CRITICAL CARE ISSUES FOR THE NEPHROLOGIST Electrolyte Disturbances in the Intensive Care Unit Martin Sedlacek, Anton C. Schoolwerth, and Brian D. Remillard Section of Nephrology and Hypertension, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire ABSTRACT The development of many electrolyte disturbances in the ICU can be prevented by attention to the use of intravenous fluids and nutrition. Hyponatremia is a relative contraindication to the use of hypotonic intravenous fluids and hypernatremia calls for the administration of water. Formulae have been devised to guide the therapy of severe hyponatremia and hypernatremia. All formulae regard the patient as a closed sys- tem, and none takes into account ongoing fluid losses that are highly variable between patients. Thus, therapy of severe hyponatremia and hypernatremia must be closely monitored with serial electrolyte measurements. The significance of hypocalcemia in the critically ill is controversial. Hypokalemia, hypophosphatemia, and hypomagnesemia should be corrected. Hyponatremia encephalopathy (5,6). Hyponatremia can even develop if excessive near isotonic lactated Ringers is administered in the postoperative period if urine tonicity is higher (6). Thus, to prevent hyponatremia, serum electrolytes should be checked daily in patients receiving intravenous fluids and isotonic saline should be used, unless clinically otherwise indicated. Intravenous fluids should be considered as pharmacological agents with specific indications and contraindications. Hyponatremia constitutes a contraindication to the administration of hypotonic fluids. Hyponatremia is predictive of increased mortality in congestive heart failure, community acquired pneumonia, and hospitalized patients in general where it may constitute a marker of severity of illness (and possibly of quality of treatment) (7). Hyponatremia can be asymptomatic, which is usually the case for chronic hyponatremia secondary to cirrhosis or heart failure. Symptoms of hyponatremia develop because of osmotic swelling of the intracellular space as extra cellular tonicity decreases. Hyponatremic encephalopathy can present with headaches, nausea, and vomiting. Worsening of brain edema leads to decreased mental status, seizures, coma, herniation, respiratory arrest, and death (8). It is important to note that it is the presence of symptoms in an often vulnerable patient (menstruating women, children, patients with liver disease, hypoxia, and hypokalemia) rather than the numeric level of the serum sodium that declares the life threatening electrolyte emergency. Thus, although most cases are seen with a serum sodium below 120 mEq/l, hyponatremic encephalopathy has been described in women with serum sodium values as high as 128 mEq/l and in children with serum sodium levels around 130 mEq/l (5). Hyponatremic encephalopathy accounts for 30% of new-onset seizures encountered in the ICU setting (9). The combination of hyponatremia with hypoxemia and underlying brain injury is worse than either alone as these factors Hyponatremia is the most common electrolyte disorder and, depending on the definition and frequency of testing, has recently been reported to occur in about 30–40% of hospitalized patients, which is even higher than previous estimates (1). For hyponatremia to develop, a relative excess of water in conjunction with an underlying condition that impairs the kidney’s ability to excrete water is required. Stimuli for the release of antidiuretic hormone and hence the impairment of water excretion are so frequent in hospitalized patients, that virtually all patients are at risk of hyponatremia (2). This is especially true in the postoperative period when nonosmotic stimuli such as nausea, pain, stress, and volume depletion lead to higher ADH levels compared with preoperative values. The risk of developing hyponatremia and its complications is higher in women and children compared with men, because of differences in respect of muscle mass and hormonal and anatomical factors (3). Hyponatremia is particularly common in the intensive care unit (ICU) where both access to water and renal water handling are impaired in critically ill patients often afflicted with multiorgan system failure. The incidence of hyponatremia in the ICU has been reported to be about 30% (4). The most important factor resulting in hospital acquired hyponatremia is the administration of hypotonic fluids. While a healthy adult male can excrete over 15 l of free water a day and maintain sodium homeostasis, it has been found that in previously healthy women in the postoperative setting as little as 3–4 l of hypotonic fluid per day can result in fatal hyponatremic