Aplastic crisis Related to parvovirus infection, it is suggested by worsening anemia and a reduction in the normally elevated reticulocyte count (10 \200\22320%). Haemolytic crisis Intravascular haemolysis with haemoglobinuria, jaundice, and renal failur e sometimes occurs. Sequestration crisis Rapid hepatic and splenic enlargement due to red cell trapping with se vere anemia. This condition is particularly serious. Management Prophylaxis against crisis includes avoidance of hypoxaemia, other known precipi tating factors, prophylactic penicillin, and pneumococcal vaccine. 1. Painful crises usuall y require prompt opiate infusions. Although psy- chological dependence is a risk in a small number of patients, analgesia should not be withheld. 2. Give oxygen to maintain SaO2 at 97 \200\22399%. Avoid hyperoxia. 3. Rehydrate with intra venous \202 uids and keep warm. 4. If infection is suspected, antibiotics should be given as indicated. 5. Transfuse blood if hemoglobin falls. In central nervous respiratory cri- sis, perform red cell exchange (manual or via apheresis). 6. Lower proportion of sickle cells to <30% by exchange transfusion. 7. Mechanical ventilat ion may be necessary for chest crises. SICKLE CELL DISEASE 475 See also: Oxygen therapy, p38; Full blood count, p220; Blood transfusion, p248; Non-opioid analgesics, p302; Opioid analgesics, p304; Antimicrobials, p326; Anemia, p472; Haemolysis, p476; Pain, p618. 476 CHAPTER 28 Hematological disorders Haemolysis Shortening of erythrocyte lifespan below the expected 120 days. Marked intravasc ular haemolysis may lead to jaundice and haemoglobinuria. Causes \200 \200 \200 \200 \200 Blood transfusion reactions. Malaria. Sickle cell haemolytic crisis. Drugs, e.g. high-dose penicillin, methyl dopa. Autoimmune (cold or warm antibody-mediated) \200\224may be idiopat hic or secondary, e.g. lymphoma, SLE, mycoplasma. Haemolytic uraemic syndrome/thrombotic th rombocytopaenic purpura (microangiopathic haemolytic anemia). Trauma (cardiac valve prosthe sis). Glucose-6-phosphate dehydrogenase de \201 ciency \200\224oxidative crises occur foll owing ingestion of fava beans or administration of drugs (e.g. primaquine, sulphonamides) l eading to rapid onset anemia and jaundice. \200 Diagnosis \200 Unconjugated hyperbilirubinaemia, increased urinary urobilinogen (increased RBC breakdown). Reticulocytosis (increased RBC production). Splenic hypertrophy (extravascular haemolysis) . Methaemoglobinaemia, haemoglobinuria, free plasma hemoglobin (intravascular haemolysis), reduced serum haptoglobins. RBC fragmentation (microangiopathic haemolytic anemia). Coombs \200\231 test (immune-mediated haemolysis). Other (including hemoglobin electrophoresis, bo ne marrow biopsy). \200 \200 \200 \200 Management 1. Identi \201 cation and speci \201 c treatment of the cause where possible. 2. Blood transfusion to maintain hemoglobin >7g/dL. 3. Massive intravascular haemolysis may lead to acute renal failure. Maintain a good diuresis and haemo(dia) \201 lter if necessary. HAEMOLYSIS 477 See also: Full blood count, p220; Blood transfusion, p248; Anemia, p472; Sickle cell diseas e, p474; Malaria, p568; SARS, VHF, and H5N1, p570. 478 CHAPTER 28 Hematological disorders Platelet disorders Thrombocytopaenia Rarely symptomatic until the platelet count <50 x 109/ L; spontaneous bleeding is more likely when the count <20 x 109/L. Although bleeding is oft en minor, e.g. skin petechiae, oozing at intravascular catheter sites, it may be massive or life-threatening, e.g. haemoptysis, intracranial hemorrhage. Causes \200 Sepsis \200\224a common cause of a low platelet count in the critically ill; it is often a barometer of either recovery or deterioration. Disseminated intravascular coagulation. Drug s. Related to antiplatelet antibody production, e.g. heparin (heparin- induced thrombocytop aenia syndrome, HITS), sulphonamides, quinine. Resulting in bone marrow suppression, e.g. c hemotherapy agents. Others, e.g. aspirin, chlorpromazine, prochlorperazine, digoxin. Follow ing massive bleeding and multiple blood transfusions. Bone marrow failure, e.g. tumor in \201 ltration, drugs. Splenomegaly. Thrombotic thrombocytopaenic purpura (TTP), haemolytic uraemic syndrome (HUS). Idiopathic thrombocytopaenic purpura (ITP). Speci \201 c infection s, e.g. measles, infectious mononucleosis, typhus. Collagen vascular diseases, e.g. SLE. \200 \200 \200 \200 \200 \200 \200 \200 \200 Management 1. Treat the cause, e.g. antibiotics for sepsis, stopping offending drugs, plasm a exchange for TTP, splenectomy and corticosteroids for ITP. 2. Platelet support: \200 Platelet transfusions in an otherwise well person with no signi \201 cant bleeding can be withheld until the count falls <10 x 109/L. Give 1 \200\2232 pools if count <50 x 109/L and either bleeding, septic or due to undergo surgery/invasive procedure. For CNS or eye surge ry, aim for