Orthostatic stress, haemorrhage and a bankrupt cardiovascular system.

Cardiovascular collapse is a term used by clinicians to describe a sudden and marked drop in blood pressure and as a result the inability of the cardiovascular system to maintain adequate perfusion pressure to key organ systems, especially the brain. The most common form of cardiovascular collapse is syncope or fainting, which has multiple causes. Some of these causes are associated with pathophysiological conditions such as cardiac arrhythmias or valvular heart disease. However, syncope is also frequently seen in young people with no apparent cardiovascular pathology. In fact, it is estimated that ∼40% or more of healthy young females have experienced one or more syncopal episodes (Ganzeboom et al. 2006). Thus, syncope is common and not always a hallmark of underlying cardiovascular pathology. A less common but especially dangerous cause of cardiovascular collapse is life-threatening haemorrhage. As is the case with syncope, there are many potential causes, but perhaps the most dramatic is acute trauma. Trauma is also a ‘disease’ that strikes young people at a disproportionate rate. While less frequent than common killers such as cardiovascular disease and cancer, the epidemiologists tell us that trauma is responsible for a huge loss of life-years (Murray & Lopez, 1997). In this context, life-threatening haemorrhage is also the final common pathway for death on the battlefield. Along these lines, one of the classic papers published in The Journal of Physiology is the 1945 study by Barcroft and Edholm who used a combination of tilting, venous congestion and bloodletting to study the pathophysiology of cardiovascular collapse. These studies were conducted during World War II and the goal was to try to better understand the sudden drop in blood pressure that can occur when central blood volume is reduced during haemorrhage. This study clearly demonstrated that peripheral vasodilatation contributed to the profound fall in blood pressure during cardiovascular collapse (Barcroft & Edholm, 1945) and confirmed observations in the 1700's by the Scottish surgeon John Hunter suggesting that vasodilatation was a key component of cardiovascular collapse (Hunter & Palmer, 1837). The idea is that cardiovascular collapse from both common syncope and life-threatening haemorrhage is caused by a loss of central blood volume, which in turn causes both central venous and arterial pressures to fall. As a result, mechanoreceptors located in the heart and lungs, aorta and carotid sinuses, are deactivated and trigger reflex reductions in vagal outflow to the heart and increases in sympathetic outflow to the peripheral circulation. Under normal conditions, these mechanisms are responsible for the remarkable ability of most humans to maintain their blood pressure in spite of marked reductions in central blood volume. These mechanisms also contribute to the difficulty in diagnosing blood loss on the basis of traditional vital signs like blood pressure and heart rate. During loss of central blood volume, these variables can be very normal until they are abruptly abnormal (Cooke et al. 2004). As Roy Freeman, a leading syncope investigator, points out, it is like Hemingway's description of bankruptcy in the Sun Also Rises: ‘How did you go bankrupt?’ Bill asked. ‘Two ways,’ Mike said. ‘Gradually and then suddenly.’ When loss of central blood volume becomes extreme, the mechanosensitive receptors that normally respond to low volumes and pressures send paradoxical signals to the brainstem cardiovascular centres that are misinterpreted and trigger increases in vagal outflow to the heart and reductions in sympathetic outflow to the peripheral circulation. This is the so-called ‘empty heart syndrome’ which has been used to explain vasovagal syncope and the physiological responses seen during severe haemorrhage. However, this explanation leaves much to be desired (Hainsworth, 2003). In a recent issue of The Journal of Physiology, Cooke et al. (2009) subjected a large number of healthy young volunteer subjects to severe orthostatic stress evoked by lower body negative pressure (LBNP). LBNP has also emerged as an experimental model with high relevance to understanding the pathophysiology of life-threatening haemorrhage in humans (Cooke et al. 2004). A critical observation in this paper is that not all humans who undergo cardiovascular collapse during severe orthostatic stress/simulated haemorrhage also manifest an abrupt reduction in efferent sympathetic traffic to blood vessels (Wallin & Sundlof, 1982). In about one-third of subjects, sympathetic nerve activity remains high when the subjects are on the verge of losing consciousness. Additionally, there is evidence that the normal pulse synchronous characteristics of sympathetic outflow are lost, suggesting that blood pressure has fallen enough to limit baroreflex modulation of sympathetic outflow. Why is this clinically relevant? As noted above, the traditional explanation for common syncope in the absence of overt cardiovascular pathology (and also cardiovascular collapse during haemorrhage) is that paradoxical firing of cardiopulmonary receptors as a result of an ‘empty heart’ leads to vagal activation and sympathetic withdrawal. However, this explanation, while handy, is an over-simplification. Anecdotal evidence suggests that syncope can occur in patients after heart transplantation with functionally deafferented hearts (Fitzpatrick et al. 1993), and the work by Cooke and colleagues (2009) demonstrates that abrupt reductions in sympathetic outflow are not an obligatory feature of cardiovascular collapse. Thus, the pathophysiology of cardiovascular collapse during syncope or haemorrhage has a more complex explanation than merely an empty heart and a loss of efferent vasoconstrictor outflow. While the ‘gradual’ part of cardiovascular collapse is well understood, many questions remain about the ‘sudden’ part.