Myocardial ischemia during endoscopic retrograde cholangiopancreatography: An overlooked issue with significant clinical impact

doi:10.1111/j.1440-1746.2010.06274.x GASTROENTEROLOGY jgh_6274 1518..1524 Myocardial ischemia during endoscopic retrograde cholangiopancreatography: An overlooked issue with significant clinical impact Ching-Tai Lee,* Thung-Lip Lee, Wei-Chih Liao, Chi-Yang Chang,* Chi-Ming Tai,* Tsung-Hsien Chiang, Chia-Hung Tu, Wei-Kung Tseng and Jaw-Town Lin*, *Division of Gastroenterology and Division of Cardiology, Department of Internal Medicine, E-Da Hospital/ I-Shou University, Kaohisung, Department of Internal Medicine, National Taiwan University Hospital, Taipei, and Division of Gastroenterology, Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan Key words endoscopic retrograde cholangiopancreatography, myocardial ischemia, post-ercp pancreatitis. Accepted for publication 7 January 2010. Correspondence Jaw-Town Lin, Division of Gastroenterology, Department of Internal Medicine, E-Da Hospital/I-Shou University, 1, E-Da Road, Jiau-shu Tsuen, Yan-chau Shiang, Kaohsiung, Taiwan. Email: jawtown@ntu.edu.tw Wei-Kung Tseng, Division of Cardiology, Department of Internal Medicine, E-Da Hospital/I-Shou University, 1, E-Da Road, Jiau-shu Tsuen, Yan-chau Shiang, Kaohsiung, Taiwan. Email: ed102384@edah.org.tw Competing interests: There was no conflict of interest. Disclosure: The authors have no disclosures to make. Abstract Background and Aim: The occurrence of peri-procedural myocardial ischemia with endoscopic retrograde cholangiopancreatography (ERCP) has been documented, but its significance remains controversial. This study aimed to investigate the incidence and risk factors of myocardial ischemia during ERCP procedures and to analyze the potential association between myocardial ischemia and post-ercp complications. Methods: Ambulatory 24-h ST-segment monitoring from 30 min prior to 24 h after ERCP was obtained on 71 patients from September 2006 to August 2007. Changes in vital signs during ERCP, post-ercp complications, and their outcomes were recorded and analyzed. Results: Cardiac ischemia occurred in 13 patients (18.3%) during ERCP and one patient developed myocardial infarction. More patients in the ischemic group (38.5%) than in the non-ischemic group (5.2%) had ST-T changes in pre-ercp resting electrocardiography (P < 0.01). Hypotension during ERCP was found only in the ischemic group (15.4% vs 0%; P = 0.03). Patients with cardiac ischemia during ERCP had a significantly higher rate of elevated serum amylase and lipase levels (53.8% vs 15.5%; P < 0.01) and post-ercp pancreatitis (30.8% vs 6.9%; P = 0.03). Multivariable logistic regression analysis revealed that cardiac ischemia during ERCP (OR: 5.21, P = 0.050) and pancreatic duct cannulation (OR: 5.7, P = 0.036) were independent predictors for post-ercp pancreatitis. Conclusions: ST-T changes on resting electrocardiography and intra-procedural hypotension are risk factors of myocardial ischemia during ERCP. Post-ERCP hyperamylasemia, hyperlipasemia, and pancreatitis were associated with myocardial ischemia during ERCP. Introduction The occurrence of myocardial ischemia in the peri-procedural period of endoscopic retrograde cholangiopancreatography (ERCP) has been described in small-scale studies, 1 5 but its clinical significance remains controversial. Fisher et al. reported that myocardial injury after ERCP was observed in 8% of patients, as evidenced by an elevation in serum cardiac troponin-i, and myocardial ischemia might be associated with post-ercp pancreatitis. 6 In contrast, on the basis of serum cardiac troponin-t concentrations, Martin et al. found that myocardial ischemia during ERCP was transient without progression into myocardial damage and was not associated with clinical outcome. 