Dyspepsia in the ED

First Off, Some Take Home Points…

• For acute management of dyspepsia in the emergency department, antacids alone may provide the fastest relief, but it is short-lived.

• The addition of lidocaine (“the GI cocktail”) does not provide an additional clinical benefit and has risks of harm.

• For longer-term relief of symptoms, consider a dose of an H2RA or PPI.

• When sending a patient home with a short-term script of acid suppressants, determine the frequency of their symptoms. If they are occurring >1 time per week, a PPI may be more useful. For more occasional symptoms, an H2RA may be sufficient. If symptoms have been persistent for >1 month despite empiric treatment, further evaluation is recommended.

Dyspepsia in the Emergency Department

Dyspepsia, or indigestion, affects up to 25% of the population each year and is a common complaint in the emergency department (1). The American College of Gastroenterology clinically defines dyspepsia as epigastric pain or discomfort which may be associated with epigastric fullness and early satiety, nausea, vomiting, or heartburn (1). Dyspepsia has been estimated to cost the United States healthcare system over $18 billion annually (1). 

Around 20% of patients with dyspepsia have an organic cause (2). Organic causes of dyspepsia include gastritis, peptic ulcer disease (PUD), gastro-esophageal reflux disease (GERD), and rarely, malignancy (2). The majority of dyspeptic patients (75%-80%) have functional dyspepsia, meaning no cause for the symptoms can be identified on endoscopy or routine evaluation (3). Various pathologic mechanisms are thought to contribute to the symptoms of functional dyspepsia including hypersensitivity to stomach distension and acid secretion, dysregulated gastroduodenal motility, low-grade inflammation, Helicobacter pylori infection, and psychological conditions such as anxiety and depression (4). 

How do you approach the dyspeptic patient?

Most patients presenting to the emergency department with dyspeptic symptoms have not had prior endoscopy and are considered to have uninvestigated dyspepsia. When evaluating a patient with dyspeptic-type symptoms, consider early referral to gastroenterology for possible endoscopy if the patient is age 55-60+ with new-onset symptoms given the higher incidence of esophageal and gastric malignancy with increasing age (1). In addition to age, risk factors for esophageal or gastric malignancy can include chronic alcohol and tobacco use, chronic untreated GERD, exposure to industrial chemicals, and living in high risk areas (East Asia, Eastern Europe, Central and Southern America) (1). 

One should also consider referral for patients with alarm symptoms that may suggest structural disease or malignancy. These alarm symptoms can include unintended weight loss, gastrointestinal bleeding, iron deficiency anemia, progressive dysphagia, and persistent vomiting (5). Fortunately, even with alarm symptoms, the prevalence of GI malignancy in dyspeptic patients is very low. In one systematic review of 46,000 dyspeptic patients with 1+ alarm symptom, the prevalence of gastrointestinal malignancy was <1% (4). 

If you do not feel your patient meets the above indications for early referral, your next step is to offer empiric treatment for 4-8 weeks with further investigation if symptoms do not improve (1). 

Treatment of Dyspepsia

Behavioral Modifications

It is recommended that patients eat smaller meals with less fat content as fat delays gastric emptying, which can contribute to GERD and functional dyspepsia symptoms (6). Avoiding eating close to bedtime can help with GERD-type symptoms. Avoiding excessive caffeine, alcohol, and smoking can also help with symptoms by reducing acid secretion and mucosal inflammation (6). Non-steroidal anti-inflammatory drugs (NSAIDs) should be discontinued if possible. NSAIDs can cause gastritis and peptic ulcer disease due to direct mucosal toxicity and inhibition of prostaglandins, which are necessary for maintaining gastric mucosal integrity. 

H2 Receptor Antagonists (H2RAs)

Bottom Line: H2RAs are best for infrequent symptoms due to tolerance with repeated doses. For recurrent symptoms, PPIs are more efficacious. 

Gastric acid suppression is a common component of dyspepsia management. H2RAs are competitive antagonists of H2 histamine receptors which reduces histamine-mediated hydrochloric acid secretion by gastric parietal cells (7). They are highly selective and do not affect H1 histamine receptors (7). They can be administered at any time in relation to meals (7). All of the H2RAs have similar efficacy (8). They are generally well-tolerated. Common adverse effects include diarrhea, headache, and dizziness. Elderly patients or those with renal impairment can develop confusion, hallucinations, or delirium (8). 

