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Harrison's Section 7: Alterations in Renal & Urinary Tract Function

Complete Master Teaching Notes (Chapters 54-58)

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CHAPTER 54 - Interstitial Cystitis / Bladder Pain Syndrome (IC/BPS)

What It Is

• Pelvic pain that worsens with bladder filling
• Associated urinary frequency and urgency
• Pain inside and/or outside the pelvis
• No identifiable infectious or structural cause

Key Concept: Only 20-25% Have Bladder-Only Disease

1. Spinal crosstalk - nerves from different pelvic organs converge
2. Phenotype progression - disease evolves over time
3. Central sensitization - amplified pain processing in CNS
4. COPCs - co-occurring conditions (IBS, fibromyalgia, endometriosis, vulvodynia)

Primary Care Workup (Table 54-1)

Clinical Phenotypes - The "Clinical Picture" Approach

• Infection phenotype - recurrent UTIs triggering flares (treat each UTI; consider UTI vaccination)
• Pelvic floor phenotype - pelvic floor dysfunction on exam
• Psychosocial phenotype - depression, anxiety, PTSD, pain catastrophization = worse outcomes
• Systemic/COPC phenotype - fibromyalgia, IBS, widespread pain

Treatment Pyramid

1. Conservative Measures (First Line - All Patients)

• Patient education - acknowledge suffering, set realistic expectations (cure is not the goal), explain the chronic pain disorder model
• Dietary modifications - elimination diet for triggers: acidic/spicy foods, caffeine, alcohol, artificial sweeteners, gluten; highly individual
• Pelvic floor physiotherapy - randomized evidence supports this when pelvic floor dysfunction is present
• Stress management - sleep hygiene, exercise

2. Oral Medications

• Pentosan polysulfate (PPS) - only FDA-approved oral therapy; glycosaminoglycan (GAG) layer replenishment; note: retinal toxicity risk with prolonged use
• Amitriptyline - low-dose TCA for pain modulation
• Hydroxyzine - antihistamine (mast cell stabilization)
• Cimetidine - H2 blocker (some evidence)
• Quercetin - anti-inflammatory supplement

3. Intravesical Therapies (specialist)

• DMSO (dimethyl sulfoxide) - anti-inflammatory, analgesic
• Heparin/lidocaine/bicarbonate cocktails - GAG layer repair + local anesthesia

4. Procedural/Surgical (specialist)

• Cystoscopy with hydrodistension - diagnostic and modestly therapeutic
• Botulinum toxin A (BTX-A) injections
• Sacral neuromodulation (InterStim)
• Cyclosporine A - for refractory cases
• Surgery - cystectomy with urinary diversion only for extreme refractory cases

Psychological Interventions

• Cognitive behavioral therapy (CBT)
• Mindfulness-based stress reduction
• Pain psychologists - critical for psychosocial phenotype

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CHAPTER 55 - Renal/Urine Unit Abnormalities (Hematuria, Proteinuria, Pyuria, Renal Tubular Disorders)

HEMATURIA

Definition

• Microscopic hematuria = ≥3-5 RBCs per high-power field (HPF) in spun first-morning urine
• Gross hematuria = visible blood in urine

Glomerular vs. Non-glomerular Hematuria

Workup of Microscopic Hematuria

1. Exclude anatomic lesions - especially urinary tract malignancy in older men
2. Think also: BPH, interstitial nephritis, papillary necrosis, hypercalciuria, kidney stones, cystic disease, renal vascular injury
3. If RBC casts present - nephrology referral, renal biopsy likely needed

PROTEINURIA

Classification by Amount

• Spot urine albumin/creatinine ratio (UACR) >30 mg/g triggers further investigation
• Benign (functional/transient) proteinuria: <1 g/24h, non-sustained; causes include fever, exercise, obesity, sleep apnea, emotional stress, CHF
• Orthostatic proteinuria: only upright; benign prognosis
• Selective proteinuria (albumin-only) = Minimal Change Disease in children
• Non-selective proteinuria = most adult glomerular diseases

