04RC2

Rational use of vasoactive drugs

Michael Haney
Institute for Surgical and Perioperative Science, Anesthesiology and Intensive Care Medicine, Ume University and Clinical Department
of Anesthesia and Intensive Care Medicine, The University Hospital of Ume, Ume, Sweden

Sunday, 12 June 2011

8:30 - 9:15

Room: Emerald Room

Introduction
In health the autonomic nervous system and peripheral vasculature maintain circulatory homeostasis, particularly with respect to
vital organ perfusion, through rapid reex adaptation of vascular tone and heart function. When there is a circulatory disturbance in
peri-operative or intensive care patients that is more than just transient, attributable to impaired or inappropriate vascular tone, clinicians
rapidly consider treating with vasoactive drugs to correct or support the circulation in order to maintain adequate perfusion of vital organs.
This review will focus on peri-operative or intensive care patient settings particularly when vascular tone is temporarily disturbed, and
when vasoactive treatment is specically considered. It will not specically address the indirect and direct vasoactive aspects of many
anaesthetic drugs.
A vasoactive agent is a drug that is chosen and administered to try to increase vascular tone that is perceived to be too low, or to
decrease vascular tone that is perceived to be too high. Rationality behind the use of such drugs refers partly to the degree to which
clinicians must make assumptions and simplify the ongoing processes in order to respond quickly to a potentially serious circulatory
disturbance. Complete information concerning both vascular volume and regional vascular tone are not always readily accessible to
the clinician, hence the need, sometimes, to make practical decisions based on limited information (and some assumptions). The better
our assumptions, even when the degree of patho-physiological disturbance is not fully known, the better the chance that our choice of
therapies will be rational and best for the patient. The optimal, or most rational, vasoactive treatment is the one where the specic problem in the peripheral circulation is identied and a therapy is chosen which best matches and replaces the deciency, with a minimum of
undesirable side-effects.

Normal vascular tone and regulation

In health, acute control of regional and local blood ow is closely regulated through management of vascular tone by local mechanisms as well as by the autonomic nervous system. Changes in vascular tone occur as part of normal reexes in order to maintain blood
pressure and organ perfusion. In the peri-operative or critical illness situation, these circulatory homeostatic responses can be blunted
[1]. Vascular smooth muscle has only one functional activity - to increase its tone (or not), although regulation of vascular tone is achieved
through a complex system of interactions between endothelial cells, vascular smooth muscle, local pericytes and, in the setting of illness
or injury, other cells. Regulation occurs through second messengers and effects on smooth muscle cell ion channels, resulting in some
degree of vascular smooth muscle tone. As local metabolic need and activity increases, a diverse array of substances are released by
parenchymal cells that lead to reduced local vascular tone and reduced resistance to local blood ow resulting in more blood ow and
more local substrate delivery, as exemplied by the multiple mechanisms involved in the capacity for dramatic increases in coronary ow
related to regulation of coronary vascular tone [2].
Vascular tone is regulated, to some degree, by three mechanisms. Local regulation of vascular tone involves potent coupling of the
by-products of metabolic activity, such as hydrogen ions, to local signaling and effectors. Humoural regulation (the result of autonomic
nervous system activity) involves release of vasoconstrictor or vasodilatory agents that act at a distance including noradrenaline, adrenaline, angiotensin II, vasopressin, endothelin and local products of inammation including bradykinin, histamine and other substances. The