Address correspondence to: Martin Sedlacek, MD, Section of Nephrology and Hypertension, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756-0001, or e-mail: martin.sedlacek@hitchcock.org. Seminars in Dialysis—Vol 19, No 6 (November–December) 2006 pp. 496–501 496 ELECTROLYTE DISTURBANCES IN THE ICU impair the ability of the brain to adapt and lead to a vicious circle of encephalopathy. Neurogenic pulmonary edema has been reported as a complication of hyponatremic encephalopathy both in the inpatient setting and in previously healthy water intoxicated marathon runners (10). Nonsteroidal anti-inflammatory agents (NSAIDS) can cause hyponatremia by inhibiting prostaglandin synthesis and potentiation on the tubular action of vasopressin (11). While this effect of NSAIDS alone is quite rare, there are many reports of NSAIDS-related hyponatremia in marathon runners, including severe cases with seizures and pulmonary edema (10,12). NSAID-related hyponatremia has also been reported in a patient with von Willebrand’s disease treated with vasopressin prior to a dental procedure (13). NSAID-related hyponatremia can also develop in other patients receiving vasopressin as treatment for diabetes insipidus or nocturnal enuresis. Thiazide diuretics are well known to predispose to hyponatremia as their action in the cortical collecting duct impairs urinary diluting capacity, in contrast to loop diuretics that affect renal concentration and diluting abilities equally (14). Use of the recreational drug ecstasy has been associated with hyponatremia as has the use of polyethylene glycol bowel preparation prior to colonoscopy (15,16). Oxcarbazepine is a new antiepileptic drug that may have a stronger association with hyponatremia than carbamazepine (17). Adrenal insufficiency and hypothyroidism can present with hyponatremia and need to be excluded. While symptomatic acute hyponatremia is a lifethreatening medical emergency, the treatment of hyponatremia may be life threatening as well, as it carries the risk of central pontine myelinolysis (CPM). This complication occurs if correction takes place too fast as brain cells require time to adapt to changes in the osmotic environment as first recognized in 1976 (18). The pons is particularly vulnerable to this type of injury because of the tight grid arrangements of axons and glial cells, limiting mechanical flexibility with osmotic changes. An assessment of the time frame in that hyponatremia developed can guide the time frame needed for its correction. Almost all reported cases of CPM have complicated treatment in patients who developed hyponatremia outside of the hospital and there are almost none in patients treated for hyponatremia that developed during their hospitalization (19). On the other hand, patients who developed hyponatremia outside the hospital only rarely die from hyponatremic encephalopathy. For example, death from hyponatremic brain edema is rare in patients with thiazide-associated hyponatremia despite the often extremely low serum sodium levels. Thus, rapid correction of the serum sodium seems to be the most beneficial and less dangerous in patients who develop acute hyponatremia in the hospital while the danger of CPM increases with the duration of hyponatremia (19). Regardless of the numeric serum sodium levels, treatment with hypertonic saline should be reserved for patients with symptomatic hyponatremia, e.g., with hyponatremic encephalopathy. Even in the context of 497 hyponatremic encephalopathy, seizures may respond to conventional seizure medications. If the patient remains in status epilepticus and hyponatremia is discovered, which usually happens after the initial treatment, a rise in the serum sodium of about 3 mEq/l/hr to a total of 4–6 mEq/l may terminate seizures; once the symptoms resolve, the remainder of the sodium deficit should be corrected slowly (19,20). There has been considerable controversy about what constitutes an optimal rate of correction and some recommendations are based on rather tenuous evidence (19). A conservative approach is to correct by no more than 8 mEq/l/day (19) or 15–20 mEq/l over 48 hours (21). Several formulae have been recommended to help determine a proper infusion rate of hypertonic saline to treat hyponatremia (22). However, even the most elaborate formula does not go without challenge to both its scientific validity and therapeutic usefulness (23,24). All formulae consider patients as closed systems and do not take into account ongoing water and electrolyte losses that may vary considerably between patients. The formula proposed by Androgue and Madias has the advantage of simplicity compared with previously advocated