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Surgery_Schwartz. is controversial, however, because no clear bene-fits have been proven by clinical trials. Protein restriction should be avoided in patients with end-stage liver disease because such patients have significant protein energy malnutrition that pre-disposes them to additional morbidity and mortality.269 Similar to patients with CKD, standard formulations are recommended initially unless the patient develops hepatic encephalopathy that is refractory to standard treatment. With regard to protein sup-plementation, data indicate that providing 1.5 gm protein/kg per day improves clinical outcomes in these patients.270Access for Enteral Nutritional SupportThe available techniques and repertoire for enteral access have provided multiple options for feeding the gut. Presently used methods and preferred indications are summarized in Table 2-10.271Nasoenteric Tubes. Nasogastric feeding should be reserved for those with intact mentation and protective laryngeal reflexes to minimize risks of


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Surgery_Schwartz. preferred indications are summarized in Table 2-10.271Nasoenteric Tubes. Nasogastric feeding should be reserved for those with intact mentation and protective laryngeal reflexes to minimize risks of aspiration. Even in intubated patients, naso-gastric feedings often can be recovered from tracheal suction. Nasojejunal feedings are associated with fewer pulmonary complications including risk of pneumonia, but access past the pylorus requires greater effort to accomplish. Therefore, routine use of small bowel feedings is preferred in units where small bowel access is readily feasible. Where there may be difficul-ties obtaining access, small bowel feedings may be considered a priority for those patients at high risk for intolerance to enteral nutrition (e.g., high gastric residuals).Blind insertion of nasogastric feeding tubes is fraught with misplacement, and air instillation with auscultation is inaccurate for ascertaining proper positioning. Radiographic confirmation is usually


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Surgery_Schwartz. insertion of nasogastric feeding tubes is fraught with misplacement, and air instillation with auscultation is inaccurate for ascertaining proper positioning. Radiographic confirmation is usually required to verify the position of the nasogastric feed-ing tube.Several methods have been recommended for the passage of nasoenteric feeding tubes into the small bowel, including use of prokinetic agents, right lateral decubitus positioning, gastric insufflation, tube angulation, and application of clock-wise torque. However, the successful placement of feeding tubes by these methods is highly variable and operator depen-dent. Furthermore, it is time consuming, and success rates for intubation past the duodenum into the jejunum by these methods are <20%. Fluoroscopy-guided intubation past the pylorus has a >90% success rate, and more than half of these intubations result in jejunal placement. Similarly, endoscopy-guided placement past the pylorus has high success rates, but attempts to


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Surgery_Schwartz. pylorus has a >90% success rate, and more than half of these intubations result in jejunal placement. Similarly, endoscopy-guided placement past the pylorus has high success rates, but attempts to advance the tube beyond the second portion of the duodenum using a standard gastroduodenoscope is unlikely to be successful.Table 2-10Options for enteral feeding accessACCESS OPTIONCOMMENTSNasogastric tubeShort-term use only; aspiration risks; nasopharyngeal trauma; frequent dislodgmentNasoduodenal/nasojejunal tubeShort-term use; lower aspiration risks in jejunum; placement challenges (radiographic assistance often necessary)Percutaneous endoscopic gastrostomy (PEG)Endoscopy skills required; may be used for gastric decompression or bolus feeds; aspiration risks; can last 12–24 mo; slightly higher complication rates with placement and site leaksSurgical gastrostomyRequires general anesthesia and small laparotomy; procedure may allow placement of extended duodenal/jejunal feeding ports;


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Surgery_Schwartz. higher complication rates with placement and site leaksSurgical gastrostomyRequires general anesthesia and small laparotomy; procedure may allow placement of extended duodenal/jejunal feeding ports; laparoscopic placement possibleFluoroscopic gastrostomyBlind placement using needle and T-prongs to anchor to stomach; can thread smaller catheter through gastrostomy into duodenum/jejunum under fluoroscopyPEG-jejunal tubeJejunal placement with regular endoscope is operator dependent; jejunal tube often dislodges retrograde; two-stage procedure with PEG placement, followed by fluoroscopic conversion with jejunal feeding tube through PEGDirect percutaneous endoscopic jejunostomy (DPEJ)Direct endoscopic tube placement with enteroscope; placement challenges; greater injury risksSurgical jejunostomyCommonly carried out during laparotomy; general anesthesia; laparoscopic placement usually requires assistant to thread catheter; laparoscopy offers direct visualization of catheter


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Surgery_Schwartz. jejunostomyCommonly carried out during laparotomy; general anesthesia; laparoscopic placement usually requires assistant to thread catheter; laparoscopy offers direct visualization of catheter placementFluoroscopic jejunostomyDifficult approach with injury risks; not commonly doneSmall-bowel feeding is more reliable for delivering nutri-tion than nasogastric feeding. Furthermore, the risks of aspi-ration pneumonia can be reduced by 25% with small-bowel feeding compared with nasogastric feeding. The disadvantages of the use of nasoenteric feeding tubes are clogging, kinking, and inadvertent displacement or removal of the tube as well as nasopharyngeal complications. If nasoenteric feeding will be required for longer than 30 days, access should be converted to a percutaneous one.272Brunicardi_Ch02_p0027-p0082.indd 7101/03/19 6:50 PM 72BASIC CONSIDERATIONSPART IPercutaneous Endoscopic Gastrostomy. The most common indications for percutaneous endoscopic gastrostomy (PEG) include


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Surgery_Schwartz. 7101/03/19 6:50 PM 72BASIC CONSIDERATIONSPART IPercutaneous Endoscopic Gastrostomy. The most common indications for percutaneous endoscopic gastrostomy (PEG) include impaired swallowing mechanisms, oropharyngeal or esophageal obstruction, and major facial trauma. It is frequently used for debilitated patients requiring caloric supplementation, hydration, or frequent medication dosing. It is also appropriate for patients requiring passive gastric decompression. Relative contraindications for PEG placement include ascites, coagu-lopathy, gastric varices, gastric neoplasm, and lack of a suitable abdominal site. Most tubes are 18F to 28F in size and may be used for 12 to 24 months.Identification of the PEG site requires endoscopic transil-lumination of the anterior stomach against the abdominal wall. A 14-gauge angiocatheter is passed through the abdominal wall into the fully insufflated stomach. A guidewire is threaded through the angiocatheter, grasped by snares or forceps, and


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Surgery_Schwartz. abdominal wall. A 14-gauge angiocatheter is passed through the abdominal wall into the fully insufflated stomach. A guidewire is threaded through the angiocatheter, grasped by snares or forceps, and pulled out through the mouth. The tapered end of the PEG tube is secured to the guidewire and is pulled into position out of the abdominal wall. The PEG tube is secured without tension against the abdominal wall, and many have reported using the tube within hours of placement. It has been the practice of some to connect the PEG tube to a drainage bag for passive decom-pression for 24 hours before use, allowing more time for the stomach to seal against the peritoneum.If endoscopy is not available or technical obstacles pre-clude PEG placement, the interventional radiologist can attempt the procedure percutaneously under fluoroscopic guidance by first insufflating the stomach against the abdominal wall with a nasogastric tube. If this also is unsuccessful, surgical gas-trostomy tube


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Surgery_Schwartz. the procedure percutaneously under fluoroscopic guidance by first insufflating the stomach against the abdominal wall with a nasogastric tube. If this also is unsuccessful, surgical gas-trostomy tube placement can be considered, particularly with minimally invasive methods. When surgery is contemplated, it may be wise to consider directly accessing the small bowel for nutrition delivery.Although PEG tubes enhance nutritional delivery, facili-tate nursing care, and are superior to nasogastric tubes, serious complications occur in approximately 3% of patients. These complications include wound infection, necrotizing fasciitis, peritonitis, aspiration, leaks, dislodgment, bowel perforation, enteric fistulas, bleeding, and aspiration pneumonia.273 For patients with significant gastroparesis or gastric outlet obstruc-tion, feedings through PEG tubes are hazardous. In such cases, the PEG tube can be used for decompression and allow access for converting the PEG tube to a transpyloric


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Surgery_Schwartz. or gastric outlet obstruc-tion, feedings through PEG tubes are hazardous. In such cases, the PEG tube can be used for decompression and allow access for converting the PEG tube to a transpyloric feeding tube.Percutaneous Endoscopic Gastrostomy-Jejunostomy and Direct Percutaneous Endoscopic Jejunostomy. Although gastric bolus feedings are more physiologic, patients who can-not tolerate gastric feedings or who have significant aspiration risks should be fed directly past the pylorus. In the percutane-ous endoscopic gastrostomy-jejunostomy (PEG-J) method, a 9F to 12F tube is passed through an existing PEG tube, past the pylorus, and into the duodenum. This can be achieved by endoscopic or fluoroscopic guidance. With weighted catheter tips and guidewires, the tube can be further advanced past the ligament of Treitz. However, the incidence of long-term PEG-J tube malfunction has been reported to be >50% as a result of ret-rograde tube migration into the stomach, kinking, or clogging.Direct


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Surgery_Schwartz. the ligament of Treitz. However, the incidence of long-term PEG-J tube malfunction has been reported to be >50% as a result of ret-rograde tube migration into the stomach, kinking, or clogging.Direct percutaneous endoscopic jejunostomy (DPEJ) tube placement uses the same techniques as PEG tube placement but requires an enteroscope or colonoscope to reach the jejunum. DPEJ tube malfunctions are probably less frequent than PEG-J tube malfunctions, and kinking or clogging is usually averted by placement of larger-caliber catheters. The success rate of DPEJ tube placement is variable because of the complexity of endo-scopic skills required to locate a suitable jejunal site. In such cases where endoscopic means are not feasible, surgical jeju-nostomy tube placement is more appropriate, especially when minimally invasive techniques are available.Surgical Gastrostomy and Jejunostomy. For a patient undergoing complex abdominal or trauma surgery, thought should be given during surgery to the


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Surgery_Schwartz. when minimally invasive techniques are available.Surgical Gastrostomy and Jejunostomy. For a patient undergoing complex abdominal or trauma surgery, thought should be given during surgery to the possible routes for sub-sequent nutritional support because laparotomy affords direct access to the stomach or small bowel. The only absolute contra-indication to feeding jejunostomy is distal intestinal obstruction. Relative contraindications include severe edema of the intestinal wall, radiation enteritis, inflammatory bowel disease, ascites, severe immunodeficiency, and bowel ischemia. Needle-catheter jejunostomies also can be done with a minimal learning curve. The biggest drawback usually is possible clogging and knotting of the 6F catheter.274Abdominal distention and cramps are common adverse effects of early enteral nutrition. Some have also reported impaired respiratory mechanics as a result of intolerance to enteral feedings. These are mostly correctable by temporarily discontinuing


Surgery_Schwartz

Surgery_Schwartz. effects of early enteral nutrition. Some have also reported impaired respiratory mechanics as a result of intolerance to enteral feedings. These are mostly correctable by temporarily discontinuing feedings and resuming at a lower infusion rate.Pneumatosis intestinalis and small-bowel necrosis are infrequent but significant problems in patients receiving jejunal tube feedings. Several contributing factors have been proposed, including the hyperosmolarity of enteral solutions, bacte-rial overgrowth, fermentation, and accumulation of metabolic breakdown products. The common pathophysiology is believed to be bowel distention and consequent reduction in bowel wall perfusion. Risk factors for these complications include cardio-genic and circulatory shock, vasopressor use, diabetes mellitus, and chronic obstructive pulmonary disease. Therefore, enteral feedings in the critically ill patient should be delayed until adequate resuscitation has been achieved. As alternatives, dilut-ing standard


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Surgery_Schwartz. chronic obstructive pulmonary disease. Therefore, enteral feedings in the critically ill patient should be delayed until adequate resuscitation has been achieved. As alternatives, dilut-ing standard enteral formula, delaying the progression to goal infusion rates, or using monomeric solutions with low osmolal-ity requiring less digestion by the gastrointestinal tract all have been successfully used.PARENTERAL NUTRITIONParenteral nutrition is the continuous infusion of a hyperosmo-lar solution containing carbohydrates, proteins, fat, and other necessary nutrients through an indwelling catheter inserted into the superior vena cava. To obtain the maximum benefit, the calorie to protein ratio must be adequate (at least 100 to 150 kcal/g nitrogen), and both carbohydrates and proteins must be infused simultaneously. When the sources of calories and nitrogen are given at different times, there is a significant decrease in nitrogen utilization. These nutrients can be given in quantities


