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ACTH analogue in treatment of acute aortic dissection
CORRESPONDENCE
ACTH analogue in treatment of acute aortic dissection Sir—Giorgio Noera and colleagues (Aug 11, p 469)1 report their use of a synthetic adrenocorticotropic hormone (ACTH) analogue in the initial treatment of acute type A aortic dissection complicated by haemorrhagic shock. With one 10 mg bolus ACTH-(1-24) administered immediately at presentation, patients arrived in the operating room in a substantially more favourable condition than did their untreated counterparts. Previous investigations have shown that haemodynamic compromise is a predictor of in-hospital death.2 The relative reduction in surgical mortality was a striking 75%, and the absolute reduction 40% (13 vs 53%). Thus, the mortality rate in the ACTH-(1-24)-treated group was clearly better than that in previous reports in larger series for this frequently fatal disorder.3 The results are referred to as 30-day mortality, but, as shown in their figure 1, the difference actually appears in the first 48 h. This finding reflects the fact that ACTH-(1-24) modifies the much deranged perioperative pathophysiology of initial severe haemorrhagic shock, as well as the postsurgical trauma, inflammatory response to cardiopulmonary bypass, effects of deep hypothermia and circulatory arrest, and a complex anaesthetic management characteristic of these patients, rather than altering the outcome at a later phase postoperatively. None of the 32 patients underwent rescue surgery (pericardiocentesis, pericardial fenestration, or thoracostomy) before definitive surgical repair of the dissection, which happens frequently under these circumstances. We would like to know whether such procedures would alter the effect of ACTH-(1-24) in any direction. Since aortic dissections are commonly given definitive surgical treatment at tertiary referral centres, preceding transportation of the severely ill patient is necessary. Noera and colleagues had the opportunity to treat the patients immediately at diagnosis, which is not commonly the case in cardiovascular departments. Therefore, study of whether the time-span of ACTH-(124) efficacy, to optimise timing of treatment, would be useful, as would identification of patients in whom this treatment is likely to fail. The risk of rebleeding because of improved
168
haemodynamic state and raised systolic blood pressure also need to be addressed. Noera and colleagues’ results are spectacular, and might herald the advent of a very simple and useful tool in the treatment of these severely ill patients. If the benefits extend to all patients in haemorrhagic shock, the perspective on treatment of such patients might become totally altered. Christian Olsson Department of Cardiothoracic Surgery, Uppsala University Hospital, S-751 85 Uppsala, Sweden (e-mail: [email protected]) 1
2
3
Noera G, Lamarra M, Guarini S, Bertolini A. Survival rate after early treatment for acute type-A aortic dissection with ACTH-(1–24). Lancet 2001; 358: 469–70. Ehrlich MP, Ergin MA, McCullough JN, et al. Results of immediate surgical treatment of all acute type A dissections. Circulation 2000; 102 (suppl III): 248–52. Sinatra R, Melina G, Pulitani I, Fiorani B, Ruvolo G, Macino B. Emergency operation for acute type A aortic dissection: neurologic complications and early mortality. Ann Thorac Surg 2001; 71: 33–38.
Authors’ reply Sir—The fact that the mortality rate in our patients who were assigned to the standard treatment, without ACTH(1-24) addition, was higher than that reported in previous studies might be explained by their severe haemodynamic compromise. We selected subjects with type A aortic dissection complicated by aortic rupture and cardiac tamponade, and with clinical and laboratory signs of haemorrhagic shock. We share Olsson’s opinion that ACTH-(1-24) essentially modifies the complex pathophysiology of the perioperative period. Not only by improving the cardiovascular function; indeed, several experimental data suggest that melanocortins have also a peculiar, adrenal-independent antiinflammatory activity. They reduce the production of proinflammatory cytokines, such as interleukins 1␣, 1, and 6, and tumour necrosis factor (TNF) ␣, and inhibit the activation of the transcription factor NF-kB, while increasing the production of the antiinflammatory cytokines interleukins 8 and 10;1 in particular, in conditions of haemorrhagic shock, melanocortins inhibit the overproduction of TNF␣, nitric oxide, and free radicals.2,3 Moreover, melanocortins protect against the outcomes either of a shortterm myocardial ischaemia followed by reperfusion or of the permanent occlusion of a coronary artery in rats.4 Our patients underwent fluid replacement en route and ventilatory
support but no rescue surgery. Our cardiac surgery unit is situated roughly in the middle of a flat territory in northern Italy, with a high population density (about 1 million people), and a reasonable road system. The time lapse from emergency call to arrival into the casualty ward, by ambulance or by helicopter, is 20–40 min. Our animal data suggest that the time span of ACTH-(1-24) efficacy is best if given within 5–15 min of shock induction. We have fewer human data, but they suggest that treatment must be made within 1 h of the first signs of shock. In case of haemorrhagic shock (road or industrial accidents, &c), we believe ACTH should be given as intravenous bolus injection at the scene, or en route in the ambulance. The effect of ACTH lasts a few hours.5 Giorgio Noera, Mauro Lamarra, *Salvatore Guarini, Alfio Bertolini Villa Maria Cecilia Hospital, Cardiac Surgery Unit, Cotignola, Ravenna, Italy; and *Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via Campi 287, 41100 Modena, Italy (e-mail: [email protected]) 1