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third mechanism is the traditionally recognized intrinsic or myogenic vascular smooth muscle cell tone, which is independent of neutrally
or humorally mediated signals. A number of ions and their channels are intimately involved in vascular tone, including calcium, potassium,
magnesium, hydrogen ions and carbon dioxide and some anions.
Well-being for a vital organ or organism is threatened if there is an uncoupling of this tight linking between acute local metabolic activity
and acute vascular tone (or ability to increase local ow). Sympathetic nervous system innervation occurs in vessels in most organs, particularly small arteries, arterioles and veins. This is mostly a vasoconstrictor sympathetic input, though some are vasodilatory (adrenaline
also has vasodilatory properties at low concentrations through beta-2 effects). Parasympathetic activity is not prominent in the regulation
of peripheral vascular tone. The vasomotor centre in the brainstem (in the medulla and pons) co-ordinates central reex control of sympathetic and parasympathetic (or vasocontrictive and vasodilatory) balance via the peripheral parts of the autonomic nervous system. The
overall result in health is that there is some resting partial tone or constriction in vascular smooth muscles that is the result of sympathetic
nervous system activity. The autonomic nervous system has the ability to cause a rapid increase (in seconds) in blood pressure if needed
through acute vasoconstriction (both arteries and veins) as well as through effects on the heart. When these reexes are blunted or not
adequate to maintain minimal adequate blood pressure, clinicians consider treatment with, among other things, vasoconstrictor agents.
Peripheral vascular tone can also be too high. When unreasonably high vascular tone leads to hypertension, either through an inappropriately overactive autonomic nervous system or through other means (essential hypertension as an example), vasodilatory therapy
may be indicated. Dangerously high blood pressure can be an exacerbating factor in heart failure, when part of the neuro-humoral response includes sympathetic nervous system activation including the rennin-angiotensin and aldosterone systems, and blunting of these
effects can be therapeutic. Specic vasodilator therapy may be indicated if the heart is stressed by an overload of either chamber pressure or volume. In that case, vasodilator therapy may be used to ofoad the heart and limit further myocardial injury.

The initial treatment of shock

In some peri-operative settings, and for some critically ill patients, shock or a threatened shock state can occur either due to a surgical or critical illness, or an undesirable response to treatment. Shock can be dened as a condition when vital organ tissue perfusion is
not maintained, affecting organ function. Initial therapies or resuscitation involve empirical support of the circulation until a specic area
of circulatory insufciency is identied. The initial empirical therapy is uid resuscitation when inadequate venous return to the heart is
suspected. Then, if aggressive uid resuscitation is not adequate to support the circulation by itself, vasoactive and possibly even inotropic support is added, while the cause of the circulatory collapse is identied. Vasopressor agents will usually lead to an acute increase
blood pressure, and at the same time, increase venous return to the heart. Inotropic agents will increase cardiac output if venous return
to the heart is already adequate.
In the setting of heart failure, aggressive uid resuscitation does not improve the circulation, but may quickly lead to worsening symptoms (for example, exacerbated pulmonary oedema). A reduction of venous return to the heart, by different means, can lead to improved
symptoms, and vasoactive therapy in the form of vasodilators (and even inotropes) may lead to an improved circulation. In summary, the
shock-like state consists of impaired circulatory function on several levels, and assessment of intravascular volume, heart function, vital
organ vascular tone, and the response to vasoactive agents should be part of the clinicians analysis.

Assessment of vascular tone

When the cause of shock may be hypovolaemia, heart failure, non-cardiogenic/obstructive, or mal-distributive (such as sepsis), it is
possible that suboptimal vascular tone contributes to the clinical problem. In peri-operative patients there are also transient or reversible
processes related to the surgical problem or anaesthetic management that can lead sub-optimal vascular tone. When there is prominent
hypovolaemia, uid resuscitation should be instituted before the clinician assesses peripheral vascular function. However, even if the
clinical setting provides a strong indication of how vascular tone might be altered, it is better to perform a direct assessment before starting potent vasoactive therapy.

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Vascular tone is assessed in-vivo by examining the pressure gradient across a vascular bed, together with the ow across the same
vessels, and deriving the resistance. Vascular tone is not the sole component of resistance for blood ow across a vascular bed, but it
is a large component, and a very highly variable component. The variability determining arterial resistance lies largely in the arterioles.
Vascular tone in the systemic venous system lies primarily in venules, where increased vascular smooth muscle tone leads to greater
venous pressure and venous return. Although clinicians may hope that both cardiac output and vascular resistance can be approximated
by blood pressure measurement and little else, this is, unfortunately, not the case. A measurement of cardiac output (and systemic blood
pressure) is necessary in order to derive systemic vascular resistance. Furthermore, when contemplating more than just momentary administration of powerful vasopressors, serial assessments of cardiac output (and vascular resistance) are indicated. Other measurements
that have been proposed in this setting include the arterial-venous gradients for oxygen and carbon dioxide [3] that show some promise
for demonstrating treatment effects during shock states and resuscitation.

