Download Inotropic and vasoactive agents

Shock, sepsis and multiple-organ failure
hydroxyethyl groups (0.5, 0.62, 0.7). Thus the first-generation high-molecular-weight HES Hetastarch has a concentration of 6%, a mean molecular weight of 450 kDa and a
molar substitution of 0.7, whereas Elohaes, for example, has
a mean molecular weight of 200 kDa and a molar substitution of 0.62. The half-life of these HES solutions is between
12 and 24 hours, whilst that of the low-molecular-weight
solutions (e.g. Pentaspan) is 4–6 hours. Elimination of HES
occurs primarily via the kidneys following hydrolysis by
amylase.
HES are stored in the reticuloendothelial system, apparently without causing functional impairment, but skin deposits have been associated with persistent pruritus (Morgan and
Berridge, 2000). This pruritis can be generalized or localized,
can have a delayed onset of up to several weeks and may be
precipitated by warmth or mechanical irritation. It is frequently persistent, lasting months or even years, and is usually
refractory to treatment. HES, especially the higher-molecularweight fractions, reduce factor VIII activity and inhibit platelet
aggregation; although these anticoagulant properties are rarely
implicated in clinical bleeding, many therefore recommend
limiting the volume of HES administered. Preparations with a
low molecular weight and low degree of substitution may be
safer in this regard. Finally, there is some evidence from animal
models to suggest that HES are more effective in avoiding or
reducing increased capillary permeability (‘plugging the capillaries’) than other preparations. On the other hand in a recent
study of patients with severe sepsis or septic shock the use of
Elohaes as opposed to gelatin was an independent risk factor
for the development of acute renal failure, although the mechanism is unknown (Schortgen et al., 2001). Moreover in a
recent randomised controlled trial the use of a low molecular
weight starch to resuscitate patients with severe sepsis was
associated with a higher rate of acute renal failure and renal
replacement therapy than was Ringer’s lactate (Brunkhorst
et al., 2008). In patients undergoing abdominal aortic aneurysm surgery, perioperative lung function was better in those
receiving HES compared to those given Gelofusine (Rittoo et
al., 2004). Anaphylactic reactions are less common than with
the gelatins.
Inotropic and vasoactive agents
If the signs of shock persist despite adequate volume replacement, and perfusion of vital organs is jeopardized, inotropic
or vasoactive agents may be administered to improve cardiac
output and blood pressure. Vasopressor therapy may also be
required to maintain perfusion in those with life-threatening
hypotension, even when volume replacement is incomplete.
It is also important at this stage to identify and if possible
correct any of the various associated abnormalities that can
impair cardiac performance and vascular responsiveness.
These include:
■
■
■
hypoxaemia;
hypocalcaemia;
the effects of some drugs (e.g. β-blockers, angiotensinconverting enzyme (ACE) inhibitors, antiarrhythmics
and sedatives).
113
CORRECTION OF METABOLIC ACIDOSIS
Conventionally, extreme acidosis is said to depress myocardial contractility and limit the response to vasopressor
agents, although there is little evidence to support this contention. Moreover, attempted correction of acidosis with
intravenous sodium bicarbonate may be detrimental. Additional carbon dioxide is generated and, as carbon dioxide but
not bicarbonate readily diffuses across the cell membrane,
intracellular and, in some cases, extracellular, pH may be
paradoxically further reduced. Other potential disadvantages of bicarbonate therapy include sodium overload,
hyperosmolality, a left shift of the oxyhaemoglobin dissociation curve and hypokalaemia. Also ionized calcium
levels may be reduced and, in combination with the fall in
intracellular pH, may contribute to impaired myocardial
performance.
In a prospective, randomized, controlled, cross-over clinical study both sodium bicarbonate and sodium chloride
produced slight increases in PAOP and cardiac output, while
MAP was unchanged. Sodium bicarbonate significantly
increased pH and plasma bicarbonate but, unlike sodium
chloride, decreased ionized calcium and increased both
PaCO2 and end-tidal carbon dioxide. The response to infused
catecholamines was unaffected (Cooper et al., 1990). In
general, therefore, treatment of lactic acidosis should concentrate on correcting the cause. In the absence of hard data,
some believe that acidosis may be most safely controlled by
hyperventilation; others suggest that administration of
bicarbonate may be indicated as a temporizing measure, and
to provide a margin of safety, in those with severe persistent
metabolic acidosis (pH < 7.15). Bicarbonate therapy is still
considered to be useful in renal tubular acidosis and in acidosis due to gastrointestinal losses of bicarbonate.