Caveats

• Incomplete acid suppression: These drugs only partially suppress gastric acid secretion, as they only block one of the many pathways that stimulate gastric acid secretion (8). As a result there are only recommended for mild and intermittent dyspepsia or GERD symptoms (<2 episodes per week) and they are considered suboptimal treatment for healing mucosal lesions such as in PUD or erosive esophagitis (8). They may be used for patients with residual dyspepsia or reflux symptoms despite maximal PPI therapy. When used in this case they are recommended to be given at bedtime (8).

• Tolerance: Significant tolerance to H2RAs develops after the first dose (9). The mechanism may involve up-regulation of parietal cell receptors for other mediators of acid secretion or sensitization of H2 receptors. This effect cannot be overcome by increasing the dose of the medication. This tolerance persists for 3+ days after the drug is used. Therefore, occasional isolated use gives the maximum benefit.

Evidence for Use in Dyspepsia

H2RAs may be best used for on-demand relief for infrequent symptoms. A single center prospective randomized double blind RCT compared IV ranitidine 50 mg (n = 33) with IV pantoprazole 40 mg (n=33) in the emergency department and found that both groups had statistically significant improvement in symptoms at 30 and 60 minutes, and there was no difference in symptom improvement between treatment groups (10). However, patients treated with ranitidine were more likely to have recurrent pain within 24 hours, likely due to their shorter duration of action. 

The evidence is mixed regarding the efficacy of H2RAs in longer-term dyspepsia symptom control. A Cochrane review of 12 RCTs from 1966-2006 compared H2RAs (oral famotidine 20 mg BID or ranitidine 150 mg oral daily) with placebo in over 2000 participants followed for 4-12 weeks and found a significant reduction in dyspepsia symptoms (RRR 23%; 95% CI 8–35%) (7). However, overall trial quality was poor with significant heterogeneity between studies. Other studies have found no significant benefit of H2RAs in management of dyspepsia symptoms (11). 

For longer-term use for frequent symptoms, H2RAs are less efficacious than PPIs, possibly related to their incomplete acid suppression, shorter duration of action, and tachyphylaxis. When compared with PPIs for uninvestigated dyspepsia symptoms, 7 RCTs involving 2400 patients found a statistically significant improvement with PPIs over H2RAs (RR .81; 95% CI 0.72–0.91) (1). 

Example H2RAs

• Famotidine (Pepcid)

  • Dose: 10-20 mg oral or IV

  • Onset of action within 1 hour (oral), 30 minutes (IV)

  • Duration of action: 10-12 hours

• Cimetidine (Tagamet)

  • Dose: 200-400 mg oral 

  • Onset of action within 1 hour

  • Duration of action: 4-5 hours

  • Cimetidine is the oldest H2RA and has the most side effects. Additional adverse effects include gynecomastia and galactorrhea in a dose-dependent fashion, rare if used <8 weeks. Potent CYP450 inhibitor, avoid giving with warfarin

• Ranitidine (Zantac)

  • FDA recommended pulling from market in 2020 due to carcinogen contaminant (NDMA) concerns

Proton Pump Inhibitors (PPIs)

Bottom Line: IV PPIs can provide symptomatic improvement in the emergency department setting, but their onset is slower than antacids. For patients with frequent dyspepsia symptoms, PPIs are first-line therapy. 

PPIs are considered part of first-line therapy for uninvestigated dyspepsia, functional dyspepsia, PUD, GERD, erosive esophagitis, NSAID-associated ulcer prevention, and treatment of H. pylori (1). PPIs are a prodrug that is converted to the active form in the stomach (12). Once activated, the drug forms a covalent bond with the H+/K+ ATPases in parietal cells inhibiting stomach acid secretion. They work best when H+/K+ ATPases are most active (post-prandially and after a prolonged fast) but require time for prodrug activation. Thus, they should be given 30-60 minutes prior to a meal, preferably before breakfast if once daily dosing (12). There does not seem to be a significant difference in efficacy between different PPIs (12). The IV and oral formulations are equally efficacious in acid suppression (12). 

