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Impact of Surgical Stress Response on Perioperative Fluid Distribution Insensible Losses
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Perioperative care is characterized by dramatic changes in fluid and electrolyte content and distribution in the various fluid spaces in the body. These changes are predictable and follow a characteristic pattern described by Cuthbertson and Tilstone5 and Moore,6,7 widely known as the "stress response." An understanding of this process is central to understanding the dynamics of fluid and electrolyte flux in the perioperative period and is helpful in guiding therapy.
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The stress response has traditionally been considered a biphasic "ebb and flow" phenomenon. Initially after an injury or surgical incision, there is significant peripheral vasoconstriction, shunting of blood from the periphery to the midline (to preserve vital organs), and a decrease in body temperature. Simultaneously, there is a decrease in capillary hydrostatic pressure, promoting a rapid shift of protein-free fluid from the interstitium into the capillaries.8 This is known as "transcapillary refill," and it includes mobilization of fluid from the splanchnic circulation, particularly the splanchnic veins.9 This induces a state of absolute hypovolemia in the extracellular space. There is a dramatic increase in the release of vasopressin (antidiuretic hormone) and activation of the renin–angiotensin–aldosterone axis to conserve salt and water.
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The second phase, the hypermetabolic or "flow" phase, occurs within hours, characterized by a dramatic increase in cardiac output, driven by catecholamines, vasodilatation, increased capillary permeability, and an increase in temperature. A generalized catabolic state ensues characterized by insulin resistance, hypercortisolism, and protein breakdown. Thus, the patient develops tachycardia, leucocytosis, hyperthermia, hyperglycemia, and tissue edema. The magnitude of this response is proportionate to the degree of injury or extent of surgery. Significant ICF deficit may be incurred to maintain circulating volume. A period of fluid sequestration occurs caused by extravasation of fluid consequent of widespread capillary leak, urinary output decreases, and tissue edema may become evident. Vasodilatation and relative intravascular hypovolemia occur. During this period, patients typically require administration of resuscitation fluids to maintain blood pressure and circulating volume. Weight gain ensues.
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Eventually, a state of equilibrium arrives, usually day 2 after surgery, when active sequestration stops. This is followed by a phase of diuresis during which the patient mobilizes fluid and recovers. Initially, there is a precipitous decrease in serum albumin. Restoration of albumin levels is associated with recovery. Moreover, ICF volume returns to normal. An inward shift of fluid from the extracellular to the intracellular space is associated with intracellular movement of ions such as potassium, magnesium, and phosphate. Hence, hypophosphatemia, hypomagnesemia, and, in particular, hypokalemia are usually evident on a serum chemistry panel at this time.
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The practicing clinician must be aware of the stages of the stress response when deciding whether to administer fluid and electrolytes. For example, early in the flow phase, significant intracellular and interstitial fluid depletion may exist despite the appearance of "normal" cardiovascular measurements (blood pressure, cardiac output, stroke volume). This requires repletion with free water and isotonic crystalloid. During the vasodilatory, hypermetabolic phase, the circulating volume requires support, taking into account the large volume of distribution of administered crystalloid. During the equilibrium phase, the administration of IV fluid depends on the objective of the clinician. The clinician may choose to continue fluid administration to keep organs well hydrated or to stop administering fluid, preventing the formation of further tissue edema. During the diuretic phase, the major objective of the clinician is to allow the patient to return to baseline body weight and to aggressively replete electrolytes.
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It can be argued that the administration of anesthesia significantly reduces the ebb or shock phase. Nevertheless, patients undergoing surgery are usually dehydrated secondary to fasting, bowel lavage, or their primary disease (eg, esophageal cancer). Consequently, the perioperative period should be viewed as follows: (1) dehydration phase, (2) shock phase, (3) relative and absolute hypovolemic phase (caused by vasodilatation, fluid sequestration, and blood loss), (4) equilibrium phase, and (5) diuresis phase. Certain operations are associated with greater blood loss because of overt or microvascular bleeding (vascular surgery); other operations are associated with greater tissue injury caused, for example, by bowel handling. Thus, within this paradigm, a "one formula fits all" approach is neither scientific nor effective. Where extensive fluid shifts are to be expected in the perioperative period, it is worthwhile to obtain a preoperative weight to have a baseline goal for the patient's postoperative diuresis.
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There is little excess water storage capacity in the human body. With the exception of CHF, perioperative patients are more than likely to present in a state of relative or absolute hypovolemia. This may be mild dehydration caused by fasting or severe dehydration caused by the administration of purgatives (for bowel lavage), persistent diarrhea, nasogastric suctioning, fistula drainage, or the inability to consume water and electrolytes. Clinical findings that may alert the clinician to dehydration include confusion, loss of skin turgor, longitudinal furrowing of the tongue, dry mucus membranes, sunken eyes, collapsed veins, cold extremities, and highly concentrated urine. A 15% to 30% loss of intravascular volume leads to resting tachycardia. Blood pressure is usually maintained despite up to 40% volume loss because of intense vasoconstriction and transcapillary refill. In addition cardiac output and cardiac index remain within normal limits, and the only hemodynamic indication of hypovolemia is a reduction in stroke volume.10
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On evaluation of the patients' chemistry panel, the clinician will be alerted by a high ratio of urea to creatinine (>10:1), hypernatremia, and metabolic (contraction) alkalosis (caused by increased SID, consequent of free water deficit). A urine specimen (assuming normal renal function) that is significantly concentrated (eg, 500-1400 mOsm/kg H2O) with a high specific gravity and low sodium content (<20 mEq/L) can confirm an ECF volume deficit.
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Of particular importance is the problem of relative hypovolemia. This occurs typically in patients who are being treated with vasodilator drugs such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, α1-receptor antagonists (phenoxybenzamine), and α2-adrenergic agonists (clonidine). Administration of anesthetic agents typically causes widespread vasodilatation and relative hypovolemia; in patients treated with these drugs, severe hypotension may ensue. Likewise, in patients who present with acute shock caused by volume loss or vasoplegia (such as occurs with sepsis), the administration of anesthesia induction agents (propofol or thiopental) followed by the application of positive-pressure ventilation may result in life-threatening hypotension (Fig. 35-2).
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The decision to rehydrate patients before and during induction of anesthesia must be guided by the clinical assessment, quantification of preoperative fluid deficits, and the nature of the surgery. Preoperative fasting of 12 hours or more may result in a fluid deficit of more than 1 L, consisting principally of free water. Ambulatory patients administered up to 30 mL/kg per have significantly less dizziness and postoperative nausea and vomiting (PONV) that those given less fluid or none at all.11-13 It is unclear whether prehydration should involve hypotonic crystalloid or BSS. The administration of dextrose-containing fluids is associated with increased pain, thirst, and blood glucose compared with patients given dextrose-free BSS.14 For patients who have preexisting GI fluid losses, significant electrolyte depletion is to be anticipated. For upper GI losses, for example, secondary to nasogastric suctioning, vomiting, or gastroparesis, hypochloremia is to be anticipated; "normal" saline is the replacement fluid of choice. For patients with lower GI system losses, significant loss of sodium and potassium are to be anticipated, and BSS should be administered. Subsequent to surgical incision, administered fluids should be isotonic because of the 50- to 100-fold increase in antidiuretic hormone (ADH) activity that persists for the duration of the stress response. Large-volume resuscitation with hypotonic fluid may result in acute severe hyponatremia, cerebral edema, and seizures.