PYURIA

• Leukocytes in urine
• Inflammatory glomerular disease (post-streptococcal GN, MPGN) can cause sterile pyuria
• Must distinguish from bacterial infection - culture is key

CLINICAL SYNDROMES FROM GLOMERULAR INJURY

RENAL TUBULAR TRANSPORT ABNORMALITIES (Ch 55)

Key Tubular Syndromes

• Fanconi syndrome - generalized PCT dysfunction: glycosuria (normal blood glucose), aminoaciduria, phosphaturia, uricosuria, bicarbonaturia → hypokalemia, metabolic acidosis, hypophosphatemia
• Causes: cystinosis, Wilson's disease, galactosemia, tenofovir toxicity, heavy metals (lead, cadmium), multiple myeloma

• Renal Tubular Acidosis (RTA) - see Ch 58 content below
• Nephrogenic Diabetes Insipidus (NDI) - ADH resistance: massive polyuria/polydipsia with dilute urine, serum sodium often normal/elevated; causes: lithium, hypercalcemia, hypokalemia, congenital (aquaporin-2 mutations)
• Bartter Syndrome - loss-of-function mutations in Na-K-2Cl cotransporter (NKCC2) in thick ascending limb of Henle → hypokalemia, metabolic alkalosis, hyperreninism, hyperaldosteronism, normal blood pressure
• Gitelman Syndrome - loss-of-function mutation of Na-Cl cotransporter (NCC) in DCT → hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria; milder than Bartter's
• Liddle's Syndrome - gain-of-function mutation of ENaC (collecting duct Na channel) → hypertension, hypokalemia, metabolic alkalosis, low renin, low aldosterone; treated with amiloride or triamterene (not spironolactone)

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CHAPTER 56 - Fluid and Electrolyte Disturbances in CKD

Sodium and Water Homeostasis in CKD

• Extracellular fluid volume (ECFV) expansion
• Hypertension → accelerates nephron hyperfiltration and injury
• Isonatric expansion (plasma sodium often NORMAL) as long as water doesn't exceed clearance capacity
• Hyponatremia is uncommon in CKD but responds to water restriction

Management of Sodium/Water Excess

• Salt restriction (dietary counseling)
• Thiazides (chlorthalidone) - effective even in stage 4 CKD for BP control
• Loop diuretics (furosemide, bumetanide, torsemide) - needed for frank sodium accumulation; resistance common in CKD → use higher doses
• Combination therapy: loop diuretic + metolazone for diuretic resistance
• Intractable edema + hypertension in advanced CKD = indication to initiate dialysis

The Volume Depletion Trap

• Leads to prerenal acute-on-chronic kidney failure
• Action: hold diuretics ± cautious NS repletion
• "Sick day rules" - tell patients to hold diuretics/antihypertensives if vomiting/diarrhea

Potassium Homeostasis in CKD

1. Aldosterone-dependent secretion in distal nephron compensates
2. Augmented GI K+ excretion compensates

Causes of Hyperkalemia in CKD

• High dietary K+ intake
• Hemolysis, stored blood transfusion
• Metabolic acidosis (K+ shifts out of cells)
• Medications (most important):
  • RAS inhibitors (ACEi, ARB)
  • Spironolactone, eplerenone, amiloride, triamterene
  • Nonsteroidal mineralocorticoid receptor antagonists (finerenone)
  • NSAIDs
  • TMP-SMX (blocks ENaC like amiloride)

Special CKD Causes of Severe Hyperkalemia

• Hyporeninemic hypoaldosteronism (type 4 RTA) - especially in diabetic nephropathy
• Obstructive uropathy
• Sickle cell nephropathy

Acid-Base in CKD

• Stage 3B CKD: hyperchloremic (normal AG) metabolic acidosis due to impaired NH4+ excretion
• Stage 4-5 CKD: transitions to high-AG metabolic acidosis (uremic anion accumulation)
• Treatment: oral alkali replacement (NaHCO3 tablets 650 mg = 7.8 mEq; or Shohl's solution [sodium citrate]) to maintain HCO3- >22-24 mmol/L
• Benefits: slows CKD progression, reduces muscle catabolism, reduces bone disease
• Fruits and vegetables (dietary alkali/citrate) can raise HCO3- and slow CKD progression safely