Common adverse effects include nausea, diarrhea, and headache. Observational studies have found an increased risk of pneumonia, Clostridium difficile infection, and fractures, although there is no RCT data supporting these associations (13, 14). There has been ongoing concern regarding PPIs reducing the anti-platelet activity of clopidogrel as PPIs inhibit the CYP enzyme required for clopidogrel prodrug activation (with omeprazole being the strongest inhibitor) (15). Observational studies raised concerns for increased risks of major adverse cardiac events (16). A systematic review and meta-analysis of 27 studies of >150,000 patients found that the apparent increase in MACE disappeared when a subgroup analysis of only RCTs was performed (RR 0.99, 95% CI 0.76–1.28, p = 0.93) (16). Regardless, it is still recommended to utilize non-omeprazole PPIs in patients on clopidogrel. 

Caveats

• Longer onset of action due to the required prodrug activation (12)

• More effective with recurrent dosing: Acid suppression improves with subsequent dosing as more proton pumps are recruited to the parietal cell membrane. So unlike H2RAs or antacids, PPIs become more effective with each consecutive dose and are generally not recommended on a single use “as needed” basis. (12)

• Rebound acid secretion: occurs due to increased gastrin levels (body’s attempt to stimulate more acid production) which can cause temporary symptom worsening upon discontinuation (12)

Evidence for Use in Dyspepsia

Oral PPIs can take a few hours to work, so they are probably less useful in the emergency department. For immediate relief of symptoms in the emergency department, IV PPIs performed equally well at pain relief as IV H2RAs at 30 and 60 minutes in one study (10). For patients already being treated with an antacid or GI cocktail in the ED, the addition of IV 80 mg pantoprazole did not provide any additional immediate pain relief in one RCT of 87 patients (17). However, the study did not follow the patients after the initial visit to determine the difference in duration of effect.   

For most patients with uninvestigated dyspepsia with recurrent symptoms, PPIs are a good choice as they are efficacious in treating symptoms as well as treating many of the organic causes of dyspepsia such as gastritis, GERD, and PUD. In a meta-analysis of 6 RCTs evaluating over 2700 uninvestigated dyspeptic patients, when PPI therapy was compared with placebo, 50% of patients treated with PPI had persistent symptoms compared with 73% of placebo patients with a NNT of 6 (RR 0.75; 95% CI=0.64–0.88) (1). 

For patients who have had negative EGD and are likely to have functional dyspepsia, PPIs may be less efficacious. 15 RCTs with 5800 patients compared PPI treatment to placebo for improvement in functional dyspepsia symptoms over a 2-8 week period. Approximately 70% of patients in the PPI group had persistent symptoms versus 75% in the control group (RR 0.87; 95% CI 0.82-0.94; p<0.00001) with a NNT of 10 (1). 

Example PPIs

• Pantoprazole (Protonix)

  • Dose: 20-40 mg oral or IV

  • Onset: 2.5 hours (oral), 30 minutes – 1 hour (IV)

  • Duration: 24 hours (oral, IV)

• Omeprazole (Prilosec)

  • Dose: 20-40 mg oral once or twice daily

  • Onset: ~1 hour (oral)

  • Duration: Up to 72 hours

• Esomeprazole (Nexium)

  • Dose: 20-40 mg oral once daily

  • Lansoprazole (Prevacid)

  • Dose: 15-30 mg oral once or twice daily

  • Onset: 1-3 hours

  • Duration: 24+ hours

Antacids

Bottom Line: Provides rapid relief of symptoms for some patients (especially if heartburn-predominant symptoms), but relief is short-lived. 

Antacids include combinations of magnesium salts, aluminum salts, and calcium carbonate (18). They are available over-the-counter in liquids, tablets, and dissolvable powders. These compounds neutralize gastric acid and reduce pepsin activity. Aluminum hydroxide may also help to bind growth factors and promote angiogenesis in injured mucosa. Antacids have the shortest duration of action of therapeutic options for dyspepsia. They are generally well-tolerated with few adverse effects. Magnesium oxide can cause diarrhea. Ingestion of large amounts of calcium carbonate can cause milk alkali syndrome (hypercalcemia, alkalosis, renal injury). Patients with renal failure can develop aluminum toxicity. Antacids can also decrease absorption of certain medications if taken too close together such as tetracyclines, digoxin, iron, fluoroquinolones (18). 