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Surgery_Schwartz. be infused simultaneously. When the sources of calories and nitrogen are given at different times, there is a significant decrease in nitrogen utilization. These nutrients can be given in quantities considerably greater than the basic caloric and nitro-gen requirements, and this method has proved to be highly suc-cessful in achieving growth and development, positive nitrogen balance, and weight gain in a variety of clinical situations. Clini-cal trials and meta-analysis of studies of parenteral feeding in the perioperative period have suggested that preoperative nutri-tional support may benefit some surgical patients, particularly those with extensive malnutrition.Historically, short-term use of parenteral nutrition (PN) in critically ill patients (i.e., duration of <7 days) when enteral Brunicardi_Ch02_p0027-p0082.indd 7201/03/19 6:50 PM 73SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2nutrition (EN) may have been instituted was associated with higher rates of


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Surgery_Schwartz. enteral Brunicardi_Ch02_p0027-p0082.indd 7201/03/19 6:50 PM 73SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2nutrition (EN) may have been instituted was associated with higher rates of infectious complications. It appears, however, that the increased mortality associated with PN may have been associated with excessive caloric delivery. More recent data have shown no mortality difference between EN and PN when caloric delivery was reduced and matched. A recent meta-analysis confirmed this result and noted no increase in infectious complications.250 That being said, the risk/benefit for PN in the ICU is much smaller and in a patient with low nutritional risk provides little benefit over the first week of hospitalization in the ICU.Rationale for Parenteral NutritionThe principal indications for parenteral nutrition are malnu-trition, sepsis, or surgical or traumatic injury in seriously ill patients for whom use of the gastrointestinal tract for feedings is not possible.247


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Surgery_Schwartz. indications for parenteral nutrition are malnu-trition, sepsis, or surgical or traumatic injury in seriously ill patients for whom use of the gastrointestinal tract for feedings is not possible.247 Parenteral nutrition should not be used based solely on the medical diagnosis or disease state. Rather, PN use is recommended for those critically ill or injured patients who are at high nutritional risk, when EN is not possible. Alter-nately, PN can also be used to supplement EN after 1 week of use if use of EN is unable to meet >60% of energy and protein requirements.247The safe and successful use of parenteral nutrition requires proper selection of patients with specific nutritional needs, expe-rience with the technique, and an awareness of the associated complications. In patients with significant malnutrition, paren-teral nutrition can rapidly improve nitrogen balance, which may enhance immune function. Routine postoperative use of paren-teral nutrition is not shown to have clinical


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Surgery_Schwartz. malnutrition, paren-teral nutrition can rapidly improve nitrogen balance, which may enhance immune function. Routine postoperative use of paren-teral nutrition is not shown to have clinical benefit and may be associated with a significant increase in complication rate. As with enteral nutrition, the fundamental goals are to provide suf-ficient calories and nitrogen substrate to promote tissue repair and to maintain the integrity or growth of lean tissue mass.Total Parenteral NutritionTotal parenteral nutrition (TPN), also referred to as central parenteral nutrition, requires access to a large-diameter vein to deliver the entire nutritional requirements of the individual. Dextrose content of the solution is high (15%–25%), and all other macronutrients and micronutrients are deliverable by this route.Peripheral Parenteral NutritionThe lower osmolarity of the solution used for peripheral par-enteral nutrition (PPN), secondary to reduced levels of dex-trose (5% to 10%) and protein (3%),


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Surgery_Schwartz. this route.Peripheral Parenteral NutritionThe lower osmolarity of the solution used for peripheral par-enteral nutrition (PPN), secondary to reduced levels of dex-trose (5% to 10%) and protein (3%), allows its administration via peripheral veins. Some nutrients cannot be supplemented because they cannot be concentrated into small volumes. There-fore, PPN is not appropriate for repleting patients with severe malnutrition. It can be considered if central routes are not avail-able or if supplemental nutritional support is required. Typi-cally, PPN is used for short periods (<2 weeks). Beyond this time, TPN should be instituted.Initiation of Parenteral NutritionThe basic solution for parenteral nutrition contains a final con-centration of 15% to 25% dextrose and 3% to 5% crystalline amino acids. The solutions usually are prepared in sterile condi-tions in the pharmacy from commercially available kits contain-ing the component solutions and transfer apparatus. Preparation in the pharmacy


Surgery_Schwartz

Surgery_Schwartz. The solutions usually are prepared in sterile condi-tions in the pharmacy from commercially available kits contain-ing the component solutions and transfer apparatus. Preparation in the pharmacy under laminar flow hoods reduces the incidence of bacterial contamination of the solution. Proper preparation with suitable quality control is absolutely essential to avoid sep-tic complications.The proper provision of electrolytes and amino acids must take into account routes of fluid and electrolyte loss, renal function, metabolic rate, cardiac function, and the under-lying disease state.Intravenous vitamin preparations also should be added to parenteral formulas. Vitamin deficiencies are rare occurrences if such preparations are used. In addition, because vitamin K is not part of any commercially prepared vitamin solution, it should be supplemented on a weekly basis. During prolonged parenteral nutrition with fat-free solutions, essential fatty acid deficiency may become clinically apparent


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Surgery_Schwartz. prepared vitamin solution, it should be supplemented on a weekly basis. During prolonged parenteral nutrition with fat-free solutions, essential fatty acid deficiency may become clinically apparent and manifests as dry, scaly der-matitis and loss of hair. The syndrome may be prevented by periodic infusion of a fat emulsion at a rate equivalent to 10% to 15% of total calories. Essential trace minerals may be required after prolonged TPN and may be supplied by direct addition of commercial preparations. The most frequent presentation of trace mineral deficiencies is the eczematoid rash develop-ing both diffusely and at intertriginous areas in zinc-deficient patients. Other rare trace mineral deficiencies include a micro-cytic anemia associated with copper deficiency, and glucose intolerance presumably related to chromium deficiency. The latter complications are seldom seen except in patients receiving parenteral nutrition for extended periods. The daily administra-tion of commercially


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Surgery_Schwartz. presumably related to chromium deficiency. The latter complications are seldom seen except in patients receiving parenteral nutrition for extended periods. The daily administra-tion of commercially available trace mineral supplements will obviate most such problems.Depending on fluid and nitrogen tolerance, parenteral nutrition solutions generally can be increased over 2 to 3 days toward the desired infusion rate. Current recommendations sug-gest that hypocaloric nutrition (high protein with lower caloric dosing) be considered in the critically ill or injured over the first week in the ICU. The suggested target dose is <20 kcal/kg per day or <80% of estimated caloric needs with adequate pro-tein (>1.2 g/kg per day). This strategy is suggested to minimize risk of both hyperglycemia and insulin resistance, which may reduce infectious complications. Insulin may be supplemented as necessary to ensure glucose tolerance, with a targeted blood glucose range of 140 or 150 to 180 mg/dL for the


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Surgery_Schwartz. resistance, which may reduce infectious complications. Insulin may be supplemented as necessary to ensure glucose tolerance, with a targeted blood glucose range of 140 or 150 to 180 mg/dL for the general ICU population.247 Administration of additional intravenous fluids and electrolytes may occasionally be necessary in patients with persistently high fluid losses.The patient should be carefully monitored for development of electrolyte, volume, acid-base, and septic complications. Vital signs and urinary output should be measured regularly, and the patient should be weighed regularly. Frequent adjust-ments of the volume and composition of the solutions are neces-sary during the course of therapy. Samples for measurement of electrolytes are drawn daily until levels are stable and every 2 or 3 days thereafter. Blood counts, blood urea nitrogen level, lev-els of liver function indicators, and phosphate and magnesium levels are determined at least weekly.The urine or capillary blood


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Surgery_Schwartz. 2 or 3 days thereafter. Blood counts, blood urea nitrogen level, lev-els of liver function indicators, and phosphate and magnesium levels are determined at least weekly.The urine or capillary blood glucose level is checked every 6 hours, and serum glucose concentration is checked at least once daily during the first few days of the infusion and at fre-quent intervals thereafter. Relative glucose intolerance, which often manifests as glycosuria, may occur after initiation of par-enteral nutrition. If blood glucose levels remain elevated or gly-cosuria persists, the dextrose concentration may be decreased, the infusion rate slowed, or regular insulin added to each bottle. The rise in blood glucose concentration observed after initiating parenteral nutrition may be temporary, as the normal pancreas Brunicardi_Ch02_p0027-p0082.indd 7301/03/19 6:50 PM 74BASIC CONSIDERATIONSPART Iincreases its output of insulin in response to the continuous car-bohydrate infusion. In patients with


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Surgery_Schwartz. pancreas Brunicardi_Ch02_p0027-p0082.indd 7301/03/19 6:50 PM 74BASIC CONSIDERATIONSPART Iincreases its output of insulin in response to the continuous car-bohydrate infusion. In patients with diabetes mellitus, additional insulin may be required.Potassium is essential to achieve positive nitrogen bal-ance and replace depleted intracellular stores. In addition, a significant shift of potassium ion from the extracellular to the intracellular space may take place because of the large glucose infusion, with resultant hypokalemia, metabolic alkalosis, and poor glucose utilization. In some cases, as much as 240 mEq of potassium ion daily may be required. Hypokalemia may cause glycosuria, which would be treated with potassium, not insulin. Thus, before giving insulin, the serum potassium level must be checked to avoid exacerbating the hypokalemia.Patients with insulin-dependent diabetes mellitus may exhibit wide fluctuations in blood glucose levels while receiving parenteral nutrition.


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Surgery_Schwartz. must be checked to avoid exacerbating the hypokalemia.Patients with insulin-dependent diabetes mellitus may exhibit wide fluctuations in blood glucose levels while receiving parenteral nutrition. This may require protocol-driven intrave-nous insulin therapy. In addition, partial replacement of dex-trose calories with lipid emulsions may alleviate these problems in selected patients.Lipid emulsions derived from soybean or safflower oils are widely used as an adjunctive nutrient to prevent the development of essential fatty acid deficiency, although recent data support reducing the overall omega-6 PUFA load in favor of omega-3 PUFA or MCT. Current recommendations are to limit intrave-nous fat emulsion infusion over the first week of hospitalization to a maximum of 100 g per week delivered in two divided doses. This is based on standard emulsions that are soy-based. As data is acquired for omega-3 PUFAs, including fish-oil or olive-oil based emulsions, these recommendations may alter.The


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Surgery_Schwartz. two divided doses. This is based on standard emulsions that are soy-based. As data is acquired for omega-3 PUFAs, including fish-oil or olive-oil based emulsions, these recommendations may alter.The delivery of parenteral nutrition requires central intra-venous access. Temporary or short-term access can be achieved with a 16-gauge percutaneous catheter inserted into a subclavian or internal jugular vein and threaded into the superior vena cava. More permanent access with the intention of providing long-term or home parenteral nutrition can be achieved by placement of a catheter with a subcutaneous port for access by tunneling a catheter with a substantial subcutaneous length or threading a long catheter through the basilic or cephalic vein into the supe-rior vena cava.Complications of Parenteral NutritionTechnical Complications. One of the more common and seri-ous complications associated with long-term parenteral feed-ing is sepsis secondary to contamination of the central venous


Surgery_Schwartz

Surgery_Schwartz. Parenteral NutritionTechnical Complications. One of the more common and seri-ous complications associated with long-term parenteral feed-ing is sepsis secondary to contamination of the central venous catheter. Contamination of solutions should also be considered, but it is rare when proper pharmacy protocols have been fol-lowed. Central line-associated blood stream infections (CLA-BSI) occur as a consequence of hematogenous seeding of the cath-eter with bacteria. One of the earliest signs of systemic sepsis from CVA-BSI may be the sudden development of glucose intolerance (with or without temperature increase) in a patient who previously has been maintained on parenteral alimen-tation without difficulty. When this occurs, or if high fever (> 38.5°C [101.3°F]) develops without obvious cause, a dili-gent search for a potential septic focus is indicated. Other causes of fever should also be investigated. If fever persists, the infu-sion catheter should be removed and submitted for


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Surgery_Schwartz. cause, a dili-gent search for a potential septic focus is indicated. Other causes of fever should also be investigated. If fever persists, the infu-sion catheter should be removed and submitted for culture. If the catheter is the cause of the fever, removal of the infectious source is usually followed by rapid defervescence. Some centers are now replacing catheters considered at low risk for infec-tion over a guidewire. However, if blood cultures are positive and the catheter tip is also positive, then the catheter should be removed and placed in a new site. Should evidence of infec-tion persist over 24 to 48 hours without a definable source, the catheter should be replaced into the opposite subclavian vein or into one of the internal jugular veins, and the infusion should be restarted.275The use of multilumen catheters may be associated with a slightly increased risk of infection. This is most likely asso-ciated with greater catheter manipulation and intensive use. The rate of


