Letters to the Editor
To the Editor
Mortality in cardiogenic shock is high. Research aiming at improving outcome is therefore needed. Because these patients are in shock, informed consent cannot be obtained from them. Consequently, ethics committees may allow deferred informed consent, and the patient’s presumed will is asked from relatives or consent obtained from a legal representative. In this issue of Shock, Perez et al. (1) report a study where norepinephrine was used to increase mean arterial blood pressure from 65 to 85 mmHg for 1 hour in patients in cardiogenic shock. The responsible ethics committee waived written informed consent but requested oral informed consent from patients or relatives before study start. The authors had declared that the procedure (increasing blood pressure for 1 hour along with measurement of tissue perfusion and a vascular occlusion test) is a standard clinical procedure in their unit. They argue that patients with previous hypertension may need higher blood pressure, e.g., for maintaining sufficient brain perfusion. While the continuous efforts of the authors to improve care of patients in shock should be acknowledged, I wonder whether a norepinephrine infusion of median of more than 1.5 µg/kg per minute (>2.6 µg/kg per minute in 25% of all patients) to “study cardiac and vascular reactivity” is in the best interest of a patient and can be considered standard “daily clinical practice.” Twenty-one of the 25 patients had an intra-aortic balloon pump to reduce afterload and improve coronary perfusion. The norepinephrine doses the authors used are much higher than those commonly used in patients in septic shock, where vasopressor responsiveness is decreased (2, 3).
Perez et al. (1) did not measure any variables indicating cerebral perfusion; norepinephrine was downtitrated after 1 hour, irrespective of the response, and the authors do not provide any evidence how their “daily clinical practice” may have helped their patients. It may be questioned whether it is meaningful to increase cardiac work further in patients after myocardial infarction—two of three after cardiac arrest—when blood pressure is already 65 mmHg and mixed venous oxygen saturation almost 70%. While it is true that low blood pressure in cardiogenic shock is associated with worse outcome, also are norepinephrine doses (4). Norepinephrine may increase tumor necrosis factor α release via α2-adrenergic receptors (5, 6). Furthermore, norepinephrine can contribute to the disproportionately reduced mesenteric perfusion in cardiogenic shock (7). The design of the study from Perez et al. (1) is problematic because potential delayed adverse effects of norepinephrine (e.g., from ischemia-reperfusion injury) will remain undetected: a bad outcome will be attributed to the underlying disease and not to the treatment.
I wonder why oral but not written informed consent is requested before study start. Informed consent should enable patients or relatives to balance potential risks versus benefits. They should be informed who is paying the study and what insurance will protect them. How can they possibly decide whether to participate if all procedures will be performed anyhow? It seems that the only thing they can decide is whether to agree with publication of the results. Also, the Declaration of Helsinki request that “every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject” (8). This has not been documented in the study by Perez et al. (1).
I believe that Shock should consider ethical issues more rigorously. It seems that the journal delegates the responsibility fully to the authors and local ethics committees.
Stephan Jakob MD, PhD
Department of Intensive Care Medicine, Inselspital, Bern
University Hospital and University of Bern, Bern, Switzerland
1. Perez P, Kimmoun A, Blime V, Levy B: Increasing mean arterial pressure in cardiogenic shock secondary to myocardial infarction: effects on hemodynamics and tissue oxygenation. Shock 41( 4): 269–274, 2014.
2. Myburgh JA, Higgins A, Jovanovska A, Lipman J, Ramakrishnan N, Santamaria JCAT Study Investigators: A comparison of epinephrine and norepinephrine in critically ill patients. Intensive Care Med 34: 2226–2234, 2008.
3. Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, Orecchioni A, D’Egidio A, D’Ippoliti F, Raffone C, et al.: Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA 310: 1683–1691, 2013.
4. Katz JN, Stebbins AL, Alexander JH, Reynolds HR, Pieper KS, Ruzyllo W, Werdan K, Geppert A, Dzavik V, van de Werf F, et al.; TRIUMPH Investigators: Predictors of 30-day mortality in patients with refractory cardiogenic shock following acute myocardial infarction despite a patent infarct artery. Am Heart J 158: 680–687, 2009.
5. Miksa M, Das P, Zhou M, Wu R, Dong W, Ji Y, Goyert SM, Ravikumar TS, Wang P: Pivotal role of the alpha(2A)-adrenoceptor in producing inflammation and organ injury in a rat model of sepsis. PLoS One 4: e5504, 2009.
6. Zhou M, Yang S, Koo DJ, Ornan DA, Chaudry IH, Wang P: The role of Kupffer cell alpha(2)-adrenoceptors in norepinephrine-induced TNF-alpha production. Biochim Biophys Acta 1537: 49–57, 2001.
7. Hirsch LJ, Glick G: Mesenteric circulation in cardiogenic shock with and without alpha-receptor blockade. Am J Physiol 225: 356–359, 1973.
8. World Medical Association: World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310: 2191–2194, 2013.