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He who asks a question may look momentarily stupid

but he who does not will remain forever ignorant 

Chinese Proverb

Blood pressure & hemodynamics

Overview of Circulation

Arterial Pressure

constant capillary flow keeps gas exchange constant and also prevents "sludging" of red cells in capillaries.  Blood is like ketchup - hard to start flow when flow is stopped.

Mean arterial pressure (MAP) is calculated as 2/3 diastolic + 1/3 systolic. 120/90 MAP = 60 + 40 = 100 mmHg.  120/80 MAP = 53 + 40 = 93 mmHg.  The reason MAP is not the average of systolic and diastolic is due to the fact that, at rest, 2/3 of the time is spent in diastole and 1/3 is spent in systole.

pulse pressure = systolic - diastolic  changes with stroke volume & aortic compliance

Control of diastolic pressure

1. heart rate  - determines "run off" time during diastole
2. total peripheral resistance (TPR) - determines slope of "run off"

MEMORY TOOL - PQR  (ABC rule)

P = QR   (use algebra to rearrange)

very useful in understanding hypertension and hypotension (shock)

R = P/Q   for whole system

R = 8nl/pi r4         for single tube   2^4 = 16

where n is viscosity; l is length; and r is radius.  Viscosity is greater with more red blood cells.  More red cells (higher Hct) = more O2 delivery but higher resistance.

There is an optimum Hct (or hemoglobin) that is close to normal Hct.  this can go up and down with blood volume

Resistance is in series; e.g. right heart and left heart or parallel; e.g., organs of body AND  capillary beds.

adding a resistance in parallel ALWAYS lowers total resistance.

e.g.,  1/R = 1/2 +1/2 +1/2 = 3/2  so R = 2/3 = .66

added R

1/R = 1/2 +1/2 +1/2 + 1/2 = 4/2  so R = 2/4 = .5

Flow = velocity x cross-sectional area

cm3/min = cm/min x cm2/min  

student question: does density change in blood to change Reynold's No.?  N = pdv/n

ans. =  no

note that in air, changes in density can be important  (why deep divers use helium),  Helium also used clinically in patients with severe airway obstruction.

Regulation of Blood Pressure  P = QR

R

slow = hormonal

fast = neural

Q

slow = hormonal

fast = neural

Cardiac Cycle

tricuspid valve   then    bicuspidvalve   memory tool:  "try it before you buy it"

Wiggers Diagram with EKG

Right heart pressures LOW due to lower resistance of lung circulation.

Importance of low right atrial pressure  = avoids edema in organs and peripheral circulation.  Sign of right heart failure = peripheral edema (e.g., swollen ankles)

Pharmacology of EKG

Pharmacology of EKG 

Class IA

e.g. procainamide, quinidine

block Na channels and K channels

drug interactions

• diuretics, steroids, amphotericin B = K loss
• low K interferes with phase 3 K efflux (K channels require bound K to function normally.
• other drugs
• tricyclic antidepressants

Class IB

e.g., lidocaine

• works on cells with long action potentials = ventricles, not atria
• little or no effect on QRS or AP  (nl EKG)

drug interactions

Hyperkalemia - lidocaine  increases chance of toxicity  

Class IC
e.g., flenainide

• effects on EKG similar but smaller than IA.
• works on both atria and ventricles

Local Regulation of Blood Flow

Local Regulation of Blood Flow

• autoregulation - most important in kidney, heart, and brain (not in lung)
• MECHANISM = matching R and P to keep Q constant  
• Q = P/R
• myogenic reflex  (stretch activated channels if P is high; K channel activation if P is low)
• range over which autoregulation occurs may change;e.g., chronic hypertension shifts range to higher values.

• metabolic regulation

• In Lungs hypoxia has opposite effect = vasoconstriction - mediated by specializes K channels that are inhibited by hypoxia = depolarization and Ca influx.

