Specific functions of electrolytes

Sodium is the major cation in ECF and thus the major contributor to extracellular (including plasma) osmolarity. The plasma osmolarity is maintained within narrow limits by balancing water intake with water losses. Small elevations in the plasma osmolarity are sensed by osmoreceptors in the hypothalamus. Thirst and water excretion are both altered in response to the secretion of antidiuretic hormone (ADH, also called arginine vasopressin). The secretion of ADH occurs in response to increased plasma osmolarity or decreased effective circulating volume. The ADH binds with vasopressin (V₂) receptors in the distal tubules and collecting ducts of the kidneys, stimulating the activation of renal epithelial Na channels. The resultant Na resorption contributes to the corticomedullary osmotic gradient that is necessary for maximum water absorption. This allows free water resorption, hence lowering sodium and increasing vascular volume [2]. In addition to the role that Na plays in fluid balance, the transmission of Na into and out of the cell is a critical part of many cellular functions. The transmembrane movement of Na is particularly important in the generation of electrical signals or currents in the brain, spinal cord, peripheral nervous system, myocardium, and muscles.

Potassium is the major intracellular cation, playing an important role in neuromuscular transmission as well as other vital cell functions. The resting cell membrane potential is dependent upon a higher intracellular to extracellular ratio of K. The K concentration must be tightly regulated. Both insulin and beta‐adrenergic catecholamines will increase cellular K uptake by stimulating cell membrane Na/K–ATPase.

The kidneys are primarily responsible for maintaining the total body K, matching excretion with intake. Under most homeostatic conditions, K delivery to the distal nephron remains small and is fairly constant. By contrast, the rate of K secretion by the distal nephron varies and is regulated according to physiological needs. Aldosterone will upregulate the basolateral Na/K pump in the principal cells in the distal renal tubule, creating a concentration gradient for the resorption of Na and the secretion of K [3]. Aldosterone synthesis is stimulated by increased concentrations of K, as well as angiotensin II, adrenocorticotropic hormone (ACTH), acidosis, and atrial stretch receptors.

Calcium, as calcium phosphate, acts as supporting material in bones, with 99% percent of the total body Ca residing in the bones and teeth. The remaining 1% of the Ca performs important life‐sustaining cellular functions. Calcium is involved in maintaining the stability of fibrin, the transmission of nerve impulses, the flow of fluid through cell membranes, and the contraction and relaxation of muscle. In addition, the Ca ion is one of the most widespread second messengers for cellular signal transduction, particularly those related to neuromuscular function and cardiac conduction. Endothelial Ca ions regulate the production of nitric oxide and the stimulation of K channels to efflux K, causing hyperpolarization and vascular smooth muscle relaxation [4].

The cytoplasmic concentration of Ca ions is a consequence of Ca ion passage through the cell membrane by way of Ca‐binding proteins or voltage‐gated calcium channels. Calcium ions can also be released into the cytoplasm from intracellular Ca stores, such as the endoplasmic or sarcoplasmic reticulum and mitochondria. However, excessive intracellular calcium may damage the cell or even cause it to undergo apoptosis, or death by necrosis. Therefore, the quantity of intracellular calcium must be tightly regulated. Extrusion of Ca from the cell is facilitated by transport proteins such as the Na/Ca exchanger and Ca/ATPase plasma exchanger.

Ionized calcium is hormonally regulated and normally maintained within narrow limits by the actions of parathyroid hormone (PTH), calcitonin, and vitamin D. Low calcium levels trigger PTH release, which promotes bone mineral dissolution and increased renal reabsorption of Ca. PTH also increases renal hydroxylation of inactive vitamin D to calcitriol, which increases gastrointestinal absorption of dietary calcium. Increased serum calcium and calcitriol levels inhibit PTH secretion. Calcitonin is released from the thyroid gland in response to high Ca concentration. As opposed to PTH, calcitonin inhibits bone resorption of Ca and renal reabsorption of Ca and P.