calculations of salt deficit; this formula estimates the effect of any infusate on serum sodium (25): Change in serum Naþ ¼ infusate Naþ  serum Naþ total body water þ 1 The ability of this formula to predict serum sodium increase with treatment has been evaluated prospectively in a recent study (24). Despite the statistical validation of the formula, some cases with considerable differences between anticipated and achieved serum sodium values were observed, stressing the need for serial measurements of serum sodium in any patient receiving hypertonic saline. An assumption that can be used to guide initial therapy is that an infusion of 1 ml/kg of 3% saline (514 mEq Na/l) will raise the serum sodium by approximately 1 mEq/l (26). Any patient receiving 3% saline should have the serum sodium checked at least every 2 hours to guide therapy, which compares with the monitoring required in patients with diabetic ketoacidosis. Central pontine myelinolysis has been described if the serum sodium rises unexpectedly rapidly, as may happen not only with hypertonic saline but also with normal saline (27). This may occur if there was unrecognized volume depletion with sudden removal of the ADH stimulus during treatment with resulting rapid water diuresis. Thiazide-induced hyponatremia is the classical situation in which this scenario may occur. Patients with psychogenic polydipsia who drink themselves into a hyponatremic coma are also at high risk for overcorrection of hyponatremia through massive water diuresis and in such a case administration of hypotonic fluids and dDAVP may be indicated to slow the rise of the serum sodium. Another risk factor of CPM is concomitant hypokalemia as potassium is the major intracellular cation and an important intracellular osmol (28). Hypophosphatemia is also associated with CPM (29). 498 Sedlacek et al. Phosphorus depletion limits the function of sodium-potassium ATPase required to adapt to osmotic changes. It is therefore advisable to correct serum potassium and phosphorus first, repleting intracellular stores before administering hypertonic saline. Other risk factors for cerebral demyelination are alcoholism and liver disease. Hypernatremia Hypernatremia occurs less frequently than hyponatremia thanks to a powerful thirst mechanism. On the other hand, patients debilitated enough to develop hypernatremia carry a very high mortality risk, as high as 40–70% (30). Cerebral dehydration can lead to demyelinization, cerebral bleeding, coma, and death. The use of saltwater as an emetic has been abandoned by the medical profession a long time ago because of the risk of fatal acute hypernatremia, but a few tragic cases are still reported from sporadic layman’s use (31). Acute diabetes insipidus with polyuria and hypernatremia can complicate traumatic brain injury, usually appearing within 5–10 days and disappearing sporadically within a few days to 1 month (32). Several factors can predispose patients in the ICU to hypernatremia: the administration of hypertonic sodium bicarbonate solutions; renal water loss through a concentrating defect from renal disease or the use of diuretics or solute diuresis from glucose or urea in patients on high protein feeds or in a hypercatabolic state; gastrointestinal fluid losses through nasogastric suction and lactulose administration; and water losses through fever, drainages, and open wounds. The majority of patients with hypernatremia are also hypovolemic, requiring the administration of isotonic or hypotonic saline (24). Because of the concomitant sodium loss the calculation of a water deficit alone is not meaningful in the majority of patients with hypernatremia but the Androgue and Madias formula (shown above) is also useful to predict the effect of any infusate on the serum sodium in hypernatremia. The same caveats apply, as ongoing losses are not taken into account by any formula and close monitoring is always required. Hypervolemic hypernatremia is unfortunately not uncommon in the ICU in patients with multiorgan failure who often receive large amounts of saline in the course of their illness and can end up with more than 30% increase of their body weight in salt water (33). Thus, hypernatremic hypervolemia is an iatrogenic complication that can develop only if renal function is compromised as hypernatremia would normally lead to sodium diuresis. Renal replacement therapy with continuous veno-venous hemofiltration (CVVH) is usually the only effective treatment. Prevention of hypernatremia would be a more advisable strategy, however, and a rising serum sodium should be considered a relative contraindication for further administration of saline and should prompt