counts >100 x 109/L. Platelet transfusion is contraindicated in TTP, HUS, and H ITS. Deranged platelet function Function may be deranged albeit with normal counts, e.g. followi ng aspirin within past 1 \200\2232 weeks, epoprostenol, uraemia. Fresh platelets may be req uired if the patient is symptomatic. In uraemia, one dose of vasopressin (20mcg IV over 30m in) may be useful before surgery. Thrombocythaemia Rare in ICU patients; platelet counts of ten exceed 800 x 109/L. Causes Prolonged disorders. Essential (idiopathic) thrombocythaemia is unusual. Management As the major risk is thrombosis, management is based upon mobilizin g the patient and administration of either prophylactic aspirin (150mg bd PO) or LMW hepari n (5000IU od SC). Dipyridamole (300 \200\223600mg tds PO) is occasionally used. low level bleeding, post-splenectomy, myeloproliferative PLATELET DISORDERS 479 See also: Plasma exchange, p114; Full blood count, p220; Blood products, p250; Anticoagulan ts, p318; Corticosteroids, p328. This page intentionally left blank 481 Chapter 29 Metabolic disorders Electrolyte management 482 Hypernatraemia 484 Hyponatraemia 486 Hyperkalaemia 488 Hypokalae mia 490 Hypomagnesaemia 492 Hypercalcaemia 494 Hypocalcaemia 496 Hypophosphataemia 498 Gene ral acid-base principles 500 Metabolic acidosis 502 Metabolic alkalosis 504 Hypoglycaemia 5 06 Hyperglycaemia 508 Diabetic ketoacidosis 510 Hyperosmolar diabetic emergencies 512 Thyro id emergencies 514 Hypoadrenal crisis 516 482 CHAPTER 29 Metabolic disorders Electrolyte management A balance must be achieved between electrolyte intake and output. In electrolyte disturbance consider: \200 \200 \200 \200 Altered intake. Impaired renal excretion. Increased body losses. Body compartment redistrib ution (e.g. increased capillary leak, secondary hyperaldosteronism). As well as Na+ and K+, consider Mg2+, Ca2+, Cl \200\223 and PO4 3 \200\223 balance. Plasma electrolyte values are poorly re \202 ective of whole body stores; however, excessi vely high or low plasma levels may induce symptoms, and deleterious physiological and metab olic sequelae. Water balance must also be taken into account; depletion or excess repletion may, respectively, concentrate or dilute electrolyte levels. Gravitational peripheral oedema implies increased total body Na+ and water though intravascular salt and water depletion may coexist. The usual daily requiremen ts of Na+ and K+ are 60 \200\22380mmol. Electrolyte losses \200 \200 \200 \200 \200 Na+, Cl \200\223 Na+, Cl \200\223 Na+, Cl \200\223, K+, Mg2+ Na+, Cl \200\223, K+, Mg2+ Na+ , Cl \200\223, K+ Large nasogastric aspirate, vomiting Sweating Polyuria Diarrhea Ascitic drainage Principles of management 1. Establish sources and degree of \202 uid and electrolyte loss es. 2. Assess patient for signs of: (i) intravascular \202 uid depletion \200\224hypotens ion (e.g. following changes in posture, PEEP, vasodilating drugs), oliguria, increasing met abolic acidosis, thirst; (ii) total body NaCl and water overload \200\224i.e. gravitational oedema. 3. Measure urea, creatinine, osmolality, and electrolyte content of plasma and urine. 4. As appropriate, either replace estimated \202 uid and electrolyte de \201 cit or incr ease excretion (with diuretics, haemo \201 ltration). For rate of \202 uid and speci \201 c electrolyte replacement, see individual sections. ELECTROLYTE MANAGEMENT 483 See also: Urea and creatinine, p210; Electrolytes (Na+, K+, Cl \200\223, HCO3 Hypernatraemi a, p484; Hyponatraemia, p486; Hyperkalaemia, p488; Hypokalaemia, p490; Hypomagnesaemia, p49 2; Hypercalcaemia, p494; Hypocalcaemia, p496; Hypophosphataemia, p498. \200\223), p212; Urinalysis, p232; 484 CHAPTER 29 Metabolic disorders Hypernatraemia Clinical features Thirst, lethargy, coma, seizures, muscular tremor and rigi dity, and an increased risk of intracranial hemorrhage. Thirst usually occurs when the plas ma sodium rises 3 \200\2234mmol/L above normal. Lack of thirst is associated with central n ervous system disease. Management Depends upon the cause and whether total body sodium stores are normal, low or e levated, and body water is normal or low. Rate of correction \200 \200 If hyperacute (<12h), correction can be rapid. Otherwise, aim for gradual correction of pla sma sodium levels (over 1 \200\2233 days), particularly in chronic cases (>2 days \200\231 duration), to avoid cerebral oedema through sudden lowering of osmolality. A rate of plasma sodium lowering <0.7mmol/h has been suggested. Hypovolaemia \200 If hypovolaemia is accompanied by haemodynamic alterations, restore the circulation with co lloid or (less ef \201 ciently) with a crystalloid such as isotonic saline or (perhaps, pr eferably to avoid hyperchloraemia), Ringer \200\231s lactate. Arti \201 cial colloid solut ions consist of hydroxyethyl starches or gelatins usually dissolved in saline solution. Nor mal total