid NaCl is reabsorbed without water in the diluting segments. Primarily the thick ascending limb of the loop of Henle. To a lesser degree, the distal tubule. See Table 23-1. Excretion of that dilute fluid Requires the collecting tubules to remain relatively impermeable to water. This requires suppression of ADH. Failure of either process can reduce free-water clearance. In almost every clinical case, the dominant problem is excess ADH activity, usually from: SIADH Decreased effective circulating volume Important exceptions include: Oliguric kidney failure Primary polydipsia Low-solute intake / “tea and toast” physiology? Not discussed here. Using Urine Osmolality as an ADH Readout Urine osmolality provides a functional assessment of ADH activity. Uosm <100 mOsm/kg: ADH is appropriately suppressed. Uosm >100 mOsm/kg: ADH effect is present. In clinically significant ADH-mediated hyponatremia, Uosm is often >300 mOsm/kg. Thought Experiment: It Doesn’t Take Much Assume: Daily solute load = 400 mOsm Daily water intake = 2 L If the kidney can dilute urine to 200 mOsm/kg: 400 mOsm ÷ 200 mOsm/kg = 2 L urine All 2 L of ingested water can be excreted. But if minimum urine osmolality rises only slightly to 220 mOsm/kg: 400 ÷ 220 = 1.8 L urine That leaves approximately 200 mL/day of retained water. Over days or weeks, even this modest impairment can produce progressive hyponatremia. Why doesn’t suppression of thirst protect the patient? Because much of human water consumption is habitual, social, or cultural rather than driven strictly by osmotic thirst. ETIOLOGY See Table 23-2. The disorders in which water excretion is impaired are much more important causes of hyponatremia than disorders in which water excretion remains normal. Effective Circulating Volume Depletion Effective circulating volume refers to the fluid that is effectively perfusing tissues. It may be reduced in patients with either decreased or increased total extracellular volume. True Volume Depletion Loss of both: Intravascular fluid Interstitial fluid Potential sources: GI tract Kidneys Skin Other Causes of Reduced Effective Circulating Volume Decreased vascular resistance Example: advanced liver disease Reduced cardiac output Example: heart failure Why Effective Volume Depletion Causes Hyponatremia Effective volume depletion affects: Thirst Potassium balance Water excretion ADH Hypovolemia sensed through arterial baroreceptors is a potent non-osmotic stimulus for ADH secretion. Reduced Delivery to the Diluting Segments Volume depletion can also cause: Reduced GFR Increased proximal Na reabsorption Reduced fluid delivery to the diluting segments This theoretically reduces free-water generation even without ADH. However, how important is this mechanism? ADH antagonists can largely reverse impaired water excretion in: Heart failure Cirrhosis Adrenal insufficiency …without necessarily improving tissue perfusion. That argues that ADH is doing much of the work. Severity of Disease Matters The tendency toward increased ADH and reduced distal delivery increases with the severity of effective volume depletion. Thus: Worse heart failure → greater risk of hyponatremia Worse cirrhosis → greater risk of hyponatremia Hyponatremia generally does not occur until disease is relatively advanced. In heart failure, even Na <137 mEq/L is associated with reduced survival. A seemingly minor reduction in sodium may therefore reflect a major impairment in renal water excretion. Water Intake Still Matters The severity of hyponatremia is strongly influenced by how much water the patient consumes. Ultramarathoners May lose 10–14 L of sweat. Sweat contains approximately 20–100 mEq/L of Na + K. Replacement fluids may contain carbohydrates but relatively little solute. Symptomatic hyponatremia can develop. Serum Na may fall below 120 mEq/L. Cholera Severe diarrhea from cholera may contain: Stool Na approximately 120–140 mEq/L. Low-solute replacement solutions increase the risk of hyponatremia. Concurrent Potassium Depletion Potassium depletion can worsen hyponatremia. K leaves cells to replenish extracellular potassium. Electroneutrality is partly maintained by Na moving into cells. This lowers extracellular Na concentration. Normally, falling plasma osmolality would suppress ADH and permit water excretion. If ADH remains elevated because of volume depletion, this compensatory mechanism is blocked. Giving KCl alone can therefore partially correct hyponatremia by reversing the transcellular cation exchange. Hard to believe Edelman isn’t invoked here.