• Flow regulation
• hemodynamic forces

Pulmonary Edema

Pulmonary Edema





It is less confusing to think of the colloid osmotic pressure as a positive number with a minimum value of zero (NO PROTEIN).





When the rate of fluid filtration from the capillary 
into the interstitium is the rate of lymphatic removal and evaporation - no net fluid accumulation.


• However, when the rate of fluid filtration from the 
capillary into the interstitium is > the rate of lymphatic removal and evaporation - there is net 


fluid accumulation PULMONARY EDEMA.



Cardiogenic Pulmonary Edema



In a normal lung, the driving force for fluid filtration is 
~1 mmHg

• If in CHF the pulmonary capillary pressure increases 
to ~25 mmHg

• Assuming that at least initially Pi ~ 8 mmHg, plasma 
protein osmotic pressure is ~28 mmHg, interstitial 

fluid protein osmotic pressure is ~14 mmHg, and 
remains 0.98

• Then [(25 8) 0.98(28 14)] = ~ 19 mmHg






Treatment for pulmonary edema


Decrease Preload: diuretics, sit patient up in bed, n
itrates, morphine, dialysis.
Improve Cardiac Performance: Nitrates, Inotropes, 
Digoxin.
Decrease Afterload: ACE inhibitors, nitroprusside
Increase Pi: Continuous positive airway pressure, 
mechanical ventilation
Decreasing LpA, or osmotic pressure has not been 
attempted.
Non-cardiogenic Pulmonary Edema

If there is endothelial damage Lp
increases and Jv increases





Capillary endothelium loses barrier function
– Does not require change in hemodynamics
– Forces that oppose Pc decrease
– LpA increases
– leaky capillaries and increased fluid filtration!

Treatment of non-cardiogenic pulmonary edema


Treatment / Removal of offending source (infection , aspiration , inhalation)
• Mechanical Ventilation if necessary (with low tidal volumes)
• Many experimental therapies (antiinflammatory among others)


DDx Cardiogenic versus Non-cardiogenic


Underlying condition: Myocardial infarction vs. severe infection
• X-ray appearance
• Estimates of Pc (central venous pressure, BNP peptide)
• Measurement of Pc (Swann-Ganz Catheter)
• Measurement of Alveolar protein concentration (estimate of πi)


Hanta virus = both cardiogenic and non-cardiogenic pulmonary edema

High altitude pulmonary edema (HAPE)

cardiogenic = pulm venoconstriction
non-cardiogenic = protein in alveolar fluid

Pulmonary Edema

into the interstitium is the rate of lymphatic 

Treatment for pulmonary edema

• Decrease Preload: diuretics, sit patient up in bed, n
  • itrates, morphine, dialysis.
• Improve Cardiac Performance: Nitrates, Inotropes, 
  • Digoxin.
• Decrease Afterload: ACE inhibitors, nitroprusside
• Increase Pi: Continuous positive airway pressure, 
  • mechanical ventilation
• Decreasing LpA, or osmotic pressure has not been 
  • attempted.

Non-cardiogenic Pulmonary Edema

If there is endothelial damage Lp

increases and Jv increases

Capillary endothelium loses barrier function

– Does not require change in hemodynamics

– Forces that oppose Pc decrease

– LpA increases

– leaky capillaries and increased fluid filtration!

Treatment of non-cardiogenic pulmonary edema

Treatment / Removal of offending source (infection , aspiration , inhalation)
• Mechanical Ventilation if necessary (with low tidal volumes)
• Many experimental therapies (antiinflammatory among others)


DDx Cardiogenic versus Non-cardiogenic


Underlying condition: Myocardial infarction vs. severe infection
• X-ray appearance
• Estimates of Pc (central venous pressure, BNP peptide)
• Measurement of Pc (Swann-Ganz Catheter)
• Measurement of Alveolar protein concentration (estimate of πi)


Hanta virus = both cardiogenic and non-cardiogenic pulmonary edema

High altitude pulmonary edema (HAPE)

