【持续性肾脏替代治疗crrt英文精品课件lacticacidosis

Lactic Acidosis, , Arterial (or serum) Lactate 5 mmol/L Arterial (or serum) pH 6 mmol/L) Anion gap : insensitive,Definition,Arterial pH 5 mmol/L *Lactate level 9 mmol/L : high mortality rate(75%),Definition,Arieff AI et al. Br J Anaesth 1991;67:165-177,Pathophysiology of Lactic Acid Metabolism,Chemical structures of L-lactic acid and D-lactic acid,Robergs RA et al, Am J Physiol Regul Integr Comp Physiol 2004;287:R502-R516,O OH C HO C H H C H H L-Lactic Acid,O OH C H C OH H C H H D-Lactic acid,Chemical structures of lactic acid and the sodium salt of lactate,Robergs RA et al, Am J Physiol Regul Integr Comp Physiol 2004;287:R502-R516,A summary of the physical properties of lactic acid,Robergs RA et al, Am J Physiol Regul Integr Comp Physiol 2004;287:R502-R516,Glucose,Fructose-6-phosphate,Fructose-1,6-diphosphate,Pyruvate,Lactate,Acetyl CoA,Biosynthetic pathways,TCA cycle,Oxaloacetate,Citrate,Cytosole,Mitochondria,Gluconeogenesis,Metabolic Pathways of Glycolysis & Gluconeogenesis,PFK,CO2 + H2O,NADH,NAD+,NAD,NADH,Inhibit H+,ATP,Stimulate OH-,ADP, AMP,-2 mmol ATP,+4 mmol ATP,+36 mmol ATP,Net : +2 ATP,LDH,PDH,PC,1. This reversible reaction occurs in the cytosole. 2. Catalyzed by the enzyme lactate dehydrogenase (LDH) 3. Lactate is a metabolic end-product, its only metabolic fate being oxidation back to pyruvate. 4. The equilibrium of equation favors the formation of lactate. 5. Under normal conditions, the concentration of lactate is a 4 to 10 times greater than that of pyruvate. 6. LDH is stereospecific for the L(+)-lactate reaction. 7. L(+)-lactate is the natural forms in mammals.,Lactate Production,CH3COCOO- + NADH + H+ CH3CH(OH)COO- + NAD+ (pyruvate) (lactate),LDH,1. Pyruvate concentration 2. NADH/NAD+ ratio 3. H+ concentration,Three Variables of Lactate Concentrations,Lactate = Keq X Pyruvate X X H+ ,NAD+,NADH,1. Plasma lactate concentration : normally in the range of 0.4 to 1 mmol/L Plasma pyruvate concentration : about 0.1 mmol/L (L/P ratio : 4 to 10:1) 2. Average basal turnover rate : - about 20 mmol/kg/day (range of 15 to 25 mmol/kg/day) - approximately 1400 mmol/day per 70 kg, or 1 mmol/min 3. Volume of distribution : 270 to 340 ml/kg in human, about 360 ml/kg in rat,Quantitative Aspects of Lactate Metabolism,1. Redox state of the cytosolic pyridine nucleotides 2. The ratio is affected by various cytosolic dehydrogenase. 3. Mitochondria-containig cells : NADH is oxidized to NAD+ by the electron transfer chains 4. Suppression of mitochondrial function reduced availability of NAD+ within cytosol. increase NADH / NAD+ ratio lactate production,NADH / NAD+ ratio,Intracellular Hydrogen Ion,Increment in intracellular H+ should lead to increased lactate concentration in the cytosole. The direct effect of H+ : overriden by pH- mediated effects on PFK - intracellular acidosis : inhibition of PFK - intracellular alkalosis : stimulation of PFK * serve as an important homeostatic function,1. Major lactate-consuming organs: liver and renal cortex 2. Fractional contribution to the total basal lactate load: Liver ; 50-60%, kidney ; 20-30% 3. Two pathways of lactate consumption: - Liver; Gluconeogenesis is the primary mode of lactate. - Kidney; About 50% of lactate uptake is oxidation and gluconeogenesis. (renal excretion: minor role),Lactate Utilization,Lactic acid-producing and -consuming Tissues Under Basal Conditions,Producers Skin Erythrocytes Brain Skeletal muscle Intestinal mucosa Leukocytes Platelets Renal medulla Tissue of the eye (cornea, lens, retina),Consumers Liver Renal cortex Salivary glands (?),Synopsis of Acid-base Effects on Lactate Metabolism,Lactate synthesis (Glycolysis) Lactate utilization (Gluconeogenesis) Liver Kidney Net lactate production in vivo,Acidosis,Alkalosis, LA is one of the common, and by far the most serious, of all high-anion gap metabolic acidosis. Approximately 1% of hospitalized nonsurgical patients are diagnosed with LA. (Luft D et al. Am J Clin Pathol 1983;80:484-489),Incidence,1. extremely variable and heavily influenced by the manifestations of the underlying disease 2. often heralded symptoms; sudden onset of malaise, weakness, anorexia,vomiting and a deterioration in mental status 3. common associated findings; hyperventilation, tachycardia, hypotension and circulatory instability,Clinical Features of Lactic Acidosis,Elevated anion gap ( AG/HCO3- 1.6:1) Hyperuricemia Hyperphosphatemia Leukocytosis Normokalemia Hyperaminoacidemia (esp, alanine),Laboratory Findings Typically Associated with Lactic Acidosis,Causes of Lactic Acidosis,Causes of Lactic Acidosis (1),Lactic Acidosis,Type A inadequate tissue oxygenation,Type B apparently adequate tissue oxygenation,There is often an overlap.,Shock (cardiogenic, septic, hypovolemic) Regional hypoperfusion (limb, mesenteric ischemia) Severe hypoxemia (PaO2 2530 mmHg) Carbon monoxide poisoning Severe asthma,Causes of Lactic Acidosis (2),Type A: clinical evidence of tissue hypoxia - decreased oxygen delivery - overproduction of lactic acid,- B1 (Lactic acidosis occuring in association with an underlying disease) - B2 (Lactic acidosis due to drugs/toxins) - B3 (Lactic acidosis due to inborn errors of metabolism) - Miscellaneous,Causes of Lactic Acidosis (3),Type B: no clinical evidence of tissue hypoxia defective oxygen utilization & impaired lactate metabolism,B1 (Lactic acidosis occuring in association with an underlying disease) Diabetes mellitus Sepsis, HIV infection Liver disease Pheochromocytoma Malignancy Thiamine deficiency Malaria Alkalosis Streneous exercise/ seizures (?),Causes of Lactic Acidosis (4),B2 (Lactic acidosis due to drugs/toxins) Biguanides Fructose/Sorbitol (phenformin/metformin?) Xylitol Acetaminophen Catecholamines Ethanol Cyanide Methanol Nitroprusside Ethylene glycol Isoniazid Propylene glycol Salicylates Ritodrine Antiretroviral agents Niacin Streptozotocin Cocaine,Causes of Lactic Acidosis (5),Most frequent cause of lactic acidosis The failure of mitochondrial oxidative chain to regenerate NAD+ stimulates the reduction of pyruvate to lactate as a source of NAD+ Both lactate utilization pathways are compromized. 1. Impaired lactate oxidation into the citric acid cycle: - The oxidation of lactate is impaired by the unavailability of NAD+ - Mitochondrial function is disrupted by the lack of oxygen. 2. Impaired gluconeogenesis - Impaired pyruvate carboxylase activity due to low intracellular levels of ATP,Type A Lactic Acidosis,Metformin Associated Lactic Acidosis; Cause or Coincidence?,Biguanides Phenformin/metformin,Binding of biguanide to complex 1 of mitochondrial respiratory chain Incidence with metformin: minimal 9 cases/ 100,000 person-yr of metformin exposure (Stang M et al. 1999) Risk factors : underlying renal, hepatic & cardiac dysfunction Treatment : insulin/glucose/dialysis,Contraindications to Metformin Therapy(1),Setter SM et al, Clinical Therapeutics 2003;25:2991-3026,Renal disease of renal dysfunction (eg. Serum creatinine 1.5 mg/dl for men, 1.4 mg/dl for women Creatinine clearance 60 