CHOICE OF INOTROPIC/VASOACTIVE AGENT
The rational selection of an appropriate pressor agent
depends on a thorough understanding of the cardiovascular
effects of the available drugs (Table 5.8), combined with an
accurate assessment of the haemodynamic disturbance. The
effects of a particular agent in an individual patient are
unpredictable and the response must therefore be closely
monitored so that the regimen can be altered appropriately
if necessary. In many cases this requires measurement of
cardiac output, monitoring of venous oxygen saturation and
calculation of derived variables (see Chapter 4). In some
patients, inodilators are administered to redistribute blood
flow (e.g. dopexamine to improve splanchnic perfusion)
and, in others, inotropic support can be usefully combined
with the administration of a vasodilator (see below). All
inotropic agents should be given via a large central vein.
Although it is recognized that β-agonists have antiinflammatory properties, mediated by reduced degradation
of IκB and increased intracellular concentrations of cyclic
adenosine monophosphate, the clinical importance of the
immune-modulating activities of adrenergic agents remains
uncertain.
114
INTENSIVE CARE
Table 5.8 Adrenergic agents
b1
b2
a1
a2
DA1
DA2
Adrenaline (epinephrine)
Low-dose
Moderate-dose
High-dose
++
++
++(+)
+
+
+(+)
+
++
++++
±
+
+++
−
−
−
−
−
−
Noradrenaline (norepinephrine)
++
0
+++
+++
−
−
Dose dependence
++++
+++
Isoprenaline
+++
+++
0
0
−
−
Dopamine
Low-dose
Moderate-dose
High-dose
±
++
+++
0
+
++
±
++
+++
+
+
+
++
++(+)
++(+)
+
+
+
Dopexamine
+
+++
0
0
++
+
++
Dobutamine
++
+
±
?
0
0
++
Receptor
Action
β1 – postsynaptic
Positive inotropism and chronotropism
Renin release
β2 – presynaptic
Stimulates noradrenaline release
β2 – postsynaptic
Positive inotropism and chronotropism
Vascular dilatation
Relaxes bronchial smooth muscle
α1 – postsynaptic
Constriction of peripheral, renal and coronary vascular smooth muscle
Positive inotropism
Antidiuresis
α2 – presynaptic
Inhibition of noradrenaline release, vasodilatation
α2 – postsynaptic
Constriction of coronary arteries
Promotes salt and water excretion
DA1 – postsynaptic
Dilates renal, mesenteric and coronary vessels
Renal tubular effect (natriuresis, diuresis)
DA2 – presynaptic
Inhibits adrenaline release
ADRENALINE (EPINEPHRINE)
Adrenaline stimulates both α- and β-receptors but, at low
doses, β effects seem to predominate. This produces a tachycardia with an increase in stroke volume and cardiac index;
peripheral resistance may fall. As the dose is increased, αmediated vasoconstriction develops. If this is associated with
an increase in perfusion pressure, urine output may improve.
Particularly at higher doses and in severe septic shock,
however, adrenaline can cause excessive vasoconstriction,
with potentially worrying reductions in splanchnic flow and
associated falls in gastric mucosal pH, indicative of gut
mucosal ischaemia (De Backer et al., 2003; Levy et al., 1997a;
Meier-Hellmann et al., 1997). Renal blood flow may fall with
adrenaline and prolonged high-dose administration can
cause peripheral gangrene. Adrenaline may also precipitate
tachyarrhythmias. Lactic acidosis is a common complication
of adrenaline administration (Day et al., 1996) and is probably explained by β2-mediated accelerated glycolysis, often
+++++
combined with other causes of increased lactate production
and, in many cases, exacerbated by impaired lactate clearance (see above). The prognostic significance of adrenalineinduced lactic acidosis is unclear, but this phenomenon
emphasizes the limitations of using blood lactate levels as a
guide to tissue hypoxia in shock, especially in those receiving
adrenaline. In an experimental septic shock model adrenaline administration was associated with dose-related reductions in cardiac index, ejection fraction and pH, as well as
increases in systemic vascular resistance and creatinine.