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Surgery_Schwartz. use of multilumen catheters may be associated with a slightly increased risk of infection. This is most likely asso-ciated with greater catheter manipulation and intensive use. The rate of catheter infection is highest for those placed in the femoral vein, lower for those in the jugular vein, and lowest for those in the subclavian vein. When catheters are indwelling for <3 days, infection risks are negligible. If indwelling time is 3 to 7 days, the infection risk is 3% to 5%. Indwelling times of >7 days are associated with a catheter infection risk of 5% to 10%. Strict adherence to barrier precautions also reduces the rate of infection as can the implementation of procedure checklists to ensure compliance with evidence-based guidelines shown to reduce infectious risk.276Other complications related to catheter placement include the development of pneumothorax, hemothorax, hydrothorax, subclavian artery injury, thoracic duct injury, cardiac arrhyth-mia, air embolism, catheter


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Surgery_Schwartz. related to catheter placement include the development of pneumothorax, hemothorax, hydrothorax, subclavian artery injury, thoracic duct injury, cardiac arrhyth-mia, air embolism, catheter embolism, and cardiac perforation with tamponade. All of these complications may be avoided by strict adherence to proper techniques. Further, the use of ultra-sonographic guidance during CV line placement has been dem-onstrated to significantly decrease the failure rate, complication rate, and number of attempts required for successful access.277Metabolic Complications. Hyperglycemia may develop with normal rates of infusion in patients with impaired glucose toler-ance or in any patient if the hypertonic solutions are adminis-tered too rapidly. This is a particularly common complication in patients with latent diabetes and in patients subjected to severe surgical stress or trauma. Treatment of the condition consists of volume replacement with correction of electrolyte abnormali-ties and the


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Surgery_Schwartz. with latent diabetes and in patients subjected to severe surgical stress or trauma. Treatment of the condition consists of volume replacement with correction of electrolyte abnormali-ties and the administration of insulin. This complication can be avoided with careful attention to daily fluid balance and frequent monitoring of blood glucose levels and serum electrolytes.Increasing experience has emphasized the importance of not overfeeding the parenterally nourished patient. This is particularly true for the depleted patient in whom excess calo-rie infusion may result in carbon dioxide retention and respi-ratory insufficiency. In addition, excess feeding also has been related to the development of hepatic steatosis or marked gly-cogen deposition in selected patients. Cholestasis and forma-tion of gallstones are common in patients receiving long-term parenteral nutrition. Mild but transient abnormalities of serum transaminase, alkaline phosphatase, and bilirubin levels occur in many


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Surgery_Schwartz. of gallstones are common in patients receiving long-term parenteral nutrition. Mild but transient abnormalities of serum transaminase, alkaline phosphatase, and bilirubin levels occur in many parenterally nourished patients. Failure of the liver enzymes to plateau or return to normal over 7 to 14 days should suggest another etiology.Intestinal Atrophy. Lack of intestinal stimulation is associ-ated with intestinal mucosal atrophy, diminished villous height, bacterial overgrowth, reduced lymphoid tissue size, reduced immunoglobulin A production, and impaired gut immunity. The full clinical implications of these changes are not well real-ized, although bacterial translocation has been demonstrated in animal models. The most efficacious method to prevent these changes is to provide at least some nutrients enterally. In patients requiring TPN, it may be feasible to infuse small amounts of feedings via the gastrointestinal tract.Brunicardi_Ch02_p0027-p0082.indd 7401/03/19 6:50 PM


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Surgery_Schwartz. some nutrients enterally. In patients requiring TPN, it may be feasible to infuse small amounts of feedings via the gastrointestinal tract.Brunicardi_Ch02_p0027-p0082.indd 7401/03/19 6:50 PM 75SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2REFERENCESEntries highlighted in bright blue are key references. 1. Horiguchi H, Loftus TJ, Hawkins RB, et al. Innate immu-nity in the persistent inflammation, immunosuppression, and catabolism syndrome and its implications for therapy. Front Immunol. 2018;9:595. doi: 10.3389/fimmu.2018.00595 2. Minei JP, Cuschieri J, Sperry J, et al. The changing pattern and implications of multiple organ failure after blunt injury with hemorrhagic shock. Crit Care Med. 2012;40(4):1129-1135. doi: 10.1097/CCM.0b013e3182376e9f 3. Xiao W, Mindrinos MN, Seok J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13): 2581-2590. doi: 10.1084/jem.20111354 4. Lowry SF. Human endotoxemia: a model for mechanistic insight and therapeutic


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Surgery_Schwartz. J, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13): 2581-2590. doi: 10.1084/jem.20111354 4. Lowry SF. Human endotoxemia: a model for mechanistic insight and therapeutic targeting. Shock. 2005;24(suppl 1):94-100. 5. Pugin J. How tissue injury alarms the immune system and causes a systemic inflammatory response syndrome. Ann Intensive Care. 2012;2(1):27. doi: 10.1186/2110-5820-2-27 6. Manson J, Thiemermann C, Brohi K. Trauma alarmins as activators of damage-induced inflammation. Br J Surg. 2012;99(suppl 1):12-20. doi: 10.1002/bjs.7717 7. Chan JK, Roth J, Oppenheim JJ, et al. Alarmins: awaiting a clinical response. J Clin Invest. 2012;122(8):2711-2719. doi: 10.1172/JCI62423 8. Bertheloot D, Latz E. HMGB1, IL-1alpha, IL-33 and S100 proteins: dual-function alarmins. Cell Mol Immunol. 2017;14(1):43-64. doi: 10.1038/cmi.2016.34 9. Fontaine M, Lepape A, Piriou V, Venet F, Friggeri A. Innate danger signals in acute injury: From bench to bedside. Anaesth Crit Care


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Surgery_Schwartz. Cell Mol Immunol. 2017;14(1):43-64. doi: 10.1038/cmi.2016.34 9. Fontaine M, Lepape A, Piriou V, Venet F, Friggeri A. Innate danger signals in acute injury: From bench to bedside. Anaesth Crit Care Pain Med. 2016;35(4):283-292. doi: 10.1016/j.accpm.2015.10.009 10. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Ann Rev Immunol. 2011;29: 139-162. doi: 10.1146/annurev-immunol-030409-101323 11. Yang H, Hreggvidsdottir HS, Palmblad K, et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci U S A. 2010;107(26):11942-11947. doi: 10.1073/pnas.1003893107 12. Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol. 2013;93(6):865-873. doi: 10.1189/jlb.1212662 13. Peltz ED, Moore EE, Eckels PC, et al. HMGB1 is markedly elevated within 6 hours of


Surgery_Schwartz

Surgery_Schwartz. activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol. 2013;93(6):865-873. doi: 10.1189/jlb.1212662 13. Peltz ED, Moore EE, Eckels PC, et al. HMGB1 is markedly elevated within 6 hours of mechanical trauma in humans. Shock. 2009;32(1):17-22. 14. Weber DJ, Gracon AS, Ripsch MS, et al. The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmo-nary dysfunction in lung transplantation. Sci Transl Med. 2014;6(252):252ra124. doi: 10.1126/scitranslmed.3009443 15. Horst K, Andruszkow H, Weber CD, et al. Thoracic trauma now and then: a 10 year experience from 16,773 severely injured patients. PLoS One. 2017;12(10):e0186712. doi: 10.1371/journal.pone.0186712 16. Leijte GP, Custers H, Gerretsen J, et al. Increased plasma levels of danger-associated molecular patterns are associ-ated with immune suppression and postoperative infec-tions in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Front Immu-nol. 2018;9:663. doi:


Surgery_Schwartz

Surgery_Schwartz. are associ-ated with immune suppression and postoperative infec-tions in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Front Immu-nol. 2018;9:663. doi: 10.3389/fimmu.2018.00663 17. Lee S, Piao C, Kim G, Kim JY, Choi E, Lee M. Production and application of HMGB1 derived recombinant RAGE-antagonist peptide for anti-inflammatory therapy in acute lung injury. Eur J Pharm Sci. 2018;114:275-284. doi: 10.1016/j.ejps.2017.12.019 18. Wang L, Liebmen MN, Wang X. Roles of mitochondrial DNA signaling in immune responses. Adv Exp Med Biol. 2017;1038:39-53. doi: 10.1007/978-981-10-6674-0_4 19. Zhang Q, Raoof M, Chen Y, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285):104-107. doi: 10.1038/nature08780 20. West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol. 2011;11(6):389-402. doi: 10.1038/nri2975 21. Hu Q, Ren J, Wu J, et al. Elevated levels of plasma mitochon-drial dna


Surgery_Schwartz

Surgery_Schwartz. AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol. 2011;11(6):389-402. doi: 10.1038/nri2975 21. Hu Q, Ren J, Wu J, et al. Elevated levels of plasma mitochon-drial dna are associated with clinical outcome in intra-abdominal infections caused by severe trauma. Surg Infect (Larchmt). 2017;18(5):610-618. doi: 10.1089/sur.2016.276 22. Simmons JD, Lee YL, Mulekar S, et al. Elevated levels of plasma mitochondrial DNA DAMPs are linked to clinical outcome in severely injured human subjects. Ann Surg. 2013;258(4):591-596; discussion 96-98. doi: 10.1097/SLA.0b013e3182a4ea46 23. McIlroy DJ, Jarnicki AG, Au GG, et al. Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery. J Crit Care. 2014;29(6):1133 e1-5. doi: 10.1016/j.jcrc.2014.07.013 24. McIlroy DJ, Bigland M, White AE, et al. Cell necrosis-independent sustained mitochondrial and nuclear DNA release following trauma surgery. J Trauma Acute Care Surg. 2015;78(2):282-288.


Surgery_Schwartz

Surgery_Schwartz. DJ, Bigland M, White AE, et al. Cell necrosis-independent sustained mitochondrial and nuclear DNA release following trauma surgery. J Trauma Acute Care Surg. 2015;78(2):282-288. doi: 10.1097/TA.0000000000000519 25. Thurairajah K, Briggs GD, Balogh ZJ. The source of cell-free mitochondrial DNA in trauma and potential therapeutic strat-egies. Eur J Trauma Emerg Surg. 2018;44(3):325-334. doi: 10.1007/s00068-018-0954-3 26. Timmermans K, Kox M, Scheffer GJ, Pickkers P. Danger in the intensive care unit: DAMPs in critically ill patients. Shock. 2016;45(2):108-116. doi: 10.1097/SHK.0000000000000506 27. Quintana FJ, Cohen IR. Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J Immunol. 2005;175(5):2777-2782. 28. Guisasola MC, Alonso B, Bravo B, Vaquero J, Chana F. An overview of cytokines and heat shock response in poly-traumatized patients. [Published online ahead of print November 3, 2017.] Cell Stress Chaperones. doi: 10.1007/s12192-017-0859-9 29. Kojima M,


Surgery_Schwartz

Surgery_Schwartz. An overview of cytokines and heat shock response in poly-traumatized patients. [Published online ahead of print November 3, 2017.] Cell Stress Chaperones. doi: 10.1007/s12192-017-0859-9 29. Kojima M, Gimenes-Junior JA, Langness S, et al. Exo-somes, not protein or lipids, in mesenteric lymph activate inflammation: unlocking the mystery of post-shock mul-tiple organ failure. J Trauma Acute Care Surg. 2017;82(1): 42-50. doi: 10.1097/TA.0000000000001296 30. Bausinger H, Lipsker D, Ziylan U, et al. Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur J Immunol. 2002;32(12):3708-3713. doi: 10.1002/ 1521-4141(200212)32:12<3708::AID-IMMU3708>3.0.CO;2-C 31. Stocki P, Dickinson AM. The immunosuppressive activity of heat shock protein 70. Autoimmune Dis. 2012;2012:617213. doi: 10.1155/2012/617213 32. Muralidharan S, Mandrekar P. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J Leukoc Biol. 2013;94(6):1167-1184.


