IL
REVIEWS
Cardiorespiratory Effects Variceal Sclerotherapy AHMETBAYDUR,
Endoscopic Esophageal
M.D., JACOB KORULA, M.D., LosAngeles,
Endoscopic variceal sclerotherapy (EVS) is an effective means of controlling variceal hemorrhage, which develops as a consequence of portal hypertension. While esophageal perforation, ulceration, strictures, and media&i&is are potential complications associated with this procedure, it is not clear whether isolated pleuropulmonary events such as pleuritis, pneumonitis, and adult respiratory distress syndrome are causally related to the EVS. Endoscopy and sedation with the attendant risk of aspiration, particularly in the background of hepatic encephalopathy, may account for some of these events. Recent controlled studies of respiratory function demonstrate that EVS as such results in minor changes in gas exchange, lung volumes, and pulmonary and systemic hemodynamics. Most pulmonary complications have been reported with the use of sodium morrhuate sclerosant. Comparative studies among different sclerosants are necessary to evaluate relative safety. Finally, there have been rare reports of myocardial ischemia and pericarditis reported in association with EVS, but these are of a transient nature. Chest symptoms, roentgenographic pleuropulmonary changes, pulmonary hemodynamics, and cardiac perturbations are transient and should not preclude offering EVS to patients with variteal hemorrhage.
From the Departments of Chest Medicine (AB) and Hepatology (JK). Rancho Los Amigos Medical Center, Downey. California, and University of Southern California School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Ahmet Baydur. M.D., Ranch0 Los Amigos Medical Center, 7601 East lmperral Highway, Downey. California 90242. Manuscript submitted September 11, 1989, and accepted in revised form June 14. 1990.
California, andDowney,
California
T
he poor long-term results of portocaval shunts as a treatment for bleeding varices led to a renewed interest in the use of endoscopic variceal sclerotherapy (EVS) for this potentially fatal complication of portal hypertension. Endoscopic sclerotherapy is carried out using flexible fiberoptic panendoscopy under sedative analgesia. Needle injectors are introduced through the biopsy channel of the endoscope, and esophageal varices are injected under direct vision using either a freehand technique or a sheath to permit injection of one variceal column at a time. An intravariceal injection is attempted usually, although it is well recognized that even if good intravariceal injections are made, paravariceal extravasation of sclerosants frequently occurs [l]. A variety of sclerosants are available although controlled comparisons of their effects in humans have not been reported. Thrombosis and necrotizing inflammation are the usual initial effects leading to obliteration of varices and fibrosis [ 11. EVS can be safely performed in the ambulatory care setting [2] or expeditiously at the bedside in cases of active hemorrhage. Esophageal complications of sclerotherapy have included necrotizing inflammation, ulceration, microabscesses, hemorrhage, perforation, and stricture [1,3,4], and have been reported to be as high as 41% in prospective studies. In addition, a variety of extraesophageal complications have been associated with EVS. Most of these are pleuropulmonary in nature, although rarely cardiac events have also been documented. In a retrospective study [5], pulmonary complications were observed in 12%, and in controlled studies [6,7], pulmonary complications have ranged from 2% to 18%. In view of the pulmonary parenchymal and vascular abnormalities commonly associated with chronic liver disease [8-111, respiratory phenomena reported during or immediately after the administration of EVS can be difficult to evaluate. Thoracic events described in association with EVS have included pleural effusions, fever, pneumonia, empyema, esophago-bronchopleural fistulas, mediastinitis, pulmonary hypertension, and adult respiratory distress syndrome (ARDS). Repeated injections may expose the patient to cumulative risks, although the chance of a serious complication is less if the injection is not paravariceal [3,12]. October
1990
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Journal
of Medicine
Volume
89
477
CARDIORESPIRATORY
EFFECTS
OF ESOPHAGEAL
VARICEAL
SCLEROTHERAPY
The effects of EVS on cardiorespiratory function must be evaluated in the background of cardiopulmonary complications occurring during gastrointestinal endoscopy, which are unusual in well-supervised units where electrocardiographic monitoring and pulse oximetry are available. In a national survey of 2,320 endoscopies for upper gastrointestinal bleeding reported by the American Society of Gastrointestinal Endoscopy [13], complications occurred in 0.9% of procedures. Major complications such as perforation, aspiration, or bleeding occurred in 0.5%. Cardiopulmonary complications account for 50% of morbidity and 60% of mortality [14-161. Electrocardiographic changes during endoscopy are also common and have been reported in patients with known prior heart disease [17,18]. Serious ventricular arrhythmias, angina, myocardial infarction, and cardiac arrest may lead to a fatal outcome rarely in this setting [ 161. Cardiac events may be related to hypoxemia [19], which in turn is related to the administration of sedatives and endoscopic size [20-221. In view of the questions concerning the association of events surrounding EVS, a widely used technique, it would be useful to briefly discuss the underlying mechanisms and the physiology involved, including a review of available clinical observations pertaining to such events.
/ BAYDUR
AND KORULA
portal vein and liver within 28 seconds. The dissemination continued to increase and eventually washed out within 5 minutes. A whole body scintiscan taken 3 hours after beginning the intravariceal injection showed uniform distribution throughout the body. This phenomenon was observed regardless of the volume injected intravariceally at EVS. Therefore, although systemic entry of sclerosant mixture is well documented, the frequency of its occurrence or its repercussions appears to be minor (Table I).