body Na+ (water loss) \200 Water replacement either added to enteral feed or as 5% glucose IV. Up to 5L/d may be neces sary. If cranial diabetes insipidus is present, restrict salt and give thiazide diuretics. Cranial diabetes insipidus (CDI) may be complete or partial. Complete CDI will require desm opressin (10mcg bd intranasal or 1 \200\2232mcg IV bd), whereas partial CDI may require des mopressin but often responds to drugs that increase the rate of ADH secretion or end-organ responsiveness to ADH, e.g. chlorpropamide, hydrochlorthiazide. Nephrogenic diabetes insipi dus is managed by a low salt diet and thiazides. High-dose desmopressin may be effective. C onsider removal of causative agents, e.g. lithium, demeclocycline. Low total body Na+ (Na+ and water losses) \200 Treat hyperosmolar non-ketotic diabetic crisis or uraemia as appropriate. Otherwise conside r 0.9% saline or hypotonic (0.45%) saline. Up to 6L/d may be needed. Increased total body Na+ (Na+ gain) \200 Water replacement either added to enteral feed or as 5% glucose IV. Up to 5L/d may be neces sary. In addition, furosemide 10 \200\22320mg IV prn may be necessary. HYPERNATRAEMIA 485 Causes of hypernatraemia Type Etiology Urine [Na+] >20mmol/L Iso- or hypotonic Low total body Na+ Renal losses: Diuretic excess, osmotic diuresis (glucose, urea, mannitol) Extra-renal losse s: Excess sweating [Na+] <10mmol/L Hypertonic [Na+] variable Hypo-, iso-, or hypertonic [Na+] variable Hyperto nic Normal total body Na+ Renal losses: diabetes insipidus Extra-renal losses: Respiratory and renal insensible losse s [Na+] >20mmol/L Iso- or hypertonic Increased total body Na+ Conn \200\231s syndrome, Cushing \200\231s syndrome, excess NaCl, hypertonic NaHCO3 See also: Electrolytes (Na+, K+, Cl \200\223, HCO3 emergencies, p512. \200\223), p212; Urinalysis, p232; Diuretics, p280; Hyperosmolar diabetic 486 CHAPTER 29 Metabolic disorders Hyponatraemia Clinical features Nausea, vomiting, headache, fatigue, weakness, muscular twi tching, obtun- dation, psychosis, seizures, and coma. Symptoms depend on the rate as well a s the magnitude of fall in the plasma [Na+]. Management Rate and degree of correction \200 In chronic (>48h) asymptomatic hyponatraemia, correction should not exceed 4mmol/L per 24h at a rate <0.3mmol/L/h. In chronic symptomatic hyponatraemia, increase plasma Na+ at 1 \200 \2231.5mmol/L/h until symptoms resolve, then as per asymptomatic cases. In acute (<48h) hyp onatraemia, the ideal rate of correction is controversial but should be < 20 mmol/L/24h. A plasma Na+ of 125 \200\223130mmol/L is a reasonable target for initial correction of both a cute and chronic states. Neurological complications, e.g. central pontine myelinolysis, may be related to the degree of correction and (in chronic hyponatraemia) the rate. Premenopau sal women are more prone to complications. Extracellular \202 uid (ECF) volume excess \200 If symptomatic (e.g. seizures, agitation) and not oedematous, give 100mL aliquots hypertoni c (1.8%) saline. If symptomatic and oedematous, consider furosemide (10 \200\22320mg IV bol us prn), mannitol (0.5g/kg IV over 15 \200\22320min), and replacement of urinary sodium los ses with aliquots of hypertonic saline. If not symptomatic, restrict water to 1 \200\2231.5 L/d. If hyponatraemia persists, consider inappropriate ADH (SIADH) secretion. If SIADH like ly, give isotonic saline and consider demeclocycline. If SIADH unlikely, consider furosemid e (10 \200\22320mg IV bolus prn), mannitol (0.5g/kg IV over 15 \200\22320min), and replacem ent of urinary sodium losses with aliquots of hypertonic saline. Check plasma levels every 2 \200\2233 h. Haemo \201 ltration or dialysis may be necessary if renal failure is establ ished. \200 Extracellular \202 uid volume (ECF) depletion \200 If symptomatic (e.g. seizures, agitation), give isotonic (0.9%) saline; consider hypertonic (1.8%) saline. If not symptomatic, give isotonic (0.9%) saline. General points \200 Equations that calculate excess water are unreliable. It is safer to perform frequent estim ations of plasma sodium levels. Hypertonic saline may be dangerous in the elderly and those with impaired cardiac function. An alternative is to use furosemide with replacement of ur inary sodium (and potassium) losses each 2 \200\2233h. Thereafter, simple water restriction is usually suf \201 cient. Many patients achieve normonatraemia by spontaneous diuresis. Use isotonic solutions for reconstituting drugs, etc. Hyponatraemia may intensify the cardi ac effects of hyperkalaemia. True hyponatraemia may occur with a normal osmolality in the p resence of abnormal solutes e.g. ethanol, ethylene glycol, glucose. \200 \200 \200 HYPONATRAEMIA 487 Causes of hyponatraemia Urine [Na+] Type Etiology >20mmol/L ECF volume depletion Renal losses: Diuretic excess, osmotic diuresis (glucose, urea, mannitol), renal tubular acidosis, salt-l osing