Postal address: Peter Roessler, Private practice, Windsor Private Hospital, Windsor, Australia, E-mail: peter@ozros.com

The author declares no conflict of interest

Received: 02-01-2017
Accepted: 22-11-2017

Abstract

Hypotension resulting from vasodilatation associated with administration of anaesthetic agents is very common. This has resulted in the almost ubiquitous use of vasopressors with a view to restoring blood pressure to pre-anaesthesia levels. In Australia, of all the medications used in anaesthesia, the cost of vasopressors is a significant factor in contributing to healthcare costs. The rationale for use of vasopressors warrants consideration with regard to their benefits as well as potential harm arising from their use. It has long been accepted that blood pressure needs to be maintained in order to maintain perfusion. However, on close scrutiny such thinking may simply be a misinterpretation of the basic laws of physics with respect to both Newton’s laws and Ohm’s law. This article develops the physics-based argument that only forces can cause objects to accelerate. For pressure to be a driver of flow it must therefore be a force. However, pressure is the result of forces acting over an area, and consequently is not a force in itself. Therefore, it cannot be a driver of flow. Blood flow is the result of the balance of propulsive and resistive forces, which raises the question as to the benefit of increasing resistive forces, which in fact will reduce flow. The use of vasopressors is challenged in this article as is the basic accepted relationship between blood pressure and blood flow.

Resumen

La hipotensión asociada con la vasodilatación inducida por el uso de agentes anestésicos es muy frecuente, un fenómeno que ha motivado la utilización casi generalizada de vasopresores, con la finalidad de restaurar la presión sanguínea a los niveles registrados antes de la anestesia. En Australia, entre todas las medicaciones que se usan en la anestesia, el costo de los vasopresores es un factor significativo en los costos de los sistemas de salud. La utilización de vasopresores debe basarse en los posibles beneficios y riesgos asociados. Desde hace tiempo se acepta que la presión arterial debe mantenerse con la finalidad de preservar la perfusión. Sin embargo, la evaluación detallada indica que este concepto podría surgir de la interpretación errónea de las leyes básicas de la física, como las leyes de Newton y de Ohm. En este trabajo se propone, en función de los principios de la física, que sólo las fuerzas pueden motivar el aceleramiento de los objetos. Para que la presión sea un conductor del flujo, debería ser una fuerza. Sin embargo, la presión es el resultado de fuerzas que actúan sobre una superficie determinada y, por ende, no representa en sí misma una fuerza y no puede ser un conductor de flujo. El flujo sanguíneo es resultado del equilibrio entre las fuerzas de propulsión y de resistencia; en este contexto se debe reconsiderar el supuesto beneficio de aumentar las fuerzas de resistencia, un fenómeno que, en realidad, motivará una reducción del flujo. En el estudio se cuestiona el uso de vasopresores, como también la relación básica, ampliamente aceptada, entre la presión sanguínea y el flujo sanguíneo.

Introduction

Hypotension is a common occurrence in association with anaesthesia. Depending on the definition of hypotension,^{1 2} which varies considerably, the incidence ranges from 5% to 99%, and for Caesarian delivery under spinal anaesthesia it ranges from 7%-74%.³

The treatment of hypotension is aimed at restoring blood pressure to within a predetermined range of the pre-anaesthesia resting level. The reason cited for this is to ensure adequate perfusion to the tissues.^{4 5} However, the possibility and risk of harm should be explored when vasopressors are used to achieve blood pressure control.

In the 16^th century, William Harvey discovered that blood flowed in a circulatory fashion. To propose and even think of this was quite a feat given the prevalence of superstition in those times. Vasopressors having become a ubiquitous method for treating hypotension with a view to restoring blood pressure have entered the realm of acceptance and belief. However, their use may not be without potential harm,^{6 7} and of questionable benefit,⁵ and as a single class of agents used in anaesthesia, considerable expense is incurred. To question their value is imperative in order to stimulate and promote research into their potential to cause harm.

Measurement of blood pressure - Accuracy and reliability

In clinical practice blood pressure may be measured at different sitesand by either indirect or direct means. Apart from the errors inherent in blood pressure measurement, variations are known to be site dependent such that readings recorded from the arm, thigh, calf, and ankle, all produce different readings.⁶

While the issue of accuracy may be dismissed by arguing that the trend in blood pressure is more relevant, the absolute reading forms the basis for thresholds for instituting blood pressure restorative measures.

