5Theory of BTSB and colon contain 1010 anaerobes and 107 aerobes Enough Endotoxins to kill us 1000 X.Magnotti & Deitch 2005 JOABAUnder certain circumstances this barrier becomes overwhelmed and its contents move into mesenteric lymph tissue and subsequent systemic tissues.
6Advantages of gastric feeding It is more physiological, is easier to begin and more convenient.Spare both gastropancreatic reflexes and gastrin release.Buffers gastric acid well.Both gastropancreatic reflexes and gastrin release contribute to pancreatic responses prior to food reaching the upper small bowelIntragastric feeding buffer gastric acid better than post-pyloric feeding
7What are The Problems Associated with Gastric Feeding in Critical Illiness ?
8Syndrome of Upper (GIT) Intolerance Gastric IlieusHigh dosesOpiatesBenzodiazepines Muscle relaxants CatecholaminesSyndrome of Upper (GIT) Intolerance
9Incidence of UGIT Intolerance to Gastric Feeding Mentec H (2001)– Crit Care Med 29 :
10What Are The Sequelae Of Upper GIT Intolerance To Enteral Nutrition?
11Hazards of UGIT Intolerance 3/25/ :08 PMHazards of UGIT IntoleranceIncidence of Nosocomial PneumoniaReferenceHerr DL, et al. J Cardiothorac Vasc Anesth. 2003;17:Feeding intoleranceMentec H (2001)– Crit Care Med 29 :
12Hazards of UGIT Intolerance 3/25/ :08 PMHazards of UGIT IntoleranceMortality RateUpper digestive intolerance during EN in critically ill patients :frequency, risk factors, and complications. Crit Care Med 29:ReferenceHerr DL, et al. J Cardiothorac Vasc Anesth. 2003;17:Feeding intoleranceMentec H (2001)– Crit Care Med 29 :
13Aspiration Syndrome.So probably the gastric feeding may not always be as safe as it is sometimes considered.The net result is Aspiration Syndrome.Heyland DK 199-AM J Respir Crit Care Med 159:Real ThreatReal Threat
142. > 70% of trauma patients at injury. Aspiration Syndrome1. 70% with altered LOC.2. > 70% of trauma patients at injury.3. > 40% of patients with EN.Bowman, et al CCNQ 2005Real ThreatReal Threat
15They Have To Balance Early commencing of enteral nutrition Early achievement of optimum caloric needsFacing the problem of upper GIT intolerance & its realted SequaeleTPNSmall Bowel FeedingProkineticsSo ICU clinicians are facing a dilemmaThey try to optimize patient outcome asTPNSmall Bowel FeedingProkinetics
16Prokinetics vs Small Bowel Feeding One study (80 patients) compared the use of prokinetic drugs (erythromycin) in patients receiving gastric feeding with small bowel feeding (without erythromycin) and it found no differences between the 2 groups in the adequacy of EN, mortality & duration of ICU stay.Gastric feeding with erythromycin is equivalent to transpyloric feeding in critically ill Crit Care Med 29:16
17Prokinetic Therapy For Feeding Intolerance Metoclopramide :Site of action : dopaminergic receptors.Role ControversialMetoclopramide act on dopaminergic receptors but its role in treatment of feeding intolerance is controversial.*Jooste C & others : Metoclopramide improves gastric motility in critically ill patients. Intensive Care Med 1999; 25:464–468*MacLaren R & othes : : A randomized, placebo-controlled, crossover study. Crit Car Med 2000; 28:438–444
18Erythromycin Site of action : motilin receptors. Dose : 3-7 mg/kg. Optimum dose : 200mg IV bid to 250mg q 6 h.Half life : 1.5hBut Antrum Motility > 5h &Feeding Tolerance up to 24h.Erythromycin act on motilin receptors(low dose 3-7mg/kg) increase post gastric emptying and success of feeding in critically ill with UGIT Intolerance.The optimum dosage of IV form is 200 mg every 12 hours to 250 q 6 hours.Rapid tachyphylaxis will develop for both drugs.The effectiveness of IV Erythromycin will diminish after 3 days.Its half life is only 1.5 hrs but it increase antral motility for>5 hours and improves the success of feeding for up to 24hrs in critically ill patients.