Evidence for Use

Antacids are best studied and best used for predominant heartburn-type symptoms. One multi-center double blind RCT of 560 patients evaluated antacid vs 10 mg oral famotidine vs placebo and found that patients treated with antacids had earlier onset of symptoms relief (as early as 10 minutes) and significantly better heartburn relief scores at 30 minutes compared with famotidine or placebo (19). 

However, for patients with dyspepsia without heartburn or GERD-predominant symptoms, one RCT found that antacids were not significantly better than placebo (RR = 1.02; 95% CI, 0.76–1.36) (7). 

Example Antacid:

• Maalox, Mylanta, Tums, Graviscon

  • Dose: Varies 

  • Onset: Minutes

  • Duration: ~60 minutes

GI Cocktail 

Bottom line: GI cocktails of antacid + lidocaine provide no greater benefit than antacid alone and have the potential for increased harm. 

The GI cocktail is a combination regimen which may include antacids, lidocaine, +/- anti-spasmodics or anti-cholinergics depending on the institution. 

One of the first studies on the use of the GI cocktail in dyspeptic emergency department patients was performed in 1990 (20). This RCT concluded that antacid with viscous lidocaine (n=34) provided statistically significant improvement in symptoms on a visual analog scale compared to antacid alone (n=39). More recent studies have failed to validate these findings. 

Berman et al. 2003 (21) performed a single center double-blind RCT evaluating antacid alone (n=38) vs antacid + viscous lidocaine (n=37) vs antacid + donnatal (n=38) for dyspepsia in emergency department patients. Of note, donnatal is a combination of phenobarbital, hyoscyamine, atropine and scolpolamine. All groups had significant reduction in symptoms at 30 minutes, but there was no difference between groups. Participants given the GI cocktail reported poor palatability and decreased satisfaction compared to antacids alone. As topical lidocaine can blunt airway reflexes and increase risk of aspiration, the authors concluded there was no additional benefit and only risk of harm. The authors recognized donnatal was also not ideal given the role of slowed motility in dyspepsia symptoms and the myriad of potential adverse effects and drug interactions. 

A 2020 RCT compared antacid alone with mixtures of antacid with 2% viscous or 2% solution lidocaine for dyspepsia symptoms (22). At 60 minutes all groups had significant improvement in symptoms but there was no difference between groups. Patients again reported worse palatability of the lidocaine mixtures, and there were more adverse events in the lidocaine groups including oral numbness, dizziness, and nausea. 

Sucralfate 

Bottom line: Not enough evidence for use in dyspepsia. 

Sucralfate is a complex polymer that binds to normal and damaged mucosa (8). This creates a protective physical barrier limiting mucosal exposure to acid and pepsin. The compound also stimulates protective mucus and bicarb release. It is generally well-tolerated due to limited systemic absorption. However, it can bind to other drugs and limit their absorption (8).

Evidence for Use in Dyspepsia

There is limited recent evidence for the use of sucralfate in dyspepsia. A systematic review of two older trials performed in the 1990s found no significant difference in clinical dyspepsia symptoms compared to placebo (RR 0.71; 95% CI 0.38–1.40) (23). There is an ongoing Cochrane review for the evaluation of antacids, sucralfate, and bismuth in the management of dyspepsia (24). 

• Sucralfate (Carafate)

  • Dose: 1 gram 2-4 times per day taken on an empty stomach

Bismuth 

Bottom Line: No clear benefit for dyspepsia symptoms. 

Bismuth salts coat and protect damaged mucosa, inhibit pepsin activity, and increase mucosal mucus and bicarbonate secretion (8). Bismuth salts react with hydrogen sulfide in the colon to form bismuth sulfide, which is black in color and responsible for the blackened stools that can occur. Bismuth subsalicylate has a salicylate group that can contribute to salicylate toxicity if taken with other salicylate products (8). 

Evidence for Use in Dyspepsia

A systematic review of 5 placebo-controlled trials reported a non-statistically significant improvement in dyspepsia symptoms (RR 0.60; 95% CI 0.35–1.03) although these trials were designed to evaluate for H. pylori eradication due to bismuth’s inclusion in combination eradication treatment (8).  

• Bismuth Subsalicylate (Pepto Bismol)

  • Dose: ~524 mg every 30 to 60 minutes or 1,050 mg every 60 minutes as needed for up to 2 days (maximum: ~4,200 mg/24 hours).