  • S1 · E33
    June 29 · 1 hr 9 min

    Chapter Twenty-Two: Introduction to Disorders of Osmolality

    References This is the famous Edelman equation from JCI in 1958 by Isodore Edelman! Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water (not to be confused by Isildur House of Isildur - Tolkien Gateway Joel mentioned his slide deck on Edelman: https://pbfluids.com/wp-content/uploads/2023/04/QN_III-The-Edelman-Equation-full-lecture-from-2020-07-30.pdf This is an excellent review (with great figures) on Osmotic homeostasis by Danziger and Zeidel in CJASN Joel and JC mentioned the work from Joseph Verbalis on hyponatremia- this is an excellent review that includes population data from NHANES plus striking images of the osteopenic bones in hyponatremic rats! Check this out! Hyponatremia‐induced osteoporosis - Verbalis - 2010 - Journal of Bone and Mineral Research - Wiley Online Library Joel and JC mentioned “reference 2” from the chapter by Kleeman and others on diuretic induced hyponatremia which invoked hypokalemia as an important player: Diuretic-Induced Hyponatremia | Annals of Internal Medicine We couldn't help flirting with diarrhea a little Secretory diarrhoea: mechanisms and emerging therapies - PMC We talked about cravings for those with salt losses and here’s one example Gitelman syndrome in a South African family presenting with hypokalaemia and unusual food cravings - PMC PBFluids classic: Saltiest Sodium. Dumbest Dude Volume Depletion versus Dehydration: How Understanding the Difference Can Guide Therapy here’s one of many articles that argues for choosing language wisely. Amy’s VOG references: PMC3041494 42321668 41846300 42195166 33374011 PMC3041494 PMC12884999 3102222 42060832 41201721 32401639 Link to Goljian Physiology Spotify! Episode 2 is Fluid and Hemodynamics: https://open.spotify.com/show/1uD6090Kkg01b4zr2ouNiM?si=e7f609e0d9634840 Outline: Chapter 22 Introduction to Disorders of Osmolality Hyponatremia and hypernatremia are common clinical problems Reflect abnormalities of water balance that may or may not be accompanied by changes in Na balance Water Distribution and Osmotic Pressure TBW makes up 60% of lean body weight in men 50% of lean body weight in women 60% intracellular 40% extracellular One-fifth of extracellular water is in the intravascular space Breakdown 70 kg man TBW = 42 L 25 L intracellular 17 L extracellular 3 L of the 17 L is intravascular Osmotic forces determine the distribution of water Each compartment has one major solute that holds water within the compartment Na → extracellular compartment K → intracellular compartment Plasma proteins → plasma space Urea is an ineffective osmole Physiologic Effects of Changes in Plasma Osmolality Figure 22-1 Na pulls water from the intracellular compartment Increases extracellular volume Decreases intracellular volume Even though Na is locked in the extracellular compartment Administering Na increases osmolality everywhere by changing water distribution Increases extracellular volume Decreases intracellular volume Example Adding 210 mEq Na to 17 L ECF would mathematically increase concentration by 12.5 mEq/L (210/17) Actually only raises serum Na by ~5 Water moves from cells Na remains trapped in ECF Ultimately diluted in TBW 210/42 L = 5 mEq/L Adding water Expands both compartments Dilutes osmolality in both compartments Giving isotonic saline Expands extracellular compartment only Does not change intracellular volume Changes in osmolality and intracellular volume Responsible for symptoms of hypo- and hypernatremia In these examples Extracellular volume is increased Sodium concentration may be high, low, or normal Meaning of Plasma Sodium Concentration Na, glucose, and urea are the primary extracellular osmoles Gives osmolality calculation Under normal conditions Glucose and BUN contribute <10 mOsm/L Therefore Plasma osmolality ≈ 2 × plasma Na Hypernatremia represents hyperosmolality Hyponatremia usually reflects hypo-osmolality Exception: hyperglycemia Plasma Sodium Concentration and Total Body Osmolality If plasma Na reflects plasma osmolality And plasma osmolality is in equilibrium with total body osmolality Then plasma Na reflects total body osmolality Since Total body osmolality = (ECF solutes + ICF solutes) / TBW And Na and K (plus accompanying anions) are the major extracellular and intracellular solutes Then Plasma Na ≈ (Na + K) / TBW Figure 22-2 Key Edelman figure Loss of potassium K moves out of cells To maintain electroneutrality Na enters cells Lowers serum Na Or Cl leaves with K Lowers intracellular osmolality Water moves from cells to ECF Dilutes serum Na Or extracellular H dissociates from buffers and enters cells Combines with intracellular buffers No net movement of solute Water still leaves cells Serum Na diluted Suggests K loss is responsible for much diuretic-induced hyponatremia (Ref 2) DKA example 0.45% NS with 40 mEq KCl is insufficient to correct hyperosmolality Hyponatremia and Hypernatremia Can result from alterations in Na K Water Usually due to water abnormalities Exception Thiazides Loss of both Na and K contributes Toxicity of K prevents excess K from producing hypernatremia Diarrhea Isosmotic to plasma Ionic composition varies Secretory diarrhea (cholera) Na + K approximately equals plasma Na Causes volume depletion Does not cause hypernatremia Osmotic diarrhea Fecal Na + K between 30 and 110 Nonreabsorbed solutes account for remainder Causes hypernatremia Diarrheal illness Often causes fever Increases insensible losses Also stimulates ADH and thirst Usually water balance remains near normal Infants commonly become hypernatremic Regulation of Plasma Osmolality Daily variation in water intake and loss alters plasma osmolality Water intake Drinking Water content of food Water of oxidation Carbohydrates metabolized to CO2 and H2O Water retention lowers plasma osmolality Water loss Urine Feces Skin Respiratory tract Water loss raises plasma osmolality Water intake and excretion are tightly regulated Osmoreceptors in hypothalamus After water load Plasma osmolality falls ADH release inhibited Urinary water loss increases Hyperosmolality Stimulates thirst Stimulates ADH Increases water intake Decreases water loss Regulation disrupted by Neurologic disorders Hypothalamus Posterior pituitary Renal disorders Impaired concentrating or diluting ability Nonosmotic stimuli Volume depletion Osmoregulation versus Volume Regulation Table 22-2 Plasma osmolality Ratio of solute to water Extracellular volume Determined by absolute amount of Na and water Two examples Exercising on a hot day Loss of dilute sweat ↑ Plasma osmolality (Na) ↓ Extracellular volume SIADH ↓ Plasma osmolality (Na) ↑ Extracellular volume Nice exercise at bottom of page 691 Isotonic saline Does not change osmolality Hypothalamus not activated Increased volume suppresses renin Increases ANP Water load Inhibits ADH Produces dilute urine Rapid restoration of volume Only transient volume expansion Little effect on renin or ANP NaCl without water Expands extracellular volume Stimulates renal NaCl loss Also stimulates thirst and ADH Produces small volume of concentrated urine Similar to intake Volume Depletion versus Dehydration They are not synonyms Urine Osmolality and Specific Gravity Relation Between Intake and Output Simply comparing ins and outs is inadequate Composition of fluids may differ markedly Replacing urinary losses with free water Produces hyponatremia

