Management Potassium replacement is the mainstay of treatment. As a guide, a 0.3mmol/l fall in serum potassium corresponds to a 100mmol total body de \201 cit. This is unreliable wh en hypokalaemia has been caused by intracellular shift of K+. Potassium chloride can be adm inistered orally or through a nasoenteric tube in divided doses up to 100mmol/day. Potassiu m phosphate and potassium bicarbonate are alter- natives in the presence of hypophosphataem ia and acidae- mia, respectively. Oral potassium supplementation has an unpleasant taste, a nd may cause GI erosion. IV potassium supplementation will rapidly correct hypoka- laemia. When administering potassium through a periph- eral vein, the concentration should not exce ed 80mmol/l, as it may cause pain and thrombophlebitis. Adminstration through a central ven ous line allows higher concentrations to be used. The rate of infusion of potassium should not Membrane stabilization Increase intracellular shift of K+ Increase K+elimination GI binding of K+ 411 CHAPTER 24.1 Electrolyte disorders Treatment Dose Mechanism of action Plasma Ca2+ 2.50mmol/l Calcium gluconate 10% 10ml over 5 \200\22310min Membrane stabilization Insulin 10U in 50ml 50% dextrose Intracellular shift Protein bound 1.16mmol/l Diffusible 1.34mmol/l Sodium bicarbonate 50 \200\223100mmol Intracellular shift Salbutamol 5mg nebulized Intracellular shift Ionized Ca2+ 1.18mmol/l Complexed 0.16mmol/l Globulins 0.24mmol/l Albumin 0.92mmol/l Furosemide 20 \200\223250mg IV Increased elimination Haemodialysis Increased elimination Sodium polystyrene sulfonate 30g oral or rectal, then 15mg 3x day GI binding Causes \200 \200 Iatrogenic End-stage renal disease. Magnesium The majority (99%) of magnesium is found intracellularly in bone, muscle and soft tissue. Normal serum levels are 0.7 \200\2231.05mmol/l. It acts as a physiological antagon ist to cal- cium and is a cofactor in all ATP reactions and numerous other enzyme reactions . Absorption of magnesium is through the small intestine. It is reabsorbed by the kidney, s o that only 1% of \201 ltered magnesium is excreted in the urine. Parathyroid hormone inc reases GI absorption and reduces renal excretion, whereas renal excretion is increased by a ldos- terone. Magnesium is used therapeutically in acute severe asthma, torsades de pointes , digoxin toxicity, atrial and ventricular arrhythmias, pre-eclampsia and eclampsia. Its us e following AMI is debatable. Clinical features Usually well tolerated, but it can cause nausea and vomit- ing. Deep tend on re \202 exes are lost, and at higher levels res- piratory paralysis can occur. Cardiova scular symptoms are of hypotension, bradycardia and increased PR interval and/ or QRS durat ion on the ECG. Management Stop magnesium administration. If necessary, systemic effects can be antagonized in severe cases by IV calcium (e.g. calcium chloride 0.5 \200\2231mg over 5 \200\22310min) . Its excretion can be increased by \202 uid administration, loop diuretics or haemodialy sis. Calcium Calcium is integral to excitation \200\223contraction coupling in myocardial, smoot h and skeletal muscle. It is also essential in bone metabolism, cardiac automaticity, coagu lation, hor- mone secretion and nerve conduction. 99% of the body \200\231s calcium is skel etal, <1% is in the plasma. Total plasma calcium level is 2.5mmol/l, and 40 \200\22350% is bound to plasma proteins. Calcium binding to plasma pro- teins is reduced by metabolic acid osis. Calcium is absorbed from the GI tract in a process regu- lated by 1,25-dihydroxychole calciferol. Parathyroid hor- mone and 1,25-dihydroxycholecalciferol promote Ca2+ release fr om bone stores. It is excreted in the kidneys, where it is \201 ltered then 99% reabsorbe d. Hypomagnesaemia Hypomagnesaemia is de \201 ned as a serum Mg2+ <0.7mmol/l, although serum levels do not correlate well with intracellular levels. It may occur in up to 65% of critic ally ill patients, and has been associated with an increased mor- tality. Causes \200 \200 Inadequate intake: malnutrition, alcoholism Excess GI losses: NG tube, small intestine dise ase, mal- absorption, diarrhea Renal loss: aminoglycosides, amphotericin, dopamine, diureti cs Chelation: citrate in blood transfusion Redistribution: refeeding syndrome, catecholamin es. Hypocalcaemia Falsely low plasma calcium levels can occur in the pre- sence of hypoalbumina emia, therefore ionized Ca2+ or corrected serum Ca2+should be used. Hypocalcaemia is de \201 ned as a serum calcium <2.0mmol/l or an ionized Ca2+ <1.1mmol/l. Corrected Ca2+(mmol/l ) = measured x [40 \200\223 albumin(g/l)] x 0.02 \200 Clinical features Cardiovascular features of hypomagnesaemia include hypertension, angina a nd arrhythmias (typically torsades de pointes). The neuromuscular signs are of stridor, dys phagia, myoclonus and tetanus. Seizures and coma can also