A Rational Approach to
Use of Inotropes Adrenergic Agents
- Why
use inotropes?
- First, normal circulatory homeostasis
- A list of goals
- The
failing pump
- Circulatory
failure
- Supply
dependency & other "myths"
- Limited
options - receptors & drugs
- Golden
minutes, hours .. and
centuries?
- A
practical approach
|
List of Abbreviations |
|
|
pHi |
Gastric intramucosal pH |
|
|
Trans-(o)esophageal echocardiography |
|
CVP |
Central Venous Pressure |
|
PCWP |
Pulmonary Capillary Wedge Pressure |
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NO |
Nitric oxide |
|
DO2 |
oxygen delivery |
|
VO2 |
oxygen consumption |
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ShvO2 |
Hepatic venous oxygen saturation |
|
A note for
Americans. We still favour the word adrenaline instead of
"epinephrine", and use noradrenaline for norepinephrine. Get
used to them - and, yes, we know that the international trend is towards using
the word epinephrine. Do we care? |
|
Inotropes are used to support the failing heart. The heart
may fail in several circumstances, and a variety of drugs may be used to
support it. Sometimes we encounter difficulty in distinguishing between drug
properties that support the heart and those that affect the peripheral
circulation. All in all, a vast fog of confusion overshadows the everyday use
and abuse of inotropes. We will try and dispel this fog, and engender in the
mind of the reader a practical approach to inotropic support. To do this, we
first need to understand some basic physiology.
Normal circulatory
homeostasis
The circulation exists to provide the tissues with oxygen
and nutrients, and to remove waste products. Over hundreds of millions of
years, an ingenious system has evolved - the cardiovascular system maintains a
head of pressure, and each organ diverts
flow to serve its needs. If the pressure decreases somewhat, then two
things happen:
- Local tissue autoregulatory mechanisms come into play;
- The cardiovascular system re-adjusts things to restore the blood
pressure to near its previous set point.
Local tissue autoregulatory mechanisms
Initially, if
the mean pressure in the vessels perfusing a tissue drops, the vessels in the
tissue dilate. This vasodilatation preserves blood flow to the tissue, and its
metabolic demands are still met. Down to a pressure of about 75% of normal,
this miraculous autoregulation still preserves tissue flow. Below this
point, tissue perfusion drops off progressively. This property of most tissues
in the body is shown in the following diagram.
Note how flow
changes little when we vary pressure from the normal level (N) down to the
lower autoregulatory threshold (LL) or indeed the upper limit (UL). Below or
above these limits, the tissue fails to autoregulate. This concept of tissue
autoregulation is vital.
Even below a pressure of 75% of normal,
the tissue tries its best to preserve its metabolic functions. It does this by
extracting more nutrients and (especially) oxygen from that small quantity of
blood still reaching it, and excreting wastes into this blood as it passes
through. Only at very low levels of tissue perfusion, does the tissue
"give up", and resort to anaerobic metabolism, with a drop in tissue
pH, and production of lactate.
Cardiovascular system compensation and failure
We know that
blood pressure depends on cardiac output and the resistance of the vessels into
which the heart is pumping. A drop in either will decrease the mean pressure in
the system. A variety of intravascular sensors exists to sense such a drop. We
can see that the body might compensate for a pressure drop in two ways - it
might increase the cardiac output, or it might increase the total peripheral
resistance of the system. In fact, when faced with a drop in pressure, compensatory
mechanisms exist to both raise peripheral resistance and increase cardiac
output. These short-term mechanisms are mainly mediated by the sympathetic
nervous system.
You can also deduce that a substantial
drop in pressure is ominous: It signifies one or more of the following:
- Normal compensatory afferent or efferent reflexes have failed;
- The heart cannot further increase its output; or
- The peripheral vasculature is inappropriately vasodilated, not
responding adequately to cries from the sympathetic nervous system that it
must vasoconstrict.
In
other words, a substantial drop in blood pressure signals failure of
compensatory mechanisms that maintain blood pressure. If such a drop is large and sustained,
it may mean the death of the organism. Little wonder that cardiac patients with
pump failure, or septic patients with severe
hypotension have such a poor prognosis! One of the main reasons to administer
inotropes is therefore to counteract or prevent the terrible effects of
hypotension in such patients.
But these are not the only patients we
see who are afflicted by failure of their cardiovascular system to provide
sufficient pressure to perfuse their organs. There are others. They include a
vast number of patients who have a definable, reversible cause for their
hypotension. Broad groups include:
- Persons who have lost intravascular volume - the heart has little
blood to pump;
- Persons with extrinsic causes of pump failure - for example those
with cardiac tamponade, or tension pneumothorax;
- Those with intrinsic pump failure due to a variety of causes -
weakness of the heart muscle, valvular lesions, or occasionally even
abnormalities of the conducting system;
- Those with peripheral circulatory failure, due to either loss of
venous or arterial tone.
