Metabolic acidosis Metabolic acidosis is characterized by: \200 low arterial blood pH (ac idemia); \200 reduced serum HCO3 \200 decreased PCO2 ( from respiratory compensation). Etiology of metabolic acidosis Metabolic acidosis may result from: \200 inability of the kidneys to excrete the obligate dietary \200\223 concentration; hydrogen load; inappropriate loss of bicarbonate in the kidneys or the gastrointestinal tract; increase in the generation of the hydrogen ions (such as in lactic acidosis or ketoacidosis). Impaired excretion of the dietary acid load \200 Uremic acidosis (usually GFR <15 \200 \22320 mL/min). \200 Type 1 (distal) renal tubular acidosis (RTA). \200 Type 4 RTA. P. GUPTA AND W. MADIRA 66 Low serum bicarbonate ? Metabolic acidosis ? Compensated respiratory alkalosis Arterial blood gasses Low pH Low pCO2 Low HCO3 Metabolic acidosis Calculate serum anion gap \210\222 AG = Na+ \200\223 Cl 3 \200\223 reference range 12 5 mmol/l \210\222 \200\223 HCO Increased AG metabolic acidosis Lactic acidosis Ketoacidosis diabetic alcohol-associated st arvation Ingestions methanol ethylene glycol aspirin Renal failure Normal AG metabolic acidosis Renal tubular acidosis (types 1, 2 and 4) Diarrhea and other i ntestinal losses (e.g. biliary or pancreatic drainage) Carbonic anhydrase inhibitors Ureter al diversion (e.g. ileal conduit) Toluene ingestion Further investigations Serum potassium (elevated in type 4 RTA) Urine pH (>5.5 in type 1 an d possibly type 4 RTA) Urine anion gap (urine AG = Urine (Na+ + K+ \200\223 Cl \210\222)) Positive value = type 1 RTA, type 4 RTA Negative value = All other causes Urine pH after bi carbonate loading Type 2 RTA: urine pH rises Type 1 RTA: urine pH unchanged Renal imaging: type 1 RTA: nephrocalcinosis and stones Further investigations Serum lactate Urine for ketones Blood glucose Renal function tests O smolal gap Ethanol, ethylene glycol and methanol levels Salicylate level Fig. 2.6.1 Algorithm for the investigaation of metabolic acidosis. Table 2.6.1 Etiology of renal tubular acidosis (RTA) Type 1 (distal RTA) Type 2 (proximal RTA) Type 4 (distal RTA) Primary or idiopathic \200 familial \200 sporadic Primary or idiopathic \200 familial \200 sporadic Hyper-reninemic hypoaldosteronism \200 Addison \200\231s disease \200 congenital adrena l hyperplasia (21-hydroxylase de \201 ciency) \200 drugs (ACEIs, ARBs, heparin, ketocona zole) Hypo-reninemic hypoaldosteronism \200 diabetes mellitus \200 drugs (NSAIDs, cyclo sporin, tacrolimus) \200 interstitial nephritis \200 urinary tract obstruction \200 s ickle cell disease \200 gout Genetic \200 Ehlers \200\223Danlos syndrome \200 Marfan \200\231s syndrome Inherited systemic diseases (Fanconi-like syndromes): \200 cystinosis \200 galactosemia \200 Wilson \200\231s disease \200 glycogen storage disease (type 1) \200 inherited fructose tolerance \200 tyrosinemia Disorders associated with hyperparathyroidism \200 primary hyperparathyroidism \200 vitamin D de \201 ciency \200 vitamin D resistance Immunological diseases \200 Sj gren \200\231s syndrome \200 systemic lupus erythematos us \200 primary biliary cirrhosis \200 chronic renal transplant rejection \200 hyperg ammaglobulinemia Diseases associated with nephrocalcinosis \200 vitamin D toxication \200 idiopathic hypercalcuria \200 primary hyperparathyroidism Distal tubule dysfunction \200 chronic tubulointerstitial disease Drugs/toxins \200 spironolactone \200 amiloride \200 triamterene \200 trimethoprim Drugs/toxins \200 lead poisoning \200 cadmium poisoning \200 mercury poisoning \200 acetazolamide \200 gentamicin and \200 topiramate and zonisamide Miscellaneous renal d iseases \200 multiple myeloma \200 amyloidosis \200 nephrotic syndrome \200 medulla ry cystic disease \200 renal transplantation (early) Drugs/toxins \200 amphotericin \200 toluene \200 lithium Signi \201 cant volume depletion CHAPTER 2.6 Clinical acid \200\223base disorders 67 An increased OG (particularly if >25 mOsm/kg) in the presence of a high AG metabolic acidos is, without evi- dence of lactic or ketoacidosis, should prompt treatment for methanol/ethy lene glycol intoxication (i.e. ethanol infusion) pending results of methanol and ethylene g lycol assays. Evaluation of metabolic acidosis The following investigations are required to evaluate pati ents with suspected metabolic acidosis (reduced serum bicarbonate). An algorithm for the ev aluation of such patients is described in Fig. 2.6.1. Renal tubular acidosis (RTA) Hyperchloremic, normal AG metabolic acidosis is the hall- mark of renal tubular acidosis. RTA results from a defect in tubular function which causes a de crease in either net tubular hydrogen secretion or \200\223 HCO3 There are three main type s of RTA: \200 type 1 (distal); \200 type 2 (proximal); \200 type 4. The causes of th ese forms of RTA and the clinical differ- ences