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CHAPTER 57 - Hypercalcemia and Hypocalcemia

Calcium Physiology - The Regulation System

1. Increases osteoclast-mediated bone resorption (via RANKL on osteocytes) → releases Ca2+ from bone
2. Increases distal tubule Ca2+ reabsorption in kidney
3. Stimulates proximal tubule 1,25(OH)2D (calcitriol) production
4. 1,25(OH)2D increases intestinal Ca2+ absorption

• ~50% ionized (physiologically active)
• ~40% albumin-bound
• ~10% complexed to anions (citrate, phosphate)

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HYPERCALCEMIA

Causes (Table 57-1) - Organized by Mechanism

• Primary hyperparathyroidism (pHPT) - #1 most common cause overall; parathyroid adenoma (~85%), hyperplasia (~15%), carcinoma (<1%); often asymptomatic, found incidentally
  • Sporadic or familial (MEN1, MEN2A)
  • ~30% of sporadic pHPT have genetic cause (cyclin D1 or menin)
  • ~50% have reduced CaSR expression due to epigenetic silencing
• Tertiary hyperparathyroidism - long-term PTH stimulation in renal failure → autonomous PTH secretion persists even after transplant
• Familial Hypocalciuric Hypercalcemia (FHH) - inactivating CaSR mutations → impaired Ca2+ sensing in parathyroid AND kidney → mild hypercalcemia + normal or low urine calcium excretion + elevated PTH; benign, no treatment needed; distinguish from pHPT (24h urine Ca/creatinine clearance ratio <0.01 in FHH)
• Lithium therapy - impairs CaSR signaling
• Ectopic PTH secretion - very rare

• PTHrP (PTH-related peptide) - most common mechanism in solid tumors (lung, breast, head/neck, renal, bladder); PTHrP shares N-terminal homology with PTH and binds same receptor → "humoral hypercalcemia of malignancy"
• Lytic bone metastases - direct osteolytic destruction (breast cancer, multiple myeloma)
• Ectopic 1,25(OH)2D production - lymphomas, some solid tumors; macrophages in tumor express CYP27B1 constitutively

• Sarcoidosis (#1), tuberculosis, leprosy, fungal infections (histoplasmosis, coccidioidomycosis), foreign body reactions, berylliosis
• Macrophage CYP27B1 converts 25(OH)D → 1,25(OH)2D without normal feedback regulation
• Treatment: glucocorticoids suppress macrophage 1α-hydroxylase

• Excessive 25(OH)D ingestion overwhelms vitamin D binding protein (DBP), freeing 25(OH)D to directly activate intestinal VDR → hypercalcemia; can persist weeks (longer half-life of 25[OH]D vs. 1,25[OH]2D)
• CYP24A1 deficiency - genetic loss of 24-hydroxylase (inactivates 1,25[OH]2D) → 1,25(OH)2D accumulation

• Hyperthyroidism (T3/T4 increase osteoclast activity directly)
• Paget's disease with immobilization
• Immobilization alone (especially in Paget's or adolescents)
• Osteolytic metastases

• Milk-alkali syndrome - calcium carbonate antacid overuse → hypercalcemia + metabolic alkalosis + renal failure (now more common with calcium supplements)

• Thiazides (increase renal Ca reabsorption)
• Lithium
• Vitamin A (excess)
• Teriparatide (PTH analog)
• Denosumab discontinuation → rebound resorption

Clinical Features ("Bones, Stones, Groans, Psychic Moans")

Diagnosis

• PTH level is the first branch point:
  • PTH elevated/inappropriately normal → primary or tertiary HPT, FHH, lithium
  • PTH suppressed → malignancy, vitamin D toxicity, granulomatous disease, excess calcium intake
• PTHrP level - if PTH suppressed and malignancy suspected
• 1,25(OH)2D level - elevated in granulomatous disease and lymphoma
• 25(OH)D level - elevated in vitamin D intoxication
• 24h urine calcium - very low in FHH vs. high in pHPT