nephritis, mineralocorticoid de \201 ciency Extra-renal losses: <10mmol/L Vomiting, diarrhea, burns, pancreatitis >20mmol/L Water intoxication: Modest ECF volume excess (no oedema) (NB. Post-operative, TURP syndrome), inappropriate ADH secretion, hypothyroidism, drugs (e. g. carbamazepine, chlorpropamide), glucocorticoid de \201 ciency, pain, emotion Acute and chronic renal failure >20mmol/L ECF volume excess (oedema) Nephrotic syndrome, cirrhosis, heart failure <10mmol/L Causes of inappropriate ADH secretion \200 Neoplasm, e.g. lung, pancreas, lymphoma. \200 Most pulmonary lesions. \200 Most central nervous system lesions. \200 Surgical and e motional stress. \200 Glucocorticoid and thyroid de \201 ciency. \200 Idiopathic. \200 Drugs, e.g. chlorpropamide, carbamazepine, narcotics. See also: Electrolytes (Na+, K+, Cl \200\223, HCO3 \200\223), p212; Urinalysis, p232; Diur etics, p280; Vomiting/gastric stasis, p406; Diarrhea, p408; Pancreatitis, p424; Chronic liv er failure, p434; Hyperosmolar diabetic emergencies, p512; Burns \200\224 \202 uid managem ent, p592. 488 CHAPTER 29 Metabolic disorders Hyperkalaemia Plasma potassium depends on the balance between intake, excretion, and the di stribution of potassium across cell membranes. Excretion is normally controlled by the kidn eys. Causes \200 Reduced renal excretion (e.g. chronic renal failure, adrenal insuf \201 ciency, diabetes, potassium sparing diuretics). Intracellular potassium release (e.g. acidosis, rapid transfu sion of old blood, cell lysis \200\224including rhabdomyolysis, haemolysis, tumor lysis, K+ channel openers (nicorandil, iso \202 urane, ciclosporin). Potassium poisoning and iatrog enic overload. A rapid rate of rise of potassium is more dangerous than a chronically eleva ted level. Cardiac arrest has been seen following 40mmol KCl infused over 1 hour. Clinical features Hyperkalaemia may cause dangerous arrhythmias, including cardiac arrest. Arrhythmias are more closely related to the rate of rise of K+ than the absolute level. Cli nical features such as paraesthesiae and are \202 exic weak- ness are not clearly related to the degree of hyperkalaemia, but usually occur after ECG changes (tall \200\230T \200 \231 waves, \202 at \200\230P \200\231 waves, prolonged PR interval, and wide QRS). Hypotension, often resistant to high doses of catecholamines, frequently occurs with hyperkalaemia related to excess K+ channel activation. Management After con \201 rmation of hyperkalaemia, potassium restriction is needed for al l cases and haemodia \201 ltration or haemodialysis may be needed for resis- tant cases. A n ECG should be performed looking for features of hyperka- laemia. Potassium-containing dru gs should be stopped. Cardiac arrest associated with hyperkalaemia Sodium bicarbonate (8.4%) 50 \200\223100mL sho uld be given in addition to standard CPR and other treatment detailed below. Potassium >7mmol/L Calcium chloride (10%) 10mL should be given urgently under ECG guid- anc e in addition to treatment detailed below. Although calcium chloride does not reduce plasma potassium levels, it stabilizes the myocardium against arrhythmias. Clinical features of hyperkalaemia or potassium >6mmol/L with ECG changes Glucose (50mL 50% ) and soluble insulin (10IU) should be given IV over 20min. Blood glucose should be monitor ed every 15min and more glucose given if necessary. In addition, calcium resonium 15g qds P O or 30g bd PR can be considered. If resistant to medical treatment, haemodialyse or haemodia \201 lter (more effective than haemo \201 ltration). Hyperkalaemia related to K+ channel opening drug Give glibenclamide (glyburide) 5 \200\22310mg via the nasogastric tube. An effect is often seen within 30 minutes. HYPERKALAEMIA 489 Key paper Singer M, Coluzzi F, O \200\231Brien A, et al. (2005) Reversal of life-threatenin g, drug-related potassium- channel syndrome by glibenclamide. Lancet 365: 1873 \200\2235. See also: Haemo(dia) \201 ltration (1), p108; Haemo(dia) \201 ltration (2), p110; Electro lytes (Na+, K+, Cl \200\223, HCO3 p212; Cardiac arrest, p340; Bradyarrhythmias, p386; Acute renal failure \200\224diagnosis, p400; Acute renal failure \200\224management, p402; Elect rolyte management, p482; Rhabdomyolysis, p612. \200\223), 490 CHAPTER 29 Metabolic disorders Hypokalaemia Plasma potassium depends on the balance between intake, excretion, and the dis tribution of potassium across cell membranes. Excretion is normally controlled by the kidne ys. Causes \200 \200 \200 Inadequate intake or replacement. Gastrointestinal losses (e.g. vomiting, diarrhea, \201 stula losses). Renal losses (e.g. diabetic ketoacidosis, Conn \200\231s syndrome, secondary hyperaldosteronism, Cushing \200\231s syndrome, renal tubular acidosis, metabolic alkalosi s, hypomagnesaemia, drugs \200\224including diuretics, corticosteroids, theophyllines). Hae mo \201 ltration losses. Potassium transfer into cells (e.g. acute alkalosis, glucose infu sion, insulin treatment, familial periodic paralysis). \200 Clinical features \200 \200 \200 \200 \200 \200 Arrhythmias (SVT, VT, and Torsades de Pointes). ECG changes (ST depression, \200\230T \200 \231 wave \202 attening, \200\230U \200\231 waves). Metabolic alkalosis. Constipation. I leus. Weakness. Management 1. Wherever possible, the cause of potassium loss should be treated. 