Metabolic, Electrolytes, and Nutritional Concerns in Critical Illness

Crit Care Clin 21 (2005) 305 – 327

Metabolic, Electrolytes, and Nutritional Concerns in Critical Illness Jean-Philippe Lafrance, MD, Martine Leblanc, MD, FRCPc* Nephrology and Critical Care, Maisonneuve-Rosemont Hospital, University of Montreal, 5415 de l’Assomption, Montreal, Quebec H1T 2M4, Canada

Carbohydrate, fat, and protein from food sources are metabolized to produce energy. Carbohydrates are stored in the form of glycogen in liver and muscle as short-term energy reserves, whereas fat is stored in adipose tissue as long-term energy reserves. Because proteins and amino acids cannot be stored in the body, they have to be metabolized; this requires energy and produces heat because of their high thermogenic coefficients. Excessive nitrogen intake may be considered as a metabolic burden. Excess amino acids will be oxidized and nitrogen will be excreted by the kidney. The Krebs cycle is the principal energy pathway for aerobic metabolism (Fig. 1). Glucose is the main source of energy for the Krebs cycle and the major fuel for anaerobic metabolism. Glucose can be provided by hydrolysis of carbohydrates, breakdown of glycogen, hydrolysis of fat-producing glycerol, and conversion of amino acids to glucose by gluconeogenesis. Protein may enter energy-producing pathways after breakdown to component amino acids by conversion to glucose or pyruvate, through acetyl-CoA, or by passing directly into the Krebs cycle [1]. In the absence of exogenous protein or amino acids, body protein will be catabolized for maintenance processes and for use as energy (Fig. 2). Body protein is an expensive energy source; the energy that is provided from its oxidation is much less than the amount of energy that was required for its synthesis. The extent to which body protein is mobilized to produce energy is a major factor in determining the net result of protein synthesis and degradation.

* Corresponding author. E-mail address: [email protected] (M. Leblanc). 0749-0704/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ccc.2004.12.006 criticalcare.theclinics.com

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Fig. 1. The Krebs cycle and its importance in energy-producing pathways. (Adapted from Nutritional Assessment and Support. Page CP, Hardin TC, Melnik G, editors. Williams & Wilkins, 1994; with permission.)

Fig. 2. Metabolic processing of amino acids and proteins in anabolic and catabolic states. (Adapted from Nutritional Assessment and Support. Page CP, Hardin TC, Melnik G, editors. Williams & Wilkins, 1994; with permission.)

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Provision of dietary energy and exogenous amino acids is mandatory to maintain protein homeostasis and to allow net protein synthesis. After a brief starvation (less than 72 hours), the body relies on glycogen reserves and on protein breakdown to provide amino acids, as primary energy sources, and as substrates for gluconeogenesis for glucose-dependent tissues [2]. During a more prolonged starvation, adaptive changes allow the mobilization of fat and reduce the breakdown of protein. Therefore, fat becomes the main source of energy and ketones become the principal exchange substrate. Endogenous proteins are protected further by a decrease in metabolic rate and energy requirements. During stress, substrate distribution is altered consequently to the presence of mediators other than insulin and glucagon. Stressful stimuli will magnify the metabolic changes that occur with brief starvation [3]. Released cytokines and hormones enhance the gluconeogenesis that comes from amino acids, suppress appetite, stimulate lipogenesis, and induce synthesis of acute phase proteins by the liver [4]. These changes are directed at enhancing immunity, repairing tissues, and surviving on endogenous substrates. During a critical illness, the demand for energy is increased, whereas there is a net energy deficit and the use of fuel is impaired. Muscle proteins are used for the enhanced hepatic synthesis of acute phase proteins. Some amino acids, usually nonessential, become critical—glutamine and cysteine for catabolic patients, tyrosine for uremic patients, and taurine for neonates. Skeletal muscle remains the main glutamine provider and reservoir of free amino acids. The sustained increase in protein breakdown results in loss of the muscle mass and detrimental consequences. In a stress situation, the intramuscular glutamine pool will become severely depleted concomitant with the increased glutamine requirement by the gut, liver, immune system, and wounds [5]. In these tissues, glutamine will serve as a major fuel for rapidly dividing cells and as a precursor for gluconeogenesis. Unlike simple starvation, the provision of exogenous energy and amino acids will not turn the process off completely. Synthesis and degradation of proteins are enhanced in stress; exogenous feeding may help synthesis but will not reduce degradation directly. Protein-calorie malnutrition is associated with increased morbidity and mortality in medical and surgical patients. In the course of starvation and stress, the decrease in muscle mass and visceral proteins is associated with impaired immune response, poor wound healing, altered organ function, and ultimately contributes to, or results in, death. In acute renal failure (ARF), protein catabolism can be substantial and especially marked, oftentimes greater than 250 g/d [6]. Depletion of amino acids (in relation to renal replacement therapies), metabolic acidosis (which may stimulate proteolysis mediated by the activation of proteases through ATPubiquitin–dependent pathways), and increased resistance to the anabolic effect of insulin contribute to the increased protein catabolism of ARF. The greater protein degradation may accelerate the elevations in potassium, acid, and phosphorus serum concentrations.

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Acidosis in renal failure and nutrition Each day the human body produces 15,000 to 20,000 mmol of CO2, 1500 to 4500 mmol of lactic acid, and 100 to 200 mmol of other nonvolatile acids as a result of metabolism and nutrition [7]. Mechanisms to counteract such an acid load include removal of CO2 by respiration, liver metabolism, kidney excretion of ions, and ion transport across cell membranes. These pathways may become additive (eg, hepatic metabolism of lactate will generate CO2 that subsequently is eliminated by the lungs). Because catabolism is enhanced in critical illness, nonvolatile and volatile acid production is increased. This contrasts with end-stage renal disease in which metabolic acid production does not significantly differ from normal [8]. In both types of renal failure, nonvolatile acid elimination is reduced, either partially or completely. Some degree of metabolic acidosis is expected when the glomerular filtration rate decreases to less than 30 mL/min, or when renal acidification mechanisms are altered significantly [9]. In the course of renal failure, hyperchloremic metabolic acidosis generally appears earlier and usually is due to renal tubular acidosis that is related to tubulo-interstitial diseases. High anion-gap metabolic acidosis tends to occur later, when the glomerular filtration rate decreases to less than 15 mL/min to 20 mL/min and follows the accumulation of unmeasured anions, such as phosphates, sulfates, various organic acids that are not oxidized completely, and other unknown molecules. In acute and chronic renal dysfunction, a mixed type of metabolic acidosis is found commonly [10,11]. Therefore, the strong ion difference in patients who have renal failure commonly is reduced. Metabolic acidosis has detrimental consequences, especially when it is prolonged; it enhances tissue catabolism and protein breakdown by activation of the ATP-dependent ubiquitin proteasome and branched-chain ketoacid dehydrogenase degradative pathways [12]. Metabolic acidosis is involved in the denutrition and muscle wasting process of patients who have end-stage renal disease [13]. Renal acidosis contributes to osteomalacia and to bone consequences of hyperparathyroidism [14,15]. Bone acts by buffering the acid, liberating calcium, and increasing its renal excretion. Loss of bone (and of calcium) can be stopped by controlling acidosis [16]. It also is a factor in the insulin resistance that most patients who have renal failure develop. Insulin resistance can be improved by the correction of acidemia [17,18]. Acidosis blunts the response to catecholamines/vasopressors, leads to a depressed myocardial contractility, and may predispose to arrhythmias [19]. Correction of renal metabolic acidosis helps to counteract most of these undesirable consequences. Although persistent renal metabolic acidosis has negative impacts in end-stage renal disease, its consequences in patients who have ARF are less apparent [20]. Metabolic acidosis remains a marker of poor outcome in critical illness and may contribute to mortality. Acidosis in ARF is explained largely by an altered excretion of several anions [21]. Moreover, in critical illness, catabolism is greater and may exceed even