• cardiogenic = pulm venoconstriction
• non-cardiogenic = protein in alveolar fluid

Potassium homeostasis

Potassium

Potassium Space is Huge

• NaK ATPase constantly bailing Na to keep K inside
• K "bath" used to stop hearts for surgery
• diarrhea loss can be much higher than nl (up to 100 mEq/day)
• creates metabolic acidosis with hypokalemia  (in most cases acidosis comes with hyperkalemia)

K homeostasis

• rhabdomyolysis may cause dangerous hyperkalemia

Physiology of K homeostasis

Death by avocado  -  response to K intake

alpha intercalated cells and principal cells fine tune the 13% of K+ that remains in the tubule after reabsoption by the proximal convoluted tubule and thick ascending limb of the loop of Henle.  alpha cells reabsorb K+ if there is hypokalemia.  principal cells secrete K+ if there is hyperkalemia.  Also, the principal cells are the target of the adrenal medulla hormone, aldosterone, which increases Na+ reabsorption and K+ excretion.

There appears to be a well-developed system for sensing potassium by the pancreas and adrenal glands. High potassium states stimulate cellular uptake via insulin-mediated stimulation of sodium-pump activity in muscle and stimulate potassium secretion by the kidney via aldosterone-mediated enhancement of distal renal expression of secretory potassium channels (ROMK).

Low potassium states result in insulin resistance, impairing potassium uptake into muscle cells, and cause decreased aldosterone release, lessening renal potassium excretion. This system results in rapid adjustments in immediate potassium disposal and helps to provide long-term potassium homeostasis.

Na and K levels Interact  --  Edelman equation

Plasma [Na +] = Na+ + K+/TBW

Kidneys reabsorb all filtered load of K (720 mEq/day) - most in collecting duct (principal cells)

Bartter's Syndrome  - thick ascending limb  = same effect as loop diuretics

Gittleman Syndrome - DCT - resembles thiazide diuretic

Potassium sparing diuretics

• amiloride - Naa channel blocker
• reduced aldosterone (ACE inhibitors) or aldosterone receptor blockers (spinolactone)

Transport in kidney

transport in kidney

Filtered Load = GFR x plasma concentration

• Transport maximum = max filtered load that nephron can reabsorb = 375 mg/min for glucose

HCO3 reabsorption in proximal tubule

• can't cross cell membrane (neg chg)
• combines with H+ to form CO2 & H2O
• CO2 = non-polar molecule = diffuses across membrane

Clearance Ratios

• Comparison of clearance of various solutes to clearance of Inulin

• Why inulin?

• Cx/Cinulin = 1.0

– Substance can be used as a filtration marker

– Not reabsorbed, secreted or metabolized: creatinine

• Cx/Cinulin < 1.0

– Either the substance is not filtered OR it is filtered and subsequently reabsorbed: glucose

• Cx/Cinulin > 1.0

– Substance is filtered (or not) and secreted: organic acids

– Penicillin!

Proximal Tubule

nephron map

67% of Na and H2O reabsorption

Loop of Henle

Early Distal Tubule

Late Distal Tubule

Renal pathology

Renal Pathology

nephritic syndrome II

Anti-GBM GN - Clinical Features (II)
• Can present as:
– pure glomerulonephritis
– GN with pulmonary hemorrhage (more 

often young men)

= Goodpasture syndrome

Anti-GBM GN - Pathogenesis
• Immune-mediated
• Pts make auto-antibodies against alpha 3 

chain of collagen IV

• Auto-antibodies bind to glomerular GBM 

and incite inflammation

• Pts have anti-GBM auto-antibodies in serum 
– inc. anti-GBM antibody titer in serum



Anti-GBM GN - Light Microscopy
• Damage to glomerular capillary walls
– leak of fibrin into Bowman’s space
• Typically crescent formation
– proliferation of Bowman’s capsule epithelial cells
• Red cell casts in interstitial tubules

