Abstract
Background: Non-occlusive mesenteric ischemia (NOMI) is due to mesenteric arterial hypoperfusion from several causes, such as hypovolemia, heart failure, shock, vasoconstrictors, and severe liver or renal disease. Vasoconstrictor-induced NOMI is usually iatrogenic or associated with cocaine use.
Objectives: Anecdotal reports suggest that cocaine-induced NOMI has the highest mortality among vasoconstrictors. This review aims to compare the outcomes of colonic NOMI secondary to cocaine versus other vasoconstrictors.
Methods: We conducted a systematic search of MEDLINE from inception through October 2016 to find articles on colonic NOMI. The study’s primary outcomes were mortality and hospital length of stay (LOS), while secondary outcomes included the need for surgery. We reported descriptive statistics as percentages or median and interquartile range (IQR). We compared continuous data with the Mann-Whitney test and categorical data with Fisher’s exact test; P<0.05 was statistically significant.
Results: Of the 59 studies, 20 case reports and three case series (n=27 patients) met the inclusion criteria. There was no difference in mortality between cocaine-induced NOMI and non-cocaine NOMI (P=1.0). There were statistically significant differences between cocaine and non-cocaine vasoconstrictor-induced colonic NOMI regarding surgery (60% vs 5.8%, P=0.03) and median LOS (7 days vs 4 days, P=0.04).
Conclusion: Cocaine-induced NOMI and non-cocaine NOMI both appear to have a relatively high but similar mortality rate, but the former is associated with increased requirement for surgery and LOS; prompt recognition of this clinical entity is required to improve outcomes.
Keywords: Intestinal ischemia, Cocaine, Iatrogenic Disease, In-Hospital Mortality, Length of Stay, Patient Outcome Assessment
Intestinal ischemia can be caused by hypoperfusion of mesenteric vasculature due to occlusive or non-occlusive etiology. Occlusive etiologies include embolic or thrombotic arterial occlusion and venous thrombosis. Non-occlusive mesenteric ischemia (NOMI) is due to severe mesenteric arterial hypoperfusion with secondary arterial spasm from several causes, such as hypovolemia, heart failure, shock, vasoconstrictors, and severe liver or renal disease. Vasopressors are used to maintain perfusion in critically ill intensive care unit (ICU) patients and part of their mechanism involves vasoconstriction. The excessive vasoconstrictive activity of these agents can produce inadequate perfusion of the organs, and if it involves mesenteric vasculature, it results in NOMI.
NOMI accounts for 10-20% of patients with acute mesenteric ischemia and has a reported mortality rate of 70-90%, mainly because of comorbid conditions that eventually result in reduced mesenteric perfusion and delays in diagnosis.1 Cocaine-induced NOMI has demonstrated significantly high mortality in prior studies compared to other causes of colon ischemia.2 Because of the alarming severity and high fatality of the condition, we systematically reviewed the published literature. This review’s scope was to examine the body of published literature regarding outcomes of iatrogenic NOMI and compare cocaine-induced NOMI with other causes of iatrogenic colonic ischemia.
Materials and Methods
Data Abstraction
A systematic literature search was conducted on MEDLINE using the PICO framework and is reported under the PRISMA guidelines (Figure 1). We used ‘mesenteric ischemia’ and ‘vasoconstrictor’ as the MESH terms. Two authors systematically extracted all the potential data separately. We included patients with colon ischemia of vasoconstrictor etiology. Of the articles generated, 50 were for colon ischemia. To avoid bias, articles were excluded if patients had a secondary or concomitant reason to develop colon ischemia (eg, adhesions, volvulus, serotonin syndrome, another definite etiology causing septic shock). Similarly, studies with small-intestinal ischemia were excluded due to extensive blood supply of the small intestine through multiple jejunal and ileal arteries, which then go on to form an extensive anastomotic network and arterial arcades before supplying the intestinal wall. The study design was simplified to case reports or case series. Patient-specific information was recorded for age, gender, race, smoking status, type of vasoconstrictor, colonoscopic findings, and whether a surgical procedure was required during the hospital or not. Cocaine use was confirmed by either a positive urine drug screen or during history taking from patients.