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more renal acidification mechanisms. The impact on acid-base balance of different modalities of renal replacement was reviewed recently [22]. Hemodialysis corrects metabolic acidosis, mostly by restoring a normal strong ion difference with a bicarbonate-enriched dialysate. In renal failure, correction of metabolic acidosis reduced protein degradation and allowed increases in body weight and midarm circumference [23–25]. Another study, however, suggested that nutritional status was not improved by hemodialysis—despite correction of the moderate metabolic acidosis—even if the protein catabolic rate was greater in the acidotic group [26]. The investigators suggested that the greater protein intake of this group explained the decreased serum bicarbonate concentration, rather than the decreased serum bicarbonate inducing a greater protein catabolic rate. Given all of the consequences of metabolic acidosis, it has been recommended to maintain a serum bicarbonate concentration that is greater than 22 mmol/L in patients who have chronic renal failure [27]. It is unclear if such a concentration should be extrapolated to ARF with or without critical illness. To help to correct metabolic acidosis, the choice of administered fluids should be made carefully and the impact of the amount infused should be considered. Similarly, the electrolyte content of parenteral nutrition formulations should be chosen appropriately. To reduce the risk of inducing or worsening metabolic acidosis, the chloride content can be decreased and the acetate concentration can be increased. Acetate, which is not a strong ion, will be metabolized and contribute to alkalinization. By giving large amounts of saline (NaCl 0.9%), an excess of strong anion chloride is provided relative to the ‘‘normal’’ blood plasma content; this makes this fluid susceptible to the induction of acidosis. To preserve blood plasma electroneutrality, the surplus of chloride will drive an increase in H+ concentration from water dissociation. Ringer’s lactate contains sodium, chloride, potassium, calcium, and lactate in concentrations that are similar to those in plasma. The strong ion difference (SID) of Ringer’s lactate is 28 mmol/L, much closer to the SID of human blood plasma. Therefore, Ringer’s lactate seems to be a more appropriate fluid for massive resuscitation; however, in presence of dehydration from excessive vomiting and chloride losses, fluid repletion with NaCl 0.9% would be more appropriate. Thus, the choice of fluids for resuscitation also should take into account the underlying acid-base balance and the type of dehydration process. When an induced imbalance occurs, usually no specific treatment is required; however, factors that may increase the acidosis further should be avoided. Under certain circumstances, sodium bicarbonate can be given, keeping in mind the risk of sodium and fluid overload. In patients who have chronic renal failure, the addition of enteral sodium bicarbonate carries the risk of increasing blood pressure; calcium carbonate or acetate that is used as a supplement or as a phosphate binder can help to alkalinize blood plasma modestly (increasing serum bicarbonate by nearly 1 mmol/L at dosages of 3–6 g/d). This represents a useful adjunct in predialysis candidates.

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Electrolytes A strong ion is dissociated almost entirely in a solution; in plasma, the strong cations are sodium (Na+), potassium (K+), calcium (Ca++), and magnesium (Mg++), and strong anions are chloride (Cl
) and lactate (until metabolized). The apparent strong ion difference between strong cations and strong anions in blood plasma can be calculated easily as: ½ðNaþ þ Kþ þ Caþþ þ Mgþþ Þ
ðCl
þ lactateÞ This provides the indirect evidence that unmeasured anions normally are present. The expected gap between routinely measured serum cations and cations mainly is due to albumin, with minor contributions of phosphate and sulfate; both are more important with renal failure [28]. The ‘‘normal’’ strong ion difference of human blood plasma is 40 mmol/L to 42 mmol/L; however, during critical illness it usually is approximately 30 mmol/L which reflects low serum albumin and points out that an underlying metabolic acidosis with an excess of unmeasured anions is frequent. One main reason for the relative inaccuracy of the anion gap in critical illness comes from the common hypoalbuminemia that is encountered, because albumin has a charge of 2.8 mEq/L at a pH of 7.4. The anion gap should be adjusted for the serum albumin, at least. In the next few pages, hypophosphatemia, hypomagnesemia, hypocalcemia, and hypokalemia will be discussed. Because hyperphosphatemia and hypercalcemia may occur in patients who have renal failure, they are reviewed briefly.

Hypophosphatemia and hyperphosphatemia Phosphorus is the major intracellular anion. A normal diet provides an average of 38 mmol to 50 mmol every day; 65% is absorbed in the duodenum and jejunum. Approximately 85% of total body phosphorus is contained in bone. Phosphorus is used for cell membranes and is essential for adenosine triphosphate and red blood cell 2,3-diphosphoglyceric acid synthesis. It also plays a role in regulation of glycolysis, ammoniagenesis, and calcium regulation [29]. Consequently, hypophosphatemia leads to decreased oxygen delivery to tissues (including the central nervous system), and rarely to hemolysis in severe cases. Myocardial and skeletal muscle contractility also may be altered which results in symptomatic muscle weakness, respiratory failure, and difficulty in weaning from mechanical ventilation. Severe myopathy with rhabdomyolysis has been described in rare cases. Symptoms mostly occur in severe hypophosphatemia, defined as a serum phosphate concentration that is less than 0.32 mmol/L, but can also be present in moderate cases (0.32–0.8 mmol/L) [30]. The prevalence of moderate or severe hypophosphatemia in critically ill patients can be as high as 28.8%, more than fivefold higher than in hospitalized medical patients [31,32].

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Three main mechanisms can induce hypophosphatemia: (1) intracellular redistribution (anabolism, glucose-insulin administration, catecholamines, acute phase of respiratory alkalosis); (2) inadequate intake or absorption (malnutrition, alcoholism [33]); and (3) increased losses (gastrointestinal, renal tubular dysfunction, hypomagnesemia) [34]. Hypophosphatemia has been reported in relation with sepsis, and some investigators emphasized a possible contributory role of cytokines [35]. A refeeding syndrome that was associated with severe cardiopulmonary and neurologic complications was described after refeeding malnourished victims of World War II [36]. In starvation, fat and muscle proteins are consumed as primary energy substrates which lead to the loss of lean muscle mass and the release of intracellular electrolytes. Normal renal regulation restores serum phosphate, even if total-body phosphate is depleted. In refeeding, insulin is secreted in response to the new exogenous intake of carbohydrates; this increases the intracellular uptake of glucose, phosphate, and potassium that are needed for ATP production, glycogenesis, and protein anabolism [37,38]. In malnourished patients, nutrition should be provided on a progressive basis and nutritional goals should be attained slowly [39]. Daily monitoring of phosphorus, magnesium, and potassium is necessary. The daily recommended dietary allowance (RDA) of oral phosphorus for healthy, nonpregnant, nonlactating adults is 22.6 mmol per day [40]. Requirements usually are greater with refeeding and many enteral nutrition formulas supply more than the RDA. Some investigators reported that 0.5 mmol/kg/d of parenteral phosphorus may not be enough in a hospitalized/critically ill patient [32]. In mild hypophosphatemia, oral supplementation may be sufficient; for example, Phosphate Novartis provides 500 mg (16.1 mmol) of phosphorus and oral Fleet contains 4.15 mmol of phosphorus in 5 mL. In more severe hypophosphatemia, intravenous repletion is preferred. Several regimens have been proposed [41–43]. For example, 15 mmol of intravenous sodium phosphate in 100 mL of 0.9% sodium chloride given over 2 hours was safe and effective for phosphorus repletion in moderate hypophosphatemia (b 0.65 mmol/L) in critically ill patients [44]. Another study evaluated a more aggressive regimen of potassium phosphate (4.4 mmol of potassium for 3 mmol of phosphate) diluted in 50 mL, and given preferentially by way of a central line. The investigators infused 30 mmol over 2 hours in moderate (b0.65 mmol/L) hypophosphatemia and 45 mmol over 3 hours in severe (b 0.40 mmol/L) hypophosphatemia. This regimen was effective; 98% of treated patients achieved serum phosphate normalization, and was found to be safe given the fact that serum potassium and creatinine levels at baseline were less than 4.0 mmol/L and 200 mmol/L, respectively [45]. A concurrent repletion of magnesium should be done if hypomagnesemia also is present in a hypophosphatemic patient. In renal failure, hyperphosphatemia is far more frequent than hypophosphatemia. Serum phosphate may start to increase when the glomerular filtration rate decreases to less than 60 mL/min. Dietary intake may have to be restricted at this point. Usually, with glomerular filtration rates of less than 30 mL/min,

