Treatment of Sepsis JoeBob Kirk D.O. Southcrest Hospital Tulsa, OK Sepsis All patients with severe sepsis require appropriate antimicrobial agents immediately. Antimicrobial therapy is often an empiric choice because of the time required for culture and sensitivity results. Many patients do not have a pathogen identified. Empiric antifungal therapy is necessary in some cases. Anti-infectives and source control Appropriate anti-infectives and source control are critical in treating severe sepsis. Treating and eradicating infection does not necessarily arrest the disease’s progression. A large number of patients develop septic shock, multiple organ dysfunction(MODS), and eventually die. Standard supportive care alone may not adequately treat sever sepsis which rates of 28-50%. The best chance for patient survival includes therapy targeted to the microvasculature, in addition to supportive care, because of the underlying progression that occurs in severe sepsis. Examples of supportive care therapy for patients with severe sepsis are : Cardiovascular support Respiratory support Renal replacement therapy Glucose control Other supportive care Cardiovascular Support Hypotension is a hallmark of severe sepsis. Patients with severe sepsis have intravascular volume deficits as a result of hemodynamic alterations. The first step in reversing hypotension is rapid fluid resuscitation with natural or artificial colloids or crystalloids Early goal-directed therapy to optimize cardiac preload, afterload, and contractility has proven beneficial in some cases. Cardiovascular Support When appropriate fluid challenge fails to improve blood pressure, patients usually require vasopressors. Even when fluid challenge is in progress and hypovolemia has not been corrected, vasopressor therapy may be required transiently if hypotension is life-threatening. Low-dose corticosteroids may improve outcomes in patients with septic shock. Respiratory Support Oxygenation and ventilation problems are common in patients with severe sepsis. The combination of hypoxemia refractory to supplemental oxygen and decreased compliance requires mechanical ventilation. Intubation and mechanical ventilation is required in almost all patients with acute respiratory distress syndrome (ARDS). Low tidal volume ventilations is commonly used. Renal Replacement Therapy Alterations in renal functioning can occur in patients with severe sepsis due to hypotension and hypoperfusion. Renal dysfunction is reflected by the following: – Decreased urine output and subsequent oliguria – Increased blood urea nitrogen – Increased creatinine Renal replacement therapy may be necessary. Glucose Control Hyperglycemia is common in severe sepsis. Blood glucose is frequently monitored. Continuous infusion of insulin and glucose may be used to maintain target blood glucose levels. Other Supportive Care Sedation Analgesia and neuromuscular blockade Deep-vein thrombosis prophylaxis Stress ulcer prophylaxis Blood product administration Nutritional support Sepsis All patients with severe sepsis require appropriate antimicrobial agents immediately. Antimicrobial therapy is often an empiric choice because of the time required for culture and sensitivity results. Many patients do not have a pathogen identified. Empiric antifungal therapy is necessary in some cases. Peritonitus and Abdominal Sepsis Peritoneal infections are classified as: – Primary (i.e., spontaneous) – Secondary (i.e., related to a pathologic process in a visceral organ) – Tertiary (i.e., persistent or recurrent infection after adequate initial therapy.) Peritonitis The most common etiology of primary peritonitis is spontaneous bacterial peritonitis due to chronic liver disease The common etiologic entities of secondary peritonitis include: – Perforated gastric and duodenal ulcer disease – Perforated (sigmoid) colon caused by diverticulitis, volvulus, or cancer – Strangulation of the small bowel Common Causes of Secondary Peritonitis Source Regions Causes Borhaave syndrome Esophagus Malignancy Trauma (mostly penetrating) latrogenic Peptic Ulcer Perforation Stomach Malignancy (e.g., adenocarcinoma, lymphoma, gastrointestinal stromal tumor) Trauma (mostly penetrating) latrogenic Peptic Ulcer perforation Duodenum Trauma (blunt and penetrating) latrogenic Cholecystitus Biliary tract Stone perforation from gallbladder (i.e., gallstones ileus) or common duct Malignancy Choledochal cyst (rare) Trauma (mostly penetrating) Latrogenic Common Causes of Secondary Peritonitis Source Regions Causes Pancreatitis Pancreas Trauma (blunt and penetrating) latrogenic Ischemic bowel Small bowel Incarcerated hernia (internal and external) Closed loop obstruction, Crohn disease Malignancy (rare) Meckel diverticulum Trauma (mostly penetrating) Ischemic bowel Large bowel and Diverticulitus, Malignancy appendix Ulcerative colitis and Crohn disease Appendicitus, Colonic volvulus Trauma (mostly penetrating ) latrogenic Pelvic inflammatory disease (e.g., salpingoophoritis, Uterus, salpinx, tuboovarian abscess, ovarian cyst) and ovaries Malignancy (rare) Trauma (uncommon) More than 90 % of cases of SBP are caused by a monomicrobial infection. Most common pathogens include gram-negative organisms: – Escherichia coli (40%) – Klebsiella pnemoniae (7%) – Pseudomonas