Chapter Sixteen, part 1
ReferencesCapillary Hemodynamics Insights into Salt Handling and Blood Pressure | NEJMAmy mentioned about the 3 phases of the interstitiumAre the precapillary sphincters and metarterioles universal components of the microcirculation? An historical review - PMCSafety factor?Renal Function during Recovery from Minimal Lesions Nephrotic Syndrome - Abstract - Nephron 1987, Vol. 47, No. 3 - Karger PublishersAre diuretics effective for idiopathic lymphedema? : Evidence-Based PracticeRapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema for fig 16-7Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart FailureAdditional notes from our chat (might be overlap with Amy’s notes belowNew insights into the pathophysiology of edema in nephrotic syndrome by Helbert RondonThe hyperlipidemia of the nephrotic syndrome. Relation to plasma albumin concentration, oncotic pressure, and viscosityPlasmin in Nephrotic Urine Activates the Epithelial Sodium ChannelLipoprotein metabolism in experimental nephrosisViscosity regulates apolipoprotein A-1 gene expression in experimental models of secondary hyperlipidemia and in cultured hepatocytesAmiloride in Nephrotic Syndrome | Clinical Research Trial Listing ( oedema | EdemaHypoalbuminemia and proteinuria contribute separately to reduced lipoprotein catabolism in the nephrotic syndromeOrigin of hypercholesterolemia in chronic experimental nephrotic syndromeExtrahepatic lipogenesis contributes to hyperlipidemia in the analbuminemic ratApolipoprotein gene expression in analbuminemic rats and in rats with Heymann nephritisAmy’s NotesJosh “Blessed are the days” https://link.springer.com/article/10.1007/s00467-013-2435-6Amy mentions mels’ article Capillary Hemodynamics Insights into Salt Handling and Blood Pressure | NEJM, the 3 phases of the interstitiumJosh 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_syndromeOutline Chapter 16 — Edematous StatesEdema is a palpable swelling produced by expansion of the interstitial fluid volumeConditions associated with this Heart failure Cirrhosis Nephrotic syndromePathophysiology of edema formationTwo steps Alteration of capillary hemodynamics that favors movement of fluid out of the capillary Dietary sodium and water are retained by the kidneyEdema 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 filtrationAlveolar 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 filtrationIncreased capillary hydraulic pressure would do it Increased interstitial oncotic pressure tooReduction in plasma oncotic pressureLymphatic obstruction too Increased capillary hydraulic pressureCapillary hydraulic pressure is insensitive to alteration in arterial pressure due to autoregulation in the pre-capillary sphincterConstricts in response to increases in arterial pressureNo 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 malignancyCalled 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 diagnosisThree factors important in the mechanism of edemaThe pattern of distribution of edema which reflects those capillaries with altered hemodynamic forcesThe central venous pressurePresence or absence of pulmonary edemaPulmonary edemaShortness of breath and orthopneaTachypnic, diaphoretic, wet rales, gallops, murmurs Check a chest x-rayCardiac disease is most commonBut differential includes primary renal Na retention and ARDSWedge pressure will exceed 18-20 mmHg with heart or primary Na retention, but is relatively normal with ARDSUncomplicated cirrhosis does not cause pulmonary edemaIncreased capillary pressure in this disorder is only seen below the hepatic veinNormal or reduced blood volume in the cardiopulmonary circulationPeripheral edema and ascitesPeripheral edema is cosmetically undesireable but produces less serious symptomsSymptoms: swollen legs, difficulty walking, increased abdominal girth, shortness of breath due to pressure on the diaphragm.Pitting edema found in dependent areasAscites found in abdomenNephrotic syndrome low tissue pressure areas like eye orbitsHeart Failure (right sided) peripheral edema, abdominal wall, SOB is due to concomitant pulmonary disease. Right sided heart failure increases venous pressureCirrhosis 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 tapPortal pressure > 12 mmHg required for fluid retentionLove the case history 16-1Primary renal sodium retentionPulmonary and peripheral edemaJugular venous pressure is elevatedNephrotic SyndromePeriorbital and peripheral edema, rarely ascitesCVP normal to highIdiopathic edemaBehaves as volume depleted (especially with diuretics)Etiology