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Carcinoid—A Diagnostic and Therapeutic Dilemma
candidates: Limitation of peak oxygen consumption. Chest 1999; 115:410 – 417
Tuberculous Mycotic Aneurysms To the Editor: We read, with great interest, the fine paper on tuberculous mycotic aneurysms by Long and colleagues (February 1999)1 that recently appeared in CHEST. This topic has been of interest to us for many years, and we appreciate Long et al referring to our 1965 article,2 concerning work that was carried out when we were still surgical residents, several times. A few comments related to our paper may add to the information gleaned by readers of the article by Long et al.1 First, little has changed in reference to this disease in the past 35 years! This is of special interest since the overall progress in medicine has been immense during this period of time, especially so in our field of thoracic and cardiovascular surgery. In 1965, our review of the world medical literature noted a total of 110 patients with tuberculous aortitis. Of these, 59 had no aneurysm formation and 51 had aneurysms (mostly false aneurysms). Currently, only 41 patients with tuberculous aneurysms are noted in the English language medical literature, including the 2 patients cited by Long et al. Successful outcome, then and now, requires combined surgical and medical therapies. The case we added to the literature in 1965 concerned a patient who underwent treatment that was, essentially, identical to that described for the management of current cases. Indeed, all of the following six concepts, which were operative in our 1965 article, were noted in the conclusion of the article by Long et al: 1. Symptomatic tuberculous aortic aneurysm is very uncommon and requires prompt diagnosis for any chance of successful management. 2. Clinical presentation may include abdominal pain and a palpable mass. 3. Medical management alone or surgical management alone is not adequate. 4. Medical and surgical therapies combined give the best chance for success. 5. Symptomatic aneurysms must be operated on urgently. 6. Options for revascularization of the lower body (after resection of the tuberculous aneurysm) include in situ reconstruction with prosthetic graft or extra-anatomic bypass, but anti-tuberculosis (TB) drugs are also required in either instance. Second, our article described a ruptured tuberculous aneurysm of the abdominal aorta managed successfully with urgent resection, in situ reconstruction with a prosthetic graft, and postoperative anti-TB therapy. Our patient was apparently the first with a ruptured tuberculous aneurysm of the abdominal aorta to survive. At the time that our paper was submitted, the patient was in good condition 17 months after aortic resection. Finally, we noted that all resected aortic aneurysms should be examined microscopically, since all patients with tuberculous aneurysms do not have a preoperative diagnosis of “tuberculous” and since gross examination of the specimen is not definitive for TB. Allen Silbergleit, MD, PhD St. Joseph Mercy-Oakland Pontiac, MI Agustin Arbulu MD, FCCP Harper Hospital Detroit, Michigan 1142
Correspondence to: Allen Silbergleit, MD, PhD, Director, Department of Surgery, St. Joseph Mercy-Oakland, 900 Woodward Ave, Pontiac, MI 48341-2985
References 1 Long R, Guzman R, Greenberg H, et al. Tuberculous mycotic aneurysm of the aorta. Chest 1999; 115:522–531 2 Silbergleit A, Arbulu A, Defever BA, et al. Tuberculous aortitis JAMA 1965; 193:83– 85
Carcinoid—A Diagnostic and Therapeutic Dilemma To the Editor: The interesting and descriptive article recently published in CHEST, “Coronary Spasm and Cardiac Arrest From Carcinoid Crisis During Laser Bronchoscopy,” (February 1999)1 merits additional clinical commentary. The article vividly describes only one of several tragedies that are known to occur in patients afflicted with carcinoid disease and illustrates to the medically unwary just how hazardous this disease can be for both the patient and the treating physician. Carcinoid disease still remains one of the most misdiagnosed and overlooked diseases in the annals of medicine, and its treatment can be one of the most difficult situations that a clinician could ever encounter. The fascinating aspect of this case report is not that the physicians encountered a clinically undiagnosable disease in a patient who was not suspected of having carcinoid disease, but that the near tragedy of a potentially fatal cardiac arrest occurred because of a coronary arterial spasm in an otherwise healthy adolescent girl who was not affected with carcinoid syndrome. Other reports have described angina pectoris in older patients with previously undiagnosed carcinoid disease who had proven noncritical coronary atherosclerosis, itself a common indicator for coronary spasm.2,3 In one