  • S1 · E32
    June 3 · 1 hr 44 min

    Chapter Twenty: Respiratory Acidosis

    References Biff Palmer! Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023 Josh what is sensed- pCO2 or pH and some exploration suggests that it is not settled! Sensing, physiological effects and molecular response to elevated CO2 levels in eukaryotes - PMC and this one with catchy title: Out of thin air: Sensory detection of oxygen and carbon dioxide - PMC If anna does VOG on Haldane- we’ll need references The Response of Extracellular Hydrogen Ion Concentration to Graded Degrees of Chronic Hypercapnia: The Physiologic Limits of the Defense of pH - PMC (this is the correct reference for figure 20-3 reference). JC shared some info from Dr. Adrogue Josh mentioned potential differences between people with respect to oxygen sensors and this study of sherpas: [Association of polymorphisms of 1772 (C-->T) and 1790 (G-->A) in HIF1A gene with hypoxia adaptation in high altitude in Sherpas] and this excellent review: Sensing hypoxia: physiology, genetics and epigenetics - PMC VOG from Amy on renal failure with respiratory acidosis https://pubmed.ncbi.nlm.nih.gov/38936337/ Joel and Roger mention these two perspectives on alkali therapy for respiratory acidosis the first from Adrogué and Madias, the second from David Goldfarb: Alkali Therapy for Respiratory Acidosis: A Medical Controversy - American Journal of Kidney Diseases Sodium bicarbonate therapy for acute respiratory acidosis Joel mentioned this paper: https://www.nejm.org/doi/pdf/10.1056/NEJM196607212750301 the “carbon dioxide response curve for chronic hypercapnia in man by Bracket, Wingo et al. NEJM 1969 Josh mentioned a study in female ewes that showed a chloride excretion. Acute renal response to rapid onset respiratory acidosis and followed up with this: No renal dysfunction or salt and water retention in acute mountain sickness at 4,559 m among young resting males after passive ascent This was also studied by Pitts and Giebisch and others: THE EXTRARENAL RESPONSE TO ACUTE ACID-BASE DISTURBANCES OF RESPIRATORY ORIGIN - PMC giebisch and Pitts (the original paper says “with the technical assistance of mary ellen parks and martha MacLeod but on the JCI website, they remedied this and made Parks and MacLeod authors) Joel mentioned the negative Diablo trial Effect of Acetazolamide vs Placebo on Duration of Invasive Mechanical Ventilation Among Patients With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial Outline: Chapter 20 Respiratory Acidosis Clinical disorder characterized by Reduced arterial pH Elevation of pCO2 Variable increase in HCO3 Increased pCO2 is also seen in metabolic alkalosis But here it is appropriate And secondary PATHOPHYSIOLOGY AND ETIOLOGY Metabolism generates 15,000 mmol of CO2 per day CO2 is not an acid, but Combines with H2O to form H2CO3 H2CO3 dissociates to HCO3 and H+ Most H+ combines with intracellular buffers Hemoglobin in RBCs HCO3 leaves the cell via the chloride exchanger Net result CO2 generated is primarily carried in blood as HCO3 Little change in pH Process reverses in the alveoli As H+Hb is oxygenated, H+ is released H+ combines with HCO3 to form H2CO3 Carbonic anhydrase breaks H2CO3 into H2O and CO2 CO2 is exhaled Control of Ventilation Alveolar ventilation Provides oxygen for oxidative metabolism Eliminates metabolically produced CO2 Main stimuli for respiration Reduced arterial pO2 Increased pCO2 Controlled in chemosensitive areas of the medulla Respond to CO2-induced changes in cerebral pH Initial hypoxic stimulation comes from carotid body chemoreceptors Figure 20-1 is wild pCO2 is maintained within narrow limits despite Large daily CO2 load Variable respiratory quotient Variable metabolic rate Minute ventilation rises 1–4 liters for every 1 mmHg rise in pCO2 pO2 does not significantly stimulate ventilation until arterial pO2 <50–60 mmHg Actually starts earlier Increased ventilation lowers pCO2 which inhibits respiration If pCO2 is fixed, pO2 of 70–80 mmHg will stimulate respiration Figure 20-2 Development of Hypercapnia Because CO2 is such a potent respiratory stimulant Respiratory acidosis is usually due to decreased minute ventilation Not increased CO2 production Table 20-1 lists causes CO2 retention in intrinsic pulmonary disease Due to ventilation/perfusion mismatch Hypercapnia is beneficial Allows excretion of produced CO2 at lower minute ventilation Consequences Increased pCO2 decreases pH Increased bone and cellular buffering Increased renal H secretion Raises serum HCO3 Relationship Between Hypercapnia and Hypoxemia All hypercapnic patients breathing room air have lower alveolar and arterial pO2 Total alveolar partial pressures must equal atmospheric pressure Hypoxemia generally occurs earlier and is more severe than hypercapnia CO2 diffuses 20× faster than O2 Compensation by increasing ventilation in normal lung segments Improves CO2 elimination Cannot substantially increase O2 because Hb already saturated Acute asthma example Mucus plugging and bronchoconstriction cause hypoxemia Hypoxemia and mechanoreceptors stimulate ventilation Produces respiratory alkalosis Respiratory acidosis is a late finding Respiratory resistance rises Maximal minute ventilation falls pCO2 rises First normalizes Then becomes elevated Therefore Normal pCO2 in acute asthma indicates severe disease Generalization to other lung diseases Even small increases in pCO2 indicate severe respiratory disease Hypoxemia-induced hyperventilation delays hypercapnia But there is 16-fold variability in sensitivity to hypoxemia Less sensitive individuals develop respiratory acidosis more readily Regulation of Ventilation in Chronic Respiratory Acidosis Two common statements Respiratory centers become less sensitive to CO2 over time Hypoxia becomes the primary respiratory stimulus Insensitivity to CO2 Chemoreceptors primarily respond to pH Chronic respiratory acidosis increases HCO3 Therefore less pH change despite elevated pCO2 Less respiratory stimulation Worsening hypercapnia and hypoxia Similarly Diuretic-induced metabolic alkalosis suppresses ventilation Dependence on hypoxemia Patients with chronic respiratory acidosis rely on hypoxia to drive breathing Loss of CO2 stimulation due to Renal compensation raising HCO3 Diuretics raising HCO3 Making pH less dependent on pCO2 Hypoxia drives ventilation when pO2 falls below ~80 Makes oxygen administration potentially dangerous Can suppress respiratory drive Oxygen also reverses hypoxic vasoconstriction Increases V/Q mismatch Acute Respiratory Acidosis Body poorly adapted to acute elevations in pCO2 HCO3 cannot buffer H2CO3 See Eq 20-4 Must use hemoglobin and proteins as buffers See Eq 20-5 HCO3 rises 1 mEq/L for every 10 mmHg increase in pCO2 Example pCO2 rises to 80 HCO3 rises to 28 pH falls to 7.17 Without buffering pH would be 7.10 Not dramatically different Etiology Acute exacerbations of lung disease Severe asthma Pulmonary edema Drug overdose Sleep apnea syndromes Central Obstructive Mixed Chronic hypercapnia uncommon in isolated OSA CO2 cleared during wakefulness OSA + structural lung disease + obesity Reduced daily alveolar ventilation Persistent CO2 retention Obesity hypoventilation syndrome Mechanical ventilation Inadequate respiratory rate can cause respiratory acidosis Fixed ventilation means increased CO2 production can cause respiratory acidosis Cardiac arrest Suggests sodium bicarbonate Arterial ABG may miss severity due to poor pulmonary blood flow Mixed venous blood may be better guide Enteral or parenteral overfeeding Chronic Respiratory Acidosis After 3–5 days HCO3 rises 3.5 mEq/L for every 10 mmHg rise in pCO2 Example pCO2 = 80 4 × 3.5 = 14 HCO3 should be 38 pH ~7.30 Allows tolerance of pCO2 values of 90–110 Exogenous alkali Unnecessary Useless Easily excreted Etiology COPD Genetic variation in sensitivity to hypoxemia and CO2 Blue bloaters Low response to CO2 Hypoxia becomes primary respiratory stimulus Pink puffers Strong CO2 response Tachypnea develops early Compensation for loss of lung tissue Pickwickian syndrome Obesity hypoventilation syndrome Book mistakenly says hyperventilation Chest wall weight impairs breathing More complex than that Weight loss only helps some patients Progesterone can improve condition Suggests central respiratory defect May coexist with OSA Unlike OSA, Pickwickian patients have chronic respiratory acidosis SYMPTOMS Neurologic Headache Blurred vision Restlessness Anxiety Can progress to Somnolence (CO2 narcosis) Tremor Asterixis Delirium Increased CSF pressure Papilledema Due to increased cerebral blood flow Symptoms due to CSF acidemia Less common in metabolic acidosis HCO3 crosses BBB poorly Less common in chronic respiratory acidosis Less severe acidemia Arrhythmias Peripheral vasodilation Hypotension Particularly when pH <7.1 Cor pulmonale Peripheral edema Can occur despite normal GFR Suggests relationship between respiratory acidosis and renal sodium handling Or possibly hypoxia DIAGNOSIS Last full paragraph on page 659 discusses ambiguity of ABGs Nicely done Figure 20-6 Two additional examples Both instructive Final sentence “In summary, the confidence bands are useful guides in the interpretation of acid-base measurements. However, this interpretation cannot proceed in a vacuum and must be correlated with a complete history and physical examination.” Use of the Alveolar-Arterial Oxygen Gradient Derivation 1 atmosphere = 760 mmHg Water vapor = 47 mmHg Nitrogen = 563 mmHg Leaves ~150 mmHg oxygen No net movement of water or nitrogen Therefore O2 + CO2 must account for remaining pressure PAO2 = PIO2 − PACO2 Must multiply CO2 by 1.25 to account for respiratory quotient PAO2 = PIO2 − (1.25 × PACO2) Since CO2 diffuses rapidly PACO2 ≈ PaCO2 Normal values PIO2 = 150 PaCO2 = 40 PAO2 = 150 − (1.25 × 40) PAO2 = 100 Normal A-a gradient 5–10 mmHg in young adults 15–20 mmHg in elderly A-a gradient = PAO2 − PaO2 Combined equation A-a gradient = PIO2 − (1.25 × PaCO2) − PaO2 A-a gradient increased in intrinsic pulmonary disease Oxygen has difficulty entering blood May also be increased in some extrapulmonary disorders No explanation given Normal A-a gradient argues against pulmonary disease Suggests Central hypoventilation Primary metabolic alkalosis Chest wall weakness Respiratory muscle weakness TREATMENT Complete discussion beyond scope of text Acute Respiratory Acidosis Give oxygen for hypoxia Correct underlying cause of hypercapnia Or intubate Sodium bicarbonate Role not well defined May help if pH <7.15 Especially severe asthmatics on ventilators Avoid in Pulmonary edema Can worsen congestion CNS effects Does not protect CNS because HCO3 does not cross BBB Increased pCO2 Must monitor mixed venous pH Late metabolic alkalosis Rare according to author Tromethamine (THAM) Binds hydrogen Rapidly cleared by kidneys “THAM is of uncertain safety” Chronic Respiratory Acidosis Goals Adequate oxygenation Improve effective alveolar ventilation if possible Rarely need to treat pH directly Beware oxygen Can act as respiratory depressant Dietary modifications Reduce carbohydrates Improves respiratory drive for unclear reasons Weight reduction Improves respiratory mechanics Target pO2 60–65 Reduces pulmonary vasoconstriction Reduces secondary polycythemia Mechanical ventilation Lower pCO2 gradually Rapid correction can induce metabolic alkalosis Seizures Coma Effect of superimposed metabolic alkalosis Metabolic alkalosis depresses ventilation Discontinue diuretics Give saline Acetazolamide Acetazolamide caveats Need appropriate bicarbonate target, not normal Can transiently increase pCO2 before diuretic effect May be due to partial inhibition of carbonic anhydrase in RBCs needed for CO2 carrying capacity