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serum phosphate levels will increase. In a critically ill patient who has acute or chronic renal failure, these figures are far from accurate, especially because phosphate is influenced greatly by several factors and can shift markedly, mainly as a result of acid-base derangements and insulin-glucose administration. During massive cellular lysis (rhabdomyolysis, severe hemolysis, tumor lysis), released metabolites enter the circulation rapidly; enhanced renal elimination soon becomes insufficient, in part, because of dehydration or underlying kidney impairment [46]. Tumor lysis syndrome (TLS) is a critical condition that results from massive cell death and leads to severe hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and ARF in patients who have high cell turnover tumors. TLS can be observed with high-grade lymphomas and highleukocyte count leukemias—and less commonly with solid tumors—during rapid cellular destruction that is induced by chemotherapy [47–50]. Although spontaneous, TLS rarely occurs before any cancer treatment; hyperphosphatemia should not be as severe as after cytoreductive treatment. The clinical profile of patients who are at risk for TLS includes age younger than 25 years, male sex, lymphoproliferative disease with extensive abdominal burden, high serum lactase dehydrogenase concentrations, volume depletion, acidic, and concentrated urine. Oliguric ARF is almost always present in severe TLS. In the physiopathology of ARF in TLS, extracellular volume depletion and overload of uric acid and phosphate play a role. Hyperphosphatemia produces precipitation of calciumphosphate complexes in renal interstitium and tubular system which results in acute nephrocalcinosis. Management of massive cell lysis includes prevention of ARF and other complications that are associated with electrolyte derangements, and dialysis. In rhabdomyolysis and TLS, sodium bicarbonate, usually administered intravenously, is used to alkalinize urine (pH target N 7) and enhance uric acid elimination. With oliguric ARF, renal replacement may be required. Peritoneal dialysis is insufficient because achieved clearances for uric acid and phosphorus are low. Intermittent hemodialysis is more effective than continuous renal replacement therapies when considering phosphate and uric acid clearances on a minute basis. In adult TLS, phosphorus influx into the extracellular milieu can exceed 6 g/d. Such a solute burden has been managed effectively using continuous renal replacement therapy and effluent flow rates of 4 L/h [51,52]. These continuous methods were found to be almost equivalent to two 4-hour hemodialysis sessions per day. Conversely, when considering continuous renal replacement therapies for critically ill patients who have chronic or ARF, hypophosphatemia develops commonly after 2 to 3 days of support. Besides the usual nutritional regimen, phosphate supplementation may be required on a daily basis. We found the addition of phosphate directly to dialysate/replacement solutions (for a final concentration of 1.2 mmol/L) to be practical and safe without fear of calcium precipitation [53]. Continuous and intermittent forms of renal replacement render patients prone to develop hypophosphatemia, by clearing phosphate, by alkalinizing blood

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(resulting in phosphate shift), and possibly by increasing serum calcium (that may complex phosphate) slightly. In some critically ill patients who already may have hypophosphatemia despite their renal failure, or who may have to be dialyzed for reasons other than azotemia (drug intoxications), the addition of phosphate to the dialysate is convenient and avoids the development of a more severe hypophosphatemia during intermittent hemodialysis. A 45 mL bottle of Fleet phospho-soda added to a 4.5-L acid concentrate was adequate to allow a phosphate concentration of 1 mmol/L in the final dialysate [54].

Hypomagnesemia Magnesium is absorbed mainly in the jejunum and ileum. The fractional absorption is extremely variable, and regulating factors are poorly understood. Moreover, the absorption is probably even less predicable in critically ill patients who oftentimes have ileus or colitis [55]. Magnesium is excreted mainly by the kidney; thus, hypermagnesemia may become problematic in renal failure. Fifty to 60% of filtered magnesium is reabsorbed passively within the thick ascending limb of the loop of Henle. Loop diuretics reduce salt absorption, diminishes lumen-positive voltage, and consequently, induces a greater urinary loss of magnesium [56]. Magnesium is mostly intracellular. Magnesium is an essential cofactor of ATP reactions. This divalent cation also is involved in DNA replication and transcription, and translation of mRNA [34]. Consequently, hypomagnesemia may have deleterious effects on energy production and protein metabolism. Serum contains only 0.3% of total body magnesium, and therefore, is a poor reflection of total stores. In addition, standard assays measure total serum magnesium; however, almost all of the ionized portion (corresponding to nearly 67% of total) is metabolically active [55]. Ionized magnesium can be measured by ion-selective electrodes; however, such analyzers are not widely available. Huigen et al [57] showed that correcting the total serum magnesium with serum albumin in a critically ill population does not predict accurately the ionized magnesium. Furthermore, in patients who have decreased serum total magnesium, only 29% were hypomagnesemic according to ionized magnesium measurements. Conversely, ionized magnesium did not correlate with a hypomagnesemic status as assessed by a magnesium-loading test in 44 patients in the ICU [58]. The magnesium-loading test is a functional evaluation that assumes a steadystate; for that last reason, it may not apply to critically ill patients. As well, this test becomes unreliable in patients who have magnesium renal wasting due to drugs (eg, diuretics) or other conditions, and is contraindicated when an altered renal function prevents the use of high magnesium load. Practically, the test consists of a baseline 24-hour urine collection, followed by an intravenous loading of magnesium. A second 24-hour urine collection determines fractional magnesium excretion. Retention of more than 50% is considered to be positive for a hypomagnesemic status [59].

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Causes of hypomagnesemia can be divided in four broad categories: decreased intake, gastrointestinal loss, renal loss, and compartmental redistribution. Many drugs (eg, loop and thiazide diuretics, cisplatin, aminoglycosides, amphotericin, cyclosporine) induce renal magnesium wasting. Redistribution occurs with administration of catecholamines, in acute pancreatitis, and in the hungry bone syndrome after parathyroidectomy [34]. Manifestations of magnesium deficiency mostly are neuromuscular (muscles cramps and weakness, positive Chvostek and Trousseau’s signs), cardiac (torsades de pointes and other arrhythmias), neurologic (apathy, seizures), and electrolytic (hypokalemia and hypocalcemia). Nonetheless, most patients are asymptomatic [55]. Difficult ventilator weaning due to magnesium deficiency seems possible, but no study has looked at the impact of correction of hypomagnesemia. Hypokalemia occurs in 40% to 60% of hypomagnesemic patients and is a frequent confounding element to the interpretation of cardiac arrhythmia that is induced by hypomagnesemia. Nevertheless, when hypokalemia coexists with hypomagnesemia, the potassium deficit usually is refractory to repletion, unless magnesium also is supplemented [60]. Two studies of patients in the ICU reported a higher mortality in hypomagnesemic patients (based on a total serum magnesium measurement) [61,62]. Two other studies did not find any correlation, even when they also measured ionized magnesium or erythrocyte magnesium content [57,63]. Recently, Soliman et al [64] evaluated the ionized magnesium of 422 critically ill patients; considering the value at admission, the mortalities were not different. The development of hypomagnesemia at some point during the ICU stay was associated with a higher mortality, however. As pointed out in their discussion, it may be only a marker of critical illness. The daily RDA of oral magnesium for healthy, nonpregnant, nonlactating adults varies from 13 mmol to 18 mmol, depending on gender and age [40]. The parenteral requirements are not established clearly and recommendations fluctuate from 5 mmol to 12 mmol per day [65]. Magnesium repletion in the ICU setting has not been assessed well. In asymptomatic patients who do not have renal failure, magnesium can be repleted orally in variable dosages that range from 10 mmol/d to 70 mmol/d or by slow parenteral infusions of 25 mmol/d to 40 mmol/d [59]. Oral supplementation may have an unpredictable absorption, and oftentimes, causes diarrhea. Most of the intravenous magnesium load will be excreted in urine [34]. In emergency cases, magnesium can be infused more rapidly. Hypocalcemia and hypercalcemia In total, 1 kg to 2 kg of calcium is present in an adult; almost 98% is located in the skeleton [66]. Serum calcium is found in three forms: ionized (50%); chelated by small anions (citrate, phosphate, bicarbonate) (10%); and protein-bound, mainly to albumin (40%). This last form is pH dependent. The ionized calcium is the diffusible, biologically active, and precisely-regulated form; therefore, a decreased albumin level will influence total serum calcium [67]. Consequently,