Figure 1.
PRISMA flowchart describing study selection and inclusion process
Clinical Significance:
Non-occlusive mesenteric ischemia (NOMI) accounts for up to 20% of patients with acute mesenteric ischemia. It has a very high mortality rate (70-90%), and cocaine-related NOMI has demonstrated significantly high mortality compared to all other causes of colon ischemia.
Published data has limited epidemiologic information related to NOMI, so we sought to examine the body of literature to compare cocaine-related NOMI with vasoconstrictor-induced NOMI.
We report that even though both groups have very high mortality rates, cocaine-related NOMI is associated with increased length of stay (LOS) and surgery requirements.
Design and Analysis
All the statistical analysis was performed using SPSS software. The study’s primary outcomes were mortality and hospital length of stay (LOS), while secondary outcomes included the need for surgery. We reported descriptive statistics as percentages or median and interquartile range (IQR). In addition, we compared continuous data with the Mann-Whitney test and categorical data with Fisher’s exact test, P<0.05 was statistically significant.
Results
Baseline Characteristics
The initial search resulted in 59 manuscripts for colon ischemia, all of which were screened for inclusion, and ultimately 23 articles met the inclusion criteria.3-25 Of these 23 articles, 20 were case reports, and three were case series (Table 1). There were a total of 10 (37.04%) patients in the cocaine-induced NOMI and 17 (62.96%) in the non-cocaine group. Baseline characteristics are presented in Table 2. Patients in the cocaine-induced NOMI group were more likely to be younger. However, the other characteristics, including gender, race, fever, leukocytosis, hypotension, and symptoms on presentation, were similar between the two patient groups. Diagnostic modalities used included colonoscopy (59.26%), sigmoidoscopy (23.07%), computed tomography (37.04%), plain abdominal films (11.54%), and laparotomy (19.23%). Combining findings from all the diagnostic modalities revealed pan-colonic involvement in 11.54%, proximal colon in 23.08%, transverse colon in 7.68%, and descending colon and sigmoid colon in 55.56%. Splenic flexure region involvement was noticed in 30.77% of cases. Most of the patients had more than one region of the colon involved in addition to the primary region of involvement. Findings of severe colon ischemia, including ulcers, hemorrhages, and gangrene, were found in 70.37% of patients on colonoscopy or autopsy. Overall, 19 patients (70.37%) were managed conservatively with broad-spectrum antibiotics, intravenous fluids, and bowel rest. Two patients died due to septic shock, while 89.47% recovered without any further complications. Surgical management was required in 29.63% of patients, and two of them suffered from septic shock, causing death. In this series, nonoperative management had a survival rate of 89%, while surgical management had a success rate of 75%. The most common vasoconstrictors were cocaine (37.04%) and triptans (37.04%). Other vasoconstrictors included in our dataset (in descending order) were: ergotamine (14.81%), vasopressin and its analogs (7.41%), and phenylpropanolamine (3.70%). The most common method of cocaine use was smoking (60%). Other methods were inhalation (20%), intravenous (10%), and oral use (10%). Among prescription vasoconstrictors, migraine was the most common indication for the use.
Table 1.