Physiological rationale for blood pressure maintenance

The perceived need to support blood pressure is based on concepts of homeostasis and tissue perfusion.^{9 10} While blood pressure is thought to be tightly controlled it varies considerably between individuals as well as within individuals as determined by their level of activity.¹¹ Indeed, the absolute blood pressure does not appear to be rigorously maintained, but rather it appears to be regulated within a range of “normal”.¹²

When considering blood flow, tissue perfusion (blood flow rate per mass of tissue) and autoregulation are cited as reasons for maintaining or supporting blood pressure.¹³ Autoregulation, by definition, implies that blood flow is maintained despite changes in blood pressure, within limits. Consequently, it could be argued that the need to support blood pressure should apply only to instances where the blood pressure falls outside autoregulatory limits.¹² Also, the limits of blood pressure and autoregulation vary for different vascular beds. For example, cerebral blood flow remains constant between 60 and 160 mm Hg,¹⁴ whereas for the kidney it is 80 to 180 mm Hg.

Discrepancies between findings in relation to proposed mechanisms of autoregulation suggest a lack of clear understanding of autoregulation.¹⁵ Tissue PO₂ is thought to be at least a contributing factor to autoregulation in the myocardium.¹⁶ In contrast, in the cerebral circulation, infusion of vasodilators increased cerebral blood flow, which resulted in elevating tissue PO₂, but did not weaken blood flow autoregulation.¹⁷

Accordingly, the issues surrounding autoregulation remain to be definitively elucidated¹⁵ and the need to treat vasodilatory mediated hypotension on the basis of autoregulation warrant re-evaluation.

When it comes to consideration of tissue perfusion there is widespread acceptance that blood pressure is a determinant. However, tissue and microcirculatory perfusion is physiologically determined by blood flow and not blood pressure.¹⁸ In their article, Dunser et al, suggest that during resuscitation of shock a context-sensitive mean arterial blood pressure of 45 to 50 mm Hg is sufficient to preserve heart and brain perfusion. Their article contains the following thought-provoking quote: “It was fatal for the development of our understanding of circulation that blood flow is relatively difficult while blood pressure so easy to measure: This is the reason why the sphygmomanometer has gained such a fascinating influence, although most organs do not need blood pressure but flow” (Jarisch A. Kreislauffragen. Deutsch Med Wochenschr 29:1211-1213, 1928).

Arithmetic relationships such as the Poiseuille equation, for example, between blood pressure and flow have been derived. However, closer inspection of the clinical application of the relationship in terms of dependent and independent variables represents an association rather than cause and effect.¹⁹

Further examination of this precept requires consideration of basic principles and laws of physics.

Physics

Movement of blood through the circulatory system is pulsatile, requiring ventricular contraction to initiate its movement, whereas its distribution thereafter is determined by local vessel resistance in the different vascular beds.

According to Newton a force must be applied in order to move a mass (first law). Similarly, a force must be applied to change the velocity of (accelerate/decelerate) a mass (second law). In the circulatory system there are major propulsive forces (cardiac contraction and aortic elastic recoil) and major resistive forces (vessel resistance). The balance of these forces determines the cardiac output and subsequent blood flow and distribution.²⁰

Based on Newton’s laws, only force scan cause a mass to move or change velocity. Blood pressure, which is considered to be a determinant of flow, however is not a force, and consequently cannot be a primary driver of flow. Pressure, by definition, is the result of forces acting over an area as described by the relationship:

P ( F/A

Pressure (P) varies directly with Force (F) and inversely with Area (A).

Applying the above relationship, in the presence of a constant force, pressure will vary inversely with area. Increasing the area over which the force is applied decreases the pressure. However, with force remaining constant, acceleration of a mass will not change despite the differences in pressure.²⁰ This confirms that pressure is the result of the application of force, but of itself, pressure is not a force. Consequently, the validity of the assumption that maintenance of blood pressure is necessary for adequate perfusion of tissues is brought to question. More importantly, is the question whether a vasopressor, which increases opposing resistive forces can assist blood flow, or whether it acts to impede blood flow.

