ALIMENTARY PROPHYLAXIS

IN INTENSIVE CARE

Dr Preethy John Chandy

Oral cavity & bowel as sources of infection in critically ill patients

Microbial invasion of body: skin v/s GIT

• Skin: multi layered keratinised surface

• GIT: single cell layer mucosa 0.1 mm thick.

microflora outnumbers that in skin

• No of bacteria in 1 gram of stool (10 to 100 billion) > the no of people on Earth (6.5 billion)

• Real threat of microbial infection comes from GIT

Microbial density in the Alimentary tract

Microbes in GIT

• Moist environment in mouth & GIT - ideal for microbial proliferation.

• 400 to 500 different species of bacteria and fungi in the adult GIT.

Levels of Protective Mechanisms from microbes in the GIT

• 1.) Lumen – Acid - anti septic

• 2.)Bowel wall – Physical barrier of Mucosa

• 3.)Extraluminal - Reticuloendothelial system (2/3rd

of it is located intra abdominally result of

frequent microbial invasion across bowel wall.)

Effect of pH on the growth of microbes- antiseptic action of gastric acid

• Gastric acid endogenous antiseptic agent that eradicates microorganisms swallowed in saliva and food.

• Drug-induced inhibition of gastric acid production recurrent Salmonella enteritis (Lancet 1990)

• Achlorhydria increased risk of bacterial gastroenteritis (Gut 1987, Scandinavian Jn Gastroenterology

1985)

• Gastric acid our own built-in method of disinfecting the food we eat.

The Acid Phobia

• Gastric acid : long-standing reputation of being a corrosive agent that can eat through an unprotected stomach wall and "burn a hole in your stomach.“

• This is more fantasy than factis a direct result of the traditional notion that gastric acid is the principal cause of PUD

• Corrosive for inorganic compounds like metals and enamel, but is not destructive for organic matter.

• Evidence indicates that local infection with H. pylori is responsible for most cases of PUD.

Predisposing Conditions for sepsis from GIT

1.)Translocation: Movement of organisms across the

bowel wall into the systemic circulation.

3 conditions that promote it: a.) microbial overgrowth in the bowel lumen

b.) disruption of the mucosal barrier

c.) defective clearance by the lymphatic system.

2.) Reduced gastric acidity:

Reduced gastric acidity: loss of antiseptic action bacterial overgrowth in stomach infections : - Gastroenteritis

- Pneumonia from aspiration of infectious gastric

contents.

-Septicemia from bacterial translocation across the

bowel wall.

• Reason to avoid the use of drugs that inhibit gastric acid secretion.

STRESS-RELATED MUCOSAL INJURYINJURY

Erosions in the gastric mucosa that occur in almost all patients with acute, life threatening illness.

-Superficial Erosions: confined to mucosa

-Stress Ulcer: deeper into submucosa

Pathogenesis.

• Mucosal lining: normally shed and replaced every 2 - 3 days.

• When nutrient blood flow is inadequate to support the replacement process, the surface of the bowel becomes denuded, superficial erosions.

Actions of gastric acid may aggravate

this , but the principal cause of stress-related mucosal injury is impaired blood flow, not gastric acidity.

Clinical Consequences

• Erosions can be demonstrated in 75% to 100% of patients within 24 hours of admission to the ICU.

Effect: 1.) Clinically silent : majority

2.) Microbial translocation

3.) Clinically apparent GI bleeding in as many as

25% ( Chest 2001)

4.) Clinically significant bleeding (i.e., significant drop in blood pressure or requires transfusion) occurs in only 1% - 5% . (NEJM 1994) Disruption of only small capillaries in superficial lesions.

High Risk Conditions for clinically significant bleeding

• 1. Mechanical ventilation for longer than 48 hours

• 2. Coagulopathy (i.e., platelets <50,000, INR >1.5, or PTT >2 X control)

• 3. Hypotension

• 4. Severe sepsis

• 5. Multisystem trauma

• 6. Severe head injury

• 7. Burns involving >30% of body surface area

• 8. Renal failure or hepatic failure

• For the other conditions, at least two must be present to consider the patient high-risk for bleeding.

• These high-risk conditions serve as indicators for prophylactic therapy to prevent GI bleeding from gastric erosions.

Preventive Strategies.

• Preserving Gastric Blood Flow

No readily available methods for monitoring gastric blood flow clinically.

• Sublingual capnometry measures PCO2

on the underside of the tongue, is promising method (Chest

2001)But experience is currently limited.

• The best strategy is to maintain systemic blood flow and O2 transport using standard markers (e.g., blood lactate levels) or invasive parameters (e.g., oxygen delivery, oxygen uptake) if available.

Enteral Nutrition

• It exerts a trophic effect on the bowel mucosa that helps to maintain the structural and functional integrity of the bowel mucosa (Int Care Med 1999).

