Kenneth A. Kudsk and Caitlin Curtis
Nutritional therapy is an integral part of the management of severely injured patients. Although malnutrition is a frequent comorbid factor in general hospitalized patients, most trauma patients are young and well nourished. Their nutritional risk is not from preexisting defects in protein stores but due to a hypermetabolic response to injury, inflammation, and sepsis. Rapid mobilization of protein from muscle supports healing, the acute-phase response, and systemic and local host barriers to infection. While tolerated for a limited time, complications during healing, sepsis, and multiple organ dysfunction syndrome (MODS) progressively drain the ability to maintain defenses and heal wounds. This chapter focuses on the role of enteral and parenteral nutritional (PN) support in reducing complications in critically injured patients with particular attention to the identification, institution, and successful management of enteral feeding.
The response to the stress of injury has been classified into “ebb” and “flow” phases, which are influenced by the magnitude of injury. Changes in oxygen consumption, hyperglycemia, and increased vascular tone characterize the “ebb” phase. Epinephrine, norepinephrine, cortisol, aldosterone, and antidiuretic hormone release and exert their central and peripheral effects. Energy expenditure and body temperature are influenced through regulatory changes within the hypothalamus.1
Oxygen consumption and delivery and body temperature increase during the “flow” phase, as amino acids are mobilized into the amino acid pool from peripheral tissues for redistribution for gluconeogenesis, acute-phase protein production, immunologic proliferation, red blood cell production, and fibroblast proliferation. The magnitude of the flow phase correlates with the magnitude and severity of injury but gradually resolves unless a complication intervenes. In uncomplicated cases, diuresis of retained intracellular and extracellular water reflects resolution of this hypermetabolism as stress hormone levels drop. Appetite and gastrointestinal (GI) function return and positive nitrogen balance reappears with repletion of fat and lean body mass.
During this hypermetabolism, patients are usually immobilized and restricted by injuries and the medical therapy. Exercise is a fundamental determinant of muscle mass and immobilization of uninjured patients results in negative nitrogen balance for approximately 3–4 weeks despite adequate nutrition. Except on a very temporary basis, “positive nitrogen balance” cannot be achieved in immobilized injured patients during the first 3 weeks of hospitalization, and attempts to overfeed the negative nitrogen balance must be avoided.
THE ENDOCRINE RESPONSE TO STRESS AND INJURY
The hypercatabolism of injury, stress, and sepsis differs from that of starvation where inadequate substrate is available to meet metabolic demands; a comparison is shown in Table 60-1.2 Starvation is characterized by a decrease in metabolic rate, lethargy, a decrease in cardiac output, and a transition to ketone bodies as a major energy source. Within 18–24 hours, glycogen stores are depleted and amino acids provide the substrate for gluconeogenesis. As serum insulin levels drop, fatty acids, ketones, and glycerol become the primary substrate in tissues over 7–10 days. Ketone bodies can meet 70% of the energy requirements of the brain, normally an obligate glucose-requiring tissue. Even at full adaptation, some tissues require glucose for function. This adaptation preserves lean tissue, since amino acid demand drops and protein synthesis and catabolism decrease compared with the fed state. The respiratory quotient (RQ, the ratio of carbon dioxide production to oxygen consumed) is approximately 0.6–0.7 in starvation, indicative of utilization of fat as a primary fuel.
TABLE 60-1 Starvation versus Severe Stress Hypercatabolism
During hypermetabolism, the RQ ranges between 0.80 and 0.85. Hyperglycemia and glucose intolerance characterize this condition. Hyperglycemia is due to elevated catecholamines, which induce hepatic glycogenolysis and gluconeogenesis while inhibiting insulin secretion. Elevated cortisol stimulates glycogenolysis, muscle proteolysis, and gluconeogenesis and induces a peripheral insulin resistance to limit glucose uptake. Cortisol also inhibits gluconeogenic enzymes, potentiates hepatic effects of epinephrine and glucagon, and stimulates muscle proteolysis.3 Overall, the circulating insulin level drops and its anabolic effects are lost, resulting in increased lipolysis, fat oxidation, glucose production,4 and dependence on amino acids for glucose production.
Other hormones released with injury include glucagon and arginine vasopressin (AVP) (formerly antidiuretic hormone). Glucagon increases gluconeogenesis, glycolysis, and lipolysis, partly by reducing the insulin to glucagon ratio. AVP stimulates hepatic glycogenolysis and gluconeogenesis. Growth hormone (GH) is normally anabolic and increases glycogen deposition and protein synthesis while mobilizing fatty acids. It is inhibited following injury and during stress, as is insulin-like growth factor I (IGF-I), which is produced by the liver in response to GH. The overall effect is an imbalance in the direction of the counterregulatory hormones, a reduction in the anabolic hormones, and an accelerated loss in lean tissue. If the hypermetabolism remains unchecked, peripheral tissues become incapable of amino acid mobilization for gluconeogenesis or protein synthesis.
CHANGES IN INTERMEDIARY METABOLISM WITH STRESS AND SEPSIS
Both protein synthesis and catabolism increase after severe trauma. Starvation, immobilization, and the hormonal and cytokine milieu factor in this response.5 Release of 3-methyl-histidine, an amino acid derived from actin and myosin metabolism in damaged and undamaged tissues, increases. Essential amino acid levels, especially branched-chain amino acids (BCAA), increase within the cell and levels of nonessential amino acids decrease, primarily through a 50% reduction in intracellular glutamine (GLN). Up to 70% of the amino acids released by skeletal muscle are alanine and GLN, although they constitute 10–15% of muscle composition. The production and metabolism of these amino acids have been studied extensively.6 During stress, skeletal muscle is capable of utilizing the BCAAs, valine, isoleucine, and leucine. While the non-BCAAs are released into the systemic amino acid pool, waste nitrogen of BCAA is disposed in two ways. In the cell, glucose is metabolized to pyruvate, which accepts a nitrogen molecule from the BCAA via transamination to create alanine. Alanine is released, cleared by the liver, deaminated, and recycled to glucose. The nitrogen is converted to urea. Additional pyruvate is converted to acetyl CoA for entry into the Krebs cycle. The transamination of nitrogen from BCAA onto alpha-ketoglutarate in the Krebs cycle produces glutamate. Transamination of a second nitrogen completes the synthesis of GLN. GLN is released and functions as a primary fuel for enterocytes and various immunologic cells (especially T-lymphocytes), and for conversion to glucose by the kidney. GLN is converted by the gut-associated lymphoid tissue (GALT) and splanchnic tissue to ammonia, ornithine, citrulline, and alanine and released into the portal circulation. Hepatic uptake clears these by-products for entry into appropriate metabolic cycles. Although serum and intracellular levels of GLN drop, overall production is increased. Waste nitrogen in the kidney is excreted as ammonia into the tubules binding hydrogen ion for elimination.
Skeletal muscle protein catabolism exceeds synthesis but there are net increases in hepatic protein production and gluconeogenesis in the liver. Synthesis of constitutive transport proteins (e.g., albumin and prealbumin) is depressed while synthesis of acute-phase proteins (e.g., C-reactive protein [CRP] and α2-acid glycoprotein) is increased. This catabolism is tolerated by well-nourished patients for a limited period, but prolonged body protein loss is associated with pulmonary, cardiovascular, metabolic, and immunologic system failure.
Hepatic gluconeogenesis remains elevated despite hyperglycemia. After glycogen depletion, protein provides the substrate since fat cannot be converted into glucose. Glucose infusions do not inhibit this accelerated gluconeogenesis.7 Alanine, GLN, increased lactate levels released by hypoxic tissues, and glycerol released from adipose tissue can be converted into glucose. Alanine levels increase by 40% while glycerol and lactate increase by as much as 100% in trauma patients.5 Data from burn patients8 suggest that glucose production is controlled by the liver since lowering of insulin and glucagon concentrations by somatostatin reduces hepatic glucose production despite elevated levels of substrate appropriate for gluconeogenesis.
There is evidence of less efficient glucose oxidation in both septic and trauma patients that may be secondary to intracellular derangements in control pathways caused by low pyruvate dehydrogenase levels. It is unlikely that reduced glucose oxidation is due only to insulin resistance, since glucose clearance from plasma is unrelated to glucose oxidation. This mobilization of glucose may be protective since experimental infusion of hypertonic glucose following hemorrhage reduces mortality in pigs and increases blood pressure clinically. Some effect may be due to fluid shifts due to hyperglycemia, but a positive pressor effect from increased myocardial glucose uptake has been postulated.
Fat is the primary fuel during stress and sepsis. Increased levels of epinephrine, glucagon, cortisol, and perhaps GH enhance lipolysis following injury despite increased levels of plasma insulin. Plasma free fatty acid levels do not correlate with the degree of trauma,9 perhaps from shunting of blood from adipose tissue or drops in serum albumin since it is a transport molecule for free fatty acids. Lactic acidosis lowers free fatty acids by augmenting reesterification. The contribution of fat is evident by the depressed RQ in septic patients. As the patient recovers, the RQ increases from 0.7 of fat to 1.0 of carbohydrate, but the RQ remains depressed in septic patients.
The type of fat administered influences cellular responses. All forms of intravenous fat currently available in the United States are omega-6 fatty acids derived from vegetable oils. The omega-6 polyunsaturated fatty acid (PUFA) linoleic acid is subsequently incorporated into membranes of both immune and nonimmune cells as arachidonic acid. During stress, increased intracellular calcium releases the fatty acids by activating phospholipase A2. The products are acted upon by cyclooxygenase and lipoxygenase to produce the prostanoid PGE2, a vasodilator prostanoid, while lipoxygenase produces leukotriene B4 and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE). At high concentrations PGE2 is immunosuppressive and reduces T-cell function and migration and generation of cytotoxic cells. Leukotrienes are powerful chemoattractants that stimulate aggregation and adherence of leukocytes and natural killer cell activity. Most contemporary enteral formulas contain omega-3 fatty acids from fish and canola oil. After their subsequent release, intracellular enzymes produce prostaglandins of the 3 series (PGE3) and leukotrienes of the 5 series, which are less immunosuppressive and not as proinflammatory as the omega-6 products. Clinically, these cell membrane increases are measurable within a few days of administration.10
Nutritional support is but one very important aspect in the overall management of the trauma patient. Most trauma patients are well nourished, although geriatric patients and younger patients with histories of substance abuse may have varying degrees of malnutrition. Debridement, drainage, resection of infected tissue, stabilization of fractures, adequate resuscitation, etc., are the priorities in early management, because early control will influence the subsequent metabolic response. If sources of inflammatory mediators are not controlled, nutrition support will not preserve catabolic lean tissue. With control, nutritional support can maintain host defenses, preserve lean body mass, improve patient outcome, and, if administered early via the GI tract, reduce infections.
Aggressive nutrition support in critically injured patients is an invasive form of therapy with risks and benefits that cannot be approached casually. In elective surgical patients undergoing general surgical procedures, the risks of therapy can, in some circumstances, outweigh benefits.11 However, in patients who are malnourished or at risk of becoming so, the benefits outweigh the risks if nutritional support is carefully instituted and monitored. There are significant clinical data demonstrating that after gaining hemodynamic stability, severely injured patients who are fed early via the GI tract have a reduced risk of septic complications and, in some circumstances, MODS.12–17 The availability of effective tools to quantitate the magnitude of injury and likelihood of subsequent septic complication allows surgeons to identify patients for whom enteral access is warranted at the time of initial celiotomy.
Not all patients can be fed enterally, particularly if enteral access is not obtained at the initial laparotomy. In these situations, intravenous nutrition should be instituted on the fifth day, since there is no evidence that early intravenous nutrition significantly improves clinical outcome. However, when it is clear that the GI tract is not functioning or will not function, PN is indicated.
ENTERAL VERSUS PARENTERAL FEEDING: THE CLINICAL ARGUMENT
The preponderance of evidence demonstrates benefits with enteral feeding and the elective use of PN early after trauma is associated with increased infections.38 The most compelling data exist in randomized, prospective clinical studies12–18 of victims of blunt and/or penetrating trauma. After the first clinical data of improved outcome with enteral feeding shown in pediatric burn patients,19 subsequent trauma studies compared various enteral products with either no feeding or intravenous feeding. Most showed reductions in intra-abdominal abscess and pneumonia in the enterally fed group. Moore et al. randomized patients with an abdominal trauma index (ATI) between 15 and 40 to early feeding with a defined-formula diet or no early feeding and showed a 3-fold reduction in sepsis (primarily intra-abdominal abscess) with enteral feeding.13 Subsequently, they showed that enteral feeding significantly reduced pneumonia compared with PN14 consistent with prior20 work showing a lower septic rate in patients receiving most of their nutrition enterally.
The Memphis group showed that enteral feeding significantly reduced pneumonia (11.8% vs. PN 31%), intra-abdominal abscess (1.9% vs. PN 13.3%), and line sepsis (1.9% vs. PN 13.3%).12 Severity of injury influenced the results since the reduced infection rate occurred in patients with an Injury Severity Score (ISS) >20 and an ATI >24 or both, where PN increased infectious rates by 6.3, 7.3, or 11 times, respectively.
A few studies produced conflicting data. One group found similar rates of infection in trauma patients receiving intravenous feeding or enteral nutrition with no difference in pneumonia or intra-abdominal infection.21 However, there were nearly twice as many head injuries, three times as many severe thoracic injuries, and three times as many pelvic fractures in the enterally fed patients. The increased incidence of severe chest injuries in the enteral group made the diagnosis of pneumonia suspect, since pneumonia was diagnosed using the standard criteria of fever, leukocytosis, and a new or changing infiltrate on chest x-ray, which overdiagnoses pneumonia in more than two thirds of cases.22
Another study randomized blunt trauma patients requiring intensive care unit (ICU) care to either early (<24 hours) or late (>72 hours) enteral feeding.23 Total infectious complications—ranging from pneumonia to an eye infection—were significantly greater in the early fed group but there was a very high dropout rate, and the early fed patients had more severe pulmonary injury, as measured by the Pao2/FiO2 ratio. Eleven of 19 patients in the early group had a Pao2/FiO2 ratio <150, while only 4 of 19 patients in the late group had severe pulmonary dysfunction. Pneumonia occurred twice as often in the early fed patients, but results were confounded by the increased chest trauma.
