Reply We are grateful to Dr Kounis and colleagues for their thoughtful insight to the pathophysiology of anaphylactic shock and their evaluation of our article entitled: “Anaphylactic Shock Decreases Cerebral Blood Flow More Than What Would Be Expected From Severe Arterial Hypotension” (1). There is no doubt that myocardial dysfunction, probably related (but no exclusively) to coronary events, participates to the pathophysiology of severe forms of anaphylactic shock. Nevertheless, we have brought proof of vasodilatation and plasma extravasation (acutely increased hemoglobin concentration due to hemoconcentration) and therefore consider that both vascular (macro- and micro-)dysfunction, decreased circulating blood volume and myocardial dysfunction contribute, to the pathophysiology of severe forms of anaphylactic shock. In addition, our results demonstrate that anaphylactic shock impairs cerebral blood flow beyond its characteristic arterial hypotension, resulting in severe brain ischemia, which contributes to the pathophysiology of severe anaphylactic shock. We have also recently showed that impairment of cerebral blood flow may persist despite correction of arterial hypotension (2). Our group considers that there are multiple mechanisms that may underline refractory anaphylactic shock both in animal (healthy) models and even more so in human clinical practice because of the interaction between the mediators of anaphylactic shock and the underlying chronic/acute comorbidities (3–6). Among our working hypothesis is also the fact that because of the “explosive” pattern of anaphylactic shock, there is no time for cells to adapt to the acute decrease in oxygen delivery, and this, coupled to the persistent oxygen consumption, results in very rapid cellular energetic failure, which will concern all organs (including the brain and the heart) that have high basal metabolic requirements (7). In addition, Dr. Kounis and colleagues point to the fact that intracoronary thrombosis may occur. Activation of platelets is a credible link. We agree with Dr. Kounis that further research is necessary to investigate the mechanism of refractory anaphylactic shock and to propose new therapeutic approaches. Paul-Michel Mertes Feng Zheng Grégoire Barthel Ionel Alb Adriana Tabarna Simon N. Thornton Dan Longrois Gérard Audibert Jean-Marc Malinovsky Groupe Choc, Contrat AVENIR INSERM U961 Faculté de Médecine, Université de Lorraine Vandœuvre-lès-Nancy Pôle Anesthésie, Réanimations Chirurgicales, SAMU Hôpitaux Universitaires de Strasbourg, Strasbourg Département d’Anesthésie-Réanimation Chirurgicale Centre Hospitalier Universitaire (CHU) Central, Nancy INSERM U961, Faculté de Médecine, Université de Lorraine Vandœuvre-lès-Nancy Département d’Anesthésie-Réanimation Chirurgicale Hôpital Bichat-Claude Bernard, Unité INSERM U698 Assistance Publique-Hôpitaux de Paris Université Paris Diderot, Sorbonne Paris Cité, Paris and Département d’Anesthésie-Réanimation Chirurgicale, CHU de Reims, Reims, France