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total calcium is adjusted frequently for albumin. Slomp et al [68] compared ionized calcium with calculated albumin-adjusted calcium in 36 patients in the ICU. None of the eight hypocalcemic patients (diagnosed by ionized calcium) were detected when using the usual equation for corrected Ca: ½CAcorrected ðmmol=LÞ ¼ totCa þ ð0:02 ð40
serum albumin concentration ðg=LÞÞÞ More recently, Dickerson et al [69] reported an average sensitivity of 25% to detect true hypocalcemia in 100 patients who had multiple trauma, using 22 published methods to estimate ionized calcium or adjusted total calcium; the average specificity was 90%. Corrected total calcium is not reliable in critically ill patients, and ideally, serum ionized calcium should be measured directly. The incidence of ionized hypocalcemia in the ICU varies from 12% to 88%, depending on the type of patient [70]. Hypocalcemia may happen by four different mechanisms: decrease in parathyroid hormone secretion or action, reduction in vitamin D synthesis or action, resistance of bone to parathyroid hormone or vitamin D, or sequestration of calcium [71]. After neck surgery for hyperparathyroidism, a profound hypocalcemia can develop rapidly. A hungry bone syndrome with increased bone uptake of calcium may follow. Rhabdomyolysis can be associated with hypocalcemia. In this setting, calcium administration may cause calcium-phosphate salt precipitation and muscle damage [72]. Hypomagnesemia may decrease parathyroid hormone (PTH) secretion, and thus, induce hypocalcemia [55]. Hypocalcemia is more frequent in continuous venovenous hemodiafiltration than in intermittent hemodialysis [73]; calcium should be monitored closely, particularly if citrate is used for regional anticoagulation of the circuit. Hypocalcemia is common in sepsis. Lind et al [74] reported 10 cases of ionized hypocalcemia in 13 critically ill septic patients. In more than 75% of septic patients, parathyroid hormone was increased. Urinary calcium excretion was not increased, whereas markers of bone resorption (deoxypyridinoline and carboxy-terminal cross-linked telopeptide of type I collagen) were increased. The investigators suggested a role for inflammation because markers (tumor necrosis factor–a, interleukin-6, C-reactive protein) were correlated inversely to ionized serum calcium. Furthermore, redistribution of calcium in tissues may be involved, given that increased free intracellular calcium in lymphocyte was reported in septic patients [75]. Earlier studies reported a correlation between ionized hypocalcemia and mortality [76]. Recently, a multivariate Cox regression model on 941 patients in the ICU showed no independent association between ionized calcium and 30-day mortality [70]. This suggests that hypocalcemia may be a marker of severity of illness, rather than a causal parameter. Usually, mild hypocalcemia (ionized calcium N 0.8 mmol/L) is asymptomatic in patients in the ICU. Clinical manifestations may include neuromuscular irritability

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and cardiovascular abnormalities [71]. There is conflicting data regarding the hemodynamic effect of calcium repletion. A study reported a significant increase in blood pressure for at least 1 hour [76]; another showed a transient augmentation of cardiac output and blood pressure [77]. Other studies revealed no effect [71,78] and even undesirable effects (inhibition of b-adrenergic agonists in some patients) [79,80]. Moreover, calcium supplementation may exacerbate cellular damage in septic and ischemic patients [78,81,82]. In this context, it has been advocated not to treat mild asymptomatic hypocalcemia in the ICU. In contrast, symptomatic and severe ionized hypocalcemia should be supplemented with parenteral calcium [71]. A 10% calcium gluconate or calcium chloride ampoule of 10 mL contains 94 mg (2.4 mmol) or 272 mg (6.8 mmol) of elemental calcium, respectively. A common protocol consists of one ampoule of calcium gluconate given as a 5- to 10-minute bolus, followed by 10 ampoules in 900 mL of 5% dextrose infused at 50 mL/h (47 mg Ca/h), then titrated to a normal ionized calcemia [67]. When the patient is stable or the hypocalcemia is chronic, calcium can be given orally, with added vitamin D. The adequate intake of oral calcium for healthy, nonpregnant, nonlactating adults varies from 1000 mg (25 mmol) per day to 1200 mg (30 mmol) per day, depending on age [40]. Most enteral feeding formulas should provide enough calcium when 1500 cal/d to 2000 cal/d is delivered. Cancer and primary hyperparathyroidism are the two most common causes of hypercalcemia in hospitalized patients [83,84]. Various cancers can cause hypercalcemia, including lung, breast, kidney, and prostate cancer, and myeloma. Cancer should be suspected in patients who have symptomatic hypercalcemia and recent weight loss, whereas chronic symptoms are found more commonly with hyperparathyroidism. An increased serum PTH-related protein (PTH-RP) level, but a normal or decreased serum PTH concentration is compatible with humoral hypercalcemia of malignancy syndrome; however, malignancy-associated hypercalcemia cannot be ruled out by the absence of elevated PTH-RP. Patients who have myeloma occasionally may present with increased serum total calcium that is due to an increase in globulin-bound fraction, without elevation in ionized calcium. Clinical manifestations of hypercalcemia relate to its degree and rapidity of appearance. Symptoms can be general (anorexia, pruritus, polydipsia, polyuria, dehydration), neuromuscular (lethargy, muscle weakness, hyporeflexia, seizure, psychosis, obtundation, coma), gastrointestinal (vomiting, constipation, ileus), or cardiac (bradycardia, prolonged P-R and shortened Q-T intervals, atrial or ventricular arrhythmias). Nephrolithiasis and nephrocalcinosis, as consequences of interstitial deposition of calcium-phosphate complexes, can occur [85]. Severe dehydration due to hypercalcemia leads to prerenal ARF (Fig. 3). Hypercalcemia also causes vasoconstriction which directly reduces the glomerular filtration rate. Hypercalcemia of malignancy essentially is due to an increase in bone resorption (osteoclastic activity), although tubular calcium reabsorption usually is increased as well. Acute severe hypercalcemia (N 3.5 mmol/L) requires immediate treatment [86,87]. Because hypercalcemia causes arteriolar vasoconstriction, nonsteroidal

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Days Fig. 3. Evolution of serum total calcium and creatinine in two cases of hypercalcemia. Large squares and triangles represent calcium concentrations, whereas small squares and triangles show respective creatinine levels. Both received hydration and furosemide (horizontal arrows). Biphosphonates were given on several occasions (vertical arrows).

anti-inflammatory drugs should be discontinued to reduce the risk of ARF. Large volumes of normal saline plus loop diuretics are administered for volume repletion and enhanced urine calcium elimination. Thiazides are avoided because they can decrease the urine calcium. Inhibition of bone resorption with bisphosphonates (eg, single intravenous dose of pamidronate, 30–90 mg; or zoledronic acid, 4 mg) is effective for many weeks, whereas calcitonin that is given subcutaneously (4 to 8 IU/kg) has a rapid onset, minimal toxicity, and a transient effect. Corticosteroids are effective in hematologic malignancies (myeloma, lymphoma, leukemia) by exerting a cytostatic effect. Peritoneal dialysis or hemodialysis with low or free-calcium dialysate may be needed for patients who have renal failure [88,89]. Hypokalemia More than 20% of hospitalized patients have hypokalemia, defined as a serum potassium value that is less than 3.6 mmol/L [90]. In patients who take diuretics, up to 50% may develop hypokalemia [91]. Data on the prevalence in the ICU setting is lacking, but it seems to be even more frequent. In the United States and Canada, median daily intakes of potassium range between 54 mmol and 87 mmol, depending on gender [92]. Almost all potassium