2. Potassiu m replacement should be intravenous with ECG monitoring when there is a clinically signi \201 cant and compromising arrhythmia (give 20mmol over 30min, repeated according to levels ). 3. Slower IV replacement (20mmol over 1 \200\2232h) can be used otherwise. 4. Oral suppleme ntation (to a total intake of 80 \200\223120mmol/d, including nutritional input) can be giv en where there are no clinical features and enteral absorption is satisfactory. HYPOKALAEMIA 491 See also: Electrolytes (Na+, K+, Cl \200\223, HCO3 Metabolic alkalosis, p504; Diabetic keto acidosis, p510. \200\223), p212; Urinalysis, p232; Diuretics, p280; Corticosteroids, p328; 492 CHAPTER 29 Metabolic disorders Hypomagnesaemia Causes \200 Excess loss, e.g. diuretics, other causes of polyuria (including poorly controlled diabetes mellitus), severe diarrhea, prolonged vomiting, large nasogastric aspirates, Inadequate in take, e.g. starvation, parenteral nutrition, alcoholism, malabsorption syndromes Clinical features Magnesium is primarily an intracellular ion involved in the production an d utilization of energy stores and in the mediation of nerve transmission. Normal plasma le vels range from 0.7 \200\2231.0mmol/L; severe symptoms do not usually occur until levels dr op below 0.5mmol/L. Low plasma levels, which do not necessarily re \202 ect either intrace llular or whole body stores, may thus be associated with features related to these function s: \200 \200 \200 \200 \200 Confusion, irritability. Seizures. Muscle weakness, lethargy. Arrhythmias. Symptoms related to hypocalcaemia and hypokalaemia which are resistant to calcium and potassium supplementa tion, respectively. Management \200 \200 Where possible, identify and treat the cause. For severe, symptomatic hypomagnesaemia, 10mm ol of magnesium sulfate can be given IV over 3 \200\2235min. This can be repeated as needed . In less acute situations or for asymptomatic hypomagnesaemia, 10 \200\22320mmol MgSO4 sol ution can be given over 1 \200\2232h and repeated as necessary, or according to repeat plas ma levels. Continuous IV infusion (e.g. 3 \200\2235mmol MgSO4 solution/h) can be given; how ever, this is usually reserved for therapeutic indications where supranormal plasma levels (1.5 \200\2232mmol/L) of magnesium are sought, e.g. treatment of supraventricular and ventr icular arrhythmias, pre- eclampsia and eclampsia, bronchospasm. Oral magnesium sulfate has a laxative effect and may cause severe diarrhea. High plasma levels of magnesium may develo p in renal failure; caution should be applied when administering IV magnesium. HYPOMAGNESAEMIA 493 See also: Calcium, magnesium, and phosphate, p214; Bronchodilators, p254; Diuretics, p280; Asthma \200\224 general management, p364; Tachyarrhythmias, p384; Generalized seizures, p44 4. 494 CHAPTER 29 Metabolic disorders Hypercalcaemia Causes \200 \200 \200 \200 \200 \200 \200 \200 Malignancy (e.g. myeloma, bony metastatic disease, hypernephroma). Hyperparathyroidism. Sar coidosis. TB. Excess intake of calcium, vitamin A or D. Drugs, e.g. thiazides, lithium. Imm obilization. Rarely, thyrotoxicosis, Addison \200\231s disease. Clinical features Usually become apparent when total (ionized and unionized) plasma levels >3.5mmol/L (normal range 2.2 \200\2232.6mmol/L) or the ionized fraction >1.7mmol/L (normal range 1.05 \200\2231.25). Symptoms depend on the patient \200\231s age, the duration and ra te of increase of plasma calcium, and the presence of concurrent medical conditions. \200 \200 \200 \200 \200 \200 \200 \200 \200 Nausea, vomiting, weight loss, pruritus. Muscle weakness, fatigue, lethargy. Depression, ma nia, psychosis. Drowsiness, coma. Abdominal pain, constipation. Acute pancreatitis. Peptic ulceration. Polyuria, renal calculi, renal failure. Arrhythmias. Management 1. Identify and treat cause where possible. 2. Monitor haemodynamics, urine output, and ECG morphology wit h frequent estimations of plasma Ca2+, PO4 3 \200\223, Mg2+, Na+, and K+. 3. Intravascular volume repletion \200\224inhibits proximal tubular reabsorption of calcium and often lowers plasma calcium by 0.4 \200\2230.6mmol/L. It should precede diuretics or o ther therapy. Either colloid or 0.9% saline should be used, depending on the presence of hy povolaemia-related features. 