Summary of the published literature on the outcomes of vasoconstrictor-induced non-occlusive mesenteric ischemia (NOMI) of colon
| Author | Year | Patients (n) |
Vasoconstrictor | Hospital score |
LACE index |
Mortality | Hospitalization (days) |
Surgery |
|---|---|---|---|---|---|---|---|---|
| Stillman et al.3 | 1977 | 1 | Ergotamine tartrate | 3 | 6 | No | 2 | ✗ |
| Lambert et al.4 | 1982 | 1 | IV vasopressin | 0 | 11 | No | 3 | ✗ |
| Johnson et al.5 | 1985 | 1 | Phenylpropranolamine | 4 | 8 | No | NR | ✓ |
| Fishel et al.6 | 1985 | 1 | Cocaine | 4 | 7 | No | NR | ✓ |
| Nalbandian et al.7 | 1985 | 1 | Cocaine | NA | NA | Yes | 60 | ✓ |
| Schmitt et al.8 | 1987 | 1 | Glypressin | NA | NA | Yes | NR | ✗ |
| Rogers et al.9 | 1989 | 1 | Ergotamine | NA | NA | Yes | NR | ✗ |
| Yang et al.10 | 1991 | 1 | Cocaine | 2 | 7 | No | 4 | ✗ |
| Endress et al.11 | 1992 | 2 | Cocaine | 2 | 7 | No | 5 | ✗ |
| Cocaine | 4 | 8 | No | 7 | ✓ | |||
| Rutgeerts et al.12 | 1993 | 1 | Dihydro-ergotamine | 0 | 5 | No | 2 | ✗ |
| Brown et al.13 | 1994 | 1 | Cocaine | 4 | 9 | No | 20 | ✓ |
| Knudsen et al.14 | 1998 | 2 | Sumatrpitan | 4 | 7 | No | 5 | ✗ |
| Sumatriptan | 5 | 7 | No | 5 | ✗ | |||
| Sanjuanbenito Dehesa et al.15 | 1995 | 1 | Cocaine | 4 | 7 | No | NR | ✓ |
| Payne et al.16 | 2000 | 1 | Ergotamine tartrate | NA | NA | Yes | 4 | ✓ |
| Linder et al.17 | 2000 | 3 | Cocaine | 1 | 6 | No | 3 | ✗ |
| Cocaine | 1 | 7 | No | 14 | ✗ | |||
| Cocaine | NA | NA | Yes | 7 | ✓ | |||
| Naik et al.18 | 2002 | 1 | Sumatriptan | 2 | 8 | No | NR | ✗ |
| Schwartz et al.19 | 2004 | 1 | Naratriptan | 0 | 8 | No | 4 | ✗ |
| Moawad et al.20 | 2009 | 1 | Sumatriptan | 0 | 5 | No | NR | ✗ |
| McClenathan et al.21 | 2008 | 1 | Sumatriptan | 0 | 7 | No | NR | ✗ |
| Hodge et al.22 | 2010 | 1 | Sumatriptan | 1 | 7 | No | 4 | ✗ |
| Westgeest et al.23 | 2010 | 1 | Narariptan | 2 | 9 | No | 4 | ✗ |
| Nguyen et al.24 | 2014 | 1 | Sumatriptan | 3 | 9 | No | 10 | ✗ |
| Akbar et al.25 | 2016 | 1 | Naratriptan | 3 | 7 | No | 5 | ✗ |
✗, no surgery; ✓, yes surgery
Table 2:
Patients and Hospitals Characteristics
| Baseline Characteristics | Cocaine (n=10) |
No Cocaine (n=17) |
P value |
|---|---|---|---|
| Age ± SD, (years) | 32.91± 8.31 | 47.18± 11.43 | <0.01 |
| Female [n (%)] | 4 (40.00) | 13 (76.47) | 0.06 |
| Fever on presentation [n (%)] | 3 (30.00) | 2 (11.76) | 0.24 |
| Leukocytosis [n (%)] | 6 (60.00) | 11 (67.71) | 0.81 |
| Hypotension [n (%)] | 3 (30.00) | 1 (5.88) | 0.09 |
| Smoking [n (%)] | 2 (20.00) | 2 (11.76) | 0.56 |
| Race* [n (%)] | 0.09 | ||
| White | 2 (20) | 6 (35.29) | |
| Black | 3 (30) | 1 (5.88) | |
| Management [n (%)] | 0.06 | ||
| Medical | 4 (40.00) | 13 (76.47) | |
| Surgical | 6 (60.00) | 4 (23.53) | |
| Presenting symptoms** [n (%)] | 0.96 | ||
| Abdominal pain | 9 (90.00) | 15 (88.23) | |
| Blood in stool | 8 (80.00) | 13 (76.47) |
Calculated based on the available data (total 44.44% of the entire data) only.