DETERMINING INDICATORS FOR ENTERAL (POSTPYLORIC) ACCESS DURING CELIOTOMY FOR TRAUMA
The ATI (Table 60-2) can be rapidly tabulated at the operating table to determine the need for direct small bowel access.24 Patients with an ATI ≥25 appear to benefit from early enteral nutrition once they are hemodynamically stable. Patients with insignificant intra-abdominal injuries will benefit from early feeding if they sustain significant extra-abdominal injuries such as a severe pulmonary contusion; multiple rib fractures; a closed head injury with a Glasgow Coma Scale (GCS) score ≤8; a spinal injury; a major soft tissue injury requiring repeated irrigation, debridement, and skin grafts; or multiple extremity fractures necessitating later surgery. In addition, patients with multiple chronic diseases or patients who will require prolonged ventilator support or have delayed resumption of oral intake are appropriate candidates. Most patients with these criteria have an ISS >20 and benefit from the early enteral feeding (Fig. 60-1). Severe intra-abdominal injuries to the colon, pancreas, liver, or duodenum increase the risk of septic complications, but enteral access is usually unnecessary with relatively minor, isolated injuries to these organs.
TABLE 60-2 Calculated Risk of Sepsis by the Abdominal Trauma Index
FIGURE 60-1 Protocol for nutrition support at the University of Wisconsin-Madison and the Elvis Presley Trauma Center at the University of Tennessee, Memphis.
Patients with Closed Head Injury
There is little evidence that early nutrition affects outcome after severe head injuries. We wait until GI tract function returns and gastroparesis resolves (generally within 3 days) before instituting intragastric feeding. Prolonged gastroparesis (>6 days) unresponsive to gastric motility agents requires that a tube be advanced into the distal duodenum and ideally beyond the ligament of Treitz. Intravenous nutrition should start if this is not possible.
This approach stems from a critical review of the head injury studies. Rapp et al.25 randomized 38 patients to PN or delayed enteral feeding (>1 week) once gastroparesis resolved. Initial work suggested improved GCS score at 3 months with early PN but no difference after this point. This result was not confirmed in a follow-up study.26 Grahm et al.27 randomized head-injured patients to enteral feeding via nasojejunal tube placed fluoroscopically within 36 hours of injury or via a gastrostomy tube once gastric atony resolved, usually within 5 days. Fewer bacterial infections and fewer ICU days occurred after early enteral feeding. However, bronchitis was the major diagnostic category separating the groups, rather than established infections such as pneumonia or abscess. Borzotta et al.28 randomized patients with severe head injuries to early enteral feeding via nasojejunal tube or delayed enteral feeding and demonstrated no reduction in infections and a slight, perhaps clinically insignificant improvement in neurologic outcome with early feeding. A Memphis study29 found no difference between an early placement of a tube beyond the ligament of Treitz and intragastric feeding, with no improvement in GCS or infectious complications.
The failure of enteral nutrition to reduce infections in head-injured patients appears contradictory to multiple trauma results, but the groups differ significantly. Prolonged intubation and pneumonia may be unavoidable after severe closed head injury, since patients with such injuries often remain intubated for weeks, while many multiple trauma patients require support only for several days.
Early enteral feeding in burn patients is well established. Alexander et al.19 randomized severely burned children to either a standard enteral diet or a protein-supplemented diet. Patients receiving the high-protein diet had a higher survival rate and a lower sepsis rate but received significantly less PN than control patients. Herndon et al.30 randomized 39 patients with 50% or greater total body burn to early IV or enteral feeding and measured significant decreases in natural killer cell activity and the T-helper/suppressor ratio with PN. Since higher survival rates occurred with enteral feedings, they concluded that PN should be used only with total enteral failure.
Intragastric feeding should be started within 12 hours of burn, since this approach reduces gastroparesis. Gastroparesis occurs in 45% of patients with intragastric feeding delayed for 18 hours, but it occurs in less than 5% of patients if feeding is instituted within 8 hours of burn. Laboratory evidence suggests a blunting of the hypermetabolic response after burn by reducing levels of cortisol and catecholamines.
INFLUENCE OF THE TYPE OF ENTERAL FEEDING ON INFECTIOUS COMPLICATIONS
Specialty “Immune-Enhancing” Diets
The concept that some nutrients became “conditionally essential” during stress and sepsis (e.g., GLN) or that other substrates such as omega-6 fatty acids could potentially aggravate inflammation through production of proinflammatory products led to the creation of a family of immune-enhancing diets (IEDs). These IEDs contain various combinations of GLN, arginine, omega-3 fatty aids, beta-carotene, and nucleotides. Liquid diets cannot be supplemented with GLN as a free amino acid because of its propensity to degrade into the toxic products pyroglutamate and ammonia after heat sterilization. Free GLN is found only in dry, powdered diets, which require reformulation prior to administration. These diets can be administered via transgastric jejunostomies (TGJs), large-bore (12–18 Fr) jejunostomies, and 7-Fr needle catheter jejunostomies (NCJs), but they tend to clog 5-Fr NCJs.
The rationale for these specific nutrient supplementations has been partly discussed above. Although skeletal muscle production of GLN increases during stress and sepsis, serum and intracellular levels decrease. GLN is a substrate for various immunologic cells and for enterocytes in the unfed state.6 Arginine promotes proliferating T cells after mitogen or cytokine stimulation in vitro and increases natural killer cell cytotoxicity, specific cytolytic T-cell activity, and macrophage tumor cytotoxicity. It also exerts a positive effect on wound healing; stimulates pituitary GH, prolactin, insulin, and IGF-I, and acts as a precursor for nitric oxide, nitrites, and nitrates as well as the growth substances putrescine, spermine, and spermidine, which may be involved in GI tract integrity. Omega-3 PUFAs from fish or canola oil can replace omega-6 PUFAs, such as linoleic acid, found mainly in vegetable oils. Omega-6 fatty acids inhibit killer cell activity, antibody formation, and cell-mediated immune response due to the inhibitory nature of their metabolic end products.10 Animal studies have shown that omega-3 supplementation reduces mortality after burn injury, reduces bacterial translocation compared with other lipids, promotes cell-mediated immunity, increases resistance to infection, reduces inflammation, and reduces mortality following bacterial peritonitis. The administration of RNA via nucleotides improves survival to a septic challenge with Candida albicans, and malnourished animals provided RNA during refeeding from a malnourished state had more rapid improvement in immune function.31Nucleotide deprivation suppresses helper T-cell and interleukin-2 (IL-2) production, largely due to uracil, since adenine does not prevent this immunosuppression. Clinically, various combinations of these nutrients have been made available in specialty nutrient diets. The majority of clinical studies carried out in critically ill patients, general surgical patient populations, trauma patients, and burn patients suggest an additional benefit with the IEDs over unsupplemented diets.16,17,32,33
Gottschlich et al.34 randomized 50 pediatric and adult patients with burns over 10–89% of their body surface area to diets including a modular feeding supplemented with arginine, cysteine, histidine, and omega-3 fatty acids. A significant reduction in wound infection, length of stay per percent body burn, and total number of infectious complications occurred in this group, with a trend (P = .06) toward reduced pneumonia. More inhalation injuries in the control group as well as more fat and less carbohydrates in the control formula were confounding variables.
Patients with an ATI between 18 and 40 randomized to an IED or a chemically defined diet generated significant increases in total lymphocyte count and T-lymphocyte and T-helper cell numbers as well as fewer intra-abdominal abscesses and less multiple organ failure with the supplemented diet.17 Since a higher nitrogen content in the IED was a confounding variable, a subsequent study randomized patients with an ATI >25 or an ISS >20 to an IED or an isonitrogenous, isocaloric diet.16 Unfed cohorts, eligible for the trial entry but without enteral access, were also prospectively followed. The IED resulted in fewer major septic complications, fewer therapeutic antibiotics, and a shorter hospital stay than in the unfed group or those receiving the control diet. The incidence of intra-abdominal abscess, pneumonia, bacteremia, major wound infections, or any major complication was highest in the unfed population. Complications and antibiotic use with the control diet were between the unfed and IED groups. Administration of a GLN-supplemented enteral diet has also been shown to reduce pneumonia, bacteremia, and sepsis.35Potential negative effects may also occur with these diets. One study noted an increase in respiratory failure with an IED.36 An increased incidence of respiratory failure in the treatment group at baseline limited the ability to implicate the diet, however.
We institute an IED in patients with an ATI >25 or an ISS >20 (Fig. 60-1) and convert to a standard high-protein enteral diet once the patients are less vulnerable to septic complications, usually within 7–10 days. Patients with less severe injuries receive a high-protein diet.
POSSIBLE DELETERIOUS EFFECTS OF IMMUNONUTRITION IN THE CRITICALLY ILL
Recently published Canadian practice guidelines for nutrition support in mechanically ventilated critically ill patients recommended that arginine-containing diets (oral immunonutrition that contains arginine supplementation) should not be used in critically ill ICU patients.37 The conclusion was reached despite significantly reduced hospital stays and trends toward reduced ventilator days and ICU days noted with these diets in trials. This meta-analysis based these recommendations on three studies. One trial of trauma, surgical, and medical ICU patients randomized patients to a diet enriched in arginine, omega-3 fatty acids, and nucleotides.33 Patients tolerating more than 821 mL per day benefited clinically in a post hoc analysis, but septic patients randomized to the arginine-containing diet had increased mortality, although overall mortality was not affected. A second randomized but unpublished prospective study conducted in 1996 randomized critically ill patients to a specialized diet containing moderate amounts of arginine and omega-3 fatty acids. Mortality increased with this supplemented diet in elderly male patients admitted with sepsis and pneumonia. However, significantly more patients with pneumonia were randomized to the specialty diet due to a randomization breakdown. Most patients who died either received less than 3 days of feeding or did not receive the specialty diet long after completion of the study period. A third study38 randomized septic patients requiring more than 4 days of nutrition support and a “higher level of care” to PN or an omega-3 fatty acid/arginine-supplemented enteral diet. Increased mortality occurred in this group but most deaths occurred in patients septic with pneumonia similar to unpublished trial noted above.
Although there are significant reservations regarding the design and implementation of these three trials, septic patients—particularly if septic with pneumonia—may have a poorer outcome with immunonutrition for unknown reasons, although increased nitric oxide production during sepsis, but not stress, has been proposed.39 Two trials noted no increase in mortality with sepsis using similar diets.40,41 With the clinical evidence of improvement in trauma patients, there is no evidence to suggest this population has increased risks with administration of these specialty diets and guidelines have recommended their use.42
POTENTIAL REASONS FOR IMPROVED OUTCOME WITH ENTERAL FEEDING
The unfed GI tract has altered function and architecture. Decreases in villus height occur in unfed human patients, but to a lesser extent than in rat models of starvation or intravenous feeding, where 40–50% of villus height is lost in the proximal intestine. Changes occur quickly in the GI tract following shock and stress, with rapid decreases in enzymes and motility and temporary increases in permeability. The reduced motility (i.e., ileus) occurs in the stomach and colon, allowing absorption of nutrients delivered into the small intestine.
Shock, trauma, and sepsis increase gut permeability, which increases bacterial translocation to mesenteric lymph nodes in animal models and under certain clinical conditions, such as bowel obstruction, inflammatory bowel disease, and shock. This does not appear to be clinically relevant following trauma.43 Increased permeability in trauma patients is unrelated to the magnitude of trauma but does correlate with the IL-6 and acute-phase protein response of severely injured patients. The level of permeability returns to baseline within a week.
The well-fed intestine is a metabolically and immunologically active organ that passively and actively maintains a bacterial barrier through peristalsis, IgA, mucin, and mucosal cell integrity. Experimentally, these systems fail in starvation, shock, and sepsis. Approximately 75% of the body’s immunoglobulin-producing cells line the GI and respiratory tracts to produce 70–80% of the immunoglobulin as secretory IgA (SIgA), which is transported across the mucosa.44 The GALT is affected by PN, producing decreases in GALT mass and reductions in intestinal and respiratory IgA. Normally, the IgA coating the surface of the epithelium binds and neutralizes viruses, bacteria, and other pathogenic antigens by trapping them in the mucin layer. As a result, these infective agents cannot attach to the mucosa, a prerequisite to invasive infection. Experimentally, PN-fed animals lose established antibacterial and antiviral immunity.44 Under conditions of stress, ischemia, and injury, Alverdy and Chang demonstrated that intraluminal bacteria respond to this hostile environment by upregulation of virulence genes and expressing adhesins that render them more virulent in vivo.45
Intraperitoneal protection can also be explained by similar mechanisms. Enteral feeding significantly improves the survival of malnourished or well-nourished animals with septic peritonitis by increasing intraperitoneal tumor necrosis factor (TNF) response, resulting in a lower systemic cytokine response and bacteremia compared with animals fed intravenously. A differential cytokine response has also been confirmed in patients. Normal volunteers administered PN demonstrate an increase in production of TNF compared with enterally fed patients following intravenous injection of endotoxin.46 Since TNF has been considered one of the precipitating stimuli for the subsequent proinflammatory cytokine response, this may be clinically relevant.
Exposure of the systemic circulation to bacterial products has been postulated to be a driving force in the development of MODS.47 Enteral stimulation maintains a normal gut cytokine response with high levels of IL-4 and IL-10.44These cytokines upregulate IgA production from mucosal protection and down-regulate adhesion molecule expression on the vascular endothelium. Parenteral feeding reduces these cytokines, leading to an upregulation of vascular adhesion molecules and accumulation of neutrophils within the intestine and priming of these neutrophils to subsequent ischemic events.82 Ischemic events within the gut have been previously related to neutrophil priming as an initial step in MODS development.48 These experimental data are consistent with the reduction in MODS in trauma patients fed enterally.17
THE NUTRIENT PRESCRIPTION: ISSUES COMMON TO ENTERAL OR PARENTERAL FEEDING
There are a number of issues common to both enteral and parenteral feedings related to the amount and type of nutrition administered to trauma patients. In the past, calculation of nutrient needs used standard equations, such as the Harris–Benedict equation, multiplied by correction factors. Indirect calorimetry has shown that these correction factors for stress and activity tend to overestimate nutrient needs. Overfeeding leads to increased oxygen consumption, increased CO2 production, hepatic lipogenesis, potential immune suppression secondary to hyperglycemia, and other negative effects without reducing weight loss or lean tissue catabolism.