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is absorbed [93] and most of it is excreted by way of the kidney (40 to 120 mmol per day); a small amount is eliminated in stools (5–10 mmol per day) [94]. Ninety-eight percent of this cation is intracellular. Different methods of estimating total body store have been evaluated [95]. Practically, with a decrease in serum potassium from 3.5 mmol/L to 3.0 mmol/L, a total body deficit of 100 mmol to 300 mmol can be suspected [91]. It was suggested that a decrease in serum potassium of 0.3 mmol/L indicates an approximate deficit of 100 mmol in total potassium [93]. The causes of hypokalemia may be classified as renal losses, extrarenal losses, and intracellular shifts. Thiazides and loop diuretics induce hypokalemia; the combination of both is worse. The hypokalemic effect of diuretics is enhanced in patients who have hyperaldosteronism (congestive heart failure, hepatic cirrhosis) by way of greater distal tubular flow [93]. Numerous other drugs may cause hypokalemia by renal losses, namely amphotericin B, polyanionic penicillins, aminoglycosides, and fludrocortisone. Diarrhea is a common cause of extrarenal losses; although in the diarrheic state, potassium concentration decreases in stools and the enlarged volume explains amplified losses [90]. Metabolic alkalosis that is due to upper gastrointestinal chloride loss (vomiting, nasogastric drainage) is accompanied frequently by hypokalemia, mostly from subsequent renal losses [91]. Because of the extreme disproportion between intracellular and extracellular potassium concentrations, a minor shift of potassium between these compartments may become significant. Catecholamines and insulin are important hormones that favor potassium uptake by cells [96]. Hypokalemia is often asymptomatic. The major complications of hypokalemia are cardiac. Patients who have cardiac ischemia, heart failure, left ventricular hypertrophy, or who take digitalis are at greater risk for developing ventricular arrhythmia. Severe hypokalemia may cause rhabdomyolysis (when b 2.5 mmol/L) and ascending paralysis (when b 2.0 mmol/L) [90]. In mild to moderate asymptomatic hypokalemia, oral repletion is preferred. Potassium chloride usually is the best choice because it will correct the chloride depletion that frequently is associated with it. Alkalinizing salts (potassium citrate, gluconate, or acetate) can be given in acidotic states. Intravenous infusion in a central venous catheter of 20 mmol, 30 mmol, and 40 mmol in 100 mL of saline over 1 hour was reported to be safe; mean increases in serum potassium were 0.5 mmol/L, 0.9 mmol/L, and 1.1 mmol/L, respectively [97,98]. Some investigators prefer to limit the infusion rate to 20 mmol per hour, except in urgent situations [90]. In severe hypokalemia, intravenous infusion of potassium chloride in dextrose solution may decrease serum potassium concentration further and precipitate neuromuscular weakness [99].

Nutrition management Hospital malnutrition remains a significant problem with an estimated prevalence as high as 30% to 50%. Malnutrition is prevalent among patients

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who have ARF and increases the likelihood of in-hospital complications and death [100]. Parameters that can be used to assess the nutritional status include medical history, anthropometry and body composition measures, biochemical markers, and immunologic indices (eg, body weight, static caloric and protein reserves, circulating proteins, lymphocyte count and skin testing, impedance) [101]. None of these parameters is perfect and complete; often, a combination of factors is considered. Despite some limitations, the subjective global assessment remains a useful tool [102]. It is simple, better than routine observation, is easily taught, and has excellent interobserver correlation. It was shown to be useful for screening and predicts an increased incidence of postoperative complications with worsening nutritional status. Combined with serum albumin level, it helps to stratify risk that is due to poor nutrition. Several studies showed—conversely to what is observed in the general population—that patients in the ICU who have low body mass index may have a greater mortality risk [103]. Usual markers of visceral proteins, such as albumin, prealbumin, and transferrin, are influenced markedly by the acute phase response; they also are affected by hydration, exudation, and blood loss (Fig. 4) [104]. Nonetheless, albumin remains one of the most powerful nutritional markers and outcome predictors in hospitalized patients, in critical illness, and in patients who have renal failure. In critical illness, energy expenditure can be influenced by several factors, namely activity, stress, and fever, which affect the metabolic rate. The total energy expenditure, expressed in kcal/24 h, includes the basal energy expenditure plus an activity factor, and a stress factor that may vary, depending on the injury (Fig. 5) [105]. It can be estimated by equations (eg, Harris-Benedict) or measured more precisely by indirect calorimetry [106].

Fig. 4. Evolution of several serum proteins early after a critical illness. (Adapted from Fleck A. Plasma proteins as nutritional indicators in the perioperative period. Br J Clin Pract Suppl 1988;63:20–4; with permission.)

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Fig. 5. Variability of the metabolic rate depending of the level of injury. (Adapted from Demling RH, DeSanti L. Complications of acute weight loss due to stress response to injury. Curr Opin Crit Care 1996;2:482–91; with permission.)

Nitrogen balance is a tool that has been used in clinical studies to evaluate the efficacy of nutritional support [107]. It reflects net protein metabolism. A negative nitrogen balance indicates a net loss of protein; however, it provides no clues at all on differences in protein kinetics between organs and tissues. Protein metabolism would be measured ideally by protein kinetics, but this is not available on clinical grounds. The amount of calories and proteins that should be provided to minimize muscle loss in a critically ill patient is unclear. In patients who receive adequate amount of calories, it was shown that an amino acid supply of 0.1 g N/kg/d resulted in a 50% improvement in nitrogen balance (when compared with adequate calories with no amino acids) [107]. Providing more amino acids (0.2 and 0.3 g N/kg/d) did not show a significant additive impact. Despite the absence of strong evidence, a reasonable goal could be to obtain a neutral or mildly positive nitrogen balance (by 2 g N/d or 15 g protein/d) in a patient in the ICU. Nitrogen balance can be calculated by comparing the urea that is eliminated in urine; this corresponds to most of the nitrogen loss to the nitrogen intake that is provided to the patient. To convert urine urea (from mmol/d) to nitrogen equivalent, one has to multiply by 0.028, and then add 3 to 4 g of N/d for insensible losses. The total value can be converted, if desired, to a protein equivalent by multiplying by 6.25. In renal failure, calculation of the nitrogen balance is more complex. If the patient is not dialyzed, one should take into account the elevation of serum urea in the 24-hour period of the urine collection, and estimate (by multiplying by volume of distribution of urea in the body) the amount of urea that should have been eliminated through urine in the same period if kidney function was normal. If the patient is dialyzed, the calculation becomes even more difficult, because the amount of urea that is eliminated through the effluent has to be included. Because access to the effluent during continuous renal replacement therapies and peritoneal dialysis is easy, such calculation is

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realizable. It is more difficult with intermittent hemodialysis (although made possible by partial or total direct dialysis quantification). Predictive equations for protein catabolic rate have been proposed for patients who have chronic renal failure; however, these have not been validated in the acute setting. A few years ago, we evaluated nitrogen appearance and protein catabolic rate in 38 patients in the ICU who had ARF that was treated by continuous renal replacement therapies [6]. We found a mean urea nitrogen appearance rate of 13.6 mg/min F 7.0 mg/min (median 12.5 mg/min) and a normalized protein catabolic rate of 1.8 g/kg/d F 0.8 g/kg/d (median 1.6 g/kg/d and a wide range 0.6–4.2 g/kg/d). The lean body mass was 38 kg F 12 kg with a lean body mass:body weight ratio of 50% F 14%. These values suggest that protein catabolism is enhanced in critically ill patients who have ARF and are supported by continuous renal replacement therapies. More recent recommendations that addressed nutrition support in critical illness have moved from the traditional energy intake of 30 kcal/kg/d to 35 kcal/kg/d to a lesser amount of 22 kcal/kg/d to 25 kcal/kg/d [108]. This latter target still may overestimate the needs of medical patients in the ICU as shown recently, because providing even less calories (9 kcal/kg/d to 18 kcal/kg/d) was associated with better outcomes [109]. If a total of 25 kcal/kg/d and 1.2 g/kg/d to 1.5 g/kg/d of protein are desired, the ratio of carbohydrates and lipids should correspond, respectively, to two thirds and one third of nonprotein calories (or approximately 45% and 30% of total calories). The main purpose for reducing total calories is to avoid the risks of overfeeding, including CO2 burden and respiratory failure, hepatic steatosis, and increased susceptibility to infections (especially with parenteral feeding). The concept of permissive underfeeding also is recommended—initiate feeding within 24 to 48 hours of ICU admission at 50% of the goal and advance over 3 to 5 days. Adverse effects of hyperglycemia include electrolyte and fluid imbalance, increased susceptibility to infections, decreased function of neutrophils and leukocytes, impaired wound healing, and possibly, increased coagulability. In surgical patients and patients who have burns, hyperglycemia was a predictor of subsequent nosocomial infections, impaired wound healing, and poor outcome. The prospective study by Van den Berghe and colleagues [110] strongly suggests that a strict control of glucose (aiming at blood glucose between 4.4–6.1 mmol/L using an intensive insulin regimen) reduces morbidity and mortality among critically ill patients in surgical ICUs. Therefore, when (re)initiating feeding, glucose should be monitored and an increase in serum glucose should be managed appropriately. Current evidence indicates that an intensive insulin therapy that aims to keep blood glucose at less than 6 mmol/L seems to be an effective approach to prevent infectious complications in patients in the ICU. The proportion of omega-3 and omega-6 fatty acids influences the choice of lipid formulation. Our usual diet contains a ratio of omega-6:omega-3 of 10:1; a ratio of 3:1 is recommended for critically ill patients. A larger proportion of omega-3 could induce less inflammation. Newer fat emulsions may become available in the near future.