be seen. Hypomagnesaemia is assoc iated with hypokalaemia, and hypocalcaemia Causes \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Septic shock Renal insuf \201 ciency Hypomagnesaemia, hyperphosphataemia Malignancy Pancre atitis Rhabdomyolysis Hypoparathyroidism Pseudohypoparathyroidism Post-parathyroidectomy Vi tamin D de \201 ciency Management Oral or IV supplementation; oral magnesium is poorly tol- erated \200\224GI upse t. IV doses of 8 \200\22364mmol can be used, at a maximum infusion rate of 8mmol/h in asymp tomatic patients. In severe symptomatic hypomagnesaemia, 8mmol can be given over 5min. Smal ler doses may be necessary in renal failure. Hypermagnesaemia Hypermagnesaemia is a plasma concentration >1.05mmol/l. It is usually iatr ogenic. 412 P O NEIL & N WEBSTER Clinical features Neuromuscular features predominate, with paraesthesia, muscle cramps, tet any, laryngospasm and seizures. Cardiovascular features include hypotension, bradycardia an d prolongation of the QT interval. Reduce bone resorption: bisphosphonates will reduce Ca2+ levels over days \200 \200 Tre at underlying disease: parathyroidectomy in hyper- parathyroidism Other treatments: glucoco rticoids, plicamycin, calcitonin and gallium nitrate have been used. Etidronate 7.5mg/kg/day over 4h for 3 \200\2237 days Pamidronate 60 \200\22390mg over 4h Management Chronic hypocalcaemia is treated with oral calcium supplementation. In severe hy pocalcaemia or sympto- matic patients, rapid correction is indicated. This is achieved usin g IV calcium gluconate 10% 10ml (94mg Ca2+) or calcium chloride 10% 10ml (272mg Ca2+) over 10min. It should be remembered that calcium salts are irritant to veins, so should ideally be given through central venous access. Calcium salts can precipitate if infused with sodiu m bicarbonate. Calcium administration to patients on digoxin may cause toxicity, so extra m onitoring is needed. Other considerations are to check and correct hypomag- nesaemia, and t o correct hypocalcaemia prior to correct- ing acidosis. Hyperphosphataemia may occur with h ypocalcaemia, and administration of calcium can lead to precipitation of calcium phosphate in tissues. Therefore, if hyperphosphataemia is present, a phosphate binder should be given . Phosphorus Phosphorus is found predominantly (85 \200\22390%) in the skele- ton. It is a vi tal constituent of ATP, cAMP and 2,3-diphos- phoglycerate. In serum, phosphorus is mostly p resent as phosphate, and normal levels are 0.8 \200\2231.4mmol/l. GI absorp- tion of phosph orus is increased by 1,25-dihydroxycholecal- ciferol. Phosphorus is filtered through glomer uli, and 85 \200\22390% reabsorbed in the proximal tubule. This process is inhibited by par athyroid hormone. Hypophosphataemia Hypophosphataemia is defined as a serum phosphate <0.75mmol/l, severe if <0.4mmol/l. It is worse in the pres- ence of hypomagnesaemia. Causes Redistribution \200 \200 \200 \200 Hypercalcaemia Hypercalcaemia is de \201 ned as a total serum calcium con- centration >2.5 5mmol/l. Refeeding following malnutrition Respiratory alkalosis Sepsis Drugs: insulin, epinephrine, glucose Causes \200 \200 \200 Primary hyperparathyroidism Malignancy Drugs: thiazide diuretics, lithium, vitamin D toxici ty, the- ophylline Hyperthyroidism Immobilization Rhabdomyolysis Granulomatous disease: tub erculosis, sarcoidosis Familial hypercalcaemia Phaeochromocytoma. Reduced GI absorption \200 \200 \200 Malabsorption Vitamin D de \201 ciency Diarrhea \200 \200 \200 \200 \200 Urinary excretion \200 \200 \200 \200 Hyperparathyroidism Renal tubular disorders Renal transplantation Metabolic or respiratory acidosis Clinical features Hypophosphataemia can cause a wide range of symptoms. Cardiac contractili ty is reduced and cardiomyopathy can occur. Respiratory function is impaired through a redu c- tion in diaphragmatic contractility. Haemolysis and throm- bocytopaenia also occur. CNS effects range from paraesthesia to seizures and coma. There may be paralysis and weakness o f skeletal muscle. Tissue hypoxaemia is mediated by reduced 2,3-DPG causing increased haemo - globin af \201 nity for oxygen. Clinical features The symptoms of hypercalcaemia usually correlate with the speed and sever ity of calcium rise. Mild hyperca- laemia is usually asymptomatic. At higher Ca2+ levels ne urological symptoms occur: depression, weakness, lethargy, even coma. GI effects of nausea, vomiting and anorexia can be seen. The cardiovascular effects are hyper- tension and arrhy thmias. Nephrogenic diabetes insipidus may cause hypovolaemia. Nephrolithiasis, metastatic calci \201 cation and renal failure may be seen with chronic hypercalcaemia. Management Serum phosphate concentrations should be kept within normal limits. Oral phospha te supplementation can be achieved with sodium or potassium phosphate. They may cause diarr hea and may