Adrenaline also adversely affected systemic perfusion, organ
function and survival when compared to noradrenaline and
vasopressin (Minneci et al., 2004b).
Despite these disadvantages, adrenaline can be a useful
agent in patients with refractory hypotension. It is very
potent and may prove successful when other agents have
failed, particularly following cardiac surgery, perhaps because
it stimulates myocardial α-receptors. Adrenaline is still pre-
Shock, sepsis and multiple-organ failure
ferred by some as a cheap, effective means of reversing
hypotension and increasing oxygen delivery in septic shock
(Bollaert et al., 1990), especially when haemodynamic monitoring is not available or is considered unwarranted. In order
to avoid adverse effects the minimum effective dose should
be used, and its administration should be discontinued as
soon as possible
NORADRENALINE (NOREPINEPHRINE)
Noradrenaline has both α- and β-adrenergic actions, but the
α-mediated vasoconstrictor effect predominates. Noradrenaline is particularly useful in those with unresponsive hypotension associated with a low systemic vascular resistance
and an adequate cardiac output, for example in septic shock
resistant to dopamine. It is also increasingly used to maintain blood pressure in vasodilated patients post cardiac
surgery. Administration of noradrenaline to patients with
vasodilatory shock is associated with an increase in systemic
vascular resistance and MAP, while cardiac output usually
falls in line with the increased afterload. In some cases,
however, cardiac output is unchanged and in patients with
dobutamine-resistant septic shock noradrenaline has been
shown to improve cardiac output and left ventricular stroke
work, as well as increasing systemic vascular resistance and
MAP (Martin et al., 1999). These findings indicate that noradrenaline can sometimes exert a positive inotropic effect in
septic shock, probably via stimulation of cardiac α and β
receptors or possibly as a consequence of improved coronary
perfusion (Martin et al., 1999). Moreover, provided cardiac
output does not fall, restoration of blood pressure with noradrenaline may be associated with maintained or improved
splanchnic perfusion and oxygenation (Marik and Mohedin,
1994; Meier-Hellmann et al., 1996) and reductions in blood
lactate levels, as well as increases in urine flow and creatinine
clearance (Martin et al., 1990). PAOP and mean pulmonary
artery pressure are usually either unchanged or slightly
increased. In some cases, large doses may be required to
overcome α-receptor downregulation but there is a risk of
producing excessive vasoconstriction and masking hypovolaemia, with impaired organ perfusion, peripheral ischaemia
and increased afterload. Administration of high doses of
noradrenaline has been implicated as a contributory factor
in the development of symmetrical peripheral gangrene
(Hayes et al., 1992). Noradrenaline administration must,
therefore, be accompanied by close haemodynamic monitoring and, certainly when higher doses are used, determination of cardiac output.
ISOPRENALINE
This β-stimulant has both inotropic and chronotropic
effects, and also reduces peripheral resistance by dilating
skin and muscle blood vessels. This latter effect means that
much of the increased flow is diverted away from vital organs
such as the kidneys and may account for the oliguria that
can be associated with its use. Most of the increase in cardiac
output produced by isoprenaline is due to the tachycardia
and this, together with the development of arrhythmias,
115
seriously limits its value. There are now few indications for
isoprenaline in the critically ill adult, except, perhaps, as a
treatment for bradycardia after cardiac surgery.
DOPAMINE
Dopamine is a natural precursor of noradrenaline that acts
on β1 and, to a lesser extent, β2 receptors, α receptors (via
noradrenaline release) and dopaminergic DA1 and DA2
receptors. When used in low doses (1–3 μg/kg per min)
dopaminergic vasodilatory receptors in the cerebral, coronary and splanchnic circulations are activated (DA1 receptors are located on postsynaptic membranes and mediate
vasodilatation, whereas DA2 receptors are presynaptic and
potentiate these vasodilatory effects by preventing the release
of noradrenaline). Peripheral resistance falls, renal and
hepatic blood flow increase, and urine output, GFR, fractional excretion of sodium and creatinine clearance can be
improved. The importance of the renal vasodilator effect of
dopamine has, however, been questioned and it has
been suggested that the increased urine output is largely
attributable to a rise in cardiac output and blood pressure,
combined with a decrease in aldosterone concentrations and
inhibition of tubular sodium reabsorption mediated via
DA1 stimulation. Despite the increase in urine output, lowdose dopamine has no effect on the need for renal replacement therapy or mortality in patients with, or at risk of,
acute renal dysfunction (Friedrich et al., 2005) (see also
Chapter 13).