RADIOGRAPHICDEMONSTRATIONOF PLEUROPULMONARYABNORMALITIES Saks and colleagues [26] demonstrated a 79% incidence of radiographic abnormalities in a series of 38 examinations taken within 48 hours of EVS in 15 patients. The most common finding was pleural effusion (occurring in half of the examinations), while lower lobe alveolar and linear densities were seen less often. Such findings tended to occur when more than 1 mL of sclerosant was injected per varix (Table I). Mauro and co-workers [27] described pleural effusions and subsegmental atelectasis seen on the computed tomographic scan in most of a small number of patients receiving EVS. There was radiographic evidence of mediastinal inflammation of varying intensity, which we believe is explained perhaps by necrotizing periesophageal inflammation and hemorrhage and by the lack of serosa covering the esophagus (Table I). Bacon and colleagues [28] noted the development of pleural effusions in 19 of 30 patients undergoing EVS with 5% morrhuate. The effusions that occurred on either side were predominantly exudative in nature. Chest pain and effusion were noted more frequently with large-volume injections that probably contributed to deep mucosal ulceration, allowing the periesophageal inflammation to extend into the mediastinum. In most cases, effusions were small and had resolved by the time of subsequent EVS [29] (Table I). Chylothorax was reported in a patient who developed acute respiratory distress and shock after EVS [30]. The autopsy after a massive variceal hemorrhage failed to reveal a tear in the thoracic duct. The possibility exists in this rare complication that the thoracic duct was perforated by the transesophageal endoscopic needle.
ENTRY OF SCLEROSANTINTO THE SYSTEMIC AND PULMONARYCIRCULATIONS
Portal blood drains into the systemic and pulmonary circulations through esophagogastric collaterals and the azygous-hemiazygous system of veins in portal hypertension. The flow direction of esophageal collaterals is usually cephalad but influenced by respiratory changes in intrathoracic pressure [23]. When sclerosant mixed with methylene blue is injected into esophageal varices, the immediate detection of methylene blue in the urine of some patients suggests systemic entry of the sclerosant mixture (unpublished observations). Entry into the pulmonary circulation has also been demonstrated in some patients by positive uptake on lung scan of technetium-99m (Tc99m) tagged sodium tetradecyl sulfate when injected into the esophageal varices at sclerotherapy in our Liver Unit (unpublished observations) (Table I). Connors and colleagues [24] have demonstrated that only 20% of Tc99m-labeled sodium morrhuate injected into esophageal varices reached the pulmonary circulation, perhaps accounting for a lack of significant change in specific EFFECTOF EVSON LUNG FUNCTION Monroe and colleagues [31] suggested that acute single-breath diffusing capacity. Similarly, Sukirespiratory failure resulting from injection of sodigara and colleagues [25] injected ethanolamineTc99m sodium pertechnetate into esophageal var- um morrhuate into the pulmonary artery of sheep may have been due to an increase in pulmonary ices of six patients undergoing EVS. They demonstrated systemic dissemination through the vascular permeability. Such a finding is supported 478
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TABLE I Summary of Cardiorespiratory Associated
Efl ects
Radiographic,
Pleuropulmonary Entry of sclerosant into Systemrc Pulmonary circulation Pleural changes
Pulmonary
parenchymal
Lung function Volumes and flow rates Gas exchange Pulmonary
Cardiac Arrhythmias Pericarditis
hemodynamics
Effects Associated with Endoscopic Esophageal Sclerotherapy
changes
Radionuclide,
or Laboratory
Findings
Clinical Significance
Positive uptake on Tc-99m lung scan Rapid systemic dissemination through the portal vein and liver, without uniform body distribution Exudative effusions Empyema Chylothorax Mediastinitis Atelectasis Pneumonia Mass effect (by CT scan) Adult respiratory distress syndrome
Minor frequency
Transient and described after large-volume injections From esophageal-pleural or esophageal-bronchial fistulas; may be confused with pneumonia May be confused
reversible
ischemic
changes on ECG
May be associated with ECG, radiographic, cardiographic changes
and echo-
with pneumonia
Increased pulmonary capillary permeability demonstrated in animal injection studies; causal relationship not proven in humans
No significant changes with injection of sodium tetradecyl sulfate; transient hypoxemia with sodium morrhuate In sheep: increase in pulmonary artery pressure and lymph flow with injection of sodium morrhuate; in humans: increase in PVR, PAP, and CVP; decrease of PO2 Transient
and consequences
None None Transient Vance
and minor changes,
with little clinical rele-
Difficult to separate from ischemic events associated with endoscopy alone Related to direct injection of sclerosant into pericardiurn; symptoms relieved by pericardiocentesis or spontaneous amelioration
= computed tomographic; PVR = pulmonary vascular resistance; CVP = central venous pressure: ECG = electrocardiogram.
by animal studies in which the systemic injection of oleic acid has resulted in an increase of alveolar epithelial permeability [32,33]. However, the efforts of Monroe and colleagues [31] failed to demonstrate an increase in pulmonary microvasculature permeability after morrhuate injection, and consequently support their hypothesis. It is uncertain if their sheep experiments are a valid explanation of their proposed pathogenesis of respiratory failure that developed in two of 30 patients who underwent EVS for esophageal variceal bleeding. The possibility of aspiration in these patients (one of whom was encephalopathic) could not be satisfactorily excluded. ARDS is known to develop in patients with chronic liver disease and acute variceal hemorrhage. In a controlled trial of acute sclerotherapy in variceal hemorrhage, 10% of control patients not receiving EVS and 2% of patients receiving EVS developed ARDS [34]. Thus, the causal relationship to sclerotherapy is poorly substantiated in the literature (Table I). Rare and sporadic reports may, however, occur. Because the premeditation and the endoscopy itself may contribute to aspiration pneumonitis or hypoxemia, it is important to compare the incidence of respiratory dysfunction in patients receiving EVS and those undergoing endoscopy for other reasons. To help answer this question, our group performed a prospective controlled study to determine the short- and long-term effects of EVS with
sodium tetradecyl sulfate on lung function in 11 patients with cirrhotic portal hypertension and variceal hemorrhage 1351. There were no statistically significant changes in FVC (forced vital capacity), FEVi (forced expiratory volume in 1 second), FEV1/FVC (forced expiratory volume in 1 second/ forced vital capacity), FEFss-75 (maximal midexpiratory flow), Vmax50 (maximal expiratory flow at 50% of expired vital capacity), Pa02 (arterial oxygen partial pressure), AaDOs (alveolar to arterial oxygen tension difference), and pH in this group and a control group of patients with chronic liver disease undergoing diagnostic endoscopy (without EVS). Likewise, there were no significant changes in these parameters in nine patients who underwent two follow-up sessions of EVS over 1 year. In addition, seven patients also demonstrated a lack of significant changes in tests for lung volumes and closing volume. Ten of 11 patients demonstrated no changes in ventilation-perfusion (V/Q) lung scans. One patient with a normal V/& scan before EVS developed an abnormal subsegmental posterior basal perfusion defect seen after EVS with a normal ventilation scan, which remained unchanged on a follow-up scan 9 months later. We concluded that in our experience, in patients with stable liver disease and without hepatic failure, EVS with tetradecyl sodium did not result in serious impairment of respiratory function over the short- or long-term (Table I).