When faced with
hypotension, always think of these groups and ..
|
Remember: Always look for a reversible
cause for hypotension. |
We will in turn look at the various
causes of hypotension, and the role of inotropes in each of them. But first, a word of caution. If you take a dog and acutely
remove sufficient blood from its circulation to drop mean arterial pressure to
say forty percent of normal, and then .. wait .. and then re-infuse the blood after say three hours, after an
initial recovery, the dog will die. Despite return of its blood, mechanisms
will be set in place that put it on the road to irreversible cardiovascular
collapse. It is this that we wish to avoid in our patients, and it is
immediately obvious that the following are all important:
- Time is of the essence;
- If the major problem is one of fluid loss, and you get in soon
enough with your fluids, you may not need inotropes. Think of the dog.
- Adequate fluid resuscitation is vital, but may not be enough,
especially if there have been delays;
- We need to define end points for any resuscitative measures that we
undertake.
In the following
sections, we talk about circulatory failure and inotropes in the context of:
- Resuscitative end-points;
- The failing pump;
- The failing peripheral vasculature;
- Inotropes in other circumstances.
Resuscitative
end-points: A list of goals
In any hypotensive patient, we should be able to establish a
short list of achievable goals. The following short list seem
reasonable:
- Find and treat the cause, if
possible;
- Establish adequate volume
resuscitation;
- Establish an adequate blood
pressure;
- Ensure organ function.
Adequate volume
resuscitation
Unfortunately, here we have a problem. What is
"adequate fluid resuscitation"? My short answer is that nobody knows!
Let's look at a few possible criteria:
- Adequate
central venous pressure
- Adequate
pulmonary capillary wedge pressure
- Adequate
left-sided filling as assessed by transthoracic echocardiogram
- Adequate
left-sided filling as assessed by trans- oesophageal echocardiogram
("
- Various
metabolic parameters, and indices of tissue perfusion (pHi, lactate)
- Evidence of
adequate vital organ function
What a
mess! Each of the above has its failings. Central venous pressure may for example
be low in someone with gross overfilling of the left side of the heart, if they
have left-sided heart failure. We know that there is extremely poor
correlation between pulmonary capillary wedge pressure and good measures of
left-sided filling such as echocardiography. [See for example Jardin F et
al, Int Care Med 1994 20 550-4 for an example of how really bad the correlation
is] "Metabolic parameters" too have their up and down-sides.
And, to make us even more miserable, our assessment of function in vital organs
such as the brain, kidney, liver, bowel and heart is often sorely lacking.
You will
also immediately note that there is a major problem in the above - if we
are waiting for our fluid resuscitation to become "adequate", might
we not miss the boat, and fail to start inotropes timeously? Remember our dog?
The real questions then are:
|
1.
When do we cut back on our fluid resuscitation? |
|
2.
When do we start inotropes? |
I know
of no definitive answer to the above. My partial answer would be:
|
1. Aim
for a reasonable CVP, or if you have the expense and luxury of a Swan-Ganz, a
reasonable PCWP; or better still, adequate filling on echocardiogram. Some
practical suggestions occur right at the end of this web page. |
|
2.
Start inotropes SOON, as discussed below. |
An adequate blood
pressure
We know that in the normal organism, a whole host of
homeostatic mechanisms exist to maintain the head of pressure perfusing the
tissues. If systemic pressure drops below a certain level, then tissues will
receive insufficient flow, and tissue autoregulatory failure will
follow. The body will move heaven and earth to prevent this state, and so a
substantially lowered arterial pressure represents failure of each and every
homeostatic mechanism.
We
therefore need to know the individual autoregulatory threshold for that
organism before we can apply any sort of rule. If we know a person's
pre-morbid blood pressure then we can confidently predict that reduction in
mean pressure of over about 30% will result in a substantial decrease in
perfusion of vital organs such as the brain. Lower values will cause gross
dysfunction! It is not simply enough to assume that the blood pressure was say
120/80, giving a mean of about 93 mmHg. In hypertensives, the curve is shifted
to the right. This has been well shown in the brain [
This
immediately gives the lie to studies that arbitrarily choose a
"target" mean arterial pressure as their resuscitative goal (many
studies in the literature) without reference to the pre-morbid mean arterial
pressure of the subject. Even if you previously recorded just one blood
pressure on that patient, and the value was 140/90, (giving a mean arterial
pressure of 90 + (140-90)/3 = 107 mmHg), it is
clearly unwise to be satisfied with a mean arterial pressure of say 75 mmHg as
your end point, with vital organs poised on the brink of autoregulatory
failure.
This
also suggests that if we have absolutely no idea of what the patient's
"normal" blood pressure runs at, we should be generous in our
estimates, especially if the person comes from a population or age group where
hypertension is prevalent, or there is other evidence of hypertension, such as
funduscopic changes, or left ventricular hypertrophy.