Goals for vasoactive therapy

While the overall goal is to prevent or reverse tissue hypoperfusion and related vital organ dysfunction (shock), more specic treatment goals or endpoints for each patient and for each therapeutic intervention need to be chosen to allow careful titration of vasoactive
therapy. The endpoints that can be measured include cardiac output or ow, blood pressure, perfusion pressure, and markers of tissue
well-being including the magnitude of metabolic or lactic acidosis. This is complicated in that ow to organs or within organs cannot be
presumed to be homogeneous. It is possible, and perhaps even common in some forms of shock, that there can be blood ow that does
not contribute functionally to substrate delivery to vital organ parenchyma, in other words a shunt. Therefore, clinicians cannot rely solely
on measured ow and vascular resistance to titrate vasoactive support when there are signs of tissue hypoperfusion and vital organ
dysfunction.
Treatment goals for vasoactive therapy in shock, therefore, are based on a combined assessment of adequacy of ow, of vascular
resistance, tissue perfusion and vital organ function, and reversal of metabolic acidosis caused by the shock state. Specic goals for
cardiac output response during resuscitation have not been widely accepted, though in a setting where cardiac output is relatively low,
and suboptimal venous return is a contributing factor, an improvement in venous return (as a possible result of vasoactive therapy) should
be regarded as a sign of response and clinical improvement. Blood pressure response to vasoactive therapy is the most obvious and
easily observable parameter, and while there are some recommendations [4], there is no clear consensus on absolute blood pressure
goals. While higher vasopressor doses and higher blood pressures can be achieved, it is not clear if mean arterial pressures > 65 mmHg
benet patients [5, 6].
Dangerously high blood pressure in peri-operative or critically ill patients also requires an immediate response from the clinician and
the adoption of appropriate treatment goals [7]. Vascular resistance goals are relatively important when treating heart failure, since it may
be acceptable to tolerate a blood pressure somewhat lower than usual if this is associated with improved cardiac output when vasodilatory therapy is administered [8].

Which vasoactive agent?

While noradrenaline and dopamine (and phenylephrine) are all commonly used potent vasopressors in the setting of shock and are
often subject to powerful local traditions or preferences, it is not clear if there is a clinical difference as far as outcome favouring one agent
over another [9]. Whether these vasopressor agents contribute to acute kidney injury is not yet resolved [10]. There are suggestions in the
shock setting that the kidney may be better with vasopressor support and relatively higher perfusion pressures [11]. Adrenaline has potent
inotropic as well as vasopressor effects at higher doses, and in addition has signicant beta-2 effects. Adrenaline infusion is chosen in
very advanced cases of shock when there is combined heart failure and vascular collapse.
When patients are not responsive to potent adrenergic vasopressors, for example with septic shock when the diminished response
may be caused by several mechanisms [12], there is support for trying a dose of corticosteroids in case the patient has a depressed
hypothalamic-adrenal response. Corticosteroids may improve the vascular response to adrenergic agents [13]. Relative vasopressin depletion has also been implicated in some forms of shock, and vasopressin infusion has been judged to be equivalent to potent adrenergic