not be absorbed. IV phosphate supplementation can be used in symptomatic patien ts and those with severe hypophosphataemia. Potassium or sodium phosphate can be used, dilu ted in 0.9% sodium chloride and infused over 6h to reduce the incidence of thrombophlebitis and severe hypocalcaemia. Patients with renal failure should receive 50% of the usual dose , although those on continuous RRT may have higher phosphate requirements. Management Mild-moderate hypercalcaemia (Ca2+ 2.58 \200\2233.23mmol/l) \200 \200 \200 \200 Severe hypercalcaemia (Ca2+ >3.24mmol/l) \200 \200 Hydration Mobilization Stop medications which may cause hypercalcaemia Surgery if due to pr imary hyperparathyroidism. Volume repletion: IV 0.9% sodium chloride 200 \200\223300ml/h Enhance renal excretion: \200 \200 furosemide 40 \200\223100mg 1 \200\2234 hourly haemodialysis 413 CHAPTER 24.1 Electrolyte disorders >4.6mmol2/l2 is associated with increased risk of tissue deposition of calcium phosphate. Hyperphosphataemia Serum phosphate levels >1.45mmol/l de \201 ne hyperphos- phataemia. Management The optimum management of hyperphosphataemia is to treat the underlying cause. O ral phosphate binders can reduce GI absorption. Causes Factitious \200 Haemolysis Increased intake \200 Further reading Bushinsky DA, Monk R Electrolyte quintet: calcium. Lancet 1998; Iatrogenic: excess phosphate administration 352: 306 \200\22311. Increased release from cells \200 \200 \200 \200 Halperin ML, Kamel KS. Electrolyte quintet: potassium. Lancet 1998; Respiratory or metabolic acidosis Rhabdomyolysis Tumor lysis syndrome Bowel infarction Redu ced excretion \200 \200 352: 135 \200\22340. Kraft MD, Btaiche IF, Sacks G, et al. Treatment of electrolyte disor- ders in adult patient s in the intensive care unit. Am J Health Syst Pharm 2005; 62: 1663 \200\22382. Rastergar A, Soleimani M. Hypokalaemia and hyperkalaemia. Postgrad Med J 2001; 77: 759 \200\22364. Renal insuf \201 ciency Hypoparathyroidism Weisinger JR, Bellorin-Font E. Electrolyte quintet: magnesium and phosphorus, Lancet 1998; 352: 391 \200\2236. Clinical features A rapid increase in serum phosphate levels causes hypocal- caemia and tet any. A serum calcium x serum phosphorus 414 DC BERGMANS Hyponatraemia Hyponatraemia is de \201 ned as a serum sodium <135mmol/l. Since most critically ill patie nts in the ICU have an impaired capacity of renal water excretion, hyponatraemia is almost always caused by an excess of total body water. Hyponatraemia due to an excess of total bod y water will not normalize with supplementation of saline. Hypona- traemia needs to be corr ected quickly in the presence of neurological symptoms (convulsions or coma), which is ofte n the case when hyponatraemia has developed rapidly. Correct rapidly if onset rapid, correc t slowly if onset slow. If correction of hyponatraemia is too rapid or too much it may prec ipitate the development of central pontine demy- elination with permanent neurological dama ge. Urine osmolality (mOsm/kg) Urine sodium (mmol/l) Cause <100 <25 Excessive water intake, TURP syndrome >100 <25 Decreased circulating volume >100 >40 SIADH, adrenal insuf \201 ciency, diuretic use, renal failure, cerebral salt wasting, salt -losing nephritis, hypothyroidism Clinical features Clinical features are secondary to intracellular cerebral oedema and incr eased ICP, are variable in presentation and depend strongly on the speed of serum sodium de crease. In sedated, mechanically ventilated intensive care patients, clinical features may be undetectable on clinical examina- tion. \200 Infusate Na+ (mmol/l) Infusate 5% sodium chloride in water 855 3% sodium chloride in water 513 0.9% sodium chloride in water 154 Serum sodium <120mmol/l (acutely): headache, agita- tion, nausea, vomiting, and lethargy Se rum sodium <120mmol/l (chronic): clinical features may be totally absent Serum sodium <110m mol/l: convulsions, coma cause. Supportive therapy should be provided if necessary. Patients with symptomatic hypona traemia due to decreased circulating volume, adrenal insuf \201 ciency or diuretic use req uire saline infusion. In the case of SIADH, congestive heart failure and exces- sive water intake, the patient requires water restriction and close observation. Severe symptoms call for infusion of hypertonic saline, if necessary in combination with furo- semide. Isotonic saline is not helpful in this condition. In general, a serum sodium >120mmol/l is asymptoma tic, rapid correction is unnecessary and should not exceed 0.5mmol/l/h. In case of symptoma tic hyponatraemia with serious neurological manifestations, rapid correction at a rate of 1 \200\2232mmol/l/h is indicated until cessation of life- threatening manifestations or the achievement of a serum sodium concentration of 120mmol/l, and no faster than 0.5mmol/l/h on ce this value is achieved. The targeted rate of