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-ATP channels
(168).
Normal concentrations of vasopressin
have little effect on blood pressure in
physiologic conditions (166), but vaso-
pressin helps maintain blood pressure
during hypovolemia, (169) and seems to
restore impaired hemodynamic mecha-
nisms and also inhibit pathologic vascu-
lar responses in shock. Increased concen-
trations of vasopressin have been
documented in several types of shock
(170, 171), but a growing body of evi-
dence indicates that this response is ab-
normal or blunted in septic shock. One
study found markedly increased concen-
trations of circulating vasopressin in 12
patients with cardiogenic shock but
much lower concentrations in 19 patients
with septic shock, concentrations that
were hypothesized to be inappropriately
low (172). One potential mechanism for
this relative vasopressin deciency would
be depletion of pituitary stores, possibly
in conjunction with impaired synthesis.
Depletion of vasopressin stores in the
neurohypophysis evaluated by magnetic
resonance imaging has in fact been de-
scribed in a small group of septic shock
patients (173). A recent prospective co-
hort study of patients with septic shock
found that vasopressin concentrations
were almost always elevated in the initial
hours of septic shock and decreased af-
terward; one third of patients developed
relative vasopressin deciency as dened
by the investigators (174).
Given this theoretical rationale, sev-
eral small observational studies have ex-
amined the effects of addition of vaso-
pressin to catecholamines in patients
with pressor-refractory septic shock. The
rst report showed that with infusion of
low dose of vasopressin (0.04 units/min)
in ve patients with septic shock, vaso-
pressin plasma concentrations reached
100 pg/mol (a concentration commensu-
rate with those in patients with normal
stress responses), and blood pressure in-
creased signicantly (172). Discontinua-
tion of vasopressin was followed by a
marked decrease in the arterial pressure.
Similar ndings were noted by the same
group with low-dose vasopressin admin-
istration in the 19 patients with sepsis
and low vasopressin concentrations in
the study cited previously (172). Other
studies have tested longer infusions. One
report examined the effects of infusion of
0.04 units/min of vasopressin for 16 hrs
in 16 patients with catecholamine-
refractory septic shock and found an in-
crease in mean arterial pressure in 14
16, with stable cardiac output, and
increased urine output in the ten patients
who were not anuric on study entry
(175). In another report, in 50 patients
with severe septic shock who had re-
ceived continuous vasopressin infusion
for 48 hrs, mean arterial pressure in-
creased by 18% in the 4 hrs after the
beginning of the infusion and then stabi-
lized at 24 and 48 hrs; catecholamine
doses were reduced by 33% at the 4th
hour (p .01) and by 50% at the 48th
hour (166). Of note, ve of the six pa-
tients with cardiac arrest during the
study had received vasopressin doses
0.05 units/min (166).
Randomized studies of vasopressin
infusion have been small. In one, ten
patients with hyperdynamic septic
shock on catecholamines were random-
ized to a low dose of vasopressin (0.04
units/min) or placebo (176). The pa-
tients who received vasopressin had a
signicant increase in systolic arterial
pressure (from 98 to 125 mm Hg, p
.05) with successful weaning of cat-
echolamines. No variation in arterial
pressure was noted in the placebo
group. The cardiac index did not differ
in the two groups. Before termination
of the study at 24 hrs, two of the ve
patients in the placebo group died of
refractory hypotension; there were no
deaths during the study in vasopressin-
treated patients. Another group ran-
domized 24 patients with septic shock
on high-dose vasopressors to a 4-hr in-
fusion of either norepinephrine or va-
sopressin, with open-label titration of
vasopressors to maintain mean arterial
pressure (177). In the vasopressin
group, norepinephrine doses were sig-
nicantly reduced at the 4th hour (25
to 5 g/min, p .001). Vasopressin
doses varied between 0.01 and 0.08
units/min. In the norepinephrine
group, doses were not signicantly
modied. Mean arterial pressure and
cardiac index were maintained in both
groups, and the gastric CO
2
gradient
was unchanged as well. Urine output
and creatinine clearance increased sig-
nicantly in the vasopressin group but
did not vary in the norepinephrine
group (177).