Helicobacter pylori Eradication

Bottom Line: This strategy may be best reserved for the outpatient setting or those who fail empiric therapy due to limited testing ability in the emergency department 

H. pylori is a gram-negative rod that is commonly acquired during childhood (25). H. pylori attaches itself to the gastric mucosa and can cause life-long infection if untreated. H. pylori causes an inflammatory response in the gastric mucosa that can lead to chronic gastritis, peptic ulcers, and in the case of long-term infection, gastric cancer (25). 

Given the role of H. pylori in gastritis, PUD, and functional dyspepsia symptoms, testing for H. pylori and treating if positive has been a proposed management strategy for dyspepsia. 2 RCTs found a statistically significant reduction in dyspepsia symptoms after testing for and treating H. pylori (RR 0.81; 95% CI 0.70–0.94) with a NNT of 7 (1). However, when 4 RCTs compared an H. pylori test and treat strategy to just treating dyspepsia symptoms with a PPI empirically, there was no significant difference in symptoms at one year (RR 0.89; 95% CI 0.77–1.04) (1).

One emergency department performed a prospective cohort study on the feasibility of implementing an H. pylori test and treat strategy (25). Symptomatic patients were tested with a point of care urea breath test and if positive treated with triple therapy (PPI, clarithromycin, and amoxicillin or metronidazole for 14 days). They found that 23% of patients were positive for H. pylori and of those who followed up for retesting (47%), there was an 87% eradication rate. While all patients reported improvement in pain regardless of their H. pylori infection status, there was no reported comparison based on treatment status. Limitations of using this strategy include necessary testing machinery that is not commonly found in the emergency department as well as the need for follow-up and retesting. 

Dyspepsia in Pregnancy

Antacids are safe in pregnancy although at very high prolonged doses magnesium trisilicate and bicarbonate-containing antacids have been associated with adverse fetal effects (26). Tums (calcium carbonate) may be the best antacid choice (26). Both H2RAs and PPIs have not been associated with fetal malformations, spontaneous abortion, or preterm delivery. Sucralfate is likely safe due to poor absorption. Bismuth should not be used in the second or third trimesters because the salicylate component may increase bleeding risk (26). 

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References

1. Moayyedi, PM, Lacy, BE, Andrews, CN et al. ACG and CAG Clinical Guideline: Management of Dyspepsia. 2017. American Journal of Gastroenterology. 112(7): 988-1013.

2. Brun R, Kuo B. Functional dyspepsia. 2010. Therapeutic Advances in Gastroenterology. 3(3):145-164. doi:10.1177/1756283X10362639

3. Soybel, D. I. Anatomy and Physiology of the Stomach. 2005. The Surgical Clinics of North America. 85(5):875-894. 

4. Koduru, P., Irani, M., and Eamonn Q. Definition, Pathogenesis, and Management of Dyspepsia. 2018. 16(4):467-479.

5. Vakil N, Moayyedi P, Fennerty MB et al. Limited value of alarm features in the diagnosis of upper gastrointestinal malignancy: systematic review and meta-analysis. 2006. Gastroenterology 131:390–401.

6. Yamawaki H, Futagami S, Wakabayashi M, et al. Management of functional dyspepsia: state of the art and emerging therapies. 2018. Therapeutic Advances in Chronic Disease. 9(1):23-32. doi:10.1177/2040622317725479

7. Moayyedi P, Soo S, Deeks J, Delaney B, Innes M, Forman D. Pharmacological interventions for non-ulcer dyspepsia. 2006. Cochrane Database Systematic Review CD001960. doi: 10.1002/14651858.CD001960. 

8. Moayyedi, P, Soo, S, Deeks, J et al. Systematic review: antacids, H2 receptor antagonists, prokinetics, bismuth, and sucralfate therapy for non-ulcer dyspepsia. 2003. Alimentary Pharmacology and Therapeutics. 17(10): 1215-1227. 

9. McRorie, JW, Kirby, JA, and Miner, PB. Histamine2-receptor antagonists: Rapid development of tachyphylaxis with repeat dosing. World Journal of Gastrointestinal Pharmacology and Therapeutics. 2014. 5:2; 57-62. 