  • S1 · E31
    March 24 · 1 hr 6 min

    Chapter Twenty One: Respiratory Alkalosis

    References Chapter 19, Part 3 August 30, 2023Biff Palmer’s Ted Talk-Why not? Biff Palmer at TEDxSMU 2013 Anna mentioned this issue of lactic acidosis in a panic disorder: The Lactic Acid Response to Alkalosis in Panic Disorder | The Journal of Neuropsychiatry and Clinical Neurosciences Reminder of important clinical lesson: Lactate: panicking doctor or panicking patient? - PMC Melanie regaled the group with an excerpt (page 351) Cohen, J. J., Kassirer, J. P. (1982). Acid-base. United States: Little, Brown. Biff Palmer! Respiratory Acidosis and Respiratory Alkalosis: Core Curriculum 2023 Melanie loves this study of chronic respiratory alkalosis on participants to traveled to the High ALpine research station on the Jungfraujoch in the Swiss Alps Chronic Respiratory Alkalosis — The Effect of Sustained Hyperventilation on Renal Regulation of Acid–Base Equilibrium | NEJM (and here’s a great picture: Services: Jungfraujoch Research Station - Climate and Environmental Physics (CEP) JC mentioned that there are cells in the carotid body which are called glomus cells Neurobiology of the carotid body. JC discussed respiratory alkalosis in cirrhosis and here’s a review he had melanie write that addresses this topic: Acid Base Disorders in Cirrhosis - Advances in Kidney Disease and Health and here are some reviews he likes: The hyperventilation of cirrhosis: progesterone and estradiol effects and Acid-base disturbance in patients with cirrhosis: relation to hemodynamic dysfunction and Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction Proteins The finding of respiratory alkalosis in pregnancy is not a new concept. Here’s a study from 1962: Acid-base balance of arterial blood during pregnancy, at delivery, and in the puerperium - American Journal of Obstetrics & Gynecology Melanie reminded us of the Charlie Brown sad face that occurs after bicarbonate infusion and delay in bicarbonate movement to the CSF! Spinal-Fluid pH and Neurologic Symptoms in Systemic Acidosis | NEJM (part 2 of chapter 11) Josh mentioned this report from Andrew Tarulli (a great neurologist previously at BIDMC who has moved to Overlook Hospital in NJ) Central Neurogenic Hyperventilation: A Case Report and Discussion of Pathophysiology | Allergy and Clinical Immunology | JAMA Neurology He also mentioned this important transporters that affect the pH. The choroid plexus sodium-bicarbonate cotransporter NBCe2 regulates mouse cerebrospinal fluid pH Refractory Central Neurogenic Hyperventilation: A Novel Approach Utilizing Mechanical Dead Space Outline: Chapter 21 Respiratory Alkalosis Increased pH, low pCO2, variable reduction in HCO3 Differentiate from metabolic acidosis where pH is decreased (but pCO2 and HCO3 are likewise decreased) PATHOPHYSIOLOGY Primary decrease in pCO2 when effective alveolar ventilation is increased beyond that needed to eliminate daily CO2 production How does the body respond to hypocapnia Mass action Reduction in H+ induced by hypocapnia can be minimized by lowering HCO3 One: rapid cell buffering Two: later decrease in net renal acid secretion → lower HCO3 These two strategies explain the difference between acute and chronic respiratory alkalosis Acute Respiratory Alkalosis Within 10 minutes, H ions move into extracellular fluid H+ combines with HCO3 → fall in plasma HCO3 Converted to CO2 and H2O H+ comes from intracellular buffers Protein, phosphate, hemoglobin H+ may also come from alkalemia-induced increase in cellular lactic acid production (1)⁉️ Enough H+ enters ECF to lower HCO3 by 2 mEq for each 10 mmHg decrease in pCO2 (Fig 20-3) Example: pCO2 falls to 20 HCO3 falls by 4 → ~20 mEq/L pH ~7.63 Not very efficient at protecting pH Without compensation pH would be ~7.70 Chronic Respiratory Alkalosis Compensatory ↓ renal H secretion Begins within 2 hours Not complete for 2–3 days Due to parallel rise in tubular cell pH Manifested by HCO3 loss Decreased NH4 in urine 4 mEq drop in HCO3 for each 10 mmHg decrease in pCO2 Example: pCO2 20 → HCO3 16 → pH ~7.53 ETIOLOGY Respiration governed by two sets of chemoreceptors Central (respiratory center in brainstem) Peripheral (carotid bodies at bifurcation, aortic bodies at arch) Central chemoreceptors Stimulated by ↑ pCO2 or metabolic acidosis Peripheral chemoreceptors Stimulated by hypoxia (and acidosis) Thus hyperventilation can be produced by Hypoxemia Anemia Reduction in arterial pH Other stimuli Pain Anxiety Mechanoreceptors Direct stimulation of respiratory center Table 21-1 Hypoxemia Respiratory response occurs in stages Stage 1 Peripheral chemoreceptor activation Hyperventilation → respiratory alkalosis Increased cerebral pH inhibits central respiratory center Limits hyperventilation No significant hyperventilation until pO2 < 50–60 mmHg If lung disease prevents pCO2 reduction Hypoxia stimulates ventilation at PaO2 < 70–80 mmHg Stage 2⁉️ Persistent hypoxemia → ↓ HCO3 Lowers pH toward normal Removes alkalosis inhibition Allows greater ventilatory response Pulmonary Disease Common in pneumonia, PE, interstitial fibrosis Also pulmonary edema (though acidosis more common) Hyperventilation may be due to hypoxemia Often not corrected by oxygen Other contributors Mechanoreceptors in airways, lungs, chest wall Signals via vagus nerve Juxtacapillary receptors (interstitium) Irritant receptors (epithelium) Activated by inflammation or inhaled irritants (asthma, pneumonia) These contribute to dyspnea even without hypoxia Direct Stimulation of Medullary Respiratory Center Cortical input (psychogenic hyperventilation) Retained amines in hepatic failure (not prostaglandins⁉️) Bacterial toxins (gram-negative sepsis) Salicylates Progesterone (pregnancy, luteal phase) Persistent acid CSF after rapid correction of metabolic acidosis NaHCO3 raises extracellular pH Peripheral chemoreceptors reduce ventilation → ↑ pCO2 CO2 crosses BBB rapidly, HCO3 does not Brain senses ↑ pCO2 → ↓ CSF pH Paradoxical prolongation of hyperventilation Neurologic disorders Pontine tumors → local acidosis → ↓ CSF pH → ↑ ventilation Hypocapnia in acute cerebral accidents Mechanical Ventilation Overventilation can cause respiratory alkalosis Correct by Increasing dead space (no explanation given 🤷🏻‍♂️) Decreasing tidal volume Decreasing respiratory rate SYMPTOMS Due to increased CNS and peripheral nerve excitability Lightheadedness Altered consciousness Paresthesias (extremities, circumoral) Cramps Carpopedal spasm Syncope Cardiac Supraventricular and ventricular arrhythmias Mechanisms Impaired cerebral function Increased membrane excitability ↓ cerebral blood flow 35–40% reduction if pCO2 drops by 20 mmHg Psychogenic hyperventilation symptoms Dyspnea Headache Chest pain Symptoms more prominent in acute disease (rapid pH change) Electrolytes ↓ phosphate (as low as 0.5–1.5 mg/dL) Due to intracellular shift Increased glycolysis → ↑ phosphorylated compounds DIAGNOSIS Tachypnea But could be acidosis or alkalosis Consider sepsis Compensation equations can be ambiguous Example: 7.48 / 20 / XX / 16 Could be chronic respiratory alkalosis Or acute respiratory alkalosis + metabolic acidosis 😖 Case 21-1 5-year-old with AMS, playing with aspirin TREATMENT Usually not necessary Do NOT give Respiratory depressants HCl Paper bag rebreathing ↑ inspired CO2 Can correct acute respiratory alkalosis If chronic → may leave patient with metabolic acidosis Can treat with NaHCO3 “Give a mouse a cookie” 😉