All of the previously cited studies in-
fused arginine-vasopressin, the vasopressin
that is naturally present in humans. Lysine-
vasopressin or terlipressin, the vasopressin
present in the pig, has been evaluated in
patients with septic shock in one reported
study (178). Terlipressin administered as a
single bolus of 1 mg to eight patients with
septic shock refractory to catecholamines,
hydrocortisone, and methylene blue im-
proved blood pressure during the rst 5 hrs
and enabled partial or total weaning of cat-
echolamines (178).
In summary, vasopressin plays an im-
portant role in normalizing blood pres-
sure in states of shock. There is evidence
that in septic shock, a relative deciency
of vasopressin may contribute to persis-
1939 Crit Care Med 2004 Vol. 32, No. 9
tent hypotension. Current evidence dem-
onstrates that in catecholamine-resistant
septic shock, the addition of low-dose va-
sopressin (0.010.04 units/min) by con-
tinuous infusion to catecholamines can
be used to increase blood pressure and
decrease catecholamine doses. There is
concern, however, that vasopressin infu-
sion in septic patients may either de-
crease splanchnic perfusion or redistrib-
ute blood ow away from the splanchnic
mucosa (179, 180). Data examining out-
comes and clinical side effects are lim-
ited.
Complications of Vasopressor
Therapy
All of the catecholamine vasopressor
agents can cause signicant tachycar-
dia, especially in patients who are inad-
equately volume resuscitated. Tachyar-
rhythmias can occur as well. In patients
with signicant coronary atherosclero-
sis, vasopressor-induced coronary ar-
tery constriction may precipitate myo-
cardial ischemia and infarction; this is
of particular concern in patients treated
with vasopressin. In the presence of
myocardial dysfunction, excessive vaso-
constriction can decrease stroke vol-
ume, cardiac output, and oxygen deliv-
ery. Should this occur, the dose of
vasopressor should be lowered, or the
addition of an inotropic agent such as
dobutamine should be considered (91).
Vasopressors can also cause limb isch-
emia and necrosis.
Administration of vasopressors may
impair blood ow to the splanchnic sys-
tem, and this can be manifested by stress
ulceration, ileus, malabsorption, and
even bowel infarction (121, 137). Gut
mucosal integrity occupies a key position
in the pathogenesis of multiple organ
failure, and countercurrent ow in
splanchnic microcirculation gives the gut
a higher critical threshold for oxygen de-
livery than other organs. If possible, epi-
sodes of intramucosal acidosis, which
might be detected either by a decrease in
gastric mucosal pHi or an increase in
gastric mucosal PCO
2
, should be avoided,
although no prospective randomized con-
trolled trial has demonstrated a decrease
in mortality rate with pHi or gastric PCO
2
-
directed care in the management of pa-
tients with septic shock.
INOTROPIC THERAPY IN
SEPSIS
Overview
Sepsis is characterized by a hyperdy-
namic state with normal to low blood
pressure, normal to high cardiac index,
and a low systemic vascular resistance (1,
29). Although cardiac output is usually
maintained in the volume-resuscitated
septic patient, a number of investigations
have demonstrated that cardiac function
is impaired (97, 181, 182). This myocar-
dial dysfunction is characterized by a de-
creased ejection fraction, ventricular di-
lation, impaired contractile response to
volume loading, and a low peak systolic
pressure/end-systolic volume ratio (a rel-
atively load-independent measure of ven-
tricular function) (183185). The mech-
anism of this cardiac dysfunction is
complex. Myocardial ischemia is unlikely,
as coronary blood ow is normal and
there is no net lactate production across
the coronary vascular bed (186, 187). An-
imal studies of endotoxemia or bacterial
infection have suggested that myocardial
edema (188), alterations in sarcolemmal
or intracellular calcium homeostasis
(189), and uncoupling or disruption of
-adrenergic signal transduction may
contribute to the cardiac contractile dys-
function (190). A variety of inammatory
mediators, including prostanoids (191),
platelet-activating factor (65), tumor ne-
crosis factor-, interleukin-1 and inter-
leukin-2, (192), and nitric oxide (193,
194) have been shown to cause myocar-
dial depression in a number of animal
models, possibly through the sphinomy-
elinase pathway (195). Although it is
clear that myocardial performance is al-
tered during sepsis and septic shock, end
points for cardiac resuscitation are un-
certain.