species – Proteus species – Gram-positive organisms (e.g. streptococcus pneumoniae (15%) – Anaerobic microorganisms are found in less than 5% of cases – Multiple isolates are found in less than 10% Microbiology of Primary, Secondary, and Tertiary Peritonitis Peritonitis Etiologic Organisms Antibiotic (Type) Class Type of Therapy Organism (Suggested) Primary Gram- Ecoli (40%) Third – K pneumoniae generation negative (7%) cephalosporin Pseudomonas species (5%) Proteus species (15%) Streptococcus species (15%) Staphylococcus species (3%) Anaerobic species (<5%) Microbiology of Primary, Secondary, and Tertiary Peritonitis Peritontis Etiologic Organisms Antibiotic Type of Organism Therapy (Type) Class (Suggested) E coli, Enterobacter Second- Secondary Gram- species generation negative Klebsiella species cephalosporin Proteus species Streptococcus species Third-generation Secondary Gram- Enterococcus species cephalosporin positive Penicillin's with anaerobic activity Bacteroide fragilis Quinolones with Secondary Anaerobic Other Bacteroides anaerobic activity species Quinolone and Eubacterium species metronidazole Clostridium species Aminoglycoside Anaerobic and metronidazole Streptococcus species Microbiology of Primary, Secondary, and Tertiary Peritonitis Peritonitis Etiologic Organisms Antibiotic Therapy (Type) Class Type of Organism (Suggested) Gram- Enterobacter Second-generation Tertiary species cephalosporin negative Third-generation Pseudomonas species Cephalosporin Gram- Staphylococcus Penicillins with Tertiary species anaerobic activity positive Fungal Candida species Quinolones with Tertiary anaerobic activity Quinolone and metronidazole Aminoglycoside and metronidazole Carbapenems Triazoles or amphotericin Tertiary Peritonitis Tertiary peritonitis represents the persistence or recurrence of peritoneal infection following apparently adequate therapy, often without the original visceral organ pathology. Tertiary peritonitis develops more frequently in patients with significant preexisting co morbid conditions Patients who are immunocompromised Tertiary peritonitis Resistant and unusual organisms (e.g. Enterococcus, Candida, Staphylococcus, Enterobacter, and Psuedomonas species) are found in a significant proportion of cases of tertiary peritonitis. Antibiotic therapy appears less effective compared to all other forms of peritonitis Enterococci may be important in enhancing the severity and persistence of tertiary peritoneal infections. This is important in light of the difficulties in eradicating Enterococcus faecalis with conventional antimicrobial therapy. Intra-abdominal abscess Abdominal infections, particularly with Candida species, are becoming increasingly common in critically ill patients. Studies suggest that the microbiology of intra- abdominal infections may be inherently different in severely ill patients. Candida albicans was the organism most commonly isolated from the peritoneum in critically ill patients with culture-proven intra-abdominal infections. Predisposing factors for the development of abdominal candidiasis Intra-abdominal abscess Prolonged use of broad-spectrum antibiotics Gastric acid suppressive therapy Central venous catheters and intravenous hyperalimentation Malnutrition, diabetes, and steroids and other forms of immunosuppression Other Supportive Care Sedation Analgesia and neuromuscular blockade Deep-vein thrombosis prophylaxis Stress ulcer prophylaxis Blood product administration Nutritional support Nutritional Support For clinicians caring for critically ill patients, the goal of nutrition support has been to deliver 100% of nutrient requirements, calculated for the specific metabolic condition, in the shortest time possible. Recently, clinical experts in intensive care medicine and nutrition and published studies in the medical literature have determined that for critically ill patients, administering nutrients at quantities less than a calculated metabolic expenditure may significantly improve outcomes. Nutritional Support This involves feeding patients suffering from sepsis, at or near 100% of nutrient requirements is associated with potentially worse, not better outcomes. In actuality, short-term moderate underfeeding, particularly during the initial phase of critical illness when there is marked inflammation, may be more beneficial than striving to administer 100% of estimated nutritional needs. Nutritional Support It has always seemed that during stress, the body requires more nutrients to fight infection, combat inflammation, support protein synthesis, maintain cellular integrity and promote growth. Nutritional Support The premise of permissive underfeeding is based on research indicating that providing 100% of nutrient requirements bacterial growth and invasion. Autoimmune processes Oxidant production Cytokine release Inflammation Energy utilitization Nutritional Support Benefits for underfeeding rely on understanding the b asic biological process call hormesis Beneficial or stimulatory effect is obtained through the application of an agent at a low dose Whereas this same agent may be detrimental or toxic at higher doses. Nutritional Support Application of hormesis to nutrition support is related to the potential benefits of caloric restriction, which include – Favors the survival