To me
this is a convincing argument that, in the absence of evidence to the contrary
(prior lowish blood pressures, no history of hypertension, normal funduscopy,
etc) we should perhaps ..
|
Aim
for the magic target of:
|
Why do I
choose 100mmHg? This allows us to cover a fairly substantial range of
pressures, and is often a realisable goal. Think about it - whether the patient
normally has a mean arterial pressure of 70mmHg (say a blood pressure of 90/60)
or one of 120mmHg, we will probably still be keeping their pressure within the
autoregulatory range of their vital organs! Note however that although lowering
the pressure below the autoregulatory threshold almost certainly implies
inadequate perfusion, the converse is not necessarily true - good
pressure need not imply adequate perfusion!
Remember
too that the autoregulatory threshold of 70% of the usual mean is for normals -
unfortunately, similar figures do not exist for the critically ill. If
anything, we should assume that in such patients tissue autoregulation is less
rather than more exact, with a consequent narrower range of tolerance for low
pressures.
Assessing organ function
A short list of criteria for assessing organ function could
include the following:
- Again, adequate perfusion pressure.
It is completely unrealistic to expect organs to function without adequate
perfusion. In other words, do not expect the brain, heart, kidneys and
other vital viscera of your (unknown to you) previously hypertensive
patient to function superbly if their mean arterial pressure is now 70% of
prior values. It may require extensive detective work on your part to
establish this rather special cutoff point,
otherwise you may just kill your patient. Remember that if the venous
pressure is raised (as may occur in the so-called "abdominal
compartment syndrome" where intra-abdominal pressure may exceed
30mmHg, or with intracranial hypertension) the venous pressure should be
subtracted from the mean arterial pressure to get an idea of the perfusion
pressure in organs exposed to this abnormal venous pressure.
- Good brain function. It is perhaps
symptomatic of brain failure on the part of the physician, if he neglects
the brain of his patient. Adequate brain assessment may be difficult to
achieve. The best way to assess brain function is not by SPECT scanning,
but by having an awake co-operative patient. This
may often not be achievable in ICU, but to needlessly sedate or even paralyse
a patient is clearly a crime of the most base
degree!
- Good heart function. This may be
difficult to assess, but is intimately associated with adequate perfusion.
There is a multiplicity of clinical clues that may provide evidence of
myocardial dysfunction, including (but not limited to) information
provided by the patient (such as anginal chest pain), and features of left
or right sided failure (such as a third heart sound, fine pulmonary
crackles, and so on..). Further tests such as echocardiography may be
valuable.
- Good kidney function. Remember
that, especially post-operatively, the ICU kidney is a confused organ! One
of the most vexing questions is how to dynamically assess renal function.
Good urine output does not necessarily imply good renal function (although
it may), correspondingly, poor output does not necessarily
imply failure. The elevated mood of the doctor or nurse
who notes an increase in urinary output in response to some arbitrary
pharmaceutical maneuver, may not be matched by long term happiness on the
part of the patient's relatives! Rely more on serial changes in creatinine
levels, with the necessary caveats. Even creatinine clearances in ICU are
not that reliable, and certainly do not get too enthusiastic about a
single creatinine value in isolation.
- Good splanchnic function. The most tricky of all! There is a tenuous web of
hypotheses linking indirect "measures" of splanchnic dysfunction
(Such as low pHi) and possible
poor outcome. Some would go so far as to titrate
resuscitative therapy against pHi, arguing that
a low pHi indicates gut
hypoperfusion, and that this in turn implies bacterial translocation,
which leads to sepsis and death. This has never been shown: to prove this
frail hypothesis, we have to show that gastric intramucosal pH correlates
very strongly with hypoperfusion throughout the gut, especially in the
colon where the major reservoir of bacteria is found, or we have to use
colonic intramucosal pH. Then we must show that this hypoperfusion in turn
results in breakdown of mucosal barriers and translocation (which
certainly occurs in rats, but is rather questionable in man), and that
this in turn results in morbidity and mortality. All rather suspect! The
best test of gut function is that it works - once adequate resuscitation
has been established, there is rarely a reason not to feed
enterally.
- Good overall metabolic function. This is the most difficult to
assess. Don't rely on one value, and especially don't rely too heavily on
magic numbers. For example, a venous lactate value of "x" in
septic shock might mean something completely different in a patient
recovering from haemorrhagic shock. Serial changes in lactate levels are
more important than isolated levels, and progressively increasing levels
have an ominous significance. [ Peretz DI et al, Ann NY Acad Sci
1965 119 pp1133-41; Weil MH & Afifi AA, Circulation 1970 41 989-1001;
Vincent JL et al, Crit Care Med 1983 11 449-51; Bakker J & Vincent JL,
J Crit Care 1991 6 pp152-9; Bakker J et al, Crit Care Med 1992 20 S56 ]
It has even been claimed that lactate is a better predictor of outcome of
septic shock that are VO2 and DO2 [Bakker J et al, Chest 1991 99
pp956-62 ], which may not be difficult,
given the controversy about the latter. Experimentally, endotoxin boluses
can increase lactate levels before tissue hypoxia is evident [Vincent
1995], which however suggests that we should exercise caution
in interpreting high lactate levels. Rather look at the overall picture,
and see each value and trend in the context of the whole patient!