of these patients, cardiac arrest occurred after the performance of a treadmill exercise test. It is well known that physical exertion or emotional stress can precipitate an acute carcinoid crisis. Vasospastic angina (variant angina or Prinzmetal’s angina) can occur in young, middle-aged patients with advanced carcinoid disease who have no evidence of coronary heart disease. Furthermore, vasospastic angina can occur in association with, or can be independent of, the “flushing” portion of the carcinoid syndrome and its associated acute events. It can be nocturnal as well and is generally not precipitated by ordinary physical activity. Administration of sublingual nitroglycerin usually relieves symptoms but nitroglycerin consumption is not without its hazards, as these patients are often seriously hypotensive. In my experience, a patient with advanced carcinoid disease and syndrome will receive very little, and usually no benefit from the use of hydrogen-ion receptor antagonists, diphenhydramine, or cyproheptadine. Semiadequate control of symptoms can be achieved only with the use of subcutaneous injections of octreotide in moderate to high doses, the efficacy of which is a Godsend to these patients and without which their suffering is inconceivable and unsurmountable, and their lifespan is made considerably shorter. Mehta et al.1 made the accepted and supposedly well-known points that anesthesia administration in patients with carcinoid tumors requires special consideration and that no anesthetic technique or pharmacologic regimen has been proven to be especially efficacious. These points are only partially correct. A great deal can be done to lessen the possibility of the potentially hazardous cardiovascular crises that can occur in patients with carcinoid tumors, especially when they are about to undergo anesthesia and surgery.4 Communications to the Editor
One needs little imagination to contemplate the catastrophe that usually occurs when a patient with advanced carcinoid disease presents unknowingly to the attending physician and surgeon while in an acute abdominal crisis, with its accompanying tachycardia and hypotension, and is taken for exploratory surgery. It is difficult enough to avoid a catastrophic event when the diagnosis is known, and the outcome is often tragic when it is not. Catecholamines, when used to treat hypotension in these patients, can further complicate the pharmacophysiology involved in the production of the carcinoid crisis, and nitrates to treat elevated ST segments may do likewise. Obviously, the patient with advanced carcinoid disease requires a more complex approach than stated in this report. The authors place emphasis on aggressive volume replacement and IV somatostatin for the treatment of hypotension and cardiac arrest. In such cases, this therapy may be too little, too late. Volume replacement, with adequate IV fluids and meticulous attention to the addition of electrolytes, is mandatory. This should include supplemental sodium chloride, magnesium, potassium chloride, and calcium—all of which are generally depleted in the patient with advanced carcinoid disease who is suffering from multiple bouts of diarrhea daily, which is still only partially controlled by the patient’s usual daily subcutaneous injections of octreotide. Volume and electrolyte replacement should be given (in appropriate amounts, dependent on the clinical status of the patient) even when the levels of the electrolytes, ascertained by laboratory testing, are normal, as cellular imbalance is often present especially if these supplements have not been prescribed for use on a daily basis. Preoperative, intraoperative, and postoperative therapy must not only involve the use of fluids, electrolytes, and subcutaneous and/or IV adminstration of octreotide, but, in my opinion, should also include bolus IV injections of methylprednisolone based on an individually selected regimen. Such therapy should be started the day before surgery and not merely as a last-minute, preoperative endeavor, except in emergency situations requiring immediate intervention. The carcinoid syndrome is, indeed, a true diagnostic and therapeutic dilemma. Basil M. RuDusky, MD, FCCP Wilkes Barre, PA Correspondence to: Basil M. RuDusky, MD, FCCP, 15 Public Square, Wilkes Barre, PA 18702-1702
References 1 Mehta AC, Rafanan AL, Bulkley R, et al. Coronary spasm and cardiac arrest from carcinoid crisis during laser bronchoscopy. Chest 1999; 115:598 – 600 2 Topol EJ, Fortuin NJ. Coronary artery spasm and cardiac arrest in carcinoid heart disease. Am J Med 1984; 77:950 –952 3 Petersen KG, Seeman WR, Plagwitz R, et al. Evidence for coronary spasm during flushing in the carcinoid syndrome. Clin Cardiol 1984; 7:445– 448 4 RuDusky BM, Marycz DK. Carcinoid syndrome: a medical, social and political odyssey. (in press).