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Signs of preoperative hypervolemia include a cardiac gallop rhythm, jugular venous distension, ankle or sacral edema, an enlarged liver, and pulmonary edema. There are no pathognomonic laboratory signs of hypervolemia; however, hyponatremia, below normal values of urea and creatinine, and low serum osmolality may be indicative of free water overload.
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Postoperative hypervolemia is an inevitable consequence of current fluid administration strategies that has generally been considered benign. Traditionally, generous volumes of IV fluid are administered in the operating room to replete fasting deficits, maintenance requirements and third-space fluid losses. The consequence is an inevitable weight gain of 4 to 6 kg for major surgery.15 This approach has been challenged, because of emerging evidence of adverse outcomes associated with perioperative fluid overload.16
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The concept of "third-space" fluid loss or functional ECF deficit derived originally from work by Shires et al17 The hypothesis behind third spacing is that as a consequence of trauma, hemorrhage, tissue injury, or tissue handling, ECF becomes sequestered in nonfunctional tissue spaces, presumably the injured tissue, the bowel lumen, and other potential spaces such as the pleura and peritoneum. This fluid serves no physiologic purpose and may lead to organ hypoperfusion and, in particular, acute renal failure. Proponents point to the dramatic difference in the incidence of acute renal failure during the Vietnam War, during which liberal fluid management strategies were used, versus the Korean War, when fluid restriction was the norm. A small body of subsequent work investigated ECF volume in the perioperative period with a series of radiolabeled tracers. Brandstrup and colleagues18 have systematically evaluated this literature and found significant flaws in the methodology. Indeed, there is little or no published evidence that significant third-space fluid loss occurs in clinical practice. Fluid resuscitation strategies based on this premise are associated with an elevated incidence of acute lung injury, abdominal compartment syndrome, prolonged ileus, myocardial ischemia, extensive tissue edema, impaired wound healing, and delayed discharge from the hospital.16,19,20
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Large-volume fluid resuscitation leads to significant sequestration of fluid in lax tissues in the splanchnic veins and peritoneum. After resolution of the stress response, this fluid is mobilized into the intravascular space, and the patient usually undergoes rapid diuresis. However, in cases of diastolic dysfunction or CHF, the patient may develop acute pulmonary edema ("flash pulmonary edema") or acute myocardial ischemia. This process has been termed deresuscitation. Gentle preemptive administration of furosemide may increase venous capacitance and induce earlier diuresis.
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Sodium is the most abundant extracellular ion, responsible for maintenance of the extracellular volume.
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There is a dynamic relationship between TBW and extracellular sodium concentration. This water balance is influenced by intakes and outputs, ADH, renin–angiotensin–aldosterone, and serum osmolality. Because sodium ion is excluded from the intracellular space and is the predominant osmotically active substance in the ECF, isolated changes in water volume are generally reflected by inverse changes in the serum sodium concentration and serum osmolality. Hyponatremia generally indicates and expansion in free water volume compared with normal. Hypernatremia generally indicates a reduction in free water concentration.
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Total body sodium concentration averages 60 mEq/kg of body weight in a healthy man (ie, 4200 mEq in a 70-kg man). Approximately 2000 to 2200 mEq is dissolved in the ECF. Another 1800 mEq resides within the skeletal system, which constitutes 15% to 16% of body weight. Thus, total body sodium is proportioned as follows: approximately 50% is extracellular, 40% is in bone, and 10% or less is intracellular.
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Body sodium is often considered in terms of exchangeable and nonexchangeable moieties. Nonexchangeable sodium is that fraction adsorbed on hydroxyapatite crystals contained deep within the long bones of the skeleton. It amounts to approximately 18 mEq/kg of the total body sodium concentration. Clinically more important is the exchangeable sodium, which represents 42 mEq/kg of total body sodium. This exchangeable fraction includes all sodium within the ECF and ICF and about half of the bone sodium. Exchangeable sodium is in diffusion equilibrium with plasma (serum) sodium and is reflected in the normal ECF concentration of sodium (ie, 136-145 mEq/1). This exchangeable reservoir serves to mitigate concentration changes when sodium is either lost (eg, sweat, diarrhea) or retained (eg, cirrhosis, CHF). As a result, the concentration of sodium may provide little useful information about the total body sodium content.
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The daily adult requirement for sodium averages 1 to 2 mEq/kg/d. Normal dietary intake ranges between 100 and 200 mEq/d. The kidney is the principal site of sodium regulation through changes in the rates of glomerular filtration and tubular resorption. Approximately 24 000 mEq of sodium are filtered and resorbed by the kidneys each day. This is modulated by the interaction of a variety of neurohormonal modulators, including the sympathetic nervous system, the renin–angiotensin–aldosterone system, atrial natriuretic peptide, and ADH. Diseases or drugs that impact normal renal function or neuroendocrine function also impact normal sodium–water homeostasis. For example, CHF is characterized by adrenergic activation, release of renin–angiotensin–aldosterone, retention of both salt and water in the renal tubules, and hypervolemia. The administration of ACE inhibitors results in vasodilatation, lowering the blood pressure, diuresis, and natriuresis.
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Hyponatremia exists when the serum (or plasma) sodium is below 135 mEq/L. It may occur in an isotonic, hypertonic, or hypotonic state (Fig. 35-3). If the blood is hypo-osmolar in relation to the brain, water enters the brain and can cause acute cerebral edema, particularly in patients who are euvolemic. This may occur with large-volume administration of hypotonic fluids or in patients who develop transurethral resection of the prostate (TURP) syndrome caused by intravasation of hypotonic fluid during TURP. This may lead to a spectrum of neurologic upsets ranging from confusion to seizures to coma to brainstem herniation. Rapid correction of low sodium can lead to osmotic demyelination of the brain or brainstem because of rapid shrinkage of the brain.
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Serum osmolality is governed by contributions from all molecules in the body that cannot easily move between the intracellular and extracellular space. Sodium is the most abundant electrolyte, but glucose, urea, plasma proteins, and lipids are also important. A patient with diabetic ketoacidosis may have hyponatremia but normal osmolality because of hyperglycemia, hypertriglyceridemia, and increased plasma ketones. Each of these compounds is osmotically active. Patients with acute renal failure may have hyponatremia caused by uremia characterized by the accumulation of urea and other nitrogenous waste products.
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If a patient has hyponatremia, with low measured and calculated serum osmolality, it is called hypotonic hyponatremia. If serum osmolality is normal or high, it is isotonic or hypertonic hyponatremia or pseudohyponatremia.
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Serum osmolality is calculated from
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Classically, pseudohyponatremia is divided into conditions in which the measured and calculated serum osmolalities are the same—hyperglycemia or uremia—and those in which there is an osmolar gap; some osmoles are clearly present as measured by serum osmolality but not identified by standard blood tests. The source of unmeasured osmoles may be endogenous (lipids or proteins) or exogenous (alcohols, including ethanol, ethylene glycol, methanol, or isopropyl alcohol). The recognition of pseudohyponatremia is important because therapy for the decreased serum sodium concentration is not indicated.
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Hypertonic hyponatremia occurs when a decreased serum sodium concentration coexists with an increased serum osmolality. An increase in concentration of any osmotically active substance, which is confined predominately to the ECF (eg, glucose, glycerol, mannitol), results in water movement out of cells along the osmolar gradient. The osmolar load usually evokes an osmotic diuresis, leading to urinary loss of both sodium and water. These losses may, in turn, potentiate both the hypertonicity and the hyponatremia. Clinically, the most frequent cause of this water and electrolyte disturbance is the occurrence of significant hyperglycemia in uncontrolled or poorly controlled diabetes mellitus. The measured serum sodium concentration decreases approximately 1.6 mEq/L for each 100-mg/dL increment of blood glucose.
