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Editorial

Using small doses of norepinephrine or phenylephrine during the peri-operative period

Gelman, Simon

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European Journal of Anaesthesiology: July 2022 - Volume 39 - Issue 7 - p 571-573
doi: 10.1097/EJA.0000000000001697
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A few recent studies in rats and mice demonstrated that the use of norepinephrine during experimental haemorrhagic shock was associated with a decrease in the total amount of infused fluid, increased fluid responsiveness and improvement in the course of haemorrhagic shock.1–3 Additionally, one of those studies demonstrated that the microcirculation within the intestinal villi was preserved when norepinephrine was added to the treatment,3 which should be beneficial. How could norepinephrine (or phenylephrine) be useful to surgical patients? Reviewing some physiological concepts may help answer this question. The purpose of this Editorial is to discuss the physiological background for future studies addressing the questions related to the proposed treatment.

There are only two clinical studies that used infusions of an α-adrenergic vasopressor during surgical intervention. Although the design of one study4 did demonstrate that the patients were not noticeably harmed by the infusion, it did not allow any conclusions concerning a beneficial effect of the norepinephrine infusion. The second study also showed no harmful effects of norepinephrine but it did show that the low doses of the vasopressor increased fluid responsiveness.5 A lack of fluid responsiveness may lead to overloading, whereas an increase in fluid responsiveness provides conditions for a more accurate assessment of a patient's need for fluid. Thus, the physiological effects of low concentrations of norepinephrine infusion may be beneficial to our patients.

Functions of adrenoreceptors

Effect of α-adrenoreceptor agonists

The activation of α-1 and α-2 adrenoceptors leads to constriction of the vessels that contain the receptors, a decrease of local blood flow possibly leading to tissue hypoxia, and to a decrease in cardiac output. Constriction of compliant veins shifts blood downstream into larger veins, increasing preload and cardiac output.6–9

However, a continuing gradual increase in concentration of the infused α-1 agonist methoxamine resulted in an initial increase followed by a decrease in cardiac output.10 The most plausible explanation for these observations is that the small doses of methoxamine led to constriction of compliant veins, shifting the blood volume downstream and leading to an increase in preload and cardiac output.6–9 Further increasing the methoxamine dose led to constriction of arteries, hypo-perfusion of tissues fed by those arteries, and a decrease in cardiac output.10,11

After initial small doses have already constricted veins, further constriction becomes nearly impossible, whereas the larger doses additionally constricted arteries, decreasing flow, venous return, and cardiac output. This is why norepinephrine or phenylephrine infusion may decrease or increase cardiac output, depending on the dose used.11

Thus, stimulation of α-adrenergic receptors may increase the venous transmural pressure thereby converting some of the unstressed volume, which is haemodynamically inactive, into stressed volume thus increasing venous return and cardiac output. However, activation of α-adrenergic receptors within the arterial wall may constrict arteries and decrease flow through tissues, decreasing venous return and cardiac output (Fig. 1). The final result would depend on the dose of the α-adrenergic agonist used: the higher density of α-adrenergic receptors in the veins than in the arteries, would make small doses constrict the veins, while large doses would affect both veins and arteries, but the decrease in flow through tissues would lower overall flow (venous return and cardiac output), leaving little room for blood volume to shift from the venous system to the systemic circulation.

F1
Fig. 1:
The effects of adrenergic agonists on hemodynamics.

Effect of β-1 and β-2 adrenoreceptor agonists

Elegant experiments on dogs have shown that isoproterenol (β-1 and β-2 adrenergic agonist) decreased splanchnic and splenic volumes and increased cardiac output.11,12 The same dose of isoproterenol, given after injection of metoprolol (β-1 adrenergic antagonist), had the same haemodynamic effect, including a similar decrease in the splanchnic and splenic volumes. However, isoproterenol administered after injection of propranolol (both β-1 and β-2 antagonist) decreased splanchnic and splenic volumes only very mildly and affected cardiac output very little. This experiment shows that the haemodynamic effect of isoproterenol results mainly from shift of blood volume from the splanchnic vasculature to the systemic circulation6,12 and it is exerted through the β-2 adrenergic receptors and the vasculature rather than through the β-1 receptors and the heart.10,11

Whenever norepinephrine is used, β-2 adrenergic receptors within the liver and hepatic veins are activated, decreasing their tone and facilitating the transfer of blood volume from the splanchnic organs into systemic circulation, reinforcing the increase in venous return and cardiac output caused by a small dose of the α- adrenoreceptor agonist.