Treatment of Hypercalcemia

1. IV hydration with normal saline (2-4 L/day) - volume expansion increases GFR → calciuresis (MOST IMPORTANT first step)
2. Loop diuretics (furosemide) - only AFTER volume repletion; promotes urinary Ca2+ excretion; do NOT use thiazides (they worsen hypercalcemia)
3. Bisphosphonates (zoledronic acid 4 mg IV or pamidronate 60-90 mg IV) - inhibit osteoclast bone resorption; onset 24-72h, peak effect 4-7 days; mainstay for malignancy-associated hypercalcemia
4. Calcitonin (4-8 IU/kg SC q6-12h) - rapid onset (hours), modest effect; tachyphylaxis within 48h; useful bridge while waiting for bisphosphonates to act
5. Denosumab (anti-RANKL) - for bisphosphonate-refractory or bisphosphonate-contraindicated (renal failure) malignancy hypercalcemia
6. Glucocorticoids (prednisone 40-60 mg/day or hydrocortisone 200-300 mg/day) - effective for granulomatous disease, lymphoma, vitamin D intoxication
7. Hemodialysis - for life-threatening, refractory hypercalcemia with renal failure

• Parathyroidectomy for symptomatic pHPT or asymptomatic with criteria (Ca >1 mg/dL above upper normal, T-score <-2.5, age <50, GFR <60, 24h urine Ca >400 mg)
• Cinacalcet (calcimimetic - activates CaSR) - for patients not surgical candidates; lowers PTH and Ca without improving bone density; also for tertiary/secondary HPT

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HYPOCALCEMIA

Causes (Table 57-2)

• Post-surgical (thyroidectomy, parathyroidectomy) - #1 acquired cause
• Autoimmune (autoimmune polyglandular syndrome type 1 - APS-1; associated with AIRE mutations)
• Activating CaSR mutations (autosomal dominant hypocalcemia - ADH; gain-of-function CaSR → inappropriately suppressed PTH)
• Hypomagnesemia - impairs both PTH secretion AND PTH action at target organs; must correct Mg first before Ca rises
• Infiltration (metastases, hemochromatosis, Wilson's, sarcoidosis)
• Hungry bone syndrome after parathyroidectomy (rapid bone uptake)
• Radiation
• Severe illness (sepsis, burns, pancreatitis - multifactorial)

• Vitamin D deficiency - dietary, malabsorption, lack of sun exposure, CKD (impaired 1α-hydroxylation), liver disease (impaired 25-hydroxylation), anti-epileptic drugs (phenytoin, phenobarbital - accelerate vitamin D catabolism)
• Pseudohypoparathyroidism (PHP) - Albright hereditary osteodystrophy; PTH is elevated but target organs (kidney, bone) are resistant (Gs-alpha mutation); PHP type 1a: Gs-alpha defect; short stature, brachydactyly, round face, ectopic calcifications
• Hypomagnesemia (PTH resistance)

• Acute pancreatitis (Ca2+ saponification)
• Rhabdomyolysis + renal failure (Ca2+ deposits in damaged muscle)
• Osteoblastic metastases (prostate cancer - rapid bone formation consumes Ca2+)
• Respiratory or metabolic alkalosis → increased albumin-Ca2+ binding → decreased ionized Ca2+
• Phosphate-containing enemas in renal disease → hyperphosphatemia → precipitation of Ca2+

• Low albumin (hypoalbuminemia from malnutrition, nephrotic syndrome, cirrhosis) - ionized Ca2+ is NORMAL; use corrected calcium formula
• Gadosetamide MRI contrast - interferes with colorimetric Ca assay

Clinical Features ("Chvostek, Trousseau, Tetany")

Treatment

• IV Calcium gluconate (preferred over Ca chloride except in cardiac arrest due to less tissue necrosis if extravasation): 1-2 g IV over 10-20 min, then continuous infusion
• IV Calcium chloride in cardiac arrest (more bioavailable per mL)
• Correct magnesium deficiency first if Mg2+ is low (otherwise Ca2+ will not respond)
• Monitor cardiac rhythm

