During my years in academic anaesthesiology, I often have witnessed a lack of interest in and understanding of basic research. I have heard, “Do I need to know this in the 21st Century?”; “Do I need to know it to provide safe anaesthesia?”. Certainly we do, for quite a few reasons. It helps us to understand better the pathophysiological disturbances in our patients, something that is important for the rational design of the treatment of our patients. This Editorial illustrates that knowledge of basic physiological concepts assures the creation of hypotheses for future research.

Some experimental data1–3 and clinical observations4–7 suggest beneficial effects of norepinephrine in small doses. Nakomoto et al.8 used small doses of norepinephrine (median 0.027 μg kg−1 min−1) in patients undergoing elective liver resection. The authors did not demonstrate any complications of norepinephrine infusion and the norepinephrine group received less fluids, although this did not reach statistical significance. Comparing controls versus norepinephrine intermittent bolus doses, there was a nonsignificant increase in fluid responsiveness in the norepinephrine group (OR 2.56, 97.5% CI, 0.82 to 8.00; P = 0.064).

If the observations mentioned above reflect reality, it begs the question: how could it happen? How could norepinephrine decrease the rate of postsurgical complications and improve overall outcome?

Relevant vascular functions of adrenoreceptors

The activation of α1 and α2 adrenoceptors leads to constriction of the vessels that contain the receptors. The constriction of arteries decreases the flow, possibly leading to tissue hypoxia. Constriction of compliant veins moves blood volume from those veins into the larger veins and thence into the systemic circulation. Quite a few studies have demonstrated that an injection of an α-adrenergic agonist was associated with an increase in preload and cardiac output (CO).9,10

Density of α-adrenergic receptors is higher in the veins than in the arteries.11,12 This is why small doses of α-adrenoceptor agonists constrict compliant veins to a greater extent than arteries.10,13 During constriction of those veins, blood volume is moved from the veins to larger veins, and thence to the heart, increasing venous return and CO. When initial small norepinephrine doses have already constricted compliant veins, further constriction of the veins would be nearly impossible and the veins would not contain enough volume to shift to the systemic circulation. Such larger doses would additionally constrict arteries, possibly decreasing flow through the tissues, venous return and CO. This is why norepinephrine infusion may decrease or increase CO, depending on the dose used.13

The baseline tone of the vessels and volume status may also play a role; a hypovolaemic patient could have an increased sympathetic tone and already constricted veins. Further constriction of the veins would not lead to significant blood volume shift. Such mechanism of blood volume mobilisation would be already exhausted and blood pressure could be maintained by constriction of arteries, without additional blood volume shift from an already empty blood reservoir within the body. An increase in norepinephrine dose in this situation may drastically constrict veins and arteries, decreasing tissue flow leading to tissue hypoxia, and a decrease in venous return and CO. This also explains why excessive doses of vasopressors may be deleterious and may cause hypoperfusion despite restoration of blood pressure.

Role of the liver and hepatic veins

Quite elegant experiments on dogs demonstrated that isoproterenol (β1 and β2 adrenergic agonist) decreased splenic and splanchnic volumes and increased CO.14 The same dose of isoproterenol, given after injection of metoprolol (β1 adrenergic antagonist), had the same effect on the cardiovascular system, including a similar decrease in the splanchnic and splenic volumes. However, isoproterenol administered after injection of propranolol (both β1 and β2 antagonist) decreased splanchnic and splenic volumes only very mildly. This experiment shows that the haemodynamic effect of isoproterenol is exerted through the β2 adrenergic-receptors and the vasculature rather than through the heart.14,15

Norepinephrine-induced activation of β2 adrenergic receptors within the liver and hepatic veins decreases their tone thereby facilitating the transfer of blood volume from the splanchnic organs into the systemic circulation, increasing venous return and CO.

Unstressed and stressed volumes

Unstressed volume (Vu) is a volume of blood under a transmural pressure (Ptm) equal to zero; such blood does not flow forward and does not participate in the active circulation. Flowing blood means that such blood is under a transmural pressure above zero. When an α-adrenergic agonist is administered, it typically increases Ptm, converting the Vu into stressed volume (Vs). Thus, the stressed and unstressed volumes are the same blood, the same blood cells; they change their function and name only because transmural pressure (Ptm) increases.