ESTIMATING NUTRITIONAL NEEDS
The most common calculation used to determine basal energy expenditure (BEE) is the Harris–Benedict formula, defined as follows:
where W is the weight in kilograms, H is the height in centimeters, and A is the age in years. These calculated values have been increased by a stress factor (ranging from 1.25 to 2) and an activity factor to account for the increases in metabolic rate by injury and stress.
Indirect calorimetry measures metabolic needs using expired gas analysis to determine overall resting energy expenditure (REE). Carbon dioxide production (co2) and oxygen consumption (o2) are used to calculate the RQ. When o2 and co2 are applied to the Weir equation, REE can be determined. There is an RQ characteristic for each fuel utilized: for example, fat is 0.7, glucose is 1.0, and protein is 0.8. Since fat deposition with overfeeding has an RQ value of approximately 8, an RQ value greater than 1.0 generally means that lipogenesis and overfeeding are occurring. In studies of patients in surgical ICUs, metabolic cart measurements were generally within 5–10% of the energy requirements calculated by the Harris–Benedict equation; addition of stress factors led to unnecessary administration of nutrients.49
There are drawbacks to indirect calorimetry. Since o2 is an integral part of the measurement, there is loss of accuracy as the FiO2 increases because of the errors between the inspired and expired oxygen consumptions. With an FiO2of 0.8, a 1% error in measurement of the inspired or expired o2 leads to 100% error in co2 calculation. Since air leaks are interpreted as increases in oxygen consumption, critically ill patients requiring a high FiO2 and high positive end-expiratory pressure are most likely to have inaccurate measurements. In addition, these calculations are labor-intensive and results are most reliable when protocols defined by trained technicians are used. Indirect calorimetry measurements only reflect caloric needs over a 20- to 30-minute period. When the patients are turned, suctioned, or receiving physical therapy, those measurements may not represent total energy expenditure. For these reasons, many practitioners increase the REE by 10–15% to calculate total energy expenditure. Because of the expenses necessary to avoid the pitfalls of indirect calorimetry, its routine use is not recommended. However, data obtained from sites proficient in the technique have provided valuable guidelines to avoid overfeeding, especially in cases of obesity, amputation, or quadriplegia, where traditional calculations are not reliable.
Current recommendations for caloric support range between 25 and 30 total kcal/kg per day. While some studies have recommended other values, if 30 kcal/kg is provided, 90% of patients will reach their energy requirement with overfeeding in approximately 15–20% of patients.49 To avoid complications of overfeeding (Fig. 60-2), we administer approximately 25–30 total kcal/kg per day to multiply injured patients initially and decrease this to 22–25 kcal/kg as they improve clinically, with diuresis, ventilator weaning, and discontinuation of antibiotics. Presumed body weight is obtained from family members or the patient, when possible, to avoid overfeeding based on weights increased by edema. As diuresis occurs, weight is rechecked with appropriate adjustments in total caloric load. In general, we withhold nutrition in patients requiring high rates of catecholamine infusion, since there is no evidence that administered glucose or protein (or amino acids) slows lean body tissue mobilization or the rate of gluconeogenesis.
FIGURE 60-2 Complications of overfeeding. (Reproduced with permission from Frankel WL, Evans NJ, Rombeau JL. Scientific rationale and clinical application of parenteral nutrition in critically ill patients. In: Rombeau JL, Caldwell MD, eds. Clinical Nutrition. Vol. 2. Parenteral Nutrition. 2nd ed. Philadelphia: Saunders; 1993:597, © Elsevier.)
Stress induces an increase in both glucose utilization and gluconeogenesis with significant recycling of glucose from lactate (the Cori cycle) and alanine. Lactic acid is produced in the periphery when pyruvate cannot enter the Krebs cycle. As NADPH is converted to NADP, hydrogen ion is transferred to pyruvate creating lactate, which is then released, transported back to the liver, and converted to glucose. Alanine is formed by transamination of pyruvate during BCAA metabolism in skeletal muscle and released for conversion back to pyruvate and glucose by the liver. Hyperglycemia occurs as hepatic gluconeogenesis increases from 2.0 to 2.5 mg/(kg min) under the normal condition to 4–5 mg/(kg min) in the stressed or septic patient. Given these conditions, high levels of infused glucose aggravate hyperglycemia causing glucosuria, hepatic fatty deposition, increased CO2 production (rarely a significant clinical problem in young trauma victims), and potentially an increased infection rate. Since the maximal rate of glucose oxidation is 5 mg/(kg min) or approximately 7.2 g/kg per day, cumulative glucose administration including enteral and parenteral products as well as intravenous fluids should not exceed these levels. In a 70-kg adult, this is 500 g of glucose at maximum, which is almost completely met by 2 L of a 25% dextrose PN solution. Ideally, blood sugars should be maintained below 180 mg/dL. With insulin, it is usually possible to keep blood sugars below 180 mg/dL except in trauma patients with insulin-dependent diabetes mellitus or those with steroid or high catecholamine needs.50
ENERGY REQUIREMENTS AND FEEDING RECOMMENDATIONS IN THE MORBIDLY OBESE
Morbid obesity is becoming more and more prevalent in the trauma and surgical ICUs. The World Health Organization now classifies obese patients into three categories: Obese Class I are patients with BMIs of 30–34.9, Obese Class II are patients with BMIs of 35–39.9, and Obese Class III are patients with BMIs ≥40. Current feeding recommendations for morbidly obese trauma or surgical ICU patients are for Class I or Class II obesity, 22 total kcal/kg ideal body weight and 2 g of protein/kg ideal body weight. For patients who are in the Obese Class III category, recommendations are for slightly higher calories of 22–25 total kcal/kg of ideal body weight and 2–2.5 g protein/kg of body weight.51 This is based on observations that nitrogen retention increases as caloric intake increases until caloric intake approaches 50–60% of total energy expenditure. Additional energy further improves nitrogen retention but less efficiently. Although weight loss occurs, this is primarily due to fat loss.
In a 2-week study of enteral feeding52 this population received 1.5–1.9 g/kg ideal body weight per day of protein with either 19 kcal/kg actual body weight per day (30 total kcal/kg ideal body weight per day) or 11 total kcal/kg actual body weight per day (hypocaloric group: 22 total kcal/kg ideal body weight per day). Prealbumin increases were similar in the two groups. Both had negative nitrogen balance due to catabolism, but the hypocaloric group had a shorter ICU stay, fewer antibiotic days, and a trend toward reduced ventilator days (P <.09).
Hypocaloric, parenteral high-protein feeding of postoperative obese patients with 2.1 g of protein and 20 total/kcal ideal body weight resulted in 1.7 kg per week of weight loss, net protein anabolism (improved serum protein concentration and positive nitrogen balance), and successful wound healing.53 Two other randomized double-blind studies of obese patients compared hypocaloric feeding with higher-calorie regimens. In the first, both groups received 2 g/kg ideal body weight per day but calories were administered at 100% or 50% of the measured energy expenditure.54 Nitrogen balances were similar. In the second, hypocaloric or higher-calorie parenteral regimens (14 ± 3 total kcal/kg actual weight per day vs. 22 ± 5 total kcal/kg actual weight per day) were given for up to 14 days with both groups receiving 2 g/kg ideal body weight of protein. Nitrogen balances were similar, but glucose control was improved and less exogenous insulin was necessary with the hypocaloric regimen.55
Free fatty acids are the primary energy source utilized during stress and sepsis. Lipolysis and mobilization of free fatty acids is enhanced by beta-adrenergic stimulation of lipases and hormone-sensitive tissues as fatty acid oxidation increases. The administration of glucose as calculated above can provide approximately 50–60% of total caloric requirements; the balance of nonprotein calories (NCPs; 20–30% of total calories) can be met by fat at a dose of 1 g/kg per day. Infusion rate for lipids should not exceed 0.11 g/kg/hr. In patients in whom ventilator weaning is an important issue, administration of fat as total calories up to 50% may be beneficial in selected patients. Increased CO2production is rarely a cause of weaning problems in trauma patients except, perhaps, in geriatric patients following flail chest injuries or those with prolonged recovery. Trauma patients with moderate to severe chronic obstructive pulmonary disease (COPD) who have trouble weaning from the ventilator may benefit from a diet higher in fat. If overfeeding is suspected, reduction in total calories administered is the most appropriate intervention. Higher doses of fat may also be useful in hyperglycemic patients as a result of diabetes or corticosteroid administration. This may cause hyperlipidemia, cholestasis, increased risk of infection, and perhaps immunosuppression. All lipid emulsions available in the United States are vegetable oils, which provide mainly omega-6 long-chain PUFAs; these may increase production of immunosuppressive prostaglandins and leukotrienes. Currently, structured lipids containing both omega-6 and medium-chain triglycerides as their primary fatty acid side chains are being tested as are intravenous fats with omega-3 fatty acids. Additional immunosuppression may come from blockade of the reticuloendothelial system by lipid particles. Omega-3 fatty acids from canola or fish oil are found in most enteral products; these can be metabolized to the less immunosuppressive 3 or 5 series of prostaglandins. Omega-3 PUFAs may increase the production of lipid peroxidases and inhibit platelet aggregation, but these concerns have not appeared to be of clinical significance.
Several investigators have determined the maximum hydrolysis rate for intravenous lipids by LPL in normal adults to be approximately 0.12 g/kg/hr (2.9 g/kg per day); above this infusion rate emulsion triglyceride particles begin to accumulate. Intravenous lipid emulsion in the critically ill adult below this infusion rate is recommended in order to avoid elevated triglyceride concentrations and other metabolic complications. Doses of intravenous lipids should be limited to the provision of essential fatty acids (e.g., 250 mL of 20% lipid emulsion once or twice weekly) when triglyceride concentrations rise above 400 mg/dL. Withholding intravenous lipids must be considered when triglyceride concentrations are greater than 500 mg/dL or in the presence of lipemic serum.
Skeletal muscle loses considerable mass as amino acids are redistributed for healing wounds, acute-phase proteins, and substrate for lymphoid tissue and the GI tract. Overall, nitrogen is lost through ureagenesis by the liver and ammonia synthesis by the kidney. Immobilization aggravates the loss. Total protein catabolism exceeds synthesis, which leads to loss of function and potential morbidity and mortality. Unfortunately, this hypercatabolism and lean tissue loss is not blunted by the administration of exogenous calories or amino acids.
In general, the recommended dose of amino acid protein for stressed or septic patients without renal dysfunction is 1.5–2 g/kg per day. Although blood urea nitrogen (BUN) may increase to approximately 40 mg/dL, these levels cause no metabolic complications and BUN generally stabilizes at that level. If urea levels climb to greater than 100 mg/dL, protein administration must be reduced. If creatinine levels are low, that is, no evidence of acute renal failure (ARF), and elevated BUN appears due to excessive protein (or amino acid) administration, protein should be decreased to 1.3–1.5 g/kg per day. As the stress phase resolves, 1–1.5 g/kg per day of protein meets nutrient requirements in most patients. In burn patients, administration of 2–2.5 g/kg per day is desirable due to excessive urinary losses and the inability to accurately assess wound losses of nitrogen.
Patients who develop ARF secondary to injury/hypotension still require high doses of protein for wound repair; however, it is practical to provide only 0.8–1.0 g/kg per day of protein until a decision on initiation of dialysis is made. Once dialysis has been initiated, the type and frequency will dictate how much the protein dose can be liberalized. Generally, 1.2–1.5 g/kg per day can be administered to a patient receiving hemodialysis three times a week (assuming that the hemodialysis is effective). Patients who cannot tolerate hemodialysis secondary to hypotension may receive continuous arterial venous hemodialysis (CAVHD) or continuous venovenous hemodialysis (CVVHD). These methods of dialysis provide the critical care practitioner volume to administer PN with nonconcentrated formulas, and protein can usually be administered as high as 2.5 g/kg per day if indicated.
Caloric density for nutrients is as follows: 1 g protein equals 4 kcal, 1 g of hydrated glucose equals 3.4 kcal, and 1 g of fat (as an enteral form) equals 9.1 kcal, but 1 g of lipid emulsion contains 10 kcal/g because of glycerol contained within the emulsion. In patients who are not critically ill or septic but at risk of developing starvation-induced malnutrition if not fed (e.g., small bowel obstruction, prolonged intestinal paresis, multiple small bowel fistulas), a calorie:nitrogen ratio between 130:1 and 160:1 is appropriate, and protein should be administered at a dose of 1–1.5 g/kg per day. In patients who are stressed or septic, however, the calorie:nitrogen ratio should drop to 80:1 to 120:1. The goal in the stressed or septic patient is approximately 30 kcal/kg total with 1.5–2 g/kg per day of protein. In burn patients, protein is administered with approximately the same low calorie:nitrogen ratio, providing 35–40 kcal/kg per day total and 2–2.5 g/kg per day of protein. Refer to Figure 60-3 for sample calculations of a PN formulation involving a 70-kg trauma patient.