This seems to be the most clear
indication for the use of inotropic support. If the cardiac pump has failed,
then surely the correct approach is to give something that will stimulate
contractility? There are however two situations where this pump fails:
- acutely, and
- chronically.
We now know that in chronic heart failure, perhaps the worst
thing we can do in the long term is to beat the heart further with inotropes -
the only approach that has consistently shown benefit is the gentle one of
afterload reduction, preferably with an angiotensin- converting enzyme
inhibitor, or agents with similar effect. A considerable part of this
beneficial effect may be related to the influence of such agents on remodelling
of the heart - paradoxically, the tissues supporting the myocyte may turn out
to be more important than the myocyte itself!
We are
therefore left with the situation of acute heart failure. Here it would seem
reasonable to administer inotropes, at least until that uneasy transition zone
where we lapse into chronic failure (Where we know that inotropy is harmful
overall) - the only problem being that nobody can tell us when this transition
from supposed benefit to near- certain harm occurs! There also seems to be
little consensus on what we should give. The general feeling in acute failure
following on acute myocardial infarction seems to be that agents with
predominant beta-agonism are desirable. The metabolic evidence is all on the
side of advocates of this approach, as agents such as dobutamine appear to have
a favourable side-effect profile, and seem to be minimally damaging to the
myocardium. Adrenaline, in contrast has been
implicated in extension of myocardial infarct size and would therefore appear
to be contra-indicated.
But
wait a bit! Consider the patient that quite literally drops dead in the street.
What does the evidence say there? Quite unequivocally, we read that in the
acute resuscitative situation, adrenaline is the drug! Even worse,
agents such as isoprenaline {isoproterenol} with predominant beta effect are
almost certainly harmful. This presents us with a rather unpleasant dilemma -
if you collapse in the street, we know you will benefit from large doses of
adrenaline, but, god help you, if you collapse somewhat less dramatically in
the coronary care unit, probably the last agent you will receive is that very
same adrenaline. (Perhaps I'm being a little unfair, but this statement should
at least cause momentary concern in those who reflexly administer agents with
predominant beta effect to their acute cardiac patients). Strangely enough it is
also the beta receptor that up-regulates in ischaemic heart muscle, and
is thought to cause problems!
These
contrasting pictures outline what I consider to be the truth - that some, less
ill "coronary" patients may well benefit from beta agonism, while the
sicker, more acute patients may actually be harmed by the very same agents, and
these unfortunates probably need inotropes with alpha effect! Again, a
knee-jerk approach to therapy is the approach of a jerk, and certainly not that
of the thinking physician.
|
Summary:
Problems with treating the failing pump |
|
|
1 |
It seems unwise to lash the chronically failing heart |
|
2 |
When does "acute" become "chronic"? |
|
3 |
When are alpha agonists (a) vital and (b) deleterious? |
The failing peripheral
vasculature
A variety of conditions exist where there appears to be
"failure of the peripheral vasculature", with or without myocardial
depression. This failure is common:
- following on
prolonged haemorrhagic shock, and
- in septic shock.
In both of the above states, there commonly is associated
myocardial depression. The mechanisms by which these two states become
established are probably quite different, and should not be equated. Certain
similarities exist, and the main one is as follows:
|
The
primary treatment of both haemorrhagic and septic shock is fluid repletion |
This is
not to say that fluid replacement is always sufficient therapy, but often in
the hurly burly of fighting over "which inotrope is best", we tend to
forget that without something to pump, a pump will not work. All studies that
use inotropes should first be assessed as to whether their primary goal was
adequate fluid resuscitation. If this primary goal was not met, then all
subsequent conclusions are meaningless.
Where
gross and excessive peripheral vasodilatation is present (as is almost always
the case in septic shock) it seems entirely reasonable to administer agents
that antagonise this vasodilatation. Where there is evidence of (or perhaps
even a suspicion of) impaired heart performance, addition of an agent that
augments such performance seems wise. We will defer discussion of actual agents
until later.
Inotropes in other
circumstances
Supply dependency, supranormalisation
& other "myths"
Discussing normal tissue regulation, we noted that tissues
have to be severely underperfused before they limit their metabolic activity
and seek energy sources other than aerobic metabolism. One might suspect that
this holds good for septic and other critically ill patients, in other words
that oxygen consumption should diminish little with declining oxygen delivery,
until a very low value of delivery is reached.