As the dose of dopamine is increased (3–10 μg/kg per
min), β1-adrenergic effects predominate, producing an
increase in heart rate and cardiac contractility. Dopamine
also increases noradrenaline release contributing to its cardiac
effects, and at higher doses (> 10 μg/kg per min), vasoconstriction occurs, increasing blood pressure and afterload and
raising ventricular filling pressures. This can be dangerous in
patients with cardiac failure in whom filling pressures are
already high. There is also some evidence to suggest that in
septic shock the use of high-dose dopamine to achieve a
target MAP > 75 mmHg may precipitate gut mucosal ischaemia, perhaps by redistributing flow, whereas noradrenaline
can improve splanchnic oxygenation (Marik and Mohedin,
1994). In another study dopamine (5 μg/kg per min) was
associated with a reduction in gastric mucosal blood flow and
pH (Neviere et al., 1996). Dopamine consistently increases
pulmonary shunt fraction and in some patients the dose of
dopamine is limited by β effects such as tachycardia and
arrhythmias. In septic shock dopamine restores MAP primarily by increasing stroke volume and cardiac index, with
minimal effect on heart rate and systemic vascular resistance.
Central venous, pulmonary artery and PAOPs are usually
unchanged. At doses higher than 20 μg/kg per min, however,
right heart pressures may increase and this dose should not
normally be exceeded. The median dose of dopamine
required to restore blood pressure in septic shock is 15 μg/kg
per min (Task Force of the American College of Critical
Care Medicine, Society of Critical Care Medicine, 1999).
116
INTENSIVE CARE
Dopamine also suppresses the circulating concentrations of
all the anterior pituitary-dependent hormones except cortisol (Van den Berghe and de Zegher, 1996). Although the
clinical implications of this effect are unclear, such changes
are unlikely to be beneficial and suggest that long-term
administration of dopamine to critically ill patients should
be avoided. Indeed an observational study has suggested that
dopamine administration may be associated with increased
mortality rates in shock (Sakr et al., 2006).
DOPEXAMINE
Dopexamine is an analogue of dopamine which activates β2
receptors as well as DA1 and DA2 receptors. It is more potent
at DA1 than DA2 receptors, is a weak β1 agonist and inhibits
neuronal reuptake of noradrenaline. Dopexamine is a very
weak positive inotrope, but is a powerful splanchnic vasodilator, reducing afterload and improving cardiac output and
blood flow to vital organs, including the kidneys. It is an
effective natriuretic and diuretic agent. At higher doses a fall
in diastolic pressure and MAP may reduce regional blood
flow. In septic shock, dopexamine can increase cardiac index
and heart rate, but causes further reductions in systemic
vascular resistance (Colardyn et al., 1989) and the dose may
be limited by tachycardia. Although some early studies
suggested that dopexamine can improve gut mucosal perfusion, in a later study in patients with severe sepsis (who were
already receiving dobutamine) dopexamine only increased
splanchnic oxygen delivery in proportion to the increase in
cardiac output and caused a dose-dependent reduction in
intramucosal pH (Meier-Hellmann et al., 1999). Moreover,
in patients with septic shock receiving noradrenaline, the
addition of dopexamine failed to improve hepatosplanchnic
haemodynamics, oxygen exchange and energy balance,
despite increases in oxygen delivery (Kiefer et al., 2000). It
has been suggested that dopexamine is likely to be most
useful in the management of low-output left ventricular
failure, but this agent is not generally recommended for the
management of sepsis/septic shock.
