The use of vasoconstrictor therapy in non‐variceal upper GI bleeds
Report by Gabby May, Senior Clinical Fellow in Emergency Medicine
Checked by John Butler, Consultant in Emergency Medicine and Intensive Care Manchester Royal Infirmary
A short cut review was carried out to establish whether vasoconstrictor therapy is indicated for patients who present with an acute upper gastrointestinal (GI) bleed without known oesophageal varices. In total, 1123 citations were reviewed, of which 16 answered the three part question. The clinical bottom line is that somatostatin (SST) should be considered in unwell patients who are likely to be bleeding secondary to peptic ulcer disease (PUD) until definitive endoscopy, or in situations when endoscopy is contraindicated or unavailable. There is no definitive evidence for the length of time treatment should continue.
Three part question
[In patients with acute severe non variceal upper GI bleed] is [the use of vasoconstrictor therapy] indicated [to control bleeding and prevent re‐bleeding].
Clinical scenario
A 65 year old man presents to the ED with a large, fresh upper GI bleed. He has a history of non‐steroidal anti‐inflammatory drug (NSAID) use and complains of increasing indigestion over the last few months. On examination, he has no stigmata of chronic liver disease and is unwell with blood pressure (BP) of 80 mmHg systolic and tachycardia of 140mmHg. In view of his history and lack of positive examination findings you feel that the most likely diagnosis is a bleeding peptic ulcer. You wonder if there is any evidence to support the use of vasoconstrictor therapy in non‐variceal upper GI bleeds.
Search strategy
Medline (Ovid interface)1966–2006: {upper gi bleed.mp. OR exp Gastrointestinal Hemorrhage/or exp Hematemesis/OR haematemesis.mp. OR hematemesis.mp. OR gastrointestinal adj5 haemorrhage.af. OR gastrointestinal adj5 hemorrhage.af. OR gi adj5 bleed.af. OR peptic ulcer disease.mp. OR exp peptic ulcer/OR gastric ulcer.af. OR duodenal ulcer.af.} AND {terlipressin.mp. OR vasopressin.mp. OR exp vasopressin/OR antidiuretic hormone.mp. OR adh.mp. OR exp somatostatin/OR somatostatin.mp OR somatostatin analogue.mp. OR octreotide.mp. OR exp octreotide/OR glypressin.mp}. Limit to human and English language.
Search outcome
In total, 1123 paperswere found. Of these, 16 randomised clinical trials, 1 laboratory study, 1 review article and 1 meta‐analysis found that were relevant to the three part question.
Table.
| Author, date and country | Patient group | Study type (level of evidence) | Outcomes | Key results | Study weaknesses | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Imperiale et al,1 1997 USA | 1829 patients from 14 randomised clinical trials comparing SST or octreotide with H2 blockers or placebo in patients with clinical or endoscopic evidence of acute nonvariceal upper GI haemorrhage. 7 trials placebo controlled, 7 used cimetidine, 5 used ranidine. 8 trials blinded | Meta‐analysis of 14 trials;database search of English language articles between 1966 and 1996 and the bibliographies of all related articles and textbook chapters. Medline Jan 66–Oct 96, Embase 1980–1996 | Continued bleed or rebleed (all trials) | RR 0.53 (95% CI 0.43 to 0.63) NNT5 | Very heterogeneous studies re protocols and doses of drugs, outcome measures, interventions and study groups (some high risk only, some excluded high risk. proportion of patients with active bleeding ranged from 13–100%)). ?Publication bias; though calculations show would need 18 trials showing no difference for p>0.05, are h2 blockers equivalent to placebo? What is the ideal treatment duration? | |||||
| Surgery (all trials) | RR 0.71 (CI 0.61 to 0.81) NNT8 | |||||||||
| Continued bleed or rebleed (SST only) | RR 0.50 (CI 0.39 to 0.60) NNT5 | |||||||||
| Continued bleed or rebleed (octreotide only) | RR 0.72 (CI 0.35 to 1.08) NS | |||||||||
| Continued bleeding (SST only) | RR 0.41 (CI 0.29 to 0.53) NNT4 | |||||||||
| Surgery (SST only) | RR 0.70 (CI 0.58 to 0.82) NNT7 | |||||||||
| Investigator blinded trials: | ||||||||||
| Continued bleeding or rebleed | RR 0.73 (CI 0.64 to 0.81) NNT11 | |||||||||
| Surgery | RR 0.94 (CI 0.87 to 1.001) | |||||||||
| For PU bleeding alone, continued/rebleed | RR 0.48 (CI 0.39 to 0.59) NNT 4 | |||||||||
| Non peptic ulcer bleeding, continued/rebleed | RR 0.62 (CI 0.39 to 1.002) | |||||||||
| Archimandritis et al,2 2000 Greece | 84 patients over a 12 month period, scoped within the first 24 hours. Randomised to ranitidine and octreotide (50 mg IV three times daily and 100 µg S/C tds)(40) or ranitidine (50 mg IV tds) alone (44). | Prospective RCT; not blinded | No. of units tx – ranitidine | 1.07± 0.24 | Not blind. Small numbers. S/C octreotide and ?wrong dose | |||||
| Ranitidine/octreotide | 1.7±0.37 p = 0.16 (NS) | |||||||||
| Days in hospital: ranitidine | 8.39±0.47 | |||||||||
| Ranitidine/octreotide | 9.20±0.53 p = 0.25 (NS) | |||||||||
| Txd patients: ranitidine | 23/44 | |||||||||
| Ranitidine/octreotide | 21/40 p = 1.0 (NS) | |||||||||
| Emergency op: ranitidine | 3 | |||||||||
| Ranitidine/octreotide | 3 p = 1.0 (NS) | |||||||||