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Adequate protein and caloric intake is essential to patients who have ARF. Although the current tendency is to provide fewer calories than previously in the ICU setting, the protein intake should reach at least 1.2 g/kg/d to 1.5 g/kg/d in patients who have ARF to maintain a neutral nitrogen balance [108]. Providing less protein to a patient who has ARF to decrease azotemia and delay dialysis as much as possible is not advocated. Because a negative nitrogen balance may accelerate endogenous proteolysis and muscle wasting and further impairs immune functions, efforts should be directed at obtaining a neutral or slightly positive nitrogen balance. Amino acid amounts that are lost through renal replacement should be accounted for (eg, with continuous renal replacement therapies [CRRT], additional 15–20 g can be lost easily daily and should be replaced) [111]. If an appropriate amount of calories already is provided, there are a few alternatives to deliver more protein, such as using a ‘‘very high protein’’ enteral formulation or adding protein powder to a standard enteral formulation (that will provide 5–6 g of protein per spoon). Feeding by way of the enteral route is preferable, by far, to parenteral alimentation, when possible, because it may keep intestinal mucosa active and may reduce bacterial translocation [112]. Nutrition that is administered in the small bowel, rather than in the stomach, is safer in some cases to avoid aspiration [113]. Immunonutrition concerns supplementation with the following substrates: glutamine, arginine, nucleotides, and omega-3 fatty acids. Recent enteral solutions contain some of these substrates (Immun-Aid and Impact) [114]. Glutamine and arginine may be associated with a reduction in infection rates. Immunomodulation may be achieved with certain nutrition formulations; supplementation with glutamine or arginine may have a positive impact on immune function and intestinal cell turnover [115,116]. This approach could be more useful in surgical patients but also could be harmful in certain subpopulations of critical illness and cannot be advocated widely at the present time. As well, supplementation with growth hormone or growth factors, despite potentially desirable effects in critically ill adults who have ARF (eg, protein sparing), has been related to increased mortality risks; therefore, routine use cannot be recommended at this point [117–119].

References [1] Hasselgren PO, Pederson P, Sax H, et al. Current concepts of protein turnover and amino acid transport in liver and skeletal muscle during sepsis. Arch Surg 1988;123:992 – 9. [2] Cahill Jr GF. Starvation in man. N Engl J Med 1970;282:668 – 75. [3] Cuthberston DP. The metabolic response to injury and its nutritional implications: retrospect and prospect. JPEN J Parenter Enteral Nutr 1979;3:108 – 29. [4] Hardin TC. Cytokine mediators of malnutrition: clinical implications. Nutr Clin Pract 1993; 8:55 – 9. [5] Lopes J, Russell D, Whitwell J, et al. Skeletal muscle function in malnutrition. Am J Clin Nutr 1982;36:602 – 10. [6] Leblanc M, Garred LJ, Cardinal J, et al. Catabolism in critical illness: estimation from urea

nutritional concerns in critical illness

[7]

[8] [9] [10] [11] [12]

[13] [14] [15] [16] [17]

[18] [19]

[20] [21] [22] [23] [24] [25] [26] [27]

[28] [29] [30]

323

nitrogen appearance and creatinine production during continuous renal replacement therapy. Am J Kidney Dis 1998;32:444 – 53. Leblanc M, Kellum JA. Biochemical and biophysical principles of hydrogen ion regulation. In: Ronco C, Bellomo R, editors. Critical care nephrology. 1st edition. Dordrecht (Netherlands)7 Kluwer Academic Publishers; 1998. p. 261 – 77. Warnock DG. Uremic acidosis. Kidney Int 1988;34:278 – 87. Goodman AD, Leeman Jr J, Lennon EJ, et al. Production, excretion and net balance of fixed acid in patients with renal acidosis. J Clin Invest 1965;44:495 – 506. Widmer B, Gerhardt RE, Harrington JT, et al. Serum electrolyte and acid base composition: the influence of graded degrees of chronic renal failure. Arch Intern Med 1979;139:1099 – 102. Wallia R, Greenberg A, Piraino B, et al. Serum electrolytes in end-stage renal disease. Am J Kidney Dis 1986;8:98 – 104. Mitch WE, Medina R, Grieber S, et al. Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes. J Clin Invest 1994;93:2127 – 33. Ballmer PE, McNurlan MA, Hulter HN, et al. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest 1995;95:39 – 45. Lefebvre A, de Vernejoul MC, Gueris J, et al. Optimal correction of acidosis changes progression of dialysis osteodystrophy. Kidney Int 1989;36:1112 – 8. Bushinsky DA. The contribution of acidosis to renal osteodystrophy. Kidney Int 1995;47: 1816 – 32. Franch HA, Mitch WE. Catabolism in uremia: the impact of metabolic acidosis. J Am Soc Nephrol 1998;9(12 Suppl):S78 – 81. Schmitz O, Alberti KG, Christensen NJ, et al. Aspects of glucose homeostasis in uremia as assessed by the hyperinsulinemic euglycemic clamp technique. Metabolism 1985;34: 465 – 73. Reaich D, Graham KA, Channon SM, et al. Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with CRF. Am J Physiol 1995;268:E121 – 6. Preziosi MP, Roig JC, Hargrove N, et al. Metabolic academia with hypoxia attenuates the hemodynamic responses to epinephrine during resuscitation in lambs. Crit Care Med 1993;21: 1901 – 7. Graham KA, Goodship THJ, Bushinsky DA, et al. Does metabolic acidosis have clinically important consequences in dialysis patients? Semin Dial 1998;11:14 – 24. Kellum JA. Metabolic acidosis in the critically ill: lessons from physical chemistry. Kidney Int 1998;53(Suppl 66):S81 – 6. Leblanc M. Acid-base balance in acute renal failure and renal replacement therapy. Best Pract Res Clin Anaesthesiol 2004;18(1):113 – 27. Graham KA, Reaich D, Channon SM, et al. Correction of acidosis in hemodialysis decreases whole-body protein degradation. J Am Soc Nephrol 1997;8:632 – 7. Stein A, Moorhouse J, Iles-Smith H, et al. Role of an improvement in acid-base status and nutrition in CAPD patients. Kidney Int 1997;52(4):1089 – 95. Williams AJ, Dittmer ID, McArley A, et al. High bicarbonate dialysate in haemodialysis patients: effects on acidosis and nutritional status. Nephrol Dial Transplant 1997;12:2633 – 7. Uribari J. Moderate metabolic acidosis and its effects on nutritional parameters in hemodialysis patients. Clin Nephrol 1997;48(4):238 – 40. National Kidney Foundation. Kidney Disease Outcomes Quality Initiative (K-DOQI) clinical practice guidelines for nutrition in chronic renal failure. Am J Kidney Dis 2000;35(Suppl 2): S38 – 9. Figge J, Mydosh T, Fencl V. Serum proteins and acid-base equilibria: a follow-up. J Clin Lab Med 1992;120:713 – 9. Stoff JS. Phosphate homeostasis and hypophosphatemia. Am J Med 1982;72:489 – 95. Bugg NC, Jones JA. Hypophosphatemia: pathophysiology, effects and management in the intensive care unit. Anaesthesia 1998;53:895 – 902.