4. Calciuresis \200\224after adequate intravascular volume rep letion, a forced diuresis with furosemide plus 0.9% saline (6 \200\2238L/d) may be attempte d. An effect is usually seen within 12h. Loop diuretics inhibit calcium reabsorption in the ascending limb of loop of Henl . More aggressive furosemide regimens can be attempted but can potentially result in complications. Thiazides should not be used as tubular reabsorpt ion may be reduced and hypercalcaemia worsened. 5. Dialysis/haemo \201 ltration \200\224may be indicated at an early stage if the patient is in established oligo-anuric renal failure 9 \202 uid overloaded. 6. Corticosteroids re duce hypercalcaemia in hematological cancers (lymphoma, myeloma), vitamin D overdose, and sarcoidosis. 7. Calcitonin has the most rapid onset of action within 12 \200\22324h. Its action is usual ly short-lived and rebound hypercalcaemia may occur. It gener- ally does not drop the plasm a level more than 0.5mmol/L. 8. Bisphosphonates (e.g. pamidronate) and IV phosphate should only be given after specialis t advice is taken in view of their toxicity and poten- tial complications. HYPERCALCAEMIA 495 Drug dosages Diuretics Furosemide 10 \200\22340mg IV 2 \200\2234h (may be increased to 80 \200\223 100mg IV every 1 \200\2232h) Corticosteroids Hydrocortisone 100mg qds IV or prednisolone 40 \200\22360mg PO for 3 \200\2235d Pamidronate 15 \200\22360mg slow IV bolus Calcitonin 3 \200\2234U/kg IV followed by 4U/kg SC bd See also: Calcium, magnesium, and phosphate, p214; Diuretics, p280; Corticosteroids, p328; Acute renal failure \200\224diagnosis, p400; Acute renal failure \200\224management, p402; Pancreatitis, p424; Diabetic ketoacidosis, p510; Thyroid emergencies, p524; Hypoadrenal cri sis, p526. 496 CHAPTER 29 Metabolic disorders Hypocalcaemia Causes \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Associated with hyperphosphataemia. Renal failure. Rhabdomyolysis. Hypoparathyroidism (incl uding surgery), pseudohypoparathyroidism. Associated with low/normal phosphate. Critical il lness, including sepsis, burns. Hypomagnesaemia. Pancreatitis. Osteomalacia. Over-hydration . Massive blood transfusion (citrate-binding). Hyperventilation and resulting respiratory a lkalosis may reduce ionized plasma Ca2+ levels and induce clinical features of low calcium. Clinical features These usually appear when total plasma calcium levels <2mmol/L and the io nized fraction is <0.8mmol/L. \200 \200 \200 \200 \200 \200 \200 Tetany (including carpopedal spasm). Muscular weakness. Hypotension. Perioral and periphera l parasthesiae. Chvostek and Trousseau \200\231s signs. Prolonged QT interval. Seizures. Management 1. If respiratory alkalosis is present, adjust ventilator settings or, if sponta - neously hyperventilating and agitated, calm 9 sedate. Rebreathing into a bag may be bene \201 cial. 2. If symptomatic, give 5 \200\22310mL 10% calcium chloride solution over 2 \200\2235min. Repeat as necessary. 3. Correct hypomagnesaemia or hypokalaemia if present. 4. If asymptomatic and in renal fail ure or hypoparathyroid, consider enteral/parenteral calcium supplementation and vitamin D a nalogs. 5. If hypotensive or cardiac output is decreased following administration of a calc ium antagonist, give 5 \200\22310mL 10% calcium chloride solution over 2 \200\2235min. HYPOCALCAEMIA 497 See also: Calcium, magnesium, and phosphate, p214; Diuretics, p280; Hypotension, p380; Acut e renal failure \200\224 diagnosis, p400; Acute renal failure \200\224management, p402; Pan creatitis, p424; Hypomagnesaemia, p492; Hypophosphataemia, p498; Rhabdomyolysis, p612. 498 CHAPTER 29 Metabolic disorders Hypophosphataemia Causes \200 \200 \200 \200 Critical illness. Inadequate intake. Loop diuretic therapy (including low-dose dopamine). P arenteral nutrition \200\224levels may fall rapidly during high-dose IV glucose therapy, es pecially with insulin. Alcoholism. Hyperparathyroidism. Refeeding syndrome \200\224occurs w hen malnourished patients are given high carbohydrate loads, with rapidly falling phosphate , magnesium and potassium, and \202 uid retention. This can precipitate acute heart failu re due to an increase in cardiac work and a sudden rise in CO2 production due to the diet-i nduced increase in RQ. \200 \200 Clinical effects Hypophosphataemia is associated with muscle weakness, rhabdomyolysis, pare sthesiae, haemolysis, platelet dysfunction, and cardiac failure. However, this is rarely cl inically apparent, even in patients with severe hypophospha- taemia where plasma levels may drop <0.1mmol/L. Management Phosphate supplements (5 \200\22310mmol) should be given by intravenous infu- si on over 6h and repeated according to the plasma phosphate level. To prevent refeeding syndr ome, recognize the possibility and start feed slowly with aggressive supplementation of K+, Mg2+, and phosphate. HYPOPHOSPHATAEMIA 499 See also: Enteral nutrition, p128; Parenteral nutrition, p130; Tight glycaemic control/inte nsive insulin therapy, p132; Calcium, magnesium and phosphate, p214; Diuretics, p280. 