Magnesium is the second most abundant intracellular cation, with most of the total body Mg found in bone and skeletal muscle. In addition, Mg is a co‐factor to more than 300 enzyme‐driven biochemical reactions occurring in the body [5]. Magnesium influences the activity of enzymes by:

• binding to ligands such as ATP in ATP‐requiring enzymes
  
• binding to the active site of the enzyme (such as pyruvate kinase)
  
• causing a conformational change during the catalytic process (such as Na/K‐ATPase)
  
• promoting the aggregation of multienzyme complexes (such as aldehyde dehydrogenase)
  
• a mixture of the above mechanisms [6].

Intracellular Mg will block Ca and K channels, regulating Ca and K entry into the cell [7,8]. By competing with Ca for membrane binding sites and by stimulating Ca sequestration by sarcoplasmic reticulum, Mg helps to maintain a low resting intracellular Ca ion concentration. Magnesium has a key role in many other important biological processes such as cellular energy metabolism, cell replication, and protein synthesis.

The electrical properties of membranes and their permeability characteristics are also affected by magnesium. It affects myocardial contractility by influencing the intracellular Ca concentration and the electrical activity of myocardial cells. Magnesium affects the movement of ions such as Na, K, and Ca across the sarcolemmal membrane of the myocardial conduction system [9]. It may also affect the vascular smooth muscle tone.

Intracellular Mg is maintained within narrow concentration limits except in extreme situations such as hypoxia or prolonged Mg depletion. Very little is known about the mechanisms involved in the regulation of intracellular Mg [10]. Most Mg is bound to anionic compounds such as ATP, ADP, citrate, proteins, RNA, and DNA or is sequestered within mitochondria and endoplasmic reticulum. The kidney plays a major role in Mg homeostasis and the maintenance of plasma Mg concentration. Most of the filtered Mg (65%) is resorbed in the ascending loop of Henle [10]. The plasma Mg concentration is a major determinant of urinary magnesium excretion. Several hormones including PTH, ADH, calcitonin, glucagon, and insulin have been shown to affect Mg reabsorption [11,12].

Chloride is the most abundant anion in the extracellular fluid and the second most important contributor to plasma tonicity. Chloride is distributed primarily to the ECF compartment and can diffuse easily across vascular endothelial membranes. Chloride transport is closely linked to Na movement. This anion helps to regulate osmotic pressure differences between fluid compartments, having an important role in maintaining proper hydration and balancing cations in the ECF to maintain electrical neutrality.

Renewed interest in the physicochemical approach to acid–base analysis (Stewart approach and semiquantitative acid–base analysis) has refocused attention on Cl as a major determinant of acid–base status (see Chapter 7). The Cl shift within the blood helps to move bicarbonate ions out of the red blood cells and into the plasma for transport. In the gastric mucosa, chlorine and hydrogen combine to form hydrochloric acid.

The kidney excretes chloride, where the paths of secretion and reabsorption of Cl ions follow the paths of Na ions. Aldosterone therefore plays an indirect role in Cl regulation.

Phosphorus is the major intracellular anion, with most of the P located in the bone. Less than 1% of the total body P is located within the ECF and ICF spaces. The intracellular organic phosphate is an important constituent of nucleic acids, phospholipids, enzymatic phosphoproteins, and nucleotide co‐factors for enzymes and proteins. Cytosolic phosphate regulates intracellular reactions such as glucose transport, lactate production, and ATP synthesis [13]. Phosphorus also acts as both a urinary and a body buffer. Urinary phosphate constitutes the majority of titratable acidity. Phosphorus shifts into cells in response to alkalemia. Similar to Ca homeostasis, PTH, calcitonin, and vitamin D regulate phosphate intestinal absorption, deposition, and resorption from bone and renal excretion. In response to low serum phosphate concentration, calcitriol increases gastrointestinal P absorption and the kidneys decrease phosphate excretion. Elevated serum PTH levels promote rapid renal phosphate excretion.