of cell populations – Attenuates the impact of exposure to toxins – Delays deterioration of many physiologic functions – Improves the response to physical stressors – Enhances immune defense and repair systems – Enhances expression of stress-and- response genes (i.e., heat, radiation) – Minimizes cytokine and inflammatory responses Nutritional Support Fever, tachycardia, tachnypnea, cytokine and oxidant generation, catabolism, stress hormone release, decreased calcium, iron and zinc levels, and anorexia characterize the acute phase response to sepsis. Nutritional Support Some degree of anorexia may be advatageous, acting as a feedback mechanism to blunt exaggerated cytokine responses, oxidant production, organ injury and hypermetabolism. Nutritional Support The integrity of the gastrointestinal tract can be maintained with lower amounts of nutrient intake. Nutritional Support Studies show that even at 50% of requirements the GI tract is able to maintain: – Hormonal release – Mass – Blood flow – Barrier function to prevent bacterial translocation – Immune function – Decreased oxidant production Nutritional Support Why does underfeeding seem to be protective? Potential mechanisms are: – Lower omega-6 fatty acid provides less substrate for proinflammatory mediator synthesis – Limited carbohydrate intake may result in less hyperglycemia – Decreased calcium, iron and zinc levels may decrease inflammatory response and cell injury – Lower nutrient oxidation – Less production of free radicals and cytokines – Less DNA damage – Less hypermetabolism results in less carbon dioxide production Nutritional Support There have been a variety of patient trials, both prospective and retrospective, to test the theoretical benefits of moderate short- term underfeeding. Nutritional Support In a prospective cohort study from Johns Hopkins Medical Center, ICU patients were divided into groups: – Group I received 0%-32% of recommended intake – Group II received 33%-65% – Group III received 66%-100% of caloric recommendations Nutritional Support Patients in Group II (33%-65% of recommended intake) exhibited the highest survival rate and experienced more sepsis free days Group III (66%-100% of the requirements) experienced the worst outcomes. Nutritional Support Another prospective cohort study from John Hopkins demonstrated that restricted feeding did not appear to increase the risk of bloodstream infection until the feeding was reduced to less than 25% of recommended intake. These studies suggest that feeding within the middle range (33%-65% of recommended intake) is optimal. Nutritional Support A retrospective analysis at Methodist Research Institute, Indianapolis, Ind., divided 120 trauma patients into groups based on nutritional intake. The intakes were averaged over the first week in the ICU, and were followed and assessed for a variety of outcomes. Groups I, II, and III were cosnidered the middle range of nutritional intake Group IV was the upper range Patients in group IV (upper range) had more infections, more days on the ventilator and longer length of stay in both ICU and hospital compared with the other three groups. Nutritional Support Dickerson et al. reported in a retrospective analysis of obese critically ill patients that patients receiving less than 20 kcal/kg adjusted weight/day. Compared with patients receiving greater than 20 kcal/kg adjusted weight/day. Experienced fewer days in the ICU Fewer days on mechanical ventilation Fewer days of antibiotic use Nutritional Support In a prospective randomized study, McCowen et al. reported: – Fewer infections (approximatelY 30% vs. 50%) – Lower mortality (9% vs. 16%) – In patients randomized to hypocaloric (1000 kcal/day, 70 g/day protein) compared to standard feeding. Nutritional Support In a prospective randomized study, Taylor and colleagues reported lower mortality, length of stay, complications, pneumonia and total infections. Patients receiving moderate intake (approximately 60% of calculated intake). Compared to patients receiving low intake (37% of calculated intakes). Nutritional Support Most evidence suggests that intake in the mid range seems to be associated with the best outcomes in critically ill patients. Nutritional Support Based upon available evidence, nutritional management of patients with sepsis, based on the following: – Begin feeding early (within 24 hours of admission) – Calculate needs based on current practice: Calories: 25 kcal/kg/day Protein: 1.2-1.5 g/kg/day (20%-25% of total kcals) Lipid: 30%-40% of total kcals Carbohydrate: 35%-50% of total kcals Nutritional Support If patient is considered a candidate for permissive underfeeding, the following are reasonable guidelines: – Begin feeding early (within 245 hours of admission) – Strive to provide 33%-66% of calculated needs – Maintain this level of moderate underfeeding for three to five days – As the patient improves, advance feeding to the 100% of calculated requirements over the next three to five days, as tolerated References Dickerson RN, Boschert KJ, Kudsk KA, et al. Nutrition 2002; 18:241 McCowen KC, Friel C, Sternberg J, et al. Crit Care Med 2000; 28:3606 Taylor SJ, Fettes SB, Jewkes C, et al. Crit Care Med 1999; 27:2525 Thank You JoeBob Kirk D.O.
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