Example: 70-kg man sustaining severe multiple long-bone fractures
Estimated kcal: 30 kcal/kg per day × kcal/day
Protein: 1.5 g/kg per day × 70 kg = 105 g/day
For 2-in-1 (dextrose/amino acid) formulation:
Using a 70% dextrose (D70W) stock solution for compounding:
Solving for x yields approximately 714 mL of D70W
Using a 10% amino acid (AA10) stock solution for compounding:
Solving for x yields 1050 mL of AA10%
Total kcal from regimen: 500 g × 3.4 kcal/g + 105 g × 4 kcal/g = 1700 + 420 = 2120 kcal
Calculation of administration rate: 714 mL dextrose + 1050 mL AA = 1764 mL AA = 1764 mL/day + 50 mL for additives = 1814 mL/day
OR using final concentrations
30 mL/kg per day × 70 kg = 2100 mL/day to meet maintenance IV fluid requirements
Solving for × yields 23.8% or approximately 25% dextrose. Protein calculation:
For 3-in-1 (dextrose, amino acid, lipid) formulation:
Estimated kcal: 30 kcal/kg per day × 70 kg = 2100 kcal/day
Lipid provision = 20% total kcal = 0.2 × (2100-2450)
= 420-490 kcal/day
Using a 20% lipid emulsion (which provides 2 kcal/mL):
Solving for total grams of lipid:
Solving for x yields 42 g lipid emulsion
Using final concentrations:
FIGURE 60-3 Calculation of PN formulation.
Fat can be used to displace glucose calories and, in fact, should meet 20–30% of total calories. Figure 60-3 illustrates how intravenous fat would be incorporated into PN formulation for the 70-kg trauma patient used in the first example. The issues are much simpler with enteral formulas, since labels contain the calorie:nitrogen ratio, allowing clinicians to determine the appropriate patient population for use. Enteral products with a calorie:nitrogen ratio between approximately 130:1 and 170:1 should be used in nonstressed patients who are malnourished or at risk of becoming malnourished, while solutions with a calorie:nitrogen ratio of 80:1 to 110:1 should be used in stressed or septic patients. Particular care should be taken, however, with the IEDs, which, because of their supplemental GLN and/or arginine and/or BCAA, have a much lower calorie: nitrogen ratio, in the range of 55:1 to 60:1. Although this would seem to provide either too few total calories or too much nitrogen for the stressed patient, the additional benefits that are gained in severely injured trauma patients with these formulas would warrant their administration in select cases. In these situations, patients are usually provided 2–2.2 g/kg of protein or amino acid (0.32–0.35 g/kg per day of nitrogen), with NCPs of approximately 20 kcal. Using these formulations, BUN often rises to 50 mg/dL but rarely higher unless there is compromised renal function.
Acute Renal Failure (ARF)
In some patients with climbing BUN and creatinine levels, it is unclear whether the changes are due to volume deficits or renal dysfunction. ARF can be confirmed by calculating the fractional excretion of sodium (FeNa) obtained from a urine specimen in the following equation:
where UNa is the urine sodium concentration, V is the urine volume, PNa is the plasma sodium concentration, Ucr is the urinary creatinine concentration, and Pcr is the serum creatinine concentration. A FeNa less than 1% reflects a reabsorption of sodium of more than 99%, suggesting an adequate renal response to hypovolemia, renal hypoperfusion, and other nontubular disorders. Damage to the renal tubules reduces the ability of the kidney to resorb sodium, and the FeNa is then usually 2–3% or greater. Calculation of the FeNa minimizes effects of inappropriate ADH, hypovolemia, or low-flow states such as congestive heart failure on variability in water and sodium absorption not due to renal dysfunction. Because of associated injuries, the hormonal milieu, and immobilization, the rate of urea accumulation is increased in these patients, compared with those suffering from chronic renal disease. A convenient method to determine urea loads, the urea nitrogen appearance (UNA), can be calculated by the following equations:
where i and f are the initial and final values for the period of measurement and SUN is the serum urea nitrogen in grams per liter. BW is body weight in kilograms, and although 0.6 is the usual number to estimate the fraction of body weight that is body water in health, following trauma, body water compartments are expanded and as much as 80% can be total body water. When dialysis is started:
UNA (g per day) = urinary urea nitrogen (g per day)
+ dialysis urea nitrogen (g per day)
+ change in body urea nitrogen (g per day).
In contrast, no benefit has been shown from protein restriction in ARF and prolonged delivery of such regimens may actually increase skeletal muscle protein breakdown. Before dialysis is started, patients should receive a normal dose of total calories and a protein dose ranging from 0.8 to 1 g/kg per day. Specialized, essential amino acid solutions have not been shown to be of benefit, and a standard mixture of amino acids can be used 56 Often both serum potassium and phosphate concentrations drop from abnormal or high normal ranges to normal ranges with the institution of PN; potassium, phosphorus, and magnesium should not be added to PN initially but supplemented as necessary over time. If the ARF is short lived, this therapy may avoid dialysis completely, particularly if the renal failure is nonoliguric. At approximately 90 mg/dL, urea exerts toxic effects on platelets. After hemodialysis is started, protein administration can be increased to 1.2–1.5 g/kg per day. Alternative renal replacement therapies such as continuous venovenous hemofiltration (CVVH), CVVHD, and continuous venovenous hemodiafiltration (CVVHDF) usually necessitate a higher protein intake (1.5–2.5 g/kg per day) due to considerable loss of amino acids with the dialysate.
As the kidneys recover, 3–5 L of urine per day may be excreted, and urinary output should be replaced with appropriate fluids. With resolving ARF, urine has 70–80 mEq of sodium/L, and the most commonly used fluid for replacement is 0.45% saline. A urine sample should be sent for electrolyte analysis. As SUN drops to 60 mg/dL or less, urinary replacement can be stopped. The urea has little osmotic effect and renal function has usually recovered adequately. Higher levels of SUN (i.e., greater than 80 mg/dL) act as an osmotic drag and, without fluid replacement, cause hypovolemia and recurrence of oliguric renal failure.
Although considerable attention has been drawn to avoiding overfeeding of patients with pulmonary dysfunction, overfeeding and lipogenesis with increased CO2 production rarely poses clinically significant problems in trauma patients. Usually, multiple rib fractures, pulmonary contusion, pneumonia, closed head injury, or spinal cord injuries delay weaning. Selected patients, who have been chronically intubated but require a low rate of ventilator support, may benefit by increasing fat as a percentage of total calories. A typical example is a geriatric patient with multiple injuries and chest trauma who has been weaned to a rate of 2–4 over several weeks but cannot tolerate prolonged continuous positive airway pressure or tracheostomy collar. Usually GI function is normal and transitioning to a high-fat enteral formula providing 1 g/kg per day of protein and a calorie:nitrogen ratio of approximately 120:1 with 40–50% of the calories as of fat may help.
Several trials support the use of an enteral feeding formula containing eicosapentaenoic acid (EPA), gamma-linolenic acid (GLA), and antioxidants for patients with acute respiratory distress syndrome (ARDS). Omega-3 fatty acids such as EPA have anti-inflammatory effects. GLA may also work to decrease inflammation, by suppressing the synthesis of leukotrienes and pushing the prostaglandin cascade toward less inflammatory compounds. Pacht et al. show that a diet enriched with EPA + GLA and antioxidants decreases levels of inflammatory cytokines in the respiratory tract.57 Singer et al. enrolled ventilated patients with acute lung injury and randomized them to receive a standard enteral diet or one enriched with GLA, EPA, and antioxidants.58 The primary outcome measures were oxygenation and respiratory mechanics. Significant results include better oxygenation in the EPA + GLA group on days 4 and 7, defined as higher Pao2/FiO2 ratios (day 4 values: 317.3 ± 90.5 in the EPA + GLA group vs. 214.3 + 56.4 in the standard diet group), P <.05. Length of ventilation, in hours, was significantly lower in the EPA + GLA group, 160.4 ± 15.2 versus 166.8 ± 5.2 in the standard diet group, P < .03. It is questionable whether this statistical significance translates into clinical significance. Finally, Pontes-Arruda et al. compared a formula with EPA + GLA and antioxidants with a standard diet in patients newly diagnosed with sepsis and septic shock requiring ventilator support.59 This trial shows a significant reduction in mortality rate, significant improvements in oxygen status, and more ventilator-free days when EPA + GLA is used compared with a standard diet. The EPA + GLA diet has promising results, but has not been trialed in large and varied populations of patients.
Following trauma, the onset of hepatic failure with MODS carries a dismal prognosis. Very few nutritional manipulations influence outcome. Excessive protein restriction should be avoided. Intravenous amino acid solutions are better tolerated (e.g., 1–1.5 g/kg per day) than the enteral protein, and high levels of glucose should be avoided. The onset of hypoglycemia with severe hepatic failure represents final stages of systemic failure. Although high branched-chain formulas specific for hepatic dysfunction are commercially available, the desperate clinical situation of severe hepatic failure usually does not warrant their usage. Unless some etiologic cause—such as sepsis, acalculous cholecystitis, or obstructive biliary pathology—can be identified and successfully treated, nutritional support probably has little bearing on the outcome from hepatic failure in trauma patients.
FLUID AND ELECTROLYTES
In the first 48 hours, lactated Ringer’s solution is the principal fluid given in the ICU. Initial expansion of both intracellular and extracellular water occurs as part of the neuroendocrine response to injury. During the hypercatabolic phase, the intracellular water and associated electrolytes (in particular potassium, magnesium, and phosphorus) associated with catabolism of protein are released into the extracellular space. As the catabolic phase improves and cells regain the ability to respond to exogenous nutrients, intracellular electrolytes associated with cytosolic fluid expansion must also be replaced or cell growth does not occur and a “refeeding syndrome” develops, which severely depresses serum potassium, phosphate, and magnesium levels. Since many of these severely injured trauma patients are intubated, respiratory muscle weakness may not be noted, but hypokalemia can reduce the effectiveness or increase the toxicity of various cardiac medications. Severe problems rarely develop if electrolytes are closely monitored and can be treated quickly if they occur.
The most common electrolyte problems noted in trauma patients are derangements in sodium. While diabetes insipidus or inappropriate ADH may occur with head injuries, producing hypernatremia and hyponatremia (see Chapter 19), respectively, the most common cause for abnormalities in sodium levels is an excess in sodium administration, fluid restriction in closed head injury patients, or administration of large volumes of fluid containing low sodium. In the first case, prolonged use of normal saline or lactated Ringer’s as a maintenance fluid in association with other hidden sources of sodium administered through multiple antibiotics, H2 blockers, etc., in saline produces a gradual and progressive hypernatremia. Many antibiotics contain large amounts of sodium, and since specific admixtures for medications are rarely ordered, intravenous “piggybacks” can reach 2–2.5 L per day in some patients. If this is administered in normal saline, hypernatremia develops. Likewise, if medications are mixed in 5% dextrose and water, significant hyponatremia develops (probably the most common etiology of hyponatremia in our ICU).
Assessment of volume status in concert with the low serum sodium concentration will usually identify the patient as hypovolemic, isovolemic, or hypervolemic. Hypovolemic patients usually respond to normal saline or lactated Ringer’s infusions. If losses of fluid are chronic and similar to serum (e.g., ileostomy losses), additional sodium may be needed in the nutrient solutions. Isovolemic, hyponatremic patients often need little treatment beyond increasing the sodium content in intravenous fluids. In severe cases where urine sodium is elevated at 100–200 mEq/L, restriction of free water is necessary by decreasing fluid administration and concentrating the nutrient solution. This problem is most commonly seen with severe head injury or pneumonia and resolves as the patient recovers. Hypervolemic, hyponatremic patients should have nutrient formulas concentrated as much as possible. Other therapy such as diuretics may occasionally be needed.
A less common cause of hyponatremia after trauma is inappropriate ADH secretion (see Chapter 19). It is usually associated with central nervous system (CNS) effects induced by head injury, meningitis, subarachnoid hemorrhage, anesthetics, meperidine, carbamazepine, or tricyclic drugs. In addition, a decrease in the vascular volume, secondary to use of diuretics in patients who are on high levels of PEEP or have large fluid losses from the GI tract, open abdominal wounds, etc., can also lead to increased ADH secretion and increased sodium loss. Typically, serum chloride concentrations decrease with the hyponatremia, and a hypokalemic metabolic alkalosis with a high serum bicarbonate occurs, especially when diuretic-induced. The diagnosis of inappropriate ADH is made by a combination of hyponatremia, a decrease in serum osmolality, a urine osmolality that is elevated relative to serum osmolality, a urine sodium greater than 20, and, if measured, an increase in ADH. Because of the effect of ADH on the kidney, water is absorbed without sodium so that urine sodium and tonicity are high relative to serum. The appropriate therapy is water restriction.
Hypernatremia is also relatively common in the critically ill trauma patient, especially in patients with severe head injury, where a mild hyperosmolar state is often used to decrease intracranial pressure (see Chapter 19). After bedside assessment, most of these patients can be categorized as hypovolemic, isovolemic, or hypervolemic. Patients with hypovolemic hypernatremia are usually treated with lactated Ringer’s solution first to ensure adequate organ perfusion, and then with solutions containing substantial free water (e.g., D5W, 0.22% or 0.45% sodium chloride injection). During free water administration, it is appropriate for the sodium to be reduced in the nutrient solution. Patients with isovolemic hypernatremia usually need free water and sodium should be removed from the PN. Patients with hypervolemic hypernatremia should have intake minimized by concentrating the nutrient formula. Exogenous sodium should be eliminated from PN, medications, and other infusions to the extent possible.
Hypokalemia is very common after trauma, especially in patients with normal renal function who require aggressive resuscitation with crystalloid. Loss of GI fluids rich in hydrogen and chloride aggravates this hypokalemia. Patients with prolonged nasogastric suction will lose considerable HCl resulting in metabolic alkalosis and substantial renal wasting of potassium. Drug therapy with loop diuretics, amphotericin B, antipseudomonal penicillins, and corticosteroids has been reported to aggravate renal wasting of potassium. Other drugs, such as inhaled beta-agonists (e.g., albuterol) and insulin, drive potassium into the cell also resulting in hypokalemia in some patients. All the above conditions will require additional potassium added to the nutrient solution above the standard of 30–40 mEq/L that is commonly used in PN or present in enteral formulas. Occasionally, up to 120 mEq of potassium/L must be added to nutrient solutions of patients who were receiving three or four of the above-mentioned drugs to keep them in potassium balance.