Electrolyte abnormalities in the critically ill small animal patient are both common and complex. The severity of Na and K disturbances remains a significant predictor of mortality in human ICUs [14].

Critical illness causes major stress on all the regulatory functions of the body, including those responsible for normal electrolyte balance. The stress of sepsis, acute renal failure, impaired perfusion, multiple organ dysfunction syndrome and the administration of vasoactive agents all affect the neuroendocrine system that controls serum electrolyte balance. Many therapies directed at maintaining vital organ function directly or indirectly affect these regulatory systems. Assessment of the patient electrolyte status can be further complicated by the infusion of electrolyte‐containing fluids and parenteral and enteral nutrition. Appropriate and timely diagnostic and monitoring procedures are required for early intervention and to improve patient outcome.

Diagnostic and monitoring procedures

The electrolyte status of the ICU patient will have an impact on every body system, with emphasis on the neurological, muscular, renal, cardiovascular, gastrointestinal, acid–base, and hematological functions. The underlying diseases, as well as the therapeutic interventions, place every ICU patient at risk for electrolyte disorders. Often one electrolyte abnormality can lead to abnormalities with the other electrolytes. Important information helping to recognize a problem, define the cause, and identify the effects of electrolyte disorders can be obtained through the history, physical examination, point of care (POC) testing, clinicopathological testing, diagnostic imaging, and monitoring tools.

Diagnostic imaging

Survey thoracic and abdominal radiographs provide the initial diagnostic imaging data once the patient has been stabilized. Abdominal and thoracic ultrasound provides a more in‐depth assessment of organ structure and an evaluation of the size and structure of the adrenal glands, a possible source of electrolyte changes.

The electrocardiogram (ECG) will provide a waveform image of the electrical activity of the cardiac conduction system which is generated by the electrolytes. Hyperkalemia will cause changes in the ECG. However, these changes are not predictive of the magnitude of the plasma K alterations, especially in cats (Figure 6.2). An example of ECG changes associated with hyperkalemia is shown in Figure 6.3. ECG changes are also seen with Ca disorders. The ECG hallmark of hypocalcemia is the prolongation of the QT interval due to lengthening of the ST segment. The exact opposite holds true for hypercalcemia [18]. Hypercalcemia produces a quicker ventricular repolarization and therefore shorter QT interval.

Monitoring methods

The physical and neurological examination should be repeated at least twice daily for early detection of clinical signs of an electrolyte alteration before life‐threatening consequences occur. The electrolyte panel is assessed at least daily, or more frequently depending upon the urgency of the anticipated or diagnosed electrolyte disorder. Assessment of the fluid balance should be ongoing and can incorporate monitoring of body weight, central venous pressure (CVP), arterial blood pressure, echocardiography (diameter of vena cava or aorta), urine output, and blood lactate. The ECG is monitored for evidence of electrolyte‐related conduction disturbances and to assess the efficacy of any therapeutic interventions.

Electrolyte disorders

Abnormalities in Na, K, Ca, Mg, Cl, and P concentrations can have serious consequences in the small animal ICU patient. The electrolyte disorder can occur as a direct result of the underlying problem, a consequence of the clinical signs associated with the underlying disease (such as vomiting, diarrhea, polyuria) or a complication of treatment (such as fluid therapy, drug administration).

Sodium disorders

Blood Na concentration reflects the ratio of Na to water in the ECF and accounts for most of the osmotic particles in the serum. Normal serum Na is 139–154 mEq/L or mmol/L in the dog and 145–158 mEq/L or mmol/L in the cat. Note that the quantity of Na expressed in mEq/L is equivalent to the same quantity in mmol/L. Abnormalities in serum Na concentration are caused most commonly by changes in water balance. Total body water is estimated to be 60% of lean body weight. The distribution of this water is one‐third extracellular (intravascular and interstitial) and two‐thirds intracellular.