DOBUTAMINE
Dobutamine is a racemic mixture of two isomers, a D-isomer
with β1 and β2 activity and an L-isomer with β1- and α1adrenergic actions. Dobutamine causes less tachycardia and
arrhythmias than isoprenaline but when compared with
dopamine the relative effects of the two agents on heart rate
and rhythm are a matter of dispute. An advantage of dobutamine is its ability to reduce systemic resistance, as well as
improve cardiac performance, thereby decreasing both afterload and ventricular filling pressures. Dobutamine is therefore useful in patients with cardiogenic shock and cardiac
failure, although the associated vasodilatation may be
complicated by hypotension. In septic shock dobutamine
increases heart rate, stroke volume, ventricular stroke work,
cardiac output, DO2 and VO2 while, in some cases, systemic
vascular resistance falls (Vincent et al., 1990). Dobutamine
may be particularly useful in septic patients with fluid overload or myocardial failure (Jardin et al., 1981). In adrenaline-
treated patients with septic shock, the addition of dobutamine
(5 μg/kg per min) selectively improved gastric mucosal perfusion without altering systemic haemodynamics (Levy
et al., 1997b) and in another study the same dose of dobutamine improved gastric mucosal perfusion in septic patients,
whereas dopamine was deleterious in this respect (Neviere
et al., 1996). Dobutamine has no specific effect on the renal
vasculature or dopamine receptors, although urine output
and, in some cases, creatinine clearance often increase as
cardiac output and blood pressure improve.
PHOSPHODIESTERASE INHIBITORS (E.G. AMRINONE,
MILRINONE, ENOXIMONE)
These agents have both inotropic and vasodilator properties.
They inhibit phosphodiesterase type III (PDE III), thereby
increasing concentrations of cyclic adenosine monophosphate (AMP) and improving cardiac contractility, whilst
inhibition of other PDE isoforms increases cGMP and produces vasodilatation. Cardiac index and stroke work indices
usually increase, whilst systemic and pulmonary vascular
resistances fall. Vasopressors such as noradrenaline may be
required to counteract excessive vasodilatation. These agents
have a relatively long half-life (e.g. 4–7 hours for enoximone)
and are usually administered as a loading dose followed by
a continuous infusion, although single doses may be sufficient for weaning from cardiopulmonary bypass. Because
PDE III inhibitors bypass the β-adrenergic receptor they
do not cause significant tachycardia, are considerably less
arrhythmogenic than sympathomimetic agents and can
potentiate the effects of β-agonists. PDE III inhibitors may
be particularly useful in patients with adrenergic receptor
downregulation, those receiving β-blockers, for weaning
patients from cardiopulmonary bypass, and for patients
with cardiac failure. In vasodilated septic patients, however,
they may precipitate or worsen hypotension, an effect which
can be prolonged. Although PDE III inhibitors are not generally recommended for patients with sepsis/septic shock,
they can occasionally be useful in combination with adrenergic agents. Indeed, one study suggested that enoximone
could improve hepatosplanchnic function in fluid-resuscitated septic shock patients in whom MAP was maintained
with noradrenaline, perhaps in part by inhibiting the inflammatory response, as well as by improving regional perfusion
(Kern et al., 2001).
VASOPRESSIN
Vasopressin is an ADH with thermoregulatory, haemostatic
and gastrointestinal effects which also acts as a potent vasopressor via activation of V1 receptors on vascular smooth
muscle. Its antidiuretic action is mediated via V2 receptor
activation in the renal collecting duct system. In addition,
vasopressin, at low concentrations, mediates vasodilatation
in coronary, cerebral and pulmonary arterial circulations.
Although circulating levels of vasopressin are usually
increased in response to stress, inappropriately low levels
have been described in patients with septic shock, possibly
because of impaired secretion or depletion of vasopressin
Shock, sepsis and multiple-organ failure
stores in the neurohypophysis (Landry et al., 1997; Sharshar
et al., 2002). Moreover, in contrast to the blunted response to
adrenergic agents, patients with vasodilatory shock appear to
be hypersensitive to the pressor effects of exogenous vasopressin and administration of vasopressin to these patients
potentiates the vasoconstrictor effects of noradrenaline. In a
randomized double-blind study, a short-term vasopressin
infusion reduced the requirement for conventional vasopressors and improved renal function (Patel et al., 2002). Cardiac
index was maintained whilst ventricular filling pressures,
pulmonary artery pressures, pulmonary vascular resistance
and heart rate were unchanged, as was gastric mucosal perfusion. The increase in urine output and creatinine clearance
following vasopressin administration may be a consequence
of increased systemic blood pressure combined with preferential constriction of renal efferent arterioles leading to
increased glomerular perfusion pressure. Also vasopressin
may directly activate oxytocin receptors, causing natriuresis
and diuresis, as well as releasing artrial natriuretic peptide. At
high doses, however, there is a danger that vasopressin will
precipitate excessive renal, coronary, mesenteric and systemic
vasoconstriction, as well as causing a significant reduction in
cardiac output. A recent randomised controlled trial, however, found that low dose vasopressin did not reduce
mortality rates when compared to noradrenaline, although
there was a suggestion of benefit in those with less severe
septic shock (Russell et al., 2008).