Body potassium needs are not proportionate to serum levels. Each 0.25-mEq drop in serum potassium levels between 3.0 and 4.0 mEq/L represents a 25- to 50-mEq deficit in total body potassium. Between 2.5 and 3.0 mEq/L, each 0.25-mEq drop represents an additional 100- to 200-mEq deficit, which must be replaced to avoid precipitous drops with refeeding.
Hyperkalemia is less common than hypokalemia after trauma, and is usually associated with compromise in renal function. In general, hyperkalemia from ARF warrants potassium removal from the nutrient solution. Once levels have decreased to 4.0 mEq/L, potassium should be added back in modest doses (e.g., 10 mEq/L). Other causes of hyperkalemia are hemolysis of the blood sample and drugs known to cause this disorder, even when renal function is normal. Most laboratories will identify hemolyzed samples that do not require treatment other than repeat analysis. Heparin and trimethoprim have been reported to cause hyperkalemia in patients. Heparin is an aldosterone antagonist that causes sodium wasting and potassium retention. This drug–nutrient interaction occurs with both systemic and low-dose heparin, especially in patients with diabetes and chronic renal dysfunction. Trimethoprim is a component of the combination product of trimethoprim/sulfame-thoxazole used frequently for gram-negative systemic infections. It is a weak diuretic with potassium-sparing activities. Patients who experience these interactions should have potassium decreased in the nutrient solution, even when renal function is normal.
Hypophosphatemia is a common metabolic complication of critically ill patients receiving nutritional support. While most practitioners add phosphorus to PN solutions routinely, several patient populations require greater amounts, including patients with a history of alcohol abuse, poor nutritional status pre-injury, or chronic use of antacids or sucralfate. Even when serum phosphorus concentrations are monitored closely, hypophosphatemia occurs in approximately 30% of patients receiving PN. Treatment of hypophosphatemia is dictated by the severity, and intravenous replacement doses are most frequently used. The enteral route should be considered in mild cases of hypophosphatemia by adding 5–10 mL of Fleet’s phosphosoda to each liter of the enteral formula in patients requiring additional phosphate. In patients requiring both potassium and phosphate, potassium phosphate (usually 15–22.5 mmol/L) can be added to the formula. For isolated potassium depression, potassium chloride can be added to the enteral formula. Brown et al. have developed a graduated dosing scheme for replacement of phosphorus in patients receiving specialized nutrition support (i.e., either PN, enteral nutrition, or both) based on the serum phosphorus concentration of the patient:60
Additional phosphorus can be added to the PN or enteral formula following correction of initial hypophosphatemia.
Hyperphosphatemia is much less prevalent than hypophosphatemia in trauma patients and is usually associated with renal compromise when it does occur. Phosphorus should be decreased or removed from the nutrient solution.
The development of hypomagnesemia is underappreciated. Magnesium is rapidly depleted in stress, particularly when diuretics and antibiotics such as aminoglycosides are administered. Dysrhythmias, hypocalcemia (an unusual problem in trauma patients), and irritability are avoided with magnesium monitoring and appropriate treatment. Patients with a history of alcohol abuse or lower GI losses, such as diarrhea, are particularly prone to develop hypomagnesemia. Amphotericin B, aminoglycosides, and loop diuretics (and in addition cisplatin and cyclosporine) have all been reported to cause renal wasting of magnesium. Intravenous magnesium replacement therapy is usually necessary in patients with moderate to severe magnesium deficiency due to poor absorption of oral magnesium salts. Magnesium has a renal tubular threshold similar to glucose, so rapid administration over a short period of time will invariably result in high urinary losses. We have developed a weight-based dosing regimen for magnesium deficiency in which intravenous doses are infused slowly over 12–24 hours to facilitate better retention:
Magnesium status should also be considered in evaluating a hypokalemic patient, as magnesium is an important cofactor for the Na/K-ATPase pump. We often administer magnesium replacement therapy for low-normal serum magnesium concentrations in the presence of hypokalemia, because magnesium is an intracellular cation and serum concentrations may not accurately reflect intracellular status. Our standard magnesium concentration in PN solutions is 12 mEq/L; however, some patients as described above need increased doses. We have safely administered as high as 28 mEq/L via PN in selected patients. Hypermagnesemia usually occurs in association with renal dysfunction or failure. Magnesium should be removed from the PN of these patients.
Electrolyte Management in Severely Injured Trauma Patients
Table 60-3 shows the composition of the various GI secretions that must be considered in fluid and electrolyte balance of patients. Two values are given for potassium in gastric drainage, 10 and 40 mEq; NG drainage contains approximately 10 mEq/L, but because of hydrogen loss, gastric loss should be calculated as 40 mEq/L because of increased renal potassium excretion. In the overall management of critically injured patients, unusual fluid losses in significant quantity (>500 mL per day) through such sources as duodenal fistulas, pancreatic fistulas, or high small bowel fistulas should be sent for electrolyte analysis and appropriate adjustments made in intravenous nutrition to account for the excessive losses. It is often helpful to calculate sodium balance by comparing losses with administered intake considering all intravenous solutions and admixtures. Most cases of hyponatremia are due to significant discrepancies (often 600–800 mEq per day) between the sodium administered and the sodium lost. There are several rules of thumb in fluid management of complex trauma patients. Gastric drainage should be replaced with 0.45% sodium chloride with 40 mEq of potassium chloride/L to avoid hypokalemia, hypochloremia, and metabolic alkalosis. Fluid losses from the GI tract distal to the pylorus, including the liver and pancreas, have a sodium of approximately 130–140 mEq/L. Losses of associated bicarbonate and chloride vary, depending on the organ. Bicarbonate is equivalent to serum in bile and small bowel fluids, and the appropriate replacement fluid for them is lactated Ringer’s. High-output pancreatic fistulas produce bicarbonate loss (80–90 mEq/L) and an appropriate replacement fluid (greater than 300 mL per day) is 0.2 sodium chloride with two ampules of sodium bicarbonate.
TABLE 60-3 Electrolyte Composition of Gastrointestinal Secretions: Average (Range)
Standard adult electrolyte requirements for PN are provided in Table 60-4 with adjustments as necessary, depending on unusual losses. Sodium can be administered as the chloride, acetate, or phosphate salt depending on needs. Generally, chloride salts are used for patients with metabolic alkalosis and acetate salts for metabolic acidosis. Patients with severe edema or anasarca generally should receive a sodium-free PN solution. Most enteral formulas have 30–40 mEq of sodium/L (i.e., approximately 0.2 saline) that should be considered in the overall fluid management. Like sodium, potassium is available as the chloride, acetate, or phosphate salts. Calcium is usually administered as the gluconate salt in PN because it is more stable and less likely to precipitate with phosphorus. Magnesium is generally given as the sulfate salt in PN. Significant fluid and electrolyte disorders are unusual unless supplemental fluids administered through admixtures to drugs are ignored.
TABLE 60-4 Electrolytes in Total Parenteral Nutrition
ISSUES OF RELEVANCE TO ENTERAL FEEDING
Patients Requiring Celiotomy
Early enteral feeding of severely injured patients reduces septic complications compared with starvation or PN, but several principles (Table 60-5) must be appreciated to avoid unacceptably high complication rates. First, ISS and ATI can identify patients benefiting from early feeding using the previously noted algorithm. Second, safe effective access should be obtained beyond the ligament of Treitz, using an NCJ, TGJ, or nasoenteric tube advanced during celiotomy. While direct small bowel access is usually successful, a recent study showed an unusually high incidence of complications.61 This section details techniques to avoid these complications. Third, an appropriate nutritional regimen should be instituted. Fourth, early small bowel feeding should be started only in hemodynamically stable patients. Finally, close monitoring and gradual advancement is paramount.
TABLE 60-5 Principles of Enteral Feeding Access
Multiple tubes are available. In general, a 5- or 7-Fr NCJ can be placed in most patients, but the life span of these devices is only about 3–4 weeks; therefore, their use should be limited to short-term enteral support. For more “permanent” access (e.g., severely injured geriatric or patients with severe closed head injury), placement of a larger (14, 16, or 18 Fr) catheter is advisable, since it can be replaced after 5–7 days, if necessary. Finally, a TGJ is helpful in patients requiring prolonged gastric drainage as well as small bowel feedings. They are also useful when surgeons prefer not to cannulate the small bowel directly.
Certain instances mandate specific tubes. The 5-Fr NCJ tube tolerates most standard enteral products, including those containing fiber, and its use need not be limited to defined-formula elemental diets. Fiber reduces diarrhea in critically ill patients. Bacteria metabolize soluble fiber to short-chain fatty acids that provide energy to the colonocyte for sodium and water reabsorption. 5-Fr NCJ tubes clog if protein supplements are added to standard enteral formulas or when IEDs are used. For these circumstances, a 7-Fr NCJ or larger-diameter catheter should be used. Medications should not be administered via NCJs, since the elixirs containing medication such as theophylline, potassium chloride, etc., coagulate the tube feedings to produce early tube loss. In general, an NCJ should be used only for the enteral formula.
Placement of jejunostomies is critically important. A site should be chosen with a long mesenteric loop to avoid traction by the afferent limb from the fixed ligament of Treitz, should distention occur. In all circumstances, we recommend creating a Witzel tunnel around the tube with five 3-0 silk sutures placed approximately 1 cm apart, leaving the needle on the first, third, or fifth suture. The sutures creating the Witzel tunnel should loosely approximate the bowel around the tube to prevent tearing if significant edema occurs in the bowel wall. If the bowel is too edematous or indurated to create a lax Witzel tunnel around a 16- or 18-Fr tube, an NCJ can be used. Another form of access should be chosen if bowel is too indurated to create a Witzel tunnel around an NCJ. The Witzel tunnel eliminates dislodgment of the tube into the peritoneal cavity. The jejunostomy should exit the peritoneal cavity at the lateral aspect of the rectus sheath. Placement at or lateral to the rectus sheath—most commonly on the left side, but acceptable on the right side if a stoma is necessary in the left upper quadrant—minimizes the chance of volvulus of intestine over the attachment point. Placement near the midline incision also interferes with reexploration. Finally, the jejunostomy itself, particularly an NCJ, should not be brought out at a 90° angle through the abdominal wall to avoid kinking the tube as it exits the fascia. The externalized jejunostomy tube should be kept short, less than 3–4 cm, and anchored securely to the anterior abdominal wall. A transparent dressing over the catheter prevents disoriented patients from pulling and dislodging the jejunostomy.
If prolonged gastric drainage is likely, TGJ allows gastric decompression and direct small bowel feeding. The distal limb of the TGJ should lie beyond the ligament of Treitz and not in the duodenum. Intraduodenal feeding with shorter tubes stimulates pancreaticoduodenal and gastric secretions, which can result in fluid and electrolyte problems. Nutrients introduced beyond the ligament of Treitz do not stimulate significant upper GI secretion. A note of caution with TGJs is in order. The gastroesophageal junction is the most dependent part of the stomach in supine patients and the stomach should be decompressed with an NG tube until the patient can be elevated to 30–40° to avoid reflux and aspiration.
As a final technique for small bowel access, long tubes can be advanced through the nose or mouth into the proximal small intestine at celiotomy. Although some institutions successfully use this technique, it requires close vigilance by nursing staff during routine patient care, transport, or ambulation.
DIET CHOICE BY THE ENTERAL ROUTE
Several clinical trials support the use of an IED in patients at high risk of developing sepsis (ATI ≥25, ISS >20; Fig. 60-1). Some powdered diets, such as Immunaid, contain free l-GLN in addition to omega-3 fatty acids, nucleotides, BCAAs, and arginine. Liquid diets such as Perative do not contain such free GLN because of the instability of that amino acid in liquid form. A recently introduced enteral liquid product has higher levels of GLN in the protein component. Liquid diets may contain soluble fiber, which serves as an energy source for enterocytes after metabolism by endogenous bacteria to the short-chain fatty acids, acetoacetate, butyrate, and propionate. In our experience, the IEDs should be administered through larger-bore catheters, such as the 7-Fr or larger NCJ, since increased clogging occurs in the 5-Fr NCJs.
In less severely injured patients, a nonprotein calorie:nitrogen (NCP:N) ratio of approximately 80:1 to 120:1 increases the protein loading without a high NPC:N load. Chemically defined diets are not mandatory, although they are still frequently used and provide an adequate nutritional substrate. Chemically defined diets are often associated with a higher incidence of diarrhea due to their high osmolarity and lack of soluble fiber. Fiber-containing diets are not contraindicated in critically ill patients; in our experience, diarrhea is reduced by their use, although impaction may occasionally mimic bowel obstruction. Typically, if intragastric feedings are being given, impaction presents as distention without high gastric residuals. The diagnosis is made by recognizing colonic distention in an x-ray. Most patients respond to colonic stimulation with enemas or suppositories. Recent reports suggest neostigmine to stimulate colonic motility but bradycardia and hypotension may occur.
If the patient improves but continued enteral feeding is necessary due to prolonged inability to take an ad libitum diet, the NPC:N should be increased to 130:1 to 160:1 and protein administration reduced to 1.2–1.5 g/kg. Total calories are given in the range of 20–25 kcal/kg per day. In diabetic patients, a formula with a higher percentage of fat may reduce hyperglycemia if hypertriglyceridemia is not a problem. In the occasional, rare patient who cannot be weaned from low levels of ventilator support, transition to a higher-fat diet may improve weaning, although this scenario is very uncommon in young trauma patients.
Diet advancement requires close monitoring. Direct small intestinal feeding should be delayed if multiple blood transfusions, fluid boluses, or pressor agents (other than low-dose dopamine) are required to maintain hemodynamic stability. Enteral feeding increases splanchnic blood flow and increases splanchnic metabolic rate. Shock, sepsis, and hemodynamic instability shunt blood away from the GI tract, and it is presumed that inability to shunt blood to the mucosa may be the cause of feeding-related small bowel necrosis. Evidence of adequate splanchnic perfusion includes adequate urine output, hemodynamic stability, warm peripheral extremities, etc.