• Can be considered adequate prophylaxis for stress-related gastric hemorrhage unless there is some other condition that raises special concern for GI bleeding, such as a coagulopathy, a prior history of bleeding from gastritis or PUD, or active PUD.

Pharmacologic Strategies

• Cytoprotection: uses an agent that provides local protection to the gastric mucosa.

• Gastric acid reduction:

Sucralfate

• Aluminum salt of sucrose sulfate forms a protective covering on the gastric mucosa and helps to preserve the structural and functional integrity of the mucosa (N Engl J Med 1990).

• Part of this effect may be due to local stimulation of prostaglandin production, which helps to preserve gastric blood flow.

• The pH of gastric secretions is not altered

• Least expensive.

• INTERACTIONS. binds to a number of drugs in the bowel

lumen and reduce their absorption.

Warfarin Digoxin

Fluoroquinolones Ketoconazole

Phenytoin Ranitidine

Quinidine Thyroxine

Tetracycline Theophylline

• To avoid potential interactions in the bowel, these drugs should be given at least 2 hours before sucralfate.

• The aluminum binds phosphate in the bowel, but hypophosphatemia is only rarely reported in association with sucralfate therapy (Nutr Clin Prc 1991). It is not advised for patients with persistent or severe hypophosphatemia.

Histamine type-2 Receptor Antangonists.

• Continuous infusion ot H2 blockers is the most effective method of maintaining gastric acid inhibition (Crit Care Med 1988); however, intermittent dosing is currently the favored regimen for stress ulcer prophylaxis.

• Famotidine is longer lasting than ranitidine [i.e., a single 20 mg i.v dose of famotidine inhibits gastric acid-for 10-12 hours , while a single 50 mg i.v dose of ranitidine inhibits gastric acid for 6-8 hrs ]

Dose adjustments

• i.v doses of are largely excreted unchanged in urine, and accumulation of these drugs in renal insufficiency can produce a neurotoxic condition characterized by confusion, agitation, and even seizures (Mosby drug consult 2005).

• Dose should be reduced in renal insufficiency.

• Benefit v/s risk: Reduces incidence of clinically significant bleeding

(JAMA 1996). Has been associated with increased risk of infection

(Lancet 1990, JAMA 2004) esp pneumonia.

Sucralfate v/s H2 Receptor Antagonists

The study involving 1,200 ventilator-dependent patients in 16 ICUs (NEJM 1998) randomized to receive sucralfate (1 gram q6H) or ranitidine (50 mg q6H).

• Clinically significant bleeding occurred more frequently in the sucralfate group ( absolute difference: 2.1%) while hospital-acquired pneumonia occurred more frequently in the Ranitidine group ( absolute difference : 2.9% not statistically significant)

• But a combined analysis of 8 other studies shows a significantly greater incidence of pneumonia in the Ranitidine group

Fewer bleeding episodes v/s Fewer pneumonias ?• Can't be based on survival benefit because the

mortality in both groups is the same.• Relative incidence of GI bleeding v/s pneumonia in

ICU patients: pneumonia occurs much more frequently fewer patients would have to be treated with sucralfate to see a benefit (i.e, fewer pneumonias) as compared to ranitidine.

• A recent survey showed that H2 blockers are used much more frequently than sucralfate for stress ulcer prophylaxis in the ICU (Crit Care Med 2004).

• However, the major reason for this was drug availability rather than clinical efficacy.

Proton Pump Inhibitors Omeprazole Lansoprazole Rabeprazole Pantoprazole Esomeprazole • PPIs-prodrugs- bind irreversibly to the membrane

pump for hydrogen ion secretion and produce complete inhibition of gastric acid secretion.

• More effective in reducing gastric acidity than H2 blockers, and unlike H2 blockers, they do not produce tolerance with prolonged use (Crit Care med

2002).

• Intragastric administration of PPIs can be problematic because of inactivation by gastric acid.

• So morning dose before first feed when gastric acid secretion in minimum is advocated.

• Enteric coated granules of omeprazole & lansoprazole mixed in 8.4% NaHCO3 (to neutralise gastric acid) via NGT has been tried (Am J

Gastro 1999), but is time consuming and with variable bioavailability (Crit Care Med 2002).

• Pantoprazole i.v 40 mg od• Esomeprazole i.v 20 mg od

• There is school of thought :Low frequency of bleeding from gastric erosions and the effectiveness of other prophylactic measures, the use of PPIs for stress ulcer prophylaxis seems unnecessary.

• Furthermore, the potency of PPIs in raising gastric pH will create even greater risks from bacterial overgrowth in the bowel than the H2 blockers.

Occult Blood Testing.

• Is not necessary for evaluating the efficacy of stress ulcer prophylaxis. NGT aspirates almost always contain occult blood in the presence of gastric erosions (Ann of Surg 1994), and as few progress to clinically significant bleeding, the presence of occult blood in NGT aspirates has no predictive value for assessing the risk of significant bleeding.