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EFFECTS
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/ BAYDUR
AND KORULA
ent volumes of alcohol were injected at EVS. No significant difference was seen when measurements between patients injected with alcohol and those Given the observation of the occurrence of ARDS and pleural effusion, Glauser and colleagues [36] injected with saline were compared. PCWP and sysstudied sheep pulmonary hemodynamics and temic arterial pressure also remained unchanged. Thus, it appears that based on these studies, EVS lymph flow after injection of sodium morrhuate. is, for unclear reasons, associated with minor They observed threefold increases in mean pulmochanges in pulmonary and systemic hemodynamics, nary artery pressure and baseline lymph flow and a which are clinically insignificant (Table I). significant decrease in the lymph/plasma albumin Finally, there may be a difference in the inciconcentration ratio. Since there was no observed dence of respiratory complications depending on increase in the pulmonary tissue water content, the type and volume of sclerosant used, since most they reasoned that EVS caused transient pulmoevents were reported with the use of sodium morrnary hypertension but not increased permeability huate (the most commonly injected sclerosant). of the pulmonary microvasculature. This pulmoThus, the intriguing possibility of sclerosant-specifnary hypertension was markedly blunted by indoic pulmonary parenchymal and hemodynamic commethacin, which suggested pulmonary vascular replications needs to be addressed with a comparative activity mediated by prostaglandins. There are no study. controlled studies in humans to support this observation (Table I). Glauser and co-workers [36] also monitored pulmonary artery pressures during EVS EFFECTOF EVSON CARDIACFUNCTION in a small number of patients and found a transient Serious cardiac complications associated with en2- to 2.5fold increase from normal baseline values doscopic examination are rare and are usually not without a change in the cardiac output or arterial detected unless accompanied by electrocardiooxygenation. graphic monitoring; Palmer and Wirts [39] have Bailey-Newton and colleagues [37] studied the reported a 0.002% cardiac mortality rate associated with endoscopy in a large retrospective survey. effect of EVS on gas exchange and hemodynamics in eight patients undergoing EVS using sodium However, both coronary spasm and pericarditis morrhuate as therapy for variceal hemorrhage. A have been reported after EVS. Charng and co-worknumber of parameters, such as mixed expired gas ers [40] described a 68-year-old man with an old anterior myocardial infarction who experienced seconcentrations, systemic arterial pressure, pulmonary capillary wedge pressure (PCWP), and cardiac vere chest pain and hypotension immediately after output, were measured. Baseline measurements EVS. The electrocardiogram showed inferior lead were obtained before and after endoscopic intubaST-segment elevation, which returned to baseline 30 minutes later, after administration of sublingual tion; measurements were subsequently repeated nitroglycerin. Transient Q waves also appeared in immediately after EVS and for 60 minutes after EVS. Pa02 decreased after endoscopy without the inferior leads, coupled with echocardiographic changes in pulmonary and systemic vascular resis- evidence of left ventricular and anteroseptal hypotance. Pulmonary arterial pressure (PAP) and cen- kinesis. In their view, these findings strongly sugtral venous pressure increased with EVS but re- gested coronary artery spasm. An allergic reaction to the sclerosant and stress-related sympathetic turned to baseline values after EVS. Pulmonary vascular resistance increased by 30% over the base- stimulation were considered as possible etiologies. line values, associated only with a transient de- Levy and Abinader [41] have reported a 24% incicrease in PaOz. This study showed small increases dence of ischemic changes during continuous elecin pulmonary and systemic vascular resistance trocardiographic monitoring during endoscopy, and without altering PCWP, PAP, or gas exchange. The which usually resolve spontaneously (Table I). authors did not record changes beyond 60 minutes Knauer and Fogel [42] reported chest pain, dysafter injection or suggest mechanisms for the findpnea, and a pericardial friction rub in one patient, ings. In a later study, Sarin and co-workers [38] and pericardial effusions in three patients who restudied the effects of absolute alcohol sclerotherapy ceived EVS with sodium morrhuate. In two paon lung function in 14 patients. Pulmonary hemotients, the pericardial effusion resolved spontanedynamics were studied and measurements com- ously while in the third, pericardiocentesis relieved pared with those of control patients who received symptoms. EVS was continued in one patient withequivalent volumes of saline injection into varices. out further problems after resolution of pericardiMean PAP increased by 27% after 1 minute but tis. The exact etiology is not clear, but it is speculatreturned to baseline after 15 minutes. The increase ed that pericarditis may have been caused either by in PAP was not significantly different when differdeep injection of the sclerosant into the pericardi-
EFFECTOF EVSON THE PULMONARY VASCULARBED
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urn or from extension of periesophageal tion into the pericardium (Table I).