  • S1 · E23
    Dec 20, 2024 · 1 hr 18 min

    Chapter Sixteen: Edematous States, part 1

    References Capillary Hemodynamics Insights into Salt Handling and Blood Pressure | NEJM Amy mentioned about the 3 phases of the interstitium Are the precapillary sphincters and metarterioles universal components of the microcirculation? An historical review - PMC Safety factor? Renal Function during Recovery from Minimal Lesions Nephrotic Syndrome - Abstract - Nephron 1987, Vol. 47, No. 3 - Karger Publishers Are diuretics effective for idiopathic lymphedema? : Evidence-Based Practice Rapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema for fig 16-7 Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure Additional notes from our chat (might be overlap with Amy’s notes below New insights into the pathophysiology of edema in nephrotic syndrome by Helbert Rondon The hyperlipidemia of the nephrotic syndrome. Relation to plasma albumin concentration, oncotic pressure, and viscosity Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel Lipoprotein metabolism in experimental nephrosis Viscosity regulates apolipoprotein A-1 gene expression in experimental models of secondary hyperlipidemia and in cultured hepatocytes Amiloride in Nephrotic Syndrome | Clinical Research Trial Listing ( oedema | Edema Hypoalbuminemia and proteinuria contribute separately to reduced lipoprotein catabolism in the nephrotic syndrome Origin of hypercholesterolemia in chronic experimental nephrotic syndrome Extrahepatic lipogenesis contributes to hyperlipidemia in the analbuminemic rat Apolipoprotein gene expression in analbuminemic rats and in rats with Heymann nephritis Amy’s Notes Josh “Blessed are the days” https://link.springer.com/article/10.1007/s00467-013-2435-6 Amy mentions mels’ article Capillary Hemodynamics Insights into Salt Handling and Blood Pressure | NEJM, the 3 phases of the interstitium Josh mentions a re: management of idiopathic edema (from up to date: https://www.uptodate.com/contents/idiopathic-edema) Amy stemmer sign: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635205/, https://pubmed.ncbi.nlm.nih.gov/31281100/ Anna in chat talking about amiloride, ENaC re: edema: https://www.researchgate.net/publication/50989884_New_insights_into_the_pathophysiology_of_edema_in_nephrotic_syndrome Outline Chapter 16 — Edematous States Edema is a palpable swelling produced by expansion of the interstitial fluid volume Conditions associated with this Heart failure Cirrhosis Nephrotic syndrome Pathophysiology of edema formation Two steps Alteration of capillary hemodynamics that favors movement of fluid out of the capillary Dietary sodium and water are retained by the kidney Edema does not become clinically apparent until interstitial volume has increased 2.5 to 3 liters If this fluid came the plasma would have hemoconcentration and shock Instead as fluid moves from vascular space to interstitium you get decreased tissue perfusion leading to kidney Na and water retention Net result is expansion of total extracellular volume with maintenance of plasma volume at close to normal levels This means that the kidney is responding appropriately. Important because therapy with diuretics will break this response and may diminish tissue perfusion. There are other situations where primary abnormality is inappropriate renal fluid retention. Here both the plasma and interstitial volumes are expanded and there is no consequences from diuretic therapy. This is over filling. Seen in cirrhosis, primary renal disease. Certain drugs Capillary hemodynamics Exchange of fluids at teh capillary is determined by the hydraulic and oncotic pressures in each compartment This can be expressed by Starlings law Net filtration = LpS (delta hydraulic pressure - delta oncotic pressure) Lp is the unit permeability or porosity of the capillary wall. S is the surface area. Sigma is the reflection coefficient ranging from zero for completely permeable to 1 for for impermeable Difficult to measure these values in humans and animals 16-1 is a table of starling force values. No reflection coefficient though Figure 16-2 shows values in subcutaneous tissues. PCap 17.3 Oncotic pressure in cap is 28. Says mean net gradient is 0.3 mmHg favoring filtration out of the vascular space. This excess net is returned to the systemic circulation by lymphatics. In the liver the values are different. The hepatic sinusoids are highly permeable to protein so oncotic pressure is neutralized by zero reflection coefficient. SO hydraulic pressure favoring filtration is unopposed. Cap hydraulic pressure is lower since two thirds of hepatic blood flow is from low pressure portal vein. Still large pressure gradient favoring filtration Alveolar capillaries are similar to the liver Low cap hydraulic pressure, more permeable to proteins so no transcapillary oncotic pressure. Edema formation requires alteration of one or more starling forces to favor net filtration Increased capillary hydraulic pressure would do it Increased interstitial oncotic pressure too Reduction in plasma oncotic pressure Lymphatic obstruction too Increased capillary hydraulic pressure Capillary hydraulic pressure is insensitive to alteration in arterial pressure due to autoregulation in the pre-capillary sphincter Constricts in response to increases in arterial pressure No sphincter at venous end, so changes in venous pressure are transmitted to capillary bed. Blood volume expanded increases pressure in enough system Heart failure Renal disease Venous obstruction Cirrhosis DVT Decreased plasma oncotic pressure Hypo albuminuria May be less common than previously suspected Increased capillary permeability Promotes edema directly and by permitting albumin to move into interstitium, decreasing the oncotic pressure gradient Burns both histamine and oxygen free radicals cause microvascular injury Therapy with IL-2 increases capillary permeability Episodic idiopathic capillary leak syndromes by IL-2 receptors on mononuclear cells or increased generations of kinins. Patients often with monoclonal gammopathy and during episodes have a massive leak of proteins and fluids, hematocrit rises 70-80%. Aminophylline and terbutaline may prevent. episodes ARDS Ischemia or sepsis induced release of cytokines such as IL-1, IL-8 or TNF may have role in creasing pulmonary capillary permeability DM also increases capillary permeability and may have a role in the edema which is primarily generated by other factors, heart failure or NS Lymphatic obstruction Most often with nodal enlargement due to malignancy Called lymphedema Hypothyroidism marked increase in interstitial accumulation of albumin and other proteins. Low lymphatic flow in hypothyroidema, myxedema. Resistant to diuretics which will put patient at risk of hypovolemia. Safety factors Needs to be 15 mmHg increase in the gradient favoring filtration before edema is seen Three factors explain this protective response Increased lymphatic flow can remove excess filtrate Fluid entry into interstitium lowers the oncotic pressure by dilution and lymphatic mediated removal of proteins Increased fluid entry to interstitium increases interstitial hydraulic pressure Talks about hypoalbuminemia and edema This is a lot of underfill vs overfill theory. Nice bullet points at bottom of 487 how heterogeneity of etiology of edema with MCD. Talks about pulmonary edema and how high interstitial protein provides large safety factor, interstitial albumin has a long way to fall to prevent pulmonary edema. Mentions kwashiorkor and how it may not be low albumin that causes this. Renal sodium retention Can be due to primary renal disease causing sodium retention NS, GN More commonly is renal salt retention is an appropriate compensatory response to decreased effective circulating volume States that decreased effective circulating volume can become compensated and renin falls back to normal. Had interesting figure 16-5 “The Compensated State” Symptoms and diagnosis Three factors important in the mechanism of edema The pattern of distribution of edema which reflects those capillaries with altered hemodynamic forces The central