• Calcium carbonate or citrate 1.5-3 g elemental Ca/day (citrate better absorbed with low gastric acid/PPIs)
• Calcitriol [1,25(OH)2D] 0.25-2 μg/day - since PTH is absent, 1α-hydroxylation is impaired → must give active form
• PTH replacement (Natpara/recombinant PTH 1-84) - for patients difficult to control
• Target: low-normal serum Ca, urine Ca <300 mg/day (to avoid nephrocalcinosis/nephrolithiasis)
• Thiazides paradoxically reduce urinary Ca2+ losses in hypoparathyroidism

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CHAPTER 58 - Acidosis and Alkalosis

NORMAL ACID-BASE HOMEOSTASIS

pH = 6.1 + log₁₀ (HCO3⁻) / (0.03 × PaCO2)

1. Respiratory (CNS + lungs) - controls PaCO2 (normal ~40 mmHg); responds in minutes
2. Renal (kidneys) - controls HCO3⁻ (normal 22-26 mmol/L); responds in hours-days

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SYSTEMATIC APPROACH TO ACID-BASE DISORDERS

Step 1: Is it acidemia (pH <7.35) or alkalemia (pH >7.45)?

Step 2: What is the primary disorder?

Step 3: Is the compensation appropriate? (Detect Mixed Disorders)

Expected PaCO2 = 1.5 × [HCO3⁻] + 8 ± 2

• Acute respiratory acidosis: HCO3⁻ rises 1 mEq/L per 10 mmHg ↑PaCO2
• Chronic respiratory acidosis: HCO3⁻ rises 3.5 mEq/L per 10 mmHg ↑PaCO2
• Acute respiratory alkalosis: HCO3⁻ falls 2 mEq/L per 10 mmHg ↓PaCO2
• Chronic respiratory alkalosis: HCO3⁻ falls 5 mEq/L per 10 mmHg ↓PaCO2 (may fully normalize pH - exception to the rule)
• Metabolic alkalosis: PaCO2 rises 0.7 mmHg per 1 mEq/L ↑HCO3⁻ (limit ~55 mmHg)

Step 4: Calculate the Anion Gap

AG = Na⁺ - (Cl⁻ + HCO3⁻)

• Normal AG: 6-12 mmol/L (average ~10 mmol/L)
• ALWAYS correct for albumin: For each 1 g/dL albumin below 4.5 g/dL, add 2.5 mmol/L to reported AG
  • Example: albumin 2.5 g/dL (2 g/dL below normal) + uncorrected AG 15 → corrected AG = 15 + (2 × 2.5) = 20 mmol/L

1. Increased unmeasured cations (hyperkalemia, hypercalcemia, hypermagnesemia)
2. Abnormal cations: lithium intoxication, cationic immunoglobulins (myeloma)
3. Reduced albumin (nephrotic syndrome, liver disease, malabsorption)
4. Hyperviscosity, severe hyperlipidemia (underestimation of Na and Cl)

Step 5: In High-AG Metabolic Acidosis - Check the Delta-Delta (Δ/Δ)

Delta Ratio = ΔAG / ΔHCO3⁻ = (AG - 10) / (24 - HCO3⁻)

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METABOLIC ACIDOSIS

High-AG Metabolic Acidosis

• Type A: Tissue hypoxia (septic shock, cardiogenic shock, mesenteric ischemia, severe anemia, CO poisoning)
• Type B: No hypoxia (metformin toxicity, liver failure, malignancy, thiamine deficiency, propylene glycol, D-lactic acidosis)
• Normal lactate <2 mmol/L; >4 mmol/L = significant lactic acidosis
• Treatment: address underlying cause; bicarbonate controversial in lactic acidosis

• Insulin deficiency + glucagon excess → unrestrained lipolysis → acetoacetate + beta-hydroxybutyrate
• Initially HAGMA; as treated, becomes mixed (non-AG hyperchloremic acidosis develops with saline infusion)
• Beta-hydroxybutyrate NOT detected by nitroprusside test (detects acetoacetate only) → can underestimate ketosis initially