Inotropic therapy in septic shock is
complex, because different approaches
endeavor to achieve different goals. In
patients with decreased cardiac output,
the goals of therapy are straightforward
and are aimed at restoring normal phys-
iology. Because of the complexity of as-
sessment of clinical variables in septic
patients, measurement of cardiac output
is advisable. Such measurements need to
be interpreted in the clinical context; a
patient with preexisting cardiac disease
may have a limited ability to increase
cardiac output, and thus values within
the normal range or even slightly below
normal may actually represent a hyper-
dynamic response for that particular pa-
tient. Thus, other end points of global
perfusion should be followed as well.
When global hypoperfusion is manifested
by decreased mixed venous oxygen satu-
ration, this measure may be followed as
an index of the efcacy of inotropic ther-
apy. Similarly, although lactate produc-
tion in sepsis is complex, a decrease in
blood lactate concentrations concomitant
with increased cardiac output is a good
prognostic sign. To further complicate
matters, the pharmacokinetics and phar-
macodynamics of inotropic agents in sep-
tic patients can be quite complex and
variable (196, 197).
Some critically ill septic patients are
hypermetabolic and may require high
levels of oxygen delivery to maintain ox-
idative metabolism. Data from the 1980s
and early 1990s suggested that a linear
relationship between oxygen delivery and
oxygen consumption (pathologic supply
dependency) was common in septic pa-
tients, (33, 198) with the inference that
oxygen delivery was insufcient to meet
the metabolic needs of the patient. These
observations led to the hypothesis that
resuscitation to predetermined elevated
end points of cardiac index and oxygen
delivery and consumption (hyperresus-
citation) might improve patient out-
come. Retrospective analyses showed that
achievement of cardiac index 4.5
Lmin
1
m
2
, oxygen delivery 600
mLmin
1
m
2
, and oxygen consump-
tion 170 mLmin
1
m
2
correlated
with improved survival (39). Other inves-
tigations, however, have challenged the
concept of pathologic supply-dependency
and hyperresuscitation (199202). Al-
though cardiac index and oxygen delivery
are correlated with outcome (39), it is
unclear if increases in these variables are
the cause of increased survival or repre-
sent the underlying physiologic reserve of
the patient. Randomized studies to test
the practice of routinely increasing oxy-
gen delivery to these predened levels in
all critically ill patients have produced
conicting results (199201, 203, 204),
and it is unclear if increases in cardiac
index and oxygen delivery are the cause of
increased survival or represent underly-
ing physiologic reserve of the patient.
Thus, a strategy of routinely increasing
oxygen delivery to predetermined ele-
vated end points of cardiac index and
oxygen delivery cannot be recommended
on the basis of current data (205). None-
theless, some clinicians believe that this
issue has not been settled denitively in
1940 Crit Care Med 2004 Vol. 32, No. 9
those patients with septic shock and ar-
gue that a subset of these patients may
benet from therapy aimed at supranor-
mal oxygen delivery.
Uncertainty exists in regard to other
end points for inotropic therapy. Decits
in oxygen delivery can clearly cause a
lactic acidosis, but the converse is not
true: elevated lactate concentrations in
patients with sepsis or septic shock do
not necessarily reect decits in oxygen
delivery (206). In adequately resuscitated
septic patients, mixed venous oxygen sat-
uration is usually normal or high, this
value correlates poorly with cardiac out-
put, and several studies have questioned
the value of SvO
2
as the end point for
inotropic therapy in critically ill patients
(207, 208). Low mixed venous oxygen sat-
uration may indicate decreased global ox-
ygen delivery, however (207).
Despite seemingly adequate resuscita-
tion, some septic shock patients develop
multiple organ failure, resulting in death.
It has been argued that even after hypo-
tension has been corrected and global
oxygen delivery is adequate in patients
with septic shock, blood ow and tissue
perfusion can remain suboptimal. Gastric
tonometry and sublingual capnometry
monitor gastric and sublingual PCO
2
as a
proxy for determining the adequacy of
gut perfusion. Although these monitors
serve as good predictors for the ultimate
outcome of critically ill patients (2225),
their utility to guide therapy in patients
with sepsis and septic shock has not been
proven. In dysoxic states with normal or
elevated blood ow, these monitors gen-
erally fail to detect an elevated intramu-
cosal-arterial PCO
2
gap (209). No current
evidence supports improved outcome
with empirical therapy to raise cardiac
output in patients with normal blood
pressure, but a subpopulation of patients
might have regional hypoperfusion that
would respond to additional therapy. One
would want to titrate such therapy to an
index of regional perfusion, although the
precise end points are uncertain. In this
context, it is important to realize that
different interventions to increase oxygen
delivery, such as uid resuscitation,
blood transfusion, or infusion of vasoac-
tive agents, can have different effects on
regional perfusion (101, 112, 121). Differ-
ent vasoactive agents have been shown to
have divergent effects on gastric intramu-
cosal pH.