The argument that pressure gradient is a factor determining flow is also questionable. Conservation of energy dictates that changes in either one of kinetic energy or potential energy is at the cost of the other. Kinetic energy produces onward motion of blood in the circulation, while potential energy exerts its influence laterally against vessel walls (detected as the measured pressure). A decrease in vessel calibre presents an impediment to flow, which serves to diminish kinetic energy, and hence forward motion. Due to conservation of energy this will result in an increase in potential energy proximally with greater lateral “collisions” against the vessel wall to produce an elevated pressure reading. The pressure gradient will also rise as a result. It is interesting to note that such lateral effects result in dissipation and wasted energy.

Increases in pressure gradients are simply a reflection of increases in resistance that will result in flow being redirected along a path of less resistance, along which the pressure gradient will be less. A comparison between the systemic and pulmonary circulations reveals that both pressure and pressure gradient in the pulmonary circulation are one-fifth of that on the systemic side, but the flow is exactly the same, in the healthy heart.²¹

In valvular stenosis the severity of the stenosis is graded by the pressure gradient and flow velocity across the valve.²² As the stenotic lesion gets worse the gradient across the valve increases, as does the velocity of blood flow, reflecting the higher resistance, but flow rate across the valve decreases. The same applies to a vascular lesion in the carotid artery, for example. Treatment involves either by passing the lesion or resecting it, which results in a reduction in the resistance, and with it the pressure gradient and velocity, but increasing flow rate through the region.

From the above it can be concluded that flow is the result of the summation ofpropulsive and resistive forces. This begs the question as to how increasing a resistive force with vasoconstriction can increase flow. The Frank-Starling relationships linking venous return and cardiac output clearly demonstrate that increasing afterload results in a downward shift of the operating point of the heart, which represents a reduced cardiac output.²³

Electricity and hydraulics

Ohm’s law and the Poiseuille equation are frequently applied to the circulatory system to provide explanations for observed activity of the circulation. However, their extrapolation and application to the circulatory system need to be examined.

Ohm’s law relating flow of electric current to voltage and resistance is often extrapolated to the relationship that relates blood flow to pressure gradient and resistance. However, the term voltage, as defined in Ohm’s law, is often confused and consequently misapplied.

V ( I/R

Voltage (V) varies directly with current (I) and inversely with resistance (R).

In the above relationship, the terms voltage (V), potential difference (PD) and EMF (electromotive force) are used interchangeably. However, they are not the same. An EMF, which is the voltage when the circuit is open, can introduce energy into a system, whereas a PD, which is the voltage when the circuit is closed, cannot. In Ohm’s law, the term V refers to the EMF.

In the circulatory system the concept of pressure gradient stems from the incorrect substitution of PD for EMF in Ohm’s law. Correct application of Ohm’s law referring to EMF would equate with the forces acting within the circulation that provide the energy and determine flow, and not any resulting pressure gradients that arise as a result of the resistance.

The Poiseuille equation is also often used to relate pressure, resistance and flow in the circulatory system, despite the fact that it applies only to Newtonian fluids under conditions of laminar flow and constant velocity. Blood is non-Newtonian and being pulsatile in nature its velocity is not constant.

Finally, the use of pressure gradient in the Poiseuille equation overlooks the factors that produce the pressure gradient, and the primary role of forces.

Control of blood pressure

It is generally agreed that the body controls blood pressure. While blood pressure may be considered to be tightly controlled within a very narrow range it can vary significantly in response to physiological factors including stress, exercise,^{24 25} and pregnancy. Depending on the level of exercise elevations in blood pressure of around 30% have been recorded during exercise.²⁶

The body directs blood flow to the different vascular beds according to their local needs. From the foregoing it is evident that this is accomplished through the combined actions of the neuro-humoral system and local metabolites that alter local vascular resistance, as well as the baroreceptor reflex during postural changes.²⁷ With diversion of blood flow between vascular beds, not requiring mobilisation of blood volume reserves or changes in myocardial contractility, there is little change in cardiac output. The apparent constancy of blood pressure may simply be a reflection of the constancy of flows rather than any attempt to control blood pressure.

In their article on blood pressure regulation, Raven et al.²⁸ raise the question that if blood pressure is the regulated variable then why is the operating pressure reset to a different blood pressure during different physiological and pathophysiological stressors. They maintain that their results clearly demonstrate that blood pressure is not well regulated around a single, absolute “set point” blood pressure and flow demands override pressure.

Hypotension associated complications

There is an abundance of articles in the literature that support the association between hypotension and postoperative morbidity,^{29 32} and they provide a strong argument for managing hypotension. However, they identify associations rather than establishing cause and effect, and do not differentiate between hypotension resulting from hypovolaemia or causes other than vasodilatation.