Air Sampling for Tuberculosis— Homage to the Lowly Guinea Pig To the Editor: The recent article by Mastorides and colleagues in CHEST (January 1999)1 on the use of micropore membrane air sampling and polymerase chain reaction (PCR) to detect airborne Mycobacterium tuberculosis (MTB) in six of seven hospitalized patients is at once both exciting and disappointing. It is exciting
because advances in the control of tuberculosis (TB) and other airborne infections have been stagnant, hampered greatly by our inability to quantitatively culture organisms from room air. There have been no successful attempts to quantitatively recover tubercle bacilli from room air under clinical conditions since Richard Riley’s classic experiments employing guinea pig air sampling almost 40 years ago.2 Although Riley’s technique is a proven methodology, its requirement of a specialized hospital ward with at least several infectious patients, with all exhaust air delivered to hundreds of guinea pigs in special exposure chambers, has discouraged replication. By comparison, the method reported by Mastorides and colleagues,1 employing micropore membrane filters to collect airborne material and PCR to detect mycobacterial DNA, seems relatively simple. However, my enthusiasm is dampened by the severe limitations of their technique, which were acknowledged by the authors in passing and which require emphasis. Unless overcome, these limitations will likely render results uninterpretable, at best, and potentially misleading. Early experience with air sampling and quantitative cultures of aerosolized tubercle bacilli demonstrated that only about 10% of organisms survived artificial aerosolization.3 More recently, the mechanisms by which aerosolization and rapid dehydration disrupt microbial cell components, and by which airborne organisms succumb to natural irradiation, oxidation, and other environmental stresses, have been elucidated.4 A serious limitation of PCR detection in its current state is that is does not distinguish between living and dead organisms. In sampling just 25 cu ft of air per patient, Mastorides and colleagues1 detected the DNA of MTB in six of seven patients whose cultures were positive for MTB. In contrast, most patients newly admitted to Riley’s experimental TB ward did not infect any guinea pigs. The average (well-mixed) air concentration over a 4-year period was less than one infectious dose (presumably one droplet nucleus) in . 10,000 cu ft of air. In an explosive episode of nosocomial transmission in an ICU, in which 10 of 13 susceptible health-care workers became infected with MTB during a 150-min exposure, a concentration of approximately one infectious dose in 70 cu ft was estimated.5 Although PCR may be much more sensitive than guinea pigs or people in detecting the airborne DNA of MTB, it is highly likely that the much higher detection rate reported by Mastorides and colleagues1 represents predominantly dead or dying organisms, of little relevance to determination of infectiousness. Similar nucleic acid amplification techniques, when applied directly to the sputum samples of patients who have completed therapy, may continue to show positive results for months after sputum cultures have become negative for MTB, again reflecting the presence of nonviable DNA. Since such positive results are not interpretable, the use of nucleic acid amplification techniques in treated TB cases is not recommended. Another concern about the study by Mastorides and colleagues1 is that air sampling was performed at a distance of only 1 m from the head of the bed, with no apparent provision that only particles of respirable size were to be sampled. Close proximity and larger particles would greatly increase the likelihood of positive results, which would have little relevance to the presence of droplet nuclei or to their concentration elsewhere in the room. Finally, the technique as presented is not quantitative. Air sampling either does or does not lead to the detection of DNA, but the number of organisms detected is not known. Given the rapid progress in molecular methods, it is likely that both quantitative detection and correlation with microbial viability, and possibly with infectiousness, will be forthcoming. In its current state, however, aside from the limited application of making possible a noninvasive bacteriologic diagnosis of TB when sputum is unavailable, it is unclear to me how this approach will advance our understanding of airborne TB transmission and its CHEST / 116 / 4 / OCTOBER, 1999
1143