correction should not exceed 10mmol/l on an y day of treatment. The rate of infusion of saline solutions can be derived by applying the formula: Change in serum Na+ = infusate Na+ \200\223 serum Na+ Differential diagnosis 1 Decreased circulating volume (GI or renal loss, burn wounds, heart failure, liver cirrhosis) 2 Syndrome of inappropriate ADH secretion (SIADH) (post-operative, pulmonary diseases, neur opsychiatric, intoxication, malignancy) 3 Adrenal insuf \201 ciency 4 Diuretic use (mainly thiazide) 5 Cerebral salt wasting (main ly in the case of SAH) 6 Renal failure 7 Excessive water intake 8 Salt-losing nephritis 9 T ransurethral resection of prostate (TURP) syndrome 10 Hypothyroidism Laboratory analysis Plasma osmolality, urine osmolality and urine sodium. When indicated: p otassium, creatinine, urea, glucose, urine- acid, TSH, FT4. total body water + 1 which estimates the effect of 1l of infusate on serum sodium. Dividing the change in serum sodium targeted for a given treatment period by the result of the formula determines the vo lume of infusate required and the rate of infusion. The sodium concentrations of commonly u sed infusates are presented above. The estimated total body water (in litres) is calculated as a fraction of body weight, 0.6 and 0.5 in non-elderly men and women, respectively; and 0.5 and 0.45 in elderly (age >65ys) men and women, respectively. Diagnosis Plasma osmolality is always decreased (<280mOsm/kg) and therefore urine osmolalit y should be low. A very low urine osmolality is invariably present in hyponatraemia due to excessive water intake and TURP syndrome. Any urine osmolality >100mOsm/kg is abnormal in t his situation. In combination with a low urine sodium (<25mmol/l) it is indicative of decre ased circulating volume. A normal or increased urine sodium (>40mmol/l) suggests SIADH, adr enal insuf \201 ciency, diuretic use, renal failure, cerebral salt wasting, salt-losing ne phritis or hypothyroidism. Further reading Adrogu HJ, Madias NE. Hyponatremia. N Engl J Med 2000; 342: Therapy The pace of correction is determined by the presence of clinical manifestations and their severity. Treat a speci \201 c 1581 \200\2239. Rose BD. Clinical physiology of acid \200\223base and electrolyte disorders. 4th edn. New York: McGraw-Hill, 1994. This page intentionally left blank 416 DC BERGMANS Hypernatraemia Diagnosis The patient history and medication/infusions will often give clues to the probabl e cause of hypernatraemia. Physical examination for signs of dehydration (mucous membranes, skin turgor), blood pressure, CVP if available, orthostatic changes and heart rate will gi ve an indication of the extra- cellular \202 uid volume of the patient. Together with uri ne osmolality, suf \201 cient information for a diagnosis is available in most cases. Urin e osmolality should be maximal (i.e. 800 \200\2231000mOsm/kg) when hypernatraemia is presen t due to pure water de \201 cit or sodium gain. In the case of large urine volume and urin e osmolality <300mOsm/kg, diabe- tes insipidus is diagnosed. Hypernatraemia is de \201 ned as a serum sodium >145mmol/l. It is always associated with h ypertonic hyperosmolality, which causes cellular dehydration. Hypernatraemia is caused by n et water loss or excessive sodium gain. The latter usually develops as a iatrogenic conditi on due to administration of sodium bicarbonate or chloride. Normally the thirst response co rrects water depletion, but critically ill patients in the ICU are often sedated and intu- bated and therefore unable to obtain water. Although infrequent in a general hospital popul ation, hypernatraemia occurs frequently in the ICU mainly due to pure water de \201 cit. Clinical features Hypernatraemia usually produces symptoms if the serum sodium exceeds 155 \200\223160mmol/l and mainly when the increase in the serum sodium concentration is large o r occurs rapidly. Clinical features include pyrexia, restlessness, irritability, drowsiness , lethargy, confusion and coma. Convulsions are uncommon, except in cases of inadvertent so dium loading or aggressive rehydration. Brain shrinkage induced by hypernatraemia can cause vascular rupture, with cerebral bleeding or SAH. The diminished extracellular \202 uid m ay reduce cardiac output, thereby reducing renal perfusion, leading to pre-renal failure. Urine osmolality (mOsm/kg) Cause <300 Diabetes insipidus >300 to <800 Osmotic loss >800 Pure water de \201 cit or sodium gain Therapy Therapy must focus on the underlying cause and on correcting the hypertonicity. Supportive therapy should be provided if necessary. Treat a speci \201 c cause. Isotonic saline is un suitable for correcting hypernatraemia \200\224 the sole indication is hypotension, in whic h case normoten- sion is achieved by supplementation of 0.9% sodium chloride IV. Thereafter only hypotonic \202 uids should