Progression is determined by the type of formula. Protocols have been defined for progression of defined-formula diets (Table 60-6). More complex diets should be started at 15 mL/h for the first 6–8 hours in patients who were previously unstable or in shock. Diets can be advanced after 6–8 hours to 25 mL/h and at increments of 25 mL/h per day depending on tolerance.
TABLE 60-6 Protocol for Advancement of Chemically Defined Diet by Jones and Moore
Moore et al.14 advanced patients with less severe injuries (i.e., an ATI >40 and no bowel injury) to goal rate within 48 hours following institution of a chemically defined diet. Patients with an ATI >40 or bowel injuries had increased bloating, cramps, and general intolerance when advanced this quickly and should be advanced more slowly, generally by 25 mL/h per day, up to the calculated goal rate, while being observed for intolerance. In our experience, approximately 50% of severely injured patients can be advanced up to or close to the goal rate within 3–4 days with few, if any, problems. Approximately 10% of patients do not tolerate feedings at all, with intolerance manifest by reflux of feedings into the stomach (which necessitates the immediate discontinuation of direct small bowel feedings), significant bloating, or complaints of cramps. The remaining 40% of patients generally tolerate feedings to approximately 50–75% of goal but develop temporary (2–3 days) intolerance, such as discomfort or diarrhea, at higher rates. Tube feedings should be slowed to the tolerated rate for 24–48 hours and then advanced. If patients tolerate at least 50% of goal rate, we do not add PN. In the minority of patients with complete tolerance, however, PN should be instituted by the fourth or fifth day, with transition to enteral feedings as soon as possible. Once PN is started, it is not weaned until patients tolerate at least 50% of the goal enteral rate and feedings are being advanced to 75% of the calculated rate.
Gastroparesis is manifested by high aspirated residual volume (>150 mL) and is one of the more troublesome GI complications. The nurse should check gastric residuals every 4–6 hours to assure that gastric residuals remain low. Acutely elevated residuals in patients who previously tolerated a high rate indicate ileus from a septic process or acute stress ulceration. Evidence of upper GI bleeding (coffee-grounds aspirate or obvious bleeding) warrants early endoscopy because of a high rate of duodenal or gastric ulceration, especially following spinal cord injuries, severe head injuries, or burns.
With gastroparesis persistent beyond 3–4 days, most practitioners use a prokinetic agent to enhance gastric emptying. The three drugs used most commonly in the critical care setting are metoclopramide, cisapride, and erythromycin. Metoclopramide is available as a tablet, syrup, or intravenous solution in the United States and is a selective dopamine-2 agonist that enhances peristalsis contractility of the esophagus, gastric antrum, and small intestine. Metoclopramide enhanced gastric emptying of acetaminophen in trauma patients and reduced time to maximal plasma concentration compared with erythromycin or placebo.62 Cisapride is no longer available in the United States because it was associated with events of cardiac arrhythmia.
Erythromycin is available as a capsule, suspension, or intravenous solution acting locally to enhance motilin release from enterochromaffin cells of the duodenum. Motilin enhances contractile activity of the gastric antrum and duodenum. Compared with placebo, erythromycin significantly increased the frequency of gastric contractions, amplitude of contractions, and the motility index. The time to reach the maximal concentration of acetaminophen (gastric emptying marker) was also shortened when compared with the placebo group in this one-dose study involving 10 critically ill patients receiving mechanical ventilation.63 In healthy volunteers, both total gastric volume and gastric volume of a continuous liquid meal decreased by 22% in patients receiving erythromycin versus placebo.
The most recent data show that using erythromycin and metoclopramide in combination is more effective in improving gastric motility than erythromycin alone. When patients were fed via a nasogastric tube, the combination prokinetic therapy resulted in more calories delivered and less need for placement of postpyloric feeding tubes. The most prominent side effect noted was watery diarrhea. No prolongation of QT interval was seen.64
Critically ill trauma patients receive a large number of pharmacological agents. A few agents influence the designing of the nutritional formula. Propofol, commonly used for sedation, is manufactured in a lipid emulsion that provides 1.1 kcal/mL. Clevidipine, an intravenous calcium channel blocking agent, is also delivered with a lipid emulsion and contains 2 kcal/mL. The caloric contribution from the lipid vehicle is negligible in small doses; however, it becomes very important with higher rates of infusion. The nutritional prescription should be modified by decreasing or eliminating lipids from the parenteral solution or by using a high-protein enteral formula with added protein powder to provide an appropriate mix of carbohydrate, fat, and protein.
Enteral nutrition influences effectiveness of drugs such as the antiepileptics, phenytoin, or carbamazepine, when given via the GI tract. Phenytoin interacts with calcium or the caseinates within the formula to decrease drug absorption. Recommendations for phenytoin administration include discontinuation of tube feedings for 2 hours before and after the drug dose, dilution of phenytoin, irrigation of the tube with 60-mL flushes, and increases in the phenytoin dosage as necessary. Serum levels should be monitored during initiation of therapy or with changes in enteral nutrition. Carbamazepine absorption is slower with continuous enteral feeding and monitoring of serum levels is appropriate.
Warfarin is commonly used in the treatment of deep venous thrombosis (DVT) prophylaxis, but enteral products can interfere due to the vitamin K in the formula or through physical/chemical interaction, which impairs drug absorption. Hydralazine, ciprofloxacin, and itraconazole are affected by enteral administration when tube feedings are in progress and necessitate close monitoring.
Addition of drugs to the enteral formula can affect stability of the fat, alter viscosity, and change the consistency and particulate size of the formula. Calcium, zinc, and iron produce jelling or curdling and a number of drug products increase clumping and change viscosity due to their acidic nature. Drugs incompatible with enteral products are listed in Table 60-7.65
TABLE 60-7 Medications Incompatible with Enteral Formulation
COMPLICATIONS OF ENTERAL FEEDING
Patients should be examined 6 hours following institution of their feedings and when cramping or diarrhea occurs. Mild abdominal distention is common in fed and unfed trauma patients and discontinuation of the tube feedings for minimal symptoms is not necessary. If, however, alert patients complain of severe discomfort, the rate should be reduced if the pain is not incisional. Colonic distension secondary to constipation or impaction is likely in patients receiving intragastric feeding even with low residuals; it responds to suppositories and/or enemas. The institution and advancement of early enteral feedings into the small bowel requires that patients be examined approximately 6 hours following institution of their feedings as well as if there are any complaints of significant cramping or diarrhea.
Diarrhea occurs commonly in fed and unfed critically ill patients. In tube-fed patients, diarrhea occurs from 5% to 25% depending on the definition of diarrhea. Five to six formed or semiformed stools per day are not diarrhea. However, watery stools that constantly soil the patient during turning eventually cause irritation and skin breakdown. While tube feedings are often implicated, diarrhea is more commonly caused by medications. Twenty percent of severely injured trauma patients administered a chemically defined diet developed significant diarrhea in our study,12 which decreased to 4% with a fiber-containing diet.
Approximately three quarters of cases of diarrhea are caused by antibiotic-induced pseudomembranous enterocolitis (see Chapter 18), magnesium medications, or sorbitol.66 Sorbitol is used for sweetness or as a solubilizing agent replacing alcohol. Surprisingly large amounts of sorbitol are present in commonly administered medications (Table 60-8) such as potassium chloride, theophylline medications, phenytoin, and even antidiarrheal drugs. On occasion, prokinetic drugs successfully instituted for gastroparesis cause diarrhea that stops after discontinuation.
TABLE 60-8 Sorbitol Content of Oral Medications
Multiple antibiotics generate bacterial overgrowth and rarely pseudomembranous colitis. Proctosigmoidoscopy should be performed for suspected Clostridium difficile, particularly in guaiac-positive patients. Specimens should be sent for fecal leukocytes and the mucosa observed for pseudomembranes. In patients receiving antibiotics and enteral nutrition, C. difficile was present in over 50% of patients with diarrhea.
Patients with diarrhea should receive an isotonic formula with soluble fiber. Prokinetic agents and enteral medications are immediately discontinued and the rate of feeding reduced to 50% of the current rate. Diarrhea commonly persists for another 12 hours as the GI tract eliminates the fluid. Sigmoidoscopy is performed and stool for C. difficile is sent, if clinically appropriate. If positive, appropriate therapy is started (see Chapter 18).
Although hypoalbuminemia was implicated as an important cause of diarrhea in critically ill patients, a prospective study using peptide formulas (promoted as a benefit in hypoalbuminemic patients) in standard isotonic formulas produced no benefit in hypoalbuminemic patients67 compared with an intact protein diet. In a very small percentage of patients, many of whom are not being fed, diarrhea persists, and administration of Lactobacillus acidophilus has been successful on occasion. Safety of using probiotics in patients with central lines is controversial, as there have been several case reports of Lactobacillus bacteremia thought to be due to contamination of central catheters when the capsule was opened at the bedside for administration down a feeding tube.68 Antidiarrheal medicines, such as tincture of opium or loperamide, are used only as a last resort.
PNEUMATOSIS INTESTINALIS AND NECROSIS
Necrosis secondary to direct small bowel feedings seems to occur in hemodynamically unstable patients often on pressor. Tachycardia (≥160/min), a temperature spike to 103°F, and rapid abdominal distention are hallmarks of this devastating complication. Although the mechanism for necrosis is unclear, potential explanations include bacterial invasion of the bowel wall with mucosal necrosis, abnormal carbohydrate metabolism, or ischemia secondary to low GI blood flow. While spontaneous necrosis has occurred in unfed critically ill patients, enteral feedings are an important factor as shown by the report of necrosis following radical cystectomy and jejunostomy feeding. Necrosis of the entire small intestine developed except for the isolated ileoconduit.69
Pneumatosis intestinalis occurs in both fed and unfed ICU patients and if diagnosed necessitates immediate discontinuation of tube feedings and initiation of antibiotic therapy against both aerobic and anaerobic organisms. The use of antibiotics is debatable but probably should be instituted. Surgery is necessary in rare cases, but if necrosis is found at exploration, immediate anastomosis should be delayed for 24 hours to eliminate progressive necrosis not initially recognized.
Tube feedings should never be administered to patients with an obstruction or immediately after release of the obstruction because of the potential for necrosis. Postoperative diuresis and resolution of abdominal distention should be complete prior to instituting enteral nutrition.
Aspiration occurs in 1–70% of patients who are enterally fed; in our experience, it is uncommon in trauma patients. While some protection is probably provided by direct small bowel feeding, gastric decompression should be continued until gastric residuals drop since mortality with aspiration can be 50% or greater. Tracheostomy or endotracheal intubation with an inflated cuff does not completely protect against lethal aspiration in ventilated patients.
Monitoring of residual gastric volumes is the major watchdog to minimize aspiration with intragastric feeding. Unfortunately, the tip of the feeding tube may not lie in the pool of residual tube feeding and the gastroesophageal junction becomes the most dependent area of the stomach in the supine position. In critically ill patients, many clinicians use gastric residual volumes to gauge patient tolerance of enteral nutrition, although clinical data fail to support this practice. Our institution holds tube feedings for residual volumes of greater than 250 mL in patients with gastrostomy tubes. If a single residual is high, feedings can be replaced into the stomach and residuals checked in 2 hours. If they remain high, feedings should not be restarted. A prokinetic agent should be started if appropriate. Critically ill patients tolerating successful intragastric feeding at goal or near goal rates who suddenly develop high residual volumes may have impending sepsis or have a pyloric channel or duodenal ulcer. This is particularly common in patients with spinal cord injuries, severe closed head injuries, or burns. If the NG aspirate is guaiac-positive, upper endoscopy is warranted, particularly if there is an unexplained drop in hematocrit. More commonly, gastroparesis signals the early onset of sepsis from pneumonia, intra-abdominal abscess, or another cause of sepsis. Patients with direct small bowel access do not need residual volumes checked, but reflux of tube feeding into the stomach require that feeding be discontinued immediately since this is a reliable marker of distal bowel obstruction or significant intolerance.
Jejunostomy tube dislodgement into the peritoneal cavity or volvulus at the jejunostomy site is avoided by the surgical techniques described earlier. Complete dislodgment can be avoided by secure suture of the tube at the anterior abdominal wall and by keeping the external segment short and covered with an occlusive dressing. While complete dislodgment of a large-bore red rubber feeding tube is considered a minor inconvenience if replaced promptly with an appropriately sized catheter, dislodgment of an NCJ loses the portal for direct small bowel access. Large-bore tubes in place for at least a week can be replaced with a tube of a smaller or similar size.
Occlusion of feeding tubes is common, but this is of little significance with a 14- or 16-Fr tube, since it can be replaced. Occlusion may necessitate removal of a 5- or 7-Fr NCJ. If NCJs occlude within the first 24–48 hours, the cause is a kink at the point where the NCJ tube pierces the fascia and enters the bowel. By applying pressure with a 10-mL saline-filled syringe while gently withdrawing the catheter, the flow restarts as soon as the kink is straightened. The catheter should be withdrawn 5 or 6 cm until the catheter can be divided beyond the kink and reattached. This rarely occurs a second time. If an NCJ occludes after 2–3 weeks, flushing may temporarily open the tube, but the life span of the NCJ is limited. Fortunately, since most patients tolerate direct intragastric feeding by this time, the NCJ has served its function. No medications are permitted via an NCJ because elixirs used to solubilize medications coagulate feedings and occlude the tube. Medications given through a larger-bore catheter should be flushed with 15–20 mL fluid prior to and another 40–50 mL water or saline after administering the medication. Use of a guidewire to disimpact a tube is not advisable, since it can perforate the tube or the intestine. Special devices are marketed that can be inserted into clogged tubes. Such a device usually consists of a small catheter fitted with an adapter for connection of a syringe. Water or declogging powder can be instilled by the syringe for irrigation. Although a variety of agents (i.e., carbonated beverages, acidic juices, meat tenderizer) have been tried to restore patency to occluded tubes, a combination of pancreatic enzymes and sodium bicarbonate appears to produce the best results.
Other devices resembling soft, threaded screws have been inserted inside a large-bore gastrostomy or jejunostomy tube and rotated to bore through a clog.