Some of the patients had overlapping symptoms as well.
Outcomes
There was no difference in mortality between cocaine-induced NOMI and non-cocaine NOMI (P=1.0) (Table 3). There were statistically significant differences between cocaine and non-cocaine vasoconstrictor-induced colonic NOMI regarding surgery (60% vs. 5.8%, P=0.035) and median LOS (7 days vs. 4 days, P=0.04). Based on the available reported dataset, mean hospitalization days for patients managed non-operatively were 4.31 (range 2-10), while for patients requiring surgery were 21 (range 4-60) due to sepsis and multiorgan failure, complicating the colon ischemia and prolonging the stay.
Table 3.
Outcomes
| Variable | Cocaine | Non-cocaine | P value |
|---|---|---|---|
| Mortality [n (%)] | 2 (20) | 3 (18) | 1.0 |
| Surgery [n (%)] | 6 (60) | 1 (5.8) | 0.03 |
| Median LOS (IQR) | 7 (12.5) | 4 (2) | 0.04 |
IQR: Interquartile range, LOS: Length of stay
Percentages compared with Fischer’s exact test
Medians were compared with Mann-Whitney test
Discussion
The most common form of intestinal ischemia is colonic ischemia, and it affects mostly older adults.26 The process can occur from either occlusive vascular disease or non-occlusive disease. This article focused on non-occlusive colonic ischemia caused by vasoconstrictors. The vasoconstrictors found in the literature associated with colon ischemia included cocaine, sumatriptan, naratriptan, ergotamine, phenylpropanolamine, and vasopressin and its analogs.
Texter et al27 suggested that cocaine acts on alpha-adrenergic receptors abundantly found in the colon, blocking the reuptake of released norepinephrine, causing severe vasoconstriction. Triptans and ergotamine bind to the serotonin receptors (5-HT1B and 5-HT1D, respectively), and these receptors are also abundantly found in the intestinal wall, as described in an animal study.28 Phenylpropanolamine has an affinity for alpha-receptors, and vasopressin binding to V1 receptors on vessels results in vasoconstriction.
Non-pharmacologic causes of NOMI include hypovolemia, heart failure, shock, and severe liver or renal disease, and overall, NOMI carries high mortality of 70-90% contributed by associated high comorbid burden.1 A hybrid case-control study by Elramah et al2 described that cocaine-induced ischemic colitis has a mortality rate of 26%. The control group in the described study included individuals who met the diagnostic criteria of ischemic colitis but had no history of cocaine use and a urine test negative for cocaine. Our review focused primarily on the colon ischemia caused solely by vasoconstrictors and compared cocaine-induced colon ischemia with other vasoconstrictors. We found a mortality rate of 20% in cocaine-induced NOMI. A plausible explanation is that the patients in this study were highly selected to exclude confounding comorbidities, including small bowel ischemia, which naturally results in a subset of significantly less ill NOMI patients. The mortality in the non-cocaine group was 18%, without any statistically significant difference between the two groups (20% vs. 18%, P=1.0).
In our dataset, ischemia was reversible, requiring conservative management only in the majority of the patients (88%) in the non-cocaine vasoconstrictor group compared with 40% of patients in the cocaine group. Although most patients will have transient ischemia with non-gangrenous colitis that can be successfully managed non-operatively, prompt recognition and surgical intervention are critical in patients with gangrenous colitis.29 Outcome indices that we used included mortality, hospital LOS, and requirement for surgery. In our subset of patients, there were statistically significant differences between cocaine and non-cocaine vasoconstrictor-induced NOMI regarding surgery (60% vs. 5.8%, P=0.03) and median LOS (7 days vs. 4 days, P=0.04), but the difference in mortality did not reach statistical significance.
Our article’s message is that in those patients with acute abdominal pain where a diagnosis of colon ischemia is being entertained, care should be taken not to miss out on the potential role of vasoconstrictors, including cocaine. Further studies to determine the prevalence of cocaine-induced colon ischemia are required to determine the population subgroups at risk. The limitation of our study is that it is not powered enough to detect a difference in mortality, as mentioned earlier, if the difference truly exists. Caution should be exercised in interpreting our results, as almost one-third of the patient data is from literature published three decades ago. The evolution in diagnostic and management strategies over the years can introduce bias and make interpretation of findings difficult. Adequate sample-sized well-designed observational studies are required in the future on this topic.
Author Contributions
Study concept and design: UF; Acquisition of data: UF, ZA; Analysis and interpretation of data: UF, AA; Drafting of the manuscript: UF, DA; Critical revision of the manuscript for important intellectual content: AA; Statistical analysis: AA, UF; Study supervision: AA
References
- 1.Mitsuyoshi A, Obama K, Shinkura N, Ito T, Zaima M.. Survival in nonocclusive mesenteric ischemia: early diagnosis by multidetector row computed tomography and early treatment with continuous intravenous high-dose prostaglandin E(1). Annals of surgery. 2007;246(2):229-35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Elramah M, Einstein M, Mori N, Vakil N.. High mortality of cocaine-related ischemic colitis: a hybrid cohort/case-control study. Gastrointestinal endoscopy. 2012;75(6):1226-32. [DOI] [PubMed] [Google Scholar]
- 3.Stillman AE, Weinberg M, Mast WC, Palpant S.. Ischemic bowel disease attributable to ergot. Gastroenterology. 1977;72(6):1336-1337. [PubMed] [Google Scholar]
- 4.Lambert M, de Peyer R, Muller AF.. Reversible ischemic colitis after intravenous vasopressin therapy. JAMA. 1982;247(5):666-667. [PubMed] [Google Scholar]
- 5.Johnson DA, Stafford PW, Volpe RJ.. Ischemic bowel infarction and phenylpropranolamine use. West J Med. 1985;142(3):399-400. [PMC free article] [PubMed] [Google Scholar]
- 6.Fishel R, Hamamoto G, Barbul A, Jiji V, Efron G.. Cocaine colitis. Is this a new syndrome? Dis Colon Rectum. 1985;28(4):264-266. [DOI] [PubMed] [Google Scholar]
- 7.Nalbandian H, Sheth N, Dietrich R, Georgiou J.. Intestinal ischemia caused by cocaine ingestion: report of two cases. Surgery. 1985;97(3):374-376. [PubMed] [Google Scholar]
- 8.Schmitt W, Wagner-Thiessen E, Lux G.. Ischaemic colitis in a patient treated with glypressin for bleeding oesophageal varices. Hepatogastroenterology. 1987;34(3):134-136. [PubMed] [Google Scholar]
- 9.Rogers DA, Mansberger JA.. Gastrointestinal vascular ischemia caused by ergotamine. South Med J. 1989;82(8):1058-1059. [DOI] [PubMed] [Google Scholar]
- 10.Yang RD, Han MW, McCarthy JH.. Ischemic colitis in a crack abuser. Dig Dis Sci. 1991;36(2):238-240. [DOI] [PubMed] [Google Scholar]
- 11.Endress C, Gray DG, Wollschlaeger G.. Bowel ischemia and perforation after cocaine use. AJR Am J Roentgenol. 1992;159(1):73-75. [DOI] [PubMed] [Google Scholar]