500 CHAPTER 29 Metabolic disorders General acid-base principles In the Stewart theory, blood pH is determined by PCO2, the str ong ion difference, and the concentration of non-volatile weak acids. Weak acids dissociate to produce weak anions (predominantly albumin, phosphate). Bicarbonate, though produced ac cording to PCO2, is also a weak anion and is not a dependent determinant of pH. Strong ions are completely ionized with pKa <4. Normally, there is a surfeit of strong cations \200 \224the strong ion difference that balances weak anions to maintain electrical equilibrium. Strong ion difference = (Na+ + K+ + Mg2+ + Ca2+) 2 \200\223) \200\223 (Cl \200\223 + Lactate + SO4 A change in charge equilibrium by altering strong ion difference or weak anion concentratio n is compensated by a change in concentration of H+ ions with resulting acid base disturban ce. With time, respiratory and renal adjustments. correct pH towards normal by altering pla sma PCO2 and strong ion difference. Factors changing pH In addition to changes in PaCO2, the following will affect pH: Increase d strong ion difference (alkalosis) \200 Chloride loss, e.g. vomiting, large gastric aspirates, diuretics, hyper- aldosteronism, cor ticosteroids. Potassium retention, e.g. renal failure, distal renal tubular acidosis. Sodiu m load. \200 Decreased strong ion difference (acidosis) \200 \200 \200 Chloride increase, e.g. saline, acetazolamide. Hyperlactataemia. Na+ or K+ loss, e.g. diarr hea, small bowel \201 stula, urethro-enterostomy, proximal renal tubular acidosis. Unmeas ured anions, e.g. ketosis, salicylate poisoning. Decreased weak acids (alkalosis) \200 Hypoalbuminaemia. Principles of management 1. Correct (where possible) the underlying cause, e.g. hypoperfusi on. 2. Avoid large volume saline-based \202 uids. Consider balanced electrolyte solutions such as Hartmann \200\231s or Ringer \200\231s lactate. 3. NaCl infusion for vomiting-induced alkalosis; insulin, Na+, and K+ in diabetic ketoacidosis. 4. Correct pH in speci \201 c circumstances only, e.g. NaHCO3 in renal failure. GENERAL ACID-BASE PRINCIPLES 501 See also: \210\222 \210\222 Blood gas analysis, p154; Electrolytes (Na+, K+, Cl ), p212; Lactate, p236; Crystalloids, p242; , HCO3 Sodium bicarbonate, p244; Metabolic acidosis, p50 2; Metabolic alkalosis, p504. 502 CHAPTER 29 Metabolic disorders Metabolic acidosis A subnormal arterial blood pH with a base de \201 cit >2mmol/L, reduced strong ion difference and/or an increase in weak acids. Outcome in criti- cally ill patien ts has been linked to severity, duration, and hyperlactataemia. Causes \200 Hyperlactataemia \200\224may be due to tissue hypoperfusion (e.g. circulatory shock) or nec rosis, cellular abnormalities (any cause of mitochondrial inhibition, e.g. sepsis, drug-rel ated inhibition of aerobic respiration), and accelerated anaerobic respiration. The latter may be due to tissue hypoxia or to excess adrenergic tone/catecholamine infusion (notably e pinephrine), increasing activity of muscle Na+ pumps. High lactate may be seen with increas ed muscle activity (e.g. post- seizure). Lung lactate release is seen in acute lung injury. Hyperchloraemia, e.g. excessive saline infusion. Ketoacidosis \200\224high levels of B-hyd roxybutyrate and acetoacetate related to uncontrolled diabetes mellitus, starvation, and al coholism. Renal failure \200\224accumulation of organic acids. Drugs \200\224in particular, aspirin (salicylic acid) overdose, acetazolamide (carbonic anhydrase inhibition), ammonium chloride, drugs inhibiting mitochondrial function (e.g. highly active antiretroviral thera py). Vasopressor agents may be implicated, possibly by inducing regional ischemia or, in th e case of epinephrine, accelerated glycolysis. Ingestion of poisons, e.g. paraldehyde, ethy lene glycol, methanol. Cation loss, e.g. severe diarrhea, small bowel \201 stulae, ileost omy. Glucose-6-phosphatase de \201 ciency. Thiamine de \201 ciency (affects glycolysis an d the Krebs \200\231 cycle). Prolonged seizures. Excessive muscular activity. \200 \200 \200 \200 \200 \200 \200 Clinical features \200 \200 \200 Dyspnoea. Haemodynamic instability. A rapidly increasing metabolic acidosis (over minutes t o hours) is not due to renal failure. Other causes, particularly severe tissue hypoperfusio n, sepsis, or tissue necrosis, should be suspected when there is associated systemic deteri oration. Management 1. The underlying cause should be identi \201 ed and treated where possible rat her than administering alkali or manipulating minute volume to nor- malise the arterial pH. 2. Urgent haemo(dia) \201 ltration may be necessary if oligoanuria persists. 3. Reversal o f the metabolic acidosis (other than simple buffering with bicarbonate) is generally an ind ication of successful therapy. An increas- ing base de \201 cit suggests that the therapeu tic maneuvers in operation are either inadequate or wrong. 