Introduction

In health the autonomic nervous system and peripheral vasculature maintain circulatory
homeostasis, particularly with respect to vital organ perfusion, through rapid refl ex 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 perioperative or intensive care patient settings particularly when vascular tone is temporarily
disturbed, andwhen vasoactive treatment is specifi cally considered. It will not specifi cally
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
specifi c problem in the peripheral circulation is identifi ed and a therapy is chosen which best
matches and replaces the defi ciency, with a minimum of undesirable side-effects.
Normal vascular tone and regulation
In health, acute control of regional and local blood fl 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 refl exes 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 fl ow resulting in more blood fl ow and more local substrate delivery, as exemplifi
ed by the multiple mechanisms involved in the capacity for dramatic increases in coronary fl 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 infl ammation including bradykinin, histamine and
other substances.

The 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 fl 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 refl ex
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 refl exes 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. Specifi c 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 offl oad 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 defi ned 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 specifi c area of circulatory insuffi ciency is identifi ed. The initial empirical
therapy is fl uid resuscitation when inadequate venous return to the heart is suspected. Then, if
aggressive fl 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 identifi ed.
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 fl 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, fl 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.
-3Vascular tone is assessed in-vivo by examining the pressure gradient across a vascular bed,
together with the fl ow across the same vessels, and deriving the resistance. Vascular tone is not
the sole component of resistance for blood fl 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 specifi c 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 fl ow, blood pressure, perfusion
pressure, and markers of tissue well-being including the magnitude of metabolic or lactic
acidosis. This is complicated in that fl 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 fl 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 fl 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 fl ow, of vascular resistance, tissue perfusion and vital organ function,
and reversal of metabolic acidosis caused by the shock state. Specifi c 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 benefi t 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 signifi cant 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 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 perioperative 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 specifi c 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 refl exes 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 insuffi ciency - 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 specifi c
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 benefi t 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 fi ndings is, so far, unclear.
Key learning points
Appropriate treatment of acute circulatory insuffi ciency must fi rst include an attempt to
identify the problem and characterize the
defi cit 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