An inotropic agent should be consid-
ered to maintain an adequate cardiac in-
dex, mean arterial pressure, SvO
2
, and
urine output. Cardiac output can be mea-
sured using a pulmonary artery catheter,
by echocardiography, with an esophageal
Doppler probe, or by pulse contour anal-
ysis. Regardless of the measurement
method chosen, clinicians should dene
specic goals and desired end points of
inotropic therapy in septic patients and
titrate therapy to those end points. These
goals and end points should be rened at
frequent intervals as patients clinical sta-
tus changes.
Therapies and Efcacy
Most investigations evaluating inotro-
pic agents have been observational and
have used the baseline hemodynamic
characteristics of the patient as the con-
trols. The majority of these studies have
used heart rate, cardiac index or output,
and/or stroke volume or stroke volume
index as the outcome variables. Only a
few studies have assessed ventricular
function by reporting left (or right) ven-
tricular stroke work index. The results
are summarized in Table 1.
Individual Inotropic Agents
Isoproterenol. Isoproterenol is a
1
-
and
2
-adrenergic agonist. Few studies
have evaluated isoproterenol in sepsis
and septic shock. In septic shock patients
with a low cardiac index (mean 2.0
Lmin
1
m
2
), isoproterenol (28 g/
min) will signicantly increase cardiac
index without decreasing blood pressure
but at the expense of increasing heart
rate (29, 210). In patients with a normal
cardiac index, however, isoproterenol can
decrease blood pressure through its
2
-
adrenergic effects. In addition, the chro-
notropic effects of
1
-adrenergic stimula-
tion can precipitate myocardial ischemia.
Dopamine. Dopamine is an adrenergic
agonist with predominant dopaminergic
properties at doses 5 gkg
1
min
1
and increased and activity at doses
5 gkg
1
min
1
. However, even at low
doses, signicant and agonism may
occur since the pharmacokinetics of do-
pamine in critically ill patients is highly
variable (197).
In patients with severe sepsis and/or
septic shock, most studies have shown
that dopamine will increase cardiac index
with a range from 4% to 44%, left ven-
tricular stroke work index by 591%, and
right ventricular stroke work index by a
modest 510% (101, 103, 104, 106, 108,
109, 111113, 137, 210213). These im-
provements in cardiac performance come
at the expense of an increase in the heart
rate of approximately 15% (range up to
23%). The greatest increase in these vari-
ables occurs at doses ranging from 3 to
12 gkg
1
min
1
. At higher doses, the
rate of improvement in cardiac function
decreases. Although dopamine may in-
crease mesenteric blood ow, it may also
decrease mesenteric oxygen consumption
(113). It is not clear whether effects of
dopamine are superior to any other ad-
renergic agent.
Dobutamine. Dobutamine is a race-
mic mixture of two isomers, a D isomer
with
1
- and
2
-adrenergic effects, and an
L isomer with
1
- and
1
-adrenergic ef-
Table 1. Summary of cardiac effects of inotropes used in sepsis and septic shock: Physiologic values are reported as percent change from baseline
Drug
Dose Range,
g kg
1
m
1
Heart
Rate
Cardiac
Index
Stroke
Volume Index SVRI LVSWI References
Isoproterenol 1.5 to 18 g/min 11 to 20 47 to 119 22 to 89 24 to 44 74 to 157 (29, 230)
Dopamine 2 to 55 1 to 23 4 to 44 7 to 32 6 to 18 5 to 91 (102, 104, 105, 107, 109, 110,
112114, 138, 211214)
Epinephrine 0.06 to 0.47 6 to 27 24 to 54 12 7 to 34 32 to 95 (135, 136, 138)
Norepinephrine 0.03 to 3.3 6 to 8 3 to 21 5 to 15 13 to 111 42 to 142 (91, 94, 102, 104, 107, 113, 120)
Dobutamine 2 to 28 9 to 23 12 to 61 15 6 to 21 23 to 58 (16, 92, 203, 215218)
Milrinone
a
0.5 1 41 to 49 47 30 to 35 51 to 56 (228, 229)
SVRI, systemic vascular resistance index; LVSWI, left ventricular stroke work index.
a
With other inotropes including dopamine, dobutamine, norepinephrine and/or epinephrine.