Access and Monitoring of Lines
The critically ill trauma patient will require reliable venous access at all times. Therefore, most patients who are hospitalized in the ICU will already have central vein access when the decision to start PN is made. This allows for the administration of central PN, which usually includes very hyperosmolar formulas that must be diluted quickly in the vasculature. Peripheral PN has been used with some success in hospitalized patients; however, it is not frequently administered to critically ill trauma patients because of fluid considerations and the resulting thrombophlebitis necessitating frequent vein rotation to maintain the infusion. To administer adequate nonprotein energy with peripheral PN, greater than 50% of energy calories is usually given as intravenous lipid. This may result in a mixture of nutritional substrates that is not optimal for the critically ill patient.
The percutaneous subclavian vein approach is the procedure of choice for obtaining central vein access in critically ill trauma patients. Alternative methods, though less desirable, include the internal jugular vein approach and the femoral vein approach. There is an increased rate of catheter sepsis with each of these techniques and a potential risk of DVT with femoral lines. When the decision to start central PN has been made, the critical care practitioner is faced with several choices regarding access: (a) use the current central line for the provision of PN (e.g., triple-lumen catheter, Swan–Ganz catheter), (b) change the present catheter to a new triple-lumen catheter using the modified Seldinger technique with a flexible guidewire, or (c) place an entirely new central line with a triple-lumen catheter dedicating one port for the provision of PN. The method used will depend on the patient’s hemodynamic stability, the length of time the existing catheter has been in place, the condition of the site where the existing central catheter was placed (e.g., redness, swelling, gross pus), and the other fluid requirements of the patient including intravenous fluid, continuous medication drips, electrolyte boluses, and other medications and blood. An open port on the Swan–Ganz catheter can be used for PN in patients who are hemodynamically unstable. This obviates the need to subject the critically ill patient to another procedure, especially one who may have a coagulopathy. Once hemodynamic stability is achieved, the Swan–Ganz catheter should be “changed out” to a triple-lumen catheter using the modified Seldinger technique with a sterile guidewire. If there is purulence present at the central vein site or a high index of suspicion that the present catheter is infected, access at an alternative site (e.g., the opposite subclavian vein) should be strongly considered.
Placement of an indwelling central catheter does include some short- and long-term risks. Pneumothorax, hemothorax, aneurysms, arterial puncture, and nerve injury may all occur during attempted cannulation of a central vein. Subclavian thrombosis and catheter-related sepsis are major problems that occur after placement of a central vein catheter. Patients with subclavian central catheters should be observed frequently for neck swelling or complaints of stiffness to aid in the diagnosis of subclavian thrombosis. Subclavian vein thrombosis may require removal of the catheter and anticoagulation. Also, the use of catheters made of silicone or polyurethane elastomers results in less thrombogenicity than that of ones made of polyvinyl or polyethylene. Catheter-related thrombotic occlusions frequently complicate the care of central venous catheters. Catheter occlusion may occur in the form of thrombotic and nonthrombotic causes. Types of thrombotic catheter occlusions include (a) intraluminal thrombus, (b) mural thrombus, (c) fibrin sheath, and (d) fibrin tail. Intraluminal thrombus development is characterized as occurring within the lumen of the catheter. This usually presents as resistance to infusion or blood aspiration from the catheter. Inadequate flushing or blood reflux may account for this type of occlusion. A mural thrombus refers to the formation of fibrin from vessel wall injury that extends to the surface of the catheter. Clinical symptoms consistent with vascular obstruction, such as neck vein distention, edema, and pain over the ipsilateral neck, may signify the presence of this type of occlusion. Fibrin sheath formation can encase the catheter and occlude the distal tip, whereas a fibrin tail refers to an accumulation of fibrin that surrounds the end of the catheter. Thrombolytic therapy is recommended for all of the preceding types of catheter occlusion that are thrombotic in nature. Due to the unavailability of urokinase, t-PA is now the recommended agent for thrombosed catheters. A 2-mg dose of t-PA administered with a 30-minute to 2-hour dwell time has been shown to restore patency to occluded catheters. Nonthrombotic causes of occlusion can arise from precipitation of drugs, intravenous lipids, and calcium-phosphate complexes. If drug or mineral deposits are suspected, 1–3 mL of 0.1N HCl is recommended for clearance. On the other hand, if waxy lipid deposits are thought to be responsible for impaired catheter flow, 1–3 mL of 70% ethanol can restore patency. Ethanol should only be used in silicone-based catheters, as there is evidence that it might damage catheters made of polyurethane.
Other problems such as air embolism may occur at anytime if there is a central catheter present. Catheter-related infection/sepsis is always a possibility for the critically ill patient with a central vein catheter. Hyperthermia, tachypnea, tachycardia, leukocytosis with “left shift,” and the presence of shaking and chills all may occur in patients who have catheter-related sepsis. With the presence of the above signs, most practitioners would “change out” the central catheter using a sterile guidewire and culture the tip of the removed catheter, as well as a central and peripheral blood culture for definitive diagnosis. If the catheter tip grows a pathologic organism with >15 colony-forming units, the replaced catheter should be removed after obtaining central access at a new site. If catheter removal is undesirable because of limited vascular access, recommendations from the Centers for Disease Control and Prevention (CDC) are available for quantitative blood culturing techniques to assist the clinician in diagnosis of a catheter-related bloodstream infection (CR-BSI).70 Testing of paired blood samples is required. Criteria for the presence of a CR-BSI are met if the colony count obtained via the central catheter is 5- to 10-fold greater than the sample obtained from the peripheral vein.
The PN admixture is made from a complex combination of macronutrients (dextrose, amino acids, and fat emulsion), micronutrients (electrolytes, vitamins, trace elements), and water. Hydrated dextrose is the most frequently used parenteral carbohydrate in the world for the preparation of PN. Fructose, sorbitol, and xylitol are other carbohydrates that have been used with varying success in PN. Each gram of hydrated dextrose yields 3.4 kcal. Stock solutions of dextrose for the preparation of PN come in strengths varying from D10W to D70W. Many institutions that make PN solutions with an automated compounder stock only D70W because it can be diluted with sterile water for injection to make many different final concentrations of dextrose, even odd strengths such as D17W. As previously mentioned, dextrose administration in PN should not exceed 5 mg/(kg min) (approximately 25 kcal/kg per day). Many critical care practitioners administer dextrose at a slightly lower dose routinely (e.g., 3–4 mg/(kg min)) to minimize CO2 production, lipogenesis, and hyperglycemia.
Intravenous fat emulsions (IVFE) are used in PN to provide essential fatty acids and to provide another source of NCPs. The commercially available IVFE in the United States are either soybean oil emulsions or a combination of soybean/safflower oil emulsions. The current products and their pertinent characteristics are listed in Table 60-9. These products are available as 10%, 20%, and 30% IVFE. The 10% and 20% IVFE may be infused directly into a patient’s vein or added to dextrose and amino acids to make a total nutrient admixture (TNA). The 30% IVFE can only be used as part of a TNA in the United States; however, it is approved for direct vein infusion in Europe. Fat is a concentrated calorie source by providing 10 kcal/g. The maximum dose of IVFE in adults is 0.11 g/kg/hr; however, most clinicians caring for critically ill patients administer approximately 1 g/kg per day as either a continuous infusion or part of a TNA administered over 24 hours in each case. Considerable controversy exists regarding the effects of IVFE on immune function. Bactericidal and migratory functions of polymorphonuclear cells and decreased bacterial clearance have been demonstrated in patients who have received excessively high or rapidly infused doses of IVFE. To date, these changes have not demonstrated significant effects on patient outcome; however, clinicians are usually cautious with the infusion of IVFE in critically ill patients. Patients who have ARDS should have IVFE given in lower doses (0.5–1 g/kg per day as a continuous infusion) because problems with oxygenation have been reported when rapid infusions (3 mg/(kg min)) have been given.71 Currently available forms of IVFE contain mainly omega-6 fatty acids, which result in products that can induce inflammation and immunosuppression. Again, cautious administration of IVFE appears to be safe and efficacious in critically ill trauma patients.
TABLE 60-9 Available Intravenous Fat Emulsions in the United States
Vitamins are necessary for normal metabolism and cellular function. There are currently 13 known vitamins, with vitamin B12 being the last one isolated, in 1948. Trauma patients receiving PN should receive a parenteral multivitamin preparation daily. Most commercially available products for adults contain 12 of the 13 known vitamins (all except vitamin K). In April 2000, the US Food and Drug Administration (FDA) amended requirements for marketing of an “effective” adult parenteral multivitamin formulation and recommended changes to the 12-vitamin formulation that has been available for over 20 years.72The new requirements for increased dosages of vitamins B1, B6, C, and folic acid as well as addition of vitamin K are based on the recommendations from a 1985 workshop sponsored jointly by the American Medical Association’s (AMA) Division of Personal and Public Health Policy and the FDA’s Division of Metabolic and Endocrine Drug Products. Specific modifications of the previous formulation include increasing the provision of ascorbic acid (vitamin C) from 100 to 200 mg per day, pyridoxine (vitamin B6) from 4 to 6 mg per day, thiamine (vitamin B1) from 3 to 6 mg per day, folic acid from 400 to 600 g per day, and addition of phylloquinone (vitamin K) 150 g per day (Table 60-10). When the 12-vitamin formulation is being used, vitamin K can be given individually as a daily dose (0.5–1 mg) or a weekly dose (5–10 mg given once weekly). Patients who are to receive warfarin should be monitored more closely when receiving vitamin K to ensure the appropriate level of anticoagulation is maintained. It is reasonable to supplement the PN with thiamine (25–50 mg per day) in trauma patients who have a history of alcohol abuse, especially when they did not receive thiamine at admission, or in times of parenteral multivitamin shortages (common in the United States in the 1990s).
TABLE 60-10 Parenteral Vitamins Recommended by New FDA Guidelines
The United States has been plagued with two periods of short supply of multiple vitamin products in the 1990s. This has resulted in vitamin deficiencies in patients receiving PN without parenteral vitamins. Several recommendations emanated from the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) following the latest parenteral vitamin shortage, which began in 1996: (a) the use of oral multivitamins when possible, especially liquid multivitamins via feeding tubes; (b) restriction of the use of multivitamin products in PN during periods of short supply, such as one infusion three times per week; (3) administration of thiamine, ascorbate, niacin, pyridoxine, and folic acid daily as individual entities in the PN during periods of short supply; and (4) administration of vitamin B12 at least once per month during periods of short supply. The shortage in 1996–1998 was caused by one manufacturer who stopped making its multivitamin product and another who was unable to meet the national demand because of manufacturing difficulties.
Trace elements are usually provided daily during PN in trauma patients as a cocktail of four or five separate metals. Trace element cocktails providing zinc, copper, manganese, chromium, and selenium should be given daily to most trauma patients receiving PN. Patients who have sustained small bowel or large bowel fluid losses should receive supplemental zinc (5–10 mg per day) in addition to the amount in the trace element cocktail (3–5 mg per day). Provision of large intakes of trace elements to thermal injury patients may facilitate wound healing and decrease length of hospital stay. Based on exudative losses from burn wounds, one group of investigators increased daily intakes of copper (4.5 mg), selenium (187 μg), and zinc (39 mg). A reduction in grafting requirements and total hospital days ( days vs. days, ) was observed in the supplemented group versus the group receiving standard trace element intakes.73 Patients who have hepatic cholestasis should have copper and manganese withheld from the PN solution because these trace elements are excreted in the bile. Neurologic damage from deposition of manganese in the basal ganglia has been reported in PN patients with chronic liver disease or cholestasis.74 Parenteral molybdenum and iodine are also available; however, these trace elements are usually reserved for long-term PN patients if they are used at all.
Water is a vital component for life and an important part of the PN formula. Trauma patients who require PN will vary considerably in their water requirements. Fluid balance should be assessed by intake and output and hemodynamic monitoring as appropriate. In many cases the trauma patient is septic and has difficulty in mobilizing fluid from third spaces. This results in edema and fluid overload. The PN prescription for these patients should be maximally concentrated and be void of free water if possible. This can be accomplished by using only the most concentrated macronutrients (e.g., D70W, 15% amino acids, 30% IVFE) for the preparation of the PN formula. Other patients, such as those with multiple GI drains or fistulas, may have water and salt requirements that exceed those provided by standard PN solutions that can meet nutritional needs. In this case, an additional intravenous fluid such as 0.45% sodium chloride injection will need to be used as a fluid supplement to keep the patient in proper water and sodium balance.
Examples of PN Formulas
There are several ways in which to prescribe PN formulas. Each institution or health care system will usually have a single method that is preferable for the respective pharmacy. Many health care systems use a preprinted order form to minimize confusion for the prescriber, especially where there are multiple prescribers. The examples used in this chapter are expressed in final concentrations of the respective macronutrients. This appears to be an effective way of teaching these concepts in systems with multiple prescribers or where there are a few prescribers who change services every month. Table 60-11 lists several PN formulas that have been used for critically ill trauma patients. PN formulas containing between D15W and D25W, 4–5% amino acids, and 2–3% lipids are usually suitable for trauma patients with normal organ function and relatively normal fluid balance. Electrolyte components of PN may vary considerably in these types of patients depending on serum concentrations, concomitant drug therapy, acid–base status, pre-injury nutritional status, and extrarenal losses of fluid and electrolytes.
TABLE 60-11 Examples of TPN Formulas Used in Trauma Patients
INSTITUTION OF THERAPY
Most patients can be started on PN and advanced to a desired goal over 2–3 days. A reasonable initiation rate is 25–50 mL/h for 12–24 hours. If glucose homeostasis is reasonable, the PN rate can be advanced by 25–40 mL/h per day until the desired goal is reached. For example, an 80-kg critically ill trauma patient with normal organ function and serum electrolyte concentrations may have a PN formula (D15W, amino acids 5%, lipids 2%) started at 50 mL/h, advanced to 85 mL/h on day 2, and then advanced to the desired goal of 115 mL/h on day 3. A different approach would be taken for the fluid-overloaded, hyperglycemic, septic trauma patient with normal renal function. The PN would be concentrated (D30W, amino acids 6%, lipids 4%), undoubtedly have regular insulin added to it (or coinfused with an infusion of insulin), and initiated at a low rate such as 15–25 mL/h. This PN formula would be advanced slowly (e.g., 25 mL/h per day) based on patient clinical status, glucose tolerance, and fluid balance.