7 The mechanisms of myocardial ischemia/injury during ERCP remain elusive, and the risk factors of myocardial ischemia or injury during ERCP have not been investigated in previous studies. Silent myocardial ischemia, defined as myocardial ischemia in the absence of angina, is one of the most common presentations of coronary artery disease. Holter monitoring is useful in the detection of silent ischemia. 8 Gibson et al. emphasized that detection of myocardial ischemia via ambulatory Holter monitoring is of greatest diagnostic and prognostic importance. 9 Because silent myocardial ischemia has been documented in patients undergoing diagnostic endoscopic procedures, 1,5,10 we hypothesize that the risk of silent ischemia might be even greater during ERCP, which is a more stressful and invasive procedure. The aim of this prospective observational study was to investigate the prevalence of and risk factors for myocardial ischemia by using Holter electrocardiogram (ECG) monitoring throughout the ERCP procedure and to determine its clinical significance in terms of post-ercp complications and outcomes. 1518 Journal of Gastroenterology and Hepatology 25 (2010) 1518 1524

Methods This prospective study was conducted at the E-Da Hospital in Taiwan. All patients who underwent ERCP between September 2006 and August 2007 were invited to participate in this study. The local institutional review board approved the study, and written informed consent was obtained from all patients. Exclusion criteria Patients who were younger than 18 years, pregnant women, those who had undergone recent myocardial infarction (within 6 weeks before ERCP), those with underlying advanced malignancy, those with bleeding tendency (prothrombin time prolongation greater than 3 s compared with control or a platelet count less than 100,000/mL), those with an intolerance to ERCP procedures, and those who refused to participate were excluded from the study. Ambulatory patients who could not be hospitalized after ERCP for complete monitoring of clinical outcomes and patients who had undergone prior ERCP procedures were also excluded. Study protocol A complete medical history was obtained before ERCP. The patients demographic and clinical data, including age, sex, comorbid diseases, cardiac risk factors, current medications, and indications for ERCP were recorded. Laboratory tests including complete blood cell counts, liver function tests, serum amylase and lipase, cardiac enzymes, and C-reactive protein levels were obtained 1 day before and the day after ERCP. Before the ERCP procedure was initiated, a 12-lead electrocardiography procedure was performed, and the results were interpreted by a cardiologist blinded to the patients clinical data. After informed consent was obtained, ambulatory 24-h ST-segment monitoring was performed with a 3-channel ambulatory cardiograph (Philips Zymed Digitrack-Plus 24 Model 3100A). The recording began from at least 30 min before the ERCP until 24 h after the procedure. Changes in vital signs during ERCP, post-ercp complications (bleeding, cholangitis, and pancreatitis), and procedure-related morbidity and mortality were recorded. Changes in vital signs were defined as hypoxemia with SpO 2 < 90% lasting at least 15 s, tachycardia (heart rate > 100 b.p.m.), bradycardia (heart rate < 50 b.p.m.), intra-procedural hypertension (mean arterial pressure > 100 mmhg), and intra-procedural hypotension (mean arterial pressure < 55 mmhg). Post-ERCP pancreatitis was defined as abdominal and/or back pain with abdominal tenderness accompanied by elevated serum levels of amylase and lipase (3 times the upper limit or greater) on the day after ERCP. 11 ERCP procedure and monitoring ERCP was performed by five endoscopists (Drs C-T. Lee, C-Y. Chang, C-M. Tai, T-H. Chiang, and C-H. Tu) who had been per- Table 1 Demographic, clinical characteristics, and baseline ECG findings Without ischemia (n = 58) With ischemia (n = 13) P-value Age (years) 63.4 15.6 70.9 15.4 0.06 Sex Male 27 (46.6%) 8 (61.5%) 0.33 Female 31 (53.4%) 5 (38.5%) CAD risk factors 1.9 1.9 Hypertension 30 (51.7%) 6 (46.2%) 0.72 DM 11 (19%) 2 (15.4%) 1.0 Hyperlipidemia 7 (12.1%) 1 (7.7%) 1.0 Documented CAD 5 (8.6%) 1 (7.7%) 1.0 Prior MI 2 (3.4%) 1 (7.7%) 0.46 Smoking 12 (20.7%) 3 (23.1%) 1.0 Medications Aspirin 4 (6.9%) 1 (7.7%) 1.0 Clopidogrel 1 (1.7%) 0 (0%) 1.0 Nitrite 1 (1.7%) 1 (7.7%) 0.34 CCB 20 (34.5%) 1 (7.7%) 0.09 Anesthetic agents (mg) Meperidine 40.5 16.1 38.5 13.0 0.67 Midazolam 3.2 3.7 4.4 3.4 0.30 Baseline resting ECG AV block 1 (1.7%) 0 (0%) 1.0 ST-depression 1 (1.7%) 0 (0%) 1.0 Invert-T 2 (3.4%) 1 (7.7%) 0.46 Q wave 2 (3.4%) 1 (7.7%) 0.46 ST-T change 3 (5.2%) 5 (38.5%) < 0.01 Values are expressed as means standard deviations. AV, atrioventricular; CAD, coronary artery disease; CCB, calcium channel blocker; DM, diabetes mellitus; ECG, electrocardiography; MI, myocardial infarction. Journal of Gastroenterology and Hepatology 25 (2010) 1518 1524 1519

forming therapeutic ERCP for more than 5 years. All patients received oxygen supplementation via nasal cannula during the procedure. Pre-procedure medications included intramuscular butyl scopolamine (10 mg) and oral dimethicone (5 ml). Conscious sedation was achieved by intravenous administration of 2.5 mg midazolam and 25 mg meperidine by endoscopists if there were no contraindications. An increment of 2.5 mg midazolam was administered if adequate sedation was not achieved after 3 min, and midazolam (2.5 mg) and meperidine (25 mg) were given during the procedure if needed according to the patient s condition. Arterial oxygen saturation and heart rate were monitored continuously with a portable bedside monitor (Philips IntelliVue MP40), and blood pressure was measured every 5 min throughout the procedure. The duration and technical details of the procedures were also recorded. Cardiac function assessment ECG recordings were analyzed with a Philips Zymed Holter 1810 Series and reviewed by an experienced cardiologist (Dr T-L. Lee), who was blinded to the patients clinical data. Ischemic ST changes were defined as the presence of ST segment elevation or depression of more than 1 mm for at least 1 min. For ST-segment depression, horizontal or downsloping depressions of 0.1 mv were considered significant. 12 Statistical analysis Categorical data were expressed as percentages and compared using the c 2 -test or Fisher s exact test as appropriate. Continuous data were expressed as means standard deviations (SD) and compared with the Mann Whitney U-test. The associations between cardiac ischemia and post-ercp complications were analyzed by multiple logistic regression with adjustment for clinicopathological factors including gender, age, endoscopic interventions (i.e. EPBD, endoscopic sphincterotomy, or pancreatic cannulation), and changes in vital signs. 13 16 Factors found to be significant in univariable analysis with the likelihood ratio test were selected as potential variables in the multivariable logistic regression model. A P-value < 0.05 was considered statistically significant. All analyses were performed using SPSS version 11.0 software (spss, Chicago, IL) for Windows. Results Demographic characteristics During the study period, 71 consecutive patients who met the inclusion criteria were enrolled in the present study. Thirteen patients (18.3%) developed cardiac ischemia on the basis of Holter monitor analysis. None of the patients had angina, cold sweats, or dyspnea. The baseline demographic and clinical characteristics of Table 2 ERCP procedures and complications Without ischemia (n = 58) With ischemia (n = 13) P-value Before ERCP History of BTI 23 (39.7%) 9 (69.2%) 0.05 History of pancreatitis 12 (20.7%) 1 (7.7%) 0.44 Indication for ERCP Diagnostic ERCP only 12 (20.7%) 1 (7.7%) 0.44 Choledocholithiasis for lithotripsy 42 (72.4%) 11 (84.6%) 0.49 Biliary obstruction for drainage 4 (6.9%) 1 (7.7%) 1.0 