EFFECTS
OF ESOPHAGEAL
inflamma-
SUMMARY The egress of blood through portal systemic collaterals of the esophagus into the pulmonary circulation underscores the vulnerability of pulmonary capillaries and endothelium to damage from sclerosants injected at EVS. Although systemic and pulmonary dissemination was demonstrated by careful studies, only a small fraction of the injected dose appears to reach the pulmonary circulation. Although transient alterations in pulmonary hemodynamics are observed, this should not preclude offering EVS to patients with variceal hemorrhage. Controlled clinical studies of pulmonary function do not demonstrate a significant impairment either acutely or over the long-term with repeated EVS, a finding of practical value and importance. The occurrence of ARDS from EVS is poorly documented and pulmonary aspiration in the setting of acute hemorrhage and encephalopathy are likely predisposing factors 1431; even if it did occur, this complication is a sporadic and rare event. Chest roentgenograms are useful in identifying pleural effusions, often exudative in nature, suggesting an associated mediastinal involvement mediated through the lymphatics or as a result of a necrotizing inflammatory process extending into and beyond the muscular wall of the esophagus. A variety of chest roentgenographic abnormalities that have been reported are not of major significance; computed tomographic abnormalities may provide an anatomic basis for pleuropulmonary effects of EVS but are not useful in determining the type of process that occurs. Pericarditis is the only convincing cardiac abnormality and may result from extension of a contiguous mediastinal inflammatory process, although the possibility of deep esophageal injections into the posterior pericardium cannot be excluded. The pericarditis is self-limited and should not preclude continuing EVS. We hope this review will place the data in the literature in the proper perspective and alert clinicians to the uncommon but potentially serious respiratory or cardiac events that may occur during EVS, particularly in patients with underlying cardiorespiratory disorders.
ACKNOWLEDGMENT We thank Virgrnra Boren and Mary Beth Cude for preparation
of the manuscript.
REFERENCES 1. Korula J. Kage M. Harada A, Mucrentes F. Kane1 G, Peter RL. The effects of endoscopic variceal sclerotherapy on the esophagus. A prospectrve clinical and histopathological study. J Clin Gastroenterol 1987; 9: 639-43.
VARICEAL
SCLEROTHERAPY
/ BAYDUR
AND KORULA
2. Korula J. Outpatient esophageal vanceal sclerotherapy: safe and cost effecbve. A prospective study. Gastrointest Endosc 1986; 31; 1-3. 3. Ayres SJ. Goff JS, Warren GH. Endoscopic sclerotherapy for bleeding esophageal varices: effects and complications. Ann Intern Med 1983; 98: 9003. 4. Santangelo WC, Dueno MI, Estes EL. Krejs GJ. Prophylactic sclerotherapy of large esophageal varices. N Engl J Med 1988; 318: 8148. 5. Barsoum MS. Mooro HA, Bolous FI, Ramzy AF. Rizk-Allah MA, Mahmoud FL. The complications of injection sclerotherapy of bleedrng esophageal varices. Br J Surg 1982; 69: 79-81. 6. Marzuk P. Schwartz SJ. Endoscopic sclerotherapy for esophageal vances. Health and Public Pokey Committee, American College of Physicians. Ann Intern Med 1984; 100: 608-10. 7. Korula J, Balart LA, Radvan G, er al. A prospective randomrzed controlled study of chronic esophageal variceal sclerotherapy. Hepatology 1985; 5: 584-9. 8. Stanley NN. Woodgate DJ. Mottled chest radiographic and gas transfer defect in chronic liver disease. Thorax 1972; 27: 315-23. 9. Daoud FS, Reeves JT. Schaefer JW. Failure of hypoxic pulmonary vasoconstnction Inpatients with liver cirrhosis. J Clin Invest 1972; 51: 1076-89. 10. Ruff F, Hughes MB, Stanley N, eta/. Regional lung funcbon rn patients with hepatic crrrhosis. J Clin Invest 1971; 50: 2403-13. 11. Robrn ED, Laman D. Horn BR, Theodore J. Platypnea related to orthodeoxia caused by true vascular lung shunts. N Engl J Med 1976; 294: 942-3. 12. Helpap B, Bollweg L. Morphological changes rn the terminal esophagus with varices. following sclerosis of the wall. Endoscopy 1981; 13: 229-33. 13. Gilbert DA, Silverstein FE, Tedesco FJ. Nabonal ASGE survey on upper gastrointestinal bleeding: complications of endoscopy. Dig DIS Sci 1981; 26 (Suppl): 55s-9s. 14. Silvls SE, Nebel 0, Rogers G, Sugawa C. Mandelstam P. Endoscopic complrcations. JAMA 1976; 235: 928-30. 15. Davis RE. Graham DY. Endoscopic complications: the Texas experience. Gastrorntest Endosc 1979; 25: 146-9. 16. Katon RM. Complicabons of upper gastrointestinal endoscopy in the gastrointestinal bleeder. Dig Dis Sci 1981; 26: 47s-54s. 17. Levy N, Abrnader E. Continuous electrocardiographrc monitoring with Holter electrocardlorecorder throughout all stages of gastroscopy. Am J Drg Dis 1977; 22: 109-4. 18. Mathew PK, Ona FV, Damevski K, Wallace WA. Arrhythmias during upper gastrointestinal endoscopy. Angiology 1979; 30: 834-40. 19. Rostykus PS. McDonald GB, Albert RK. Upper intestinal endoscopy Induces hypoxemia in patients with obstructtve pulmonary disease. Gastroenterology 1980; 78: 488-91. 20. Rozen P. Fireman 2. Gilat T. The causes of hypoxemia in elderly patients during endoscopy. Gastrorntest Endosc 1982; 28: 243-6. 21. Whorwell PJ, Smith CL, Foster KJ. Arterial blood gas tensions duringgastrointestinal endoscopy. Gut 1976; 17: 797-W. 22. Lieberman DA, Wuerker CK, Katon RM. Cardiopulmonary risk of esophagogastroduodenoscopy. Role of endoscope diameter and systemrc sedation. Gastroenterology 1985; 88: 468-72. 23. McCormack TT, Rose JD, Smith PM, Johnson AG. Perforating veins and blood flow in esophageal veins. Lancet 1983; 2: 1442-4. 24.Connors AF, Bacon BR, Miron SD. Sodium morrhuate delivery to the lung during endoscopic variceal sclerotherapy. Ann Intern Med 1986; 105: 539-42. 25. Sukigara M, Omoto R. Miyamae T. Systemic dissemination of ethanolamine oleate after infection sclerotherapy for esophageal varices. Arch Surg 1985; 120: 833-6. 26. Saks BJ, Kilby AE, Dietrtch PA, Coffin LM. Krawitt EL. Pleuralandmediasbnal changes following endoscopic infection sclerotherapy of esophageal sclerotherapy. Radiology 1983; 149: 63942. 27. Mauro MA, Jaques PF, Swantkowski TM, Staab EV, Bozynskr EM. CT after uncomplicated esophageal sclerotherapy. J Roentgen01 1986; 147: 57-60. 28. Bacon BR. Bailey-Newton RS. Connors AF. Pleural effusions after endoscopic variceal sclerotherapy. Gastroenterology 1985; 88: 1910-4. 29. Bacon BR. Connors AF. Pleural effusrons following endoscopic vanceal sclerotherapy [Letter]. Gastroenterology 1984; 86: 395-6. 30. Gertsch AP. Mosrmann R. Chylothorax complicating sclerotherapy for bleedtng esophageal varices. Br J Surg 1983; 70: 562-6. 31. Monroe P. Morow CF Jr, Miller JE, Fairman RP. Glauser FI. Acute respiratory failure after sodium morrhuate esophageal sclerotherapy. Gastroenterology 1983; 85: 693-9.