Surgery_Schwartz

Surgery_Schwartz. 10.1155/2012/617213 32. Muralidharan S, Mandrekar P. Cellular stress response and innate immune signaling: integrating pathways in host defense and inflammation. J Leukoc Biol. 2013;94(6):1167-1184. doi: 10.1189/jlb.0313153 33. Calderwood SK, Murshid A. Siglecs take a TOLL on inflammation: deciphering the Hsp70 riddle. EMBO J. 2015;34(22):2733-2734. doi: 10.15252/embj.201593172 34. Fong JJ, Sreedhara K, Deng L, et al. Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14. EMBO J. 2015;34(22):2775-2788. doi: 10.15252/embj.201591407 35. Ren B, Zou G, Huang Y, et al. Serum levels of HSP70 and other DAMP proteins can aid in patient diagnosis after trau-matic injury. Cell Stress Chaperones. 2016;21(4):677-686. doi: 10.1007/s12192-016-0694-4 36. Timmermans K, Kox M, Vaneker M, et al. Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients. Intensive Care Med. 2016;42(4):551-561. doi:


Surgery_Schwartz

Surgery_Schwartz. K, Kox M, Vaneker M, et al. Plasma levels of danger-associated molecular patterns are associated with immune suppression in trauma patients. Intensive Care Med. 2016;42(4):551-561. doi: 10.1007/s00134-015-4205-3Brunicardi_Ch02_p0027-p0082.indd 7501/03/19 6:50 PM 76BASIC CONSIDERATIONSPART I 37. Moreth K, Iozzo RV, Schaefer L. Small leucine-rich proteogly-cans orchestrate receptor crosstalk during inflammation. Cell Cycle. 2012;11(11):2084-2091. doi: 10.4161/cc.20316 38. Babelova A, Moreth K, Tsalastra-Greul W, et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem. 2009;284(36): 24035-24048. doi: 10.1074/jbc.M109.014266 39. Donato R, Cannon BR, Sorci G, et al. Functions of S100 proteins. Curr Mol Med. 2013;13(1):24-57. 40. Xia C, Braunstein Z, Toomey AC, Zhong J, Rao X. S100 Proteins as an important regulator of macrophage inflammation. Front Immunol. 2017;8:1908. doi: 10.3389/fimmu.2017.01908 41. Schenten V, Plancon


Surgery_Schwartz

Surgery_Schwartz. C, Braunstein Z, Toomey AC, Zhong J, Rao X. S100 Proteins as an important regulator of macrophage inflammation. Front Immunol. 2017;8:1908. doi: 10.3389/fimmu.2017.01908 41. Schenten V, Plancon S, Jung N, et al. Secretion of the phos-phorylated form of S100A9 from neutrophils is essential for the proinflammatory functions of extracellular S100A8/A9. Front Immunol. 2018;9:447. doi: 10.3389/fimmu.2018.00447 42. Joly P, Marshall JC, Tessier PA, et al. S100A8/A9 and sRAGE kinetic after polytrauma; an explorative observational study. Scand J Trauma Resusc Emerg Med. 2017;25(1):114. doi: 10.1186/s13049-017-0455-0 43. Oris C, Pereira B, Durif J, et al. The biomarker S100B and mild traumatic brain injury: a meta-analysis. Pediatrics. 2018;141(6). pii: e20180037. doi: 10.1542/peds.2018-0037 44. Rainey T, Lesko M, Sacho R, Lecky F, Childs C. Predict-ing outcome after severe traumatic brain injury using the serum S100B biomarker: results using a single (24h) time-point. Resuscitation.


Surgery_Schwartz

Surgery_Schwartz. T, Lesko M, Sacho R, Lecky F, Childs C. Predict-ing outcome after severe traumatic brain injury using the serum S100B biomarker: results using a single (24h) time-point. Resuscitation. 2009;80(3):341-345. doi: 10.1016/j.resuscitation.2008.11.021 45. Soares MP, Bozza MT. Red alert: labile heme is an alar-min. Curr Opin Immunol. 2016;38:94-100. doi: 10.1016/j.coi.2015.11.006 46. Figueiredo RT, Fernandez PL, Mourao-Sa DS, et al. Char-acterization of heme as activator of Toll-like receptor 4. J Biol Chem. 2007;282(28):20221-20229. doi: 10.1074/jbc.M610737200 47. Dutra FF, Alves LS, Rodrigues D, et al. Hemolysis-induced lethality involves inflammasome activation by heme. Proc Natl Acad Sci U S A. 2014;111(39):E4110-E4118. doi: 10.1073/pnas.1405023111 48. Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood. 2014;123(24):3818-3827. doi:


Surgery_Schwartz

Surgery_Schwartz. G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood. 2014;123(24):3818-3827. doi: 10.1182/blood-2013-10-529982 49. Haimovich B, Reddell MT, Calvano JE, et al. A novel model of common Toll-like receptor 4and injury-induced transcriptional themes in human leukocytes. Crit Care. 2010;14(5):R177. doi: 10.1186/cc9283 50. McGhan LJ, Jaroszewski DE. The role of toll-like receptor-4 in the development of multi-organ failure following traumatic haemorrhagic shock and resuscitation. Injury. 2012;43(2): 129-136. doi: 10.1016/j.injury.2011.05.032 51. Mollen KP, Levy RM, Prince JM, et al. Systemic inflammation and end organ damage following trauma involves functional TLR4 signaling in both bone marrow-derived cells and paren-chymal cells. J Leukoc Biol. 2008;83(1):80-88. doi: 10.1189/jlb.0407201 52. Zettel K, Korff S, Zamora R, et al. Toll-like receptor 4 on both myeloid cells and


Surgery_Schwartz

Surgery_Schwartz. both bone marrow-derived cells and paren-chymal cells. J Leukoc Biol. 2008;83(1):80-88. doi: 10.1189/jlb.0407201 52. Zettel K, Korff S, Zamora R, et al. Toll-like receptor 4 on both myeloid cells and dendritic cells is required for systemic inflammation and organ damage after hemorrhagic shock with tissue trauma in mice. Front Immunol. 2017;8:1672. doi: 10.3389/fimmu.2017.01672 53. Huber-Lang M, Lambris JD, Ward PA. Innate immune responses to trauma. Nat Immunol. 2018;19(4):327-341. doi: 10.1038/s41590-018-0064-8 54. Qian C, Cao X. Regulation of Toll-like receptor signaling pathways in innate immune responses. Ann N Y Acad Sci. 2013;1283:67-74. doi: 10.1111/j.1749-6632.2012.06786.x 55. Ulrichts P, Bovijn C, Lievens S, Beyaert R, Tavernier J, Peelman F. Caspase-1 targets the TLR adaptor Mal at a cru-cial TIR-domain interaction site. J Cell Sci. 2010;123(pt 2): 256-265. doi: 10.1242/jcs.056002 56. Lahiri R, Derwa Y, Bashir Z, et al. Systemic inflam-matory response syndrome after major


Surgery_Schwartz

Surgery_Schwartz. at a cru-cial TIR-domain interaction site. J Cell Sci. 2010;123(pt 2): 256-265. doi: 10.1242/jcs.056002 56. Lahiri R, Derwa Y, Bashir Z, et al. Systemic inflam-matory response syndrome after major abdominal sur-gery predicted by early upregulation of TLR4 and TLR5. Ann Surg. 2016;263(5):1028-1037. doi: 10.1097/SLA.0000000000001248 57. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nat Rev Immunol. 2013;13(6):397-411. doi: 10.1038/nri3452 58. Jo EK, Kim JK, Shin DM, Sasakawa C. Molecular mecha-nisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2016;13(2):148-159. doi: 10.1038/cmi.2015.95 59. Kesavardhana S, Kanneganti TD. Mechanisms governing inflammasome activation, assembly and pyroptosis induc-tion. Int Immunol. 2017;29(5):201-210. doi: 10.1093/intimm/dxx018 60. Stow JL, Murray RZ. Intracellular trafficking and secretion of inflammatory cytokines. Cytokine Growth Factor Rev. 2013;24(3):227-239. doi: 10.1016/j.cytogfr.2013.04.001 61. Zhang


Surgery_Schwartz

Surgery_Schwartz. JL, Murray RZ. Intracellular trafficking and secretion of inflammatory cytokines. Cytokine Growth Factor Rev. 2013;24(3):227-239. doi: 10.1016/j.cytogfr.2013.04.001 61. Zhang AQ, Zeng L, Gu W, et al. Clinical relevance of single nucleotide polymorphisms within the entire NLRP3 gene in patients with major blunt trauma. Crit Care. 2011;15(6):R280. doi: 10.1186/cc10564 62. Osuka A, Hanschen M, Stoecklein V, Lederer JA. A protec-tive role for inflammasome activation following injury. Shock. 2012;37(1):47-55. doi: 10.1097/SHK.0b013e318234f7ff 63. Adamczak S, Dale G, de Rivero Vaccari JP, Bullock MR, Dietrich WD, Keane RW. Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomark-ers of functional outcome: clinical article. J Neurosurg. 2012;117(6):1119-1125. doi: 10.3171/2012.9.JNS12815 64. Kerr N, de Rivero Vaccari JP, Abbassi S, et al. Traumatic brain injury-induced acute lung injury: evidence for activa-tion and inhibition of a neural-respiratory-inflammasome


Surgery_Schwartz

Surgery_Schwartz. N, de Rivero Vaccari JP, Abbassi S, et al. Traumatic brain injury-induced acute lung injury: evidence for activa-tion and inhibition of a neural-respiratory-inflammasome axis. [Published online ahead of print June 8, 2018.] J Neu-rotrauma. doi: 10.1089/neu.2017.5430 65. Chiffoleau E. C-Type Lectin-like receptors as emerging orchestrators of sterile inflammation represent potential thera-peutic targets. Front Immunol. 2018;9:227. doi: 10.3389/fimmu.2018.00227 66. Richardson MB, Williams SJ. MCL and Mincle: C-type lec-tin receptors that sense damaged self and pathogen-associated molecular patterns. Front Immunol. 2014;5:288. doi: 10.3389/fimmu.2014.00288 67. Hupfer T, Schick J, Jozefowski K, Voehringer D, Ostrop J, Lang R. Stat6-dependent inhibition of Mincle expression in mouse and human antigen-presenting cells by the Th2 Cytokine IL-4. Front Immunol. 2016;7:423. doi: 10.3389/fimmu.2016.00423 68. Brown GK. Glucose transporters: structure, function and consequences of deficiency. J


Surgery_Schwartz

Surgery_Schwartz. antigen-presenting cells by the Th2 Cytokine IL-4. Front Immunol. 2016;7:423. doi: 10.3389/fimmu.2016.00423 68. Brown GK. Glucose transporters: structure, function and consequences of deficiency. J Inherit Metab Dis. 2000;23(3): 237-246. 69. Nicolls MR, Laubach VE. Traumatic brain injury: lungs in a RAGE. Sci Transl Med. 2014;6(252):252fs34. doi: 10.1126/scitranslmed.3010259 70. Oczypok EA, Perkins TN, Oury TD. All the “RAGE” in lung disease: the receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses. Paediatr Respir Rev. 2017;23:40-49. doi: 10.1016/j.prrv.2017.03.012 71. Kunes P, Holubcova Z, Kolackova M, Krejsek J. Pentraxin 3(PTX 3): an endogenous modulator of the inflamma-tory response. Mediators Inflamm. 2012;2012:920517. doi: 10.1155/2012/920517Brunicardi_Ch02_p0027-p0082.indd 7601/03/19 6:50 PM 77SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2 72. Kleber C, Becker CA, Schmidt-Bleek K, Schaser KD, Haas NP. Are


Surgery_Schwartz

Surgery_Schwartz. 7601/03/19 6:50 PM 77SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2 72. Kleber C, Becker CA, Schmidt-Bleek K, Schaser KD, Haas NP. Are pentraxin 3 and transsignaling early markers for immunologic injury severity in polytrauma? A pilot study. Clin Orthop Relat Res. 2013;471(9):2822-2830. doi: 10.1007/s11999-013-2922-x 73. Fung A, Vizcaychipi M, Lloyd D, Wan Y, Ma D. Central nervous system inflammation in disease related conditions: mechanistic prospects. Brain Res. 2012;1446:144-155. doi: 10.1016/j.brainres.2012.01.061 74. Czura CJ, Tracey KJ. Autonomic neural regulation of immunity. J Intern Med. 2005;257(2):156-166. doi: 10.1111/j.1365-2796.2004.01442.x 75. Pavlov VA, Tracey KJ. Neural regulation of immunity: molecular mechanisms and clinical translation. Nat Neuro-sci. 2017;20(2):156-166 doi: 10.1038/nn.4477 76. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458-462.