ml/min Congestive heart failure requiring pharmacologic treatment Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma,Contraindications to Metformin Therapy (2),Setter SM et al, Clinical Therapeutics 2003;25:2991-3026,Radio logic studies involving the use of IV contrast media Surgical procedure-metformin should be suspended temporarity before all surgical procedures except minor procedures not associated with restricted intake of food and fluids. Excessive alcohol intake Known hypersensitivity to metformin,Salperter SR et al, Arch Intern Med 2003;163:2594-2602,Risk of fatal and non fatal LA with metformin use in Type 2 DM,Method: comprehensive search was performed to identify all comparative trials or obsrvation cohort studys published between January 1, 1959, and March 31,2002. Results: Pooled data from 194 studies revealed no cases of fatal or nonfatal LA in 36893 patients-years in the metformin group or in 30109 patients-years in the nonmetformin group. True incidence of LA was 8.1 and 9.9 cases per 105 patient-years.,Risk of fatal and non fatal LA with metformin use in Type 2 DM,Conclusion : There is no evidence to date that metformin therapy is associated with an increased risk of LA or with increased levels of lactate compared with other antihyperglycemic treatments if the drugs are prescribed under study conditions, taking into account contraindications.,Salperter SR et al, Arch Intern Med 2003;163:2594-2602,Evidence-Based answer: no evidence that metformin causes LA, even in patient with renal insufficiency or other cormorbidities Practice pointers: Phenformin was withdrawn from the market after a rate of 40 to 64 cases of LA per 100,000 patient-years was reported. There was no difference in intermediate physiologic outcomes, such as change in lactate levels. The authors cite data showing that contraindications to the use of metformin are largely ignored in clinical practice.,Link between metformin and LA?,Ebell M, Am Fam Physician 2004;70:2109-2110,Misbin RI et al, Diabetes Care 2004;27:1792-1793,The Phantom of LA due to metformin in patients with diabetes(1),Metformin rarely, if ever, causes LA when it is used as labeled. Metformin is associatd with LA in patients with conditions that can themselves cause LA (heart failure, hypoxia, sepsis etc). Metformin may contribute to the development of LA in any individual case. When metformin is used as labeled, the increased risk of LA is either zero of so close to zero that it cannot be factored into ordinary clinical decision making.,Misbin RI et al, Diabetes Care 2004;27:1792-1793,The Phantom of LA due to metformin in patients with diabetes(2),Thus, the accumulation of metformin in the setting of renal insufficiency might be expected to precipitate LA in some patients who are at risk. If one excludes overdoses, most cases of metformin-associated LA, particularly the fatal ones, were probably not caused by metformin.,Metformin and LA : cause or coincidence? A review of case reports,Stades AME. et al, J Intern Med 2004;255:179-187,Conclusion: Given the low interobserver agreement and the lack of any relationship between metformin levels and outcome parameters, the concept that there is a simple, causal relationship between metformin use and LA in diabetic patients has to be reconsidered.,Lactic Acidosis in HIV patients treated with antiretroviral agents,Anion gap acidosis,Lactic acidosis,Non-lactic acidosis,Type A,Patel V and Hedayati SS, Nature Clinical Practice Nephrology 2006;2:109-114,D/D of AG Metabolic