treatment with water either via a feeding tube or as a hypotonic intravenous solution. Volume Overload Assessment of volume status is notoriously difficult in the ICU and errors in volume management are more difficult to detect than electrolyte abnormalities, which can be directly measured. There also is a great deal of controversy about what constitutes adequate volume management. It is generally accepted that resuscitation with large fluid volumes as needed is indicated in the ebb phase of shock (34). However, at a later stage, a conservative fluid management strategy seems preferable (35). Practically speaking, the presence of edema and elevated central venous and pulmonary artery occlusion pressures does not necessarily indicate that the intravascular space is replete. In patients on mechanical ventilation the absence of arterial pulse pressure variation indicates fluid loading. Pulse pressure variation has been shown to predict fluid responsiveness in a small study in patients who underwent coronary artery bypass surgery (36). Daily chest X-rays may be helpful in assessing volume status by checking for Kerley B lines, pulmonary vascular engorgement, or by measuring the vascular pedicle width (37). Rather than being ‘‘cosmetic,’’ the complications of massive volume overload include delayed wound healing, a dilutional coagulopathy, and abdominal compartment syndrome (38). Intra-abdominal pressure can be measured with a Foley catheter to confirm the presence of an abdominal compartment syndrome, which has a very high mortality if surgical decompression is not performed. Hypocalcemia Hypocalcemia defined as an ionized calcium level less than normal is one of the most frequent electrolyte abnormalities encountered in the ICU, affecting 80–90% of patients. Hypocalcemia is associated with increased mortality in this population (39). Multiple mechanisms for hypocalcemia in the critically ill have been described: precipitation into tissues, complex formation with citrate from blood products or lactate, decreased renal calcitriol production or tissue resistance, and suppression of the parathyroid gland by hypo- or hypermagnesemia or inflammatory mediators. Calcium is a critical intracellular messenger and regulator of cell function. As calcium is involved in cell injury and cell death and studies in animal models of sepsis have shown no benefit or even harm from calcium administration, it has been proposed that decreased ionized calcium concentrations during sepsis may have evolved as a protective mechanism to limit cell injury during the acute inflammatory response (40). A recent study from France showed that resuscitation-induced hemodilution is an important causative factor of early hypocalcemia in trauma patients (41). As an iatrogenic complication of treatment rather than a natural adaptation, hypocalcemia could have potential deleterious effects on blood coagulation and cardiovascular function. To complicate things more, most standard coagulation tests are performed in recalcified plasma at supranormal calcium concentrations so that in vivo 499 ELECTROLYTE DISTURBANCES IN THE ICU abnormalities secondary to hypocalcemia would not be detected by these tests. Despite the frequency of hypocalcemia in critically ill patients it remains unknown if treatment is beneficial unless, of course, if a specific cause other than critical illness can be found. There has been some concern that propofol sodium edetate (EDTA) could lower ionized calcium concentrations but this effect was found to be minimal with no clinically significant adverse effects (42). More importantly, propofol can cause propofol infusion syndrome in the ICU with unexplained myocardial failure, metabolic acidosis, and rhabdomyolysis with renal failure. An unusual green discoloration of the urine can be a hint to the presence of this syndrome (43). Spurious hypocalcemia can be observed after the administration of gadolinium contrast for magnetic resonance imaging. Gadolinium chelates interfere with colorimetric-based calcium assays but ionized calcium measurements remain unaffected, allowing rapid diagnosis of this laboratory artifact (44). been well tolerated (50). The infusion rate is limited by the serum potassium level and in any case should not exceed more than 40 mEq potassium per hour to prevent hyperkalemia. Acute phosphorus loading can produce severe hypocalcemia with tetany, seizures, and respiratory failure as well as acute renal failure through tissue precipitation of calcium phosphate. Cases of acute phosphorus poisoning have been described secondary to phosphorus containing enemas and ingestion of cloth washing detergent. Calcium and phosphorus