Surgery_Schwartz

Surgery_Schwartz. doi: 10.1038/nn.4477 76. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405(6785):458-462. doi: 10.1038/35013070 77. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine recep-tor alpha 7 subunit is an essential regulator of inflammation. Nature. 2003;421(6921):384-388. doi: 10.1038/nature01339 78. Rezende-Neto JB, Alves RL, Carvalho M, Jr., et al. Vagus nerve stimulation improves coagulopathy in hemorrhagic shock: a thromboelastometric animal model study. J Trauma Manag Outcomes. 2014;8:15. doi: 10.1186/1752-2897-8-15 79. Heitzer MD, Wolf IM, Sanchez ER, Witchel SF, DeFranco DB. Glucocorticoid receptor physiology. Rev Endocr Metab Dis. 2007;8(4):321-330. doi: 10.1007/s11154-007-9059-8 80. Silverman MN, Sternberg EM. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci. 2012;1261:55-63. doi:


Surgery_Schwartz

Surgery_Schwartz. MN, Sternberg EM. Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction. Ann N Y Acad Sci. 2012;1261:55-63. doi: 10.1111/j.1749-6632.2012.06633.x 81. Hardy RS, Raza K, Cooper MS. Endogenous glucocorti-coids in inflammation: contributions of systemic and local responses. Swiss Med Wkly. 2012;142:w13650. doi: 10.4414/smw.2012.13650 82. Annane D, Pastores SM, Arlt W, et al. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med. 2017;43(12): 1781-1792. doi: 10.1007/s00134-017-4914-x 83. Walker ML. Critical illness related corticosteroid insufficiency in trauma—a review. J Trauma Treat. 2012;1(6):139-144. 84. Yang Y, Liu L, Jiang D, et al. Critical illness-related cor-ticosteroid insufficiency after multiple traumas: a multi-center,


Surgery_Schwartz

Surgery_Schwartz. insufficiency in trauma—a review. J Trauma Treat. 2012;1(6):139-144. 84. Yang Y, Liu L, Jiang D, et al. Critical illness-related cor-ticosteroid insufficiency after multiple traumas: a multi-center, prospective cohort study. J Trauma Acute Care Surg. 2014;76(6):1390-1396. doi: 10.1097/TA.0000000000000221 85. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1): 296-327. doi: 10.1097/01.CCM.0000298158.12101.41 86. Annane D, Pastores SM, Rochwerg B, et al. Guidelines for the diagnosis and management of critical illness-related corticosteroid insufficiency (CIRCI) in critically ill patients (Part I): Society of Critical Care Medicine (SCCM) and European Society of Intensive Care Medicine (ESICM) 2017. Intensive Care Med. 2017;43(12):1751-1763. doi: 10.1007/s00134-017-4919-5 87. Pawig L, Klasen C, Weber C, Bernhagen J, Noels H. Diver-sity and inter-connections in the


Surgery_Schwartz

Surgery_Schwartz. Care Medicine (ESICM) 2017. Intensive Care Med. 2017;43(12):1751-1763. doi: 10.1007/s00134-017-4919-5 87. Pawig L, Klasen C, Weber C, Bernhagen J, Noels H. Diver-sity and inter-connections in the CXCR4 chemokine recep-tor/ligand family: molecular perspectives. Front Immunol. 2015;6:429. doi: 10.3389/fimmu.2015.00429 88. Flaster H, Bernhagen J, Calandra T, Bucala R. The mac-rophage migration inhibitory factor-glucocorticoid dyad: regulation of inflammation and immunity. Mol Endocrinol. 2007;21(6):1267-1280. doi: 10.1210/me.2007-0065 89. Roger T, David J, Glauser MP, Calandra T. MIF regulates innate immune responses through modulation of Toll-like receptor 4. Nature. 2001;414(6866):920-924. doi: 10.1038/414920a 90. Hayakawa M, Katabami K, Wada T, et al. Imbalance between macrophage migration inhibitory factor and corti-sol induces multiple organ dysfunction in patients with blunt trauma. Inflammation. 2011;34(3):193-197. doi: 10.1007/s10753-010-9223-2 91. Agnese DM, Calvano JE, Hahm SJ,


Surgery_Schwartz

Surgery_Schwartz. inhibitory factor and corti-sol induces multiple organ dysfunction in patients with blunt trauma. Inflammation. 2011;34(3):193-197. doi: 10.1007/s10753-010-9223-2 91. Agnese DM, Calvano JE, Hahm SJ, Calvano SE, Lowry SF. Insulin-like growth factor binding protein-3 is upregulated in LPS-treated THP-1 cells. Surg Infect (Larchmt). 2002;3(2): 119-125; discussion 25-26. doi: 10.1089/109629602760105781 92. Takala J, Ruokonen E, Webster NR, et al. Increased mortal-ity associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341(11):785-792. doi: 10.1056/NEJM199909093411102 93. Jeschke MG, Finnerty CC, Kulp GA, Przkora R, Mlcak RP, Herndon DN. Combination of recombinant human growth hor-mone and propranolol decreases hypermetabolism and inflam-mation in severely burned children. Pediatr Crit Care Med. 2008;9(2):209-216. doi: 10.1097/PCC.0b013e318166d414 94. Cheyuo C, Jacob A, Wang P. Ghrelin-mediated sympathoinhi-bition and suppression of inflammation in sepsis.


Surgery_Schwartz

Surgery_Schwartz. children. Pediatr Crit Care Med. 2008;9(2):209-216. doi: 10.1097/PCC.0b013e318166d414 94. Cheyuo C, Jacob A, Wang P. Ghrelin-mediated sympathoinhi-bition and suppression of inflammation in sepsis. Am J Physiol Endocrinol Metab. 2012;302(3):E265-E272. doi: 10.1152/ajpendo.00508.2011 95. Qi L, Cui X, Dong W, et al. Ghrelin protects rats against trau-matic brain injury and hemorrhagic shock through upregula-tion of UCP2. Ann Surg. 2014;260(1):169-178. doi: 10.1097/SLA.0000000000000328 96. Wong DL, Tai TC, Wong-Faull DC, et al. Epinephrine: a shortand long-term regulator of stress and development of illness: a potential new role for epinephrine in stress. Cell Mol Neuro-biol. 2012;32(5):737-748. doi: 10.1007/s10571-011-9768-0 97. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF. Epinephrine inhibits tumor necrosis factor-alpha and poten-tiates interleukin 10 production during human endotoxemia. J Clin Invest. 1996;97(3):713-719. doi: 10.1172/JCI118469 98. Flierl MA, Rittirsch D,


Surgery_Schwartz

Surgery_Schwartz. inhibits tumor necrosis factor-alpha and poten-tiates interleukin 10 production during human endotoxemia. J Clin Invest. 1996;97(3):713-719. doi: 10.1172/JCI118469 98. Flierl MA, Rittirsch D, Huber-Lang M, Sarma JV, Ward PA. Catecholamines-crafty weapons in the inflammatory arsenal of immune/inflammatory cells or opening pandora’s box? Mol Med. 2008;14(3-4):195-204. doi: 10.2119/2007-00105.Flierl 99. Kolmus K, Tavernier J, Gerlo S. beta2-Adrenergic recep-tors in immunity and inflammation: stressing NF-kappaB. Brain Behav Immun. 2015;45:297-310. doi: 10.1016/j.bbi.2014.10.007 100. Padro CJ, Sanders VM. Neuroendocrine regulation of inflammation. Semin Immunol. 2014;26(5):357-368. doi: 10.1016/j.smim.2014.01.003 101. Gilbert KC, Brown NJ. Aldosterone and inflammation. Curr Opin Endocrinol Diabetes Obes. 2010;17(3):199-204. 102. Van den Berghe G. How does blood glucose control with insu-lin save lives in intensive care? J Clin Invest. 2004;114(9): 1187-1195. doi:


Surgery_Schwartz

Surgery_Schwartz. Curr Opin Endocrinol Diabetes Obes. 2010;17(3):199-204. 102. Van den Berghe G. How does blood glucose control with insu-lin save lives in intensive care? J Clin Invest. 2004;114(9): 1187-1195. doi: 10.1172/JCI23506 103. Sung J, Bochicchio GV, Joshi M, Bochicchio K, Tracy K, Scalea TM. Admission hyperglycemia is predictive of outcome in critically ill trauma patients. J Trauma. 2005;59(1):80-83. 104. Kansagara D, Fu R, Freeman M, Wolf F, Helfand M. Inten-sive insulin therapy in hospitalized patients: a system-atic review. Ann Intern Med. 2011;154(4):268-282. doi: 10.7326/0003-4819-154-4-201102150-00008 105. Alazawi W, Pirmadjid N, Lahiri R, Bhattacharya S. Inflammatory and immune responses to surgery and their clinical impact. Ann Surg. 2016;264(1):73-80. doi: 10.1097/SLA.0000000000001691Brunicardi_Ch02_p0027-p0082.indd 7701/03/19 6:50 PM 78BASIC CONSIDERATIONSPART I 106. Yang Y, Bazhin AV, Werner J, Karakhanova S. Reactive oxygen species in the immune system. Int Rev Immunol.


Surgery_Schwartz

Surgery_Schwartz. 7701/03/19 6:50 PM 78BASIC CONSIDERATIONSPART I 106. Yang Y, Bazhin AV, Werner J, Karakhanova S. Reactive oxygen species in the immune system. Int Rev Immunol. 2013;32(3):249-270. doi: 10.3109/08830185.2012.755176 107. Preiser JC. Oxidative stress. JPEN J Parenter Enteral Nutr. 2012;36(2):147-154. doi: 10.1177/0148607111434963 108. C. N, Cunningham-Bussell A. Beyond oxidative stress: an immunologist’s guide to reactive oxygen species. Nat Rev Immunol. 2013;13:349-361. 109. Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10(3):210-215. doi: 10.1038/nri2725 110. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reac-tive oxygen species in inflammation and tissue injury. Anti-oxid Redox Signal. 2014;20(7):1126-1167. doi: 10.1089/ars.2012.5149 111. Belikov AV, Schraven B, Simeoni L. T cells and reactive oxygen species. J Biomed Sci. 2015;22:85. doi: 10.1186/s12929-015-0194-3 112. Schroder


Surgery_Schwartz

Surgery_Schwartz. 2014;20(7):1126-1167. doi: 10.1089/ars.2012.5149 111. Belikov AV, Schraven B, Simeoni L. T cells and reactive oxygen species. J Biomed Sci. 2015;22:85. doi: 10.1186/s12929-015-0194-3 112. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem. 2005;74:739-789. doi: 10.1146/annurev.biochem.73.011303.074134 113. Grootjans J, Kaser A, Kaufman RJ, Blumberg RS. The unfolded protein response in immunity and inflammation. Nat Rev Immunol. 2016;16(8):469-484. doi: 10.1038/nri.2016.62 114. Jeschke MG, Boehning D. Endoplasmic reticulum stress and insulin resistance post-trauma: similarities to type 2 diabetes. J Cell Mol Med. 2012;16(3):437-444. doi: 10.1111/j.1582-4934.2011.01405.x 115. D’Osualdo A, Anania VG, Yu K, et al. Transcription factor ATF4 induces NLRP1 inflammasome expression during endo-plasmic reticulum stress. PLoS One. 2015;10(6):e0130635. doi: 10.1371/journal.pone.0130635 116. Smith JA. Regulation of cytokine production by the unfolded protein


Surgery_Schwartz

Surgery_Schwartz. inflammasome expression during endo-plasmic reticulum stress. PLoS One. 2015;10(6):e0130635. doi: 10.1371/journal.pone.0130635 116. Smith JA. Regulation of cytokine production by the unfolded protein response; implications for infection and autoimmunity. Front Immunol. 2018;9:422. doi: 10.3389/fimmu.2018.00422 117. Jeschke MG, Finnerty CC, Herndon DN, et al. Severe injury is associated with insulin resistance, endoplasmic reticulum stress response, and unfolded protein response. Ann Surg. 2012;255(2):370-378. doi: 10.1097/SLA.0b013e31823e76e7 118. Thiessen SE, Van den Berghe G, Vanhorebeek I. Mitochondrial and endoplasmic reticulum dysfunction and related defense mechanisms in critical illness-induced multiple organ failure. Biochim Biophys Acta. 2017;1863(10 pt B):2534-2545. doi: 10.1016/j.bbadis.2017.02.015 119. Salminen A, Kaarniranta K, Kauppinen A. Integrated stress response stimulates FGF21 expression: systemic enhancer of longevity. Cell Signal. 2017;40:10-21. doi:


Surgery_Schwartz

Surgery_Schwartz. doi: 10.1016/j.bbadis.2017.02.015 119. Salminen A, Kaarniranta K, Kauppinen A. Integrated stress response stimulates FGF21 expression: systemic enhancer of longevity. Cell Signal. 2017;40:10-21. doi: 10.1016/j.cellsig.2017.08.009 120. Thiessen SE, Vanhorebeek I, Derese I, Gunst J, Van den Berghe G. FGF21 response to critical illness: effect of blood glucose control and relation with cellular stress and survival. J Clin Endocrinol Metab. 2015;100(10):E1319-E1327. doi: 10.1210/jc.2015-2700 121. Jones SA, Mills KH, Harris J. Autophagy and inflamma-tory diseases. Immunol Cell Biol. 2013;91(3):250-258. doi: 10.1038/icb.2012.82 122. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011;469(7330):323-335. doi: 10.1038/nature09782 123. Yen YT, Yang HR, Lo HC, et al. Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury. Surgery. 2013;153(5):689-698. doi: 10.1016/j.surg.2012.11.021 124. Jean-Baptiste E.