The potential for harm from vasoconstrictor therapy may appear to be at odds with current evidence; however, it is unclear whether the studies pointing to adverse effects of hypotension involve administration of vasoconstrictors once blood pressure falls to predetermined levels. In those studies, where vasopressors had been administered, the question whether the ensuing harm is due to the hypotension or due to the effects of the vasoconstriction reducing flow, increasing turbulence, and increasing myocardial work has not yet been established. Nonetheless, there are grounds to suspect possible adverse effects.

Interposition of a constriction in a tube results in increased resistance and decreased flow rate, but fluid accelerates through the constricted area resulting in an increase in the velocity of flow and turbulence. The relevant fluid dynamics can be explained by applying Bernoulli’s theorem and Toricelli’s theorem, which are discussed in Semat’s article on hydrodynamics.³³ Fry’s article considers this issue and attempts to evaluate the acute vascular endothelial changes associated with increased velocity gradients.³⁴ He showed that endothelial cell disruption and damage occurs once the velocity reaches a threshold.

The effect of fluid acceleration with increased velocity, turbulence, and momentum, on the arterial endothelium and adherent plaques in this context may be a significant factor in post-anaesthesia hypotensive morbidity.

The complications usually attributed to anaesthesia-associated hypotension include stroke,³⁵ myocardial ischaemic events,³⁶ renal dysfunction,³⁷ and postoperative cognitive dysfunction.³⁸ However, some studies have suggested that intraoperative hypotension is not a factor.³⁹ In the case of postoperative cognitive dysfunction, it is proposed that swings in blood pressure are correlated to the incidence rather than hypotension.⁴⁰ This lends strength to the hypothesis that alterations in velocity of blood flow may have deleterious effects yet undetermined.

In the case of strokes, these are most frequently thromboembolic,⁴¹ which again may implicate constrictive vascular changes as the cause of hypoperfusion rather than vasodilatation.

Hypotension arises as a result of either hypovolaemia, cardiac dysfunction, or vasodilatation, and as such, is an indicator of the existence of these events. Management should be aimed at correcting the underlying problem including restoration of circulating volume or cardiac support, rather than inducing vasoconstriction.

Continuing debate as to the best vasopressor agent to use in view of their outcomes and side effects^{42 43} is a testament to the existence of side effects and other concerns.

With regard to cerebral blood flow, a recent study by Cho et al., into cerebral blood flow during surgery in the “beach chair” position showed that use of vasoconstrictors adversely affected cerebral blood flow.⁴⁴ In their paper the use of vasopressors was associated with higher mean arterial pressure but the reduction in cerebral tissue oxygen saturation was greater in the group treated with vasopressors.

From the cardiac perspective vasodilatation and reduced afterload may be beneficial. Abrahams explains the mechanism of actions of nitroglycerin and nitric oxide in treating myocardial ischaemia, which supports the benefits of vasodilatation.⁴⁵ Carabello’s update on the use of vasodilators in aortic stenosisis further support for myocardial benefit through reductions in afterload.⁴⁶

Conclusion

The purpose of this review is to critically appraise the current approach to blood pressure and the management of hypotension. The intention is to promote and encourage research to elucidate the basic fundamental concepts that underlie clinical management, and to improve outcomes and minimise harm.

This review has identified that hypotension associated with anaesthesia is common but the incidence is dependent on the definition; and that management frequently involves administration of vasopressors to manipulate blood pressure. The rationale for this is explored and the basis for their use is questioned. The relevant laws of physics, as well as physiological principles, are reviewed and used to account for differences in interpretations. The potential for risk and harm associated with vasopressors is raised, and possible mechanisms are proposed.

Evidence is presented suggesting that hypotension associated with vasodilatation may not be associated with hypoperfusion, and may not be the causative mechanism for morbidity. Indeed, the treatment of hypotension with vasopressors may, in fact, be the culprit. Permissive hypotension, given the limits of autoregulation, could feasibly provide some protective benefits by maintaining blood flow via a reduction in afterload, and reduced myocardial work.

Further research is required to establish the actual mechanisms of morbidity, which may include studies comparing outcomes between instances where vasopressors are administered and those where they are not.

References

1. Lonjaret L, Lairez O, Minville V, Geeraerts T. Optimal perioperative management of arterial blood pressure. Integrated Blood Pressure Control 7:49-59, 2014.