Tuberculous Mycotic Aneurysms To the Editor: We read, with great interest, the fine paper on tuberculous mycotic aneurysms by Long and colleagues (February 1999)1 that recently appeared in CHEST. This topic has been of interest to us for many years, and we appreciate Long et al referring to our 1965 article,2 concerning work that was carried out when we were still surgical residents, several times. A few comments related to our paper may add to the information gleaned by readers of the article by Long et al.1 First, little has changed in reference to this disease in the past 35 years! This is of special interest since the overall progress in medicine has been immense during this period of time, especially so in our field of thoracic and cardiovascular surgery. In 1965, our review of the world medical literature noted a total of 110 patients with tuberculous aortitis. Of these, 59 had no aneurysm formation and 51 had aneurysms (mostly false aneurysms). Currently, only 41 patients with tuberculous aneurysms are noted in the English language medical literature, including the 2 patients cited by Long et al. Successful outcome, then and now, requires combined surgical and medical therapies. The case we added to the literature in 1965 concerned a patient who underwent treatment that was, essentially, identical to that described for the management of current cases. Indeed, all of the following six concepts, which were operative in our 1965 article, were noted in the conclusion of the article by Long et al: 1. Symptomatic tuberculous aortic aneurysm is very uncommon and requires prompt diagnosis for any chance of successful management. 2. Clinical presentation may include abdominal pain and a palpable mass. 3. Medical management alone or surgical management alone is not adequate. 4. Medical and surgical therapies combined give the best chance for success. 5. Symptomatic aneurysms must be operated on urgently. 6. Options for revascularization of the lower body (after resection of the tuberculous aneurysm) include in situ reconstruction with prosthetic graft or extra-anatomic bypass, but anti-tuberculosis (TB) drugs are also required in either instance. Second, our article described a ruptured tuberculous aneurysm of the abdominal aorta managed successfully with urgent resection, in situ reconstruction with a prosthetic graft, and postoperative anti-TB therapy. Our patient was apparently the first with a ruptured tuberculous aneurysm of the abdominal aorta to survive. At the time that our paper was submitted, the patient was in good condition 17 months after aortic resection. Finally, we noted that all resected aortic aneurysms should be examined microscopically, since all patients with tuberculous aneurysms do not have a preoperative diagnosis of “tuberculous” and since gross examination of the specimen is not definitive for TB. Allen Silbergleit, MD, PhD St. Joseph Mercy-Oakland Pontiac, MI Agustin Arbulu MD, FCCP Harper Hospital Detroit, Michigan 1142
Correspondence to: Allen Silbergleit, MD, PhD, Director, Department of Surgery, St. Joseph Mercy-Oakland, 900 Woodward Ave, Pontiac, MI 48341-2985
References 1 Long R, Guzman R, Greenberg H, et al. Tuberculous mycotic aneurysm of the aorta. Chest 1999; 115:522–531 2 Silbergleit A, Arbulu A, Defever BA, et al. Tuberculous aortitis JAMA 1965; 193:83– 85
Carcinoid—A Diagnostic and Therapeutic Dilemma To the Editor: The interesting and descriptive article recently published in CHEST, “Coronary Spasm and Cardiac Arrest From Carcinoid Crisis During Laser Bronchoscopy,” (February 1999)1 merits additional clinical commentary. The article vividly describes only one of several tragedies that are known to occur in patients afflicted with carcinoid disease and illustrates to the medically unwary just how hazardous this disease can be for both the patient and the treating physician. Carcinoid disease still remains one of the most misdiagnosed and overlooked diseases in the annals of medicine, and its treatment can be one of the most difficult situations that a clinician could ever encounter. The fascinating aspect of this case report is not that the physicians encountered a clinically undiagnosable disease in a patient who was not suspected of having carcinoid disease, but that the near tragedy of a potentially fatal cardiac arrest occurred because of a coronary arterial spasm in an otherwise healthy adolescent girl who was not affected with carcinoid syndrome. Other reports have described angina pectoris in older patients with previously undiagnosed carcinoid disease who had proven noncritical coronary atherosclerosis, itself a common indicator for coronary spasm.2,3 In one of these patients, cardiac arrest occurred after the performance of a treadmill exercise test. It is well known that physical exertion or emotional stress