COMPLICATIONS OF PARENTERAL NUTRITION AND THEIR TREATMENT
The complications of PN are often divided into three broad categories: mechanical, metabolic, and infectious. The major mechanical and infectious complications are covered in Section “Access and Monitoring of Lines,” and are therefore not repeated here.
The most common metabolic complication of PN is glucose homeostasis. Hyperglycemia is a common finding in critically ill patients receiving PN not only because of the administered dextrose but also because of the accompanying stress associated with injury (e.g., increased corticosteroids, cytokines), dextrose administration from intravenous fluids and medications, chronic diseases such as diabetes, and coadministration of drugs that can exacerbate glucose homeostasis such as gluco-corticosteroids. One recent study correlates hyperglycemia in parenterally fed patients to poor outcomes in hospitalized patients.75 Recent trials have explored the benefits of tighter glucose control in the ICU. The trial by Van den Berghe et al. showed benefits from strict glycemic control in cardiac patients receiving specialized nutrition support (EN and PN).76 This study compared patients with strict glycemic control (keeping blood glucose between 80 and 110 mg/dL) with those treated with conventional treatment (keeping blood glucose between 180 and 200 mg/dL). This trial showed that intensive insulin therapy reduced mortality and morbidity. Limitations of the trial include the large percentage of cardiac surgery patients, large percentage of patients receiving PN, and dedicated research nursing staff whose only role was to adjust insulin drips. It did not appear that general surgical or trauma patient benefited from this approach. In the most recent glycemic control trial, NICE-SUGAR, the investigators question the need for tight control of blood glucose, and propose that a wider range of blood glucose control (180 mg/dL) will be just as beneficial.50 The NICE-SUGAR trial was a multicenter study involving 42 hospitals and randomizing a population of mixed medical and surgical ICU patients. Patients were randomized to receive an intensive insulin regimen to keep blood glucose between 80 and 108 mg/dL, or a “conventional” insulin regimen to keep blood glucose between 70 and 180. Results showed a mortality benefit in favor of the conventional insulin group. Of the patients in the intensive insulin group, 27.5% of the 3,010 patients died; in comparison, 24.9% of the 3,012 patients in the conventional group died, which is an absolute difference in mortality of 2.6% (95% CI, 0.4–4.8). Also, severe hypoglycemia (defined as blood glucose less than 40 mg/dL) was reported significantly more often in the intensive insulin group at 6.8% than in the conventional insulin group at 0.5% (P <.001). Investigators conclude that the intensive insulin regimen results in a higher mortality rate and do not recommend using it in an ICU setting. The investigators note the differences in the trial, that is, a mixed medical and surgical ICU, more patients receiving enteral nutrition rather than PN, and the use of existing personnel (no research nursing staff) as reasons for the results. Also, researchers of the NICE-SUGAR trial note that there were excess deaths in the intensive insulin group due to cardiovascular events, and suggest that reducing blood glucose with insulin may affect the cardiovascular system. Most practitioners agree that blood glucose in the ICU should be kept between 70 and 180 mg/dL, and that insulin drips should be initiated for blood glucose levels >200 mg/dL.
We administer regular insulin intravenously or subcutaneously when the glucose values exceed 150 mg/dL or glucosuria becomes moderate to severe (500 mg/dL or greater). Table 60-12 contains an algorithm for intravenous or subcutaneous administration of regular insulin. While fingersticks for glucose are routinely checked every 6 hours in most patients, they can be increased to every 3 or 4 hours in patients who need better control. Direct addition of regular human insulin to the PN solution usually begins with 0.1 U of insulin/g of dextrose (i.e., 15 U/L in 15% dextrose, 20 U/L in 20% dextrose). A continuous insulin infusion of regular human insulin is used in patients who continue to be intolerant with the above interventions (see Table 60-13). Strategies other than insulin drips have been recommended for optimizing glycemic control in patients receiving PN. Avoiding overfeeding with hypocaloric regimens for obese patients and limiting caloric goals to 25 total kcal/kg per day for nonobese individuals have been effective. Dextrose should be restricted to less than 200 g on day 1 of PN, with patients at high risk for hyperglycemia (i.e., history of diabetes, corticosteroid use, etc.) receiving no more than 100 g per day. When baseline serum glucose concentrations exceed 300 mg/dL, PN should be instituted when serum glucose concentrations are below 200 mg/dL. Daily intake of dextrose calories should be advanced toward goal only when serum glucose concentrations can be maintained under this level.
TABLE 60-12 Algorithm for Regular Insulin Administration
Patients who have experienced significant glucosuria resulting in an osmotic diuresis will often need to be supplemented with intravenous fluid to prevent dehydration. Intravenous solutions such as 0.45% sodium chloride or 0.22% sodium chloride injection are very effective in these situations.
Essential Fatty Acid Deficiency
As long as at least 2–4% of total calories from PN are given as essential fatty acids (i.e., linoleic acid and linolenic acid), essential fatty acid deficiency (EFAD) should be prevented. Most trauma patients will receive from 15% to 25% of total calories as IVFE during PN, which easily prevents EFAD and also provides a source of NCPs. Occasionally, a critically ill patient who is receiving PN will have sustained hypertriglyceridemia (e.g., >500 mg/dL). Most practitioners would withhold intravenous lipid in this situation until the serum triglyceride concentration falls below 400 mg/dL. After 2 weeks of fat-free PN in the adult, biochemical evidence of EFAD occurs, with symptoms following as early as 1 week later. Some practitioners have administered small doses of intravenous lipid cautiously to prevent EFAD during hypertriglyceridemia, while others have attempted to give essential fatty acids with the topical administration of safflower or sunflower oil.
Zinc is a trace element that is concentrated in small and large bowel fluids. Patients who have substantial ostomy losses are prone to develop zinc deficiency and should be supplemented with extra zinc in the PN solution. The stress of injury will cause enhanced urinary excretion of zinc, so the recommendation is to give at least 5 mg per day during PN administration in trauma patients. Trauma patients with a history of alcohol abuse who are to receive PN often need supplemental thiamine and folic acid added to the solution over and above standard vitamin additives. Although not widely appreciated, thermal injury patients experience high rates of postburn bone disease. Klein et al. recently found a defect in the skin conversion of 7-dehydrocholesterol into previtamin D3.77 In children with a mean time of 14 months after their burn injury, skin 7-dehydrocholesterol was significantly lower in the burn scar than in unburned controls, and previtamin D3 was significantly lower than controls in both burn scar and unburned skin adjacent to the scar. Low serum 25-hydroxyvitamin D concentrations were also found. Obviously, adults are at risk for developing postburn bone disease, especially in women after menopause and as both men and women attain ages beyond 50 years. These findings also suggest that vitamin D supplementation should be encouraged to prevent bone disease in this particular population of patients.
TRANSITION TO ENTERAL NUTRITION
Most trauma patients who receive PN have a GI tract that becomes functional with recovery. Nasogastric tubes for suction can be removed as the patient regains bowel function. As oral nutrition is introduced and progressed, weaning of the PN solution becomes an important issue. Generally, weaning of PN only begins when the trauma patient has demonstrated tolerance to at least a full liquid diet (i.e., one that can be nutritionally complete). Once the patient is ingesting at least one half a nutritionally complete diet, the PN can be decreased to a lower rate. As the patient approaches an intake of two thirds to three fourths of the diet, the PN can be discontinued.
Many trauma patients will be unable to or will not eat orally when the GI tract is recovering. These patients become excellent candidates for enteral tube feeding, either temporarily until oral intake is established or permanently in the patient in a chronic vegetative state where the decision has been made to provide adequate nutrition. Generally, the PN solution is weaned as the rate of enteral tube feeding is increased. This way the patient continues to receive adequate nutrition during the transition to nutritional support via the GI tract. Once patients are receiving three fourths to complete enteral nutrition, the PN can be discontinued. Most trauma patients eventually progress to an oral diet and ingest sufficient amounts so that the enteral tube feeding can be discontinued as well.
The fluid administered during PN in critically ill patients provides anywhere from 50% to 95% of the patient’s intake once the goal rate is attained. Therefore, all general monitoring measurements become exceedingly important to the critical care practitioner responsible for prescribing the administration of PN. Fluid status and fluid balance should be assessed each day in critically ill trauma patients. The PN formula should be concentrated and reduced in sodium for the overloaded patients. Patients who are euvolemic but require large volumes of fluid can have the PN solution administered with addition of IVF to keep the patient in proper water balance. Laboratory measurements for glucose, sodium, potassium, acid/base status, and renal function should be done daily in the critically ill trauma patient. Laboratory measurements for calcium, phosphorus, and magnesium should be performed at least three times a week, while triglyceride concentrations should be assessed weekly during the acute phase of injury in this patient population.
After collection of a 24-hour urine for volume and urea nitrogen, nitrogen balance can be calculated by finding the difference between nitrogen intake from PN (and enteral tube feeding or oral intake if applicable) and nitrogen output (see Table 60-13). Generally, nitrogen equilibrium in the young, stressed, previously healthy trauma patient is an appropriate goal. Patients who have spinal cord or severe head injuries will remain in negative nitrogen balance even when a dose of protein of 2 g/kg per day is given because of disuse atrophy. Nitrogen equilibrium usually can be attained 3–4 weeks after injury in these cases.
TABLE 60-13 Equation for Calculating Nitrogen Balance
Other practitioners favor the serial monitoring of serum proteins during administration of PN. Serum albumin concentration is usually depressed following trauma mainly due to redistribution from the intravascular space to the interstitial space. It takes several months for this protein to normalize, so it is not a good marker of nutrition support efficacy. Serum proteins with short half-lives such as prealbumin (2 days) and transferrin (7 days) have the potential of rising acutely with adequate nutritional support. They are also very sensitive to the clinical course of the patient and will rise and fall independently of nutrition intake when the patient is recovering or decompensating, respectively. Assessment of CRP will help determine whether the decline in short-term serum proteins (i.e., prealbumin) is associated with an acute-phase response or nutritional deficiency. CRP is recognized as a positive acute-phase protein, defined as one whose plasma concentration increases by at least 25% during inflammatory disorders. If CRP is elevated and prealbumin has fallen, this is more indicative of the systemic response to inflammation. However, a falling prealbumin with a concurrent low CRP concentration may represent an inadequate intake of energy or protein. Use of these basic principles can assist the clinician in determining the appropriate time to alter a patient’s nutritional regimen.
ANABOLIC AGENTS IN TRAUMA PATIENTS
It is recognized that standard nutritional support in patients subjected to severe trauma rarely allows them to attain nitrogen equilibrium during the first 2 weeks following injury. In fact, some severely injured patients may lose up to 30–40 g of nitrogen per day during the early flow phase of injury. Because there are toxicities associated with excessive administration of specialized nutrition support, anabolic agents as adjunctive therapy with parenteral or enteral nutrition to enhance recovery have been considered. There are some data supporting the administration of GH, IGF-I, or anabolic steroids to patients with polytrauma. Petersen et al. reported significantly improved nitrogen balance and whole-body protein synthesis following the administration of GH with PN when compared with a group receiving PN alone.78Our work has shown that GH affects visceral protein status and increases serum albumin in critically injured patients but has relatively little effect on nitrogen retention in severely immobilized patients.79Unfortunately, patients receiving GH tended to be hyperglycemic, particularly if there were infectious complications. The safety of GH therapy use has been further questioned based on two well-designed multicenter trials conducted in Europe, which reported an increase in mortality among critically ill patients treated with GH. These two independent, prospective, double-blind, randomized trials were conducted in parallel involving 247 Finnish patients and 285 patients from other European countries, and the results were published as one report in the New England Journal of Medicine. A total of 532 critically ill patients received high-dose GH (0.1 ± 0.02 mg/kg per day) or placebo until discharge from the ICU or for a maximum of 21 days. In the Finnish study, mortality rate was significantly higher in the GH group as compared with the placebo group (39% vs. 20%, P <.001).80 A similar finding was observed in the multinational study conducted in other European countries, with a 44% mortality rate in the treatment group versus 18% in the placebo group. Previous trials in ICU patients and thermal injury patients demonstrated improvements in lean tissue mass accretion or wound healing and none demonstrated a decrease in survival. Herndon et al. have demonstrated improved healing of donor sites and shorter length of stay/percent burn in thermally injured children who received recombinant GH as adjunctive therapy to nutrition support.81 However, the Finnish and multinational studies excluded patients with burns or septic shock and trauma patients accounted for less than 10% of the total population. Demographic data also revealed that 95% of patients from both trials combined had respiratory failure on enrollment and the average age of patients was 60 years. Despite these differences in patient characteristics and study methodology, these results sharply diminished the enthusiasm of practitioners to use recombinant GH therapy in adult trauma patients.
Much of the effects of GH occur because of IGF-I. IGF-I is produced by the liver in response to GH but does not have the hyperglycemic effects induced by direct GH administration. In a phase II safety and efficacy trial using IGF-I in patients with moderate or severe head injury, Hatton et al.82 reported that patients receiving the hormone had significantly decreased nitrogen excretion. A subset of patients with GCS scores of 5–7 who received IGF-I demonstrated improved neurologic outcome at 6 months postinjury.83 One group of investigators has published several positive studies evaluating the use of oxandrolone, a newer anabolic agent, in thermal injury patients.84Reductions in weight loss and net nitrogen loss accompanied by increases in donor site wound healing and rates of weight restoration in the recovery phase have been observed in burn patients (total body surface area burns of 40–70%) receiving oxandrolone 20 mg per day. One study85 evaluated oxandrolone in multiple trauma patients and showed no significant differences in length of hospital stay, length of ICU stay, body cell mass, or infectious complications between oxandrolone 20 mg per day and placebo. Thus, more clinical research with IGF-I and anabolic steroids is needed in trauma patients.
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