- 12.Rutgeerts L, Ghillebert G, Drognee W, Tanghe W, Vuylsteke P, Decoster M.. Ischemic colitis in a patient with Crohn’s disease taking an oral contraceptive and an ergotamine alkaloid. Acta Clin Belg. 1993;48(1):48-51. [DOI] [PubMed] [Google Scholar]
- 13.Brown DN, Rosenholtz MJ, Marshall JB.. Ischemic colitis related to cocaine abuse. Am J Gastroenterol. 1994;89(9):1558-1561. [PubMed] [Google Scholar]
- 14.Knudsen JF, Friedman B, Chen M, Goldwasser JE.. Ischemic colitis and sumatriptan use. Arch Intern Med. 1998;158(17):1946-1948. [DOI] [PubMed] [Google Scholar]
- 15.Sanjuanbenito Dehesa A, Fernandez Cebrián JM.. Ischaemic colitis induced by cocaine abuse. Br J Surg. 1995;82(1):138. [DOI] [PubMed] [Google Scholar]
- 16.Payne B, Sasse B, Franzen D, Hailemariam S, Gemsenjäger E.. Manifold manifestations of ergotism. Schweiz Med Wochenschr. 2000;130(33):1152-1156. [PubMed] [Google Scholar]
- 17.Linder JD, Mönkemüller KE, Raijman I, Johnson L, Lazenby AJ, Wilcox CM.. Cocaine-associated ischemic colitis. South Med J. 2000;93(9):909-913. [PubMed] [Google Scholar]
- 18.Naik M, Potluri R, Almasri E, Arnold GL.. Sumatriptan-associated ischemic colitis. Dig Dis Sci. 2002;47(9):2015-2016. [DOI] [PubMed] [Google Scholar]
- 19.Schwartz DC, Smith DJ.. Colonic ischemia associated with naratriptan use. J Clin Gastroenterol. 2004;38(9):790-792. [DOI] [PubMed] [Google Scholar]
- 20.Moawad FJ, Goldkind L.. An unusual case of colonic ischemia. South Med J. 2009;102(4):405-407. [DOI] [PubMed] [Google Scholar]
- 21.McClenathan J. Mesenteric Ischemia After Sumatriptan Use. The Internet Journal of Surgery. 2008. Volume 19 Number 2. [Google Scholar]
- 22.Hodge JA, Hodge KD.. Ischemic colitis related to sumatriptan overuse. J Am Board Fam Med. 2010;23(1):124-127. [DOI] [PubMed] [Google Scholar]
- 23.Westgeest HM, Akol H, Schreuder TC.. Pure naratriptan-induced ischemic colitis: a case report. Turk J Gastroenterol. 2010;21(1):42-44. [DOI] [PubMed] [Google Scholar]
- 24.Nguyen TQ, Lewis JH.. Sumatriptan-associated ischemic colitis: case report and review of the literature and FAERS. Drug Saf. 2014;37(2):109-121. [DOI] [PubMed] [Google Scholar]
- 25.Akbar A, Nissan G, Chaudhry P, Rangasamy P, Mudrovich S.. Isolated naratriptan-associated ischemic colitis. Proc (Bayl Univ Med Cent). 2016;29(4):410-411. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Higgins PD, Davis KJ, Laine L.. Systematic review: the epidemiology of ischaemic colitis. Alimentary pharmacology & therapeutics. 2004;19(7):729-38. doi: 10.1111/j.1365-2036.2004.01903.x. [DOI] [PubMed] [Google Scholar]
- 27.Texter EC, Jr., Chou CC, Merrill SL, Laureta HC, Frohlich ED.. Direct effects of vasoactive agents on segmental resistance of the mesenteric and portal circulation. Studies with 1-epinephrine, levarterenol, angiotensin, vasopressin, acetylcholine, methacholine, histamine, and serotonin. The Journal of laboratory and clinical medicine. 1964;64:624-33. [PubMed] [Google Scholar]
- 28.Banes AK, Watts SW.. Enhanced contraction to 5-hydroxytryptamine is not due to “unmasking” of 5-hydroxytryptamine(1b) receptors in the mesenteric artery of the deoxycorticosterone acetate-salt rat. Hypertension. 2001;38(4):891-895. [DOI] [PubMed] [Google Scholar]
- 29.Washington C, Carmichael JC.. Management of ischemic colitis. Clinics in colon and rectal surgery. 2012;25(4):228-35. [DOI] [PMC free article] [PubMed] [Google Scholar]