between them are indicated in Tables 2.6.1 and 2.6.2 respectively. Renal tubular acidosis is discussed in more detail in Chapter 5.3. Initial investigations Step 1 Measure the blood pH on an arterial blood sample (arterial bl ood gasses (ABGs)) to: \200 con \201 rm the presence of acidemia \200\223 \200 exclud e respiratory alkalosis as cause of low HCO3 Step 2 Calculate the serum anion gap: \200 \223 + Cl \200\223) \200 Serum AG = Na+ \200\223 (HCO3 \200 (reference range 12 5 m mol/L) or \200 Serum AG = (Na+ +K+) \200\223 (HCO3 \200 (reference range 16 5 mmol/ L). In the critically ill patient, a correction for the albumin concentration (AGc) may be necessary: AGc = AG + 0.25[40 \200\223 albumin] reabsorption. \200\223 + Cl \200\223) Uremic acidosis Metabolic acidosis occurs in renal failure due to a decreased ability to ex crete H+ or due to an inability to produce ammonia. In the early stages of chronic kidney d isease (CKD) (GFR <40 mL/min), metabolic acidosis with a normal anion gap (AG) (see below) may become evident. As CKD progresses (GFR <20 mL/min) a high AG metabolic acidosis may res ult. In 80% of patients with CKD and GFR <20 \200\22330 mL/min, there is mild to moderate metabolic acidemia with the pH usually remaining >7.2 and bicarbonate levels of 12 \200\223 22 mmol/L. In advanced CKD an increased AG is typical due to the presence of retained acids such as sulfates, phosphates, urate and hippurate. The presence of normal AG acidosis in t his setting would imply a second pathology such as \200\223 wasting. HCO3 \200\223 concen tration <10 mmol/L and an AG A serum HCO3 >20 mmol/L are infrequent in renal failure and ma y be indicative of coexistent disorders, e.g. lactic acidosis or ketoacidosis. \200\223 an d pH in dialysis patients are Serum levels of HCO3 determined by the dialysis process, exog enous alkali inges- tion and endogenous acid production. \200\223] of 17.5 \200\223 In hem odialysis patients, a predialysis [HCO3 20 mmol/L has been shown to be associated with the lowest risk of death. Postdialysis metabolic alkalosis which may result from complete corre ction of predialysis metabolic acidosis may lead to hypoventilation, phosphate transfer int o cells and vascular calci \201 cation. Although there is no general agreed guidance on th e optimal pre-dialysis bicarbonate concentration, a value of 20 \200\22326 mmol/L has been recommended as good practice. The anion gap will be either: \200 normal: due to the presence of an acid in which the an ion is Cl \200\223 (hyperchloremic metabolic acidosis); or \200 high: due the presence of an acid in which the anion (unmeasured) is not Cl \200\223 The causes of \200\230normal \200\231 and \200\230high \200\231 AG metabolic acidosis are listed in Fig. 2.6.1. Investigations to determine the etiology of the acidosis \200 Serum electrolytes, urea, c reatinine (uremic acidosis). \200 Blood glucose (ketoacidosis). \200 Liver function tes ts (lactic acidosis). \200 Full blood count (sepsis and profound anemia). \200 Plasma l actate (lactic acidosis). \200 Serum osmolality. \200 Serum osmolal gap (methanol/ethyl ene glycol). \200 Urine pH (see Fig. 2.6.1). \200 Urine anion gap = Urine (Na+ + K+ \200\223 Cl \200\223) (see Fig. 2.6.1). \200 Toxin assays as appropriate, e.g. methanol, ethylene glycol, paraldehyde, salicylates, lead, mercury. Bacteriological culture(s) as appropriate. Serum osmolal gap (OG) This is the measured \200\223 calculated serum osmolality. Calculated osmolality = 2(Na+ + glucose + urea). Norm al OG is <10 mOsm/kg. An OG >10 mOsm/kg when accompanied by a high AG metabolic acidosis sh ould raise the possibility of methanol or ethylene glycol intoxication. However, late prese ntation after intoxication may show a normal OG and a raised AG. Ketoacidosis and lactic ac idosis can also increase the OG (usually by only a modest amount, i.e. <25 mOsm/kg), but th ese can usually be readily identi \201 ed (clinically and with urgent investigations). Eth anol will also increase the OG, making interpretation difficult. The measured ethanol conce ntration can be included in the calculated osmolality to correct for this. Lactic acidosis Lactic acidosis is classically de \201 ned as a plasma lactate level >5 mm ol/L associated with a high AG metabolic acidosis (lactate is the unmeasured anion). P. GUPTA AND W. MADIRA 68 Table 2.6.2 Clinical manifestations of renal tubular acidosis (RTA) Type 1 (distal RTA) Type 2 (proximal RTA) Type 4 (distal RTA) Low Low or normal Low (i urine bicarbonate) Increased High Plasma potassium Low Low Plasma bicarbonate Increased Increased Plasma chloride >5.5 <5.5 <5.5 or >5.5 Urine pH with acidosis <5% >10 \200\22315% <5 \200\22310% Fractional bicarbonate excretion Hypercalciuria and nephrolithiasis does not occur Nephrocalcinosis, rickets, osteomalacia and nephrolithiasis Rickets and osteomalacia (hypercalciuria and nephrolithiasis rare) Bone and calcium metabolism Good Fair Poor Response to treatment Lactate itself cannot be broken down for energy production. Reduction of pyruvate to lactat e is reversible and excessive production of lactate will lead to depletion of NADH. Approxi mately 1400 mmol of lactate are produced per day and under normal conditions the plasma lac tate level is maintained at 1 \200\2232 mmOl/L. This is achieved by the buffering capacity of bicarbonate and the metabolism of lactate by the liver (60%), kidneys (30%) and perhaps muscle. Approximately 50% of lactate is converted to glucose by gluconeugenesis and the re st is metabolized to pyruvate and then CO2 and H2O. From the above it can be seen that an i ncreased lactate concentration can result from three processes: 1 Increased pyruvate synthe sis with a normal lactate/pyru- vate ratio (glucose infusion, epinephrine administration, r espiratory alkalosis). Lactate usually <5 mmol/L. Table 2.6.3 Causes of lactic acidosis Type A lactic acidosis (tissue hypoxia) Left ventricular failure Septic shock Cardiogenic shock Hemorrhagic shock Respiratory failu re Carbon monoxide poisoning Acute anemia Methemoglobinemia Type B lactic acidosis (No tissue hypoxia) Renal failure Sepsis Hepatic failure Inborn errors of metabolism Leukemia, lymphoma, large tumors Grand mal seizures Strenuous muscular exercise Drugs or toxins 2 Increase in the NADH/NAD+ ratio resulting in an increased lactate/pyruvate ratio. Ethanol, methanol, ethylene glycol Biguanides Salicylates Isoniazid Iron Nitroprusside Cyan ide Nalidixic acid Paracetamol Cocaine, amphetamines Paraldehyde Theophylline Lactulose Par enteral nutrition Antiretroviral drugs 3 Combination of 1 and 2. This results in severe metabolic acidosis. Lactic acidosis is classi \201 ed into two types (A and B), and the causes are outlined in Table 2.6.3. D-Lactic acidosis Lactic acid exists in two forms: L-lactate and D-lactate. D-Lactate canno t be metabolized, and is produced by gut bacteria in patients with short bowel syndrome and other malabsorptive disorders. D-Lactate is not measured by the routine laboratory meth- o ds but can cause an increased AG metabolic acidosis. Ketoacidosis Diabetic ketoacidosis (DKA) DKA is characterized by hyperglycemia, usually wit h a high AG metabolic acidosis due to the accumulation of ketone bodies (acetoacetate, B-hy droxybutyrate). A normal AG metabolic acidosis may also be seen in DKA particularly when th e extracellular volume is near normal. Acetoacetate and B-hydroxybutyrate are metabolically interchangeable and the primary determinant of the bal- ance is the NADH/NAD+ ratio. A hig h ratio favors the formation of B-hydroxybutyrate and lactate. Glucose metabolism generates pyruvate during anaerobic glycolysis. Pyruvate is converted to lactate by reduction under anaer- obic conditions. The entry of pyruvate into the tricarbo xylic acid (TCA) cycle depends on aerobic oxidation. Glucose \206\222 pyruvate \206\224 l actate Pyruvate + NADH + H+ \206\224 lactate + NAD+ CHAPTER 2.6 Clinical acid \200\223base disorders 69 A relative or absolute insulin de \201 ciency and a compensa- tory rise in counter-regulat ory hormones such as glucagon, cortisol, growth hormone and catecholamines occur in all cas es of DKA. The usual precipitant of DKA is infection or inadequate/ missed insulin therapy. The severity of DKA is graded as: \200 moderate (when pH is 7.0 \200\2237.24); \200 se vere (when pH is <7.0). A pH <6.7 is thought to be incompatible with life. In DKA periphera l glucose utilization is impaired and glu- coneogenesis is stimulated. This results in an o smotic diu- resis leading to volume depletion and loss of electrolytes (sodium, potassium, magnesium, phosphate). Methanol Toxic exposure to methanol is usually through ingestion but may also occur by inha lation or absorption through the skin. Methanol is metabolized in the liver and converted t o for- maldehyde and formic acid which accounts for most of the toxic features. Methanol ha s few toxic effects before it is metabolized. In addition, lactic acid, keto acids, and oth er unidenti \201 ed organic acids may contribute to the metabolic acidosis. The toxic effe cts of methanol metabolites are pancreatitis, blindness, seizures and coma. A delayed onset parkinsonian syndrome may also develop due to hemorrhage in the putamen. Salicylate Adult patients with salicylate overdose usually present with respiratory alkalos is as a direct effect of salicylate poi- soning or have a mixed respiratory alkalosis \200 \223metabolic acidosis. Salicylate also uncouples oxidative phosphorylation, lead- ing to o verproduction of lactic and other organic acids. In children, ketoacid production may also be increased. Alcoholic ketoacidosis Alcoholic ketoacidosis is a recognized complication of ethanol abuse . The