1941 Crit Care Med 2004 Vol. 32, No. 9
fects; its predominant effect is inotropic
via stimulation of
1
receptors, with a
variable effect on blood pressure.
A number of studies have investigated
the effect of dobutamine on cardiac func-
tion during sepsis or septic shock at doses
ranging from 2 to 28 gkg
1
min
1
(91,
202, 214218). In these studies, increases
in cardiac index ranged from 12% to
61%. However, heart rate increases, often
signicantly (923%). Two studies re-
ported that left ventricular stroke work
index increased by 2358% at mean do-
butamine doses of 512 gkg
1
min
1
(214, 215). Similar increases in right ven-
tricular stroke work were also observed in
these studies.
Although dobutamine does not inu-
ence the distribution of blood ow, ther-
apy is often aimed at increasing blood
ow to organs such as the gut or the
kidneys.
Epinephrine. Epinephrine stimulates
both and receptors. At low doses, the
-adrenergic effects predominate. A few
recent studies have examined the hemo-
dynamic effects of epinephrine in septic
shock at doses ranging from 0.1 to 0.5
gkg
1
min
1
(134, 135, 137). The in-
crease in cardiac index varied from 24%
to 54%, and the heart rate response was
variable. Increases in left ventricular
stroke work index as high as 95% have
been noted (135). Other studies indicated
that lactic acidosis is increased and per-
fusion to the gut is altered with the use of
epinephrine (121, 127, 137).
Norepinephrine. Like epinephrine,
norepinephrine stimulates both and
receptors; however, the -adrenergic re-
sponse is the predominant effect. The ef-
fect of norepinephrine on cardiac index is
modest, with the majority of studies
showing no change or increases of up to
21% while heart rate is unaffected or
even decreases by up to 8% (91, 93, 101,
103, 106, 112, 119). However, several
studies have shown a marked increase in
left and right ventricular stroke work in-
dex due to increased blood pressure (93,
101, 112, 119).
Combination and Comparative Stud-
ies. A number of studies have investigated
catecholamine combinations (86, 94,
121, 126, 219222). The majority of these
studies did not study the catecholamine
combination in a standardized fashion,
thus limiting the conclusions that can be
drawn about the effects of these catechol-
amine combinations on cardiac function.
Patients who do not respond to dopamine
with an increase in cardiac index may
reach the desired end point with a dopa-
mine/norepinephrine combination (106).
Dobutamine and norepinephrine appear
to be an effective combination to improve
cardiac index and blood pressure (91) In
addition, some (223) but not all (224,
225) studies have shown that dobutamine
or a dobutamine/norepinephrine combi-
nation will also enhance mesenteric per-
fusion.
A few investigations have been per-
formed comparing different inotropic
regimens (8790, 101, 112, 121, 137).
Epinephrine appears to be as good if not
better at improving cardiac performance
than dopamine or a dobutamine/norepi-
nephrine combination (121, 137). How-
ever, with one exception (140), studies
have shown that when epinephrine is
compared with other adrenergic agents
or their combinations, there are in-
creases in arterial lactate and decreases in
gastric intramucosal pH, suggesting that
perfusion to regional vascular beds may
be impaired (121, 127, 137, 139, 226). In
several studies, dopamine increased car-
diac index and stroke volume index to a
greater extent than norepinephrine, but
increases in left and right ventricular
stroke volume index were about the same
with the two agents (101, 112). There was
less prominent tachycardia with norepi-
nephrine, and one unconrmed pilot
study suggested that mesenteric perfu-
sion is impaired with dopamine com-
pared with norepinephrine (101, 112).
Phosphodiesterase Inhibitors. Phos-
phodiesterase inhibitors are vasodilators
with long half-lives, raising the potential
for prolonged decreases in blood pressure
when used in septic patients. There are a
few small studies of these agents in pa-
tients with sepsis, but meaningful con-
clusions cannot be made because of the
size of the studies and the concomitant
use of disparate adrenergic agents (227
230).