324

lafrance

&

leblanc

[31] Zazzo JF, Troche´ G, Ruel P, et al. High incidence of hypophosphatemia in surgical intensive care patients: efficacy of phosphorus therapy on myocardial function. Intensive Care Med 1995;21:826 – 31. [32] Sacks GS, Walker J, Dickerson RN, et al. Observations of hypophosphatemia and its management in nutrition support. Nutr Clin Pract 1994;9(3):105 – 8. [33] Elisaf MS, Siamopoulos KC. Mechanisms of hypophosphatemia in alcoholic patients. Int J Clin Pract 1997;51(8):501 – 3. [34] Weisinger JR, Bellorı´n-Font E. Magnesium and phosphorus. Lancet 1998;352:391 – 6. [35] Barak V, Schwartz A, Kalickman I, et al. Prevalence of hypophosphatemia in sepsis and infection: the role of cytokines. Am J Med 1998;104:40 – 7. [36] Salomon SM, Kirby DF. The refeeding syndrome: a review. JPEN J Parenter Enteral Nutr 1990;14:90 – 7. [37] Brown GR, Greenwood JK. Drug- and nutrition-induced hypophosphatemia: mechanisms and relevance in the critically ill. Ann Pharmacother 1994;28:626 – 32. [38] Crook MA, Hally V, Panteli JV. The importance of the refeeding syndrome. Nutrition 2001; 17:632 – 7. [39] Marik PE, Bedigian MK. Refeeding hypophosphatemia in critically ill patients in an intensive care unit. Arch Surg 1996;131:1043 – 7. [40] Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, DC7 National Academy Press; 1997. [41] Perreault MM, Ostrop NJ, Tierney MG. Efficacy and safety of intravenous phosphate replacement in critically ill patients. Ann Pharmacother 1997;31:683 – 8. [42] Kingston M, Al-Siba’I MB. Treatment of severe hypophosphatemia. Crit Care Med 1985; 13(1):16 – 8. [43] Vannatta JB, Whang R, Solomon P. Efficacy of intravenous phosphorus therapy in the severely hypophosphatemic patient. Arch Intern Med 1981;141:885 – 7. [44] Rosen GH, Boullata JI, O’Rangers EA, et al. Intravenous phosphate repletion regimen for critically ill patients with moderate hypophosphatemia. Crit Care Med 1995;23(7):1204 – 10. [45] Charron T, Bernard F, Skrobik Y, et al. Intravenous phosphate in the intensive care unit: more aggressive repletion regimens for moderate and severe hypophosphatemia. Intensive Care Med 2003;29:1273 – 8. [46] Vanholder R, Sever MS, Erek E, et al. Rhabdomyolysis. J Am Soc Nephrol 2000;11:1553 – 61. [47] Arrambide K, Toto R. Tumor lysis syndrome. Semin Nephrol 1993;13:273 – 80. ¨ hler L, Watzke H, et al. The spectrum of acute renal failure in tumor lysis syndrome. [48] Haas M, O Nephrol Dial Transplant 1999;14:776 – 9. [49] Boles J, Dutel J, Briere J, et al. Acute renal failure caused by extreme hyperphosphatemia after chemotherapy of an acute lymphoblastic leukemia. Cancer 1994;53:2425 – 9. [50] Kanfer A, Richet G, Roland J, et al. Extreme hyperphosphatemia causing acute anuric nephrocalcinosis in lymphosarcoma. Br Med J 1979;1:1320 – 1. [51] Agha-Razzi M, Amyot S, Pichette V, et al. Continuous veno-venous hemodiafiltration for the treatment of spontaneous tumor lysis syndrome complicated by acute renal failure and severe hyperuricemia. Clin Nephrol 2000;54:59 – 63. [52] Pichette V, Leblanc M, Bonnardeaux A, et al. High dialysate flow rate continuous arteriovenus hemodialysis: a new approach for the treatment of acute renal failure and tumor lysis syndrome. Am J Kidney Dis 1994;23:591 – 6. [53] Troyanov S, Geadah D, Ghannoum M, et al. Phosphate addition to hemofiltration solutions during continuous renal replacement therapy. Intensive Care Med 2004;30:1662 – 5. [54] Dorval M, Pichette V, Cardinal J, et al. The use of an ethanol- and phosphate-enriched dialysate to maintain stable serum ethanol levels during haemodialysis for ethanol intoxication. Nephrol Dial Transplant 1999;14(7):1774 – 7. [55] Noronha JL, Matuschak GM. Magnesium in critical illness: metabolism, assessment, and treatment. Intensive Care Med 2002;28:667 – 79.

nutritional concerns in critical illness

325

[56] Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int 1997;52:1180 – 95. [57] Huigen HJ, Soesan M, Sanders R, et al. Magnesium levels in critically ill patients: what should we measure? Am J Clin Pathol 2000;114:688 – 95. [58] Hebert P, Metha N, Wang J, et al. Functional magnesium deficiency in critically ill patients identified using a magnesium-loading test. Crit Care Med 1997;25(5):749 – 55. [59] Salem M, Munoz R, Chernow B. Hypomagnesemia in critical illness: a common and clinically important problem. Crit Care Clin 1991;7(1):225 – 52. [60] Hamill-Ruth RJ, McGory R. Magnesium repletion and its effect on potassium homeostasis in critically ill adults: Results of a double-blind, randomized, controlled trial. Crit Care Med 1996;24(1):38 – 45. [61] Chernow B, Bamberger S, Stoiko M, et al. Hypomagnesemia in patients in postoperative intensive care. Chest 1989;95(2):391 – 7. [62] Rubeiz GJ, Thill-Baharozian M, Hardie D, et al. Association of hypomagnesemia and mortality in acutely ill medical patients. Crit Care Med 1993;21(2):203 – 9. [63] Gue´rin C, Cousin C, Mignot F, et al. Serum and erythrocyte magnesium in critically ill patients. Intensive Care Med 1996;22(8):724 – 7. [64] Soliman HM, Mercan D, Lobo SSM, et al. Development of ionized hypomagnesemia is associated with higher mortality rates. Crit Care Med 2003;31(4):1082 – 7. [65] Inadomi DW, Kopple JD. Fluid and electrolyte disorders in total parenteral nutrition. In: Narins RG, editor. Maxwell & Kleeman’s clinical disorders of fluid and electrolyte metabolism. 5th edition. New York7 McGraw-Hill; 1994. p. 1437 – 62. [66] Pollak M. Disturbances of calcium metabolism. In: Brenner BM, Rector’s C, editors. The kidney. Philadelphia7 W.B. Saunders Company; 2000. p. 1037 – 54. [67] Bushinsky DA, Monk RD. Calcium. Lancet 1998;352:306 – 11. [68] Slomp J, van der Voort PH, Gerritsen RT, et al. Albumin-adjusted calcium is not suitable for diagnosis of hyper- and hypocalcemia in the critically ill. Crit Care Med 2003;31(5):1389 – 93. [69] Dickerson RN, Alexander KH, Minard G, et al. Accuracy of methods to estimate ionized and dcorrected’ serum calcium concentrations in critically ill multiple trauma patients receiving specialized nutrition support. JPEN J Parenter Enteral Nutr 2004;28(3):133 – 41. [70] Hastbacka J, Pettila V. Prevalence and predictive value of ionized hypocalcemia among critically ill patients. Acta Anaesthesiol Scand 2003;47(10):1264 – 9. [71] Zaloga GP. Hypocalcemia in critically ill patients. Crit Care Med 1992;20(2):251 – 62. [72] Davis AM. Hypocalcemia in rhabdomyolysis. JAMA 1987;257(5):626. [73] Tan HK, Bellomo R, M’Pisi DA, et al. Ionized serum calcium levels during acute renal failure: intermittent hemodialysis vs. continuous hemodiafiltration. Ren Fail 2002;24(1):19 – 27. [74] Lind L, Carlstedt F, Rastad J, et al. Hypocalcemia and parathyroid hormone secretion in critically ill patients. Crit Care Med 2000;28(1):93 – 9. [75] Zaloga GP, Washburn D, Black KW, et al. Human sepsis increases lymphocyte intracellular calcium. Crit Care Med 1993;21(2):196 – 202. [76] Vincent JL, Bredas P, Jankowski S, et al. Correction of hypocalcemia in the critically ill: what is the haemodynamic benefit. Intensive Care Med 1995;21:838 – 41. [77] Porter DL, Ledgerwood AM, Lucas CE, et al. Effect of calcium infusion on heart function. Am Surg 1983;49(7):369 – 72. [78] Jankowski S, Vincent JL. Calcium administration for cardiovascular support in critically ill patients: when is it indicated? J Intensive Care Med 1995;10(2):91 – 100. [79] Zaloga GP, Strickland RA, Butterworth JF, et al. Calcium attenuates epinephrine’s b-adrenergic effects in postoperative heart surgery patients. Circulation 1990;81:196 – 200. [80] Butterworth JF, Royster GP. Calcium inhibits the cardiac stimulating properties of dobutamine but not amrinone. Chest 1992;101:174 – 80. [81] Zaloga GP, Sager A, Black KW, et al. Low dose calcium administration increases mortality during septic peritonitis in rats. Circ Shock 1992;37(3):226 – 9. [82] Malcolm DS, Zaloga GP, Holaday JW. Calcium administration increases the mortality of entotoxic shock in rats. Crit Care Med 1989;17(9):900 – 3.