2. Bijker JB, Van Klei WA, Kappen TH, Van Wolfswinkel L, Moons KG, Kalkman CJ. Incidence of intraoperative hypotension as a function of the chosen definition: literature definitions applied to a retrospective cohort using automated data collection. Anaesthesiology 107(2):213-220. 2007

3. Klohr S, Roth R, Hofmann T, Rossaint R, Heesen M. Definitions of hypotension after spinal anaesthesia for caesarian section: literature search and application to parturients. Acta Anaesthesiaol Scand 54(8):909-921, 2010.

4. Sivertsson R. Effect of blood pressure reduction on tissue perfusion. Journal of Internal Medicine 205(S628):13-16, 1979.

5. Dubin A, Pozo MO, Casabella CA, Palizas Jr F, Murias G, Moseinco MC, Edul VSK, Palizas F, Estenssoro E, Ince C. Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study. Crit Care 13(3):R92, 2009.

6. Currigan DA, Hughes RJA, Wright CE, Angus JA, Doeding PF. Vasoconstrictor responses to vasopressor agents in human pulmonary and radial arteries. Anaesthesiology 121(5):930-936, 2014.

7. Meng L, Tran NP, Alexander BS, Laniing K, Chen G, Kain ZN, Cannesson M. The impact of phenylephrine, ephedrine, and increased preload on third-generation vigileo-flo trac and esophageal Doppler cardiac output measurements. Anaesthesia & Analgesia 113(4):751-757, 2011.

8. Moore C, Dobson A, Kinagi M, Dillon B. Comparison of blood pressure measured at the arm, ankle, and calf. Anaesthesia 63(12):1327-3131, 2008.

9. Hulin I, Kinova S, Paulis L, Slavkovsky P, Duris I, Mravec B. Diastolic blood pressure as a major determinant of tissue perfusion: potential clinical consequences.Bratisl. Lek Listy 111(1):54-56, 2010.

10. Sivertsson R. Effects of blood pressure reduction on tissue perfusion. Journal of Internal Medicine 205:13-16, 1979.

11. Parati G, Di Rienzo M, Omboni S, Ulian L, Mancia G. Blood pressure variability over 24 hours: its different components and its relationship to the arterial baroreflex. J Sleep Res 4(Suppl 1):21-29, 1995.

12. Raven PB, Chapleau MW. Blood pressure regulation xi: overview and future research directions. Eur J Appl Physiol 114(3):579-586, 2014.

13. Johnson PC. Autoregulation of Blood flow. Circulation Research 59(5):483-495, 1986.

14. Langfitt TW et al (eds). Cerebral circulation and metabolism. New Yor, Berlin, Heidelberg, Springer-Verlag, pp. 3-6, 1975.

15. Cupples WA, Braam B. Asessment of renal autoregulation. Am J Renal Physiol 292;F1105-F1123, 2007.

16. Schubert RW, Whalen WJ, Nair P. Myocardial PO2 distribution: Relationship to coronary autoregulation. Am J Physiol 234:361-370, 1978.

17. Ekstrom-Jodal B. On the relation between blood pressure and blood flow in the canine brain with particular regard to the mechanism responsible for cerebral blood flow autoregulation. Acta Physiol Scand (Suppl)350:1-61, 1970.

18. Dunser MW, Takala J, Brunauer A, Bakker J. Re-thinking resuscitation: leaving blood pressure cosmetics behind and moving forward to permissive hypotension and a tissue perfusion-based approach. Critical Care 17:326-331, 2013.

19. Levy M. The cardiac and vascular factors that determine systemic blood flow. Circ Research 44(6):739-747, 1979.

20. Peterson LH. The dynamics of pulsatile blood flow. Circ Res 2(2):127-139, 1954.

21. Pinsky MR. The right ventricle: interaction with the pulmonary circulation. Crit Care 20:266-274, 2016.

22. Minners J, Allgeier M, Gohlke-Baerwolf D, Kienzle RP, Neumann FJ, Jander N. Inconsistencies of echocardiographic criteria for the grading of aortic vlave stenosis. Eur Heart J 29:1043-1048, 2008.

23. Henderson WR, Griesdale DEG, Walley KR, Sheel AW. Clinical review: Guyton - the role of mean circulatory filling pressure and right atrial pressure in controlling cardiac output. Crit Care 14(6):243-248, 2010.