Vasopressin is relatively contraindicated in hypovolaemia, heart failure and in those with a history of coronary
artery disease, although there are studies showing utility in
cardiogenic shock. An alternative is to use terlipressin, a
cheaper, longer-acting, synthetic analogue of vasopressin.
Small doses (0.25–0.5 mg), repeated at 20-minute intervals
to a maximum of 2 mg, should be used with close observation for signs of peripheral ischaemia and with cardiac
output monitoring. In sepsis patients a single dose is often
sufficient to improve blood pressure, reduce vasopressor
requirements and improve renal function (Leone et al.,
2004).
Angiotensin has been used in resistant septic shock (Wray
and Coakley, 1995) but there is a danger of excessive vasoconstriction with associated falls in cardiac output and tissue
perfuison. This agent is no longer available in the UK.
INHIBITION OF NITRIC OXIDE SYNTHESIS
Experimental studies have demonstrated that the vascular
hyporeactivity to adrenergic agonists and the peripheral vascular failure associated with endotoxaemia can be reversed
by inhibiting NO synthesis with L-arginine analogues, and
prevented by inhibiting the induction of inducible NOS with
dexamethasone. There is evidence that NO production is
increased in human sepsis (Evans et al., 1993) and preliminary studies in patients with septic shock suggested that
administration of the non-selective NOS inhibitor Nmonomethyl-L-arginine hydrochloride (L-NMMA) was safe
and could restore vasomotor tone and maintain blood pres-
117
sure (Grover et al., 1999). At higher doses, however, cardiac
output and oxygen delivery fell, although oxygen consumption was maintained by an increase in oxygen extraction.
There were also concerns about the effects of inhibiting NO
production on regional perfusion, the microcirculation, the
pulmonary vasculature, coagulation, free radical injury and
immune function. These concerns were highlighted when a
phase III study of L-NMMA was terminated prematurely
because of excess mortality in the treatment group, perhaps
partly explained by the inclusion of patients with hypodynamic septic shock in this trial and the deleterious effect of
higher doses of NOS inhibitor (Lopez et al., 2004).
Methylene blue inhibits guanylate cyclase and possibly
also NOS. Administration of methylene blue to patients with
septic shock can increase arterial blood pressure, although
stroke volume, left ventricular stroke work and oxygen delivery are unchanged (Kirov et al., 2001). Further studies are
required to determine whether this agent has a role in
routine clinical practice.
LEVOSIMENDAN
This novel agent sensitizes troponin C to calcium, thereby
improving myocardial contractility, and causes vasodilation
by opening ATP-sensitive potassium channels. Myocardial
oxygen demand is not increased. In patients with severe
low-output heart failure, levosimendan improved haemodynamic performance more effectively than dobutamine
and was associated with a lower mortality (Follath et al.,
2002).
RECEPTOR DOWNREGULATION
Many of the most seriously ill patients become increasingly
resistant to the effects of pressor agents, an observation
attributed to downregulation of adenergic receptors. This
may be due to a reduction in receptor numbers, a decreased
affinity of the receptor for its ligand induced by overstimulation, or a direct effect of inflammatory mediators on signal
transduction either at or distal to the receptor. This affects
intracellular calcium levels and the resultant vascular hyporeactivity to both endogenous and exogenous catecholamines is a particular feature of septic shock.
Guidelines for the use of inotropic and vasopressor
agents (Task Force of the American College of
Critical Care Medicine, Society of Critical
Care Medicine, 1999)
Many still consider dopamine in low to moderate doses to be
the first-line agent for restoring blood pressure, although
others favour dopexamine as a means of increasing cardiac
output and organ blood flow. High-dose dopamine is usually
best avoided. Dobutamine is particularly indicated in patients
in whom the vasoconstriction caused by dopamine could be
dangerous (i.e. patients with cardiac disease, those with a low
cardiac output after fluid resuscitation and septic patients
with fluid overload or myocardial failure). The combination
of dobutamine and noradrenaline is currently popular for
the management of patients who are hypotensive with a low
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