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 diseases 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 Esophagus Causes
Borhaave syndrome Malignancy Trauma (mostly penetrating) latrogenic

Stomach

Peptic Ulcer Perforation Malignancy (e.g., adenocarcinoma, lymphoma, gastrointestinal stromal tumor) Trauma (mostly penetrating) latrogenic
Peptic Ulcer perforation Trauma (blunt and penetrating) latrogenic Cholecystitus Stone perforation from gallbladder (i.e., gallstones ileus) or common duct Malignancy Choledochal cyst (rare) Trauma (mostly penetrating) Latrogenic

Duodenum Biliary tract

Common Causes of Secondary Peritonitis

Source Regions Pancreas Small bowel Causes
Pancreatitis Trauma (blunt and penetrating) latrogenic Ischemic bowel Incarcerated hernia (internal and external) Closed loop obstruction, Crohn disease Malignancy (rare) Meckel diverticulum Trauma (mostly penetrating) Ischemic bowel Diverticulitus, Malignancy Ulcerative colitis and Crohn disease Appendicitus, Colonic volvulus Trauma (mostly penetrating ) latrogenic Pelvic inflammatory disease (e.g., salpingoophoritis, tuboovarian abscess, ovarian cyst) Malignancy (rare) Trauma (uncommon)

Large bowel and appendix

Uterus, salpinx, and ovaries

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 (Type) Etiologic Class Organisms Type of Organism
Ecoli (40%) K pneumoniae (7%) Pseudomonas species (5%) Proteus species (15%) Streptococcus species (15%) Staphylococcus species (3%) Anaerobic species (<5%)

Antibiotic Therapy (Suggested) Third generation cephalosporin

Primary

Gramnegative

Microbiology of Primary, Secondary, and Tertiary Peritonitis

Peritontis (Type) Etiologic Class
Organisms Type of Organism E coli, Enterobacter species Klebsiella species Proteus species Antibiotic Therapy (Suggested) Secondgeneration cephalosporin

Secondary Gramnegative

Secondary Grampositive
Secondary Anaerobic

Streptococcus species Enterococcus species

Third-generation cephalosporin Penicillin's with anaerobic activity

Quinolones with anaerobic activity Quinolone and metronidazole Aminoglycoside and metronidazole

Bacteroide fragilis Other Bacteroides species Eubacterium species Clostridium species Anaerobic Streptococcus species

Microbiology of Primary, Secondary, and Tertiary Peritonitis

Peritonitis (Type) Etiologic Class Organisms Type of Organism Antibiotic Therapy (Suggested) Second-generation cephalosporin Third-generation Cephalosporin Penicillins with anaerobic activity Quinolones with anaerobic activity Quinolone and metronidazole Aminoglycoside and metronidazole Carbapenems Triazoles or amphotericin

Tertiary

Gramnegative Grampositive Fungal

Enterobacter species Pseudomonas species Staphylococcus species

Candida species

Tertiary Tertiary

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 intraabdominal 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 shortterm 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.