Anti-GBM GN - IF and EM
• By immunofluorescence
– LINEAR deposits of IgG and C3 along glomerular basement membrane - only GN with linear staining
• By electron microscopy
– wrinkling of glomerular basement membrane
– focal breaks in glomerular basement membrane
– no deposits

Pauci-Immune GN - (=ANCA Disease)
ANCA = Anti-Neutrophil Cytoplasmic Antibodies
Clinical
• Acute renal failure - medical emergency:
– oliguria, hematuria, red cell casts, Inc. creatinine
• More common in adults, also occurs in children

Pauci-immune GN – Pathogenesis I
• Caused by circulating auto-antibodies
• Auto-antibodies are called “Anti-Neutrophil Cytoplasmic Antibodies” (=ANCA)
• ANCAs bind to proteins in cytoplasm of neutrophils
• ANCAs activate neutrophils
• Activated neutrophils incite inflammation in glomeruli

Pauci-immune GN - Pathologic Features
• Light microscopy:
– Crescentic GN
• Immunofluorescence:
– NO GLOMERULAR STAINING (or slight non-specific staining)
– That’s why it’s called PAUCI-immune GN

pau·ci·ty  

Noun The presence of something only in small or insufficient quantities or amounts; scarcity.

Synonyms scarcity - shortage - dearth - lack - want - deficiency Lupus Nephritis - secondary disease to LE - most danderous aspect of LE Lupus Erythematosus – Definition • Auto-immune disease • More common in females than males (10:1) • Affects multiple organ systems → multi-system disease • Clinical presentation highly variable • Glomerulonephritis WHO class I – VI • Caused by immune deposits: – IgG, IgA, IgM, C3, C1q  all stain = only in Lupus  "Full House" Lupus – Criteria defined by American College of Rheumatology Criterion Definition -  need 3 of the following 1. Malar rash - erythema over malar excrescences 2. Discoid rash - skin rash 3. Photosensitivity - skin rash after UV exposure 4. Oral ulcers - usually painless 5. Arthritis - joint tenderness, swelling, effusion 6. Serositis - pleual effusion, pericardial effusion 7. Renal disorder - Proteinuria or glomerulonephritis 8. Neurologic disorder - Seizures or psychosis 9. Hematologic disorder - anemia, leukopenia, thrombocytopenia 10. Immunologic disorder - anti-ds DNA, anti Sm, antiphospholipid auto-antibodies 11. Antinuclear antibodies - positive ANA auto-antibodies Alport Syndrome and Thin GBM Disease

• Hereditary nephritis = group of familial diseases
– Alport sydrome
– Thin basement membrane disease (=benign familial hematuria)
• Thin basement membrane disease:
– asymptomatic hematuria (miscrocopic)
– familial, but fairly common
– diffuse thinning of GBM
– prognosis excellent



• Cause:
– X-linked inheritance most common 
– mutation in gene for alpha 5 chain of collagen IV
• Pathogenesis:
– abnormal assembly of collagen IV
– altered structure and functions of GBM and other basement membranes

Clinical features:
– nephritis
– nerve deafness
– eye abnormalities (lens dislocation, corneal dystrophy)
– express full syndrome
– are carriers
• Renal abnormalities:
– hematuria (micro- or macroscopic)
– proteinuria
– renal failure in adult 




Tubulo-Interstitial Diseases
more common than glomerular diseases

• Anatomy of normal nephron
• each normal kidney has 800,000 -1,200,000 nephrons
• Acute tubular necrosis
• Definition:
• – damage to tubular epithelial cells and necrosis
• → acute loss of renal function (renal failure)
• – is clinico-pathologic entity
• Causes:
• – ischemia (typically pre-renal) = first affects tubules
• – toxic (intra-renal)
• – acute tubulo-interstitial nephritis (intra-renal)
• – urinary obstruction (post-renal)