Complications
In the septic patient who has been
inadequately volume resuscitated, all of
the inotropic agents can cause signicant
tachycardia and other cardiac arrhyth-
mias (77). In patients with coexisting cor-
onary disease, the change in myocardial
oxygen consumption may precipitate
myocardial ischemia and infarction
(199). Excessive doses of catecholamines
can also result in myocardial band necro-
sis independent of the presence of coro-
nary disease.
Sole use of inotropic agents that also
have vasodilatory activity (e.g., isoproter-
enol, milrinone) is likely to reduce blood
pressure. These reductions can be long-
lasting with agents that have long half-
lives.
Administration of inotropic agents
that have pressor activity may impair
blood ow to other organ beds, such as
the splanchnic circulation (121, 137). Ef-
forts to ensure adequate volume resusci-
tation and to assess end-organ function
must be made.
RECOMMENDATIONS FOR
HEMODYNAMIC SUPPORT OF
SEPTIC PATIENTS
Basic Principles
1. Resuscitation of patients with sepsis
should be initiated expeditiously
and pursued vigorously. Measures
to improve tissue and organ perfu-
sion are most effective when applied
early.
2. Patients with septic shock should
be treated in an intensive care unit,
with continuous electrocardio-
graphic monitoring and monitoring
of arterial oxygenation.
3. Arterial cannulation should be per-
formed in patients with shock to
provide a more accurate measure-
ment of intra-arterial pressure and
to allow beat-to-beat analysis so
that decisions regarding therapy
can be based on immediate and re-
producible blood pressure informa-
tion.
4. Resuscitation should be titrated to
clinical end points of arterial pres-
sure, heart rate, urine output, skin
perfusion, and mental status, and
indexes of tissue perfusion such as
blood lactate concentrations and
mixed venous oxygen saturation.
5. Assessment of cardiac lling pres-
sures may require central venous or
pulmonary artery catheterization.
Pulmonary artery catheterization
also allows for assessment of pul-
monary artery pressures, cardiac
output measurement, and measure-
ment of mixed venous oxygen satu-
ration. Echocardiography may also
be useful to assess ventricular vol-
umes and cardiac performance.
1942 Crit Care Med 2004 Vol. 32, No. 9
Fluid Resuscitation
Recommendation 1Level B. Fluid
infusion should be the initial step in he-
modynamic support of patients with sep-
tic shock. Initial uid resuscitation
should be titrated to clinical end points.
Recommendation 2Level B. Iso-
tonic crystalloids or iso-oncotic colloids
are equally effective when titrated to the
same hemodynamic end points.
Recommendation 3Level D. Inva-
sive hemodynamic monitoring should be
considered in those patients not respond-
ing promptly to initial resuscitative ef-
forts. Pulmonary edema may occur as a
complication of uid resuscitation and
necessitates monitoring of arterial oxy-
genation. Fluid infusion should be ti-
trated to a level of lling pressure asso-
ciated with the greatest increase in
cardiac output and stroke volume. For
most patients, this will be a pulmonary
artery occlusion pressure in the range of
1215 mm Hg. An increase in the varia-
tion of arterial pressure with respiration
may also be used to identify patients
likely to respond to additional uid ad-
ministration.
Recommendation 4Level C. Hemo-
globin concentrations should be main-
tained between 8 and 10 gm/dL. In pa-
tients with low cardiac output, mixed
venous oxygen desaturation, lactic acido-
sis, widened gastric-arterial PCO
2
gradi-
ents, or signicant cardiac or pulmonary
disease, transfusion to a higher concen-
tration of hemoglobin may be desirable.
Vasopressor Therapy
Recommendation 1Level C. Dopa-
mine and norepinephrine are both effec-
tive for increasing arterial blood pres-
sure. It is imperative to ensure that
patients are adequately uid resuscitated.
Dopamine raises cardiac output more
than norepinephrine, but its use may be
limited by tachycardia. Norepinephrine
may be a more effective vasopressor in
some patients.
Recommendation 2Level D. Phenyl-
ephrine is an alternative to increase blood
pressure, especially in the setting of
tachyarrhythmias. Epinephrine can be
considered for refractory hypotension, al-
though adverse effects are common, and
epinephrine may potentially decrease
mesenteric perfusion.
Recommendation 3Level B. Admin-
istration of low doses of dopamine to
maintain renal function is not recom-
mended.