ketoacidosis occurs after binge drinking in chronic alcohol abusers who have decrease d food intake. It is often accompanied with gastritis, nausea, vomiting and abdomi- nal pai n, and occasionally with acute pancreatitis. The symptoms may render the patients incapable of fur- ther ethanol consumption, and at presentation ethanol may not be detectable in blo od. The acidosis is thought to be due to an exaggerated nor- mal response to fasting, i.e. low insulin levels and increased counter-regulatory hormones leading to lipolysis. Lactic a cidosis often coexists with ketoacidosis in alcohol abusers, in particular if hypoxia, hypo perfusion, hypother- mia and convulsions are present. Treatment principles in metabolic acidosis Patients with metabolic acidosis are often very ill and their condition tends to deteriorate rapidly. The cause of the acidosis should be e stablished quickly and accurately as treatment needs to be directed towards the underlying cause. Below are a few examples of speci \201 c treatments for under- lying disorders. Flu id, insulin and electrolyte replacement should be admin- istered for diabetic ketoacidosis. Severe lactic acidosis may be associated with a high mor- tality and if there is evidence of hypovolemia, \202 uid resusci- tation with colloid should be commenced promptly while the diagnosis is being established. Certain toxins may require speci \201 c antidotal ther apies (e.g. ethanol or fomepizole for methanol or ethylene glycol, pyridoxine for isoniazid ) and/or hemodialysis (e.g. lithium, salicylate, methanol, ethylene glycol). Hemodialysis i s often required for toxin-induced metabolic acidosis complicated by renal failure. The rou tine administration of sodium bicarbonate in meta- bolic acidosis is controversial. The pot ential complications of sodium bicarbonate admin- istration include volume overload, especi ally in patients with renal or cardiac function impairment, hypernatremia, hypokalemia, hyp ocalcemia and alkalosis. A rapid elevation of plasma sodium concentration may also occur wh ich can induce demyelination of subcortical brain structures. However, in cases of methanol or ethylene glycol poisoning, sodium bicarbonate should be given in order to maintain an a rterial pH of up to 7.2 (plasma bicarbonate of 10 mmol/L) whilst avoiding the adverse hemo dynamic effects. Starvation ketoacidosis Mild ketoacidosis may appear after an overnight fast but typically severe acidosis requires 3 \200\22314 days of starvation. This is accentuated by exercise a nd pregnancy. Similar to the ketosis of alcohol abuse, starvation ketoaci- dosis is also th ought to be due to an exaggerated normal response to fasting, with low insulin levels and i ncreased lipolysis. More fulminant ketoacidosis is unlikely as the islet cells respond to s ynthesis of ketone bodies by increasing insulin release which inhibits further lipolysis. T his compensatory process does not take place in patients with type 1 diabetes mellitus. Ethylene glycol The ingestion of ethylene glycol (motor vehicle antifreeze), typically by a lcoholics, leads to a high AG gap metabolic acidosis. The high AG is caused by the generati on of ethylene glycol metabolites, particularly oxalate, glycolate and glyoxylate. These me tabolites are more toxic than the parent com- pound and lead to an increase in the NADH/NAD + ratio, favoring the production of lactate from pyruvate. Ingestion of 50 \200\223100 mL of ethylene glycol may be enough to cause severe toxicity. A fatal dose is 100 mL. The ear ly toxic effects of ethylene glycol are cardiovascular collapse and noncardiogenic pulmonar y edema. Later \202 ank pain and renal failure ensue due to extensive intratubular calciu m oxalate crystal deposition. P. GUPTA AND W. MADIRA 70 If ethanol or fomepizole are not administered in methanol or ethylene glycol poisoning, org anic acids may continue to be produced. This may lead to the so-called bicarbonate- resista nt acidosis where the administration of larger amounts of bicarbonate may be required with the potential hemodynamic complications. In salicylate poisoning, bicarbonate should be giv en to maintain blood pH >7.4 to promote renal salicylate elimination and reduce salicylate penetration into the tissues. The amount of bicarbonate required (in mmol) can be estimated as follows: Systemic effects of metabolic alkalosis Pulmonary \200 Hypoventilation. \200 Impaired u nloading of oxygen peripherally (oxygen dissociation curve shifted to the left). Cardiovascular \200 Arrhythmias, especially in patients with hypoxemia. \200 Decreased myocardial contractility. \200 Nitric oxide-mediated vasodilatation. Nervous system \200 Decreased cerebral blood \202 ow. \200 Neuromuscular excitability. \200 Confusion, lethargy and seizures. Renal \200 Increased tubular reabsorption of calcium. Investigatio n of metabolic alkalosis