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True hyponatremia may result from increased TBW associated with edema (liver failure, CHF, renal failure, or nephrotic syndrome), hypotonic fluid overload, or sodium loss in excess of free water. Total-body sodium concentration is increased, and there is a concomitant defect in the excretion of solute-free water. Water retention is proportionately greater than sodium retention, resulting in hypervolemic hyponatremia. This may be associated with extensive tissue edema. Despite the dramatic increase in ECF volume, there is a tendency toward venous pooling and accumulation of fluid in lax tissues and in the peritoneum. Consequently, the plasma volume and stroke volume may be reduced, leading to renal hypoperfusion and activation of volume defense mechanisms by way of the juxtaglomerular apparatus and renin–angiotensin–aldosterone axis. This leads to a vicious cycle of hypervolemia, characteristically associated with CHF.
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Dehydration associated with hyponatremia (hypovolemic hyponatremia) may be of renal or extrarenal origin. Renal losses are identified by a urinary sodium greater than 40 mEq/L and are characterized by the inability of the body to retain sodium. This may be caused by loop, thiazide, or osmotic diuretics; carbonic anhydrase inhibitors; primary aldosterone deficiency (Addison disease or adrenal insufficiency); or cerebral salt wasting (CWS; associated with subarachnoid hemorrhage). If the urinary sodium is less than 20 mEq/L, then the site of sodium loss is outside the kidney, usually the lower GI tract, and associated with diarrhea. The mechanism of hyponatremia is the in-built priority of preservation of volume over osmolality. Hence, in this situation, there is a dramatic increase in plasma ADH levels.
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A number of diseases and drugs cause abnormal release of ADH, either caused by ectopic production of ADH (ADH-secreting tumors) or increased release of this compound from the posterior pituitary gland (Table 35-2). The result is a paradoxically concentrated urine with dilute blood (the urinary osmolality is higher [>300 mOsm] than the serum osmolality [<300 mOsm]). The result is a state of hypervolemic or euvolemic hyponatremia. The syndrome of inappropriate secretion of ADH (SIADH) is easily confused with CSW; whereas SIADH improves with fluid restriction, CWS does not.
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Several factors in perioperative medicine can contribute to functional SIADH. These include emotional stress, anxiety, nausea, pain, the administration of opiates, and mechanical ventilation. Obstetric patients frequently receive oxytocin to increase uterine contractility. Indeed, the acute stress response should be seen as a state of free water retention, and for that reason, large-volume resuscitation hypotonic fluids should be avoided. Conversely, SIADH from other causes (Table 32-1) is treated initially with water restriction (Table 35-3). Patients with chronic SIADH may be treated by inducing a state of nephrogenic diabetes insipidus, for example, by administering drugs such as lithium and demeclocycline.
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A potentially fatal cause of hyponatremia, particular to perioperative medicine, is TURP syndrome. This procedure requires continuous irrigation of the operative field to improve visibility and distend the bladder or prostatic urethra. The systemic absorption of these irrigating solutions can produce acute and sometimes dramatic hyponatremia. The irrigating fluids cannot contain electrolytes to prevent current dispersion from the resectoscope; hence, distilled water solutions containing isotonic glycine, mannitol, or sorbitol are usually used. During TURP, systemic absorption of the irrigating solutions is influenced by the duration of exposure, the number and size of venous sinuses opened, extravasation of the fluid into tissues outside the bladder or prostatic capsule, and the hydrostatic pressure of the fluid. The majority of patients undergoing TURP probably intravasate some hypotonic fluid, and there are few sequelae. However, when large volumes are absorbed, severe hyponatremia leading to cerebral edema may ensue. Consequently, urologists routinely administer furosemide when resection is complete. On occasion, it is necessary to administer hypertonic fluids to replete a sodium deficit.
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If HS is to be use, the sodium deficit must be calculated (the normal serum sodium is 140 mEq/L):
- Step 1: Find out the patient's weight is kilograms before illness.
- Step 2: Calculate the sodium deficit.
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It is usual to correct only half the sodium deficit (NaD) (hence the deficit/2)
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If the patient's weight is 70 kg and the serum sodium is 120 mEq/L, then the desired change is 10 mEq/L
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Total body deficit of sodium is the sodium deficit × TBW
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Using the formula: 10 × (70 × 0.6) = 420 mEq
- Step 3: Calculate the rate of replacement.
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Most physicians replace the deficit at no more than 0.5 mEq/h. The patient has a deficit of 10 mEq, so at this rate, it will be replaced over 20 hours (10/0.5).
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- Step 4: Replace the sodium deficit with the fluid of your choice.
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The amount of fluid required depends on the sodium content of that fluid (Table 35-4):
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If one is using 3% saline in this 70-kg male patient with a serum sodium of 120 mEq/L:
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That is, after 20 hours, assuming no other fluids are given, the patient's serum sodium will increase to 130 mEq/L. If 0.9% saline is given:
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Care must be taken when repleting sodium deficits to avoid the problem of osmotic demyelination (central pontine myelinolysis). Rapid correction of hyponatremia may trigger demyelination of pontine or extrapontine neurons, leading to neurologic dysfunction that may include quadriplegia, pseudobulbar palsy, seizures, coma, and even death.21 For this reason, serum sodium is increased slowly, and only 50% of the deficit is corrected.
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A serum sodium of greater than 145 mEq represents a hypertonic and hyperosmolar state. There is a net deficit of water in relation to sodium. This implies neither an increase in total body sodium nor a deficit in TBW. Hypernatremia is rarely encountered in routine perioperative patients; however, it is a common finding in the intensive care unit (ICU) and consequently in patients traveling to the operating room from the ICU for subsequent procedures. When the serum osmolality exceeds 305 to 310 mOsm/kg H2O, ADH secretion is stimulated, and the urine becomes severely concentrated (ie, osmolality >800-1000 mOsm/kg H2O). The thirst response is activated in an attempt to stem cellular dehydration. Hypertonicity and hypernatremia rarely develop in the presence of an intact thirst mechanism and access to water. However, critically ill patients are often too sedated to express thirst or unable to drink water.
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The imbalance between TBW and sodium that occurs in hypernatremia may develop from either water loss or sodium gain (Fig. 35-4 and Table 35-5).22 This may result from pure dehydration, the presence of a free water deficit (hypovolemic hypernatremia) such as occurs with administration of loop or osmotic diuretics, excessive evaporative losses (nonhumidified breathing systems), or diabetes insipidus (either cranial or nephrogenic). Patients with diabetes insipidus may present to the operating room in 3 circumstances. First, patients with traumatic brain injury (TBI) complicated by diabetes insipidus may present for neurosurgery, such as for decompressive craniectomy. Second, a patient who has undergone devastating brain injury, either traumatic or hemorrhagic, complicated by diabetes insipidus, may present for organ harvest after brain death. Finally, a patient who has been chronically treated with lithium for bipolar disorder complicated by diabetes insipidus, may present for routine surgery. In each of these situations, the major risk to the patient (or his or her organs) is not hypernatremia but hypovolemia, and the anesthesiologist must be careful to replenish perioperative urinary losses.
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Hypernatremic hypernatremia is associated with sodium gain in the presence of either euvolemia or hypervolemia. This may result from administration of HS, sodium bicarbonate, blood transfusion (sodium citrate), or parenteral nutrition (sodium acetate). Hypernatremia may be accompanied by metabolic alkalosis associated with an increase in the SID from either dehydration of sodium gain (see below).