Surgery_Schwartz

Surgery_Schwartz. al. Enhancing autophagy with activated protein C and rapamycin protects against sepsis-induced acute lung injury. Surgery. 2013;153(5):689-698. doi: 10.1016/j.surg.2012.11.021 124. Jean-Baptiste E. Cellular mechanisms in sepsis. J Intensive Care Med. 2007;22(2):63-72. doi: 10.1177/0885066606297123 125. Kaczmarek A, Vandenabeele P, Krysko DV. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 2013;38(2):209-223. doi: 10.1016/j.immuni.2013.02.003 126. Duprez L, Takahashi N, Van Hauwermeiren F, et al. RIP kinase-dependent necrosis drives lethal systemic inflamma-tory response syndrome. Immunity. 2011;35(6):908-918. doi: 10.1016/j.immuni.2011.09.020 127. Vande Walle L, Lamkanfi M. Pyroptosis. Curr Biol. 2016;26(13):R568-R572. doi: 10.1016/j.cub.2016.02.019 128. Man SM, Karki R, Kanneganti TD. Molecular mecha-nisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev.


Surgery_Schwartz

Surgery_Schwartz. doi: 10.1016/j.cub.2016.02.019 128. Man SM, Karki R, Kanneganti TD. Molecular mecha-nisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 2017;277(1):61-75. doi: 10.1111/imr.12534 129. Wang YC, Liu QX, Liu T, et al. Caspase-1-dependent pyrop-tosis of peripheral blood mononuclear cells predicts the devel-opment of sepsis in severe trauma patients: a prospective observational study. Medicine (Baltimore). 2018;97(8):e9859. doi: 10.1097/MD.0000000000009859 130. Waters JP, Pober JS, Bradley JR. Tumour necrosis factor in infectious disease. J Pathol. 2013;230(2):132-147. doi: 10.1002/path.4187 131. Khalil AA, Hall JC, Aziz FA, Price P. Tumour necrosis factor: implications for surgical patients. ANZ J Surg. 2006;76(11): 1010-1016. doi: 10.1111/j.1445-2197.2006.03921.x 132. Dekker AB, Krijnen P, Schipper IB. Predictive value of cyto-kines for developing complications after polytrauma. World J Crit Care Med. 2016;5(3):187-200. doi:


Surgery_Schwartz

Surgery_Schwartz. 10.1111/j.1445-2197.2006.03921.x 132. Dekker AB, Krijnen P, Schipper IB. Predictive value of cyto-kines for developing complications after polytrauma. World J Crit Care Med. 2016;5(3):187-200. doi: 10.5492/wjccm.v5.i3.187 133. Di Paolo NC, Shayakhmetov DM. Interleukin 1alpha and the inflammatory process. Nat Immunol. 2016;17(8):906-913. doi: 10.1038/ni.3503 134. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117(14):3720-3732. doi: 10.1182/blood-2010-07-273417 135. Sitia R, Rubartelli A. The unconventional secretion of IL-1beta: handling a dangerous weapon to optimize inflamma-tory responses. [Published online ahead of print April 4, 2018.] Semin Cell Dev Biol. doi: 10.1016/j.semcdb.2018.03.011 136. Stylianou E, Saklatvala J. Interleukin-1. Int J Biochem Cell Biol. 1998;30(10):1075-1079. 137. Sun M, Brady RD, Wright DK, et al. Treatment with an interleukin-1 receptor antagonist mitigates neuroinflamma-tion and brain damage after


Surgery_Schwartz

Surgery_Schwartz. Int J Biochem Cell Biol. 1998;30(10):1075-1079. 137. Sun M, Brady RD, Wright DK, et al. Treatment with an interleukin-1 receptor antagonist mitigates neuroinflamma-tion and brain damage after polytrauma. Brain Behav Immun. 2017;66:359-371. doi: 10.1016/j.bbi.2017.08.005 138. Dinarello CA, Fantuzzi G. Interleukin-18 and host defense against infection. J Infect Dis. 2003;187(suppl 2):S370-S384. doi: 10.1086/374751 139. Kaplanski G. Interleukin-18: Biological properties and role in disease pathogenesis. Immunol Rev. 2018;281(1):138-153. doi: 10.1111/imr.12616 140. Novick D, Kim S, Kaplanski G, Dinarello CA. Interleukin-18, more than a Th1 cytokine. Semin Immunol. 2013;25(6): 439-448. doi: 10.1016/j.smim.2013.10.014 141. Dolinay T, Kim YS, Howrylak J, et al. Inflammasome-regu-lated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med. 2012;185(11):1225-1234. doi: 10.1164/rccm.201201-0003OC 142. Kinoshita M, Miyazaki H, Ono S, Seki S. Immunoenhanc-ing therapy


Surgery_Schwartz

Surgery_Schwartz. are critical mediators of acute lung injury. Am J Respir Crit Care Med. 2012;185(11):1225-1234. doi: 10.1164/rccm.201201-0003OC 142. Kinoshita M, Miyazaki H, Ono S, Seki S. Immunoenhanc-ing therapy with interleukin-18 against bacterial infection in immunocompromised hosts after severe surgical stress. J Leukoc Biol. 2013;93(5):689-698. doi: 10.1189/jlb.1012502 143. Molofsky AB, Savage AK, Locksley RM. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity. 2015;42(6):1005-1019. doi: 10.1016/j.immuni.2015.06.006 144. Bessa J, Meyer CA, de Vera Mudry MC, et al. Altered sub-cellular localization of IL-33 leads to non-resolving lethal inflammation. J Autoimmun. 2014;55:33-41. doi: 10.1016/j.jaut.2014.02.012Brunicardi_Ch02_p0027-p0082.indd 7801/03/19 6:50 PM 79SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2 145. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13-25. doi:


Surgery_Schwartz

Surgery_Schwartz. TO INJURY AND METABOLIC SUPPORTCHAPTER 2 145. Liao W, Lin JX, Leonard WJ. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity. 2013;38(1):13-25. doi: 10.1016/j.immuni.2013.01.004 146. Bachmann MF, Oxenius A. Interleukin 2: from immunos-timulation to immunoregulation and back again. EMBO Rep. 2007;8(12):1142-1148. doi: 10.1038/sj.embor.7401099 147. Jawa RS, Anillo S, Huntoon K, Baumann H, Kulaylat M. Interleukin-6 in surgery, trauma, and critical care part II: clini-cal implications. J Intensive Care Med. 2011;26(2):73-87. doi: 10.1177/0885066610395679 148. Rose-John S. IL-6 trans-signaling via the soluble IL-6 recep-tor: importance for the proinflammatory activities of IL-6. Int J Biol Sci. 2012;8(9):1237-1247. doi: 10.7150/ijbs.4989 149. Song M, Kellum JA. Interleukin-6. Crit Care Med. 2005;33(12 suppl):S463-S465. 150. Qiao Z, Wang W, Yin L, et al. Using IL-6 concentrations in the first 24 h following trauma to predict immunological


Surgery_Schwartz

Surgery_Schwartz. M, Kellum JA. Interleukin-6. Crit Care Med. 2005;33(12 suppl):S463-S465. 150. Qiao Z, Wang W, Yin L, et al. Using IL-6 concentrations in the first 24 h following trauma to predict immunological com-plications and mortality in trauma patients: a meta-analysis. [Published online ahead of print November 14, 2017.] Eur J Trauma Emerg Surg. 2017. doi: 10.1007/s00068-017-0880-9 151. Hutchins AP, Diez D, Miranda-Saavedra D. The IL-10/STAT3-mediated anti-inflammatory response: recent devel-opments and future challenges. Brief Funct Genomics. 2013; 12(6):489-498. doi: 10.1093/bfgp/elt028 152. Vignali DA, Kuchroo VK. IL-12 family cytokines: immuno-logical playmakers. Nat Immunol. 2012;13(8):722-728. doi: 10.1038/ni.2366 153. Weijer S, Florquin S, van der Poll T. Endogenous interleu-kin-12 improves the early antimicrobial host response to murine Escherichia coli peritonitis. Shock. 2005;23(1): 54-58. 154. Abboud A, Namas RA, Ramadan M, et al. Computa-tional analysis supports an early, type 17


Surgery_Schwartz

Surgery_Schwartz. the early antimicrobial host response to murine Escherichia coli peritonitis. Shock. 2005;23(1): 54-58. 154. Abboud A, Namas RA, Ramadan M, et al. Computa-tional analysis supports an early, type 17 cell-associated divergence of blunt trauma survival and mortality. Crit Care Med. 2016;44(11):e1074-e1081. doi: 10.1097/CCM.0000000000001951 155. Seshadri A, Brat GA, Yorkgitis BK, et al. Phenotyping the immune response to trauma: a multiparametric sys-tems immunology approach. Crit Care Med. 2017;45(9): 1523-1530. doi: 10.1097/CCM.0000000000002577 156. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Ann Rev Immunol. 2009;27:485-517. doi: 10.1146/annurev.immunol.021908.132710 157. Veldhoen M. Interleukin 17 is a chief orchestrator of immu-nity. Nat Immunol. 2017;18(6):612-621. doi: 10.1038/ni.3742 158. Rauch I, Muller M, Decker T. The regulation of inflamma-tion by interferons and their STATs. JAK-STAT. 2013;2(1): e23820-1-13. 159. Kernbauer E, Maier V, Rauch I, Muller M,


Surgery_Schwartz

Surgery_Schwartz. doi: 10.1038/ni.3742 158. Rauch I, Muller M, Decker T. The regulation of inflamma-tion by interferons and their STATs. JAK-STAT. 2013;2(1): e23820-1-13. 159. Kernbauer E, Maier V, Rauch I, Muller M, Decker T. Route of infection determines the impact of type I interferons on innate immunity to Listeria monocytogenes. PLoS One. 2013;8(6):e65007. doi: 10.1371/journal.pone.0065007 160. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75(2):163-189. doi: 10.1189/jlb.0603252 161. Kamp VM, Leentjens J, Pillay J, et al. Modulation of granu-locyte kinetics by GM-CSF/IFN-gamma in a human LPS rechallenge model. J Leukoc Biol. 2013;94(3):513-520. doi: 10.1189/jlb.0213066 162. Ott J, Hiesgen C, Mayer K. Lipids in critical care medi-cine. Prostaglandins Leukot Essent Fatty Acids. 2011;85(5): 267-273. doi: 10.1016/j.plefa.2011.04.011 163. Stringham JR, Moore EE, Gamboni F, et al. Mesenteric lymph diversion abrogates


Surgery_Schwartz

Surgery_Schwartz. care medi-cine. Prostaglandins Leukot Essent Fatty Acids. 2011;85(5): 267-273. doi: 10.1016/j.plefa.2011.04.011 163. Stringham JR, Moore EE, Gamboni F, et al. Mesenteric lymph diversion abrogates 5-lipoxygenase activation in the kidney following trauma and hemorrhagic shock. J Trauma Acute Care Surg. 2014;76(5):1214-1221. doi: 10.1097/TA.0000000000000231 164. Stormann P, Auner B, Schimunek L, et al. Leukotriene B4 indicates lung injury and on-going inflammatory changes after severe trauma in a porcine long-term model. Prostaglandins Leukot Essent Fatty Acids. 2017;127:25-31. doi: 10.1016/j.plefa.2017.09.014 165. Zhang MJ, Spite M. Resolvins: anti-inflammatory and pro-resolving mediators derived from omega-3 polyunsaturated fatty acids. Ann Rev Nutr. 2012;32:203-227. doi: 10.1146/annurev-nutr-071811-150726 166. Calder PC, Adolph M, Deutz NE, et al. Lipids in the intensive care unit: recommendations from the ESPEN Expert Group. Clin Nutr. 2018;37(1):1-18. doi:


Surgery_Schwartz

Surgery_Schwartz. doi: 10.1146/annurev-nutr-071811-150726 166. Calder PC, Adolph M, Deutz NE, et al. Lipids in the intensive care unit: recommendations from the ESPEN Expert Group. Clin Nutr. 2018;37(1):1-18. doi: 10.1016/j.clnu.2017.08.032 167. Calder PC. n-3 fatty acids, inflammation, and immunity—relevance to postsurgical and critically ill patients. Lipids. 2004;39(12):1147-1161. 168. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Comple-ment: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785-797. doi: 10.1038/ni.1923 169. Huber-Lang M, Gebhard F, Schmidt CQ, Palmer A, Denk S, Wiegner R. Complement therapeutic strategies in trauma, hemorrhagic shock and systemic inflammation—closing Pandora’s box? Semin Immunol. 2016;28(3):278-284. doi: 10.1016/j.smim.2016.04.005 170. Ekdahl KN, Teramura Y, Hamad OA, et al. Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. Immunol Rev.