• Metabolized to oxalic acid → calcium oxalate crystals in urine (envelope-shaped)
• High osmolar gap early; high AG later (as metabolism occurs)
• Renal failure, cerebral edema, hypocalcemia
• Treatment: fomepizole (alcohol dehydrogenase inhibitor); dialysis

• Metabolized to formic acid → optic nerve toxicity (blindness)
• High osmolar gap early; high AG later
• Treatment: fomepizole; dialysis; folate (augments formate metabolism)

• Direct stimulation of CNS chemoreceptors → respiratory alkalosis (early)
• Uncoupling of oxidative phosphorylation → metabolic acidosis (late)
• Classic presentation: high AG metabolic acidosis + respiratory alkalosis
• High osmolar gap typically absent
• Treatment: urine alkalinization (Na bicarbonate infusion) to trap ionized salicylate in urine; dialysis for severe cases

• Metabolized to acetone (not an acid) → osmolar gap ELEVATED, but AG NORMAL (distinguishes from methanol/EG)
• Treatment: supportive; dialysis for severe coma, hemodynamic instability, or levels >400 mg/dL

• Acetaminophen + glutathione depletion → 5-oxoproline (pyroglutamic acid) accumulation
• Suspect in unexplained HAGMA WITHOUT elevated osmolar gap in malnourished/critically ill patients on acetaminophen
• Treatment: stop acetaminophen; IV NaHCO3; consider N-acetylcysteine

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Non-Anion Gap (Hyperchloremic) Metabolic Acidosis

Renal Tubular Acidosis (RTA) - Detailed

UAG = Urine (Na⁺ + K⁺) - Urine Cl⁻

• Negative UAG = NH4⁺ high in urine → appropriate renal acid excretion → GI cause (diarrhea)
• Positive UAG = NH4⁺ low in urine → renal acid excretion failure → RTA

Urine osmolar gap = Measured urine osmolality - 2(Na+K) + glucose/18 + BUN/2.8

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METABOLIC ALKALOSIS

Causes (Table 58-6)

• Gastrointestinal: Vomiting/NG suction (#1 cause) → HCl loss; pyloric stenosis in infants; congenital chloridorrhea
• Renal: Diuretics (thiazides, loop diuretics); post-hypercapnic state; recovery from lactic/ketoacidosis; non-reabsorbable anions (IV penicillin); Mg2+ deficiency; K+ depletion; Bartter's syndrome (TALH transporter mutations); Gitelman's syndrome (DCT Na-Cl cotransporter mutation)

• High renin: renal artery stenosis, renin-secreting tumor, malignant hypertension, estrogen therapy
• Low renin/low aldosterone: Liddle's syndrome (ENaC gain-of-function)
• Low renin/high aldosterone: Primary aldosteronism (Conn's syndrome - adenoma or hyperplasia), 11β-hydroxylase/17α-hydroxylase deficiency, Cushing's syndrome
• Low renin/low aldosterone: Licorice (glycyrrhizin inhibits 11β-HSD2 → cortisol activates mineralocorticoid receptor), carbenoxolone

Pathophysiology of Vomiting-Induced Metabolic Alkalosis

1. Generation phase: HCl loss from gastric juice → plasma HCO3⁻ rises; Na loss → ECFV depletion → secondary hyperaldosteronism; K+ loss → hypokalemia
2. Maintenance phase: Volume depletion stimulates proximal HCO3⁻ reabsorption; hypokalemia drives K+/H+ exchange in collecting duct → paradoxical aciduria (kidney excretes acid despite alkalosis); hyperaldosteronism stimulates H+ secretion

Urine Cl⁻ in Metabolic Alkalosis - Key Diagnostic Tool

Treatment of Metabolic Alkalosis

• Saline-responsive (most common): IV NS + KCl to correct ECFV and chloride depletion; if due to diuretic use, discontinue diuretic
• Mineralocorticoid-mediated: Spironolactone (primary aldosteronism); amiloride or triamterene (Liddle's - ENaC blockers, NOT spironolactone); surgical (adenoma resection for Conn's); adrenalectomy or ketoconazole (Cushing's)
• Bartter's/Gitelman's: K+ supplements, K+-sparing diuretics, NSAIDs (indomethacin for Bartter's), Mg supplements for Gitelman's
• Vomiting-induced: Treat underlying cause; correct ECFV + electrolytes