Unfortunately,
some disagree. For example, Danek et al. found that in some critically ill
patients there appeared to be co-variation of supply and oxygen consumption. [Am
Rev Respir Dis 1980 122 pp387-95 ] This has
been termed "pathological O2 supply
dependency". The implication of Danek's and many subsequent studies is
that supply may be inadequate in some critically ill patients, even if oxygen
delivery appears to be in the normal range, and that
consequently such patients have a metabolic demand that is not being fulfilled.
A hypothesis has been tagged onto this - that increasing supply will improve
tissue function and decrease morbidity and mortality. This has two practical
implications:
- Some patients
may benefit from aggressive attempts at increasing oxygen delivery to
supranormal levels (this is termed "supranormalisation");
- It might be
possible to plot oxygen consumption against delivery for the individual,
and find that level of delivery where the curve flattens out - further
increases in delivery are not met with increases in consumption.
Neither
of the above has held up well to scrutiny.
Supra-normalisation
For some years now, it has been postulated that certain
critically ill patients benefit from aggressive inotropic support. Since the
seminal article of Shoemaker
et al appeared, claiming the benefits of using of a Swan- Ganz catheter to
enhance cardiac output above mere "resuscitative" levels, others have
endorsed (or occasionally even tried to duplicate) this approach, with varying
degrees of failure. Currently, people seem to be shying away from "supranormalisation",
based on the paucity of evidence that it works, [
Gattinoni L et al, NEJM 1995 333 1025-32] and some
articles that suggest it may even increase morbidity and mortality [Hayes
et al, N Engl J Med 1994 330 1717-1722 ].
Titrating supply against demand
The dream of
increasing supply to the point where demand suddenly levels off does not
unfortunately appear to have a strong base in reality! There are several
possible reasons for this:
- It is possible that, the more we lash the cardiovascular system
into a supranormal frenzy, the more demand
increases due to (1) the extra work imposed on the cardiovascular system
itself and (2) unwanted hypermetabolism that results from stimulating
non-cardiac beta-2 receptors. Even non-beta mediated increases in blood
flow to certain organs may result in increased metabolism
[De Backer, et al, Crit Care Med 1993 21 pp1658-64 ; Schlichtig et al J Appl Physiol 1991 70 pp1957-62 ] - Some have even argued that the variation of VO2 and DO2 is a
spurious result of "mathematical coupling" - that a systematic
error in estimating the cardiac output is propogated into calculation of
both DO2 and VO2, creating a false correlation between the two.
Vincent & De Backer have reviewed the
concept of supply dependency [Acta Anaesthesiol Scand 1995 39 S107 pp229-37 ] and, despite some rather tortuous arguments,
conclude probably correctly that "instead of aiming at a given level of
supranormal DO2 in all patients, it is probably more desirable to tailor
therapy according to the needs of the patient at any given time, based on an
assessment of organ system function."
|
Summary: Problems with
supranormalisation |
|
|
1 |
Little
evidence of benefit, concerns about risk |
|
2 |
Poor
standardisation of methodology |
|
3 |
Concerns about
unnecessarily beating the failing organism |
Which inotrope?
Receptors and drugs
It can be seen that in our use of catecholamines as
inotropes, we are limited to a relatively small selection of receptors that we
can stimulate. The main factor difference then between the various inotropes is
their differing potency and efficacy at various receptor types:
|
Receptor
Stimulation by various Catecholamines |
||||||
|
AGENT |
Alpha 1 |
Alpha 2 |
Beta 1 |
Beta 2 |
Beta 3 |
Dopaminergic |
|
Adrenaline |
+++ |
+++ |
++ |
++ |
++ |
- |
|
Noradrenaline |
++ |
++ |
++ |
- |
+++ |
- |
|
Dobutamine |
+- |
- |
+++ |
+ |
? |
- |
|
Dopamine |
++ |
++ |
++ |
+ |
? |
+++ |
|
Dopexamine |
- |
- |
+ |
+++ |
? |
++ |
|
Isoprenaline |
- |
+- |
+++ |
+++ |
+++ |
- |
|
Ephedrine |
+ |
? |
++ |
++ |
? |
- |
|
Phenylephrine |
+++ |
? |
- |
- |
- |
- |
The above table is
extremely simplistic, especially as there are three subtypes of the alpha-1 and
alpha-2 receptors. There are at least two dopaminergic receptors (DA1 and DA2).
Ephedrine also has an indirect action, depending on noradrenaline release for
some of its effects. Dobutamine is a racemic mixture: the (-) isomer is a
potent alpha-1 agonist and is ten times more potent as a beta agonist than is
the (+) enantiomer which is also a potent alpha-1 blocker!! (See Hardman 1996 ).
Source texts differ slightly concerning the effects of various agents at
various receptors, and ideally the above table should contain receptor
affinities and tissue responses for a variety of different tissues. The table
is thus almost useless in its current form.
A wealth of controversy has developed
over the competing merits of the various agents. This has been fuelled by the
prices of the agents - adrenaline and noradrenaline are cheap, while agents
such as dobutamine are rather pricey.