2
3
4
5
Wikberg JES, Muceniece R, Mandrika I, et al. New aspects on the melanocortins and their receptors. Pharmacol Res 2000; 42: 393–420. Guarini S, Bazzani C, Mattera Ricigliano G, Bini A, Tomasi A, Bertolini A. Influence of ACTH-(1-24) on free radical levels in the blood of haemorrhage-shocked rats: direct ex vivo detection by electron spin resonance spectrometry. Br J Pharmacol 1996; 119: 29–34. Altavilla D, Cainazzo MM, Squadrito F, Guarini S, Bertolini A, Bazzani C. Tumour necrosis factor-␣ as a target of melanocortins in haemorrhagic shock, in the anaesthetised rat. Br J Pharmacol 1998; 124: 1587–90. Bazzani C, Guarini S, Botticelli AR, et al. Protective effect of melanocortin peptides in rat myocardial ischemia. J Pharmacol Exp Ther 2001; 297: 1082–87. Bertolini A. The opioid/anti-opioid balance in shock: a new target for therapy in resuscitation. Resuscitation 1995; 30: 29–42.
Sir—Giorgio Noera and colleagues1 report that administration of singledose ACTH nearly doubles the survival rate in patients with type-A aortic dissection. Administration of ACTH temporarily reversed hypotension and lowered concentrations of the inflammatory cytokine tumour necrosis factor ␣ (TNF␣) by up to three orders of magnitude. Noera and colleagues build on previous animal work and raise the possibility that ACTH might be useful in patients with other kinds of shock. I suggest that inhaled anthrax might be one such example. The anthrax bacterium is susceptible to a diverse array of antibiotics at almost all stages of its life cycle, but
THE LANCET • Vol 359 • January 12, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
ACTH analogue in treatment of acute aortic dissection Sir—Giorgio Noera and colleagues (Aug 11, p 469)1 report their use of a synthetic adrenocorticotropic hormone (ACTH) analogue in the initial treatment of acute type A aortic dissection complicated by haemorrhagic shock. With one 10 mg bolus ACTH-(1-24) administered immediately at presentation, patients arrived in the operating room in a substantially more favourable condition than did their untreated counterparts. Previous investigations have shown that haemodynamic compromise is a predictor of in-hospital death.2 The relative reduction in surgical mortality was a striking 75%, and the absolute reduction 40% (13 vs 53%). Thus, the mortality rate in the ACTH-(1-24)-treated group was clearly better than that in previous reports in larger series for this frequently fatal disorder.3 The results are referred to as 30-day mortality, but, as shown in their figure 1, the difference actually appears in the first 48 h. This finding reflects the fact that ACTH-(1-24) modifies the much deranged perioperative pathophysiology of initial severe haemorrhagic shock, as well as the postsurgical trauma, inflammatory response to cardiopulmonary bypass, effects of deep hypothermia and circulatory arrest, and a complex anaesthetic management characteristic of these patients, rather than altering the outcome at a later phase postoperatively. None of the 32 patients underwent rescue surgery (pericardiocentesis, pericardial fenestration, or thoracostomy) before definitive surgical repair of the dissection, which happens frequently under these circumstances. We would like to know whether such procedures would alter the effect of ACTH-(1-24) in any direction. Since aortic dissections are commonly given definitive surgical treatment at tertiary referral centres, preceding transportation of the severely ill patient is necessary. Noera and colleagues had the opportunity to treat the patients immediately at diagnosis, which is not commonly the case in cardiovascular departments. Therefore, study of whether the time-span of ACTH-(124) efficacy, to optimise timing of treatment, would be useful, as would identification of patients in whom this treatment is likely to fail. The risk of rebleeding because of improved
168
haemodynamic state and raised systolic blood pressure also need to be addressed. Noera and colleagues’ results are spectacular, and might herald the advent of a very simple and useful tool in the treatment of these severely ill patients. If the benefits extend to all patients in haemorrhagic shock, the perspective on treatment of such patients might become totally altered. Christian Olsson Department of Cardiothoracic Surgery, Uppsala University Hospital, S-751 85 Uppsala, Sweden (e-mail: [email protected]) 1
2
3
Noera G, Lamarra M, Guarini S, Bertolini A. Survival rate after early treatment for acute type-A aortic dissection with ACTH-(1–24). Lancet 2001; 358: 469–70. Ehrlich MP, Ergin MA, McCullough JN, et al. Results of immediate surgical treatment of all acute type A dissections. Circulation 2000; 102 (suppl III): 248–52. Sinatra R, Melina G, Pulitani I, Fiorani B, Ruvolo G, Macino B. Emergency operation for acute type A aortic dissection: neurologic complications and early mortality. Ann Thorac Surg 2001; 71: 33–38.