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RESPIRATORY ACIDOSIS

Definition

Causes

• CNS depression: Opioids, sedatives, benzodiazepines, anesthetics, head trauma, intracranial tumors, stroke, obesity-hypoventilation syndrome (OHS), primary alveolar hypoventilation
• Neuromuscular: ALS, Guillain-Barré, myasthenia gravis, muscular dystrophies, phrenic nerve injury
• Airway obstruction: COPD (#1 chronic), severe asthma, OSA, foreign body
• Pulmonary parenchyma: Severe pneumonia, ARDS, pulmonary fibrosis
• Chest wall: Kyphoscoliosis, flail chest, morbid obesity
• Mechanical ventilation: Improper settings (low respiratory rate/TV); auto-PEEP

Clinical Features

• Acute hypercapnia: Anxiety, dyspnea, confusion, psychosis, hallucinations → coma; CO2 narcosis
• Chronic hypercapnia: Sleep disorders, memory loss, daytime somnolence, personality changes, tremor, myoclonic jerks, asterixis
• "CO2 narcosis" signs: Papilledema, focal weakness, headache, abnormal reflexes (mimics raised ICP)

Compensation

• Acute: HCO3⁻ rises ~1 mEq/L per 10 mmHg ↑PaCO2
• Chronic (days): HCO3⁻ rises ~3.5 mEq/L per 10 mmHg ↑PaCO2

Treatment

• Correct underlying cause
• Non-invasive ventilation (NIV/BiPAP): COPD exacerbation, OHS, neuromuscular disease
• Intubation and mechanical ventilation: If NIV fails or contraindicated
• Avoid rapid correction of chronic respiratory acidosis → metabolic alkalosis ("post-hypercapnic alkalosis") if HCO3⁻ remains elevated after PaCO2 is lowered

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RESPIRATORY ALKALOSIS

Definition

Causes

• Pain, anxiety/panic disorder, fever, CVA (especially pontine lesions), meningitis/encephalitis, head trauma, tumor

• High-altitude acclimatization (#1 cause in altitude)
• Pneumonia, pulmonary edema, aspiration, PE, severe anemia

• Pregnancy (progesterone stimulates respiratory center) → chronic respiratory alkalosis of pregnancy
• Salicylates (early) - direct CNS stimulation
• Cardiac failure

• Hemothorax, flail chest, cardiac failure, pulmonary embolism (important cause)

• Septicemia (gram-negative bacteria/LPS stimulate CNS chemoreceptors) - respiratory alkalosis is the earliest acid-base sign of sepsis
• Hepatic failure (ammonia + progesterone levels stimulate breathing)
• Mechanical hyperventilation

Clinical Features

• Acute hypocapnia: paresthesias (perioral, extremities), lightheadedness, tetany (due to decreased ionized calcium as alkalosis increases protein-Ca binding), carpopedal spasm
• Chronic: usually asymptomatic; compensated by renal HCO3⁻ excretion
• ECG: may show ST changes and arrhythmias
• Importantly: chronic respiratory alkalosis is the one disorder where compensation can fully normalize pH

Compensation

• Acute: HCO3⁻ falls ~2 mEq/L per 10 mmHg ↓PaCO2
• Chronic: HCO3⁻ falls ~5 mEq/L per 10 mmHg ↓PaCO2

Treatment

• Treat underlying cause
• Anxiety/hyperventilation: reassurance, breathing into paper bag, anxiolytics
• Hepatic failure, sepsis: treat underlying disease

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MIXED ACID-BASE DISORDERS

Common Clinically Important Mixed Disorders

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EXAM PEARL SUMMARY TABLE

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Sources: Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw-Hill Medical), Chapters 54-58; Section 7: Alterations in Renal and Urinary Tract Function.