If infused fluid does not increase stroke volume and cardiac output, it probably means that the fluid did not increase venous transmural pressure and flow within the venous system. This is almost always the case during the time interval between the start of the infusion and an increase in stroke volume. Such excess of fluid may increase transmural pressure and flow, increasing stroke volume, but may reflect some degree of overloading. Continuous infusion of fluid may aggravate overloading, possibly leading to well-known complications such as tissue oedema, pulmonary dysfunction, leakage of gastrointestinal anastomoses, impeded healing and others. An increase in fluid responsiveness, by using norepinephrine or phenylephrine in this case, may lead to a situation in which a smaller total amount of blood in the body is needed to achieve adequate haemodynamic improvement.

An increase in contractility per se can only increase ejection fraction for a short time as the heart does not make blood, it just passes on blood that comes from the venous return. Therefore, preload must be increased to sustain an increase in stroke volume. The α-adrenoreceptor agonist does this by constricting compliant veins. The β-1 agonist may be very effective in conditions of cardiac failure when the contractility is reduced and the preload is increased, but when there is no cardiac failure (i.e. no increased preload) and contractility is normal, the β-1 agonists are less effective. To achieve a sustained increase in stroke volume, blood volume (preload, an increase in stressed volume) is needed.

However, activation of α-adrenergic receptors within the arterial wall with a larger dose of the α-adrenoreceptor agonists may constrict arteries and decrease flow through tissues, thereby decreasing venous return and cardiac output (Fig. 1). The final result would depend on the dose of the α-adrenergic agonist used. Due to the higher density of α-adrenergic receptors in the veins as compared with the arteries, small doses would mostly affect veins, assuring the volume shift and thus an increase in venous return, preload, and cardiac output. Large doses would affect both veins and arteries, but the decrease in flow through tissues would lower overall flow (venous return and cardiac output), leaving little room for a blood volume shift from the venous system into the systemic circulation. Thus, small doses of norepinephrine or phenylephrine may improve the peri-operative course during noncardiac surgery.

The baseline tone of the vessels and overall volume status can play important roles in the general haemodynamic response to changing situations. For example, a hypovolemic patient could already have constricted veins; further constriction of compliant veins would not lead to an additional significant blood volume shift, because that mechanism of blood volume mobilisation is already exhausted. Maintenance of blood pressure could only be achieved by constriction of the arteries, without any additional blood volume shift from an already depleted blood reservoir.

Spinal and epidural anaesthesia produce vasodilation that impedes the shift of blood volume from the reservoirs (splanchnic vasculature is the main one) into the systemic circulation. The usual treatment is an infusion of fluid and/or administration of a vasopressor. Infusion of a large amount of fluid would be less than optimal because after anaesthesia, the vascular tone recovers and the body may end up with a significant volume of unnecessary fluid. Fortunately, for most of our patients, such infusions are usually relatively small, and it is mainly patients who have renal and/or cardiac failure who may be at serious risk.

The main purpose of this Editorial is to provide a physiological basis for designing studies that would answer the question whether small doses of these two drugs could provide clinically important benefits to our patients. The work by Nakamoto et al.5 may serve as an illustration of the probable usefulness of such an approach.

Summarising, the small doses of norepinephrine or phenylephrine given during the peri-operative period of noncardiac surgery may increase fluid responsiveness, improve conditions for the assessment of volume status, prevent overloading, and optimise haemodynamic status (stroke volume, cardiac output) with a smaller blood volume. Only a couple of years ago in the EJA, the idea was expressed that Goal-directed Hemodynamic Therapy was not dead.13 The use of a continuous infusion of small dose norepinephrine or phenylephrine may represent a next step in the improvement of our peri-operative care. Probably norepinephrine would demonstrate some advantage over phenylephrine because of an additional effect on β-2 adrenergic receptors that may enhance the conversion of unstressed to stressed volume to achieve the desired haemodynamic effects with a smaller blood volume.11

Acknowledgements relating to this article

Assistance with the article: none.

Financial support and sponsorship: none.

Conflicts of interest: none.

Comment from the Editor: this Editorial was checked by the editors but was not sent for external peer review.

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