and treatmentGeneral principles of treatmentWhen must edema be treatedWhat are the consequences of the removal of fluidHow rapidly should fluid be removedWhenPulmonary edema is the only form of generalized edema that is life threatening and demands immediate treatmentImportant for note: laryngeal edema and angioedema. Cerebral edemaWhat are the consequencesIf 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 increasesSays to be careful in diuresis leads to increases in CrHow rapidly should edema fluid be removedRemoving 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 difficultyAn exception is cirrhosis and ascites without peripheral edema. Mobilizing ascites is limited to 500-750 ml/dayHeart failureEdema is due to increase in venous pressure raising capillary hydrostatic pressureIschemic and hypertensive CM impairs left ventricular function causing pulmonary but little peripheral edemaIn 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 extremitiesCardiomyopathies 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 retentionEdema is absent and patients can be compensated at the expense of increased LVEDP see Figure 16-6Figure 16-6 A to B to C with compensationEventually 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 outputPotential harmful elevation in venous pressureBenefit 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 dysfunctionDecreased compliance in diastolic dysfunction can lead to flash pulmonary edema More common with hypertensionLook to the ejection fractionNeurohormonal adaptation Initial benefit long term adverse effectsNorepi, renin, ADH all are vasoconstrictors They raise cardiac outputRaise BP which is maladaptive in the long termTreatment of cardiogenic pulmonary edemaMorphineOxygenLoop diureticNTG/nitroprussideIf patient remains in pulmonary edema and has systolic dysfunction consider inotropic agentTreatment of chronic heart failure Feels datedMentions dig and loop diureticBut also ACEi/BB and AADeep diveLoop diureticsACEiCor Polminale Edema here comes with increased CO2Associated with increased HCO3 which means increasedHCO3 reabsorption int he proximal tubule which leads to more sodium retentionHypoxemia can increase Na retentionCirrhosis and AscitesBoth lymphatic obstruction and increased capillary permeability contributeSinusoidal obstruction leads to increased hydraulic pressure in the sinusoids. Portal hypertension is necessary for ascites> 12 mmHgThe low albumin is often present but is not contributory to edemaSinusoids are freely permeable to albumin so no oncotic pressure from albumin hereMechanism of ascitesRenal sodium conservation is an early finding and some evidence for primary sodium retention but…Mostly underfill is thought to drive Na retentionSplanchnic vasodilation starts this ofNO drives thisEndotoxin absorption stimulates NoNormally endotoxin is detoxed in liver but portosystemic shunting allows endotoxin to escape the liver.Hepatorenal syndromeProgressive hemodynamically mediated fall in GFRInduced by intense renal vasocontstrictionWhere are the PGE and KininsFall in GFR is masked by decreased muscle mass and decreased BUN productionHyponatremia is a grave prognostic sign, as it is in heart failure, Indicates increased activation of vasopressinTreatmentLow Na intakeLow water intakeCare with diuretics, can only mobilize 300-500 ml of ascetic fluid a dayAvoid hypokalemia Stimulates NH3 productionTalks about the mechanism in proximal tubuleAlso discusses pKA of NH3->NH4 reaction and if the pH rises, this will shift the Eq to produce NH3Important aspect in NH3 is lipid soluble and NH is not Says that Spiro is diuretic of choiceStates it is more effective than furosemide in this conditionEffectiveness related to slower rate of drug excretionin urine (compromises furosemide but not spiro) competition with bile saltsRecommends 40 furosemide and 100 of spiroResistant ascitesOptionsparacentesisTIPSComplicated by higher mortality Peritoneovenous shunt Largely abandoned,Primary renal sodium retentionCKD or AKI where low GFR linits excretion of Water and NaAcute 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 NADrugsDirect vasodilators like minoxidilRequire super high furosemide doses to counterOther antihypertensives either block sympathetic NS, Na retention directly or block RAAS explains why they don’t cause Na retentionNSAIDSFludrocortisonePregnancyNormal pregnancy is associated with retention of 900 to 1000 mEq of NaAnd! 6-8 liters of waterRefeeding edemaInsulin stimulate Na retention
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