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vasopressor support [14]. Other vasopressors, including some vasopressin derivatives such as terlipressin or angiotensin II, are used in
extreme settings to treat refractory hypotension.
Mixed sympathomimetics, including ephedrine, have been popular for many years in peri-operative practice to treat brief episodes
of hypotension related to transient anaesthetic-related sympatholytic effects. However, these agents have modest vasopressor and inotropic effects and are not used in the setting of shock.
Mixed vasodilator/inotropes are sometimes used to treat patients with shock when ventricular dysfunction or heart failure is suspected.
These include dobutamine, milrinone, levosimendan [8]. There is no clear indication that these agents provide a survival advantage to
patients in shock, though there is intense on-going study concerning selected aspects of circulatory failure and these agents. More details of the pharmacological aspects of these vasopressors and inotropes can be found, for example, in tabular form in the an article by
Overgaard and Dzavk [15].
Vasodilators are used to treat acute hypertension, heart disease, and pulmonary hypertension. In the setting of suspected ischaemic
heart disease [16] nitrates or calcium channel antagonists are employed. For hypertension [7], heart failure with normotension or hypertension, or suspected microcirculatory compromise related to vasoconstrictors [17] a variety of vasodilator agents can be considered,
including nitrates, alpha-2 adrenergic agonists, calcium channel antagonists, ACE inhibitors, and angiotensin-II receptor blockers.

Special cases in peri-operative medicine

There are a number of special cases that are specic to peri-operative medicine and anaesthetic practice, and each has its own traditions and guidelines which are beyond the scope of this review. These include, among others, different forms of hyperadrenergic status
including phaeochromocytoma, surgically indicated intra-operative hypotension, vasoactive treatment related to local vascular disease
(for example, aneurysms), stroke, traumatic brain injury, and pre-eclampsia, to name a few. Vasoactive drugs are often used to counteract
transiently blunted circulatory homeostatic reexes or the sympatholytic effects of anaesthetics which work either centrally or regionally,
though there are no widely accepted guidelines for the choice of vasoactive agent in this setting. In relation to vasoactive treatment of the
maternal/fetal circulation and hypotension related to spinal anesthesia or oxytocin during Caesarean section delivery, it has been widely
recognized that the commonly employed vasopressors - phenylephrine and ephedrine - have different haemodynamic patterns of response. Correctly dosed phenylephrine may be preferable, particularly with regard to blunting the haemodynamic effects of oxytocin [18].
While discussion of chronic treatment of pulmonary arterial hypertension with endothelin blockers and phosphodiesterase type 5 inhibitors is beyond the scope of this review, acute right ventricular failure is a condition that can lead to circulatory collapse. The principles
for treatment of acute right ventricular failure are similar to that of circulatory collapse, in that after being certain that the underlying disease is treated, there is a careful titration of intravascular volume followed by treatment using vasopressors, inotropes, or inodilators [19].

Potential pitfalls of vasoactive therapy

While peri-operative clinicians are quick to treat circulatory insufciency - often with short-term circulatory support and rapid resolution
of the problem, persistent impairment of circulatory function is more complex. While the initiation of vasoactive therapy may be empirical,
based on relatively simple clinical indicators and with help from general guidelines, the specic clinical context for each patient is very
important, and individualization of vasoactive therapy is necessary. The clinician must treat aggressively, but also be aware that there can
be both benet and harm associated with use of many of the potent vasoactive treatments that are available [20].
One issue is which aspect of the circulation will the clinician choose to observe for improvement or deterioration; and, with which
assessment tools? For example, while much of this review has focused on support for the circulation during vasodilatory shock with vasopressors, it has been recognized for many years that vasodilators in the same setting may in also improve the circulation, particularly
when considering the problems of shunting in the microcirculation and the driving pressure at the capillary level [21]. While central circulatory parameters may improve with vasoactive support, there may or may not be improvement in microcirculatory function [17]. To what
extent therapeutic decisions should be based on microcirculatory ndings is, so far, unclear.