Therapeutic procedure 45 (77.6%) 12 (92.3%) 0.44 EST/needle knife 22 (37.9%) 6 (46.2%) 0.58 EPBD 28 (48.3%) 6 (46.2%) 0.89 ENBD/ERBD 4 (6.9%) 3 (23.1%) 0.11 Biliary lithotripsy 42 (72.4%) 11 (84.6%) 0.49 Pancreatic duct cannulation 13 (22.4%) 5 (38.5%) 0.29 Procedure time (minutes) 30.6 20.1 38.7 20.3 0.14 Alteration of vital signs during ERCP 29 (50%) 8 (61.5%) 0.45 Hypoxemia 2 (3.4%) 1 (7.7%) 0.46 Tachycardia 23 (39.7%) 5 (38.5%) 0.94 Bradycardia 2 (3.4%) 0 (0%) 1.0 Hypertension 20 (34.5%) 6 (46.2%) 0.53 Hypotension 0 (0%) 2 (15.4%) 0.03 Complications after ERCP 9 (15.5%) 8 (61.5%) < 0.01 Elevated amylase and lipase 9 (15.5%) 7 (53.8%) < 0.01 Post-ERCP pancreatitis 4 (6.9%) 4 (30.8%) 0.03 Delay duodenal bleeding 0 (0%) 0 (0%) 1.0 Cholangitis 1 (1.7%) 2 (15.4%) 0.08 Bowel perforation 0 (0%) 0 (0%) 1.0 Myocardial infarction 0 (0%) 1 (7.7%) 0.18 BTI, biliary tract infection; ENBD, endoscopic transnasal biliary drainage; EPBD, endoscopic papillary balloon dilatation; ERBD, endoscopic retrograde biliary drainage; ERCP, endoscopic retrograde cholangiopancreatography; EST, endoscopic sphincterotomy. 1520 Journal of Gastroenterology and Hepatology 25 (2010) 1518 1524

ischemic and non-ischemic patients are summarized in Table 1. No significant differences in sex, comorbid diseases, coronary artery disease risk, or medication use were observed between the ischemic and non-ischemic patients, except that the ischemic patients were slightly older (P = 0.06). There were no significant differences among patients with versus without ischemia in the type or dose of anesthetics administered. More patients in the ischemic group (38.5%; 5/13) than in the non-ischemic group (5.2%; 3/58) had ST-T changes on resting ECG before ERCP (P < 0.01). complications than did the non-ischemic patients (61.5% vs 15.5%; P < 0.01). Patients with cardiac ischemia during ERCP had a significantly higher rate of elevated serum amylase and lipase (53.8% vs 15.5%; P < 0.01) and post-ercp pancreatitis (30.8% vs 6.9%; P = 0.03). Multivariable logistic regression analysis revealed that cardiac ischemia during ERCP (P = 0.05, OR: 5.21), and pancreatic cannulation (P = 0.036, OR: 5.7) were independent predictors for post-ercp pancreatitis (Table 3). None of the patients died from the procedure or from cardiac ischemia. ERCP procedure and clinical course The ERCP procedures and complications are shown in Table 2. The most common indication for ERCP was for stone extraction (n = 53). Fifty-seven (80.3%) of the 71 patients underwent therapeutic procedures, including sphincterotomy, endoscopic papillary balloon dilatation (EPBD), biliary drainage, or lithotripsy. Patients with ischemia had more cases of biliary tract infection before ERCP (69.2% vs 39.7%; P = 0.05). Hypotension during the procedure was found in the ischemic group but not in the nonischemic group (15.4% vs 0%, relative risk 6.3, 95% CI 3.6 10.8; P = 0.03) (Table 2). Post-ERCP complications and outcome Patients with cardiac ischemia had a higher risk of post-ercp Case with myocardial infarction after ERCP One patient developed myocardial infarction after ERCP. This 56-year-old woman presented with shock and had a diagnosis of choledocholithiasis and cholangitis. After the patient was resuscitated, ERCP with biliary drainage and lithotripsy was successfully performed. Transient hypoxemia and hypotension developed during the ERCP procedure and the total duration of the procedure was 60 min. Although her vital signs recovered well after ERCP, she had an episode of myocardial infarction the next day and had an elevated serum troponin-i level (0.934 mg/ml; normal < 0.3 mg/ml). She recovered well after treatment for 5 days in the intensive care unit. Holter monitor data showed frequent short runs of ventricular tachycardia during the procedure and two episodes of ST-segment depression after ventricular tachycardia attacks (Fig. 1). Table 3 Predictors of