650 Alzheimer dementia This is often considered the worst neuropsychiatric disorder of our time s. Suspect AD in adults with any persistent, acquired deficit of memory and cognition; e.g. , as revealed in the mental test score and other neuropsy- chometric tests. Onset may be fr om 40 yrs (or earlier; e.g., in Down \200\231s syn- drome), so the notions of \200\234seni le \200\235 and \200\234presenile \200\235 dementia are irrelevant. Diagnosis is often hap hazard. Specialist assessment with neuroimaging for all would be ideal (this would help rul e out frontal lobe and Lewy body dementias, and Pick \200\231s disease). Histology (rarely used) \212 e n i c i d e m c i r t a i r e G Deposition of in the amyloid precursor protein) Neurofibrillary tangles and an increased nu mber of senile plaques \200\223 amyloid protein in cortex (a few patients have mutations \212 Presentation Early (stage I) in AD, there is failing memory and spatial disorientation. In stage II (follows after several years), personality changes (e.g., increased aggression and focal parietal signs \200\224dysphasia, apraxia, agnosia, and acalculia). Parkinsonism may occur. In stage III, the patient becomes apathetic, wasted, bedridden, and incontinent. Se izures and spasticity are common. Mean survival 7 yrs from onset. Management Theoretical is sues: Potential strategies: \212 \212 Preventing the breakdown of acetylcholine (e.g., donepezil; see below) Augmenting nerve gro wth factor (NGF), which is taken up at nerve end- ings and promotes nerve cell repair Stimu lating nicotinic receptors that may protect nerve cells Inhibiting the enzymes that snip-ou t cursor protein (APP), so preventing fibrils and plaques Using anti-inflammatories to prev ent activation of microglial cells to secrete neurotoxins (e.g., glutamate, cytokines), whi ch stimulates forma- tion of APP Regulating calcium entry (mediates the damage of neurotoxi ns) Preventing oxidative damage by free radicals \212 \212 \200\223 amyloid peptide from amyloid pre- \212 \212 \212 Practical issues: Treat concurrent illnesses (they contribute significantly to confusion). In most people, the dementia remains and will progress. Involve relatives and c ommunity services. Consult with an expert; if the dementia is mild or moderate, consider in creas- ing acetylcholine availability by inhibiting acetylcholinesterase (e.g., donepe- zil 5 mg PO every night at bedtime; increasing to 10 mg after 1 month). Effects may be minimal , but subtle cognitive changes can cause significant behavioral improvement even without \200\234objective \200\235 improvement in bedside tests of cognition. The need for institut ional care may be delayed. Prevention There are no clear ways to avoid this disease. Hormon e replacement therapy (HRT) and controlling vascular risk factors may offer some protection . 651 Preventive geriatrics Although even the most fit elderly will have continued declines in mo st organ systems with aging, evidence clearly supports that exercise can ame- liorate many of these losses substantially and help preserve function and independence. It may help impr ove range of movement and decrease pain associated with knee osteoarthritis. It has been sh own to both treat osteo- porosis and, in retrospective studies, prevent it. Exercise, parti cularly exer- cises that incorporate some aspect of balance training, have been shown to re duce falls, even in high-risk individuals. As with their younger counterparts, exercise may lower BP and favorably alter lipid profiles. Clearly, the most fit individuals tend to have the longest life expectancy and longest period of functional independence. Ep idemiologic studies demonstrate that improving fitness state is associated with beneficial effects on mortality, even when this change is enacted in older age. Although the best exer cise regimen has not been firmly established, most elderly are remarkably sedentary and wil l gain substantially simply from reducing their inactivity by altering lifestyle. Examples of this include watch- ing less television, taking the stairs rather than the elevator, par king farther away from the entrance of stores, and walking up and down every aisle in the g rocery store. Walking is an inexpensive exercise that has functional rel- evance. The physi cian may assist in improving fitness by endorsing exercise and identifying barriers and fac ilitators to exercise with patients. Most authorities endorse screening examinations for ol der individuals similar to those of younger individuals when the projected life expectancy is >10 yrs and when such screening (and subsequent decisions based on the results) is consi stent with the overall goals of care of the individual. Although accurate prognosis is extr emely difficult in patients with severe chronic conditions that exacerbate and remit, some evidence suggests that most physicians tend to underestimate life expectancy in the elderly when considering these decisions. Be particularly cautious of the risk of ageism. For exam ple, the life expectancy of an 85-yr-old woman who is in the top quartile of functional sta tus is nearly 10 yrs. Screening decisions about patients with cognitive impairment are part icularly vexing and must take into careful consideration the ability of the patient to part icipate in the test- ing, the risks of such testing, the ability of the patient to undergo treatments if a disease is found, and, most important of all, the overarching goals of care . Prevention of injury in the elderly would include assessment for falls; discussions about firearms, particularly if a demented individual is in the home; use of seat belts in cars; evaluation for continued ability to drive; and home safety assessment. Smoking cessation r educes the risk of lung cancer at any age. Although not proven for primary prevention of co ronary artery disease (CAD), it continues to have an important role in prevention of MI in patients with established CAD. Thus, cessation of smoking is important to endorse and encou rage even in the elderly. Finally, several periodic immunizations are advised in the elderl y, although their benefits for all subgroups is often debated. Pneumococcal vaccination is recommended at least once over the age of 65 yrs, with consideration of revaccination in ce rtain subgroups. Influenza vaccination is advised annu- ally for all elderly; although like ly the most effect approach to preventing influenza in nursing homes is to aggressively imm unize staff. Periodic (every 10 yrs) revaccination for tetanus is also advised. Vaccination to prevent shingles is now advised once in a lifetime >50 yrs. 652 This page intentionally left blank Biochemistry Paul E. Segal , D.O. and Joshua D. King , M.D. y r t s i Contents m e h c o B On being normal in the society of numbers 654 The laboratory and ward tests 656 IV fluid th erapy 658 Acid-base balance 660 Urate and the kidney 665 Electrolyte physiology 666 Sodium: Hyponatremia 668 Sodium: Hypernatremia 671 Potassium 671 Hyperkalemia 671 Hypokalemia 673 Calcium: Physiology 674 Hypercalcemia 675 Hypocalcemia 675 Magnesium 677 Trace elements 677 Plasma proteins 678 Plasma enzymes 679 Tumor markers 680 The porphyrias 682 i 7 1 On being normal in the society of numbers Laboratory medicine reduces our patients to a few easy-to-handle numbers: This is the discipline \200\231s great attraction \200\224and its greatest danger. The normal range (reference interval) is usually that which includes 95% o f patients. If variation is randomly distributed, 2.5% of our results will be \200\234too high \200\235 and 2.5% \200\234too low \200\235 when dealing with apparently normal people using this statistical definition of normality. Other definitions may be normative \200 \224i.e., stating what an upper or lower limit should be (see Table 17.1). For example, the upper end of the reference interval for low-density lipoprotein (LDL) cholesterol may be g iven as 130 mg/dL because this is what preventative cardiologists state to be the desired m aximum, although the risk of coro- nary heart disease (CHD) increases above 100 mg/dL (and even 70 mg/dL). The World Health Organization (WHO) definition of anemia in pregnancy is an Hgb of <11 g/dL, which makes 20% of mothers anemic. This \200\234lax \200\235 criterion h as the presumed benefit of triggering actions that result in fewer deaths by hemorrhage. So do not just ask \200\234What is the normal range? \200\235; also question who set the ran ge, for what population, and for what reason. 654 y r t s i Table 17.1 The essence of laboratory medicine Only do a test if the result will influence management. Make sure you look at the result! E xplain to the patient where this test fits into his or her overall plan of management. Do n ot interpret laboratory results except in the light of clinical assessment. If there is dis parity, trust clinical judgment and repeat the test. Reference intervals (normal ranges) ar e usually defined as the interval, symmetrical about the mean, containing 95% of results on the popula- tion studied. The more tests you run, the greater the probability of an \200 \234abnormal \200\235 result of no clinical significance. Artifacts Delayed analysis for pl asma potassium Anion gap (AG) Reflects unmeasured anions (e.g., lactate, uremic toxins, org anic acids) Biochemistry results: Major disease patterns ( \206\221 = raised, \206\223 = lowered) Hypovolemia: Urea \206\221 , albumin \206\221 (useful to plot change in a patien t \200\231s condition). Hematocrit (PCV) \206\221 , creatinine \206\221 ; also urine volu me \206\223 ; skin turgor \206\223 Renal failure: Creatinine \206\221 , urea \206\221 , AG \206\221 , K + \206\221 , PO 4 3 \200\223 \206\221 , HCO 3 \200\223 \206\223 Diur etic use Serum Na + Serum K + Serum HCO 3 - Serum Ca 2+ Serum Mg 2+ Serum uric acid m e h c o B i Loop Normal, \206\221 \206\223 \206\221 \206\223 \206\223 \206\221 Thiazide \206\223 \206\223 \206\221 \206\221 \206\223 \206\221 3- PO4 K + -sparing Normal, \206\223 \206\221 \206\223 Normal, \206\223 \206\221 \206\221 Bone disease Ca 2+ Alk phos Osteoporosis Osteomalacia Paget \200\231s Myeloma Bone metastases 1 Hyper parathyroidism Hypoparathyroidism Renal failure (low glomerular Normal \206\223 Normal \206\221 \206\221 \206\221 \206\223 \206\223 Normal \206\223 Normal \206\221 , Normal Normal \206\221 ,Normal \206\223 , Normal Norm al, \206\221 \206\221 \206\221 Normal \206\221 \206\221 \206\221 \206\221 Normal Normal, \206\221 filtration rate;GFR) Hepatocellular disease Bilirubin \206\221 , aspartate aminotransferase (AST) \206\221 (al k phos slightly \206\221 , albumin \206\223 ) Cholestasis: Bilirubin \206\221 , -glut amyl transpeptidase (GGT) \206\221 \206\221 , alk phos \206\221 \206\221 , AST \206\221 Myocardial infarct (MI): AST \206\221 , lactate dehydrogenase (LDH) \206\221 , creatine k inase (CK) \206\221 , troponin T/I \206\221 Diabetes mellitus: Glucose \206\221 (bicarbo nate \206\223 and AG \206\221 if diabetic ketoacidosis) Addison \200\231s disease: Potass ium \206\221 , sodium \206\223 Cushing \200\231s syndrome: May show potassium \206\223 , bicarbonate \206\221 , sodium \206\221 Hyperaldosteronism: May present with potassium \206\223 , bicarbonate \206\221 (and high blood pressure [BP]); sodium normal or \206\221 655 (Continued) Table 17.1 (Continued) Diabetes insipidus (DI): Sodium \206\221 , plasma osmolality \206\221 , urine osmolality \206\223 (both hypercalcemia and hypokalemia may cause nephrogenic DI) Inappropriate antid iuretic hormone (ADH) secretion: Na + \206\223 with normal or low urea and creatinine, pla sma osmolality \206\223 ; urine osmolality \206\221 (can be > than plasma osmolality), ur ine Na \206\221 (>20 mmol/L) Excess alcohol intake: Evidence of hepatocellular disease. Ea rly evidence in GGT \206\221 , mean cellular volume (MCV) \206\221 , ethanol in blood bef ore lunch Some immunodeficiency states: Normal serum albumin but low total pro- tein (low a s immunoglobulins are missing \200\224also making cross-matching difficult because expected hemagglutinins are absent) Life-threatening biochemical derangements (See pp. 657 \200\223 658). The laboratory and ward tests Laboratory staff like to have contact with you. Consult with a clinical pathologist for unusual or uncommon laboratory tests; their input may be invalua ble. 10 tips to better laboratory results 1 Interest someone from the laboratory in your patient \200\231s problem. 2 Fill in the request form fully. 3 Give clinical details, not your pre ferred diagnosis. 4 Ensure that the lab knows who to contact. 5 Label specimens as well as the request form. 6 Follow the hospital labeling routine for cross-matching. 7 Find out whe n analyzers run, especially batched assays. 8 Talk with the lab before requesting an unusua l test. 9 Be thoughtful: Don \200\231t \200\234shoot the messenger. \200\235 10 Plot resul ts graphically: Abnormalities show sooner (see Table 17.2). Artifacts and pitfalls in laboratory tests \212 \212 \212 \212 Do not take blood sample from an arm that has IV fluid running into it. Repeat any unexpect ed result before acting on it. For clotting time, do not sample from a heparinized IV cathe ter. Serum K venipuncture is difficult). If using Vacutainers, fill nation from previous tu bes can cause errors. Total calcium results are affected by albumin concentration. Internat ional normalized ratio (INR) may be overestimated if citrate bottle is underfilled. Drugs m ay cause tisol). Be suspicious if results are unexpected. Food may affect result (e.g., ban anas raise urinary hydroxyindoleacetic acid [HIAA]). + is overestimated if sample is old or hemolyzed (this occurs if \212 plain tubes first; otherwise, anticoagulant contami- \212 \212 \212 analytic errors (e.g., prednisolone cross-reacts with cor- 656 \212 Using urine dipsticks Store dipsticks in a closed container in a cool, unrefrigerated place . If improperly stored, or past expiration date, do not use. For urine tests, dip the dipst ick briefly in urine, run edge of strip along container, and hold strip horizontally. Read at the specified time \200\224check instructions for the type of stick. Urine specific grav ity (SG) can be measured by dipstick. It is not a good measure of osmolality. Causes of low SG (<1.003) are DI, water diuresis. Causes of high SG (>1.025) are hypovolemia, diabetes mellitus, adrenal insufficiency, liver disease, heart failure. Sources of error in interpreting dipstick results Bilirubin: False positive: Phenothiazines. False negative: Urine not fresh, rifampicin. Urobilinogen: False negative: Urine not fresh. (Normally present in urine due to metabolism of bilirubin in th e gut by bacteria and subsequent absorption.) Ketones : L - dopa affects color (can give fa lse-positive). \222-hydroxybutyrate gives a false-negative result. Blood: False-positive: Myoglobin, profuse bacterial growth. False-negative: Ascorbic acid. Urine glucose: Depends on test. Pads with glucose oxidase are not affected by other reducing sugars (unlike Clinit est ) but can give false-positive to peroxide, chlorine; and false-negative with ascorbic acid, salicylate, L-dopa. Protein: Highly alkaline urine can give false-positive. Blood glu cose: Sticks use enzymatic method and are glucose specific. A major source of error is appl ying too little blood (a large drop to cover the pad is necessary) and poor timing. Reflect ance meters increase precision but introduce new sources of error. y r t s i m e h c o B i Table 17.2 Laboratory results: When to take action NOW \212 \212 On receiving a dangerous result, first check the name and date. Go to the bedside. If the p atient is conscious, turn off any IVF (until fluid is checked: A mistake may have been made ) and ask the patient how he or she is. Any seizures, syncope, or unexpected symptoms? Be s keptical of an unexpected wildly abnormal result with a well patient. Could the specimens b e mixed up? Is there an artifact? Was the sample taken from the \200\234drip \200\235 arm? A low calcium may be due to a low albumin. Perhaps the lab is using a new analyzer with a faulty wash cycle? When in doubt, repeat the test . \212 The values chosen below are somewhat arbitrary and must be taken as a guide only. Many resu lts less extreme than those below will be just as dangerous if the patient is elderly, immu nosuppressed, or has some other pathology, such as pneumonia. Plasma biochemistry Beware el ectrocardiological central nervous system (CNS) events (e.g., seizures) Calcium (correct ed for albumin) >13 mg/dL: If shortening QT interval on electrocardiogram (ECG) or symptoms , then dangerous hypercalcemia. Calcium (corrected for albumin) <7.5 mg/dL + symptoms such as tetany or long QT: Dangerous hypocalcemia . Magnesium <1.5 mg/dL + ventricular arrhythmi a or long QT: Dangerous hypomagnesemia. Phosphorus <1 mg/dL or <2 mg/dL + symptoms of muscu lar weakness: Dangerous hypophosphatemia. Glucose <60 mg/dL: Hypoglycemia. Glucose 50 mL 50 % IV if symptoms; can give oral glucose if asymptomatic. Glucose >400 mg/dL: Severe hypergl ycemia. Is parenteral insulin needed? Potassium <2.5 mEq/L: Dangerous hypokalemia, especial ly if on digoxin. Potassium >6.5 mEq /L: Dangerous hyperkalemia . Sodium <120 mEq /L: Dange rous hyponatremia. Sodium >155 mEq /L: Dangerous hypernatremia. 657 (Continued) Table 17.2 (Continued) Blood gasses PaO 2 <60 mm Hg: Severe hypoxia. Give O 2 . pH <7.1: Dangerous acidemia. pH >7 .55: Dangerous alkalemia. Hematology results Hbg <7 g/dL with low mean cell volume (<75 fL) or history of bleeding: This patient may need urgent transfusion (no spare capacity). Neut rophils <1,000/ L: Dangerous neutropenia. Treat any fever as an emergency and give early a ntibiotic therapy. Platelets <40 \227 10 9 /L: May need a platelet transfusion; consult a hematologist. Plasmodium falciparum seen: Start antimalarials now; consult infectious disea ses. CSF results >1 neutrophil/mm 3 : Consider meningitis. Positive Gram stain: Talk to a m icrobiologist; urgent broad-spectrum therapy. Conflicting, equivocal, or inexplicable resul ts Get prompt help; repeat test. IV fluid therapy There are three reasons to use intravenous fluids (IVFs): To prevent volum e depletion and hypotension, to maintain normal plasma osmolality, and to replace ongoing l osses/match insensible losses if the patient is unable to keep up with oral fluids (see Tab le 17.3). There are only two instances to use both IVF therapy and diuretics: Hypercalcemia ( only use loop diuretics after repletion of intravascular volume or symptomatic fluid ove rload) and Rhabdomyolysis ( only use loop diuretics if evidence of volume overload). Principles of IVF therapy \212 \212 Pay careful attention to intake, output, and daily whether IVF should be continued: Always evaluate \212What are your goals? Does lab data and exam support the continued need for IV F? Does the patient have evidence of extracellular fluid excess or depletion on exam? Does the patient have an inability to access oral fluids (decreased mental status or debility pr eventing access)? daily morning weights. \212Maintenance IVF therapy: Replaces normal ongoing losses (see insensible losses below). It is used when a patient is unable to drink (postoperative states or ventilator use). Wat er losses lead to \206\221 serum sodium, stimulat- ing thirst and \206\221 ADH. A patient with access to water will typically not become hypernatremic. Typical maintenance IVF regi men consists of: \212Total fluid requirements per day = 2,000 mL/d = IVF at 84 mL/h. \212Which fluid to use? Total Na requirements per day = 50 \200\223150 mEq/d (77 mEq Na/L = isotonic fluid = 0.45% normal saline (NS) if not volume depleted or with large ongoing fluid losses. Total K requirements per day = 20 \200\22360 mEq/d = addition of 20 mEq KCL/L of IVF. KCL should not be added if there are concerns for acute kidney injury or worsening renal failure . Addition of dextrose to prevent ketosis = D 5 W. Example of maintenance IV F: D 5 W 0.45% NS with 20 mEq KCL/L @ 84 mL/h . \212 658 \212The original solution may need to be modified if there is increased GI or third-space losses (sequestration of fluid in a body compartment not equilibrated with the extracellula r fluid [ECF]). This may require a change to 0.9% NS. If serum sodium falls, use a more con centrated solu- tion (NS), or, if serum sodium rises secondary to increased insensible loss es, use a more dilute solution ( NS or D 5 W); see Table 17.4. \212Daily fluid balance : Normal intake: 2 \200\2232.9 L/d. Ingested fluids = 1 \200\2231.5 L/d. Water from food = 1 L/d. Water from oxidation (of carbohydrates) = 300 \200\223400 mL/d. y r t s i m e h c o B i Normal output : 2 \200\2232.7 L/d. Urine output = 1 \200\2231.5 L/d. Insensible losses: Los ses of fluid from skin, respiratory and GI tract. Normal insensible losses = 500 \200\22380 0 mL/d. Fever, excessive sweating, burns, drains, increased GI losses and can increase inse nsible losses. For each degree >37 C, water loss increases by 100 \200\223150 mL/d. \212R eplacement therapy: Corrects existing water and electrolyte deficits in excess of normal lo sses (e.g., nasogastric tube, vomiting, diarrhea, drains) The volume deficit may be estimat ed based on the change between pre- morbid and current weight. Rate of replacement depends on the degree of hypovolemia. If the patient has shock, this is best treated by bolus thera py (i.e., 200 \200\223250 mL or 3 mL/kg over 5 min of 0.9% NS (total of 1 \200\2232 L of 0. 9% NS IV over 30 min to 1 h. Choice of replacement fluid; see Table 17.4. \212 \212 \212 \212Colloids : Given their large size, tend to stay in the intravascular space. Albu min administration is safe except in traumatic brain injury. The \200\234rule \200\235 of 3 \200\2234 mL of crystalloid to 1 mL of colloid for fluid resuscitation needs to be re-eva luated in clinical trials. Hydroxyethyl starch and dextrans may carry a risk of bleeding an d acute kidney injury. Table 17.3 Examples of fluid replacement based on total fluid requirements For each kilogram 100:50:20 Rule (daily requirements) 4:2:1 Rule (Holliday and Segar)(hourly requirements) 1st 10 kg 100 mL 4 mL/h 2nd 10 kg For each kg >20 kg Example: 70 kg person 50 mL 20 mL/kg 1st 10 kg \227 100 mL = 1,000 mL 2nd 10 kg \227 50 mL = 500 mL 50 kg \227 20 mL = 1,000 mL Total = 2,500 mL 24 h = 104 mL/h 2 mL/h 1 mL/h 1st 10 kg \227 4 mL/h = 40 mL/h 2nd 10 kg \227 2 mL/h = 20 mL/h 50 kg \227 1 mL/h = 50 mL/h Total = 110 mL/h 659 Table 17.4 Replacement fluids Soln D 5 W LR b 0.9%NS 3% Saline Glu Na K CL Ca 2+ HCO 3 - 0 Lactate Osm 50 a 0 0 0 0 0 252 0 0 0 130 154 513 4 0 0 109 154 513 3 0 0 c 0 0 28 0 0 275 308 1026 Glucose (g/dL), Na, K, Cl, Ca2+, HCO 3 - and Lactate units are mEq/L a 1 g of glucose = 4 calories b LR, lactated Ringer \200\231s; NS, normal saline c Lactate acts as a source of b icarbonate when normal production and utilization of lactic acid is not impaired (adjusted pH of solution = 6.6 \200\2236.75). Acid-base balance Arterial blood pH is closely regulated as processes necessary for life ar e pH sensitive and cannot occur outside a range of body fluid pH of 6.8 \200\2237.8. The ca rbonic acid (H 2 CO 3 - ): bicarbonate (HCO 3 - ) buffer system is the most rel- evant clin ically and is regulated by both the kidneys (which regulate HCO 3 - ) and the lungs (which regulate CO 2 ). How to approach an arterial blood gas (ABG) Use the Henderson-Hasselbalch equation to determine the pH (and consis- tency) of the data. Arterial pH = 6.1 + log [HCO 3 - ] / 0.03 \227 CO 2 Evaluate the pH: Acidemia refers to the pH level, versus acidosis, which refers to the process. Simultaneously measure an ABG and electrolytes. Normal pH = 7. 36 \200\2237.44. A pH <7.35 is acidemia and a pH >7.45 is alkalemia. A normal pH does not r ule out an acid-base disorder. Respiratory disorders : pH, HCO 3 - , and CO 2 move in oppos ite directions . Normal CO 2 = 35 \200\22345 mm Hg. Metabolic disorders : pH, HCO 3 - , and CO 2 move in the same direction . Normal HCO 3 - = 22 \200\22326 mEq/L. The HCO 3 - record ed on the ABG is cal- culated from the Henderson-Hasselbalch equation from the ratio of CO 2 / HCO 3 - . The HCO 3 - on a basic metabolic panel is measured as the total CO 2 (include s dissolved CO 2 ) and is 1.2 mEq/L greater than calculated CO 2 Primary changes in HCO 3 - are termed metabolic , whereas primary changes in CO 2 are termed respiratory . Calculate the AG and, if elevated, calculate an osmolar gap if toxic alcohol ingestion is suspected. Osmolar gap = measured \200\223 calculated. Calculated osmolality = 2 \227 Na + + blood urea nitrogen (BUN)/2.8 + glucose/18. Normal osmolar gap = (-) 10 to (+) 10 with a normal p lasma osmolality = 285 \200\223295 mOsm/L. A normal osmolar gap does not rule out toxic alc ohol inges- tion. Note: Early in toxic alcohol ingestion, the AG will be mildly elevated an d the osmolar gap will be high ; Late in a toxic alcohol ingestion, the AG will be high, an d the osmolar gap may be mildly elevated. See Table 17.5. Differential diagnosis of an elev ated AG is listed below under metabolic acidosis. Check the degree of compensation (Table 1 7.6): Determine the \200\234delta-delta \200\235 or delta AG/delta HCO 3 - ratio (see exam ple below). This allows you to determine if a non-AG metabolic acidosis or metabolic alkalo sis is present in addition to an AG metabolic acidosis. 660 y r t s i Table 17.5 Differential diagnosis of an elevated osmolar gap based on AG category m e h c o B Low AG Lithium Normal AG Isopropanol (isopropyl alcohol) High AG Methanol i Glycine Mannitol Severe hypertriglyceridemia Ethylene glycol Diethylene glycol Propylene glycol Ethanol (ETOH) End-stage renal disease D iabetic ketoacidosis (TG >1,500 mg/dL) Table 17.6 Degree of compensation Disorder Metabolic acidosis Compensation CO 2 = 1.5 \227 HCO 3 - + 8 2 (Winter \200\231s formula) CO 2 = HCO 3 - + 15 CO 2 = \206\221 0.5 \200\2230.7 mm Hg for each 1 mEq \206\221 HCO 3 - CO 2 = HCO 3 - + 15 CO 2 = 0.7*([measured HCO 3 - ]-24) + 40 Metabolic alkalosis Metabolic acidosis Primary disturbance is a decreased pH and HCO 3 - . Overproduction (or i ngestion)of a fixed acid or loss of base will produce a decrease in arterial pH (acidemia) and HCO 3 - will be used to buffer the extra fixed acid, resulting in a decrease in arteria l HCO 3 - . The development of acidemia will lead to hyperventilation, which provides the r espiratory compensation (by lowering the CO 2 ) to decrease the initial fall in pH. Metabol ic acidosis is further divided into either increased (high) AG meta- bolic acidosis or norm al AG (hyperchloremic, due to the \206\221 in CL - ) meta- bolic acidosis by calculating t he AG: AG = [Na + \200\223 (CL - + HCO 3 - )] with a normal range of 8 4 (if ion selec- tive electrodes are used).In healthy individuals, the AG is 11 2.5 mEq/L 1 AG is an est imate of unmeasured anions . It is important to know what the patient \200\231s normal AG i s prior to the development of an acidosis. Individual \200\231s maximum AG = (albumin \227 2.5) + phos \227 0.5). Clinical pearl : Always correct the AG for albumin (major source o f unmea- sured anions). The AG decreases 2.5 mEq/L for every 1.0 g/dL decrease in albumin from normal. Example : AG = 12 and serum albumin = 2.0 gm/dL. Normal serum albumin minus me asured serum albumin = 4.0 \200\223 2.0 = 2.0 \227 2.5 = 5 mEq/L. You add 5 mEq/L to the current AG of 12 = 17 (corrected AG). See Table 17.7. 661 1 Kraut JA, Madias NE. Serum anion gap:Its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007;2:162 \200\223174. Table 17.7 Differential diagnosis of an AG Low Normal/ Hyperchloremic Mnemonic = HARDUP Elevated Mnemonic = GOLDMARK * Lab error H = Hyperventilation/ Hyperalimentation A = Acetazolamide (carbonic anhydrase inhibitors) A ddison \200\231s disease/ Amphotericin B R = Renal tubular acidosis (RTA) Urine AG = Positi ve with distal and type 4 RTA (hyporenin- hypoaldosteronemia D = Diarrhea Urine AG = Negati ve U = Uretero-enteric diversion/fistula/urinary obstruction P = Pancreatico- duo- denal fi stula/ parenteral saline G = Glycols (ethylene, propylene) O = Oxoproline (pyroglutamic acid) Hypoalbuminemia L = L-Lactate/Linezolid Hypercalcemia Hypermagnesemia Hyperkalemia Lithium toxicity D = D-Lactate Multiple myeloma (IgG = cationic protein) M = Methanol/meds (Metformin, INH) A = Aspirin R = Renal failure K = Ketoacidosis (diabetic, alcoholic, or starvation) Adapted from Mehta AN, Emmett JB, Emmett M. GOLD MARK: An anion gap mnemonic for the 21st c entury. Lancet . 2008;372:892. Example : pH = 7.2, pCO 2 = 25 mm Hg, HCO 3 - = 10 mEq/L, Na + = 135 mEq/L, CL - = 100 mEq/ L, glucose = 130 mg/dL, BUN = 15 mg/dL, albumin = 4.0 g/dL, measured osmolality = 290 mOsm/ L. Internal consistency via Henderson-Hasselbalch = correct (pH = 7.22). pH <7.35 = acidemi a (with both the pH and HCO 3 - low = Metabolic). AG = 135 \200\223 (97 + 10) = 25 = eleva ted ; osmolar gap = 290 \200\223 (270 + 5 + 7) = 8 (normal). Expected pCO 2 compensation = 1.5 \227 HCO 3 - + 8 2 = 21 \200\22325 = Compensated. 662 Delta-Delta : Typically, when a fixed acid accumulates in the extracellular fluid, the decr ease in HCO 3 - is equivalent to the increase in AG (ratio 1:1). When a non-AG (hyperchlore mic) metabolic acidosis occurs with an increased AG acidosis, the decrease in HCO 3 - is gr eater than the increase in AG ( delta-delta <1 ) = coexistent non-AG metabolic acidosis. Ad ditionally, the chloride change equals the bicarbonate change (for every 1 mEq \206\221 in chloride, t he bicarbonate \206\223 1 mEq). If the delta-delta is >2.0, then the decrease in HCO 3 - i s less than the increase in AG = coexistent metabolic alkalosis. From the example, delta-de lta calculated by: (measured AG-8)/(normal HCO 3 - \200\223 10) = 17/14. Clinical pearl : Only used when there is an already noted elevated AG metabolic acidosis. Metabolic alkalosi s Primary disturbance is an increased pH and HCO 3 - . Occurs either from excess base (from intake, loss of acid (H + ), or generated by kidneys) or a failure of the kidneys to excre te excess bicarbonate. The work-up of metabolic alkalosis hinges on measurement of spot uri ne chloride, BP, serum potassium, plasma renin activity, and serum aldoster- one. See Table 17.8. Typically, there are two phases: Generation (initiation) and maintenance . Respirato ry acidosis Primary disturbance is decreased pH and increased CO 2 . Typically divided into CNS causes, neuromuscular disorders, or acute-chronic lung disease. Always consider overse dation with narcotics as a cause of respiratory aci- dosis. Need to look at P a O 2 to eval uate if oxygen therapy is needed. See Table 17.9. Respiratory alkalosis Primary disturbance is increased pH and decreased CO 2 . Typically divided into CNS causes or Other causes. Cl inical pearl: Sepsis and salicylate intoxication can cause both a respiratory alkalosis and metabolic acidosis. See Table 17.9. y r t s i m e h c o B i Table 17.8 Metabolic alkalosis Chloride depleted saline responsive (urine chloride <15 mEq/L) Vomiting/nasogastric tube (N GT) suction Saline unresponsive (urine chloride >15 mEq/L) Current diuretics Prior diuretics Post hypercapnia Villous adenoma Laxative abuse /chloride-rich Primary hyperaldosteronism Bartter \200\231s or Gitelman \200\231s syndrome Liddle \200\231 s syndrome Cushing \200\231s syndrome or ectopic diarrhea adrenocorticotropic hormone (ACTH) production Profound K + depletion Exogenous or endogenous miner- alocorticoid production (certain forms of licorice, chewing tobacco, or carbenoxolone) 663 Severe Mg ++ depletion Cystic fibrosis Hypertension (HTN) + Metabolic Alkalosis Differential Renin Low Aldosterone Low Causes Glycyrrhizic acid (certain forms of licorice or chewing tobacco) Carbenoxolone Exoge nous mineralocorticoids Liddle \200\231s syndrome Cushing \200\231s Syndrome Congenital adr enal hyperplasia Deoxycorticosterone (DOC) producing tumor Low High Primary hyperaldosteronism Glucocorticoid remediable aldosteronism (GRA) High High Renovascular HTN Malignant HTN Renin-secreting tumor Secondary Hyperaldosteronism Table 17.9 Respiratory acidosis ACUTE = HCO3 CHRONIC = HCO 3 \206\221CO 2 by 10 mm Hg \206\221 by 1 \206\221 by 3 Compensation respiratory disorders for Respiratory alkalosis ACUTE = HCO 3 CHRONIC = HCO 3 \206\223 by 2 \206\223CO2 by 10 mm Hg \206\223 by 5 664 Urate and the kidney Causes of hyperuricemia Hyperuricemia may result from either \206\221 turnover or \206\223 excretion of urate. Associated conditions may include: Gout and neph rolithiasis . Drugs: Diuretics (both thiazide and loop diuretics), chemotherapy (cisplatin, cyclophosphamide and vincristine), alcohol, cyclosporine, low-dose salicy- lates, ketocona zole, ethambutol, pyrazinamide, theophylline, and levodopa. Increased cell turnover: Lympho ma, leukemia, myeloproliferative disorders, hemolysis, rhabdomyolysis or tumor lysis syndro me (see below). Reduced excretion: Primary hyperuricemia ( gout), chronic kidney disease (CKD), volume depletion, lead nephropathy, pre-eclampsia or toxemia of pregnancy. Miscellan eous: syndrome. Hyperuricemia is normally defined as a serum uric acid >7.0 mg/ dL . In CKD , serum urate increases. Hyperuricemia in CKD has been defined as 3 \212 \212 \212 There is an association between hyperuricemia and CKD. The mechanism may be inflammatory from de position of urate crystals in the interstitium \206\222 progressive tubulointerstitial inj ury. y r t s i m e h c o B i G6PD deficiency, Lesch-Nyhan syndrome, metabolic >9 mg/dL for serum creatinine >10 mg/dL for serum creatinine of 1.5 \200\2232.0 mg/dL >12 m g/dL for serum creatinine of 2.1 \200\2233.0 mg/dL \211 1.5 mg/dL Tumor lysis syndrome (TLS) Constellation of metabolic abnormalities including hyperuricemia , hyperkalemia, hyperphosphatemia, hypocalcemia; frequently associated with acute kidney in jury (AKI; see p. 277, Oncology; see p. 430; Table 17.10) Table 17.10 Pathophysiology and risk factors Rapid cell breakdown post chemotherapy with release of intracel- lular contents. Hyperurice mia can lead to deposition of uric acid crystals within the tissues and renal tubules \206 \222 AKI. Highest risk of development: Burkitt \200\231s lymphoma,lymphoblastic lym- phoma, B-cell ac ute lymphoblastic lymphoma, acute leukemia (especially if WBC count \211 100,000/ L) C airo-Bishop * definition of tumor lysis syndrome Serum values included in the definition of laboratory TLS: \212 \212 \212 \212 \211 7 mg/dL or 25% \206\223 from baseline Crit eria included in the definition of clinical TLS: \212 Uric acid Potassium Phosphorus Calcium \211 8 mg/dL or 25% \206\221 from baseline \211 6 mEq/L or 25% \206\221 from baseline \211 4.5 mg/dL or 25% \206\221 from baseline 665 Serum creatinine of the age-adjusted normal range Cardiac arrhythmia or sudden death Seizur e \211 1.5 mg/dL greater than the value of the upper limit \212 \212 Cairo MS, Bishop M. Tumor lysis syndrome: New therapeutic strategies and clas- sification . Brit J Haematol. 2004;127(1):3 \200\22311. 3 Murray T and Goldberg M. Chronic Interstitial Nephritis: Etiologic Factors. Annals of Int ernal Medicine. 1975;82(4):453 \200\223459. Treatment Prevention is the cornerstone, based on recognizing which patient population is a t risk for TLS. Treatment may include: \212Aggressive hydration intravenously, minimum of 2 \200\2233 L/d, maintaining a urine output of 100 \200\223200 mL/h (typically started 48 h before chemotherapy). \212Allopurinol (a competitive inhibitor of xanthine oxidase) admin istered prior to the onset of chemotherapy at a dosage of 300 \200\223800 mg/d (dosage redu ction if CKD or AKI). \212Rasburicase (recombinant urea oxidase that converts uric acid to water-soluble allanto in), IV at a dose of 0.20 mg/kg in a 30-min infusion for up to 5 d. Considered first-line t herapy over allopurinol in patients at significant risk for TLS. Rasburicase typically resu lts in a shorter time to control of uric acid than does allopurinol. \212Urinary alkalinization is controversial as it requires a urine pH of 7.0 to be effecti ve, which may promote calcium-phosphate crystallization and precipitation. \212 Currently If progressive oliguric AKI develops, intermittent hemodialysis or \212 continuous forms o f renal replacement therapy may be required. not recommended in the therapeutic management of TLS. Gout See p. 408. Electrolyte physiology Sodium is pumped out of the cell in exchange for K + by the sodium-p otassium pump, which requires energy from adenosine triphosphate (ATP). Sodium is the major extracellular cation; potassium is the major intracellular cation. \212Osmolarity is the number of osmoles per L of solution. \212Osmolality is the number of osmoles per kg of sol vent ( normal: 280 \200\223300). To calculate plasma osmolality 2(Na + ) + urea/2.8 + gluco se/18. If the measured osmolality >10 mmol/L higher than the calculated osmolality, an osmo lar gap is present. Consider the presence of ketones, ethanol, methanol, or ethylene glycol (see page xxx). Fluid compartments For 70 kg man: Total fluid = 42 L (60% body weight). In tracellular fluid = 28 L (67% body fluid), extracellular fluid = 14 L (33% body fluid). Int ravascular component = 5 L of blood (see Figure 17.1). Figure 17.1 Distribution between intra- and extravascular compartments is determined by osm otic equilibrium and the \200\234oncotic pressure \200\235 exerted by non-diffusible prote ins 666 juxtaglomerular Control of sodium apparatus responds to decreased renal blood flow and cata lyzes conversion of angiotensinogen to angiotensin I . This is then converted by angiotensi n-converting enzyme (ACE), located in the lung and blood vessels, to angiotensin II, which increases efferent renal arteriolar constriction ( \206\221 perfusion pressure), systemic vasoconstriction, and stimulation of the adrenal cortex to produce aldosterone , which acti vates the sodium-potassium pump and other ion channels in the collecting duct, leading to r eabsorption of sodium and water from the urine in exchange for potassium and hydrogen. High renal peritubular blood flow and hemodilution \206\223 sodium reabsorption in the proxima l tubule. Control of water Controlled mainly by sodium concentration. Increased plasma osmo lality stimulates thirst and the release of ADH from the posterior pituitary, which increas es the water reabsorption from the collecting duct by opening water channels to allow water to flow from the hypotonic luminal fluid into the hypertonic renal interstitium. See Table 17.11. Renin produced by the y r t s i m e h c o B i Table 17.11 Natriuretic peptide Brain natriuretic peptide (BNP) is a hormone originally identified from pig brain (hence th e B) and is mostly secreted from ventricular myocardium. Plasma BNP is closely related to l