Based on the above, we can identify three
broad groups of agents:
- Predominant beta agonists (dobutamine,
dopexamine, isoprenaline);
- Predominant alpha agonists (phenylephrine)
- Those with mixed beta and alpha effects
(adrenaline and noradrenaline).
A simplistic glance would lead us to
believe that where the heart is failing, and the peripheral vasculature appears
to be in good order, an agent with predominant beta effect (especially a beta-1
selective inotrope) would be a good choice; where there is vasodilatation,
perhaps an agent with alpha agonism is good, and with the combination of
failing heart and dilated peripheral vasculature, we should either give an
agent with mixed effect, or combine agents with alpha and beta effects. Not so!
Controversy rages about this topic, perhaps more so than anywhere else in the
field of intensive care medicine. Claims and counter-claims proliferate. Here
is a brief (and biased) review of the agents.
Dobutamine
As mentioned above, this is considered by many a reasonable choice with
moderate degrees of myocardial dysfunction, especially in the presence of
myocardial ischaemia. Sometimes it fails outright, even in these circumstances.
Many have advocated its use in septic shock - we can find little justification
for this. Dobutamine administered in severe septic shock, even up to doses of
20-30micrograms/kg/minute frequently fails to meet realistic goals in terms of
adequate perfusion pressures, and this is not surprising in view of its
minuscule of alpha agonist effect in the face of the gross peripheral
vasodilatation seen in such patients. According to Leier,
a substantial part of dobutamine's central haemodynamic effects may be mediated
through peripheral vasodilatation!
Some have shown increases in DO2 and VO2 with dobutamine administration [Vincent
JL et al, Crit Care Med 1990 18 pp689-93 ],
and associated improvement in pHi [Silverman et al, Chest 1992 102 pp184-8; Gutierrez et al,
Am J Resp Crit Care Med 1994 150 pp324-9 ] with for example 5
micrograms/kg/min of the same drug. Not everyone agrees, for example Schneider
et al [Circ Shock 1987 23 pp93-106 ]
showed that volume replacement alone restored splanchnic flow in septic pigs
(with doubtamine adding nothing).
Isoprenaline
There seem to be few or no indications for use of this obsolescent drug, with
its nonspecific beta effects.
Dopexamine
Marvellous results have been claimed for this drug, including a 75% reduction
in mortality (22% to 6%) when administered pre-and post-operatively in
high-risk surgical patients. [Boyd O et al, JAMA 1993 270 pp2699-707]
This study involved an extremely mixed bag of patients, and some were admitted
pre-operatively, others only post-operatively. It is not clear why eight
patients in the control group had substantial post-operative haemorrhage
compared with one in the treatment group. Nevertheless, a
study worth reading.
Some researchers have claimed that
"markers of visceral hypoperfusion" such as pHi may be improved by
this agent. [See Smithies et al, Crit Care Med 1994 22 789-95;
Dopamine
The enthusiasm of some groups for this agent appears almost boundless. We
cannot see why. Evidence for its efficacy is limited and contradictory. It is
also relatively expensive. In the past dopamine has been used for:
- "Renal protection". This is a myth. So-called
"renal-dose" dopamine has never been shown to protect the kidney
or improve outcome - in fact, it may increase renal energy use and be
deleterious. It is traditionally taught that low dose dopamine minimal
alpha or beta effects, but this is clearly not the case in some patients,
for example, hypertensive patients may have a marked pressor response to
low doses of dopamine, or indeed other pressor agents. (We have known for
years that any person with increased arterial wall/lumen ratio will have a
steeper pressure response curve to agonist agents [Sivertsson R
& Olander R, Life Sci 1968 7.1 pp1291-7 ] )
- Inotropic support in septic shock. Unfortunately, the dopaminergic
agonist effect may here be harmful, although there is little truly
convincing evidence either way. Despite increasing total splanchnic blood
flow, dopamine may decrease mucosal blood flow, potentially causing harm [Giraud
GD & MacCannell KL, J Pharm Exp Ther 1984 230 pp214-20
; Pawlik W et al, Ref 79 of Meier-Hellmann
& Reinhart 1995 ], but this is probably an alpha
adrenergic effect, shared with adrenaline! Whether this effect is
clinically relevant remains to be seen.
Adrenaline
This is our initial agent of choice in a variety of conditions, particularly in
septic shock. Many people would disagree with this choice, for a variety of
reasons. Some claim that splanchnic perfusion is impaired if adrenaline is
used. We would answer that in our opinion this is not the case if the
patients have been adequately resuscitated, but hard evidence is lacking. In
cases where the peripheral vascular resistance remains low in the face of high
doses of adrenaline (say, over 0.5 micrograms/kg/min), we would add a pure
alpha agonist such as phenylephrine to achieve adequate vasoconstriction.