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Hypernatremia can be associated with significant neurologic sequelae: Initially, the brain shrinks because of volume depletion, which makes the blood vessels vulnerable to rupture. The brain adapts to dehydration by expressing more solute, which may lead to cerebral edema, a neurologic deficit, or convulsions.
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The clinical approach to the management of patients with hypernatremia is to identify and treat the source and replace the free water deficit. To correct hypernatremia, fluid and electrolyte losses must be restored. The rate of correction depends on the duration of hypernatremia: In general, for critically ill patients, correction at a rate of 1 mEq Na/L/h is appropriate; if hypernatremia is prolonged, 0.5 mEq Na/L/h is more advisable (to reduce the risk of rebound cerebral edema).
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Calculation of the free water deficit:
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where 0.6 × weight* = Estimated body water and 140 = Desired sodium.
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So, for a 70-kg man with a serum sodium of 150 mEq/L = 3 L.
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Any fluid can be used to replace the free water loss, either isotonic or hypotonic. However, the more hypotonic the fluid administered, the more rapidly the deficit will be replaced.
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In the example above, one wished to reduce the patient's serum sodium by 10 mEq/L, how much of what fluid does one use? This depends on the amount of sodium in the chosen fluid and then applying this figure to the formula below (Table 35-6):
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If one chose D5% (dextrose 5% in water) and planned to correct this patient's sodium at a rate of 1 mEq/L/h: Because each liter will correct 3.5mEq, the rate of fluid infusion would be 1000 mL/3.5 = 285 mL/h.
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Clearly, for simple hypernatremia, the choice of fluid determines the volume required to correct the sodium abnormality (a much larger volume of LRS is required compared with D5%). The administration of free water, for example, via the enteral route, is probably the most effective method replenishing extracellular water deficit.
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*This represents TBW for young men; for women and elderly men, multiply the weight in kilograms by 0.5.
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Potassium is the major intracellular cation in the body and has several roles, the most important being the generation of the resting cell membrane potential and the action potential, as well as protein synthesis, acid–base balance, and maintenance of intracellular osmolality.
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The total body potassium content ranges from 50 to 55 mEq per kg of body weight. Potassium is an intracellular cation, and approximately 98% of the body stores are located within the ICF compartment (ie, only a total of 60-70 mEq exists in the ECF). A huge concentration gradient exists between the ICF and ECF compartments (150 mEq/L and 3.5 to 5.5 mEq/L, respectively). The primary mechanism for establishing and maintaining this concentration gradient is the sodium-potassium–activated ATPase "pump" that is located in the plasma membrane of all body cells. These membrane-bound ionic transport pumps and the selective permeability characteristics of cell membranes are responsible for the transmembrane electrical potential difference found in all living cells. Potassium is the ion responsible for generating cellular electrical activity. Hence, hypo- and hyperkalemia result in significant neuromuscular dysfunction.
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The total amount of potassium present in the body is approximately 3200 mEq, 90% of which is intracellular, and this is regulated by a variety of homeostatic mechanisms. Of total body potassium, approximately 135 to 150 mEq/L is intracellular compared with plasma levels of 3.5 to 5.5 mEq/L. The daily requirement is about 1 mEq/kg/d absorbed from the small intestine. Potassium excretion exactly matches intake, and body stores are quantitatively stable. Potassium balance is predominately governed by urinary loss. The kidney can adjust urinary potassium excretion from less than 1 mEq/L to greater than 100 mEq/L. In addition, there is some secretion of potassium in the colon.
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Two factors impact renal handling of potassium, renal tubular fluid flow and aldosterone. The majority of filtered potassium is reabsorbed in the proximal tubule. The distal tubules then secrete potassium. This is influenced by the intracellular potassium concentration, the rate of urinary flow, and the anionic charge of the urine. As the rate of flow increases, there is a significant increase in potassium excretion. This explains hypokalemia associated with diuresis. Conditions that increase distal tubular sodium delivery promote potassium excretion and sodium reabsorption, particularly in the presence of aldosterone.
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One of the most important roles of potassium is the resting membrane potential and in the repolarization phase of action potentials. The normal cell membrane is relatively permeable to potassium ions and impermeable to sodium and anions. The anions generate a negative intracellular potential. Potassium is held intracellularly against the electrochemical gradient by the action of the Na+/K+ ATPase pump that maintains the resting membrane potential. The relative ratio for intracellular to extracellular potassium is responsible for electrochemical activity. Hence, abnormalities of potassium concentration directly impact neuromuscular activity.
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Hyperkalemia is generally defined as a serum potassium concentration of greater than 5.5 mEq/L. Numerous conditions, diseases, and drugs produce hyperkalemia by disrupting the normal external or internal potassium balance (Table 35-7) (or both). Factitious hyperkalemia is associated with hemolysis of the blood sample.
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Several factors may produce a transient increase in serum potassium concentration caused by a transcellular shift. This includes administration of succinylcholine (0.3-0.5 mEq/L in normal subjects), burns, diabetes, metabolic acidosis, and nonselective β-blockers.
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Succinylcholine may be associated with significant hyperkalemia is certain circumstances. These include conditions with muscle membrane degeneration (eg, trauma, burns, primary muscle disorders) or neural denervation (eg, stroke, multiple sclerosis, Guillain-Barre syndrome, spinal cord injuries). Impaired potassium excretion is associated with acute and chronic renal failure, adrenal insufficiency, hypoaldosteronism (for any reason), and the use of ACE inhibitors.
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In hyperkalemia, the resting membrane potential is decreased toward the threshold potential (Fig. 35-5). With mild hyperkalemia (ie, serum potassium concentration of <6-7 mEq/L), there is increased automaticity as reflected by atrial or ventricular ectopy. Progressive hyperkalemia enhances rapid repolarization (phase 3), which causes shortening of the T-wave interval and symmetrical peaking of the T wave. If the serum potassium concentration continues to increase, the inward movement of sodium (phase 0) and calcium (phase 2) diminishes, the PR interval becomes prolonged and eventually the P waves (atrial phase 0) disappear. Within the ventricular muscle mass, both conduction velocity and the height of the action potential are reduced. The net result is a widened QRS complex and reduced contractility. If the hyperkalemia progresses, the QRS complex become smooth, wide, and sinusoidal as it merges with the T wave (serum potassium concentration of >10 mEq/L). Without treatment, ventricular fibrillation will ensue.
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Emergency treatment is aimed at quickly stabilizing the myocardium and restoring normal transmembrane electrical potentials. A total of 10 to 30 mL of 10% calcium gluconate can be administered over 3 to 5 minutes (or 5-10 mL calcium chloride may be substituted). Calcium reduces both the threshold potential and the excitability of cell membranes. The duration of action is roughly 30 to 60 minutes; a second dose may be necessary. Alternative temporizing measures include administration of sodium bicarbonate, nebulized albuterol, or insulin and dextrose in combination. Both have the impact of sending potassium into cells, the former by increasing SID and the latter by a direct effect. One unit of regular insulin is recommended for each 2 g of dextrose. For example, 1 ampule of D50 (ie, 50 mL of 50% dextrose) would be immediately followed by 12 units of regular insulin.
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More definitive treatment of hyperkalemia can be achieved by administering exchange resins administered orally or rectally. These include calcium or sodium polystyrene sulfonate in combination with sorbitol, which facilitates potassium excretion through colonic exchange of calcium or sodium for potassium. If this approach fails, hemodialysis may be required.