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1990
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Journal
of Medicine
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CAR~IORESPIRA~~RY EFFECTS0~ CS~PHAGEAL VARICEAL SCLEROTHERAPY/ BA~DuR AND KORULA 32. Sugerman
HG. Strash AM, Hirsch JI. Tatum
JL, Sharp DE. Sensitivity
of
sclerotherapy
scintigraphy for detection of pulmonary capillary albumin leak in canine oleic acid ARDS. J Trauma 1981; 21: 520-7. 33. Jones JG, Minty BD. Beeley JM. Royston D. Crow J, Grossman RF. Pulmonary epithelial permeability is immediately increased after embolisation with oleic acid but not with neutral fat. Thorax 1982; 37: 169-74. 34. Larson AW, Cohen H, Zweiban B, Gourdji M, Korula J. Acute esophageal variceal sclerotherapy: results of a prospective controlled trial. JAMA 1986; 255: 497-500. 35. Korula J, Baydur A, Sassoon C. Sakimura I. Effect of esophageal variceal sclerotherapy (EVS) on lung function. A prospective controlled study. Arch Intern Med 1986; 1446: 1517-20. 36.Glauser FL, Fairman RP, Monroe P, Hammond B. Transient pulmonary hypertension associated with esophageal sclerotherapy. Chest 1984; 86: 6589. 37. Bailey-Newton RS, Connors AF, Bacon BR. Effect of endoscopic variceal
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1990
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Journal
of Medicine
Volume
on gas exchange
and hemodynamics
in humans. Gastroenterolo-
gy 1985; 89: 368-73. 38. Sarin SK, Sethi KK, Nandi R. Pulmonary hemodynamic variceal sclerotherapy with absolute alcohol. Gastrointest
changes after intraEndosc 1988; 34:
403-6. 39. Palmer ED, Wirts CW. Survey of gastroscopic and esophagoscopic accidents. JAMA 1957; 164: 2012-6. 40. Charng M-1. Wang S-P, Chang M-S. Chiang BN. Coronary spasm complicating sclerotherapy of esophageal varices. Chest 1988; 93: 204-5. 41. Levy N. Abinader E. Continuouselectrocardiographic monitoringwith Holter electrocardiorecorder throughout all stages of gastroscopy. Am J Dig Dis 1977; 22: 1091-4. 42. Knauer CM, Fogel MR. Pericarditis: complication of esophageal sclerotherapy. Gastroenterology 1989; 93: 287-90. 43. Korula J. Baydur A. Acute respiratory failure and sclerotherapy [Letter]. Gastroenterology 1984; 86: 395-6.
89
REVIEWS
Cardiorespiratory Effects Variceal Sclerotherapy AHMETBAYDUR,
Endoscopic Esophageal
M.D., JACOB KORULA, M.D., LosAngeles,
Endoscopic variceal sclerotherapy (EVS) is an effective means of controlling variceal hemorrhage, which develops as a consequence of portal hypertension. While esophageal perforation, ulceration, strictures, and media&i&is are potential complications associated with this procedure, it is not clear whether isolated pleuropulmonary events such as pleuritis, pneumonitis, and adult respiratory distress syndrome are causally related to the EVS. Endoscopy and sedation with the attendant risk of aspiration, particularly in the background of hepatic encephalopathy, may account for some of these events. Recent controlled studies of respiratory function demonstrate that EVS as such results in minor changes in gas exchange, lung volumes, and pulmonary and systemic hemodynamics. Most pulmonary complications have been reported with the use of sodium morrhuate sclerosant. Comparative studies among different sclerosants are necessary to evaluate relative safety. Finally, there have been rare reports of myocardial ischemia and pericarditis reported in association with EVS, but these are of a transient nature. Chest symptoms, roentgenographic pleuropulmonary changes, pulmonary hemodynamics, and cardiac perturbations are transient and should not preclude offering EVS to patients with variteal hemorrhage.
From the Departments of Chest Medicine (AB) and Hepatology (JK). Rancho Los Amigos Medical Center, Downey. California, and University of Southern California School of Medicine, Los Angeles, California. Requests for reprints should be addressed to Ahmet Baydur. M.D., Ranch0 Los Amigos Medical Center, 7601 East lmperral Highway, Downey. California 90242. Manuscript submitted September 11, 1989, and accepted in revised form June 14. 1990.