Antagonists of adrenaline use for septic
shock include Meier-Hellman
& Reinhart (1995), who have done a fair amount of work on hepatic
venous oxygen saturation. They describe 'very preliminary' results (n=3)
suggesting that adrenaline is bad news for ShvO2, and have followed this up with a report
(n=8) comparing adrenaline to dobutamine + noradrenaline, that also knocks
adrenaline [Crit Care Med 1997 25 pp399-404 ],
as do Levy et al [Intens Care Med 1997 23 pp282-7 ].
Noradrenaline
Use of this agent is still a vexing question - noradrenaline, has been used to induce
renal failure in animals, [Mills et al, Am J Physiol 1960 198 p1279 ] and many authorities thus avoid it, although
it has been used in extremis, sometimes with startling success (even combined
with dopamine)! Meier-Hellmann
& Reinhart (1995) describe various studies of noradrenaline which show
conflicting and indeed confusing results. Paul Marik, for example, showed
improved pHi with
noradrenaline administration when compared with dopamine! Meier-Hellman &
Reinhart prefer the combination of noradrenaline + dobutamine to adrenaline.
Regional Perfusion
The effects of the various agents on
regional perfusion may be extremely important. Experimental results
obtained on animals or normal humans may not be relevant in the septic state.
Inter-individual variation and pre-existing disease (for example hypertension)
may also play a role. The modifying effect of septic shock on regional
perfusion may also be complex:
Some studies have even shown that
baseline splanchnic perfusion is increased in septic patients [Dahn
MS et al, Surgery 1987 101 pp69-80 ;
In contrast cerebral autoregulation
appears to be preserved in patients with sepsis [Matta BF & Stow PJ,
B J Anaesth 1996 76 790-4]].
Effects on the Heart
Our traditional
view that the inotropic properties of the heart are mainly dependent on beta-1
receptors is probably inaccurate. More evidence is emerging that there are
beta-2 receptors in the myocardium, and that the large number of alpha
adrenergic receptors there may also play an inotropic role. Also of interest is
the rapid down-regulation that occurs with chronic stimulation of beta
receptors - this does not appear to occur to the same degree with alpha receptors.
An added concern is the role of the beta-3 receptor, which appears to (a) be
present in the normal myocardium (b) to result in negative inotropy when
stimulated, and (c) to lack the normal beta mechanisms for down regulation! [Gauthier C et al, J Clin Invest 1996 98 pp556-62, worth a
read!]
Which agent?
Actual studies
comparing the various inotropes have usually been performed on small numbers of
patients, and have generally been contradictory. It may be that certain agents
have more favourable effects on the perfusion of certain vital organs, and this
may even translate into improved outcome in some patients, but the evidence
supporting most assertions of this nature is very scanty. What should we then
do?
|
Summary: Which Inotrope? |
|
|
1 |
Nobody can say
for sure! |
|
2 |
Several bad
& often conflicting studies do not help |
|
3 |
Choose your
poison according to your expertise and patient. We generally favour
adrenaline, but may add in phenylephrine!! If you have expertise (and good
results) with dobutamine, dopamine and/or noradrenaline, good for you! Use
what works for you. |
The final section of this document
proposes further guidelines that we feel are reasonable. But first, a word of
warning!
Golden minutes, hours .. centuries?
For years now trauma specialists have hammered home the
concept of the "golden hour". Trauma victims, we are informed must be
attended to early on and resuscitated adequately as soon as possible, to
prevent extreme morbidity and mortality. There is impeccable evidence from many
trauma studies that this is the case. Unfortunately, we have neglected to apply
this concept in patients with sepsis, who are often more compromised that a
trauma patient with a similar blood pressure, and equally impaired vital organ
perfusion.
Consider
now the patient with septic shock. How often have you seen the following
scenario: the patient is found to be in shock.
Depending on the level of care prior to this finding, he/she may have been
wallowing in septic shock for minutes, hours, or even longer. The attending physician administers fluids (perhaps in sufficiently vast amounts)
and after a further delay (often let us say, half an hour to an hour, or
even more) this good doctor decides that - eureka - inotropes are required...
Time is
taken in preparing the inotrope infusion. Dosages may have to be calculated,
drugs drawn up. Then what? Often the doctor, if he is junior and inexperienced,
will start an initial, homeopathic infusion of say 0.01
micrograms/kilogram/minute of adrenaline (or say 5 micrograms per kilogram per
minute of dobutamine). This will frequently fail, even if the syringe driver
pump that the doctor is using is reliable at low infusion rates (many are not)!
So, after perhaps five, ten or even fifteen minutes (can it be that he might
even delay half an hour or an hour?) the good doctor will tentatively increase
the infusion rate a fraction, and carry on.
During
all this time, the patient is progressively building up a tissue oxygen
deficit, and, basically dying! Can we not apply the trauma concept of a
"golden hour" to all patients with circulatory failure? Surely
to do anything less is a crime of pure neglect!
Our suggested approach to the patient who may require
inotropes:
- Assess
the patient rapidly and thoroughly.