be administered. For pure water depletion, the treatment is administration of water, orally if possible. If IV \202 uid is required, 5% dextrose or hypotonic saline solutions are administered guided by urine output and plasma sodium. Si nce rapid rehydration may give rise to cerebral oedema, the fall in serum sodium should be no greater than 2mmol/ l/h, with a maximum correction of 10 mmol/l/day. Initially check ser um sodium concentration every 2 \200\2234h until <150mmol/l. In the case of diabetes insipi dus, desmopressin may be nec- essary while awaiting the effect of treatment of the under- l ying cause. After selecting the appropriate infusate, the rate of infusion can be derived b y applying the formula: change in serum Na+ = infusate Na+ \200\223 serum Na+ Differential diagnosis 1 Net water loss a Pure water \200 \200 insensible losses (respiratory or dermal) hypodipsia neurogenic diabetes insipidus (post-tr aumatic, caused by tumors, cysts or TB, idiopathic, caused by aneurysms, meningitis, enceph alitis or GBS) nephrogenic diabetes insipidus (congenital, hyper- calcaemia, hypokalaemia, drugs mainly lithium, foscarnet, amphotericin B, renal diseases such as pyelonephritis, med ullary sponge kidney or poly- cystic kidney) b Hypotonic \202 uid renal causes (loop diuretics, osmotic diuresis driven by urea, mannitol or glucose, post-ob structive diu- resis, polyuric phase of acute tubular necrosis, intrinsic renal disease) GI causes (diarrhea, vomiting, lactulose use, ente- rocutaneous \201 stulas, NG drainage) c utaneous causes (excessive sweating, burns) total body water + 1 2 Hypertonic sodium gain a Hypertonic sodium chloride infusion b Hypertonic sodium bicarbonate infusion c Hypertonic feeding preparation or ingestion d Primary hyperaldosteronism e Cushing \200\231s syndrome which estimates the change in the serum sodium concen- tration caused by the retention of 1 l of any infusate. Dividing the change in serum sodium concentration tar- geted for a given treatment period by the result of the formula determines the volume of infusate required a nd the rate of infusion. The sodium concentrations of com- monly used infusates are present ed below. The estimated total body water (in litres) is calculated as a fraction of body we ight, 0.6 and 0.5 in non-elderly men and women, respectively; and 0.5 and 0.45 in elderly ( age >65yrs) men and women, respectively. Laboratory analysis Urine osmolality. When indicated: plasma osmolality, urine sodium, pota s- sium, urea, glucose, creatinine, bicarbonate, and blood gas analysis. 417 CHAPTER 24.3 Hypernatraemia Further reading Adrogu HJ, Madia NE. Hypernatremia. N Engl J Med 2000; 342: Infusate Na+ (mmol/l) Infusate 5% dextrose in water 0 1493 \200\22399. Rose BD. Clinical physiology of acid \200\223base and electrolyte disorders. 0.2% sodium chloride in 5% dextrose in water 34 4th edn. New York: McGraw-Hill, 1994. 0.45% sodium chloride in water 77 Ringer \200\231s lactate solution 130 0.9% sodium chloride in water 154 418 MA BUTKUS & JA KELLUM Categorizing metabolic acidoses Ureteral diversion, \200 \200 Post-hypercapnia Renal failure Acidifying agents Ammonium chloride \200 Calcium chloride \200 Arginine \200 Sulfur toxicity For explanations o f the mechanism of these acidoses, see Chapter 24.5. In addition to the AG, standard base e xcess (SBE) is commonly employed to quantify the metabolic component of a given acid-base d isorder. The human body produces acid quite readily, and employs a number of mechanisms designed to maintain normal arterial pH between 7.35 and 7.45 (e.g. respiratory com- pensation for vola tile acid (CO2) production, renal excre- tion to compensate for fixed acid production). Any pathology which compromises these compensatory mech- anisms will produce an acidosis. Diso rders of CO2 are characterized as respiratory acidoses/alkaloses, while dis- orders of all other factors are characterized as metabolic acidoses/alkaloses, which includes disorders o f weak and strong acids and bases. Metabolic acidoses occur when the serum pH falls below 7 .35, and typically are categorized as either pure vs mixed (dependent on whether there is o ne or multiple processes producing acidaemia), or anion gap (AG) vs non-AG aci- doses (depe ndent on the presence or absence of unmeas- ured anions in the blood). AG acidoses produce changes in \200\223]}. the AG, where AG = {[Na+] + [K+] \200\223 [Cl \200\223] \200\223 [HCO3 Typically, the AG = 8 \200\22312mEq/l, and represents the relative \200\230gap \200 \231 between unmeasured cations (generally magnesium, and calcium) and unmeasured anions (g enerally plasma proteins, phosphate, sulfate, lactate and organic anions). An abnormal AG i ndicates the presence of unmeasured, patho- physiological anions such as lactate, ketones, sulfate, etc. A high AG can indicate a metabolic acidosis due to