Symptoms of metabolic alkalosis may be evident but the diagnosis i s made following routine biochemical investigations. The diagnosis of metabolic alkalosis i s often suspected from the clinical and drug history, physical examination and the presence of hypertension. \200\223 (mmol/L) \200\223 current plasma (target plasma HCO3 HCO3 \200\223 (mmol/L)) \227 40% of body weight (kg) The management of patients with severe me tabolic acido- sis should be carried out on the critical care unit and liai- son with the t oxicology/poison services is essential. Metabolic alkalosis Metabolic alkalosis is characterized by: \200 high arterial blood pH (alkalemia); \200 increased serum HCO3 \200 increased PCO2 (from respiratory compensati on). The clinical effects of metabolic alkalosis are in part due to coexisting problems suc h as hypovolemia, hypokalemia, hypophosphatemia, reduced ionized calcium concentration and chloride depletion. \200\223 concentration; Routine biochemical investigations \200 Arterial blood gas analysis: con \201 rm the presence of alkalemia; \200\223. exclude respiratory acidosis as cause of high HCO3 \200 Serum urea, creatinine, electrolytes, chloride and bicar- \200 Etiology of metabolic alkalosis Metabolic alkalosis may result from: \200 alkali administ ration; \200 accumulation of HCO3 \200 HCO3 bonate. due to acid loss; \200\223 retention or intracellular shift of H+ as occurs in Spot urine sodium, potassium, chloride and pH. \200 ECG. Specialized investigations \200 Plasma renin activity and aldosterone concentration. \200 Serum cortisol and ACTH conce ntration. \200 Urine laxative and diuretic assay. An algorithm for the evaluation of pati ents with suspected metabolic alkalosis is described in Fig. 2.6.2. In addition, the follow ing points can help to clarify the underlying cause of the metabolic alkalosis. hypokalemia. Exogenous alkali \200 Antacids, milk alkali syndrome. \200 Sodium bicarbonate, sodium c itrate, gluconate, acetate administration. Massive blood transfusion. Loss of hydrogen \200 Gastrointestinal loss: vomiting; nasogas tric suction; chloride losing diarrhea; villous adenoma; antacid therapy; laxative abuse. \200 \200 \200 \200 \200 Chloride-responsive alkalosis A urine chloride <10 mmol/L. In the presence of normotension the causes include: \200 vomiting; \200 nasogastric aspiration; \200 diuretics; \200 potassium de \201 ciency; \200 bicarbonate therapy; \200 diarrhea; \200 ingestion of nonabsorbable antacids. Chloride-resistant alkalosis A urine chloride >20 mmol/L. In the presence of normotension or hypotension causes include: \200 severe magnesium de \201 c iency; \200 severe potassium de \201 ciency; Renal loss: loop and thiazide diuretics; mineralcorticoid excess (renovascular hypertension, primary al doesteronism, Cushing \200\231s, liquorice); hypercalcemia; magnesium de \201 ciency; Bart ter \200\231s syndrome; Gitelman \200\231s syndrome; Liddle \200\231s syndrome. H+ redistri bution into cells \200 Hypokalemia. \200 \200 \200 \200 \200 CHAPTER 2.6 Clinical acid \200\223base disorders 71 High serum bicarbonate ? Metabolic alkalosis ? Compensated respiratory acidosis Arterial blood gasses High pH High pCO2 High HCO3 \200\223 Metabolic alkalosis \210\222 \210\222 Urine [Cl Prior diuretic use Vomiting Upper gastrointestinal losses Chloride depleting diar rhea Congenital chloride diarrhea Villous adenoma of the colon ] <10 mmol/L Urine [Cl ] >20 mmol/L Normal BP Diuretic use Bartter \200\231s syndrome Gitelman \200\231s syndrome High BP High renin Renal artery stenosis Hypertension with diuretic use Malignant hypertension Reni n-secreting tumor Low renin Low aldosterone Cushing \200\231s syndrome Apparent mineralocorticoid excess Licorice inges tion Liddle \200\231s syndrome High aldosterone Primary aldosteronism Glucocorticoid remediable aldosteronism Fig. 2.6.2 Algorithm for the investigation of metabolic alkalosis. Bartter \200\231s syndrome; \200 Gitelman \200\231s syndrome; \200 diuretics. In the pr esence of hypertension causes include: \200 primary hyperaldosteronism; \200 Cushing \200\231s syndrome; \200 renal artery stenosis; \200 congenital adrenal hyperplasia (11 B-hydroxylase or 17A- However, if the patient is edematous, normal saline should be avoided. Potassium-sparing di uretics (e.g. spironolac- tone, amiloride, triamterene) or a carbonic anhydrase inhibitor ( acetazolamide) may be used to correct the alkalosis. Chloride-resistant alkalosis A urinary chloride >20 mmol/L suggests a chloride- unresponsive form of alkalosis and these patients rarely bene \201 t from volume expansion. Treatment of chloride- resistant metabolic alka losis will depend on the underlying etiology, e.g. primary hyperaldosteronism may be treate d with aldosterone antagonists, adrenal adenoma or carci- noma with surgery, and glucocorti coid remediable hyperal- dosteronism