10. Senay E, Eken C, Yildiz M, et al. Comparison of intravenous pantoprazole and ranitidine in patients with dyspepsia presented to the emergency department: a randomized, double blind, controlled trial. 2016. World Journal of Emergency Medicine. 7(1):30-34. doi:10.5847/wjem.j.1920-8642.2016.01.005

11. Veldhuyzen van Zanten SJ, Chiba N, et al. A randomized trial comparing omeprazole, ranitidine, cisapride, or placebo in helicobacter pylori negative, primary care patients with dyspepsia: the CADET-HN Study. 2005. American Journal of Gastroenterology. 100(7):1477-88. doi: 10.1111/j.1572-0241.2005.40280.x. PMID: 15984968.

12. Joseph, J and Prem, PA. Comparison between proton pump inhibitors and H2 Receptor Antagonist. 2017. International journal for Innovative Research in Multidisciplinary Fields. 3(3):192-195. 

13. Trifan A, Stanciu C, Girleanu I, et al. Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis. 2017. World Journal of Gastroenterology. 23(35):6500-6515. doi: 10.3748/wjg.v23.i35.6500. 

14. Nassar Y, Richter S. Proton-pump Inhibitor Use and Fracture Risk: An Updated Systematic Review and Meta-analysis. 2018. Journal of Bone Metabolism. 25(3):141-151. doi:10.11005/jbm.2018.25.3.141

15. Bhatt DL, Cryer, BL, and Contant CF. Clopidogrel with or without Omeprazole in Coronary Artery Disease. 2010. New England Journal of Medicine. 363:1909-1917

16. Demcsak, A, Lantos, T, Balint, E et al. PPIs are not responsible for elevating cardiovascular risk in patients on clopidogrel – a systematic review and meta-analysis. 2018. Frontiers in Physiology. 

17. Musikatavorn, K, Tansangngram, P, Lumlertgul, S et al. A randomized controlled trial of adding intravenous pantoprazole to conventional treatment for the immediate relief of dyspeptic pain. 2012. The American Journal of Emergency Medicine 30(9):1737-1742.

18. Salisbury, B. Antacids. 2020. StatPearls. 

19. Holtmeier W, Holtmann G, Caspary WF, et al. On-demand treatment of acute heartburn with the antacid hydrotalcite compared with famotidine and placebo: randomized double-blind cross-over study. 2007. Journal of Clinical Gastroenterology. 41(6):564-70. doi: 10.1097/MCG.0b013e31802e7efb. PMID: 17577112.

20. Welling, LR and Watson, WA. The Emergency Department Treatment of Dyspepsia with Antacids and Oral Lidocaine. 1990. Annals of Emergency Medicine. 19(7):785-788.

21. Berman, D. A., Porter, R. S., and Graber, M. The GI Cocktail is no more effective than plain liquid antacid: a randomized, double blind clinical trial. 2003. Journal of Emergency Medicine. 25(3):239-244.

22. Warren J, Cooper B, Jermakoff A, et al. Antacid monotherapy is more effective in relieving epigastric pain than in combination with lidocaine: a randomized double-blind clinical trial. 2020. Academic Emergency Medicine.27(9):905-909. 

23. Talley, N. J., Vakil, N. B., Moayyedi, P. American Gastroenterological Association Technical Review on the Evaluation of Dyspepsia. 2005. Gastroenterology. 129 (5): 1756-1780.

24. Abdar Esfahani M, Ahmadi N, et al. Antacids, sucralfate and bismuth salts for functional dyspepsia. 2017. Cochrane Database Systematic Review. 6:CD012686. Published 2017 Jun 8. doi:10.1002/14651858.CD012686

25. Meltzer, AC, Winter, LEL, Kulie, P. et al. Treating gastritis, peptic ulcer disease, and dyspepsia in the emergency department: The feasibility and patient-reported outcomes of testing and treating for Helicobacter pylori infection 

26. Law R, Maltepe C, Bozzo P, et al. Treatment of heartburn and acid reflux associated with nausea and vomiting during pregnancy. 2010. Canadian Family Physician. 56(2):143-144.

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Authorship

Written by - Justine Milligan, MD, PGY-1, University of Cincinnati Department of Emergency Medicine

Peer Review, Editing, Graphics, and Posting - Jeffery Hill, MD MEd