Enteral Nutrition In Critically Ill Patients Role of Prokinetics Focus on IV Erythromycin Done by Dr Khaled Al Sewify MD, MRCP, EDIC 1

Artificial Nutritional Support Improves wound healing Improves outcome Decreases complications Decreases the hypermetabolic response to tissue injury (DO2/VO2)

Enteral Nutrition Preserves the intestinal mucosal integrity : Maintains mucosal immunity. Prevents of increased mucosal permeability. Decreases bacterial translocation. Marik, Zaloga CCM 2005

The Gut is the Motor of Sepsis

Theory of BT SB and colon contain 1010 anaerobes and 107 aerobes Enough Endotoxins to kill us 1000 X. Magnotti & Deitch 2005 JOABA Under certain circumstances this barrier becomes overwhelmed and its contents move into mesenteric lymph tissue and subsequent systemic tissues.

Advantages 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 bowel Intragastric feeding buffer gastric acid better than post-pyloric feeding

What are The Problems Associated with Gastric Feeding in Critical Illiness ?

Syndrome of Upper (GIT) Intolerance Gastric Ilieus High doses Opiates Benzodiazepines Muscle relaxants Catecholamines Syndrome of Upper (GIT) Intolerance

Incidence of UGIT Intolerance to Gastric Feeding Mentec H (2001)– Crit Care Med 29 : 1955-1961

What Are The Sequelae Of Upper GIT Intolerance To Enteral Nutrition?

Hazards of UGIT Intolerance 3/25/2017 12:08 PM Hazards of UGIT Intolerance Incidence of Nosocomial Pneumonia Reference Herr DL, et al. J Cardiothorac Vasc Anesth. 2003;17:576-584. Feeding intolerance Mentec H (2001)– Crit Care Med 29 : 1955-1961

Hazards of UGIT Intolerance 3/25/2017 12:08 PM Hazards of UGIT Intolerance Mortality Rate Upper digestive intolerance during EN in critically ill patients :frequency, risk factors, and complications. Crit Care Med 29:1955-1961 Reference Herr DL, et al. J Cardiothorac Vasc Anesth. 2003;17:576-584. Feeding intolerance Mentec H (2001)– Crit Care Med 29 : 1955-1961

Aspiration 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 159:1249-1256. Real Threat Real Threat

2. > 70% of trauma patients at injury. Aspiration Syndrome 1. 70% with altered LOC. 2. > 70% of trauma patients at injury. 3. > 40% of patients with EN. Bowman, et al CCNQ 2005 Real Threat Real Threat

They Have To Balance Early commencing of enteral nutrition Early achievement of optimum caloric needs Facing the problem of upper GIT intolerance & its realted Sequaele TPN Small Bowel Feeding Prokinetics So ICU clinicians are facing a dilemma They try to optimize patient outcome as TPN Small Bowel Feeding Prokinetics

Prokinetics 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.2001. Crit Care Med 29:1916-1919. 16

Prokinetic Therapy For Feeding Intolerance Metoclopramide : Site of action : dopaminergic receptors. Role Controversial Metoclopramide 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

Erythromycin Site of action : motilin receptors. Dose : 3-7 mg/kg. Optimum dose : 200mg IV bid to 250mg q 6 h. Half life : 1.5h But 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.

Erythromycin 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 TOP Objective: 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; 28:2334–2337 17. 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; 23:1356–1362 18. Reignier J,et al: Erythromycin and early enteral nutrition in mechanically ventilated patients. Crit Care Med 2002; 30:1237–1241 19. Berne J, et al: Erythromycin reduces delayed gastric emptying in critically ill trauma patients: A randomized, controlled trial. J Trauma 2002; 53:422–425 Nguyen NQ & others : Erythromycin is more effective than metoclopramide for treatment of feed intolerance in critical illness. Crit Care Med 2007; 35:483–489

Erythromycin 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 < 0.0001 Erythromycin is much more effective than Metoclopramide Metoclopramide became intolerant early

Australian double blinded RCT Prokinetic therapy for feed intolerance in critical illnes : one drug or two ? Australian double blinded RCT 75 Patients enrolled. Erythromycin (200mg IV bd) alone vs Erythromycin Metocclopramide (10mg q 6h). 1ry endpoint : successful feeding over 7 days 2ry 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

Gastric residual volume was significantly lower after 24 hrs 136 ± 23 mL 293 ±45 mL P =.04

Tolerance &Failure of therapy 4.5 0.5 6.5 Erythromycin alone Erythromycin Metoclopramide Erythromycin alone Erythromycin plus Metoclopramide

Combination Therapy vs Erythromycin Alone Over 7 Days Greater feeding success Received more daily calories Lower requirement for post pyloric feeding Over 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 alone Nguyen NQ - Crit Care Med. 2007 Nov;35(11):2561-7.

Oral vs IV Erythromycin Most of the well powered trials used erythromycin IV. No head to head trials. Thirty-five clinical trials were identified, and five met inclusion criteria. One study each involved gastroparesis caused by surgery and systemic sclerosis. Three studies evaluated patients with diabetic or idiopathic gastroparesis. No study used symptoms as a primary endpoint. Improvement was reported in 26 of 60 (43%) patients. Individual symptom scores were available for 23 of 60 subjects in these studies, and symptom improvement was seen in 11 of 23 (48%) patients. One study compared erythromycin and metoclopromide in an open-label, crossover fashion, and found no difference between the two agents. All studies were methodologically weak and highly subject to bias. Four of five studies were open-label trials. Sample sizes in all studies were 13 subjects, and treatment duration was 4 wk in all studies In 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.

Pro-kinetic drugs are not free from side effects .

Side Effects of Prokinetics Metoclopramide : extrapyramidal syndrome. Erythromycin : bacterial resistance & cardiac toxicity. Both : rapid tachyphylaxis. Erythromycin A in an acidic medium such as gastric juice is degraded into its anhydrous hemiketal and spiroketal forms.1 Both forms are inactive microbiologically, but they have motilin-like activity that is 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

What is new ? Motilin derivatives : Long term efficacy is unknown. Very rapid tachyphylaxis. Cholecystokinin antagonist : Loxiglumide Very 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;100:625-663 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

SUMMARY 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.

SUMMARY Combination of both Metoclopramide and Erythromycin is much more effective than either of them alone with much less incidence of tachyphylaxis.

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