The flow of water in and out of cells, particularly brain cells, is primarily responsible for the symptoms of both hyponatremia and hypernatremia. Clinical signs of Na disorders are nonspecific and may be difficult to separate from the clinical signs of the underlying disease. Central nervous system signs are most common with alterations in Na and can range from lethargy and weakness to ataxia, seizures, coma, and death. The severity of neurological dysfunction is related to the rapidity of onset and the degree of deviation from “normal.”

The most life‐threatening consequence of Na disorders and their treatment is the excessive movement of water into or out of the brain cells in response to the osmotic shift that Na disorders cause in the interstitium and blood. A high interstitial Na (hypernatremia) will draw water out of the cells, causing cell shrinkage. In response to this, the cells will make idiogenic osmoles or osmolytes (taurine, glysine, glutamine, sorbitol, and inositol) to generate an intracellular osmolarity that is now similar to the extracellular hyperosmolarity.

In contrast, a low interstitial Na (hyponatremia) will cause water to move from the interstitium into the cells where the osmolality is higher. This can lead to dangerous cell swelling and cerebral edema. The key to surviving a Na disorder is to manage clinical signs and restore the osmolar balance slowly.

Hypernatremia

Hypernatremia is defined as a serum sodium concentration >155 mEq/L (>155 mmol/L) in dogs and >162 mEq/L (>162 mmol/L) in cats (see Table 6.4). One or more of the following mechanisms will be responsible for this hyperosmolar Na‐water imbalance: (1) Na gain greater than water gain, often due to the administration of hypertonic sodium‐containing solutions (such as hypertonic saline, sodium bicarbonate or hypertonic parenteral nutrition); (2) water loss greater than Na loss (such as osmotic diuresis, diuretics, gastrointestinal secretions); and (3) loss of solute‐free water (such as diabetes insipidus, adipsia, fever) (see Table 6.1).

Normally, hypernatremia stimulates the thirst mechanism and renal water conservation through the action of ADH. In patients with intact thirst mechanisms and the ability to drink, serum Na levels can remain more normal despite possible ongoing water losses. However, several factors can contribute to the onset of hypernatremia in the ICU patient, including the inability to drink (such as orders for nil per os, vomiting, mental impairment, inability to swallow), impaired renal ability to resorb water (such as nephrogenic diabetes insipidus, renal medullary washout, glucosuria) and the administration of IV fluids and medications that affect water or Na concentrations (such as diuretics, Na‐containing fluids and drugs). Persistently elevated serum Na (>155 mEq/L or >155 mmol/L) in association with protracted hypotension portends a dismal prognosis in hospitalized hypernatremic human patients [19].

Possible causes of hypernatremia in the small animal ICU patient are listed in Table 6.1. Hypernatremia has been generally classified as hypovolemic (inadequate water intake or loss of water over Na), euvolemic (diabetes insipidus), and hypervolemic (intake of hypertonic fluids, hyperaldosteronism, salt poisoning). The more common causes are attributable to a relative lack of free water.

Early symptoms of hypernatremia include lethargy and weakness, progressing to muscular rigidity, seizures, and coma. Untreated hypernatraemia (170–190 mmol/L) resulted in brain lesions demonstrating myelinolysis and cellular necrosis in rats and rabbits [20]. Normalization of the hypernatraemia over 4–24 hours resulted in cerebral edema, due primarily to failure of brain amino acids and idiogenic osmoles to dissipate as plasma Na is decreased to normal.

Therapy for hypernatremia is first directed at correcting any concurrent perfusion deficits, and subsequently, correcting the serum Na with hypotonic fluids. An algorithm to guide the lowering of serum Na is presented in Figure 6.4. A four‐step plan for making the necessary calculations for the quantity of fluid required to lower the serum Na to the desired concentration is presented in Box 6.2 with sample calculations. The replacement method outlined estimates the Na‐lowering effect of possible choices of IV fluid formulations on the patient serum Na [21]. An advantage of this method is that Na values are known rather than estimated. Box 6.2 also lists the Na content of common fluid infusates. These formulas serve as a guideline, with frequent monitoring of serum Na and adjustments in fluid infusion made to meet the specific needs of the individual patient.