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Key learning points

Appropriate treatment of acute circulatory insufciency must rst include an attempt to identify the problem and characterize the
decit in the circulatory system
An initial, sometimes empirical and temporary choice of vasoactive agent is needed to start aggressive therapy when the circulation is dangerously inadequate
Vigilance and rational treatment goals are needed in order to provide the best vasoactive therapy
Finally, aggressive treatment of the underlying problem is needed in order to help the patient reduce their need for vasoactive support

References
1. Peters J, Mack GW, Lister G. The importance of the peripheral circulation in critical illnesses. Intensive Care Medicine 2001; 27:
1446-58.
2. Duncker DJ, Bache RJ. Regulation of coronary blood ow during exercise. Physiology Review 2008; 88: 1009-86.
3. Futier E, Robin E, Jabaudon M, et al. Central venous O2 saturation and venous-to-arterial CO2 difference as complementary
tools for goal-directed therapy during high-risk surgery. Critical Care 2010; 14: R193.
4. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis
and septic shock: 2008. Intensive Care Medicine 2008; 34: 17-60.
5. Jhanji S, Stirling S, Patel N, Hinds CJ, Pearse RM. The effect of increasing doses of norepinephrine on tissue oxygenation and
microvascular ow in patients with septic shock. Critical Care Medicine 2009; 37: 1961-6.
6. Dubin A, Pozo MO, Casabella CA, et al. Increasing arterial blood pressure with norepinephrine does not improve microcirculatory
blood ow: a prospective study. Critical Care 2009; 13: R92.
7. Slama M, Modeliar SS. Hypertension in the intensive care unit. Current Opinions in Cardiology 2006; 21: 279-87.
8. Task Force for Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of European Society of Cardiology, Dickstein
K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008:
the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology.
European Heart Journal 2008; 29: 2388-442.
9. De Backer D, Biston P, Devriendt J, et al. Comparison of dopamine and norepinephrine in the treatment of shock. New England
Journal of Medicine 2010; 362: 779-89.
10. Bellomo R, Wan L, May C. Vasoactive drugs and acute kidney injury. Critical Care Medicine 2008; 36(Suppl): S179-86.
11. Redfors B, Bragadottir G, Sellgren J, Swrd K, Ricksten SE. Effects of norepinephrine on renal perfusion, ltration and
oxygenation in vasodilatory shock and acute kidney injury. Intensive Care Med 2010 (Epub ahead of print).
12. Levy B, Collin S, Sennoun N, et al. Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside.
Intensive Care Med 2010; 36: 2019-29.
13. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis and septic shock in adults: a
systematic review. Journal of the American Medical Association 2009; 301: 2362-75.
14. Maybauer MO, Walley KR. Best vasopressor for advanced vasodilatory shock: should vasopressin be part of the mix? Intensive
Care Medicine 2010; 36: 1484-7.
15. Overgaard CB, Dzavk V. Inotropes and vasopressors: review of physiology and clinical use in cardiovascular disease. Circulation
2008 118: 1047-56.
16. Poldermans D, Bax JJ, Boersma E, et al. Guidelines for pre-operative cardiac risk assessment and perioperative cardiac
management in non-cardiac surgery: the Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac
Management in Non-cardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of
Anaesthesiology (ESA). European Journal of Anaesthesiology 2010; 27: 92-137.
17. Boerma EC, Ince C. The role of vasoactive agents in the resuscitation of microvascular perfusion and tissue oxygenation in
critically ill patients. Intensive Care Medicine 2010; 36: 2004-18.
18. Dyer RA, Reed AR, van Dyk D, et al. Hemodynamic effects of ephedrine, phenylephrine, and the coadministration of
phenylephrine with oxytocin during spinal anesthesia for elective cesarean delivery. Anesthesiology 2009; 111: 753-65.
19. Lahm T, McCaslin CA, Wozniak TC, et al. Medical and surgical treatment of acute right ventricular failure. Journal of the American
College of Cardiology 2010; 56: 1435-46.
20. Mongardon N, Dyson A, Singer M. Pharmacological optimization of tissue perfusion. British Journal of Anaesthesia 2009; 103:
82-8.
21. Buwalda M, Ince C. Opening the microcirculation: can vasodilators be useful in sepsis? Intensive Care Medicine 2002; 28: 120817.

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