In clinical reality, fluid is often infused until an increase in stroke volume (SV) and CO is observed. In conditions of a normally functioning heart and relatively normal blood volume, the situations when fluid is infused without inducing a concomitant increase in SV and CO might mean that infused fluid was increasing the Vu, but was not yet noticeably increasing Ptm and flow within the venous system and circulation. It often takes place at the beginning of the infusion until an increase in SV and CO is observed. Such an increase in Vu is functionally useless because venous return (and CO) is not changing, and it may represent harmful overloading. However, continuous infusion might increase Ptm effectively enough to convert the Vu to Vs.

Thus, stimulation of α-adrenergic receptors may increase the Vs by converting Vu to Vs, thereby increasing venous return and CO. However, activation of α-adrenergic receptors within the arterial wall may constrict arteries and decrease flow through tissues, decreasing venous return and CO (Fig. 1). The result would depend on a few factors: baseline blood volume and vascular tone, the dose of norepinephrine. Due to the higher density of α-adrenergic receptors in the veins than in the arteries, small doses would affect veins, assuring the volume shift, an increase in preload, venous return and CO. Large doses affect both veins and arteries, but the decrease in flow through tissues would decrease overall flow (venous return and CO) and there would not be much room left for blood volume shift from the venous system to the systemic circulation.

Fig. 1:

Main haemodynamic effects of norepinephrine.

General anaesthesia (equally spinal and epidural anaesthesia), increases Vu (vasodilation), decreases Vs and impedes the ability of the body to mobilise blood from the Vu to Vs (in other words, to convert the Vu to Vs). The usual treatment would be infusion of fluid and administration of a vasopressor (α-adrenergic agonist, for example). An infusion of large amounts of fluid at that moment could be less beneficial because, after anaesthesia, vascular tone would recover and the body would end up with a load of unnecessary fluid. Fortunately for our patients, in the majority of situations, such amounts of infused fluid are relatively small and it is mainly patients with renal and/or cardiac failure that may be at serious risk.

Thus, unstressed volume is a reservoir of blood that can be mobilised, or rather converted into Vs. Such transition from Vu to Vs may be vitally important. On the other hand, when Ptm is not increasing, Vu remains Vu. With time such excess of fluid could be absorbed, possibly increasing Ptm and flow, but possibly giving rise to signs of overload with all associated consequences, including tissue oedema, pulmonary dysfunction, leakage of gastrointestinal anastomoses and impeded healing.

Thus, in the end, such fluid may convert the Vu to Vs, affecting haemodynamic status (an increase in CO) or may remain as Vu that would reflect overloading, possibly leading to well known complications.

If the infusion continues and the heart is functioning normally, the SV and CO increase. This means that at that time Ptm increased, Vu is converted to Vs, and the flow forward has increased. This occurs in clinical reality when fluid is continually infused until SV and CO increases. But until this occurs, this fluid, a mixture of existing blood and infused fluid, is still Vu and does not yet affect haemodynamic activity.

Norepinephrine decreases the Vu and converts the Vu to Vs at the lower Vu value. This leads to a situation when a smaller total amount of fluid is needed to achieve adequate CO, representing an advantage that should benefit the patients. Quite a few studies have demonstrated that patients treated with restricted fluid load do better than patients who received luxurious fluid regimens.4–7 There is a clear difference between the active restriction of fluid infusion and decreasing the demand for fluid infusion. In other words, it is physiologically better to decrease demand for fluid infusion than just to decrease the amount of infused fluid.

Obviously, hypovolaemia must be prevented by maintaining adequate CO.

One needs to keep in mind that a decrease in Vu means a decrease in the reservoir of blood that usually is mobilised when needed. Such a decrease in blood reservoir might be dangerous if unexpected additional bleeding occurs. The treating physician must be aware of such a possibility and be ready to transfuse blood or fluid if such need occurs.13,15

The appropriate use of small norepinephrine doses during the peri-operative period may represent the next step in improving the results of surgical interventions.

Conclusion (1) There are several animal experimental studies and clinical observations suggesting that the use of small doses of norepinephrine during the peri-operative period may be associated with achieving adequate haemodynamic stability, a decrease in the total amount of fluid administered, an increase in sensitivity to fluid challenges, a reduced rate of postoperative complications and a shorter length of stay in ICU and hospital.13 (2) This article provides a physiological basis for speculating that such effects of norepinephrine in small doses might be due to a decrease in unstressed volume and are reasonable to expect. (3) Small doses of norepinephrine may achieve adequate haemodynamic status (meaning adequate CO, not blood pressure) with a smaller amount of total fluid infused. This possibly may play an important role in improving the overall peri-operative course. Acknowledgements relating to this article

Assistance in preparation of the manuscript: none.

Sponsorship and financial support: none.

Conflicts of interest: none.

This manuscript was handled by Michelle S. Chew.

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