24. Daniels JW, Mole PA, Shaffrath JD, Stebbins CL. Effects of caffeine on blood pressure, heart rate, and forearm blood flowduring dynamic leg exercises. J Appl Physiol 85(1):154-159, 1998.

25. Cardoso Jr CG, Gomides RS, Quieroz ACC, Pinto LG, Lobo FS, Tinucci T, Mion Jr D, Forjaz CLM. Acute and chronic effects of aerobic and resistance exercise on ambulatory blood pressure. Clinics 65(3);317-325, 2010.

26. Pescatello LS, Fargo AE, Leach Jr CN, Scherzer HH. Short-term effect of dynamic exercise on arterial blood pressure. Circulation 83(5):1557-1561, 1991.

27. Mette SO, Ottesen JT, Tran HT, Ellwien LM, Lipsitz LA, Novak V. Blood pressure and blood flow cariation during postural change from sitting to standing: model development and validation. J Appl Phsiol 99(4):1523-1537, 2005.

28. Raven PB, Chapleau MW. Blood pressure regulation X!: Overview and future research directions. Eur J Appl Physiol 114(3):579-586, 2014.

29. Lindop MJ. Complications and morbidity of controlled hypotension. BJA 47:799-803, 1975.

30. Enderby GEH. A report on mortality and morbidity following 9,107 hypotensive anaesthetics. BJA 33:109-113, 1961.

31. Monk TG, Bronsert MR, Henderson WG, Mangione MP, Sum-Ping STJ, Bentt DR, Nguyen JD, Richman JS, Meguid RA, Hammermeister KE. Association between intraoperative hypotension and hypertension and 30-day postoperative mortality in noncardiac surgery. Anaesthesiology 123(2):307-319, 2015.

32. Walsh M, Devereaux PJ, Garg AX, Kurz A, Turan A, Rodseth RN, Cywinski J, Thabane L, Sessler DI. Relationship between intraoperativee mean arterial pressure and clinical outomes after noncardiac surgery. Toward an empirical definition of hypotension. Anaesthesiology 119(3):507-515, 2013.

33. Semat H. Physics, Chapter 9: Hydrodynamics (Fluids in Motion). Robert Katz Publications 143:165-180, 1958.

34. Fry DL. Acute vascular endothelial changes associated with increased velocity gradients. Circulation Research 22:165-197, 1968.

35. Limburg M, Wijdicks EFM, Li H. Ischaemic stroke after surgical procedures. Neurology 50(4):895-901, 1998.

36. Steen PA, Tinker JH, Tarhan S. Myocardial reinfarction after anehsthesia and surgery. JAMA 239(24):2566-2570, 1978.

37. Abuelo JG. Mormotensive ischaemic acute renal failure. NEJM 357(8):797-805, 2007.

38. Fodale V, Santamaria LB, Schifilliti D, Mandal PK. Anaesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking Alzheimer's disease. Anaesthesia 65:388-395, 2010.

39. Kam PCA, Calcroft RM. Peri-operative stroke in general surgical patients. Anaesthesia 25;879-883, 1997.

40. Hirsch J, DePalma G, Tsai TT, Sands LP, Leung JM. Impact of intraoperative hypotension and blood pressure fluctuations on early postoperative delirium after non-cardica surgery. BJA 115(3):418-426, 2015.

41. Selim M. Perioperative stroke. NEJM 356(7):706-713, 2007.

42. Thiele RH, Nemergut EC, Lynch C. The clinical implications of isolated alpha(1)adrenergic stimulation. Anaesth Analg 113(2):297-304, 2011.

43. Mets B. Should norepinephrine, rather than phenylephrine, be considered the primary vasopressor in anaesthetic practice? Anaesth Analg 122(5):1707-1714, 2016.

44. Cho SY, Kim SJ, Jeong CW, Jeong CY, Chung SS, Lee J, Yoo KY. Under gerneal anaesthesia arginine vasopressin prevents hypotension but impairs cerebral oxygenation during arthroscopic shoulder surgery in the beach chair position. Anaesth Analg 117(6):1436-1443, 2013.

45. Abrahams J. Mechanisms of action of the organic nitrates in the treatment of myocardial ischaemia. Am J Cardiol 70(8):B30-B42, 1992.

46. Carabello BA. Georg Ohm and the changing character of aortic stenosis, it's not your grandfather's Oldsmobile. Circulation 125:2295-2297, 2012.