• Ischemia:
• sudden drop in blood pressure (pre-renal)
• shock (severe blood loss, burns, sepsis, acute heart failure, dehydration, prolonged diarrhea)
• → decrease in circulating blood volume
• → hypo-perfusion of kidneys 
• → renal tubules oxygen-deprived
• → necrosis of tubular epithelial cells
• Vasculitis:
• vascular inflammation → narrowing of renal 
• vessels → hypo-perfusion of kidneys → → → 
• Ischemia:
• – tubular cell injury
• → detachment
• → tubular obstruction
• → impaired urine flow in tubules
• → increased intra-tubular pressure
• → decreased GFR
• → tubulo-glomerular feedback (renin-angiotensin, dec. NO, dec. prostaglandin I2)
• → constriction of afferent arteriole supplying the nephron
• → acute renal failure
• Toxic:
• drugs (e.g. antibiotics)
• radio-contrast dyes
• poisons (e.g. mercury, organic solvents)
• myoglobin (released from muscles in crush injury)
• hemoglobin (hemolysis e.g. due to transfusion reaction)

• Acute tubulo-interstitial nephritis
• Definition:
• acute inflammation of tubules and interstitium - nl glomerulus
• Two main causes:
• Infection (typically ascending!)
• drugs - esp. antibiotics, diuretics, NSAIDS
• others (see Robbins p. 996, Table 20-9)
• Clinical features:
• begins 15 days after exposure
• fever, blood eosinophilia, rash
• hematuria, mild proteinuria, leukocyturia with eosinophils
• inc. serum creatinine or acute renal failure
• Pathogenesis: abnormal immune reaction
• Typically: acute hypersensitivity immune reaction
• IgE-mediated hypersensitivity (type I hypersensitivity reaction)
• drug binds to proteins in tubular cells and becomes immunogenic (i.e. functions as a hapten)
• idiosyncratic, i.e. NOT dose-related
• When granulomas present (less common):
• – delayed-type hypersensitivity (type IV hypersensitivity reaction)

• Acute pyelonephritis
• Very common:
• – one of the most common kidney diseases !!!
• Cause: bacterial infection
• ascending from urethra and bladder, typically from pt’s own fecal flora
• Gram-negative bacilli:
• E. coli, Proteus, Klebsiella, Streptococcus faecalis
• hematogeneous via bloodstream (less common)
• Factors that promote infection and inflammation:
• obstruction: stones, tumors, enlarged prostate, pregnancy
• bladder dysfunction (e.g. spinal cord injury, diabetes)
• vesico-ureteral reflux - due to incompetent vesicoureteral valve
• Complications:
• papillary necrosis, typically in diabetics
• areas of gray-white necrosis in tips of renal papillae
• pyelonephrosis
• pus fills renal pelvis, calyces, ureter
• peri-nephric abscess
• inflammation spreads into retro-peritoneal soft tissue
• sepsis → septic shock → potentially life-threatening!!!
• Evolution into chronic inflammation with scarring
• Chronic Pyelonephritis
• polar scars with blunted calices
• tubular atrophy, chronic lymphocytic infiltrate, interstitial fibrosis
• Chronic pyelonephritis

• Urinary tract obstruction (hydonephrosis, obstructive uropathy)
• • Urinary tract obstruction:
• caused by stones, tumors, enlarged prostate, others
• → dilatation of ureter, renal pelvis, renal calices
• → atrophy of renal cortex
• → hydronephrosis

• Myeloma cast nephropathy (myeloma kidney)
• Multiple myeloma = malignant proliferation of 
• plasma cells in bone marrow
• Typically associated with Bence-Jones proteins in 
• urine
• = immunoglobulin light chains produced by malignant plasma cells
• – appear in the urine
• – can combine with Tamm-Horsfall protein 
• → form casts that obstruct tubular lumina
• – cast in tubules cause obstruction and inflammation
• → cast nephropathy
• Sir Henry Bence Jones in 1848:
• – observed peculiar thermoreactivity of urine from multiple myeloma patient
• – urine becomes turbid only between 40 C and 60 C
• Bence-Jones proteins are monoclonal immunoglobulin light chains
• monoclonal protein increased in serum (Mprotein, M-component, or myeloma protein)

Water Balance

Water Balance

Water Balance

Sodium and Water balance:

Volume First!