Obtain a good history, and examine the patient diligently and speedily. Manage acute resuscitation appropriately. Establish if there is significant hypotension, and a working hypothesis as to why this is present.
Try and address the underlying cause if this is remotely possible. - Ensure
adequate volume status. Fluid must be titrated according to the
patient's specific needs, rather than blindly relying on formulae.
- If there is
no reason to suspect a discrepancy between left and right-sided cardiac
function, titrate fluid replacement according to central venous pressure
(obtained through a central venous line). It is far better to look at the
trend of the central venous pressure than absolute readings, but
if you need a number as a target, then 10 to 12cm H20 is a vaguely
reasonable one in the average patient!
- If there is
left or right heart dysfunction, consider using a flow-directed pulmonary
artery catheter (although some have suggested that this causes more harm
than good), provided you have the expertise to
use this effectively. [For criticism, see Connors AF et al, JAMA
1996 276 pp889-897, and the subsequent furore.]
- Aggressively
sustain the blood pressure. Base your target upon premorbid
patient mean arterial pressure, if known, or failing this, choose a target
of say 100mmHg MEAN, as justified in the preceding discussion. This goal
may need to be adjusted according to the peculiarities of the particular
patient.
- We
reiterate: AGGRESSIVELY MAINTAIN BLOOD PRESSURE.
Do not wait for your fluids to fail. Very soon after you start aggressive fluid resuscitation, if the pressure is low, institute near-immediate, relatively high-dose inotropic support, given through a central line via an infusion pump that is known to be reliable. The dilution of the inotrope should be such that the pump is delivering at least 5 ml/hour, as the vast majority of pumps are unreliable at rates less than this. A practical starting dose of adrenaline, which is an inexpensive and effective inotrope in most situations is 0.05 to 0.1 micrograms per kilogram per minute. If there is no response to your infusion after five minutes, DOUBLE THE - Consider
the administration of a small bolus of inotrope to
"capture" the arterial blood pressure. In a 70kg adult, one
might consider taking 1mg of adrenaline, diluting it up to 20 millilitres,
and then observing the response to half to one ml of this solution given
intravenously. Depending on the response, this may need to be repeated
while you inotrope infusion starts to take effect.
- Adjust
the above to the clinical situation. Each
patient is an individual, with their own potential complications of
inotropic therapy. Use clinical judgement, rather than blindly following
guidelines!
- Once you
have achieved your target pressure (within minutes, not hours),
MAINTAIN this pressure, and re-evaluate. Pay particular attention to
organ function, and most importantly, address the underlying condition
that caused this crisis of cardiovascular dysregulation.
- Wean the
inotropes as rapidly as you can. Remember that beta receptors,
especially, down- regulate rather catastrophically. It might be wise to
try and wean off the inotropes immediately after you have evidence of substantial
improvement in metabolic status (clearing of raised lactate levels,
improvement of serum bicarbonate, improvement in
pHi). But do not permit autoregulatory failure to become re- established,
by allowing the blood pressure to drop significantly below your target
level! If you drop the infusion too rapidly, you may have to take it back
up to levels *above* your recent ones, but this should not stop you from
trying!
References
A. Some Fairly Good References:
- Guyton AC & Hall JE, Textbook of Medical
Physiology, 9ed, 1996 p162 et seq.
A brilliant exposition of how tissues autoregulate, the cardiovascular system mainly serving to provide a head of pressure - Meier-Hellman
A & Reinhart K, Acta Anaes Scand 1995 39 S107
pp239-48
A fair review of catecholamines & regional perfusion. - Vincent JL,
Acta Anaes Scand 1995 39 S107 pp261-6
A good summary of lactate in the critically ill - Hardman JG et
al, 1996. Goodman & Gilman's The
Pharmacological Basis of Therapeutics, 9 ed. McGraw-Hill. This book
has a substantial section on catecholamines (Chapter 10) and discusses
them further in the chapter on neurotransmission (Chapter 6).
- Leier CV, Am J
Cardiol 1988 62 pp86E-93E
A good discussion of regional flow in heart failure, and changes effected by a variety of agents.
- Shoemaker W et al, Chest 1988 94
p1176
- Shoemaker W et al, Crit Care Med
1988 16 pp117-20
- Fleming A et al, Arch Surg 1992 127
p1181
- Shoemaker W et al, Crit Care Med
1993 21 pp977-90
- Tuchschmidt J et al, Crit Care Med 1989
17 pp719-23
- Edwards JD et al, Crit Care Med
1989 17 pp1098-103
- Boyd O et al, JAMA 1993 270
pp2699-707
- Russell JA et al, Am Rev Resp Dis
1990 141 pp659-665
- Cryer HG et al, Arch Surg 1989 124
pp1378-85
|
Date of First
Publication: 1999 |
Date of Last Update:
2000-7-9 |
Web page author: J
van Schalkwyk |