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Hypokalemia is typically considered a potassium level of less than 3.5 mmol/L, although patients may be asymptomatic until the level is less than 2.5 mmol/L. Although the relative decrease in extracellular potassium may appear small (1-2 mEq/L), this represents a significant total body deficit of potassium, up to 500 mEq. On average, plasma potassium decreases by 0.3mmol/L for each 100-mmol reduction in total body stores.
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Acute hypokalemia is associated with either inadequate intake or absolute loss of potassium from the body, governed by the law of mass conservation, or transcellular movement (Fig. 35-6 and Table 35-8). Causes of absolute loss include vomiting, diarrhea, bowel fistulae, loop and osmotic diuretics, and the diuretic phase of acute renal failure. Causes of intracellular potassium shifting include metabolic alkalosis, use of β2-adrenergic agonists, hyperadrenergic states (including the acute stress response), administration of insulin, and hypothermia. Chronic causes of hypokalemia include malnutrition, malabsorption, diuretic usage, corticosteroid administration, and Conn syndrome (hyperaldosteronism).
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Potassium depletion causes muscle weakness. The ratio of intracellular to extracellular potassium increases, thereby reducing the resting potential (phase 4) and creating a state of hyperpolarization. When the action potential is initiated (phase 0), it is of super-normal magnitude. The time allotted for calcium entry (phase 2) is shortened, and repolarization (phase 3) is prolonged, leading to a greater relative refractory period. The diminished calcium entry affects skeletal muscle and may lead to myalgia, cramps, and weakness. The smooth muscle components of the bladder, GI tract, and the peripheral vasculature are also affected, leading to urinary retention, ileus, and postural hypotension. The ensuing vasoplegia may be catecholamine insensitive.
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Hypokalemia impacts cardiac conduction and contractility. Progressive electrocardiographic (ECG) changes are typical (Fig. 35-7): T-wave amplitude decreases, QT interval lengthens, the U wave appears or becomes broader and taller, the ST segment sags, and P-wave amplitude and QRS duration increase. Cardiac arrhythmias are relatively common. The most common dysrhythmias are atrial fibrillation and premature ventricular systoles, but supraventricular tachycardia, junctional tachycardia, and Mobitz type I second-degree atrioventricular block may also occur. Hypokalemia may induce digitalis toxicity.
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It is probably unnecessary to administer potassium supplements to patients with mild hypokalemia. If moderate to severe hypokalemia (<3.0 mEq/L) is present, IV potassium chloride or potassium phosphate is usually administered. The maximal recommended rate of infusion is 0.5 to 0.7 mEq/kg/h. The repletion of total body potassium stores requires approximately 200 mEq for each 1-mEq/L reduction in the serum potassium concentration. Magnesium is an essential cofactor for transcellular sodium–potassium ion pumps. If hypomagnesemia coexists, magnesium supplements should be administered to ensure intracellular potassium repletion.
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Calcium is an essential inorganic element that plays a crucial role in many biologic functions. It is the single most abundant electrolyte in the human body. A normal adult contains between 1000 and 1400 g of calcium, of which 99% is located in bone, where it is the primary structural component. Approximately 1% of the total calcium pool resides in the soft tissues and the ECF compartment. Circulating calcium exists in 3 forms, a free ionized fraction (50%); a fraction bound to protein (mostly albumin) (40%); and a diffusible, nonionized fraction (10%) in which calcium is chelated with circulating anions (eg, bicarbonate, phosphate, citrate). The ionized fraction is the calcium that is physiologically active, and it is the concentration of this fraction that is closely regulated by parathyroid hormone (PTH), vitamin E, and calcitonin. These substances alter the resorption of calcium from various target organs, including the skeletal system, GI tract, and kidneys.
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A measurement of total serum calcium (the analysis most often performed when a calcium level is requested) reflects the quantitative contribution of all 3 forms of circulating calcium. The normal value varies depending on the particular laboratory but is generally in the range of 8.5 to 10.5 mg/dL (4.5-5.5 mEq/L or 0.96-1.27 mmol/L). The reported quantity may be misleading because of albumin binding, and calcium concentration measured in this way must be corrected for albumin concentration. Modern laboratories have the capability of directly measuring ionized calcium. The normal values for this measurement usually range from 4 to 5 mg/dL (2.1-2.6 mEq/L or 1.17-1.29 mmol/L).
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Calcium has a number of important physiologic functions. As an essential component in neuromuscular transmission, calcium is involved in myocardial contractility by way of voltage-sensitive calcium channels in the myocardium. Calcium is involved in both depolarization and the magnitude of muscle contraction. Calcium is stored in the sarcoplasmic reticulum. Neurochemical activation leads to an increase in cytoplasmic calcium concentration. Calcium binds to troponin C, and this complex binds to tropomycin, which facilitates the interaction between actin and myosin, resulting in cardiac muscular contraction. Increased intracellular calcium is associated with increased contractility, inotropy, and cardiac output. Calcium is removed by reuptake into the sarcoplasmic reticulum and by extrusion via the Ca2+-Na+ pump located in the plasma membrane. This results in relaxation. Calcium is also an essential component in both skeletal muscle and smooth muscle contractility.
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Calcium is an important cofactor for blood coagulation. The cytoplasm of platelets contains contractile filaments of actin and myosin that enable activated platelets to change their shape and release the contents of their granules. This process is driven by intracellular calcium. Calcium is important in the activation of thrombin, acting as a cofactor with factors VII, IX, and X.
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Calcium is absorbed by the small intestine under the influence of calcitriol, a derivative of vitamin D. Calcitriol also facilitates absorption of phosphate from the intestine and absorption of calcium from the nephron and influences bone formation and osteoclastic activity. The major control hormone for calcium metabolism is PTH. This hormone causes release of calcium and phosphate from bone. It also enables renal calcium reabsorption and renal phosphate excretion and activates calcitriol. Calcitonin has the opposite impact on serum calcium to PTH. It inhibits renal reabsorption of calcium and osteoclastic bone formation.
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Hypercalcemia is associated with numerous conditions and disorders, including hyperparathyroidism, immobilization, chronic renal failure, adrenal insufficiency, thyrotoxicosis, sarcoidosis, and various drugs (Table 35-9).
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The commonest cause of hypercalcemia is hyperparathyroidism. Anesthesiologists encounter these patients because they are frequently scheduled for parathyroidectomy. The second most common cause of acute hypercalcemia is malignancy secondary to bone destruction by metastases or caused by secretion of calcemic factors by the tumor. This problem is most frequently encountered in patients with breast cancer, myeloma, bronchogenic, and renal cell carcinoma.
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A wide variety of clinical symptoms are characteristic of hypercalcemia, often described as "bones, stones, groans, and moans." Patients develop bony pain, renal calculi, abdominal symptoms, and neuropsychiatric problems. Abdominal problems include nausea and vomiting, constipation, and acute and chronic pancreatitis. Hypercalcemia may impact cardiac electrical conduction by progressive shortening of the QT interval, leading to arrhythmias and possible cardiac arrest. Hypertension caused by contraction of vascular smooth muscle is common. Hypercalcemia has varying effects on the kidneys. It may cause polyuria and polydipsia (mimicking diabetes mellitus) by interfering with ADH activity on the collecting ducts. It may reduce renal blood flow and glomerular filtration. It may cause nephrocalcinosis, interstitial nephritis, and urolithiasis. In the central nervous system, hypercalcemia may cause anxiety, depression, irritability, lethargy, confusion, and psychosis.