• Guaiac and Hemoccult tests give false+ and false- when pH is less than 4 (J Clin Gastro 1984).

• The Gastroccult test (Smith Kline Laboratories) is not influenced by pH (J Clin Gastro 1984) and is the more appropriate test.

DECONTAMINATION OF THE ALIMENTARY TRACT

1.) Oral Decontamination

2.) Selective digestive decontamination

Oral Decontamination

The aspiration of mouth secretions into the upper airways inciting event in most cases of hospital-acquired pneumonia.

• Aspiration of one micro liter of saliva will introduce about one million microbes into the airways. Fortunately, normal mouth flora are harmless saprophytes (e.g lactobacillus and a-hemolytic streptococci).

• Critically ill patients are not as fortunate

• In hospitalized patients colonization of oral cavity occurs with pathogenic organisms eg aerobic gram-negative bacilli like P.aeruginosa (Int Care Med 1995).

• The change in microflora is not environmentally driven, but is directly related to the severity of illness in each patient.

• Highlights the importance of host-specific factors

in the microbial colonization of body surfaces.

BACTERIAL ADHERENCE

• Colonization requires microbes to adhere to the underlying surface. Epithelial cells on body surfaces have specialized receptor proteins that can bind to adhesion proteins ( adhesins) on bacterial surface.

• Healthy subjects, express receptors that bind harmless organisms (e.g., lactobacillus)

• But seriously ill patients, express receptors thatbind pathogenic organisms prelude to hospital-acquired infections.

• Bacterial adherence hold promise as an exciting field of study prevent colonization & infection.

Oral Decontamination Regimen

• Successful regime in ICU

Nonabsorbable antibiotics applied locally in the mouth.

• Preparation: mixture of 2% gentamicin, 2% colistin, and 2% vancomycin as a paste.

• Regimen: Apply paste to the buccal mucosa with a gloved finger q6h until the patient is extubated.

• Eradicates most aerobic bacteria and Candida species from the mouth in about one week.

• This was a study of ventilator-dependent patients (39)

• Decontamination reduced the incidence of pneumonia ( 27% 10%) : 60% reduction

• and mortality rate ( 38% 29%) : 23% reduction.

• Prolonged use of this locally applied antibiotic regimen has not resulted in the emergence of antibiotic resistant organisms.

• Success of oral decontamination in reducing the incidence of nosocomial pneumonia has prompted the Centers for Disease Control (CDC) to include a recommendation for oral decontamination in their updated guidelines on preventing pneumonia in health-care.

Condition in the ICU that might benefit from decontamination of the alimentary tract.

Selective digestive decontamination (SDD) • More extensive version of oral decontamination covering entire

alimentary tract. • Is selective as it does not eliminate normal inhabitants of the bowel

which are important in preventing colonization with opportunistic pathogens.

• A successful SDD regimen (Int Care Med 1984):

• Oral cavity: A paste of 2% polymyxin, 2% tobramycin, and 2% amphotericin is applied to the inside of the mouth with a gloved finger q6H.

• GI tract: A 10 mL solution containing 100 mg polymyxin E, 80 mg tobramycin, and 500 mg amphotericin is given via a NGT q6H.

• Systemic: i.v cefuroxime, 1.5 grams q8H for the first 4 days of therapy.

• It will eradicate most gram-negative aerobic bacteria and yeasts after 1 week.

• The i.v antibiotic provides systemic protection until the bowel regimen is fully effective at 1 week.

• Some SDD regimens do not include an i.v antibiotic, but they are less successful

• The oral and GI components of SDD are continued until the patient is well enough to be discharged from the ICU.

• This study shows the influence of SDD on the incidence of ICU-acquired infections.

• All 3 infections (pneumonia, urinary tract infections, and septicemia from vascular catheters) were significantly less frequent in SDD group.

• Similar results were reported in 10 other clinical trials of SDD, which showed a combined 40% relative reduction in the frequency of acquired infections in the ICU (Br Med J 1998).

• The Never-Ending Debate• Despite over 20 years of experience with SDD and

numerous reports of efficacy there is a continuing debate over its merits.

1.)Impact on Mortality : most of the early studies showed no• reduction in mortality despite the decreased rate of

infections. • However a recent large-scale study with 1,000 ICU patients

using an iv antibiotic for the first few days showed a relative 35% reduction in mortality (Lancet 2003).

• Many of the early SDD regimens did not include an i.v antibiotic may explain the improved results of the most recent study.

• 2.)Fear of antibiotic resistance: there is no evidence to support this (Curr Opin Crit Care 2002).

• The debate overlooks one simple fact: the goal of SDD is to reduce hospital-acquired infections and it achieves this goal consistently.

• Therefore, SDD must be considered an effective method of infection control in the ICU.