an accu- mulation of organ ic acids or toxins (e.g. salicylate) The AG is insensitive, and can vary in critically ill patients based on changes in albumin concentration or unmeasured cations, the addition of a bnormal cations (e.g. lithium, immunoglob- ulins), hyperviscosity and hyperlipidaemia. Addi tionally, the \200\230normal \200\231 AG range may vary from patient to patient. A cor- re cted anion gap (AGc) is more sensitive for estimating unknown anions and is given by the eq uation: AGc = {[Na+] + [K+] \200\223 [Cl \200\223] \200\223 [HCO3 Ureterosigmoidostomy, Ileal bladder or ureter \200 \200 \200 Standard base excess The SBE is calculated by SBE = HCO3 \200\223 24.4) + (8.0Alb + 0.30Ph os) x (pH 7.4); the typical reference range is \200\2232.0 to +2.0mEq/l, with SBE less tha n \200\2232.0mEq/l indicating meta- bolic acidosis and SBE >2.0mEq/l indicating metabolic alka- losis. The offset of the calculated SBE from zero indicates approximately how much co mpensation is needed to restore homeostasis. Recent research and clari \201 cation have sh own that the change in SBE equals the change in strong ion difference (SID). Strong ion difference (SID) and strong ion gap (SIG) The SID can be calculated by the diffe rence between the sum of strong cations and sum of strong anion concen- trations \200\224th e apparent SID (SIDa). The effective SID can be calculated by the difference between the su m of the concentrations of weak acids [A \200\223] and the bicarbo- \200\223] (SIDe). The strong ion gap nate concentration [HCO3 (SIG) is a quantitative methodology for determining unmeasured ions based on the difference between SIDa \200\223 SIDe = SIG. Normally, SIDa = SIDe and SIG=0; if SIDa \211 SIDe, unmeas- ured ions must be present (anions if SIDa > SIDe, cations if SIDe > SIDa). The SIG does not change in relation to pH alterations or alb umin concentration. The AGc approxi- mates SIG. \200\223]} \200\223 {2[albumin 2-(mg/dl)] + [lactate]} (g/dl)] + 0.5[PO4 Or for international units: AGc = {[Na+] + [K+] \200\223 [Cl \200\223] \200\223 [HCO3 \200\223]} \200\223 {0.2[albumin 2 \200\223(mmol/dl)] + [lactate]} (g/l)] + 1.5[PO4 AG acidoses refer to acidemias that increase the AG, and include acidoses induced by: \200 \200 \200 \200 \200 \200 Epidemiology Because metabolic acidoses typically occur as the result of other pathophysiol ogy, the incidence and prevalence of the disorders are dif \201 cult to characterize. Howe ver, metabolic acidosis is quite common in the critically ill and injured. Methanol Uraemia Diabetic ketoacidosis Paraldehyde, phenformin Isopropyl alcohol, isoniazid Lactic acidosis (patients should also be evaluated for shock) Ethylene glycol, ethyl alcoh ol Salicylates Hyperalbuminaemia, administered anions Causes Acid \200\223base disturbances are caused by pCO2, the total weak acid (Atot) and/or the SID present. According to physical chemical principles: \200 \200 \200 In plasma only three independent variables determine hydrogen ion concentration (pH): 1 str ong ion difference (SID) 2 partial pressure of carbon dioxide (pCO2) 3 total weak acid conc entration (Atot) All buffering mechanisms, such as respiratory compensa- tory mechanisms, b lood buffers and ion excretion through the kidneys regulate pH only by modulating the above three independent variables. Non-AG/normal AG acidoses are essentially abnor- malities in chloride regulation (hyperchlo raemic aci- doses), and include acidoses due to: \200 \200 \200 Diarrhea Renal tubular acidosis (proximal or distal) Carbonic anhydrase inhibitors \200 \200 Acetazolamide Mefenamic acid 419 CHAPTER 24.4 Categorizing metabolic acidoses Complications Potential clinical sequelae of metabolic acidoses include: The kidneys primarily modulate the SID by regulating the excretion of chloride (Cl \200\223 ) ions. Each Cl \200\223-ion that is \201 ltered but not reabsorbed increases the SID, wh ich subsequently increases the pH. Renal ammoniagenesis occurs to allow the co-excretion of Cl \200\223 without Na+ or K+ excretion. This is achieved by +) to excrete with Cl \200 \223, supplying a weak cation (NH4 thereby decreasing the SID. Cardiovascular changes \200 Decreased inotropy \200 Conduction defects \200 Arterial vasodilation \200 Venous vasoconstriction Electrolyte imbalances \200 \200 \200 Risk factors \200 Hyperkalaemia Hypercalcaemia Hyperuricaemia Fluid loading with saline (greater Cl \200\223 increase relative to sodium produces hyperch loraemic acidosis) Bicarbonate loss (diarrhea) Gastrointestinal effects \200 Clinical features Pure metabolic acidoses are diagnosed by the presence of acidaemia (arter ial pH <7.35), hypobicarbonataemia \200\223 <22mmol/l), hypocarbia (PCO2 <40mm Hg) and a ( HCO3 reduced SBE (less than \200\2233mEq/l). Mixed metabolic acidoses or a mixed acidosis/ alkalosis may produce the appearance of balanced