can precipitate an acute carcinoid crisis. Vasospastic angina (variant angina or Prinzmetal’s angina) can occur in young, middle-aged patients with advanced carcinoid disease who have no evidence of coronary heart disease. Furthermore, vasospastic angina can occur in association with, or can be independent of, the “flushing” portion of the carcinoid syndrome and its associated acute events. It can be nocturnal as well and is generally not precipitated by ordinary physical activity. Administration of sublingual nitroglycerin usually relieves symptoms but nitroglycerin consumption is not without its hazards, as these patients are often seriously hypotensive. In my experience, a patient with advanced carcinoid disease and syndrome will receive very little, and usually no benefit from the use of hydrogen-ion receptor antagonists, diphenhydramine, or cyproheptadine. Semiadequate control of symptoms can be achieved only with the use of subcutaneous injections of octreotide in moderate to high doses, the efficacy of which is a Godsend to these patients and without which their suffering is inconceivable and unsurmountable, and their lifespan is made considerably shorter. Mehta et al.1 made the accepted and supposedly well-known points that anesthesia administration in patients with carcinoid tumors requires special consideration and that no anesthetic technique or pharmacologic regimen has been proven to be especially efficacious. These points are only partially correct. A great deal can be done to lessen the possibility of the potentially hazardous cardiovascular crises that can occur in patients with carcinoid tumors, especially when they are about to undergo anesthesia and surgery.4 Communications to the Editor
One needs little imagination to contemplate the catastrophe that usually occurs when a patient with advanced carcinoid disease presents unknowingly to the attending physician and surgeon while in an acute abdominal crisis, with its accompanying tachycardia and hypotension, and is taken for exploratory surgery. It is difficult enough to avoid a catastrophic event when the diagnosis is known, and the outcome is often tragic when it is not. Catecholamines, when used to treat hypotension in these patients, can further complicate the pharmacophysiology involved in the production of the carcinoid crisis, and nitrates to treat elevated ST segments may do likewise. Obviously, the patient with advanced carcinoid disease requires a more complex approach than stated in this report. The authors place emphasis on aggressive volume replacement and IV somatostatin for the treatment of hypotension and cardiac arrest. In such cases, this therapy may be too little, too late. Volume replacement, with adequate IV fluids and meticulous attention to the addition of electrolytes, is mandatory. This should include supplemental sodium chloride, magnesium, potassium chloride, and calcium—all of which are generally depleted in the patient with advanced carcinoid disease who is suffering from multiple bouts of diarrhea daily, which is still only partially controlled by the patient’s usual daily subcutaneous injections of octreotide. Volume and electrolyte replacement should be given (in appropriate amounts, dependent on the clinical status of the patient) even when the levels of the electrolytes, ascertained by laboratory testing, are normal, as cellular imbalance is often present especially if these supplements have not been prescribed for use on a daily basis. Preoperative, intraoperative, and postoperative therapy must not only involve the use of fluids, electrolytes, and subcutaneous and/or IV adminstration of octreotide, but, in my opinion, should also include bolus IV injections of methylprednisolone based on an individually selected regimen. Such therapy should be started the day before surgery and not merely as a last-minute, preoperative endeavor, except in emergency situations requiring immediate intervention. The carcinoid syndrome is, indeed, a true diagnostic and therapeutic dilemma. Basil M. RuDusky, MD, FCCP Wilkes Barre, PA Correspondence to: Basil M. RuDusky, MD, FCCP, 15 Public Square, Wilkes Barre, PA 18702-1702
References 1 Mehta AC, Rafanan AL, Bulkley R, et al. Coronary spasm and cardiac arrest from carcinoid crisis during laser bronchoscopy. Chest 1999; 115:598 – 600 2 Topol EJ, Fortuin NJ. Coronary artery spasm and cardiac arrest in carcinoid heart disease. Am J Med 1984; 77:950 –952 3 Petersen KG, Seeman WR, Plagwitz R, et al. Evidence for coronary spasm during flushing in the carcinoid syndrome. Clin Cardiol 1984; 7:445– 448 4 RuDusky BM, Marycz DK. Carcinoid syndrome: a medical, social and political odyssey. (in press).