venous pressure Presence or absence of pulmonary edema Pulmonary edema Shortness of breath and orthopnea Tachypnic, diaphoretic, wet rales, gallops, murmurs Check a chest x-ray Cardiac disease is most common But differential includes primary renal Na retention and ARDS Wedge pressure will exceed 18-20 mmHg with heart or primary Na retention, but is relatively normal with ARDS Uncomplicated cirrhosis does not cause pulmonary edema Increased capillary pressure in this disorder is only seen below the hepatic vein Normal or reduced blood volume in the cardiopulmonary circulation Peripheral edema and ascites Peripheral edema is cosmetically undesireable but produces less serious symptoms Symptoms: swollen legs, difficulty walking, increased abdominal girth, shortness of breath due to pressure on the diaphragm. Pitting edema found in dependent areas Ascites found in abdomen Nephrotic syndrome low tissue pressure areas like eye orbits Heart Failure (right sided) peripheral edema, abdominal wall, SOB is due to concomitant pulmonary disease. Right sided heart failure increases venous pressure Cirrhosis develop cirrhosis and lower extremity edema, pressure above the hepatic vein is normal or low. Tense ascites can increase the pressure above the diaphragm but is relieved with a tap Portal pressure > 12 mmHg required for fluid retention Love the case history 16-1 Primary renal sodium retention Pulmonary and peripheral edema Jugular venous pressure is elevated Nephrotic Syndrome Periorbital and peripheral edema, rarely ascites CVP normal to high Idiopathic edema Behaves as volume depleted (especially with diuretics) Etiology and treatment General principles of treatment When must edema be treated What are the consequences of the removal of fluid How rapidly should fluid be removed When Pulmonary edema is the only form of generalized edema that is life threatening and demands immediate treatment Important for note: laryngeal edema and angioedema. Cerebral edema What are the consequences If the edema fluid is compensatory (heart failure, cirrhosis, capillary leak syndromes) then removal of fluid with diuretics will diminish effective circulating volume. Despite this drop in effective circulating volume, most patients benefit from the appropriate use of diuretics. Cardiac output falls 20% with diuresis of pulmonary congestion but exercise tolerance increases Says to be careful in diuresis leads to increases in Cr How rapidly should edema fluid be removed Removing vascular fluid changes starling forces (reduced venous pressure) so fluid rapidly mobilized from interstitium. 2-3 liters per 24 hours can often be removed without difficulty An exception is cirrhosis and ascites without peripheral edema. Mobilizing ascites is limited to 500-750 ml/day Heart failure Edema is due to increase in venous pressure raising capillary hydrostatic pressure Ischemic and hypertensive CM impairs left ventricular function causing pulmonary but little peripheral edema In acute pulmonary edema the LV disease results in increased LVEDP and increased left atrial pressure which transmit back to the pulmonary vein When wedge exceeds 18-20 (normal is 5-12) get pulmonary edema Cor pulmonale due to pure right heart failure prominent edema in the lower extremities Cardiomyopathies tend to affect right and left ventricles leading to simultaneous onset of pulmonary and peripheral edema. Discusses forward hypothesis in which reduction in cardiac output triggers decreased tissue perfusion activation of SNS and RAAS. Catecholamines increase cardiac output RAAS increase Sodium retention Edema is absent and patients can be compensated at the expense of increased LVEDP see Figure 16-6 Figure 16-6 A to B to C with compensation Eventually the increased sodium retention and increased intracranial pressure are enough to cause edema. He then brings up multiple important points (in bullets none the less) Dual effects of fluid retention: Increased cardiac output Potential harmful elevation in venous pressure Benefit is found with increase in LVEDP from 12 to 15, after that it seems mostly deleterious Vascular congestion (elevated LVEDP) and a low cardiac output do not have to occur together. See points B and C on 16-6. Frank-Starling relationship varies with exercise. Patients with moderate heart disease may be okay at rest but fail with mild exertion. This leads to more neurohormonal activation. This can worsen sodium retention and ischemia. Rest here can help augment diuretic effect. Doubling diuretic response. 40% increase in GFR. Mild to mod heart disease may have no edema with dietary Na restriction. Na intake will initially increase preload and improve cardiac output and allow the Na to be excreted but as the Frank Starling curves flatten then excess sodium cannot be excreted. Diastolic vs Systolic dysfunction Decreased compliance in diastolic dysfunction can lead to flash pulmonary edema More common with hypertension Look to the ejection fraction Neurohormonal adaptation Initial benefit long term adverse effects Norepi, renin, ADH all are vasoconstrictors They raise cardiac output Raise BP which is maladaptive in the long term Treatment of cardiogenic pulmonary edema Morphine Oxygen Loop diuretic NTG/nitroprusside If patient remains in pulmonary edema and has systolic dysfunction consider inotropic agent Treatment of chronic heart failure Feels dated Mentions dig and loop diuretic But also ACEi/BB and AA Deep dive Loop diuretics ACEi Cor Polminale Edema here comes with increased CO2 Associated with increased HCO3 which means increased HCO3 reabsorption int he proximal tubule which leads to more sodium retention Hypoxemia can increase Na retention Cirrhosis and Ascites Both lymphatic obstruction and increased capillary permeability contribute Sinusoidal obstruction leads to increased hydraulic pressure in the sinusoids. Portal hypertension is necessary for ascites > 12 mmHg The low albumin is often present but is not contributory to edema Sinusoids are freely permeable to albumin so no oncotic pressure from albumin here Mechanism of ascites Renal sodium conservation is an early finding and some evidence for primary sodium retention but… Mostly underfill is thought to drive Na retention Splanchnic vasodilation starts this of NO drives this Endotoxin absorption stimulates No Normally endotoxin is detoxed in liver but portosystemic shunting allows endotoxin to escape the liver. Hepatorenal syndrome Progressive hemodynamically mediated fall in GFR Induced by intense renal vasocontstriction Where are the PGE and Kinins Fall in GFR is masked by decreased muscle mass and decreased BUN production Hyponatremia is a grave prognostic sign, as it is in heart failure, Indicates increased activation of vasopressin Treatment Low Na intake Low water intake Care with diuretics, can only mobilize 300-500 ml of ascetic fluid a day Avoid hypokalemia Stimulates NH3 production Talks about the mechanism in proximal tubule Also discusses pKA of NH3->NH4 reaction and if the pH rises, this will shift the Eq to produce NH3 Important aspect in NH3 is lipid soluble and NH is not Says that Spiro is diuretic of choice States it is more effective than furosemide in this condition Effectiveness related to slower rate of drug excretionin urine (compromises furosemide but not spiro) competition with bile salts Recommends 40 furosemide and 100 of spiro Resistant ascites Options paracentesis TIPS Complicated by higher mortality Peritoneovenous shunt Largely abandoned, Primary renal sodium retention CKD or AKI where low GFR linits excretion of Water and Na Acute GN or nephrotic syndrome Broken glom with intact tubules, mean the tubules see less Na so they think “underperfused” and then they increase renal retention of NA Drugs Direct vasodilators like minoxidil Require super high furosemide doses to counter Other antihypertensives either block sympathetic NS, Na retention directly or block RAAS explains why they don’t cause Na retention NSAIDS Fludrocortisone Pregnancy Normal pregnancy is associated with retention of 900 to 1000 mEq of Na And! 6-8 liters of water Refeeding edema Insulin stimulate Na retention