Acidosis,Type B,Tissure hypoperfusion,Hypoxemia,Cardiac arrest,Methanol,Ethylene glycerol,Salicylates,Uremia,Ketoacidosis, DM, ethanol, starvation,Paraldehyde,Isoniazid,Acute thiamine deficiency,Inherited mitochondirial dis,Pyruvate carboxylase deficiency,Toxin Biguanides (metformin), NRTI therapy,Short bowel syn, hepatic failure,Mechanisms of NRTI-induced LA,Patel V and Hedayati SS, Nature Clinical Practice Nephrology 2006;2:109-114,Accumulation of triglyceride,DNA -polymerase,NRTI,Lactate + NAD+,Pyruvate + NADH,Glycolysis,Glucose,-oxidation,Free fatty acids,Cytoplasm,Mitochondrion,Acetyl coenzyme A,Electron transport chain,ATP,ATP,Krebs cycle,Mechanism of NRTIs induced LA,A possible mechanism for NRTI-induced lactate synthesis in a generic cell,Ogedegbe A-EO et al, Lancet Infect Dis 2003;3:329-337,*NRTI: Nucleoside analogue reverse transcriptase inhibitor,Cytosol,NRTI,Blocked,Mitochondrion,Electron transport chain/ oxidative phosphorylation,Glucose,Pyruvate,Lactate,Glycolysis,NADH accumulation,NAD+ depletion,NAD+ depletion,Lactate dehydroganase,A possible mechanism for NRTI-induced hepatic steatosis,Ogedegbe A-EO et al, Lancet Infect Dis 2003;3:329-337,Blocked,Mitochondrion,NRTI,-oxidation,CO2+H2O +ATP,Hepatocyte cytosol,Low NAD+/NADH environment,Fatty acids,Esterification,Triglyceride,Accumulation,Fatty droplets,Antiretroviral Agents Used to Treat HIV Infection,Lesho EP et al, Am Pham Physician 2003;68:675-686,Class; NRTI Abacavir(Ziagen) Abacavir/lamivudine/zidovudine(Trizivir) Didanosine(videx) Emtricitabine(Emtriva) Lamivudine/Zidovudine(Combivir) Stavudine(Zerit) Zalcitabine(Hivid) Zidovudine(Retrovir) Class; NtRTI Tenofovir(Viread) Class; NNRTI Delavirdine(Rescriptor) Efavirenz(Sustiva) Nevirapine(Viramune),Class; PI Amprenavir(Agenerase) Atazanavir(Reyataz) Indinavir(Crixivan) Lopinavir/ritonavir(Kaletra) Nelfinavir(Viracept) Ritonavir(Norvir) Saquinavir(Fortovase) Saquinavir mesylate(Invirase) Class; FI Enfuvirtide(Fuzeon),Most cases of LA: stavudine, didanosine Relative affinities of NTRIs for mitochondrial DNA polymerase and relative potencies with regard to the drug inhibitory effect on mtDNA replication in vitro. Potency of NTRIs in reducing mtDNA content: zalcitabine didanosine stavudine lamivudine zidovudine abacavir Abacavir and tenofovir: very low affinity and potency inhibiting the mtDNA production.,NTRIs induced LA,Calza L et al, Clinical Nutrition 2005;24:5-15,Nucleoside and non-nucleoside RTIs in 48 HIV-infected patients with symptomatic hyperlactaemia or LA,Calza L et al, Clinical Nutrition 2005;24:5-15,Stavudine,Didanosine,Lamivudine,Nevirapine,Zidovudine,Efavirenz,Current antiretroviral drugs,Prevalence of patients (%),0,20,40,60,80,100,NRTIs (stavudine, didanosisne, zalcitabine, zidovudine, lavmivudine) Long duration of NRTIs therapy Female sex Pregnancy High BMI,Risk factors associated with hyperlactaemia or LA in HIV patients receving NRTIs therapy,Calza L et al, Clinical Nutrition 2005;24:5-15,Symptoms Asthenia Painful dysesthesias Muscular weakness Anorexia Weight loss Fever or hypothermia Nausea and vomiting Abdominal pain Dyspnea,Clinical features of NRTI-induced LA (1),Patel V and Hedayati SS, Nature Clinical Practice Nephrology 2006;2:109-114,Physical exam Tachypnea Hepatomegaly,Radiologic exam Hepatomegaly & fatty infiltration of liver on US,Laboratory exam Elevated serum lactic acid concentration Low serum bicarbonate concentration Elevated transaminases Elevated amylase and lipase Elevated lactate dehydrogenase Elevated creatinine