19Erythromycin VS Metoclopramide Nguyen 2007 trial :RCT, Multicenter,Double blind.107 patients enrolled.Metoclopramide 10mg/6h vs Erythromycin 200mg/12hrs.1ry endpoint : tolerance to gastric feed and tachyphylaxis.Abstract TOPObjective: This study aimed to a) compare the efficacy of metoclopramide and erythromycin in the treatment of feed intolerance in critical illness; and b) determine the effectiveness of rescue combination therapy in patients who fail monotherapy.Design: Randomized controlled trial.Setting: Level III mixed medical and surgical intensive care unit.Patients: Ninety mechanically ventilated, medical patients with feed-intolerance (gastric residual volume ≥250 mL).Interventions: Patients received either metoclopramide 10 mg intravenously four times daily (n = 45) or erythromycin 200 mg intravenously twice a day (n = 45) in a double-blind, randomized fashion. After the first dose, nasogastric feeding was commenced and 6-hourly nasogastric aspirates were performed. If a gastric residual volume ≥250 mL recurred on treatment, open-label, combination therapy was given. Patients were studied for 7 days. Successful feeding was defined as 6-hourly gastric residual volume <250 mL with a feeding rate ≥40 mL/hr.Measurements and Main Results: Demographic data, blood glucose levels, and use of inotropes, opioids, and benzodiazepines were similar between the two groups. After 24 hrs of treatment, both monotherapies reduced the mean gastric residual volume (metoclopramide, 830 ± 32 mL to 435 ± 30 mL, p < .0001; erythromycin, 798 ± 33 mL to 201 ± 19 mL, p < .0001) and improved the proportion of patients with successful feeding (metoclopramide = 62% and erythromycin = 87%). Treatment with erythromycin was more effective than metoclopramide, but the effectiveness of both treatments declined rapidly over time. In patients who failed monotherapy, rescue combination therapy was highly effective (day 1 = 92%) and maintained its effectiveness for the study duration (day 6 = 67%). High pretreatment gastric residual volume was associated with poor response to prokinetic therapy.Conclusions: In critical illness, erythromycin is more effective than metoclopramide in treating feed intolerance, but the rapid decline in effectiveness renders both treatments suboptimal. Rescue combination therapy is highly effective, and further study is required to examine its role as the first-line therapy.16. Chapman M,et al: Erythromycin improves gastric emptying in critically ill patients intolerant of nasogastric feeding. Crit Care Med 2000; 28:2334–233717. Dive A,et al: Effect of erythromycin on gastric motility in mechanically ventilated critically ill patients: A double-blind, randomized, placebo-controlled study. Crit Care Med 1995; 23:1356–136218. Reignier J,et al: Erythromycin and early enteral nutrition in mechanically ventilated patients. Crit Care Med 2002; 30:1237–124119. Berne J, et al: Erythromycin reduces delayed gastric emptying in critically ill trauma patients: A randomized, controlled trial. J Trauma 2002; 53:422–425Nguyen NQ & others : Erythromycin is more effective than metoclopramide for treatment of feed intolerance in critical illness.Crit Care Med 2007; 35:483–489
20Erythromycin versus Metoclopramide After 24 hrs of rescue combination therapy 92% achieved & remained tolerant for 5 days.By 24 hrs, successful enteral feeding was achieved in 87% of erythromycin-treated patients and 62% of patients treated with metoclopramide.Thereafter, both treatments became significantly less effective (erythromycin, day 3 = 47% and day 7 = 31%, p = .02; metoclopramide, day 3 = 27% and day 7 = 16%, p = .02).Erythromycin was associated with more successful feeding than metoclopramide at all time points (p = .02; Fig. 3a). Patients treated with metoclopramide became feed-intolerant earlier than those treated with erythromycin (median [interquartile range], 2 [1-4] days vs. 3 [2-8] days; respectively; p = .002).After 24 hrs of combination therapy, successful enteral feeding was achieved in 92% of the patients who had failed monotherapy. Fifty-seven of the 67 patients who failed monotherapy were enrolled into open-label combination therapy.Successful feeding was maintained for the first 5 days (day 3, 89%; day 5, 71%; p > .05), but therapy was marginally less effective on day 6 (67%, p = .03)P <Erythromycin is much more effective than MetoclopramideMetoclopramide became intolerant early