  • S1 · E21
    May 13, 2024 · 2 hr

    Chapter Fifteen: Clinical Use of Diuretics, part 1

    Outline Chapter 15 — Clinical Use of Diuretics - Among most commonly used drugs - Block NaCl reabsorption at different sites along the nephron - The ability to induce negative balance has made them useful in multiple diseases - Edematous states - Hypertension - Mechanism of action - Three major classes - Loop - NaK2Cl - Up to 25% of filtered sodium excreted - Thiazide - NCC - Up to 3-5% of filtered sodium excreted - Potassium sparing - ENaC - Up to 1-2% of filtered sodium excreted - Each segment has a unique sodium channel to allow tubular sodium to flow down a concentration gradient into the cell - Table 15-1 is interesting - Most of the sodium 55-655 is reabsorbed in the proximal tubule - Proximal diuretics would be highly effective if it wasn’t for the loop and other distal sites of Na absorption - Loop Diuretics - Furosemide - Bumetanide - Torsemide - Ethacrynic acid - NaK2Cl activated when all four sites are occupied - Loop diuretic fits into the chloride slot - In addition to blocking Na reabsorption results in parallel decrease in calcium resorption - Increase in stones and nephro albinos is especially premature infants which can increase calcium excretion 10-fold - Thiazide - Even though they are less potent than loops they are great for hypertension - “Not a problem in uncomplicated hypertension where marked fluid loss is neither necessary nor desirable” - Some chlorothiazide and metolazone also inhibit carbonic anhydrase in the proximal tubule - Increase Calcium absorption. Mentions that potassium sparing diuretics do this also - Potassium sparing diuretics - Amiloride - Spironolactone - Triamterene - Act at principal cells in the cortical collecting tubule, - Block aldosterone sensitive Na channels. - Discusses the difference between amiloride and triamterene and spiro - Mentions that trimethoprim can have a similar effect - Spiro is surprisingly effective in cirrhosis and ascites - Talks about amiloride helping in lithium toxicity - Partially reverse and prevent NDI from lithium - Trial Terence as nephrotoxin? - Causes crystaluria and casts - These crystals are pH independent - Faintly radio opaque - Acetazolamide - Blocks carbonic anhydrase - Causes both NaCl and NaHCO3 loss - Modest diuresis de to distal sodium reclamation - Mannitol - Nonreabsorbable polysaccharide - Acts mostly in proximal tubule and Loop of Henle - Causes water diuresis - Was used to prevent ATN - Can cause hyperosmolality directly and through the increased water loss - This hyperosmolality will be associated with osmotic movement of water from cells resulting in hyponatremia, like in hyperglycemia. - Docs must treat the hyperosmolality not the hyponatremia - Time course of Diuresis - Efficacy of a diuretic related to - Site of action - Dietary sodium action - 15-1 shows patient with good short diuretic response but other times of low urine Na resulting in no 24 hour net sodium excretion. - Low sodium diets work with diuretics to minimize degree of sodium retension while diuretic not working - Also minimizes potassium losses - Increase frequency - Increase dose - What causes compensatory anti-diuresis - Activation of RAAS and SNS - ANG II, aldo, norepi all promote Na reabsorption - But even when prazosin to block alpha sympathetic and capto[pril to block RAAS sodium retention occurs - Decrease in BP retains sodium with reverse pressure natriuresis - Even with effective diuresis there is reestablishment of a new steady state - Diuresis is countered by - Increases in tubular reabsorption at non-diuretic sensitive sites (neurohormonal mediated) - Flow mediated in creases in Tubular reabsorption distal to the diuretic from increased sodium delivery. - Hypertrophy - Increased Na-K-ATPase activity - Decreased tubular secretion of diuretic if renal perfusion is impaired - Getting to steady state requires - Diuretic dose and sodium intake be constant - Sodium balance is reestablished with 3 days of a fixed diuretic dose - K balance in 6-9 days - Figure 15-2 - Which means that people on stable doses of diuretics don’t need regular labs, the abnormalities will emerge quickly. - Maximum diuresis happens with first dose - Figure 15-3 - Fluid and Electrolyte complications - Volume depletion - “Effective circulating volume depletion also can develop in patients who remain edematous. Although fluid persists, there may be a sufficient reduction in intracranial filling pressures and cardiac output to produce a clinically important reduction in tissue perfusion.” - Azotemia - Decreased effective circulating volume with diuretic therapy also can diminish renal perfusion and secondarily the GFR. - Describes the traditional reason for increased BUN:Cr ratio - Then states that as much as a third of of the rise in BUN may reflect increased urea production; it is possible, for example, that reduced skeletal muscle perfusion leads to enhanced local proteolysis. This increases urea production. - Hypokalemia - Loop and thiazide increase urinary potassium losses - Often lead to hypokalemia - 50 mg of HCTZ drop K by 0.4 to 0.6 mEq/L with 15% falling below 3.5 - He uses “associated” I think this is a place where we can use cause - 50 mg of chlorthalidone - K falls 0.8 to 0.9 mEq/L - Etiology - Increased distal delivery of Na and water - Increased aldo - From volume depletion - Underlying disease: cirrhosis and heart failure - Talk a lot about significance. - Info sounds dated - Increased risk of SCD in MRFIT trial - Association with increased ventricular arrhythmia with hypokalmia - Increased PVC and complex PVC by 27% with each drop in K of 0.5 mEq/L - Says that stress can induce epinephrine which can shift potassium inside cells leading to fatal arrhythmia especially if the patient begins at a low potassium concentration - Says v-fib two fold likely in MI patients with hypokalemia - Talks about crazy doses of HCTZ and Chlorthalidone 50+mg - Recommends 12.5 to 15 mg respectively - Metabolic alkalosis - Caused by loop and thiazide diuretics - Two factors cause this - Increased urinary H loss - Partly UE to secondary hyperaldo - Contraction of extracellular volume around remaining bicarb - Why not contraction hypernatremia, contraction hyperkalemia, etc? - Aldosterone contributes by stimulate ing H-ATPase - Stimulating Sodium reabsorption creating lumen negative charge that promotes Hydrogen secretion - Loop diuretics can also stimulate net H loss by increased Hsecretion in the cortical aspect of the thick limb - This segment has two luminal entry points for na, the traditional NaK2Cl and Na-H exchanger - Blocking NaK2Cl with loop diuretic stimulates the Na-H exchanger - Can use NaCl or acetazolamide to treat - Metabolic acidosis - K-sparing diuretics reduce both K and H secretion in the collecting tubule - Avoid if renal failure or on an ACEi - Good advice to avoid K supplement with the K sparing diuretic - Hyponatremia - Diuretics can cause volume depletion leading to enhanced secretion of ADH and to increased water intake - Almost always due to a thiazide - Loops destroy the concentrated medullary gradient making ADH less effective - Hyperdrive is - Increased urate reabsorption in the proximal tubule - Process mediated by parallel Na-H and urate OH exchangers see figure 3-13a - Urate reabsorption varies directly with proximal Na transport and in patients with diuretic-induced volume deficiency both Na and urate excretion are reduced. - May be related to Ang II - Do not need to treat the hyperuricemia in asymptomatic patients - Do not develop urate nephropathy because tubular urateis actually low - Hypomagnesemia - Generally mild - Loop diuretics since most reabsorbed in the loop - Thiazides