California, andDowney,
California
T
he poor long-term results of portocaval shunts as a treatment for bleeding varices led to a renewed interest in the use of endoscopic variceal sclerotherapy (EVS) for this potentially fatal complication of portal hypertension. Endoscopic sclerotherapy is carried out using flexible fiberoptic panendoscopy under sedative analgesia. Needle injectors are introduced through the biopsy channel of the endoscope, and esophageal varices are injected under direct vision using either a freehand technique or a sheath to permit injection of one variceal column at a time. An intravariceal injection is attempted usually, although it is well recognized that even if good intravariceal injections are made, paravariceal extravasation of sclerosants frequently occurs [l]. A variety of sclerosants are available although controlled comparisons of their effects in humans have not been reported. Thrombosis and necrotizing inflammation are the usual initial effects leading to obliteration of varices and fibrosis [ 11. EVS can be safely performed in the ambulatory care setting [2] or expeditiously at the bedside in cases of active hemorrhage. Esophageal complications of sclerotherapy have included necrotizing inflammation, ulceration, microabscesses, hemorrhage, perforation, and stricture [1,3,4], and have been reported to be as high as 41% in prospective studies. In addition, a variety of extraesophageal complications have been associated with EVS. Most of these are pleuropulmonary in nature, although rarely cardiac events have also been documented. In a retrospective study [5], pulmonary complications were observed in 12%, and in controlled studies [6,7], pulmonary complications have ranged from 2% to 18%. In view of the pulmonary parenchymal and vascular abnormalities commonly associated with chronic liver disease [8-111, respiratory phenomena reported during or immediately after the administration of EVS can be difficult to evaluate. Thoracic events described in association with EVS have included pleural effusions, fever, pneumonia, empyema, esophago-bronchopleural fistulas, mediastinitis, pulmonary hypertension, and adult respiratory distress syndrome (ARDS). Repeated injections may expose the patient to cumulative risks, although the chance of a serious complication is less if the injection is not paravariceal [3,12]. October
1990
The American
Journal
of Medicine
Volume
89
477
CARDIORESPIRATORY
EFFECTS
OF ESOPHAGEAL
VARICEAL
SCLEROTHERAPY
The effects of EVS on cardiorespiratory function must be evaluated in the background of cardiopulmonary complications occurring during gastrointestinal endoscopy, which are unusual in well-supervised units where electrocardiographic monitoring and pulse oximetry are available. In a national survey of 2,320 endoscopies for upper gastrointestinal bleeding reported by the American Society of Gastrointestinal Endoscopy [13], complications occurred in 0.9% of procedures. Major complications such as perforation, aspiration, or bleeding occurred in 0.5%. Cardiopulmonary complications account for 50% of morbidity and 60% of mortality [14-161. Electrocardiographic changes during endoscopy are also common and have been reported in patients with known prior heart disease [17,18]. Serious ventricular arrhythmias, angina, myocardial infarction, and cardiac arrest may lead to a fatal outcome rarely in this setting [ 161. Cardiac events may be related to hypoxemia [19], which in turn is related to the administration of sedatives and endoscopic size [20-221. In view of the questions concerning the association of events surrounding EVS, a widely used technique, it would be useful to briefly discuss the underlying mechanisms and the physiology involved, including a review of available clinical observations pertaining to such events.
/ BAYDUR
AND KORULA
portal vein and liver within 28 seconds. The dissemination continued to increase and eventually washed out within 5 minutes. A whole body scintiscan taken 3 hours after beginning the intravariceal injection showed uniform distribution throughout the body. This phenomenon was observed regardless of the volume injected intravariceally at EVS. Therefore, although systemic entry of sclerosant mixture is well documented, the frequency of its occurrence or its repercussions appears to be minor (Table I).
RADIOGRAPHICDEMONSTRATIONOF PLEUROPULMONARYABNORMALITIES Saks and colleagues [26] demonstrated a 79% incidence of radiographic abnormalities in a series of 38 examinations taken within 48 hours of EVS in 15 patients. The most common finding was pleural effusion (occurring in half of the examinations), while lower lobe alveolar and linear densities were seen less often. Such findings tended to occur when more than 1 mL of sclerosant was injected per varix (Table I). Mauro and co-workers [27] described pleural effusions and subsegmental atelectasis seen on the computed tomographic scan in most of a small number of patients receiving EVS. There was radiographic evidence of mediastinal inflammation of varying intensity, which we believe is explained perhaps by necrotizing periesophageal inflammation and hemorrhage and by the lack of serosa covering the esophagus (Table I). Bacon and colleagues [28] noted the development of pleural effusions in 19 of 30 patients undergoing EVS with 5% morrhuate. The effusions that occurred on either side were predominantly exudative in nature. Chest pain and effusion were noted more frequently with large-volume injections that probably contributed to deep mucosal ulceration, allowing the periesophageal inflammation to extend into the mediastinum. In most cases, effusions were small and had resolved by the time of subsequent EVS [29] (Table I). Chylothorax was reported in a patient who developed acute respiratory distress and shock after EVS [30]. The autopsy after a massive variceal hemorrhage failed to reveal a tear in the thoracic duct. The possibility exists in this rare complication that the thoracic duct was perforated by the transesophageal endoscopic needle.