326

lafrance

&

leblanc

[83] Mundy G, Guise T. Hypercalcemia of malignancy. Am J Med 1997;103:134 – 45. [84] Rankin W, Grill V, Martin T. Parathyroid hormone-related protein and hypercalcemia. Cancer 1997;80:1564. [85] Massry S, Friedler R, Coburn J. Excretion of phosphate and calcium: physiology of their renal handling and relation to clinical medicine. Arch Intern Med 1973;131:828. [86] Suki WN, Yium JJ, Von Minden M, et al. Acute treatment of hypercalemia with furosemide. N Engl J Med 1970;283:836 – 40. [87] Mazzaferri EL, O’Dorisio TM, LoBuglio AF. Treatment of hypercalcemia associated with malignancy. Semin Oncol 1978;5:141 – 53. [88] Hamilton J, Lasrich M, Hirszel P. Peritoneal dialysis in the treatment of severe hypercalcemia. J Dial 1980;4:129 – 38. [89] Kaiser W, Biesenbach G, Kramar R, et al. Calcium-free hemodialysis: an effective therapy in hypercalcemic crisis-report of 4 cases. Intensive Care Med 1989;15:471 – 4. [90] Gennari FJ. Hypokalemia. N Engl J Med 1998;339(7):451 – 8. [91] Weiner ID, Wingo CS. Hypokalemia—consequences, causes, and correction. J Am Soc Nephrol 1997;9:1179 – 88. [92] Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for water, potassium, sodium, chloride, and sulfate. Washington, DC7 National Academy Press; 2004. [93] Weisberg LS, Szerlip HM, Cox M. Disorders of potassium homeostasis in critically ill patients. Crit Care Clin 1987;5(4):835 – 54. [94] Rose BD. Clinical physiology of acid-base and electrolyte disorders. 4th edition. New York7 McGraw-Hill; 1994. [95] Krishna GG, Steigerwalt SP, Pikus R, et al. Hypokalemic states. In: Narins RG, editor. Maxwell & Kleeman’s clinical disorders of fluid and electrolyte metabolism. 5th edition. New York7 McGraw-Hill; 1994. p. 659 – 96. [96] Halperin ML, Kamel KS. Potassium. Lancet 1998;352:135 – 40. [97] Hamill RJ, Robinson LM, Wexler HR, et al. Efficacy and safety of potassium infusion therapy in hypokalemic critically ill patients. Crit Care Med 1991;19(5):694 – 9. [98] Kruse JA, Clark VL, Carlson RW, et al. Concentrated potassium chloride infusions in critically ill patients with hypokalemia. J Clin Pharmacol 1994;34:1077 – 82. [99] Argawal A, Wingo CS. Treatment of hypokalemia. N Engl J Med 1999;340:154 – 5. [100] Fiaccadori E, Lombardi M, Leonardi S, et al. Prevalence and clinical outcome associated with pre-existing malnutrition in acute renal failure: a prospective cohort study. J Am Soc Nephrol 1999;10:581 – 93. [101] Jeejeebhoy KN, Detsky AS, Baker JP. Assessment of nutritional status. JPEN J Parenter Enteral Nutr 1990;14(Suppl 5):193S – 6S. [102] Detsky AS, McLaughlin JR, Baker JP, et al. What is subjective global assessment of nutritional status? JPEN J Parenter Enteral Nutr 1987;11:8 – 13. [103] Galanos AN, Pieper CF, Kussin PS, et al. Relationship of body mass index to subsequent mortality among seriously ill hospitalized patients. SUPPORT Investigators. The Study to Understand Prognoses and Preferences for Outcome and Risks of Treatments. Crit Care Med 1997;25(12):1962 – 8. [104] Fleck A. Plasma proteins as nutritional indicators in the perioperative period. Br J Clin Pract Suppl 1988;63:20 – 4. [105] Demling RH, DeSanti L. Complications of acute weight loss due to stress response to injury. Curr Opin Crit Care 1996;2:482 – 91. [106] Kinney JM. Indirect calorimetry in malnutrition: nutritional assessment or therapeutic reference? JPEN J Parenter Enteral Nutr 1987;11(5 Suppl):90S – 4S. [107] Larsson J, Lennmarken C, Martensson J, et al. Nitrogen requirements in severely injured patients. Br J Surg 1990;77(4):413 – 6. [108] Cerra FB, Benitez MR, Blackburn GL, et al. Applied nutrition in ICU patients. Chest 1997;111: 769 – 78.

nutritional concerns in critical illness

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[109] Krishnan JA, Parce PB, Martinez A, et al. Caloric intake in medical ICU patients. Chest 2003;124:297 – 305. [110] Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359 – 67. [111] Mokrzycki MH, Kaplan AA. Protein losses in continuous renal replacement therapies. J Am Soc Nephrol 1996;7:2259. [112] Baumgart DC, Dignass AU. Intestinal barrier function. Curr Opin Clin Nutr Metab Care 2002; 5:685 – 94. [113] Heyland DK, Dhaliwal R, Drover JW, et al. Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr 2003;27:355 – 73. [114] Beale RJ, Bryg DJ, Bihari DJ. Immunonutrition in the critically ill: a systematic review of clinical outcome. Crit Care Med 1999;27:2799 – 805. [115] Clark EC, Patel SD, Chadwick PR, et al. Glutamine deprivation facilitates tumor necrosis factor induced bacterial translocation in Caco-2 cells by depletion of enterocyte fuel substrate. Gut 2003;52:224 – 30. [116] Piccirillo N, DeMatteis S, Laurenti L, et al. Glutamine-enriched parenteral nutrition after autologous peripheral blood stem transplantation: effects on immune reconstitution and mucositis. Haematologica 2003;88:192 – 200. [117] Kuemmerle N, Krieg Jr RL, Latta K, et al. Growth hormone and insulin-like growth factor in non-uremic acidosis and uremic acidosis. Kidney Int 1997;58:S102 – 5. [118] Takala J, Ruokonen E, Webster NR, et al. Increased mortality associated with growth hormone treatment in critically ill patients. N Engl J Med 1999;341:785 – 92. [119] Biolo G, Grimble G, Preiser JC, et al. Position paper of the ESICM Working Group on Nutrition and Metabolism. Metabolic basis of nutrition in intensive care unit patients: ten critical questions. Intensive Care Med 2002;28(11):1512 – 20.