with dexamethasone. In severe metabolic alkalemia (e.g . pH >7.6), particularly if associated with \202 uid overload, hemodialysis/hemo \201 lt ration may be required. hydroxylase de \201 ciencies); apparent mineralcorticoid excess; \200 renin producing tumor; \200 Liddle \200\231s syn drome. Treatment of metabolic alkalosis The underlying cause must be identi \201 ed and tr eated, with particular attention to the correction of hypovolemia and hypochloremia. Chlori de-responsive alkalosis Urinary chloride <10 mmol/L indicates signi \201 cant renal chlori de reabsorption and hence a chloride-responsive cause; therefore these patients should be t reated with nor- mal saline until the urinary chloride rises to >25 mmol/L and the urine pH normalizes. If chloride-responsive alkalosis occurs with volume deple- tion, it should be treated with normal saline; if there is associated hypokalemia, this should be treated with potas- sium replacement. Respiratory acidosis Respiratory acidosis is characterized by: \200 low arterial blood pH (acidemia); \200 increased PCO2; \200 normal or increased serum HCO3 \200\223 concentration (due to renal compensation). Respiratory acidosis and elevated PCO2 (hypercapnia) is due to alveolar hypoventilation whi ch results in a lower HCO3 \200\223/PCO2 ratio and a decreased blood pH. P. GUPTA AND W. MADIRA 72 Thus, hypercapnia and respiratory acidosis occur when there is an imbalance between the pro duction of CO2 by the tissues and its elimination by the lungs. Respiratory acidosis can be acute such as when there is abrupt failure of ventilation, or chronic such as in chronic o bstructive pulmonary disease (COPD). Respiratory acidosis results from: \200 severe pulmo nary disease; \200 respiratory muscle fatigue; \200 depression of the ventilatory drive . Etiology of respiratory acidosis Lung/chest disorders \200 Emphysema, COPD, asthma. \200 Laryngospasm. \200 Restrictive lung disease. \200 Aspiration. \200 Pneumoconios is. \200 Bronchitis, infections. \200 Pulmonary edema. \200 Respiratory distress synd rome. \200 Inadequate mechanical ventilation. \200 Chest trauma: \202 ail chest, cont usion, hemothorax. Neuromuscular disease \200 Diaphragm paralysis. \200 Severe kyphosco liosis. \200 Guillan \200\223Barr syndrome. \200 Muscle relaxant drugs. \200 Multip le sclerosis. \200 Poliomyelitis. \200 Tetanus. \200 Myasthenia gravis. \200 Variou s myopathies. \200 Toxins, e.g. organophosphates, snake venom. Central nervous system dis ease (with a direct effect on the respiratory center) \200 Drugs: narcotics, sedatives, a nesthetics, alcohol Depending on the degree of hypercapnia, the clinical effects of a rapid increase in PCO2 ma y result in: \200 increased intracranial pressure; \200 anxiety; \200 confusion; \200 psychosis; \200 hallucinations; \200 depressed tendon re \202 exes. If severe an d prolonged this may progress to: \200 stupor; \200 seizures; \200 coma; \200 death . In chronic hypercapnia, the clinical effects may be less severe and include: \200 heada ches (due to the vasodilator effects of CO2); \200 personality changes; \200 daytime so mnolence; \200 sleep; \200 memory and motor disturbances e.g. tremor, myoclonic jerks. The effects of hypercapnia on the respiratory system include breathlessness, central and pe ripheral cyanosis (especially when breathing room air) and pulmonary hypertension. The effe cts on the cardiovascular system are varied and will also depend on the severity of the hyp ercapnia. These include warm/ \202 ushed skin, bounding pulse, diaphoresis, cor pulmonale, decreased cardiac output with systemic hypotension, cardiac arrhythmias, renal impairment and peripheral edema. When there is concomitant renal impairment, mixed acid \200\223base d isturbances should be suspected. Investigation of respiratory acidosis The clues to the diagnosis of respiratory acidosis ca n be obtained from a detailed history, physical examination and ultimately measurement of a rterial blood gasses. Investigations include Arterial blood gas analysis: \200 con \201 rm the presence of aci demia; \200\223. \200 exclude metabolic alkalosis as cause of high HCO3 If chronic respi ratory acidosis then the pH may be normal. Serum/plasma urea, creatinine, electrolytes, bic arbonate (usually a compensatory rise in HCO3 Full blood count: in chronic hypercapnia, pat ients may have secondary polycythemia. Drug screens as appropriate. Chest X-ray. CT and MRI scans of the chest and brain as appropriate when chest radiography inconclusive. Pulmonary function tests, e.g. spirometry. intox ication. Cerebrovascular disorders. \200 CNS infections/encephalitis. \200 CNS trauma, infarct, hemorrhage or tumor. \200 Primary alveolar hypoventilation. Miscellaneous causes \200 O besity. \200 Cervical cord trauma/lesions. \200 Cardiac arrest with cerebral hypoxia. S ystemic effects