post- endoscopic retrograde cholangiopancreatography pancreatitis Factor Univariable analysis Multivariable analysis OR (95% CI) P-value OR (95% CI) P-value Sex Female 1 0.433 Male 1.83 (0.40 8.34) Age 60 1 0.230 > 60 3.76 (0.43 32.52) Cardiac ischemia No 1 0.006 1 0.050 Yes 8.44 (1.86 38.19) 5.21 (1.00 27.14) Biliary tract infection No 1 0.622 Yes 0.68 (0.15 3.11) Pancreatic cannulation No 1 0.019 1 0.036 Yes 6.41 (1.35 30.38) 5.70 (1.13 28.85) EPBD No 1 0.899 Yes 1.10 (0.25 4.79) EST No 1 0.383 Yes 0.47 (0.09 2.54) Vital sign change No 1 0.564 Yes 1.56 (0.34 7.11) CI, confidence interval; EPBD, endoscopic papillary balloon dilatation; EST, endoscopic sphincterotomy; OR, odds ratio. Journal of Gastroenterology and Hepatology 25 (2010) 1518 1524 1521

(a) (b) (c) Figure 1 (a) Baseline 12-lead electrocardiography of a patient with post-endoscopic retrograde cholangiopancreatography (ERCP) myocardial infarction. No ST-T change or arrhythmia was noted. (b) Frequent short-run ventricular tachycardia (VT) during ERCP on Holter monitoring. (c) Significant ST depression over V2-V6 and inferior leads following short-run VT during ERCP on Holter monitoring. Discussion Several studies have clearly indicated a risk of cardiac complications, such as myocardial ischemia and myocardial infarction, during endoscopic procedures. 1,2,5,10,17 Although ERCP is reportedly safe, even in elderly and seriously ill patients with significant risk factors, it is not surprising that such a stressful endoscopic procedure is associated with a 1.6 30% risk of myocardial ischemia. 1,2,6,7,18 Our study showed that up to 18.3% of the patients experienced myocardial ischemia during the ERCP procedure. Although a previous prospective study reported that up to 8% of patients experienced myocardial injury after an ERCP procedure, 6 only one (1.4%) of 71 patients in the present study experienced myocardial infarction after ERCP. Our observation suggests that although myocardial infarction is an uncommon complication after ERCP, silent myocardial ischemia during ERCP is not a rare event. Continuous ST-segment monitoring with Holter ambulatory ECG is a widely available modality for detecting silent myocardial ischemia in high-risk patients. Silent ischemia detected by Holter monitoring often predicts advanced atherosclerotic heart disease and multi-vessel diseases. Because atherosclerotic heart disorders 1522 Journal of Gastroenterology and Hepatology 25 (2010) 1518 1524

are responsible for the sudden death that occurs in approximately 50% and 64% of asymptomatic male and female patients, 3 respectively, it is reasonable to use a Holter ambulatory ECG device to continuously monitor the ST-segment to identify episodes of silent ischemia in high-risk patients. Our results confirmed the effectiveness of Holter ECG monitoring during ERCP at identifying persons at risk of myocardial infarction after an ERCP procedure. Older patients may be at particular risk of cardiopulmonary complications because of pre-existing cardiovascular disease, sedation, and prolonged procedure times. This study suggested that besides old age and hypotension during ERCP, pre-existing ST-T changes in resting ECG is a predictor for myocardial ischemia during ERCP. Our results suggested that patients with pre-existing ST-T changes in resting ECG may need further evaluation or preventive measures to reduce cardiovascular risk during ERCP. Although two previous studies had failed to detect an association between resting ECG and ischemia during ERCP, those two studies involved a small number of patients (only nine and 16 patients had ischemia, respectively) with limited study power. 