Surgery_Schwartz

Surgery_Schwartz. KN, Teramura Y, Hamad OA, et al. Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. Immunol Rev. 2016;274(1):245-269. doi: 10.1111/imr.12471 171. Saxena P, Thompson P, d’Udekem Y, Konstantinov IE. Kallikrein-kinin system: a surgical perspective in post-aprotinin era. J Surg Res. 2011;167(1):70-77. doi: 10.1016/j.jss.2009.12.020. 172. Faerber L, Drechsler S, Ladenburger S, Gschaidmeier H, Fischer W. The neuronal 5-HT3 receptor network after 20 years of research—evolving concepts in management of pain and inflammation. Eur J Pharmacol. 2007;560(1):1-8. doi: 10.1016/j.ejphar.2007.01.028 173. Duerschmied D, Suidan GL, Demers M, et al. Platelet sero-tonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood. 2013;121(6):1008-1015. doi: 10.1182/blood-2012-06-437392 174. de Esch IJ, Thurmond RL, Jongejan A, Leurs R. The hista-mine H4 receptor as a new therapeutic target


Surgery_Schwartz

Surgery_Schwartz. acute inflammation in mice. Blood. 2013;121(6):1008-1015. doi: 10.1182/blood-2012-06-437392 174. de Esch IJ, Thurmond RL, Jongejan A, Leurs R. The hista-mine H4 receptor as a new therapeutic target for inflammation. Trends Pharmacol Sci. 2005;26(9):462-469. doi: 10.1016/j.tips.2005.07.002 175. O’Mahony L, Akdis M, Akdis CA. Regulation of the immune response and inflammation by histamine and histamine recep-tors. J Allergy Clin Immunol. 2011;128(6):1153-1162. doi: 10.1016/j.jaci.2011.06.051 176. Villarino AV, Kanno Y, O’Shea JJ. Mechanisms and conse-quences of Jak-STAT signaling in the immune system. Nat Immunol. 2017;18(4):374-384. doi: 10.1038/ni.3691 177. Moodley D, Yoshida H, Mostafavi S, et al. Network phar-macology of JAK inhibitors. Proc Natl Acad Sci U S A. 2016;113(35):9852-9857. doi: 10.1073/pnas.1610253113 178. Leonard WJ, O’Shea JJ. Jaks and STATs: biological impli-cations. Ann Rev Immunol. 1998;16:293-322 doi: 10.1146/annurev.immunol.16.1.293 179. Perez-Baos S,


Surgery_Schwartz

Surgery_Schwartz. doi: 10.1073/pnas.1610253113 178. Leonard WJ, O’Shea JJ. Jaks and STATs: biological impli-cations. Ann Rev Immunol. 1998;16:293-322 doi: 10.1146/annurev.immunol.16.1.293 179. Perez-Baos S, Prieto-Potin I, Roman-Blas JA, Sanchez-Pernaute O, Largo R, Herrero-Beaumont G. Mediators and patterns of muscle loss in chronic systemic inflammation. Front Physiol. 2018;9:409. doi: 10.3389/fphys.2018.00409 180. Duncan SA, Baganizi DR, Sahu R, Singh SR, Dennis VA. SOCS proteins as regulators of inflammatory responses induced by bacterial infections: a review. Front Microbiol. 2017;8:2431. doi: 10.3389/fmicb.2017.02431 181. Zhou D, Chen L, Yang K, Jiang H, Xu W, Luan J. SOCS molecules: the growing players in macrophage polarization Brunicardi_Ch02_p0027-p0082.indd 7901/03/19 6:50 PM 80BASIC CONSIDERATIONSPART Iand function. Oncotarget. 2017;8(36):60710-60722. doi: 10.18632/oncotarget.19940 182. Trengove MC, Ward AC. SOCS proteins in development and disease. Am J Clin Exp Immunol.


Surgery_Schwartz

Surgery_Schwartz. CONSIDERATIONSPART Iand function. Oncotarget. 2017;8(36):60710-60722. doi: 10.18632/oncotarget.19940 182. Trengove MC, Ward AC. SOCS proteins in development and disease. Am J Clin Exp Immunol. 2013;2(1):1-29. 183. Sun L, Ye RD. Role of G protein-coupled receptors in inflam-mation. Acta Pharmacologica Sinica. 2012;33(3):342-350. doi: 10.1038/aps.2011.200 184. Yoshimura A, Wakabayashi Y, Mori T. Cellular and molecular basis for the regulation of inflammation by TGF-beta. J Biochem. 2010;147(6):781-792. doi: 10.1093/jb/mvq043 185. Licciardi PV, Karagiannis TC. Regulation of immune responses by histone deacetylase inhibitors. ISRN Hematol. 2012;2012:690901. doi: 10.5402/2012/690901 186. Halaweish I, Nikolian V, Georgoff P, Li Y, Alam HB. Creat-ing a “prosurvival phenotype” through histone deacetylase inhibition: past, present, and future. Shock. 2015;44(suppl 1):6-16. doi: 10.1097/SHK.0000000000000319 187. Chang P, Weykamp M, Dennahy IS, et al. Histone deacety-lase inhibitors: isoform


Surgery_Schwartz

Surgery_Schwartz. deacetylase inhibition: past, present, and future. Shock. 2015;44(suppl 1):6-16. doi: 10.1097/SHK.0000000000000319 187. Chang P, Weykamp M, Dennahy IS, et al. Histone deacety-lase inhibitors: isoform selectivity improves survival in a hemorrhagic shock model. J Trauma Acute Care Surg. 2018;84(5):795-801. doi: 10.1097/TA.0000000000001824 188. Georgoff PE, Nikolian VC, Bonham T, et al. Safety and tol-erability of intravenous valproic acid in healthy subjects: a phase I dose-escalation trial. Clin Pharmacokinet. 2018;57(2): 209-219. doi: 10.1007/s40262-017-0553-1 189. Ameres SL, Zamore PD. Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol. 2013;14(8):475-488. doi: 10.1038/nrm3611 190. O’Neill LA, Sheedy FJ, McCoy CE. MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol. 2011;11(3):163-175. doi: 10.1038/nri2957 191. Wang J. Neutrophils in tissue injury and repair. Cell Tissue Res. 2018;371(3):531-539. doi: 10.1007/s00441-017-2785-7 192. Day RB,


Surgery_Schwartz

Surgery_Schwartz. Nat Rev Immunol. 2011;11(3):163-175. doi: 10.1038/nri2957 191. Wang J. Neutrophils in tissue injury and repair. Cell Tissue Res. 2018;371(3):531-539. doi: 10.1007/s00441-017-2785-7 192. Day RB, Link DC. Regulation of neutrophil trafficking from the bone marrow. Cell Mol Life Sci. 2012;69(9):1415-1423. doi: 10.1007/s00018-011-0870-8 193. Hazeldine J, Hampson P, Lord JM. The impact of trauma on neutrophil function. Injury. 2014;45(12):1824-1833. doi: 10.1016/j.injury.2014.06.021 194. Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol. 2012;189(6):2689-2695. doi: 10.4049/jimmunol.1201719 195. Alves-Filho JC, Tavares-Murta BM, Barja-Fidalgo C, et al. Neutrophil function in severe sepsis. Endocr Metab Immune Dis Drug Targets. 2006;6(2):151-158. 196. Wang J, Hossain M, Thanabalasuriar A, Gunzer M, Meininger C, Kubes P. Visualizing the function and fate of neutro-phils in sterile injury and repair. Science. 2017;358(6359): 111-116. doi:


Surgery_Schwartz

Surgery_Schwartz. J, Hossain M, Thanabalasuriar A, Gunzer M, Meininger C, Kubes P. Visualizing the function and fate of neutro-phils in sterile injury and repair. Science. 2017;358(6359): 111-116. doi: 10.1126/science.aam9690 197. Peiseler M, Kubes P. Macrophages play an essential role in trauma-induced sterile inflammation and tissue repair. Eur J Trauma Emerg Surg. 2018;44(3):335-349. doi: 10.1007/s00068-018-0956-1 198. Rosas M, Davies LC, Giles PJ, et al. The transcription fac-tor Gata6 links tissue macrophage phenotype and prolifera-tive renewal. Science. 2014;344(6184):645-648. doi: 10.1126/science.1251414 199. Venereau E, Schiraldi M, Uguccioni M, Bianchi ME. HMGB1 and leukocyte migration during trauma and sterile inflam-mation. Mol Immunol. 2013;55(1):76-82. doi: 10.1016/j.molimm.2012.10.037 200. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11(11):723-737. doi: 10.1038/nri3073 201. Wynn TA, Chawla A, Pollard JW. Macrophage biol-ogy in


Surgery_Schwartz

Surgery_Schwartz. PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 2011;11(11):723-737. doi: 10.1038/nri3073 201. Wynn TA, Chawla A, Pollard JW. Macrophage biol-ogy in development, homeostasis and disease. Nature. 2013;496(7446):445-455. doi: 10.1038/nature12034 202. Xiang M, Yuan Y, Fan L, et al. Role of macrophages in mobi-lization of hematopoietic progenitor cells from bone marrow after hemorrhagic shock. Shock. 2012;37(5):518-523. doi: 10.1097/SHK.0b013e318249b81d 203. Niesler U, Palmer A, Radermacher P, Huber-Lang MS. Role of alveolar macrophages in the inflammatory response after trauma. Shock. 2014;42(1):3-10. doi: 10.1097/SHK.0000000000000167 204. Safavian D, Leung CH, Kapus A, et al. Hemorrhagic shock/resuscitation reduces the M2 phenotype of alveolar macro-phages: a potential mechanism contributing to increased LPS-induced lung injury. [Published online ahead of print February 27, 2018.] Shock. doi: 10.1097/SHK.0000000000001135 205. Manson J, Cole E,


Surgery_Schwartz

Surgery_Schwartz. a potential mechanism contributing to increased LPS-induced lung injury. [Published online ahead of print February 27, 2018.] Shock. doi: 10.1097/SHK.0000000000001135 205. Manson J, Cole E, De’Ath HD, et al. Early changes within the lymphocyte population are associated with the development of multiple organ dysfunction syndrome in trauma patients. Crit Care. 2016;20(1):176. doi: 10.1186/s13054-016-1341-2 206. Rendon JL, Choudhry MA. Th17 cells: critical mediators of host responses to burn injury and sepsis. J Leukoc Biol. 2012;92(3):529-538. doi: 10.1189/jlb.0212083 207. Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Miyazaki M. Immunosuppression following surgical and traumatic injury. Surg Today. 2010;40(9):793-808. doi: 10.1007/s00595-010-4323-z 208. Pillay J, Tak T, Kamp VM, Koenderman L. Immune suppres-sion by neutrophils and granulocytic myeloid-derived sup-pressor cells: similarities and differences. Cell Mol Life Sci. 2013;70(20):3813-3827. doi:


Surgery_Schwartz

Surgery_Schwartz. J, Tak T, Kamp VM, Koenderman L. Immune suppres-sion by neutrophils and granulocytic myeloid-derived sup-pressor cells: similarities and differences. Cell Mol Life Sci. 2013;70(20):3813-3827. doi: 10.1007/s00018-013-1286-4 209. Gallo PM, Gallucci S. The dendritic cell response to clas-sic, emerging, and homeostatic danger signals. Implications for autoimmunity. Front Immunol. 2013;4:138. doi: 10.3389/fimmu.2013.00138 210. Islam MN, Bradley BA, Ceredig R. Sterile post-traumatic immunosuppression. Clin Transl Immunology. 2016;5(4):e77. doi: 10.1038/cti.2016.13 211. Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P. Platelets express functional Toll-like receptor-4. Blood. 2005;106(7):2417-2423. doi: 10.1182/blood-2005-03-0916 212. Clark SR, Ma AC, Tavener SA, et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13(4):463-469. doi: 10.1038/nm1565 213. Sillesen M, Johansson PI, Rasmussen LS, et al. Platelet


Surgery_Schwartz

Surgery_Schwartz. TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007;13(4):463-469. doi: 10.1038/nm1565 213. Sillesen M, Johansson PI, Rasmussen LS, et al. Platelet acti-vation and dysfunction in a large-animal model of traumatic brain injury and hemorrhage. J Trauma Acute Care Surg. 2013;74(5):1252-1259. doi: 10.1097/TA.0b013e31828c7a6b 214. Bachelet I, Levi-Schaffer F. Mast cells as effector cells: a co-stimulating question. Trends Immunol. 2007;28(8):360-365 doi: 10.1016/j.it.2007.06.007 215. Johansson PI, Henriksen HH, Stensballe J, et al. Traumatic endotheliopathy: a prospective observational study of 424 severely injured patients. Ann Surg. 2017;265(3):597-603. doi: 10.1097/SLA.0000000000001751 216. Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159-175. doi: 10.1038/nri3399 217. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte


Surgery_Schwartz

Surgery_Schwartz. function in health and inflammation. Nat Rev Immunol. 2013;13(3):159-175. doi: 10.1038/nri3399 217. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7(9):678-689. doi: 10.1038/nri2156 218. Almahmoud K, Namas RA, Zaaqoq AM, et al. Prehospital hypotension is associated with altered inflammation dynam-ics and worse outcomes following blunt trauma in humans. Crit Care Med. 2015;43(7):1395-1404. doi: 10.1097/CCM.0000000000000964 219. Zaaqoq AM, Namas R, Almahmoud K, et al. Induc-ible protein-10, a potential driver of neurally controlled Brunicardi_Ch02_p0027-p0082.indd 8001/03/19 6:50 PM 81SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORTCHAPTER 2interleukin-10 and morbidity in human blunt trauma. Crit Care Med. 2014;42(6):1487-1497. doi: 10.1097/CCM.0000000000000248 220. Namas RA, Mi Q, Namas R, et al. Insights into the role of chemokines, damage-associated molecular patterns, and