of respiratory acidosis The systemic and clinical effects of respiratory ac idosis will vary depending on its severity and duration, the underlying cause, and the seve rity of accompanying hypoxemia. In acute respiratory acidosis, the initial response is cell ular buffering which occurs over minutes or hours and slightly \200\223. This is followed by renal compen- elevates plasma HCO3 sation in the next 3 \200\2235 days when carbonic aci d excretion \200\223 reabsorption are both increased. and HCO3 The acidosis tends to incre ase the concentration of plasma ionized calcium and causes the extracellular shift of potas sium. These changes are rarely signi \201 cant, however. ). Treatment of respiratory acidosis The treatment of respiratory acidosis will depend on its severity, rate of onset, and etiology. The underlying cause must be identi \201 ed and tre ated, and adequate alveolar ventilation must be restored; mechanical ventilation may even b e required. CHAPTER 2.6 Clinical acid \200\223base disorders 73 Aspiration. \200 Right-to-left shunts. Stimulation of chest receptors \200 Pneumothorax /hemothorax. \200 Pneumonia. \200 Pulmonary edema, pulmonary embolism. \200 Aspiratio n. \200 Flail chest. \200 Cardiac failure. \200 Interstitial lung disease. Miscellane ous \200 Septicemia. \200 Mechanical ventilation. \200 Heat exhaustion. \200 Recove ry phase of metabolic acidosis. \200 Thyrotoxicosis. Systemic effects of respiratory alka losis The systemic and clinical effects of respiratory alkalosis will depend primarily on t he duration, severity and underlying cause. The cardiovascular effects of acute hypocapnia are gener- ally minimal in the awake individual but may be signi \201 cant in anesthetized or mechanically ventilated patients. This may be due to a concomitant fall in cardiac outp ut and systemic blood pressure resulting from the effects of seda- tion and positive pressu re ventilation on venous return, systemic vascular resistance and heart rate. Cardiac contr actility may also be reduced in patients with hypocapnia. Patients with ischemic heart dise ase and respiratory alka- losis are more susceptible to cardiac arrhythmias as a result of the left shift in the hemoglobin \200\223oxygen dissociation curve, thus impairing oxygen u nloading. Acute hypocapnia may cause cerebral vasoconstriction, leading to reduced blood \202 ow, resulting in a variety of neu- rological symptoms. These include: \200 paresthes ias (circumoral tingling, numbness); \200 tetany and carpopedal spasm; \200 dizziness; \200 mental confusion; \200 syncope; \200 seizures. Acute respiratory alkalosis may a lso result in reduced ion- ized calcium, intracellular shifts of potassium and phos- phate but these effects are rarely signi \201 cant. Oxygen should be used with care in patients with severe COPD who are breathing spontaneousl y. In this situation, aggressive use of oxygen may worsen respiratory acidosis (through los s of hypoxic respiratory drive). Furthermore, rapid correction of hypercapnia may pro- voke complications such as cardiac arrhythmias and reduced cerebral perfusion which may lead to seizures. In chronic respiratory acidosis, general measures such as cessation of cigarette smoking, use of oxygen, bronchodila- tors, corticosteroids and diuretics should be careful ly considered. Respiratory alkalosis Respiratory alkalosis is characterized by: \200 high arterial blood pH (alkalemia); \200 reduced PCO2; \200 normal or reduced serum HCO3 \200\223 concentration (due to renal compensation). Respiratory alkalosis and decreased PCO2 (hypocapnia) is due to increased alveolar ventilat ion which increases the HCO3 Thus hypocapnia develops when ventilation is increased and the elimination of PCO2 from the lungs is increased relative to its production in the tissues. The most commonly observed acid \200\223base disturbance in critically ill patients is res piratory alkalosis and when severe it is associated with a poor prognosis. It may be associ ated with mechanical ventilation and many cardiopulmonary disorders. Increased bicarbonate excretion occurs in acute respira- tory alkalosis and within hours is followed by reduced n et acid excretion. In chronic hypocapnia, the serum bicarbonate concentra- tion is reduced but rarely falls to <12 mmol/L in uncompli- cated respiratory alkalosis. \200\223/PCO2 ratio as well as the blood pH. Etiology of respiratory alkalosis Central nervous system disease (with a direct effect on t he respiratory center) \200 Head injury. \200 Pain. \200 Anxiety, psychogenic. \200 Fever. \200 Meningitis/encephalitis. \200 Cerebovascular accident. \200 Tumor. \200 Trauma. \200 Various endogenous toxins, e.g. toxins in patients with chronic liver dise ase, progesterone in pregnancy, cytokines during sepsis. Investigation of respiratory alkalosis The diagnosis and evaluation of respiratory