21Australian double blinded RCT Prokinetic therapy for feed intolerance in critical illnes : one drug or two ?Australian double blinded RCT75 Patients enrolled.Erythromycin (200mg IV bd) alone vsErythromycin Metocclopramide (10mg q 6h).1ry endpoint : successful feeding over 7 days2ry endpoint : daily caloric intake, vomiting, post pyloric feeding requirement, LOS & mortality.The current study is the first prospective, double-blind, randomized controlled trial to examine the impact of combination therapy with erythromycin and metoclopramide as the first-line treatment on the outcomes of critically ill patients who did not tolerate enteral feeding. The major findings were that, compared with erythromycin alone,2 drugs better than erythromycin alone based on Australian double blinded RCT.The 1ry endpoint was Successful feeding over 7 days as gastric residual volume <250ml with feeding rate>40ml/h.Secondary endpoint included daily caloric intake, vomiting, postpyloric feeding requirement, length of stay and mortality.21
22Gastric residual volume was significantly lower after 24 hrs 136 ± 23 mL293 ±45 mLP =.04
23Tolerance &Failure of therapy 18.104.22.168Erythromycin aloneErythromycin MetoclopramideErythromycin aloneErythromycin plus Metoclopramide
24Combination Therapy vs Erythromycin Alone Over 7 Days Greater feeding successReceived more daily caloriesLower requirement for post pyloric feedingOver the 7 days, patients treated with combination therapy had greater feeding success, received more daily calories, and had a lower requirement for postpyloric feeding, compared with erythromycin aloneNguyen NQ - Crit Care Med Nov;35(11):
25Oral vs IV Erythromycin Most of the well powered trials used erythromycin IV.No head to head trials.Thirty-five clinical trials were identified, and fivemet inclusion criteria. One study each involved gastroparesiscaused by surgery and systemic sclerosis. Three studiesevaluated patients with diabetic or idiopathic gastroparesis.No study used symptoms as a primary endpoint. Improvementwas reported in 26 of 60 (43%) patients. Individualsymptom scores were available for 23 of 60 subjects in thesestudies, and symptom improvement was seen in 11 of 23(48%) patients. One study compared erythromycin and metoclopromidein an open-label, crossover fashion, and foundno difference between the two agents. All studies weremethodologically weak and highly subject to bias. Four offive studies were open-label trials. Sample sizes in all studieswere 13 subjects, and treatment duration was 4 wkin all studiesIn the gastric antrum, erythromycin significantly increased the total duration, amplitude, and area under contractions from 0 to 60 minutes and frequency of contractions from 0 to 30 minutes from the start of its infusion in the fasted state. A similar response in the fed state occurred mostly from 0 to 30 minutes after the start of erythromycin infusion. By contrast, erythromycin inhibited the frequency and decreased the duration of small intestinal contractions in the fed state but had no effect in the fasted state. . The strong antral contractions induced by erythromycin are not mediated by the release of motilin.
26Pro-kinetic drugs are not free from side effects .
27Side Effects of Prokinetics Metoclopramide : extrapyramidal syndrome.Erythromycin : bacterial resistance & cardiac toxicity.Both : rapid tachyphylaxis.ErythromycinA in an acidic medium such as gastricjuice is degraded into its anhydrous hemiketal andspiroketal forms.1 Both forms are inactive microbiologically,but they have motilin-like activity thatis several times greater than that of erythromycinERYTHROMYCIN has the potential of increasing bacterial resistancce.Rapid tachyphylaxis will develop for both drugs.The effectiveness of IV Erythromycin will diminish after 3 days.Although subinhibitory concentrations of antibiotics can exert selective pressure on bacteria for resistance development (27), there are currently no data to support the clinical relevance of this concern regarding a short course of low-dose erythromycin
28What is new ? Motilin derivatives : Long term efficacy is unknown.Very rapid tachyphylaxis.Cholecystokinin antagonist : LoxiglumideVery recent.Accelerate gastric emptying in healthy humans.No trials in critically ill patients.* Castllo E, et al .Am J Physiol 2004;287:G363-G369* Cremonini F,et al.Am J Gastroenterol 2005;100:Motilin derivatives have been specifically developed to avoid bacterial resistance, their long term efficacy has been questioned due to rapid development of tachyphylaxis.Loxiglumide, a cholecystokinin antagonist has been demonstrated recentely to accelerate gastric emptying in healthy human but its role in the treatment of feeding intolerance in critical illness requires further invistigations.28
29SUMMARY Enteral Nutrition is very Crucial for critically ill patients. UGIT Intolerance is very common with critical illness.Prokinetics are the easiest option to overcome this problem.Erythromycin in IV form is more effective than Metoclopramide in achieving tolerance to gastric feeding but both therapy are associated with tachyphylaxis.
30SUMMARYCombination of both Metoclopramide and Erythromycin is much more effective than either of them alone with much less incidence of tachyphylaxis.