infusions have to be strictly separated because of the danger of precipitation which can trigger aggregate anaphylaxis similar to what has been described with the use of protamine to reverse heparin after cardiopulmonary bypass (51). Oral supplementation and prevention of severe hypophosphatemia is therefore more desirable than intravenous supplementation. Hypokalemia Hypophosphatemia The association between hypophosphatemia and sepsis has been known for a long time and hypophosphatemia has even been suggested as a diagnostic tool with a level < 0.2 mg/dl being suggestive of gram-negative sepsis (45). In patients with sepsis, the severity of hypophosphatemia is predictive of mortality (46). Hypophosphatemia is also frequent following open heart surgery and hepatectomy (47). Risk factors to develop hypophosphatemia include malnutrition, alcoholism, use of diuretics, and antacids. Acute respiratory alkalosis stimulating glycolysis via phosphofructokinase activation, the infusion of glucose, and the effect of hormones such as insulin, glucagon, and cortisol all can decrease serum phosphorus concentrations by redistribution into the intracellular space. Catecholamines and hence hypothermia during cardiac surgery have a similar effect on transcellular phosphorus shifting as do interleukin-6 and other cytokines (48). Severe hypophosphatemia has thus been called a humoral marker of a more intense acute phase response (49). True phosphate depletion occurs in refeeding and regenerative processes. Phosphorus is critical for metabolic processes. In particular, severe hypophosphatemia has been linked to granulocyte dysfunction, cardiac arrythmias, and respiratory muscle weakness (46). Hypophosphatemia reduces oxygen delivery to tissues by decreasing 2,3-diphosphoglycerate levels in red blood cells, which increases hemoglobin affinity for oxygen. Clinical manifestations of hypophosphatemia reflect the importance of phosphorus in body homeostasis and are reversed by correction of the phosphorus level. The size of the possible total body phosphorus deficit cannot be determined from the serum level and correction must be empiric, following phosphorus levels closely. Phosphorus is supplemented intravenously in symptomatic patients, usually 15–30 mmol potassium phosphate diluted in saline over 3–12 hours but faster rates of 30 mmol over 2 hours or 45 mmol over 3 hours have Potassium is perhaps the most frequently supplemented electrolyte. Clinical features associated with hypokalemia include abnormalities of cardiovascular, metabolic, and neurologic functioning. Tachyarrhythmia and muscle weakness are potentially life-threatening complications of hypokalemia. The extracellular potassium concentration is determined by catecholamines, the renin–angiotensin–aldosterone system, glucose and insulin metabolism, as well as direct release from exercising or injured muscle. The hyperkalemia associated with hypothermia provides an impressive illustration of catecholamine-associated intracellular potassium shifting. Differences in potassium concentration in ischemic and nonischemic myocardium can result in different degrees of depolarization, setting up electrical forces that can potentiate arrythmias (52). Intravenous potassium is not given faster than 10– 40 mEq/hr because of the danger of inducing hyperkalemia (53). Saline is used instead of dextrose in water because dextrose-induced insulin release can lead to transient worsening of the hypokalemia. Potassium can be supplemented in different forms: potassium chloride is chosen in the presence of a hypochloremic alkalosis while potassium phosphate is a good choice if there is a concomitant hypophosphatemia and potassium citrate, potassium acetate, or potassium bicarbonate can be used in the presence of a nonanion gap acidosis. ‘‘Salt substitute’’ is a palatable and stomach-friendly oral potassium supplement. Tubular dysfunction secondary to medication toxicity can present either as a Fanconi-like syndrome of proximal tubular injury with metabolic acidosis, hypohosphatemia, glucosuria, and frequently elevated serum creatinine or, more rarely, as a Bartter-like syndrome of distal tubular injury with hypokalemic metabolic alkalosis, hypocalcemia, hypomagnesemia, and without significant serum creatinine elevation. Aminoglycosides are the most frequently implicated antibiotics to cause the Bartter-like tubular injury pattern, other causative agents include diuretics, amphotericin B, and cisplatin 500 Sedlacek et al. (54). A similar syndrome with renal magnesium and potassium loss has recently been attributed to Piperacillin (55). Hyperkalemia A number of underlying conditions can predispose patients