• Serum sodium level usually reflect water balance.

• The body will normally adjust ADH and Aldosterone to protect intravascular volume, even at the expense of osmolality (reflected by serum sodium).

• When you see an abnormality of serum sodium, look at volume status and ask what ADH and Aldosterone are (or should be) doing?

Water Disorders:

• Diabetes Insipidus
• Inability of kidneys to concentrate urine appropriately
• • Due to an Anti-Diuretic Hormone (ADH) problem.
• ADH Deficiency- Central D.I.
• ADH Resistance- Nephrogenic D.I.
• • Symptoms
• – Polyuria and Polydipsia (ie: nocturnal urinating / drinking)
• • Recurrent episodes of dehydration whenever PO intake limited
• • Craving for water or Ice water.
• • Lab
• • Blood: High Sodium and High osmolality
• • Urine: Low Osmolality and variable sodium 
• • Other electrolytes and pH are normal 
• Diagnosis
• • Diabetes Insipidus
  • • High Urine output with Low Urine Osmolality and High Serum Osmolality.
  • Water Deprivation test:
  • – Restrict fluids:
  • Minimal or no change in Urine Output
  • Minimal increase in Urine Osmolality
  • inc Serum Osmolality
  • inc Serum Na+
  • • Serum ADH
  • – Low = Central DI
  • – High = Nephrogenic DI
• SIADH: Syndrome of Inappropriate Anti-diuretic Hormone
• • Inappropriately High ADH levels
• – Blood: Low sodium and Low Osmolality
• – Urine: Low volume and High osmolality
• Normal (or mild increase) in volume status
• Primary Polydipsia
• Excessive Water Intake >>> ability of kidney to excrete
• – Blood: Low sodium and Low osmolality 
• – Urine: High volume and Low osmolality
• Seen mostly with alcoholism (beer) and psychiatric disorders.

Summary

CAPACITY OF KIDNEY TO GET RID OF WATER = 16 ml/min

Congenital heart disease

Congenital heart disease

cyanois  - most sources say 5 g deoxyHb

PDA dependent  (ductal dependent)
keep open with PGE

Top three side effects
 Apnea
 Apnea
 Apnea

Total Mixing Lesions
 All of systemic venous return and pulmonary venous return mixes at some level.
 Saturation determined by how much blue blood is mixing with the red.
 All these lesions have ability for high pulmonary blood flow.

Total Anomalous Pulmonary Venous Return
 Total Mixing at the level of the right atrium
 Common Vein never incorporated into the left atrium.
 Most of venous flow stays on the right side.
 Need PFO to maintain preload to left ventricle

Cyanotic Heart Disease 

 2 month old born term. Apgars 8/9. 
Saturation 98% at the time of discharge 

from the hospital.

 Now presenting with increasing irritability 

blueness with feedings and crying.

 Saturation in the ER is 60%.

Tetralogy of Fallot

•  The squatting child - increases peripherall vascular resistance = stops R - L shunt
•  Should never be seen in this country
•  Classic Tetralogy Spell
•  Typically in the morning
•  Sleeps all night
•  Pulls self up in the crib
•  Becomes irritable

What About ASDs? 
 Typically do not cause symptoms in childhood
 Close them to prevent right heart failure, atrial arrhythmias and pulmonary 
hypertension as an adult.
 Close around 3-4 years of age, before 8-10 years of age.
 Typical scenario
 Small child growing on their curve
 Perhaps some exercise intolerance
 SEM LUSB with radiation to the back and fixed split of S2