ENTRY OF SCLEROSANTINTO THE SYSTEMIC AND PULMONARYCIRCULATIONS
Portal blood drains into the systemic and pulmonary circulations through esophagogastric collaterals and the azygous-hemiazygous system of veins in portal hypertension. The flow direction of esophageal collaterals is usually cephalad but influenced by respiratory changes in intrathoracic pressure [23]. When sclerosant mixed with methylene blue is injected into esophageal varices, the immediate detection of methylene blue in the urine of some patients suggests systemic entry of the sclerosant mixture (unpublished observations). Entry into the pulmonary circulation has also been demonstrated in some patients by positive uptake on lung scan of technetium-99m (Tc99m) tagged sodium tetradecyl sulfate when injected into the esophageal varices at sclerotherapy in our Liver Unit (unpublished observations) (Table I). Connors and colleagues [24] have demonstrated that only 20% of Tc99m-labeled sodium morrhuate injected into esophageal varices reached the pulmonary circulation, perhaps accounting for a lack of significant change in specific EFFECTOF EVSON LUNG FUNCTION Monroe and colleagues [31] suggested that acute single-breath diffusing capacity. Similarly, Sukirespiratory failure resulting from injection of sodigara and colleagues [25] injected ethanolamineTc99m sodium pertechnetate into esophageal var- um morrhuate into the pulmonary artery of sheep may have been due to an increase in pulmonary ices of six patients undergoing EVS. They demonstrated systemic dissemination through the vascular permeability. Such a finding is supported 478
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TABLE I Summary of Cardiorespiratory Associated
Efl ects
Radiographic,
Pleuropulmonary Entry of sclerosant into Systemrc Pulmonary circulation Pleural changes
Pulmonary
parenchymal
Lung function Volumes and flow rates Gas exchange Pulmonary
Cardiac Arrhythmias Pericarditis
hemodynamics
Effects Associated with Endoscopic Esophageal Sclerotherapy
changes
Radionuclide,
or Laboratory
Findings
Clinical Significance
Positive uptake on Tc-99m lung scan Rapid systemic dissemination through the portal vein and liver, without uniform body distribution Exudative effusions Empyema Chylothorax Mediastinitis Atelectasis Pneumonia Mass effect (by CT scan) Adult respiratory distress syndrome
Minor frequency
Transient and described after large-volume injections From esophageal-pleural or esophageal-bronchial fistulas; may be confused with pneumonia May be confused
reversible
ischemic
changes on ECG
May be associated with ECG, radiographic, cardiographic changes
and echo-
with pneumonia
Increased pulmonary capillary permeability demonstrated in animal injection studies; causal relationship not proven in humans
No significant changes with injection of sodium tetradecyl sulfate; transient hypoxemia with sodium morrhuate In sheep: increase in pulmonary artery pressure and lymph flow with injection of sodium morrhuate; in humans: increase in PVR, PAP, and CVP; decrease of PO2 Transient
and consequences
None None Transient Vance
and minor changes,
with little clinical rele-
Difficult to separate from ischemic events associated with endoscopy alone Related to direct injection of sclerosant into pericardiurn; symptoms relieved by pericardiocentesis or spontaneous amelioration
= computed tomographic; PVR = pulmonary vascular resistance; CVP = central venous pressure: ECG = electrocardiogram.
by animal studies in which the systemic injection of oleic acid has resulted in an increase of alveolar epithelial permeability [32,33]. However, the efforts of Monroe and colleagues [31] failed to demonstrate an increase in pulmonary microvasculature permeability after morrhuate injection, and consequently support their hypothesis. It is uncertain if their sheep experiments are a valid explanation of their proposed pathogenesis of respiratory failure that developed in two of 30 patients who underwent EVS for esophageal variceal bleeding. The possibility of aspiration in these patients (one of whom was encephalopathic) could not be satisfactorily excluded. ARDS is known to develop in patients with chronic liver disease and acute variceal hemorrhage. In a controlled trial of acute sclerotherapy in variceal hemorrhage, 10% of control patients not receiving EVS and 2% of patients receiving EVS developed ARDS [34]. Thus, the causal relationship to sclerotherapy is poorly substantiated in the literature (Table I). Rare and sporadic reports may, however, occur. Because the premeditation and the endoscopy itself may contribute to aspiration pneumonitis or hypoxemia, it is important to compare the incidence of respiratory dysfunction in patients receiving EVS and those undergoing endoscopy for other reasons. To help answer this question, our group performed a prospective controlled study to determine the short- and long-term effects of EVS with
sodium tetradecyl sulfate on lung function in 11 patients with cirrhotic portal hypertension and variceal hemorrhage 1351. There were no statistically significant changes in FVC (forced vital capacity), FEVi (forced expiratory volume in 1 second), FEV1/FVC (forced expiratory volume in 1 second/ forced vital capacity), FEFss-75 (maximal midexpiratory flow), Vmax50 (maximal expiratory flow at 50% of expired vital capacity), Pa02 (arterial oxygen partial pressure), AaDOs (alveolar to arterial oxygen tension difference), and pH in this group and a control group of patients with chronic liver disease undergoing diagnostic endoscopy (without EVS). Likewise, there were no significant changes in these parameters in nine patients who underwent two follow-up sessions of EVS over 1 year. In addition, seven patients also demonstrated a lack of significant changes in tests for lung volumes and closing volume. Ten of 11 patients demonstrated no changes in ventilation-perfusion (V/Q) lung scans. One patient with a normal V/& scan before EVS developed an abnormal subsegmental posterior basal perfusion defect seen after EVS with a normal ventilation scan, which remained unchanged on a follow-up scan 9 months later. We concluded that in our experience, in patients with stable liver disease and without hepatic failure, EVS with tetradecyl sodium did not result in serious impairment of respiratory function over the short- or long-term (Table I).