phosphokinase Biopsy of tissue Hepatic biopsy: macrovacuolar and microvacuolar steatosis Muscle biopsy: red-ragged fiber, lipid droplets, muscle fiber atropy,Clinical features of NRTI-induced LA (2),Patel V and Hedayati SS, Nature Clinical Practice Nephrology 2006;2:109-114,LA in HIV patients treated with antiretroviral agents (1),Claessens YE et al, Crit Care 2003;7:226-232.,N=39,LA in HIV patients treated with antiretroviral agents (2),Claessens YE et al, Crit Care 2003;7:226-232.,N=39,Clinical manifestations of hyperlactataemia and LA associated with increasing serum level of lactic acid and decreasing arterial blood pH value,Calza L et al, Clin Nutr 2005;24: 5-15,Hyperlactataemia syndromes associated with HIV therapy,Ogedegbe A-EO et al, Lancet Infect Dis 2003;3:329-337,Frequency of USE Individual NRTIs by Years,Tripuraneni NS et al, AIDS Patient Care STDS 2004;18:379-389,Hyperlactataemia (lactate 2 mmol/L) on NRTI therapy,Absence of symptoms and lactate ranging from 2 to 5 mmol/L,Presence of Sx and/or lactate 5 mmol/L,Arterial blood pH and bicarbonate measurement,Hyperlactataemia and LA in HIV infected patients receving antiretroviral therapy,Algorithm suggested for the management of symptomatic hyperlactataemia,Calza L et al, Clin Nutr 2005;24: 5-15,Therapy interruption,Supportive treatment,Retest and R/O artefactual causes,Normal lactate,End evaluation,Still elevated,Frequent clinical and Lab evaluation,Worsening Sx therapy interruption therapy change supportive tx,Algorithm for the management of hyperlactataemia in HIV-infected patients taking NRTIs,Ogedegbe A-EO et al, Lancet Infect Dis 2003;3:329-337,Asymtomatic plus Lactate 5.0 mmol/L,Continue NRTIs cautiously Monitor for symptoms Repeat lactate weekly,Still raised,End evaluation,Normal Lactate,Retest and rule out Artifactual causes,Hyperlactataemia (2-2.5 mmol/L),Presence of symptoms or lactate 5.0 mmol/L,If persistently 2.1-5.0 mmol/L without symptoms, consider substituting culprit NRTI with abacavir, tenfovir, or lamivudine, or changing to NRTI-sparing HAART regimen,Stop NRTIs,Statin induced or precipitated LA ?,CASE REPORT: Statin precipitated LA?,Neale R et al, J Clin Pathol 2004;53:1807-1094,Neale R et al reported on unusual case of LA thought to be caused by a mitochondrial defect resulting from a deficiency of two cofactors: ubiquinone and thiamine. The deficiency in ubiquinone was a result of inhibition by treatment with Atorvastatin and the thiamine deficiency was dietary in origin. When treatment with Atorvastatin was stopped, the patients acid-base balance returned to normal.,Lipid-lowering drugs and mitochondrial function,Pinieux GD et al, Br J Clin pharmacol 1996;42:333-337,2.690.20,0.690.04,13.10.6,Controls (n=20),2.020.17,0.950.16,15.90.7,Untreated patients (n=20),2.310.24,0.910.09,18.01.1,Fibrate-treated patients (n=20),1.690.07,0.750.04,19.00.8,Statin-treated patients (n=40),Ubiquinone/ LDL-cholesterol ( x 10-4),Ubiquinone(mg/-1),Lactate/ pyruvate,Groups,Lactate/pyruvate ratio, ubiquinone serum level, and molar ratio ubiquinone/LDL cholesterol,Lipid-lowering drugs and mitochondrial function,In all subjects, two evaluations of lactate and pyruvate were performed. High L/P: patients with one or two abnormal evaluations(20); normal L/P: patients with two normal evaluations.,Pinieux GD et al, Br J Clin pharmacol 1996;42:333-337,Lipid-lowering drugs and mitochondrial function,Pinieux GD et al, Br J Clin pharmacol 1996;42:333-337,Statin therapy can be associated with high blood lactate/pyruvate ratio s