don’t affect Mg (why with gitelmans?) - Hypokalemia may directly inhibit tubular cell mg uptake - Aldosterone increases Mg excretion, so K sparing diuretics decrease Mg secretion - Determinants of Diuretic responsiveness - 2 important determinants of diuretic response - Site of action - Presence of counterbalancing antinatriuretic forces - Ang2 - Aldo - Low systemic BP - Adds rate of drug excretion as # 2 and a half - Almost all diuretics are protein bound - So not well filtered - Enter tubule through organic anion and organic cation transporter - This can limit diuretic effectiveness - Natriuretic response plateaus at higher rates of diuretic excretion due to complete inhibition of the diuretic target - This plateau in normal people is 1 mg of bumetanide and 40 mg of furosemide given IV - Double this for oral furosemide, no adjustment needed for bumetanide - 15-6 - Refractory edema - Start with a loop diuretic - Initial aim is to find the effective single dose - From the paragraph this is about threshold dosing - Double ineffective doses until good effect - Suggests maximum furosemide dose is 200 mg IV and 400 mg oral - Excess sodium intake - High sodium diet can work to prevent patients from achieving negative sodium balance. - Suggests diets after leaving the hospital maybe higher in sodium - Decreased or delayed intestinal absorption - Decreased intestinal perfusion, reduced intestinal motility and mucosal edema may contribute. - But why is this worse with furosemide than with bumetidine or torsemide? - Decreased drug entry into the tubular lumen - Thiazides don’t work below a GFR of 20 - CLICK - Renal failure - Increased organic anions compete for diuretic secretion - Bumetidine isn’t as dependent as furosemide on GFR - Use 1/20th rather than 1/40th the dose - Maximum of 8 to 10 mg - Furosemide has ototoxicirty at high doses, he advises against 2400 mg/day - There is a Na-K-2Cl carrier in the endolymph producing cells - Ethacrynic acid has the most ototoxicity - Only loop or thiazide that isn’t a sulfonamide derivative - Cirrhosis - Spiro is diuretic of choice - More effective than loops alone - Does not induce hypokalemia that can cause hepatic encephalopathy - Cirrhosis causes marked hyperaldo - Loop diuretics have to compete with bile salts for secretion in the proximal tubule - Spiro does not need to be secreted in the proximal tubule - Recommends to 100 to 40 spiro to furosemide ratio - And can double this to 200 and 80/day - and a maximum of of 400/160 - Hypoalbuminemia - <2 g/dL associated with decreased diuretic entry into the lumen - Protein binding keeps diuretics in the blood, reduces the volume of distribution - This maximizes the delivery to the kidney - In nephrotic syndrome tubular albumin can bind diuretic and prevent its activity - Co administration of albumin with diuretic has resulted in modest improvements in diuretic effectiveness in various studies - Intravenous infusion of loop diuretics - Infusions are greater than bolus - But if patient is not responding to blouses unlikely to respond to infusions since bolus provides a temporary spike in plasma level - Increased distal reabsorption - Increased distal sodium reabsorption decreases the effectiveness of proximal diuretics - Due to aldo and increased sodium delivery - Mentions that thiazides have a proximal effect (is that inhibition of carbonic anhydrase?) - 15-8 is very cool - Says all thiazides are created equal - Article from 1972 is why people use metolazone in advanced renal disease - When doing sequential nephron blocked be careful - Loss of lots of fluid - Loss of lots of potassium - Loss of 5 liters and 200 mEq of K a day is possible with sequential nephron blockade - Decreased loop sodium delivery - With heart failure and cirrhosis increased proximal resorption mediated by Ang II markedly reduces delivery of fluid to the diuretic sensitive sites. - Acetazolamide makes sense here - Supine or 10 degree head down can increase cardiac output possibly increased venous return - Can double Na excretion - Increase CrCl 40% - CAVH enters the chat! - Other uses of diuretics - Met alk, RTA, DI, hyponatremia due to SIADH, hypokalemia - Diuretics and prostaglandins - Loops and thiazides increase renal generation of prostaglandins - Can cause venous dilation may help with acute pulmonary edema - Can help without increased diuresis - NSAIDS counter the effect of loop diuretics - Is this natriuretic effect of PGE? Or due to renal ischemia due to unopposed Ang2 and norepi - They also raise BP and reduce cardiac output due to increased vascular resistance - Vasoconstrictor effect of loop diuretics - One hour after loop diuretics increase vasoconstriction and rise in systemic blood pressure - Increased Renin and norepinephrine, resolved 4 hours later - Seen in heart failure and cirrhosis - In cirrhosis decrease in RPF and GFR of 30-40% with furosemide References Melanie noted that thiazide diuretics were the Project MUSE - Releasing the Flood Waters: Diuril and the Reshaping of Hypertension Furosemide early review of furosemide effect in a range of different clinical conditions. Na+, K+, and BP homeostasis in man during furosemide: Effects of prazosin and captopril This article is quoted in Rose’s book-(Figure 2 is 5-1). The authors provide a figure with a balance study that shows how an initial “diuresis” is followed Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology - American Journal of Kidney Diseases https://jasn.asnjournals.org/content/30/2/216 Thiazide induced hyponatremia, a detailed phenotypic and genotypic analysis (NephJC) https://www.sciencedirect.com/science/article/pii/B9780126356908500025 Classic paper on diuretics in NEJM from Craig Brater: https://www.nejm.org/doi/full/10.1056/NEJM199808063390607 Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders https://linkinghub.elsevier.com/retrieve/pii/S0085253820314046 Nephrocalcinosis of 17% in preemies: https://pubmed.ncbi.nlm.nih.gov/35348900/ Nephrocalcinosis with loop diuretics in neonates: https://pubmed.ncbi.nlm.nih.gov/38296790/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941622/ We wondered whether the effect of hypercalemia on loop is complete –did we go too far saying that loop diuretics have no effect Anna’s VOG on hypercalciuria and lasix, etc. NEJM Paper describing the dose of lasix needed for calciuria Meta analysis of lasix used for calciuric effects . David Ellison and Robert Schrier experiment showing NCC activation with chronic loops. NCC activation occurs with hypercalcemia as well via CASR Thiazide Treatment in Primary Hyperparathyroidism—A New Indication for an Old Medication? | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades - PMC Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) | Acute Coronary Syndromes | JAMA Uromodulin upregulates TRPV5 by impairing caveolin-mediated endocytosis - University of Iowa Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance Regulation of Potassium Homeostasis | American Society of Nephrology Biff Palmer’s review. Distal Convoluted Tubule - PMC we did not discuss this paper by Subramanya and Ellison but it is a gem It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis | American Society of Nephrology Thiazide Effects and Adverse Effects | Hypertension A comparison of the potassium and magnesium-sparing properties of amiloride and spironolactone in diuretic-treated normal subjects. - PMC SGLT2i case series for hypomag: SGLT2 Inhibitors for Treatment of Refractory Hypomagnesemia: A Case Report of 3 Patients - PMC Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomized controlled trials Anti-EGFR monoclonal antibody-induced hypomagnesaemia - The Lancet Oncology

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