alkalosi s requires measurement of arterial pH and PCO2 as well as a detailed clinical history and p hysical examination. Drugs \200 Salicylates. \200 Analeptics (respiratory stimulants). \200 Methylxanthine s. \200 Nicotine. Hypoxemia \200 High altitude. \200 Severe anemia. \200 Pneumonia. \200 Pulmonary edema Investigations include Arterial blood gas analysis: \200 con \201 rm the presence of alkalemia; \200\223. \200 exclude metabolic acidosis as cause of low HCO3 Serum/plasma urea, creatinine, electr olytes, bicarbonate and chloride. Drug screen as appropriate. Chest X-ray. P. GUPTA AND W. MADIRA 74 In the evaluation of a patient suspected of hyperventilation syndrome, the organic and meta bolic disorders such as pulmonary embolism, cardiac ischemia and hyperthy- roidism should b e considered and excluded. Kraut JA, Krutz I. Metabolic acidosis of CKD: diagnosis, clinical char- acteristics and treatment. Am J Kidney Dis 2005; 45: 978 \200\223993 Kraut JA, Krutz I. Use of base in the treatment of severe acidaemic states. Am J Kidney Dis 2001; 38: 703 \200\223727. Morgan TJ. What exactly is the strong ion gap and does anybody Treatment of respiratory alkalosis As respiratory alkalosis is rarely life-threatening, tre atment should focus on identifying and alleviating the underlying cause. Rebreathing from a paper bag during symptomatic attacks, reassurance, and awareness of the underlying psychol ogi- cal stress are useful in the management of patients with the hyperventilation syndrome . care? Crit Care Resusc 2004; 6: 155 \200\223159. Penney MD, Oleesky DA. Renal tubular acidosis. Ann Clin Biochem 1999; 36: 408 \200\223422. Schwartz GJ. Plasticity of intercalated cell polarity: effect of meta- bolic acidosis. Nephron 2001; 87: 304 \200\223313. Wagner CA, et al. Renal acid \200\223base transportation: old and new players. Nephron Physiol 2006; 103: 1 \200\2236. Internet resources The Renal Association (2007) Clinical Practice Guidelines: Further reading Chairat SA, Seth LA. Inherited renal tubular acidosis. Curr Opin http://www.renal.org/guidelines/index.html Review of the management of metabolic acidosis: Nephrol Hypertens 2000; 9: 541 \200\223546. Dubin A, et al. Comparison of three different methods of evaluation of metabolic acid \200 \223base disorders. Crit Care Med 2007; 35: 1264 \200\2231270. http://www.intox.org/databank/documents/treat/ treate/trt34_e.htm Review of the management of metabolic alkalosis: Dubose Jr, TD. Acid \200\223base disorders. In: Brenner BM (ed.), Brenner and Rector \200 \231s \200\234The Kidney \200\235. Philadelphia: WB Saunders; 2004. pp. 921 \200\223996. http://www.intox.org/databank/documents/treat/ treate/trt35_e.htm Review of renal physiolog y: English P, Williams G. Hyperglycaemic crises and lactic acidosis in diabetes mellitus. Postgrad Med J 2004; 80: 253 \200\223261 Fall PJ, Szerlip HM. Lactic acidosis: from sour milk to septic shock. http://www.brucegilbertmd.com/publications/ chapters/BRGcambells.htmL Review of acid \200 \223base disorders: J Intens Care Med 2005; 20: 255 \200\223271. Figge J, et al. Anion gap and hypoalbuminaemia. Crit Care Med 1998; 26: 1807 \200\2231810. Gluck SL. Acid \200\223base. Lancet 1998; 352: 9126. Heusel JW, Siggaard-Andersen O, Scott MG. Physiology and disor- ders of water, electrolyte, and acid \200\223base metabolism. In: Burtis CA, Ashwood ER (eds), Tietz Textbook of Clinical Chemistry. Philadelphia: Saunders; 1999. pp. 1095 \200\223124. http://www.kidneyatlas.org/book1/adk1_06.pdf Overview of acid \200\223base physiology: http://www.anaesthesiamcq.com/AcidBaseBook/ ABindex.php Hood VL, Tannen RL. Mechanisms of disease: protection of acid \200\223base balance by pH re gulation of acid production. N Engl J Med 1998; 339: 819 \200\223826. See also Hypo-/hyperkalemia, p. 46 Renal tubular acidosis, p. 208 Hypokalemic tubular disorders, p. 214 Dialysis and hemoperfusion treatment of acute poisoning, p. 336 Kellum JA, et al. The \201 rst international consensus conference on continuous renal rep lacement therapy. Kidney Int 2002; 62: 1855 \200\2231863. Kopple JD, Kalantar-Zadeh K, Mehrotra R. Risks of chronic meta- bolic acidosis in patients with chronic kidney disease. Kidney Int 2005; 67: S21 \200\223S27. 75 Chapter 3 Glomerular disease Chapter contents Proteinuria and/or hematuria 76 Nephrotic syndrome 80 Minimal change disease 86 Focal segme ntal glomerulosclerosis 92 Immunoglobulin A nephropathy and Henoch \200\223Sch nlein purpu ra 100 Membranous nephropathy 106 Mesangiocapillary glomerulonephritis 112 Acute endocapill ary glomerulonephritis 116 Crescentic glomerulonephritis 120 Antiglomerular basement membra ne (Goodpasture \200\231s) disease 124 Infection-related glomerulonephritis 128 Malignancy- associated glomerular disease 134 Glomerular disease in the tropics 138 J. FEEHALLY 76 Proteinuria and/or hematuria