in the ICU to hyperkalemia such as renal insufficiency, adrenal insufficiency, insulin deficiency and resistance, and tissue damage from rhabdomyolysis, burns, or trauma. A long list of therapeutic agents used in the ICU can also cause or contribute to hyperkalemia: beta blockers and digoxin by decreasing sodium potassium ATPase activity; angiotensin converting enzyme inhibitors, angiotensin receptor blockers, heparin and derivatives, and azole antifungals by inhibiting adrenal aldosterone synthesis; potassium sparing diuretics, trimethoprim, and pentamidine by decreasing renal tubular potassium secretion; NSAIDS by interfering with renal prostaglandin metabolism, and cyclosporine and tacrolimus by suppressing renin release. Succinylcholine can cause catastrophic hyperkalemia by triggering potassium release from damaged muscle in predisposed patients. Hyperkalemia is best treated with insulin plus glucose, beta-agonists, and furosemide. In case of electrocardiography (ECG) changes, calcium should be administered as a temporizing membrane stabilizer unless hyperkalemia is secondary to digoxin intoxication or the patient is treated with digoxin, although the observations relevant to the interaction with digoxin date from the 1930s. Data on the usefulness of bicarbonate are equivocal and bicarbonate is usually not a first choice. Sodium polystyrene sulfate removes potassium from the gut in exchange for sodium and is administered together with sorbitol to promote diarrhea. The onset of action is delayed as the medication takes hours to reach the colon after oral administration before it takes effect. Complications include sodium retention and bowel necrosis which has been described with both oral and rectal administration (56). Hyperkalemia caused by tissue ischemia can be overwhelming so that insulin plus glucose are ineffective and even dialysis can provide only temporary relief and surgery may be required for potassium control. Hypomagnesemia Hypomagnesemia is associated with a two to three fold increased mortality in critically ill and postoperative patients (57). Clinically hypomagnesemia is often associated with hypokalemia and hypocalcemia. Because of the role of magnesium in transmembrane potassium transport, simultaneous correction of hypomagnesemia is required to correct hypokalemia. Symptoms of hypomagnesemia include respiratory muscle weakness, fasciculations, cramps, tetany, convulsions, coronary artery vasospasm, and supra- and ventricular arrythmias. Hypomagnesemia is produced by obligatory digestive losses that are often exacerbated by gastrointestinal pathology and by exacerbation of variable renal losses. Magnesium is the second intracellular ion after potassium and as a result, plasma magnesium does not reflect well the total magnesium pool and possible state of deficiency. Oral magnesium can produce vomiting and diarrhea. In intensive care, the preferred administration route is IV in the form of slow infusions of magnesium sulfate of up to 10 gm/day to correct a magnesium deficit. Magnesium is used as a pharmacological agent for a variety of conditions, usually as a more rapid infusion of 1–2 g of magnesium sulfate over a 10-minute period with ECG monitoring followed by a continuous infusion of 0.5–1 g/hr (58). Hypermagnesemia is an infrequent and dangerous complication of magnesium administration, usually occurring in patients with renal insufficiency. Magnesium is a first line treatment of torsades de pointes and arrythmias induced by digitalis. In critically ill patients, magnesium has been found to be more effective than amiodarone to treat atrial tachyarythmias (59). Magnesium is used to treat hypertension and to prevent the onset or recurrence of seizures in pre-eclampsia and eclampsia. Magnesium can prevent coronary spasms in variant angina (60) and can be used in anesthesia during induction or pheochromocytoma surgery to control adrenergic response (61). Magnesium has been found to be a very useful treatment in patients with tetanus as it allows control of spasms and sympathetic overactivity without inducing sedation, thus decreasing the need for mechanical ventilation (62). Magnesium is also showing a lot of promise in treating cerebral vasospasm associated with subarachnoid hemorrhage (63). Conclusion It must be emphasized that many electrolyte disturbances in the ICU can be prevented by close attention to the prescription of intravenous fluids and nutrition. Prevention of electrolyte disturbances is preferable to treatment. In particular, ICU physicians should act when serum sodium starts to rise or fall before there is overt derangement. 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