acid \200\223base status. Electrolyte leve ls can offer clues to acid \200\223base status, but require con \201 rmation by ABG measur ements. Emesis Immunological changes \200 Changes in in \202 ammatory mediators Metabolic changes \200 Protein wasting \200 Bone demineralization \200 Catecholamine, parathryroid hormone and aldosterone stimulation Insulin resistance Treatment/management Metabolic acidoses frequently occur as sequelae of other pathologies; the best means of treatment for metabolic aci- dosis is to treat the underlying cause. Gene ral guidelines: \200 Neuromuscular changes \200 \200 Respiratory depression Decreased awareness Many metabolic acidoses are acute, self-limiting and do not require speci \201 c therapies (e.g. lactic acidosis due to exercise or seizures will resolve with rest). Acute meta- bol ic acidoses can also resolve via respiratory compen- sation (reduction of pCO2). Treatment of acute acidosis with NaHCO3 is not recommended, is of dubious bene- \201 t and may be h armful in some patients. Acidoses due to toxin ingestion require separate inter- ventions ( e.g. methanol ingestion requires therapeutic intervention for both the methanol and the sub sequent acidosis). Chronic acidoses (e.g. those due to renal injuries or chronic mineraloco rticoid disorders) require therapy to restore the SID (e.g. oral NaHCO3). Distal renal tubu lar acidosis is associated more fre- quently with severe acidosis and hypokalaemia than is proximal renal tubular acidosis. Non-HCO3 buffers may be effective in severe metabolic acid osis. In severe metabolic acidosis, continuous RRT may be needed. Additionally, limited dat a suggest that non-bicar- bonate buffers may be effective. In acidosis complicated by hypok alaemia, K+ must be corrected before the pH is corrected (serum [K+] will fall precipitousl y if pH is corrected \201 rst). Decreased oxygenation \200 \200 Decreased oxy-Hb binding Decreased 2,3-DPG (late) Further reading Androgue H, Madias N. Management of life-threatening acid \200\223base disorders. First of two parts. N Engl J Med 1998; 338: 26 \200\22334. Androgue H, Madias N. Management of life-threatening acid-base disorders. Second of two par ts. N Engl J Med 1998; 338: 107 \200\22311. Kellum J. Closing the gap on unmeasured anions. Critical Care. 2003; 7: 219 \200\22320. Kellum J. Determinants of blood pH in health and disease. Critical Care. 2000; 4: 6 \200\22314. Kellum J, Song M, Li J. Science review: extracellular acidosis and the immune response: cli nical and physiological implications. Crit Care 2004; 8: 331 \200\2236. Schlichtig R, Grogono AW, Severinghaus JW. Human PaCO2 and standard base excess compensatio n for acid-base imbalance. Crit Care Med 1998; 26: 1173 \200\2239. Wooten EW. Science review: quantitative acid \200\223base physiology using the Stewart model. Crit Care 2004; 8: 448 \200\22352. 420 R MURUGAN & JA KELLUM Metabolic acidosis etiology Ketoacidosis Ketones are formed by B-oxidation of fatty acids, a process inhibited by insul in. In insulin-de \201 cient states (e.g. diabetes), ketogenesis is accelerated due to hig h glucose-induced osmotic diuresis which may lead to volume contraction. This state is asso ciated with elevated cortisol and catecho- lamine secretion, which further stimulates free fatty acid production. In addition, increased glucagon, relative to insu- lin, leads to dec reased malonyl co-enzyme A and increased carnitine palmityl acyltransferase, the combinatio n of which increases ketogenesis. Ketone bodies include acetone, acetoacetate and B-hydroxy butyrate. Both acetoacetate and B-hydroxybutyrate are strong anions that decrease the SID a nd increase the H+ concentration. Ketoacidosis may result from diabetes (DKA) or alcohol (A KA). Pure metabolic acidosis is characterized by \200 \200 \200 \200 Acidaemia (arterial pH <7.35) Hypobicarbonatqemia (HCO3 Hypocarbia (PCO2 <40mm Hg) and a De creased SBE (less than \200\2233mEq/l) \200\223 <22 mmol/l) Metabolic acidoses are categorized according to the pres- ence or absence of unmeasured ani ons \200\224which are rou- tinely detected by examining the plasma electrolytes and calcula ting the AG. Metabolic acidosis with an increased AG Lactic acidosis During critical illness, lactate is the most important cause of metabolic acidosis and correlates with outcome in patients wit h haemorrhagic and septic shock. The assumption that hypoperfusion is the most likely cause has been seriously challenged, especially in well resuscitated patients. The aeti- ology o f hyperlactataemia during critical illness is complex, multi-factorial and arises due to se veral mechanisms (Table 24.5.1). Lactate is released from the mesentry during gut ischaemia and from the lungs during ALI. Hyperlactataemia in sepsis usually occurs as a consequence of increased aero- bic metabolism rather than tissue hypoxia. Lactate