4. Bicarbonate therapy may be appropriate when tissue hypoperfusion has been corrected/excl uded. This is particularly the case for ongoing loss of alkali (e.g. biliary \201 stula, diarrhea) or inability to acidify urine. 5. The bene \201 ts of buffers such as Carbicarb and THAM (tris-hydroxy- methyl-aminomethane) remain unproven. METABOLIC ACIDOSIS 503 Key paper Levy B, Gibot D, Franck P, et al. (2005) Relation between muscle Na+K+ ATPase act ivity and raised lactate concentrations in septic shock: a prospective study. Lancet 365: 8 71 \200\2235. See also: \210\222 \210\222 Blood gas analysis, p154; Electrolytes (Na+, K+, Cl ), p212; Lactate, p236; Crystalloids, p242; , HCO3 Sodium bicarbonate, p244; Acute renal failure \200\224diagnosis, p400; General acid-base principles, p500; Diabetic ketoacidosis, p510; S ystemic in \202 ammation/multi-organ failure \200\224causes, p556; Sepsis and septic shock \200\224treatment, p560. 504 CHAPTER 29 Metabolic disorders Metabolic alkalosis A supranormal arterial blood pH with a base excess >2mmol/L and an incr eased strong ion difference caused either by loss of (non-carbonic) acid or gain of base. A s the kidney is usually ef \201 cient at excreting large quantities of bicarbonate, persis tence of a metabolic alkalosis usually depends on either chronic renal failure or a diminis hed extracellular \202 uid volume with severe depletion of K+, resulting in an inability to reabsorb Cl \200\223 in excess of Na+. \200 The patient is usually asymptomatic althou gh, if spontaneously breathing, will hypoventilate. A metabolic alkalosis will cause a left shift of the oxyhaemoglobin curve, reducing oxygen availability to the tissues. If severe (pH >7.6), metabolic alkalosis may result in encephalopathy, seizures, decreased coronary b lood \202 ow, and cardiac contractility. Causes \200 \200 \200 \200 Diuretics. Large nasogastric aspirates, vomiting. Secondary hyperaldosteronism with potassi um depletion. Use of haemo \201 ltration replacement \202 uid containing excess buffer ( e.g. lactate). Renal compensation for chronic hypercapnia (increasing strong ion difference ). This can develop within 1 \200\2232 weeks. Though more apparent when the patient hyperve ntilates or is hyperventilated to normocapnia, an overcompensated metabolic alkalosis can o ccasionally be seen in the chronic state (i.e. a raised pH in an otherwise stable long-term hypercapnic patient). Excess administration of bicarbonate. Excess administration of citra te (large blood transfusion). Drugs, including laxative abuse, corticosteroids. Rarely, Cus hing \200\231s, Conn \200\231s, Bartter \200\231s syndrome. \200 \200 \200 Management 1. Replacement of \202 uid, sodium chloride (i.e. give 0.9% saline), and potas - sium losses are often suf \201 cient to restore acid-base balance. 2. With distal renal causes related to hyperaldosteronism, addition of spironolactone (or potassium canrenoate) can be considered. 3. Active treatment is rarely necessary. If so, give ammonium chloride 5g tds PO. Hydrochlo ric acid has been used on occasion for severe metabolic alkalosis (pH >7.7). It should be g iven via a central vein in a concentration of 1mmol HCl per mL water at a rate <1mmol/kg/h. 4. Compensation for a longstanding respiratory acidosis, followed by cor- rection of that acidosis, e.g. with mechanical ventilation, will lead to an uncompensated metabolic alkalos is. This usually corrects with time though acetazolamide (or rarely, mechanical \200\230hy poventilation \200\231, i.e. main- taining hypercapnia) can be considered. METABOLIC ALKALOSIS 505 See also: Haemo(dia) \201 ltration (1), p108; Haemo(dia) \201 ltration (2), p110; Blood g as analysis, p154; Electrolytes (Na+, K+, Cl \200\223, HCO3 Acute renal failure \200\224dia gnosis, p400; Vomiting/gastric stasis, p406; General acid-base principles, p500; Diabetic k etoacidosis, p510; Systemic in \202 ammation/multi-organ failure \200\224causes, p556; Sep sis and septic shock \200\224treatment, p560. \200\223), p212; Diuretics, p280; Sodium bicarbonate, p244; Blood transfusion, p248; 506 CHAPTER 29 Metabolic disorders Hypoglycaemia Causes \200 \200 \200 \200 \200 \200 Inadequate intake of carbohydrate. Excess insulin or sulphonylurea. Liver failure with depl etion of glycogen stores. Alcohol. Hypoadrenalism (including Addison \200\231s disease), hy popituitarism. Quinine, aspirin. Clincal features \200 Nausea, vomiting. \200 Increased sympathetic activity, e.g. sweat ing, tachycardia. \200 Altered behavior and conscious level. \200 Seizures, focal neuro logical signs. Management 1. Monitor carefully with regular bedside estimations. The frequency should be i ncreased in conditions known to precipitate hypoglycaemia, e.g. insulin infusion, liver fai lure, quinine treatment of malaria. 2. Administer 25mL 50% glucose solution if the blood gl ucose is: