Which of the following conditions is associated with elevated serum chloride levels

Chloride

Chloride is the most abundant extracellular anion. Measurements of serum chloride are not useful for routine screening but may help in the evaluation of acid-base disturbances. The reference range of chloride is 98 to 109 mmol/L. In volume expansion, serum chloride generally increases, and in volume depletion, serum chloride is reduced. Hypochloremia occurs with loss of chloride-containing body fluids, such as with prolonged vomiting, burns, diuretic use, and salt-wasting nephropathy. Hypochloremia is commonly seen with metabolic alkalosis. Hyperchloremia occurs with non–anion gap metabolic acidosis, usually related to diarrhea or renal tubular acidosis, and with administration of large amounts of sodium chloride.

Urine chloride levels are useful in the evaluation of metabolic alkalosis. Low urine chloride (<10 mmol/L) is present with chloride-responsive causes of alkalosis, such as vomiting with volume depletion. Elevated levels of urine chloride (>20 mmol/L) are present in conditions associated with mineralocorticoid excess, such as hyperaldosteronism and hypercortisolism.

Clotting-based protein C assay

Plasma Anion Gap

The anion gap helps differentiate hyperchloremic metabolic acidosis (normal AG) from high AG metabolic acidosis. In hyperchloremic metabolic acidosis, there is an increase in plasma chloride equivalent to the fall in plasma bicarbonate, so that the sum of these two anions remains unchanged. The plasma anion gap in pure hyperchloremic metabolic acidosis is not increased, and may even be reduced due to buffering of protons by proteins. In hyperchloremic metabolic acidosis, hyperchloremia ensues due to enhanced renal NaCl retention caused by the attendant volume contraction (18).

A clinical setting in which the AG may be misleadingly low is hypoalbuminemic states (65, 106, 166). Albumin is negatively charged and therefore makes up a significant portion of unmeasured anions (64). Therefore, hypoalbuminemia will lead to an underestimation of the size of the AG and potentially to a failure to recognize a clinically important high AG metabolic acidosis. To circumvent this issue, the effect of serum albumin on the plasma AG must be taken into account in the analysis of acid–base disturbances. Figge et al. derived a formula for the plasma AG that takes into account serum albumin, which is based on a mathematical model of plasma and has been verified by experiments in vitro (65). This formula is as follows:

(Eq. 21)Albumin-corrected AG=AG +2.5×(4.4-albumin ing/dl)

In other words, for each 1-g/dl decrease in serum albumin below 4.4 g/dl, the observed AG underestimates the actual concentration of unmeasured anions by 2.5 mEq/L (65). This estimation has been shown to correlate more or less with other formulas (64).

A low plasma AG is seen in IgG myeloma because the cationic nature of the paraprotein causes a rise in chloride anions in order to neutralize the protein's cationic charge (18). In contrast, the plasma anion gap is normal in other types of multiple myeloma, which is due to the differences in the isoelectric points of IgA and IgG paraproteins (54). IgG paraproteins have isoelectric points that are higher than physiologic pH and are positively charged. The converse takes place with IgA paraproteins, which have isoelectric points below physiologic pH. They behave like anions and when present in large concentrations, the anion gap should increase. In IgA myeloma, however, the AG is usually normal as a result of co-existing hypoalbuminemia, which may reduce an otherwise elevated AG to a normal level. Thus, the interpretation of the plasma AG requires a careful review of all the possible variables that may affect it.

An additional limitation with the use of plasma AG occurs in the detection of mixed metabolic acid–base disturbances (106). Traditionally, the relationship between changes in the concentration of unmeasured anions (ΔAG) and change in serum bicarbonate concentration (ΔHCO−3) helps uncover the presence of a mixed acid–base disorder (typically a high AG metabolic acidosis accompanied by either a metabolic alkalosis or a normal AG metabolic acidosis). Deviation from the presumed 1:1 ratio in this relationship (ΔAG/ΔHCO−3) that is present in a high AG metabolic acidosis has been used to diagnose these complex acid–base disturbances (106). When the ΔHCO−3 (using a mean normal value for bicarbonate of 24 mEq/L) exceeds the ΔAG, a normal AG metabolic acidosis co-exists. Conversely, when the ΔAG exceeds the ΔHCO−3, a metabolic alkalosis is present in addition to the high AG metabolic acidosis. Several studies, however, have indicated that there is variability in this ratio, such that a deviation from a 1:1 ratio may not necessarily indicate the presence of a coexisting normal AG acidosis or metabolic alkalosis. This is due to the fact that this 1:1 ratio may be transient and/or depend on the type of metabolic acidosis present (4, 100, 106, 131, 134, 176). Studies involving ketoacidosis or lactic acidosis, as well as rarer causes of organic acid accumulation such as toluene poisoning, showed that ratios either greater than 1 or less than 0.8 (the latter being less common) were observed in the absence of an apparent co-existing metabolic alkalosis or normal AG acidosis (3, 4, 35, 36, 41, 100, 129, 132). This underscores the importance of considering patient history, physical examination, or other laboratory data in accurately defining an acid–base disorder (106). Nonetheless, the plasma AG, with all the previously mentioned caveats, provides a convenient “starting point” in the evaluation of metabolic acidosis and helps to evaluate the reason underlying changes in plasma bicarbonate over time.

Food Ingestion-Related Changes on Clinical Laboratory Values

Food ingestion activates in vivo metabolic signaling pathways that significantly affect laboratory test results [35]. First, the stomach secretes HCl in response to food consumption, which causes a decrease in plasma chloride concentrations. This mild metabolic alkalotic state (alkaline tide phenomenon) results from exaggerated circulating bicarbonate concentrations in the stomach’s venous blood with an accompanying decreased ionized calcium (by 0.05 mmol/L, 0.2 mg/dL) [36]. Second, postprandial-associated impairment in the liver leads to increased bilirubin and enzyme activities. Depending on the content of the meal ingested, the effects on commonly measured analytes may be short- or long-lasting. Thus, an overnight fasting for at least 12 hr is necessary to obtain an accurate representation of in vivo glucose, lipids, iron, phosphorus, urate, urea, and ALP concentrations. Interestingly, Lewis a secretors (blood groups B and O) experience spikes in ALP concentrations following ingestion of high-fat meals. Lipemia can also interfere with a variety of analytical methods, such as indirect potentiometry. Prior to analysis, lipids can be removed from lipemic samples via ultracentrifugation or by the use of lipid-clearing reagents [37]. Carbohydrate (increases glucose and insulin and decreases phosphorus concentrations) and protein meals (increases cholesterol and growth hormone concentrations within 1 hr of food consumption and also increases glucagon and insulin concentrations) have differential effects on serum analytes. High-protein diets significantly affect various analytes measured in 24-hr urine test. A standard 700-calorie meal markedly increases triglycerides (~50%), AST (~20%), bilirubin and glucose (~15%), and AST concentrations (~10%) [3]. Rapid changes in lipid concentrations are consistent with dietary changes, medications, or disease.

Caffeine intake has significant effects on the human body. Varying concentrations of this stimulant are present in a variety of foods (coffee, tea, chocolate, soft drinks, and energy drinks). The short half-life of caffeine (3–7 hr) also varies among individuals. Caffeine induces catecholamine excretion from the adrenal medulla. In addition, increased gluconeogenesis, which subsequently increases glucose concentrations and impairs glucose tolerance, is evident following caffeine intake. The adrenal cortex is also vulnerable to caffeine’s stimulatory effects, as evidenced by increased cortisol, free cortisol, 11-hydroxycorticoids, and 5-hydroxindoleaceatic acid concentrations. Caffeine is responsible for a threefold increase in nonesterified fatty acids, which interfere with the accurate quantification of albumin-bound drugs and hormones. Spuriously high ionized calcium concentrations are present following caffeine ingestion. Caffeine induces elevations in free fatty acids causing a rapid decrease in pH that frees calcium from protein.

Noni juice contains significant amounts of potassium (~56 mEq/L). Ingestion of noni juice leads to hyperkalemia. Specifically, hyperkalemia is apparent in vulnerable populations such as individuals with renal dysfunction and/or populations receiving potassium-increasing regimens such as spironolactone or angiotensin-converting enzyme inhibitors. Bran stimulates bile acid synthesis within 8 hr of ingestion [38]. However, bran inhibits gastrointestinal absorption of vital nutrients, including calcium (decreased by 0.3 mg/dL, 0.08 mmol/L), cholesterol, and triglycerides (decreased by 20 mg/dL, 0.23 mmol/L) [3]. Serotonin (5-hydroxytryptamine) is an ingredient present in a myriad of fruits and vegetables, such as bananas, black walnuts, kiwis, pineapples, and plantains. Bananas markedly increase 24-hr urinary excretion of 5-hydroxyindoleacetic acid in the absence of disease. Avocados suppress insulin secretion, causing impaired glucose tolerance.

Hyperchloremia

Hyperchloremia is a common iatrogenically induced entity as a result of fluid resuscitation during shock.40 Iatrogenic hyperchloremic metabolic acidosis stems from excess chloride administration relative to sodium, commonly seen in 0.9% normal saline solution use. This results in a large increase in plasma chloride concentration relative to the plasma sodium concentration, causing a decreased strong ion difference (SID), the difference between positive and negative charged ions, resulting in acidosis to preserve the law of electroneutrality in serum as described by the quantitative acid-base analysis approach.41–42 Hyperchloremia has been identified in and potentially contributes to worsening kidney injury as well as contributes to increased morbidity and resource utilization.40 Diagnosis of hyperchloremia is achieved more commonly by looking at the relative increase in the chloride-to-sodium ratio rather than the absolute value of chloride.41,43

For many years, the consequences of hyperchloremic metabolic acidosis have been downplayed and attributed to aggressive saline resuscitation in septic shock. However, recent studies may change this benign view of iatrogenic hyperchloremia, especially in patients with concomitant acute kidney injury and respiratory failure requiring mechanical ventilation. Patients with non-anion gap metabolic acidosis secondary to hyperchloremia almost always experience an increase in their baseline minute ventilation to compensate for the extra acid. This may make it difficult for patients to be liberated from mechanical ventilation. A chloride level of more than 110 mEq/L in critically ill patients in septic shock was associated with an increase in all-cause hospital mortality.42 Treatment of non-anion gap hyperchloremic metabolic acidosis focuses on conservative use of normal saline during resuscitation. Once hyperchloremic metabolic acidosis and a normal anion gap exist, analysis of urine serum gap can help determine the presence of a renal tubular acidosis. Supplemental sodium bicarbonate may be of benefit particularly in intubated patients who have too high of a minute ventilation to liberate from mechanical ventilation.44

Hyperchloremic metabolic acidosis

Several recently published studies have suggested that saline, both when used alone and as a component of colloids in large quantities, can cause a hyperchloremic metabolic acidosis. This is probably not seen with the use of Hartmann's solution. It was initially thought to be a dilutional effect on plasma concentration of bicarbonate, but this was later ruled out as there was no change in plasma volume as measured both pre- and postoperatively by the Evans blue dye dilution technique. Instead, it has been shown that there is a strong relationship between total chloride given and base excess changes. Several hypotheses have been postulated.

The administration of saline, which has equal amounts of sodium and chloride, raises plasma chloride by a larger amount as its initial level is lower in plasma. The rise in plasma chloride increases the dissociation of water, resulting in more free hydrogen ions, as measured by a fall in pH. This has also been attributed to a reduced ‘plasma strong ion difference’ (SID). The ions in plasma can be broadly grouped into three classes: a) the respiratory group, bicarbonate and carbon dioxide; b) the weak acids such as albumin and phosphate, which are not completely dissociated; and c) the strong ion group, which are completely dissociated: sodium, chloride, potassium, calcium, magnesium, and lactate. The difference between the cations (Na+ K++ Ca2++ Mg2+) and the anions (lactate + Cl−) of the strong ion group is known as the strong ion difference. The SID is normally around 40 in health and it makes the blood alkaline. When excess saline is infused into blood, the chloride concentration goes up more than the sodium concentration, which increases the amount of H+. To preserve the electrical neutrality water dissociates, thereby raising the free hydrogen ion concentration.

The effect of this hyperchloremic metabolic acidosis on morbidity and outcome is not clear. Hyperchloremic acidosis is not encountered with infusions of Hartmann's solution. Randomized double-blind studies comparing saline with Hartmann's following major surgery have not shown any difference in duration of mechanical ventilation, intensive care stay, hospital stay, or incidence of complications, including raised urea, raised creatinine, and subsequent renal failure.

Secondary Physiologic Response

Adaptation to acute hypocapnia is characterized by an immediate drop in plasma [HCO3−], principally as a result of titration of nonbicarbonate body buffers. This adaptation is completed within 5 to 10 minutes after the onset of hypocapnia. Plasma [HCO3−] declines, on average, by approximately 0.2 mEq/L for each 1 mm Hg acute decrement in Pco2; consequently, the plasma [H+] decreases by about 0.75 nEq/L for each 1 mm Hg acute reduction in Pco2. The limit of this adaptation of plasma [HCO3−] is on the order of 17 to 18 mEq/L. Concomitant small increases in plasma chloride, lactate, and other unmeasured anions balance the decline in plasma [HCO3−]; each of these components accounts for about one third of the bicarbonate decrement. Small decreases in plasma sodium (1 to 3 mEq/L) and potassium (0.2 mEq/L for each 0.1 unit increase in pH) may be observed. Severe hypophosphatemia can occur in acute hypocapnia because of the translocation of phosphorus into the cells.

A larger decrement in plasma [HCO3−] occurs in chronic hypocapnia as a result of renal adaptation to the disorder, which involves suppression of both proximal and distal acidification mechanisms. Completion of this adaptation requires 2 to 3 days. Plasma [HCO3−] decreases, on average, by about 0.4 mEq/L for each 1 mm Hg chronic decrement in Pco2; as a consequence, plasma [H+] decreases by approximately 0.4 nEq/L for each 1 mm Hg chronic reduction in Pco2. The limit of this adaptation of plasma [HCO3−] is on the order of 12 to 15 mEq/L. About two thirds of the decline in plasma [HCO3−] is balanced by an increase in plasma chloride concentration, and the remainder reflects an increase in plasma unmeasured anions; part of the remainder results from the alkaline titration of plasma proteins, but most remains undefined. Plasma lactate does not increase in chronic hypocapnia, even in the presence of moderate hypoxemia. Similarly, no appreciable change in the plasma concentration of sodium occurs. In sharp contrast with acute hypocapnia, the plasma concentration of phosphorus remains essentially unchanged in chronic hypocapnia. Although plasma potassium is in the normal range in patients with chronic hypocapnia at sea level, hypokalemia and renal potassium wasting have been described in subjects in whom sustained hypocapnia was induced by exposure to high altitude. Patients with end-stage kidney disease are obviously at risk for development of severe alkalemia in response to chronic hypocapnia, because they cannot mount a renal response. This risk is higher in patients receiving peritoneal dialysis rather than hemodialysis, because the former treatment maintains, on average, a higher plasma level [HCO3−].

Electrolytes

Sodium is the major extracellular cation in plasma, and its concentration is closely related to osmotic homeostasis, maintenance of body fluid volumes, and neuromuscular excitability. Plasma sodium is freely filtered via the renal glomeruli, but about 70% is reabsorbed in the proximal tubules and 25% in the loop of Henle together with chloride ions and water. Plasma chloride is the major extracellular anion, and in most instances, changes in plasma sodium and chloride concentrations tend to parallel each other. Decreases in the plasma concentration of sodium and chloride can occur with gastrointestinal losses (vomiting or diarrhea in nonrodents), and renal losses through alteration of electrolyte handling (diuretics and decreased aldosterone production). Decreases in plasma chloride may also be reflected in changes in acid–base balance and alterations of plasma bicarbonate.

In a series of subacute studies (7 days duration) conducted internally with a specific class of compounds, a lowering of plasma chloride of ≥4% from concurrent controls was a reproducible and unexpected finding. This was demonstrated, through investigation, to be a signal of acute primary electrolyte changes (increased urinary sodium and electrolyte excretion and hemoconcentration within 4 h). Ion-channel gene expression analysis in the kidney identified reduced transcription of most genes examined (mainly involving sodium, potassium, and chloride transport). Compensatory mechanisms reflected by increases in plasma bicarbonate and aldosterone were evident after 12 h [230]. Increased plasma sodium concentration, which is a less common finding in toxicology studies, can reflect increased sodium intake, sodium retention, reductions in ECF volume, or increased mineralocorticoid and glucocorticoid administration. Potassium is the major intracellular cation, with plasma values approximately 20-fold less than the intracellular concentrations. The intracellular potassium gradient is maintained by an ATP-dependent active extrusion of sodium, which is balanced by the pumping of potassium and hydrogen ions into cells. Investigations into potassium balance within the circulation should primarily be based on plasma rather than serum (since potassium is released from platelets and red cells during the clotting process and can influence artifactual increases in serum).

Increases in plasma potassium concentration may reflect increased intake, reduced excretion due to hormonal effects, renal effects, metabolic and respiratory acidosis, cellular necrosis, intravascular hemolysis, and artifactual increases from hemolysis, release from leucocytes and platelets (eg, thrombocytosis) or difficult blood collections, and potassium-containing anticoagulant, commonly EDTA. Decreases in plasma potassium may reflect decreased intake, extra-renal loss (vomiting, diarrhea), increased fecal loss, compounds that increase GI loss, hyperaldosteronism, renal tubular injury, drugs, and alteration of renal excretion. Pharmaceutical compounds such as aldosterone agonists, aminoglycosides, diuretics, and antineoplastic agents can cause hypokalemia [231]. At high doses, the β2-adrenergic agonist salmeterol produces an acute and rapid hypokalemia (within 1 h) in healthy human subjects. This is considered to be due to increased intracellular uptake by both liver and skeletal muscle secondary to an activation of cell membrane sodium potassium ATPase [232]. In toxicology studies where blood sampling is routinely performed 24 h post dosing, plasma potassium concentrations were observed to be mildly increased following β2-adrenergic agonist administration [233]. This is considered to reflect overcompensation in reestablishing osmotic equilibrium between the ECF and ICF.

Calcium is involved in neuromuscular transmission, cardiac and skeletal muscle contraction and relaxation, bone formation, coagulation, cell growth, membrane transport mechanisms, and enzymatic reactions. Approximately 40–50% is free or ionized and the remainder is bound to proteins, principally albumin. Consideration of total protein, albumin levels (and by inference globulin) should be made when interpreting plasma/serum total calcium levels. Higher levels are observed in younger animals. Increases in serum calcium concentration may result from hyperparathyroidism, hyperthyroidism, increased total protein (increased albumin and/or gamma globulin levels), poor venipuncture technique ,and exposure to drugs such as thiazides, lithium, and calciferol. Decreases in serum calcium may occur with renal failure, fasting or inadequate intake of calcium, protein loss, hypoparathyroidism, acute pancreatitis, and increased calcitonin or drug/toxin exposure (diuretics, anticonvulsants, fluoride, ethylene glycol) [227].

Phosphate is the major intracellular anion. Serum/plasma phosphate concentration is primarily inorganic orthophosphate and is protein bound, free anion, or complexed to sodium, calcium, or magnesium. Concentrations of serum phosphate are affected by diurnal cycle and pH. Phosphate is more sensitive than calcium to dietary intake and renal excretion and higher levels are normally observed in younger animals [49]. Increased serum phosphate is observed with reductions of GFR, and increased concentrations parallel changes in serum urea and creatinine concentration. Other increases in serum phosphate may reflect increased dietary intake, tissue necrosis, acidosis, altered bone metabolism, decreased renal excretion, artifactually delayed sample separation, or hemolysis. Compounds that increase plasma inorganic phosphate include anabolic steroids, furosemide, and thiazides. Causes of decreased serum phosphate may reflect redistribution of phosphate between ECF and ICF, decreased nutritional intake, hepatic disease, hyperparathyroidism, infection, and increased excretion. Examples of compounds that lower serum phosphate include antacids, renal tubular toxins, ethanol, intravenous glucose, and insulin.

Magnesium is an important structural component of bone and muscle that predominates in the ICF and is found free, complexed, or protein-bound in blood. This cation is essential for many enzyme reactions, neuromuscular activity, and bone formation; however, it is not well characterized or routinely assessed in preclinical studies [49]. Increases in serum magnesium may reflect decreased excretion in acute and chronic renal failure, increased intake, cellular necrosis, and adrenal hypofunction. Decreased serum magnesium levels may reflect reduced nutritional intake, malabsorption, increased gastrointestinal loss, pancreatitis, increased renal excretion, hypoparathyroidism, hyperthyroidism, hypocalcemia, and hypokalemia. Examples of compounds that lower plasma magnesium include aminoglycosides, cisplatin, cyclosporine, and loop diuretics [231].

HYPOKALEMIC SALT-WASTING KIDNEY DISORDERS

With the exception of the MCD that is primarily responsible for the absorption of water, re-absorption of sodium chloride from the glomerular filtrate at least in quantitative terms constitutes the key function of all nephron segments. Given the normal daily amount of 170 liters of glomerular filtrate produced by adult kidneys, at a normal plasma sodium concentration of 140 mmol/L and plasma chloride concentration of 105 mmol/L, the filtered load of sodium and chloride per 24 hours amounts to 23.8 mol (about 550 g) and 17.9 mol (about 630 g), respectively. Healthy kidneys manage the reabsorption of more than 99% of the filtered load, with about 60% by the proximal tubule, 30% by the TAL, 5% by the DCT1, and the remainder by the aldosterone-sensitive distal nephron (ASDN). Impairment of sodium transport in any of these nephron segments causes a permanent reduction in extracellular fluid volume, which in turn causes compensatory activation of sodium-conserving mechanisms, that is, stimulation of renin secretion and aldosterone synthesis. Accordingly, with intact ASDN function, the primary symptoms of renal salt wasting like hypovolemia with tendency for reduced arterial blood pressure, mix with those of secondary hyperaldosteronism, which increases ASDN sodium retention at the expense of an increased potassium excretion that eventually results in hypokalemia. In case of renal salt wasting, hypokalemia thus indicates proper function of the ASDN and points to the involvement of nephron segments more proximal to the ASDN.

As mentioned above, sodium reabsorption along the TAL and DCT1 is coupled to the reabsorption of chloride. Sodium wasting caused by defects in these nephron segments hence is accompanied by decreased reabsorption of chloride. Unlike sodium, which at least partially may be recovered by compensatory increased reabsorption along the ASDN, chloride irretrievably gets lost with the urine. Accordingly, the urinary chloride loss exceeds that of sodium, and for the sake of electroneutrality has to be balanced by other cations like ammonium or potassium. Loss of ammonium, the main carrier of protons in the urine, results in metabolic alkalosis; potassium loss in addition aggravates hypokalemia caused by secondary hyperaldosteronism. For this reason, hypochloremia with metabolic alkalosis, in addition to severe hypokalemia, characterizes salt wasting due to defects along the TAL and DCT1.

Finally, sodium reabsorption along the proximal tubule via the sodium proton exchanger and carboanhydrase is indirectly coupled to the reabsorption of bicarbonate. Proximal tubular salt wasting thus—in addition to hypokalemia—is accompanied by urinary loss of bicarbonate resulting in hyperchloremic metabolic acidosis.

Taken together, in the state of renal salt-wasting determination of plasma potassium, chloride, and bicarbonate concentrations allows for the rapid assessment of the affected nephron segment. Of note, in this context the determination of the plasma sodium concentration is not very helpful, since changes in plasma sodium—the more or less exclusive extracellular cation accounting for plasma osmolality—reflects disturbances in the osmoregulation (i.e., water balance) rather than in the regulation of sodium balance.

Apart from more general disturbances of proximal tubular function, which among other transport processes affect proximal tubular sodium reabsorption (the Fanconi renotubular syndromes), no hereditary defects specifically affecting the proximal tubular sodium proton exchanger have been described in humans. By contrast, several genetic defects affect sodium chloride transport along the TAL and DCT1, and are the focus of the following section.

Blood

Electrolyte concentrations vary slightly between cardiac and peripheral blood under physiological conditions, altered in pathological states from various causes before death and modified by postmortem redistribution, mainly depending on concentration gradients. Factors that can influence the postmortem redistribution of electrolytes in the blood include blood cell components and surrounding tissues, that is, mainly myocardium and skeletal muscles for heart and peripheral blood. Physiological concentration gradients between plasma and the ICF of blood cells, as described above, have the greatest influences on postmortem redistribution, involving postmortem time-dependent decreases in plasma sodium and chloride, and an increase in plasma potassium; these phenomena depend on ambient temperature and the site (Table 8; Coe, 1993; Maeda et al., 2011; Palmiere and Mangin, 2012). Calcium and magnesium concentrations are also increased immediately after death and become stable thereafter, followed by a final decrease of calcium due to decomposition (Maeda et al., 2011). In addition, extreme regional alterations immediately before death can enhance postmortem redistribution, typically due to aspiration of an immersion medium in drowning or gastric juice in vomitus for left heart blood, and massive skeletal muscle injury due to burns or blunt injury for peripheral blood.

In the evaluation of electrolyte disturbances for investigating the cause of death, minor deviations should not be regarded as significant, considering postmortem changes. The data should be assessed in combination with reference markers, such as urea nitrogen and creatinine, and also in consideration of other autopsy findings: evidently high blood plasma sodium and chloride concentrations (>150 mEq l−1 and >105 mEq l−1, respectively), accompanied by moderately elevated urea nitrogen (around 50–80 mg dl−1) without an increase of creatinine (<2 mg dl−1), indicate severe dehydration. Hyperthermia (heatstroke) often presents with an increase of creatinine with lower sodium and chloride concentrations, as well as decreased calcium. Blood plasma calcium concentration is also low in prolonged deaths involving extensive skeletal muscle damage, such as severe blunt injury and burns, as well as intoxication and under-/malnutrition. High magnesium concentration is detected in intoxication and hyperthermia (heatstroke). Evaluation of hyponatremia or hypochloremia is obstructed by postmortem decreases; however, massive data analysis suggested that substantial decreases (sodium <110 mEq l−1 and chloride <75 mEq l−1) can be regarded as significant when other autopsy findings are considered, in cases such as water overload (water intoxication), severe salt losses due to vomiting, diarrhea, or profuse sweating (hyperthermia), and prolonged deaths involving edema due to undernutrition, chronic heart failure, renal or hepatic failure, or delayed traumatic death without clinical intervention. Interpretation of potassium concentration is not practical, but it usually remains lower in hypothermia (cold exposure) but higher in hyperthermia (heatstroke).

In the diagnosis of drowning, it is essential to establish evidence of water aspiration and systemic dysfunction as the consequence. To investigate fatal water aspiration, topographic analyses of nonprotein nitrogen compounds and electrolytes/minerals in blood are useful. Urea nitrogen and creatinine levels are mildly lower in the left heart blood than in the right, irrespective of the drowning medium (salt or fresh water), suggesting blood dilution due to significant water aspiration. Significant changes are detected in sodium, chloride, calcium, and magnesium levels in left heart blood and pericardial fluid (< 48 h postmortem), depending on the drowning medium. These changes correlate with total lung weight (the sum of combined lung weight and amount of pleural effusion). Bilateral cardiac blood strontium (Sr) and bromide (Br) are also suggested as chemical markers of saltwater drowning.