Air Sampling for Tuberculosis— Homage to the Lowly Guinea Pig To the Editor: The recent article by Mastorides and colleagues in CHEST (January 1999)1 on the use of micropore membrane air sampling and polymerase chain reaction (PCR) to detect airborne Mycobacterium tuberculosis (MTB) in six of seven hospitalized patients is at once both exciting and disappointing. It is exciting
because advances in the control of tuberculosis (TB) and other airborne infections have been stagnant, hampered greatly by our inability to quantitatively culture organisms from room air. There have been no successful attempts to quantitatively recover tubercle bacilli from room air under clinical conditions since Richard Riley’s classic experiments employing guinea pig air sampling almost 40 years ago.2 Although Riley’s technique is a proven methodology, its requirement of a specialized hospital ward with at least several infectious patients, with all exhaust air delivered to hundreds of guinea pigs in special exposure chambers, has discouraged replication. By comparison, the method reported by Mastorides and colleagues,1 employing micropore membrane filters to collect airborne material and PCR to detect mycobacterial DNA, seems relatively simple. However, my enthusiasm is dampened by the severe limitations of their technique, which were acknowledged by the authors in passing and which require emphasis. Unless overcome, these limitations will likely render results uninterpretable, at best, and potentially misleading. Early experience with air sampling and quantitative cultures of aerosolized tubercle bacilli demonstrated that only about 10% of organisms survived artificial aerosolization.3 More recently, the mechanisms by which aerosolization and rapid dehydration disrupt microbial cell components, and by which airborne organisms succumb to natural irradiation, oxidation, and other environmental stresses, have been elucidated.4 A serious limitation of PCR detection in its current state is that is does not distinguish between living and dead organisms. In sampling just 25 cu ft of air per patient, Mastorides and colleagues1 detected the DNA of MTB in six of seven patients whose cultures were positive for MTB. In contrast, most patients newly admitted to Riley’s experimental TB ward did not infect any guinea pigs. The average (well-mixed) air concentration over a 4-year period was less than one infectious dose (presumably one droplet nucleus) in . 10,000 cu ft of air. In an explosive episode of nosocomial transmission in an ICU, in which 10 of 13 susceptible health-care workers became infected with MTB during a 150-min exposure, a concentration of approximately one infectious dose in 70 cu ft was estimated.5 Although PCR may be much more sensitive than guinea pigs or people in detecting the airborne DNA of MTB, it is highly likely that the much higher detection rate reported by Mastorides and colleagues1 represents predominantly dead or dying organisms, of little relevance to determination of infectiousness. Similar nucleic acid amplification techniques, when applied directly to the sputum samples of patients who have completed therapy, may continue to show positive results for months after sputum cultures have become negative for MTB, again reflecting the presence of nonviable DNA. Since such positive results are not interpretable, the use of nucleic acid amplification techniques in treated TB cases is not recommended. Another concern about the study by Mastorides and colleagues1 is that air sampling was performed at a distance of only 1 m from the head of the bed, with no apparent provision that only particles of respirable size were to be sampled. Close proximity and larger particles would greatly increase the likelihood of positive results, which would have little relevance to the presence of droplet nuclei or to their concentration elsewhere in the room. Finally, the technique as presented is not quantitative. Air sampling either does or does not lead to the detection of DNA, but the number of organisms detected is not known. Given the rapid progress in molecular methods, it is likely that both quantitative detection and correlation with microbial viability, and possibly with infectiousness, will be forthcoming. In its current state, however, aside from the limited application of making possible a noninvasive bacteriologic diagnosis of TB when sputum is unavailable, it is unclear to me how this approach will advance our understanding of airborne TB transmission and its CHEST / 116 / 4 / OCTOBER, 1999
1143