produc- tion alters c ytosolic, and hence mitochondrial redox state such that the increased NADH/NAD supports oxi dative phosphorylation as the dominant source of ATP produc- tion. Catecholamines, especial ly epinephrine, result in lactic acidosis presumably by stimulating cellular metabolism (e. g. increased hepatic glycolysis and muscle Na+,K+ ATPase) and is a common source of lactic acidosis in the ICU. Diagnosis \200 \200 Diagnosis is established by measuring serum ketones. Nitroprusside reaction only measures a cetone and ace- tate, but not B-hydroxybutyrate. Measured ketosis is dependent on the ratio of acetoac- etate to B-hydroxybutyrate. Ketones may even appear to increase as B-hydroxybu - tyrate is converted to acetoacetate during treatment. Treatment \200 The treatment of DKA includes insulin and large amounts of isotonic IV \202 uids Potassiu m replacement is often required Fluid resuscitation reverses the hormonal stimuli for keton e body formation and insulin allows for the metab- olism of ketones and glucose Sodium bica rbonate is rarely necessary and should prob- ably be avoided except in extreme cases Respon se to therapy is observed by monitoring pH and AG more than by the assay of serum ketones T he treatment of alcoholic ketoacidosis consists of \202 uids and glucose instead of insul in. Thiamine must also be given to avoid precipitating Wernicke s encephalopathy \200 Table 24.5.1 Mechanisms of hyperlactataemia during critical illness. Tissue hypoxia Hypodynamic shock Organ ischaemia Hypermetabolism Increased aerobic glycolysis Increased protein catabolism Hematologic malig nanciesal Renal failure Renal failure allows the build up of sulfates and other acids, thereby increa sing the AG. Uncomplicated renal failure rarely produces severe acidosis except when it is accompa- nied by high rates of acid generation such as from hyper- metabolism. In all cases , the SID is decreased and is expected to remain so unless some therapy is provided. Haemod ialysis will permit the removal of sulfate and other ions and allow normal Na+ and Cl \200 \223 balance to be restored, thus returning the SID to normal. However, patients not yet re quiring dialysis and those who are between treat- ments often require some other therapy to increase the SID. Sodium bicarbonate is used as long as the plasma Na+ concentration is no t already elevated. Other options include Ca2+ which usually requires replacement. Ca2+ rep lacement cannot increase the SID much given the rather narrow range of free Ca2+. Poisons M etabolic acidosis with an increased AG is a major feature of various types of drug and subs tance intoxications. It is important to recognize these disorders so that speci \201 c the rapy can be provided rather than to treat the acid \200\223base Decreased clearance of lactate Liver failure Shock Inhibition of pyruvate dehydrogenase Thiamine de \201 ciency Endotoxin Treatment \200 Treatment of underlying cause is the most important measure to correct lactic acidosis; how ever, this may not always be possible. Therapy aimed at increasing oxygen delivery may not always be effective. Although treatment with sodium bicarbonate and dichloroacetate (the en zyme that stimulates pyruvate dehydrogenase (PDH)) improves pH, they do not improve outcome ; nevertheless, Na-bicarbonate is used particularly when lactic acidosis is severe or refra ctory. 421 CHAPTER 24.5 Metabolic acidosis etiology Cl \200\223 and the balance of each anion can be adjusted depend- ing on the acid \200\223b ase status of the patient. If suf \201 cient amounts of weak anions are not provided, the plasma Cl \200\223 concentration will increase, decreasing the SID and result- ing in acido sis. A similar condition may arise when saline is used for \202 uid resuscitation, result ing in a so-called \200\230dilu- tional acidosis \200\231. The clinical implication for ma nagement of patients in the ICU is that when large volumes of \202 uid are used for resus citation they should be more physiological than saline. One alternative is lactated Ringer \200\231s solution. This \202 uid contains a more physiological difference between Na+ an d Cl \200\223 concentrations and thus the SID is closer to normal ( 28mEq/l compared with s aline which has a SID of 0mEq/l). disorder that they produce. The use of the osmolar gap can often detect toxins with high os molality (e.g. methanol). Unknown causes Recently, some unknown causes of an increased AG have been reported in non-k etotic hyperosmolar state of diabe- tes, sepsis, liver disease and in experimental animals given endotoxin. Also unknown cations appear in the blood of some critically ill patients; the significance of these is unknown, but increased mortality has been reported in some stu dies. Non-anion gap (hyperchloraemic) acidoses Hyperchloraemic acidosis occurs as a result of eit