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The mainstay of therapy is hydration, either with or without the use of loop diuretics such as furosemide. Renal clearances of sodium and chloride are closely linked, so the co-administration of salt solutions and diuretics allows rehydration and naturesis. Other alternative therapies include chelators (eg, phosphates and EDTA), osteoclast inhibitors (eg, mithramycin, glucocorticoids, calcitonin, diphosphonates), and calcium channel blockers (verapamil).
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Ionized hypocalcemia develops when there is significant calcium loss from the body. In perioperative medicine, this may be associated with massive blood transfusion, massive crystalloid resuscitation, or after parathyroidectomy (Table 35-10). Other causes include acute and chronic renal failure, vitamin D deficiency, hypomagnesemia, rhabdomyolysis, malnutrition, burns, sepsis, and acute pancreatitis. Critically ill patients frequently have hypocalcemia. During massive transfusion, the presence of citrate in the blood may result in significant hypocalcemia. The hallmark of hypocalcemia is neuromuscular irritability, with symptoms ranging from paresthesia to tetany and seizures. In addition, hypocalcemia may augment the neuromuscular blockade caused by nondepolarizing muscle relaxants. Mild hypocalcemia (ionized calcium levels of 3.2-3.9 mg/dL), even in critically ill patients, usually does not evoke symptoms. Patients undergoing parathyroidectomy may develop acute postoperative hypocalcemia, requiring supplementation.
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The clinical features of acute hypocalcemia are listed in Table 35-11. Acute hypocalcemia is associated with increased neuromuscular irritability. In mild hypocalcemia, the patient may complain of paraesthesia of the fingers and toes and numbness (and burning) around the lips and mouth. With more severe hypocalcemia (ionized Ca <1.0 mmol/L), the patient may complain of painful muscles spasms, particularly of the fingers and thumb (carpal spasm). The term tetany has been used to describe this process, whereby there is repetitive neuromuscular discharge after a single stimulus. Tetany can be elicited by tapping over the facial nerve proximal to the auricle; this leads to twitching of the ipsilateral facial muscles, particularly around the eyes and mouth (Chvostek sign). Carpal spasm can be elicited by inflating a blood pressure cuff around the arm for several minutes, presumably causing mild ischemia and provoking muscle contraction (Trousseaus sign). Pain, anxiety, and hyperventilation may precipitate muscular spasms in postoperative patients, potentially causing stridor or laryngospasm.
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Acute symptomatic hypocalcemia is a medical emergency that warrants the IV administration of calcium. Therapy should not be withheld even if the cause of the hypocalcemia is unclear. In adults, the recommended treatment is a 100-mg bolus of elemental calcium (over 5-10 minutes) followed by a continuous infusion administered at a rate of 0.5 to 2 mg/kg/h. Note that a bolus dose of calcium will only increase the ionized calcium concentration for 1 to 2 hours. Consequently, repeated boluses or an infusion is required.
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Two different calcium salt preparations are readily available for IV administration, calcium chloride and calcium gluconate. Calcium chloride 10% contains 27.2 mg of elemental calcium in 10 mL. Calcium gluconate contains 9.3 mg of elemental calcium per 10 mL. Calcium chloride is very irritating to the peripheral vasculature and should be administered directly into the central venous circulation, if at all possible. In addition, the chloride salt is acidifying and theoretically should not be used when acidemia coincides with hypocalcemia. Thus, in the presence of significant metabolic acidosis, calcium gluconate should be used.
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Magnesium is the fourth most abundant cation within the body and is the second most prevalent intracellular cation next to potassium. Within the body, magnesium is distributed such that 50% to 60% resides in the skeletal system and another 20% is located within muscle tissue. The ICF-to-ECF concentration ratio is about 15:1. At any one time, less than 1% of total body magnesium circulates within the intravascular fluid compartment, and thus serum levels do not reflect total body stores.
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Depending on the particular laboratory, the normal total serum magnesium concentration ranges from 1.5 to 2.0 mEq/L. Similar to calcium, the circulating magnesium consists of 3 components: a chelated fraction (5%); a protein-bound fraction (33%); and an ionized, diffusible fraction (62%). It is this that is physiologically active and carefully regulated to maintain homeostasis. Currently, laboratories cannot report ionized magnesium, hence total magnesium is used.
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Magnesium is a cofactor for more than 300 enzymatic reactions involving energy metabolism and nucleic acid synthesis. It is also involved with hormone receptor binding, calcium channel gating, transmembrane ion flux, regulation of adenylate cyclase, muscle contraction, neuronal activity, vasomotor tone, cardiac excitability, and neurotransmitter release.23 From many perspectives, magnesium can be viewed as a physiological calcium antagonist.
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Both PTH and vitamin D have regulatory influences on renal and GI magnesium absorption. In turn, the ionized magnesium concentration influences PTH secretion. The circulating ionized magnesium is primarily regulated by the kidneys; the majority of filtered magnesium is conserved through proximal tubular resorption. Renal magnesium wasting occurs with hypermagnesemia, hypercalcemia, hypophosphatemia, hypercalciuria, loop diuretics, ACE inhibitors, aminoglycosides, amphotericin, cyclosporine, and cisplatin. Hypomagnesemia is almost universal in patients undergoing major surgery. Hypomagnesemia may also result from malnutrition, malabsorption, inadequate administration (including ECF dilution), diarrhea, laxatives, vomiting, and diabetes (Table 35-12).
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Hypomagnesemia is associated with a variety of clinical manifestations that involve the neuromuscular and cardiovascular systems (Table 35-13). One interesting manifestation of hypomagnesemia is a cardiac arrhythmia known as torsade de pointes. This is derived from a French ballet expression for "twisting of the points." It refers to a specific polymorphous ventricular tachyarrhythmia in which the morphology of the QRS complexes varies from beat to beat. The ventricular rate varies from 150 to 250 beats/min. The arrhythmia is effectively treated with potassium and magnesium boluses.
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In cases of hypomagnesemia, the total deficit is often greater than anticipated because this is primarily an intracellular cation. The deficit of magnesium is often l to 2 mEq/kg, and effective repletion may require a total dose of elemental magnesium in the range of 2 to 4 mEq/kg (given over several days). For mild acute hypomagnesemia, 4 to 6 g of magnesium can be added into IV fluids and infused over 30 minutes. Rapid infusion is associated with an unpleasant hot flash and may induce acute hypotension. A continuous maintenance infusion of magnesium sulfate should then be administered for 4 to 7 days. This maintenance fluid should contain a total daily dose of 600 to 900 mg of elemental magnesium. In emergency situations, the loading dose can be infused more rapidly as long as continuous ECG monitoring is performed, and the rate of administration does not exceed 15 mg/min of elemental magnesium. For the duration of IV magnesium therapy, patients should be carefully monitored for evidence of magnesium toxicity, and frequent assessment of the total serum magnesium concentration is mandatory.
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Hypermagnesemia results from magnesium-containing antacids, enemas, total parenteral nutrition, acute renal failure, adrenal insufficiency, hypothyroidism, and nephrogenic diabetes insipidus.
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Hypermagnesemia impairs neuromuscular function and produces progressive neuromuscular blockade. There is a heightened sensitivity to both depolarizing and nondepolarizing muscle relaxants. Magnesium has significant cardiac and hemodynamic effects. As a functional calcium channel blocker, magnesium may cause vasodilatation and hypotension.