Authors’ reply Sir—The fact that the mortality rate in our patients who were assigned to the standard treatment, without ACTH(1-24) addition, was higher than that reported in previous studies might be explained by their severe haemodynamic compromise. We selected subjects with type A aortic dissection complicated by aortic rupture and cardiac tamponade, and with clinical and laboratory signs of haemorrhagic shock. We share Olsson’s opinion that ACTH-(1-24) essentially modifies the complex pathophysiology of the perioperative period. Not only by improving the cardiovascular function; indeed, several experimental data suggest that melanocortins have also a peculiar, adrenal-independent antiinflammatory activity. They reduce the production of proinflammatory cytokines, such as interleukins 1␣, 1, and 6, and tumour necrosis factor (TNF) ␣, and inhibit the activation of the transcription factor NF-kB, while increasing the production of the antiinflammatory cytokines interleukins 8 and 10;1 in particular, in conditions of haemorrhagic shock, melanocortins inhibit the overproduction of TNF␣, nitric oxide, and free radicals.2,3 Moreover, melanocortins protect against the outcomes either of a shortterm myocardial ischaemia followed by reperfusion or of the permanent occlusion of a coronary artery in rats.4 Our patients underwent fluid replacement en route and ventilatory
support but no rescue surgery. Our cardiac surgery unit is situated roughly in the middle of a flat territory in northern Italy, with a high population density (about 1 million people), and a reasonable road system. The time lapse from emergency call to arrival into the casualty ward, by ambulance or by helicopter, is 20–40 min. Our animal data suggest that the time span of ACTH-(1-24) efficacy is best if given within 5–15 min of shock induction. We have fewer human data, but they suggest that treatment must be made within 1 h of the first signs of shock. In case of haemorrhagic shock (road or industrial accidents, &c), we believe ACTH should be given as intravenous bolus injection at the scene, or en route in the ambulance. The effect of ACTH lasts a few hours.5 Giorgio Noera, Mauro Lamarra, *Salvatore Guarini, Alfio Bertolini Villa Maria Cecilia Hospital, Cardiac Surgery Unit, Cotignola, Ravenna, Italy; and *Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via Campi 287, 41100 Modena, Italy (e-mail: [email protected]) 1
2
3
4
5
Wikberg JES, Muceniece R, Mandrika I, et al. New aspects on the melanocortins and their receptors. Pharmacol Res 2000; 42: 393–420. Guarini S, Bazzani C, Mattera Ricigliano G, Bini A, Tomasi A, Bertolini A. Influence of ACTH-(1-24) on free radical levels in the blood of haemorrhage-shocked rats: direct ex vivo detection by electron spin resonance spectrometry. Br J Pharmacol 1996; 119: 29–34. Altavilla D, Cainazzo MM, Squadrito F, Guarini S, Bertolini A, Bazzani C. Tumour necrosis factor-␣ as a target of melanocortins in haemorrhagic shock, in the anaesthetised rat. Br J Pharmacol 1998; 124: 1587–90. Bazzani C, Guarini S, Botticelli AR, et al. Protective effect of melanocortin peptides in rat myocardial ischemia. J Pharmacol Exp Ther 2001; 297: 1082–87. Bertolini A. The opioid/anti-opioid balance in shock: a new target for therapy in resuscitation. Resuscitation 1995; 30: 29–42.
Sir—Giorgio Noera and colleagues1 report that administration of singledose ACTH nearly doubles the survival rate in patients with type-A aortic dissection. Administration of ACTH temporarily reversed hypotension and lowered concentrations of the inflammatory cytokine tumour necrosis factor ␣ (TNF␣) by up to three orders of magnitude. Noera and colleagues build on previous animal work and raise the possibility that ACTH might be useful in patients with other kinds of shock. I suggest that inhaled anthrax might be one such example. The anthrax bacterium is susceptible to a diverse array of antibiotics at almost all stages of its life cycle, but
THE LANCET • Vol 359 • January 12, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.