2,5 Therefore, the lack of association observed in those studies probably represented false-negative results. Future large-scale studies should be conducted to confirm our observations and to assess its significance in general ERCP practice. The pathogenic mechanisms involved in myocardial ischemia related to ERCP appear to be multi-factorial and involve the interaction between pre-existing organic cardiovascular disease and acute cardiac response. Viscerocardiac reflexes that cause coronary vasospasm and endocrine stress syndrome and that enhance sympathetic activity contribute to the occurrence of myocardial ischemia. 18,19 This might explain our observation that patients with biliary tract infection and intra-procedural hypotension had a higher risk of cardiac ischemia during the ERCP procedure. Although anesthetic agents such as benzodiazepine and opioid analgesics have also been linked to cardio-respiratory events during ERCP, 2,20 in this study and a recent study by Fisher et al.no significant association was noted between the type of anesthetics and ischemia during ERCP. 6 Further research is needed to clarify this issue. Another interesting finding of the present study was the association of post-ercp pancreatitis and intra-procedural cardiac ischemia. The frequency of post-ercp pancreatitis ranges from 1% to 40%, but a rate of 4% to 8% has been reported in most prospective studies involving non-selected patients. 13 16,21 Differences in the criteria for defining pancreatitis, in methods of data collection, and in patient populations are factors that are likely to affect the varying frequency of post-ercp pancreatitis. In the present study, 22.5% of the patients had elevated pancreatic enzyme concentrations after ERCP, whereas 11.3% of the patients had post-ercp pancreatitis. Because most (80.3%) of our patients underwent therapeutic ERCP for procedures such as sphincterotomy, biliary sphincter balloon dilation, and lithotripsy, the rate of post-ercp pancreatitis in the present study was within the range reported by previous studies. 13 16,21 However, patients with intraprocedural cardiac ischemia were found to have a higher risk of post-ercp pancreatitis. This observation agrees with that of a previous study. 6 Although the pathogenic mechanisms responsible are not completely understood, splenic vessel insufficiency and reperfusion injury to the pancreas resulting from cardiac ischemia may play an important role. Ischemia-reperfusion is considered to be a trigger mechanism for distinct types of acute pancreatitis. 22 25 It is possible that the benefits of glyceryl trinitrate in reducing the frequency of post-ercp pancreatitis may be related not only to a reduction in sphincter of Oddi pressure, 26,27 but also to systemic vasodilatation and an improved blood supply to the pancreas. Calcium-channel blockers (CCB) may also have a beneficial role. Although nifedipine was ineffective at preventing post-ercp pancreatitis in two previous randomized control trials in average-risk patients, 28,29 the focus of the investigators was on reducing the sphincter of Oddi pressure. CCB may be effective at preventing cardiac ischemia and decreasing the risk of post-ercp pancreatitis in high-risk patients. In this study, patients without ischemia during ERCP had a higher rate of CCB use than did those with ischemia. Additional studies are needed to address this point. In conclusion, myocardial ischemia during ERCP is not unusual, especially in elderly patients. In addition to risk of myocardial infarction, myocardial ischemia during ERCP is also associated with post-ercp pancreatitis. ST-T changes during resting ECG, and intra-procedural hypotension are clinically important risk factors for myocardial ischemia during ERCP and adequate monitoring and care should be given for these patients. Acknowledgments This study was supported by a project from the E-Da hospital (grant number: EDAH-P98029). References 1 Christensen M, Milland T, Rasmussen V, Schulze S, Rosenberg J. ECG changes during endoscopic retrograde cholangio-pancreatography and coronary artery disease. 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