Surgery_Schwartz

Surgery_Schwartz. trauma. Crit Care Med. 2014;42(6):1487-1497. doi: 10.1097/CCM.0000000000000248 220. Namas RA, Mi Q, Namas R, et al. Insights into the role of chemokines, damage-associated molecular patterns, and lymphocyte-derived mediators from computational models of trauma-induced inflammation. Antioxid Redox Signal. 2015;23(17):1370-1387. doi: 10.1089/ars.2015.6398 221. Fortin CF, McDonald PP, Fulop T, Lesur O. Sepsis, leu-kocytes, and nitric oxide (NO): an intricate affair. Shock. 2010;33(4):344-352. doi: 10.1097/SHK.0b013e3181c0f068 222. Bogdan C. Nitric oxide synthase in innate and adaptive immu-nity: an update. Trends Immunol. 2015;36(3):161-178. doi: 10.1016/j.it.2015.01.003 223. Darwiche SS, Pfeifer R, Menzel C, et al. Inducible nitric oxide synthase contributes to immune dysfunction fol-lowing trauma. Shock. 2012;38(5):499-507. doi: 10.1097/SHK.0b013e31826c5afe 224. Garcia-Ortiz A, Serrador JM. Nitric oxide signaling in T cell-mediated immunity. Trends Mol Med. 2018;24(4):412-427. doi:


Surgery_Schwartz

Surgery_Schwartz. trauma. Shock. 2012;38(5):499-507. doi: 10.1097/SHK.0b013e31826c5afe 224. Garcia-Ortiz A, Serrador JM. Nitric oxide signaling in T cell-mediated immunity. Trends Mol Med. 2018;24(4):412-427. doi: 10.1016/j.molmed.2018.02.002 225. Cauwels A. Nitric oxide in shock. Kidney Int. 2007;72(5): 557-565. doi: 10.1038/sj.ki.5002340 226. Su F, Huang H, Akieda K, et al. Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock. Shock. 2010;34(3):243-249. doi: 10.1097/SHK.0b013e3181d75967 227. Villalba N, Sackheim AM, Nunez IA, et al. Traumatic brain injury causes endothelial dysfunction in the systemic microcir-culation through arginase-1-dependent uncoupling of endothe-lial nitric oxide synthase. J Neurotrauma. 2017;34(1):192-203. doi: 10.1089/neu.2015.4340 228. Zardi EM, Zardi DM, Dobrina A, Afeltra A. Prostacyclin in sep-sis: a systematic review. Prostaglandins Other Lipid Mediat. 2007;83(1-2):1-24. doi: 10.1016/j.prostaglandins.2006.12.004 229. Wahlstrom MR,


Surgery_Schwartz

Surgery_Schwartz. EM, Zardi DM, Dobrina A, Afeltra A. Prostacyclin in sep-sis: a systematic review. Prostaglandins Other Lipid Mediat. 2007;83(1-2):1-24. doi: 10.1016/j.prostaglandins.2006.12.004 229. Wahlstrom MR, Olivecrona M, Ahlm C, et al. Effects of pros-tacyclin on the early inflammatory response in patients with traumatic brain injury-a randomised clinical study. Springer-plus. 2014;3:98. doi: 10.1186/2193-1801-3-98 230. Yeager ME, Belchenko DD, Nguyen CM, Colvin KL, Ivy DD, Stenmark KR. Endothelin-1, the unfolded protein response, and persistent inflammation: role of pulmonary artery smooth muscle cells. Am J Respir Cell Mol Biol. 2012;46(1):14-22. doi: 10.1165/rcmb.2010-0506OC 231. Piechota M, Banach M, Irzmanski R, et al. Plasma endothelin-1 lev-els in septic patients. J Intensive Care Med. 2007;22(4):232-239. 232. Duan C, Yang G, Li T, Liu L. Advances in vascular hyporeac-tivity after shock: the mechanisms and managements. Shock. 2015;44(6):524-534. doi:


Surgery_Schwartz

Surgery_Schwartz. patients. J Intensive Care Med. 2007;22(4):232-239. 232. Duan C, Yang G, Li T, Liu L. Advances in vascular hyporeac-tivity after shock: the mechanisms and managements. Shock. 2015;44(6):524-534. doi: 10.1097/SHK.0000000000000457 233. Rondina MT, Weyrich AS, Zimmerman GA. Platelets as cellular effectors of inflammation in vascular dis-eases. Circ Res. 2013;112(11):1506-1519. doi: 10.1161/CIRCRESAHA.113.300512 234. Zimmerman GA, McIntyre TM, Prescott SM, Stafforini DM. The platelet-activating factor signaling system and its regula-tors in syndromes of inflammation and thrombosis. Crit Care Med. 2002;30(5 suppl):S294-S301. 235. Varpula M, Pulkki K, Karlsson S, Ruokonen E, Pettila V. Pre-dictive value of N-terminal pro-brain natriuretic peptide in severe sepsis and septic shock. Crit Care Med. 2007;35(5): 1277-1283. doi: 10.1097/01.CCM.0000261893.72811.0F 236. Qian A, Zhang M, Zhao G. Dynamic detection of N-terminal pro-B-type natriuretic peptide helps to predict the outcome of patients


Surgery_Schwartz

Surgery_Schwartz. 2007;35(5): 1277-1283. doi: 10.1097/01.CCM.0000261893.72811.0F 236. Qian A, Zhang M, Zhao G. Dynamic detection of N-terminal pro-B-type natriuretic peptide helps to predict the outcome of patients with major trauma. Eur J Trauma Emerg Surg. 2015;41(1):57-64. doi: 10.1007/s00068-014-0406-7 237. Mitch WE, Price SR. Mechanisms activating proteolysis to cause muscle atrophy in catabolic conditions. J Ren Nutr. 2003;13(2):149-152. doi: 10.1053/jren.2003.50019 238. Uehara M, Plank LD, Hill GL. Components of energy expen-diture in patients with severe sepsis and major trauma: a basis for clinical care. Crit Care Med. 1999;27(7):1295-1302. 239. Guirao X. Impact of the inflammatory reaction on intermediary metab-olism and nutrition status. Nutrition. 2002;18(11-12):949-952. 240. Souba WW. Nutritional support. N Engl J Med. 1997;336(1): 41-48. doi: 10.1056/NEJM199701023360107 241. Bistrian BR. Clinical aspects of essential fatty acid metabo-lism: Jonathan Rhoads Lecture. JPEN J Parenter Enteral


Surgery_Schwartz

Surgery_Schwartz. support. N Engl J Med. 1997;336(1): 41-48. doi: 10.1056/NEJM199701023360107 241. Bistrian BR. Clinical aspects of essential fatty acid metabo-lism: Jonathan Rhoads Lecture. JPEN J Parenter Enteral Nutr. 2003;27(3):168-175. 242. Dahn MS, Mitchell RA, Lange MP, Smith S, Jacobs LA. Hepatic metabolic response to injury and sepsis. Surgery. 1995;117(5):520-530. 243. Vidal-Puig A, O’Rahilly S. Metabolism. Controlling the glucose factory. Nature. 2001;413(6852):125-126. doi: 10.1038/35093198 244. Volpi E, Sheffield-Moore M, Rasmussen BB, Wolfe RR. Basal muscle amino acid kinetics and protein synthesis in healthy young and older men. JAMA. 2001;286(10):1206-1212. 245. Kondrup J, Rasmussen HH, Hamberg O, Stanga Z, Ad Hoc EWG. Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials. Clin Nutr. 2003;22(3):321-336. 246. Heyland DK, Dhaliwal R, Jiang X, Day AG. Identifying critically ill patients who benefit the most from nutrition therapy: the


Surgery_Schwartz

Surgery_Schwartz. of controlled clinical trials. Clin Nutr. 2003;22(3):321-336. 246. Heyland DK, Dhaliwal R, Jiang X, Day AG. Identifying critically ill patients who benefit the most from nutrition therapy: the development and initial validation of a novel risk assessment tool. Crit Care. 2011;15(6):R268. doi: 10.1186/cc10546 247. Taylor BE, McClave SA, Martindale RG, et al. Guide-lines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Paren-teral and Enteral Nutrition (A.S.P.E.N.). Crit Care Med. 2016;44(2):390-438. doi: 10.1097/CCM.0000000000001525 248. Singer P, Anbar R, Cohen J, et al. The tight calorie control study (TICACOS): a prospective, randomized, controlled pilot study of nutritional support in critically ill patients. Intensive Care Med. 2011;37(4):601-609. doi: 10.1007/s00134-011-2146-z 249. Heslin MJ, Brennan MF. Advances in perioperative nutrition: cancer. World J Surg.


Surgery_Schwartz

Surgery_Schwartz. support in critically ill patients. Intensive Care Med. 2011;37(4):601-609. doi: 10.1007/s00134-011-2146-z 249. Heslin MJ, Brennan MF. Advances in perioperative nutrition: cancer. World J Surg. 2000;24(12):1477-1485. 250. Elke G, van Zanten AR, Lemieux M, et al. Enteral versus parenteral nutrition in critically ill patients: an updated systematic review and meta-analysis of randomized con-trolled trials. Crit Care. 2016;20(1):117. doi: 10.1186/s13054-016-1298-1 251. Reignier J, Boisrame-Helms J, Brisard L, et al. Enteral ver-sus parenteral early nutrition in ventilated adults with shock: a randomised, controlled, multicentre, open-label, parallel-group study (NUTRIREA-2). Lancet. 2018;391(10116):133-143. doi: 10.1016/S0140-6736(17)32146-3 252. Heslin MJ, Latkany L, Leung D, et al. A prospective, ran-domized trial of early enteral feeding after resection of upper gastrointestinal malignancy. Ann Surg. 1997;226(4):567-577; discussion 77-80. 253. Reintam Blaser A, Berger MM. Early or


Surgery_Schwartz

Surgery_Schwartz. ran-domized trial of early enteral feeding after resection of upper gastrointestinal malignancy. Ann Surg. 1997;226(4):567-577; discussion 77-80. 253. Reintam Blaser A, Berger MM. Early or late feeding after ICU admission? Nutrients. 2017;9(12):E1278. doi: 10.3390/nu9121278 254. Oshima T, Deutz NE, Doig G, Wischmeyer PE, Pichard C. Protein-energy nutrition in the ICU is the power couple: a hypothesis forming analysis. Clin Nutr. 2016;35(4):968-974. doi: 10.1016/j.clnu.2015.10.016 255. Hoffer LJ. High-protein hypocaloric nutrition for non-obese critically ill patients. Nutr Clin Pract. 2018;33(3):325-332. doi: 10.1002/ncp.10091 256. Di Girolamo FG, Situlin R, Fiotti N, Biolo G. Intermittent vs. continuous enteral feeding to prevent catabolism in acutely ill adult and pediatric patients. Curr Opin Clin Nutr Metab Care. 2017;20(5):390-395. doi: 10.1097/MCO.0000000000000397Brunicardi_Ch02_p0027-p0082.indd 8101/03/19 6:50 PM 82BASIC CONSIDERATIONSPART I 257. Bankhead R, Boullata J,


Surgery_Schwartz

Surgery_Schwartz. Curr Opin Clin Nutr Metab Care. 2017;20(5):390-395. doi: 10.1097/MCO.0000000000000397Brunicardi_Ch02_p0027-p0082.indd 8101/03/19 6:50 PM 82BASIC CONSIDERATIONSPART I 257. Bankhead R, Boullata J, Brantley S, et al. Enteral nutrition practice recommendations. JPEN J Parenter Enteral Nutr. 2009;33(2):122-167. doi: 10.1177/0148607108330314 258. Heyland DK, Murch L, Cahill N, et al. Enhanced protein-energy provision via the enteral route feeding protocol in critically ill patients: results of a cluster randomized trial. Crit Care Med. 2013;41(12):2743-2753. doi: 10.1097/CCM.0b013e31829efef5 259. Exner R, Tamandl D, Goetzinger P, et al. Perioperative GLY-GLN infusion diminishes the surgery-induced period of immunosuppression: accelerated restoration of the lipo-polysaccharide-stimulated tumor necrosis factor-alpha response. Ann Surg. 2003;237(1):110-115. doi: 10.1097/01.SLA.0000041040.98684.CB 260. van Zanten AR, Hofman Z, Heyland DK. Consequences of the REDOXS and METAPLUS trials: the