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Magnesium has been used in a variety of clinical situations, including perioperative care (Table 35-14). Magnesium has been used to control blood pressure and prevent seizures in preeclampsia. Magnesium may be used to control heart rate in ventricular and supraventricular arrhythmias, particularly when hypokalemia coexists. It has been used to treat torsade de pointes and digitalis toxicity. Magnesium has been used to reduce the adrenergic response to induction of anesthesia and intubation.24 It has been used therapeutically as a smooth muscle relaxant in patients with acute severe asthma.25 Other therapeutic roles for magnesium in perioperative medicine and critical illness include perioperative analgesia, treatment of myocardial infarction, and treatment of tetanus.26 The analgesic properties of magnesium appear to be associated with its antagonistic properties on neuromuscular depolarizing receptors and calcium channel blockade. Calcium channel blockers are antinociceptive and potentiate the effects of morphine.26
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The clinical manifestations of hypermagnesemia correlate well with the total serum magnesium concentration. These include somnolence, hypoventilation, postural hypotension, and, at higher doses, respiratory and cardiac arrest. In patients treated with high-dose magnesium, (eg, in obstetric patients with preeclampsia and eclampsia), careful monitoring of neuromuscular function must be performed to avoid devastating neuromuscular blockade, leading to respiratory arrest.
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Treatment for hypermagnesemia includes enhancing urinary excretion, principally by combining saline infusion and furosemide. Direct antagonism of toxic effects can be provided by IV calcium, although the duration of action is relatively short. In circumstance in which reversal of effect is not possible because of acute renal failure, hemodialysis is required.
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Phosphorous is the most abundant intracellular anion; its concentration is approximately 100 mmol/L. One hundredth of the body's mass is made up of phosphate. Most of this is stored as hydroxyapatite crystals in the bone matrix. Only 15% is metabolically active, and 1% is present in the blood. The average diet provides 800 to 1400 mg of phosphorous daily. Of this, 70% is absorbed through the gut, mainly by passive transport, but there is also some active transport stimulated by vitamin D metabolites. Normal plasma range is between 2.8 and 4.5 mg/dL. The main organ of regulation of phosphate is the kidney. Phosphorous is filtered by the nephron, and mostly reabsorbed in the proximal tubule in co-transport with sodium. This co-transport is regulated by phosphorous intake (ie, serum phosphorous levels) and PTH. PTH inhibits the co-transport mechanism and increases urinary excretion of phosphorous. In the blood, phosphate is present in multiple forms as phospholipids, PO43-, H2PO4-, and HOP42-.
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Every metabolic action in the body requires chemical energy, principally in the form of adenosine triphosphate (ATP). The high-energy bonds in ATP are derived from phosphate. This is essential for muscle contractility, neuronal transmission, and electrolyte transport. Phosphate is a key building block for many essential intracellular compounds, including nucleic acids, phospholipids, enzymes, and nucleoproteins. Many of the intracellular messenger chemicals employ phosphate, these include cyclic AMP and cyclic GMP. Phosphate has an essential role in both aerobic and anaerobic metabolism and in 2,3-DPG (2,3-diphosphoglycerate), which is involved with hemoglobin–oxygen interactions at the tissue level. Phosphate is involved in cascades within the coagulation and immune systems. Finally, phosphate is the main intracellular buffer in the body and is a component of the extracellular weak acid buffering system (ATOT).
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Hypophosphatemia is caused by inadequate intake, excessive loss, or redistribution within the body (Table 35-15). Inadequate intake may result from malnutrition or malabsorption (short bowel syndrome, tropical sprue, celiac and Crohn disease, radiation enteritis). Agents that bind with phosphate may reduce its absorption. These include magnesium and aluminium antacids and sucralfate (which contains aluminium).
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Excessive loss of phosphate is associated with diuresis and dialysis. Osmotic diuretics and hyperglycemia cause increase urinary loss, as does theophylline and acetaminophen in overdose. The most phosphaturic diuretics are carbonic anhydrase inhibitors. Hypophosphatemia may rapidly occur during intermittent and continuous renal replacement therapies.
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Hypophosphatemia may result from intracellular redistribution, during administration of catecholamines or beta-adrenergic agonists, insulin surges (hyperglycemia), and alkalosis for any reason.
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In general, muscles do not function well in hypophosphatemic states (Table 35-16). This relates to the importance of phosphate as the body's source of chemical energy. Hypophosphatemic causes weakness of respiratory muscles, particularly the diaphragm, and causes a leftward shift of the oxyhemoglobin dissociation curve (increasing the tendency for hemoglobin to cling onto oxygen). Patients who are hypophosphatemic may be slow to wean from mechanical ventilation.27,28 As one would expect, hypophosphatemia causes skeletal muscle weakness, which may mimic myopathy. In addition, low serum phosphate may interfere with blood cell function and cause increased red blood cell (RBC) fragility.
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Hypophosphatemia may cause myocardial dysfunction29 and may make the myocytes less sensitive to the stimulatory effects of catecholamines. This effect is reversible. Other complications of hypophosphatemia are listed in table below.
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A particularly important cause of hypophosphatemia is the "refeeding syndrome." Severely malnourished individuals develop a total-body depletion of phosphorous; serum phosphorous levels are maintained by redistribution from the intracellular space. The body uses endogenous fuel stores as its main source of energy. Fat and protein (from muscle) are metabolized. Glucose delivery, either enterally or parenterally, as part of a feeding strategy leads to a dramatic increase in circulating insulin levels. This results in rapid uptake of glucose, potassium, phosphate, and magnesium into cells. The serum concentration of these species decreases dramatically. Simultaneously, there is a dramatic increase in ECF volume. There is an increase in cardiac workload, with increased stroke work, heart rate, and oxygen consumption. This sudden increase in demand for nutrients and oxygen may outstrip supply. Moreover, in patients with cardiovascular disease, the sudden increase in cardiac work and circulating fluid can precipitate acute heart failure. The sudden administration of carbohydrates exerts a considerable strain on the respiratory system, whose musculature may well be atrophied because of starvation. There is an increase in CO2 production and O2 consumption and a resultant increase in the respiratory quotient. The consequence of this is an increase in minute ventilation, leading to dyspnea and tachypnea and potentially acute respiratory failure.
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The serum phosphorous level decreases precipitously with refeeding because of a shift of phosphate from the extracellular to the intracellular compartment. This results from increased intracellular demand for the synthesis of phosphorylated compounds. This may result in respiratory failure, cardiac failure, cardiac arrhythmias, rhabdomyolysis, seizures, coma, and RBC and leukocyte dysfunction.
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Perioperative patients are vulnerable to hypophosphatemia, because of the catecholamine surge associated with the stress response. If severe malnutrition is suspected, the anesthesiologist should be careful to avoid the administration of glucose-containing IV fluids and aggressively supplement intracellular ions, potassium, magnesium, calcium, and phosphate (Table 35-17).
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Hyperphosphatemia is caused by increased administration or absorption, decreased loss, or increased production (Table 35-18). Increased intake can occur as a result of excessive IV administration or oral supplementation or vitamin D intoxication. Occasionally, hyperphosphatemia results from recurrent administration of phosphate-containing enemas. There is reduced excretion in renal failure, hypoparathyroidism, and hypomagnesemia. Increased serum phosphate levels may result from diseases that cause widespread cell destruction, including tumor lysis syndrome, rhabdomyolysis, bowel ischemia, hemolysis, and malignant hyperthermia. Pseudohyperphosphatemia may occur because of hypertriglyceridemia.
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Acute hyperphosphatemia is associated with hypocalcemia, muscle weakness, and tetany. In chronic hyperphosphatemia, as occurs in chronic renal failure, calcium may be deposited in the tissues (ectopic or metastatic calcification). The treatment for acute hyperphosphatemia is administration of phosphate-binding salts (ie, calcium, magnesium, and aluminum).