| Saruc et al,3l 2003 Turkey | 21 patients with bleeding peptic ulcer‐endoscoped within 6 hours. Given SST 250 µg/hr for 72 hrs after bolus 250.Each patient had SMA‐V, SMA‐PI, PV‐F and RA‐RI measured by doppler on day 1 of infusion infusion and 6 hours post‐infusion | Observational lab trial ‐not blind | PV‐F‐during infusion | 33.7±12.7 cm3/s | Laboratory trial. Not blind. Small numbers. High no of exclusions including NSAID use. ?Correlation between large vessel flow and clinical picture. ?Influence of mucosal bleeding | |||||
| PV‐F‐post infusion | 56.3±16.0 p = 0.001 | |||||||||
| SMA‐V during infusion | 39.7±13.1 | |||||||||
| SMA‐V post infusion | 64.4±15.1p = 0.01 | |||||||||
| SMA‐PI during infusion | 2.0±0.8 | |||||||||
| SMA‐PI post infusion | 2.8±0.8 p = 0.02 | |||||||||
| Correlation between PV‐F and risk of rebleed | r = 0.55, p = 0.03 (r = 0.2 is correlation) | |||||||||
| Correlation between SMA‐V and risk of rebleed | r = 0.22, p‐0.22 | |||||||||
| No change in RA‐RI | ||||||||||
| Avgerinos et al,3 2005 Greece | 43 patients with malaena/haematemesis with endoscopic signs of stages 2c and 3 Forrest classification. Randomised to SST (15), pantoprazole (14) or placebo (14) and then had gastric pH monitoring for 24 hrs | Prospective RCT (placebo controlled)‐double blind | Mean gastric pH ‐SST | 1.94±0.18 to 6.13±0.37 p<0.0001 | pH study only with no correlation to actual risk of rebleed or need for surgical intervention according to power calculations, study sample not large enough; however, study stopped as SST appeared superior to placebo high no of patients excluded from trial (143). | |||||
| PAN | 1.93±0.16 to 5.65±0.37 p<0.0001 | |||||||||
| Placebo | 1.86±0.12 to 2.10±0.15 p = 0.0917 |
IV, intravenous, S/C, subcutaneous; tds, three times daily, NS, non‐significant; GI, gastrointestinal, PU, peptic ulcer; SST, somatostatin; SMA‐V superior mesenteric artery velocity; SMA‐PI, SMA pulsatility index; PV‐F, portal venous volume flow; RA‐RI, renal artery resistance index.
Comment(s)
In approximately 80% of non‐variceal upper GI bleeds, bleeding stops spontaneously. However, the remaining 20% will require treatment for either continued bleeding or rebleed.(the majority will survive the primary bleed). This high risk group mainly comprise those patients with continued oozing at endoscopy or non‐bleeding visible vessel. Despite the use of diagnostic and therapeutic endoscopy and improved medical treatment over the last 40 years, the mortality for patients with non variceal UGI bleeds remains at 6–7%. Hence, the search for other effective medical interventions, such as the use of vasoconstrictors.
SST has a number of effects on the GI tract including inhibition of gastric acid secretion, pancreatic secretion and biliary secretion. It also reduces gatsric mucosal blood flow, gastric perfusion and stimulates mucus production. Octreotide has a similar secretory effect but it is unknown whether it elicits the same effect on the mucosa or blood flow.
The meta‐analysis covering 14 RCTs show good evidence for the use of SST in acutely bleeding peptic ulcer to reduce the risk of continued bleeding, and a trend for reducing the need for surgery. The pH study and doppler studies theoretically support its use, as SST is shown to increase gastric pH (and thus allow optimum platelet function and decrease fibrinolysis) and decrease arterial blood flow, though with no date re clinical correlation.
The two octreotide studies included in the meta‐analysis have completely different conclusions—the blinded trial showing no effect on outcome, the non‐blinded trial concluded that octreotide stopped PU bleed, decreased Tx requirements and need for surgery. The further non blinded RCT by Archimandritis concluded that octreotide is not superior to ranitidine.
There were no published studies on the use of terlipressin.
In conclusion, there is an evidence base for the use of SST in severe, acute, non variceal peptic ulcer bleeding, but not for other vasoconstricors at present.
What is needed is a large study looking at the efficacy of SST in specific patient groups, defined by source of, and severity of bleeding (ie active/non bleeding visible vessel).
Clinical bottom line
SST should be considered in unwell patients who are likely to be bleeding secondary to PUD until definitive endoscopy, or in situations when endoscopy is contraindicated or unavailable. There is no definitive evidence for the length of time treatment should continue.
References
- 1.Imperialeet al Somatostatin or Octreotide compared with H2 antagonists and placebo in the management of acute non variceal upper. GI haemorrhage Annals of internal medicine 1997:127(12):1062-71. [DOI] [PubMed] [Google Scholar]
- 2.Archimandritis at al Ranitidine versus ranitidine plus octreotide in the treatment of acute non‐variceal upper gastrointestinal bleeding:A prospective randomised study. Current Medical and Research Opinion 2000;16(No3):178-183. [PubMed] [Google Scholar]
- 3.Sarucet al Somatostatin infusion and hemodynamic changes in patients with non‐variceal upper gastrointestinal bleeding: a pilot study.Med Sci Monit 2003;9(7):184-87. [PubMed] [Google Scholar]
- 4.Avgerinoset al Somatostatin inhibits gastric acid secretion more effectively than pantoprazole in patients with peptic ulcer bleeding:A prospective randomised, placebo controlled trial. Scandinavian Journal of Gastroenterology 2005;40:515-522. [DOI] [PubMed] [Google Scholar]