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ent volumes of alcohol were injected at EVS. No significant difference was seen when measurements between patients injected with alcohol and those Given the observation of the occurrence of ARDS and pleural effusion, Glauser and colleagues [36] injected with saline were compared. PCWP and sysstudied sheep pulmonary hemodynamics and temic arterial pressure also remained unchanged. Thus, it appears that based on these studies, EVS lymph flow after injection of sodium morrhuate. is, for unclear reasons, associated with minor They observed threefold increases in mean pulmochanges in pulmonary and systemic hemodynamics, nary artery pressure and baseline lymph flow and a which are clinically insignificant (Table I). significant decrease in the lymph/plasma albumin Finally, there may be a difference in the inciconcentration ratio. Since there was no observed dence of respiratory complications depending on increase in the pulmonary tissue water content, the type and volume of sclerosant used, since most they reasoned that EVS caused transient pulmoevents were reported with the use of sodium morrnary hypertension but not increased permeability huate (the most commonly injected sclerosant). of the pulmonary microvasculature. This pulmoThus, the intriguing possibility of sclerosant-specifnary hypertension was markedly blunted by indoic pulmonary parenchymal and hemodynamic commethacin, which suggested pulmonary vascular replications needs to be addressed with a comparative activity mediated by prostaglandins. There are no study. controlled studies in humans to support this observation (Table I). Glauser and co-workers [36] also monitored pulmonary artery pressures during EVS EFFECTOF EVSON CARDIACFUNCTION in a small number of patients and found a transient Serious cardiac complications associated with en2- to 2.5fold increase from normal baseline values doscopic examination are rare and are usually not without a change in the cardiac output or arterial detected unless accompanied by electrocardiooxygenation. graphic monitoring; Palmer and Wirts [39] have Bailey-Newton and colleagues [37] studied the reported a 0.002% cardiac mortality rate associated with endoscopy in a large retrospective survey. effect of EVS on gas exchange and hemodynamics in eight patients undergoing EVS using sodium However, both coronary spasm and pericarditis morrhuate as therapy for variceal hemorrhage. A have been reported after EVS. Charng and co-worknumber of parameters, such as mixed expired gas ers [40] described a 68-year-old man with an old anterior myocardial infarction who experienced seconcentrations, systemic arterial pressure, pulmonary capillary wedge pressure (PCWP), and cardiac vere chest pain and hypotension immediately after output, were measured. Baseline measurements EVS. The electrocardiogram showed inferior lead were obtained before and after endoscopic intubaST-segment elevation, which returned to baseline 30 minutes later, after administration of sublingual tion; measurements were subsequently repeated nitroglycerin. Transient Q waves also appeared in immediately after EVS and for 60 minutes after EVS. Pa02 decreased after endoscopy without the inferior leads, coupled with echocardiographic changes in pulmonary and systemic vascular resis- evidence of left ventricular and anteroseptal hypotance. Pulmonary arterial pressure (PAP) and cen- kinesis. In their view, these findings strongly sugtral venous pressure increased with EVS but re- gested coronary artery spasm. An allergic reaction to the sclerosant and stress-related sympathetic turned to baseline values after EVS. Pulmonary vascular resistance increased by 30% over the base- stimulation were considered as possible etiologies. line values, associated only with a transient de- Levy and Abinader [41] have reported a 24% incicrease in PaOz. This study showed small increases dence of ischemic changes during continuous elecin pulmonary and systemic vascular resistance trocardiographic monitoring during endoscopy, and without altering PCWP, PAP, or gas exchange. The which usually resolve spontaneously (Table I). authors did not record changes beyond 60 minutes Knauer and Fogel [42] reported chest pain, dysafter injection or suggest mechanisms for the findpnea, and a pericardial friction rub in one patient, ings. In a later study, Sarin and co-workers [38] and pericardial effusions in three patients who restudied the effects of absolute alcohol sclerotherapy ceived EVS with sodium morrhuate. In two paon lung function in 14 patients. Pulmonary hemotients, the pericardial effusion resolved spontanedynamics were studied and measurements com- ously while in the third, pericardiocentesis relieved pared with those of control patients who received symptoms. EVS was continued in one patient withequivalent volumes of saline injection into varices. out further problems after resolution of pericardiMean PAP increased by 27% after 1 minute but tis. The exact etiology is not clear, but it is speculatreturned to baseline after 15 minutes. The increase ed that pericarditis may have been caused either by in PAP was not significantly different when differdeep injection of the sclerosant into the pericardi-
EFFECTOF EVSON THE PULMONARY VASCULARBED
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urn or from extension of periesophageal tion into the pericardium (Table I).
EFFECTS
OF ESOPHAGEAL
inflamma-
SUMMARY The egress of blood through portal systemic collaterals of the esophagus into the pulmonary circulation underscores the vulnerability of pulmonary capillaries and endothelium to damage from sclerosants injected at EVS. Although systemic and pulmonary dissemination was demonstrated by careful studies, only a small fraction of the injected dose appears to reach the pulmonary circulation. Although transient alterations in pulmonary hemodynamics are observed, this should not preclude offering EVS to patients with variceal hemorrhage. Controlled clinical studies of pulmonary function do not demonstrate a significant impairment either acutely or over the long-term with repeated EVS, a finding of practical value and importance. The occurrence of ARDS from EVS is poorly documented and pulmonary aspiration in the setting of acute hemorrhage and encephalopathy are likely predisposing factors 1431; even if it did occur, this complication is a sporadic and rare event. Chest roentgenograms are useful in identifying pleural effusions, often exudative in nature, suggesting an associated mediastinal involvement mediated through the lymphatics or as a result of a necrotizing inflammatory process extending into and beyond the muscular wall of the esophagus. A variety of chest roentgenographic abnormalities that have been reported are not of major significance; computed tomographic abnormalities may provide an anatomic basis for pleuropulmonary effects of EVS but are not useful in determining the type of process that occurs. Pericarditis is the only convincing cardiac abnormality and may result from extension of a contiguous mediastinal inflammatory process, although the possibility of deep esophageal injections into the posterior pericardium cannot be excluded. The pericarditis is self-limited and should not preclude continuing EVS. We hope this review will place the data in the literature in the proper perspective and alert clinicians to the uncommon but potentially serious respiratory or cardiac events that may occur during EVS, particularly in patients with underlying cardiorespiratory disorders.
ACKNOWLEDGMENT We thank Virgrnra Boren and Mary Beth Cude for preparation
of the manuscript.
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