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Chloride is the second most abundant extracellular ion and the most important extracellular anion. Chloride is absorbed in roughly equimolar concentrations with sodium in the small bowel. In addition, chloride is actively secreted into the gastric lumen with potassium that is subsequently pumped back into the parietal cell. The consequence is a significant decrease in pH (gastric acidity). Chloride has a wide variety of other functions in the body. It represents one-third of extracellular osmoles and is involved in volume homeostasis; regulation of pH in the kidneys; organic solute transport; and cell migration, proliferation, and differentiation.
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Chloride channels are abundant in the body.30 These are involved in a variety of functional roles in diverse processes, such as blood pressure regulation, cell cycle and apoptosis, muscle tone, volume regulation, synaptic transmission, and cellular excitability.31 The benzodiazepine receptor gates a chloride channel, a key element in anesthesia pharmacology. A significant number of diseases appear to result from chloride channel abnormalities (Table 35-19). Mutations that result in a loss of function of the voltage-gated chloride channel, CLC-5, are associated with Dent disease, which is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and renal failure.32 Mutations of another voltage-gated chloride channel, CLC-Kb, are associated with a form of Bartter syndrome; other forms of Bartter syndrome are caused by mutations in the bumetanide-sensitive sodium–potassium–chloride cotransporter (NKCC2) and the renal outer medullary potassium channel (ROMK). Mutations of the thiazide-sensitive sodium-chloride cotransporter (NCCT) are associated with Gitelman syndrome.32 Mutations of chloride transport proteins are responsible for cystic fibrosis, renal tubular acidosis, neuromuscular disorders, and some forms of epilepsy.
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The role of chloride in acid–base chemistry is discussed in that section below. Essentially, hyperchloremia is associated with metabolic acidosis; hypochloremia is associated with metabolic alkalosis. Chloride has an important role in renal function.32 Thiazide diuretics may modulate blood pressure by controlling serum chloride concentration by way of a sodium–chloride cotransporter. Hyperchloremia produces progressive renal vasoconstriction and a decrease in glomerular filtration.33 In addition, hyperchloremia results in splanchnic hypoperfusion.34 Administration of chloride-rich solutions such as 0.9% saline may result in hyperchloremia, renal dysfunction, nausea and vomiting, and hyperventilation.
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Albumin is the most abundant extracellular protein. It is a single polypeptide with 585 amino acids and a molecular weight range of 65 000 to 69000 D. It is thus a medium-sized compound (IgG is 150 000) which, in addition to being highly soluble, is small enough to pass through fenestrated endothelium, such as in the nephron. Proteinuria does not occur in normal individuals because of the strong negative charge (–17 mEq) carried by albumin, which rebuts the protein in the glomerulus. Albumin is a weak acid whose concentration significantly impacts extracellular buffering capacity.
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Albumin is manufactured in the liver at a rate of 9 to 12 g/d. The normal serum albumin level is 30 to 50 g/L (3-5 g/dL). There are no storage and no reserve. Being the major source of oncotic pressure in health, the rate of production of albumin is controlled by changes in osmotic pressure and the osmolality of the extravascular perihepatic space. There is limited capacity to increase production. Increased synthesis is driven by the neuroendocrine system, chiefly by insulin, thyroid hormones, and cortisol.
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Albumin is catabolized at a rate of 9 to 12 g/d (the same rate as it is produced) by pinocytosis in cells adjacent to the vascular endothelium. Albumin is not catabolized in starvation; under these circumstances, protein is derived from muscle after exhaustion of fat stores.
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Although albumin is perceived as intravascular protein, the total extravascular albumin actually exceeds the total intravascular amount by 30%.35 The ratio of albumin to water is, however, higher in the intravascular space (the ECF is two-thirds interstitial and one-third intravascular), hence the colloidal effect. Albumin cyclically leaves the circulation through the endothelial barrier at the level of the capillaries, passes into the interstitium, and returns to the bloodstream through the lymph system via thoracic duct. The circulation half-time for this process is 16 to18 hours. A total of 4% to 5% of total intravascular albumin extravasates in this way per hour; this rate of movement is known as the transcapillary escape rate, and this is determined by capillary and interstitial free albumin concentration, capillary permeability to albumin, and movements of solvent or solute and the electrical charges across the capillary wall. The concentration of albumin in lymph protein content is approximately 80% that of plasma.
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Albumin has a variety of physiologic and pharmacologic roles (Table 35-20). Albumin binds drugs and ligands and reduces the serum concentration of these compounds (Table 35-20). An example is the serum calcium, the free (ionized) concentration of which needs to be corrected for albumin. There are actually 4 binding sites on albumin, and these have varying specificity for different substances. Competitive binding of drugs may occur at the same site or at different sites (conformational changes; eg, warfarin and diazepam). The drugs that have important albumin binding are warfarin, digoxin, nonsteroidal anti-inflammatory drugs, midazolam, and thiopental. The relevance of a low albumin and drug binding is unknown.
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Albumin is a major source of sulfhydryl groups; these "thiols" scavenge free radicals (nitrogen and oxygen species). Albumin has anticoagulant and antithrombotic effects that are poorly understood.
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Low serum albumin is a nonspecific marker of disease. A decrease in the albumin concentration appears to reflect deterioration; an increase reflects recovery. Very low levels of albumin appear to reflect a poor outcome. The relevance of low albumin on ligand binding is unknown.
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In critical illness, there is a reduction in the production of albumin because of favored hepatic production of acute-phase proteins such as globulins, fibrinogen, and haptoglobin. Other proteins whose levels decease in this situation include prealbumin, retinal-binding protein, transferrin, and somatomedin C. This process is known as "hepatic reprioritization." During conditions of stress or tissue injury, such as major surgery, trauma, or critical illness, a generalized increase in vascular permeability develops associated with release of cytokines and cytotoxic material. This leads to leakage of protein-rich fluid into the interstitium (capillary leak). Aggressive volume resuscitation with crystalloid, gelatins, or hydroxyethyl starch (HES) significantly reduces the albumin concentration by a dilutional effect. Hence, hypoalbuminemia during the stress and systemic inflammatory response is caused by hemodilution, redistribution, and hepatic reprioritization. Low serum albumin (and prealbumin) represents a negative acute-phase response.
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In critical illness, there is a stronger correlation between colloid oncotic pressure (COP) and total protein than with albumin. In these patients, the decreased albumin is compensated for by an increase in acute-phase proteins.36 Nonetheless, there is increased leakage of albumin, and this drags fluid into the extravascular space. The overall fluid flux is less than would be predicted if albumin was the only protein responsible for oncotic pressure in the Starling equation. Thus, low serum albumin does not necessarily mean low plasma oncotic pressure and does not always cause edema.
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Hypoalbuminemia has been associated with various disease states (Table 35-21). These include liver dysfunction, nephropathies (particularly nephrotic syndrome), preeclampsia and eclampsia, and burns. Hypoalbuminemia in preoperative patients is indicative of severe malnutrition and is a known indicator of poor surgical outcomes. Preoperative nutrition targeting an increase in albumin has been shown to improve outcomes.37 In critically ill patients, there is a strong relationship between the dynamic decrease in serum albumin concentration and patient outcomes.38 The lower the serum albumin plunges, the greater the mortality, morbidity, length of stay, and complication rate. Blunt and colleagues39 have shown that nonsurvivors in the ICU had lower mean albumin concentrations than survivors, and there was, significantly, no difference between the COPs of the 2 groups. Finally, changes in albumin concentration have significant impact on acid–base balance, which is discussed in detail in the following section.
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