Recommendation 4Level C. Pa-
tients with hypotension refractory to cat-
echolamine vasopressors may benet
from addition of replacement dose ste-
roids.
Recommendation 5Level D. Low
doses of vasopressin given after 24 hrs as
hormone replacement may be effective in
raising blood pressure in patients refrac-
tory to other vasopressors, although no
conclusive data are yet available regard-
ing outcome.
Inotropic Therapy
Recommendation 1Level C. Dobut-
amine is the rst choice for patients with
low cardiac index and/or low mixed ve-
nous oxygen saturation and an adequate
mean arterial pressure following uid re-
suscitation. Dobutamine may cause hy-
potension and/or tachycardia in some pa-
tients, especially those with decreased
lling pressures.
Recommendation 2Level B. In pa-
tients with evidence of tissue hypoperfu-
sion, addition of dobutamine may be
helpful to increase cardiac output and
improve organ perfusion. A strategy of
routinely increasing cardiac index to pre-
dened supranormal levels (4.5
Lmin
1
m
2
) has not been shown to im-
prove outcome.
Recommendation 3Level C. A vaso-
pressor such as norepinephrine and an
inotrope such as dobutamine can be ti-
trated separately to maintain both mean
arterial pressure and cardiac output.
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For personal use. Only reproduce with permission from The Lancet publishing Group.
970 THE LANCET Vol 363 March 20, 2004 www.thelancet.com
INPATIENT SAFETY I
It may seem a strange principle to enunciate as the very
first requirement in a hospital that it should do the sick
no harm. Florence Nightingale.
Notes on hospitals (London, 1859)
Patients safety has come to characterise the first decade
of the third millennium just as managed care and cost-
containment did the 1990s. According to the much-
quoted Institute of Medicine (IOM) report To err is
human,
1
between 44 000 and 98 000 patients die every
year in the USA as a result of clinical errors; the lower
estimate makes clinical error the seventh most common
cause of death.
2
Health care expenditure incurred as a
result of clinical errors is thought to be US$1729 billion
in the USA,
1
Au$47 billion in Australia,
3
and 6 billion in
the UK.
4,5
Those countries, and also Canada and
Denmark, are implementing systems for improving
patients safety,
68
and evidence-based recommendations
to improve safety are emerging.
9
Medical trainees quickly learnand soon come to
acceptthat some background rate of clinical error is an
unfortunate yet seemingly ineradicable feature of patient
care. What is new is the characterisation of clinical error
as an epidemic, the recognition that most errors go
undetected and unreported, and the realisation that the
public perceives clinical errors as neither acceptable nor
inevitable. In the USA, more than 40% of people report
personal or family experiences with clinical errors, and
62% favour public disclosure of serious hospital errors.
10
Causation, taxonomy, and detection
Causation
The term medical error has served as a convenient half-
truth by which adverse clinical events arising from a
presumed chain of causation are attributed to the last link
of that chain, usually a doctor or nurse. Health-care
institutions have failed to scrutinise the primary elements
in a causation pathway
11
or search for root causes,
12
even
Lancet 2004; 363: 97077
See Commentary page 913
University Department of Anaesthesia and Intensive Care
Medicine, Queen Elizabeth Hospital, Birmingham B15 2TH, UK
(J F Bion FRCA); and Center for Clinical Effectiveness and Patient
Safety, Medical University of South Carolina, Charleston, South
Carolina, USA (J E Heffner MD)
Correspondence: Dr J F Bion
(e-mail: j.f.bion@bham.ac.uk)
though other industries have been implementing error
analysis for decades. Error-reduction efforts in health care
have focused on the doctor-patient interface that might
seem to casual observers to be the most obvious cause of
medical accidents. Although failures by clinicians do
contribute to unsafe acts, efforts to correct the
performance of individual health-care providers seldom
contribute to a general improvement in patients safety
throughout a health-care system.
Studies of human error in industrial and transportation
accidents
13
have refocused our understanding of clinical
errors as a systems problem that requires systems-oriented
solutions. Latent failures embedded in organisational
design set the stage for unsafe practices. Failures such as
poorly designed equipment and monitoring alarms, paper
records with illegible physician orders, and work
conditions that promote fatigue and inattention lie
dormant within organisations structures until a fatigued
clinician with poor handwriting, for example, or a high
patient turnover triggers error. Heinrich surveyed
14
industrial accidents in the 1940s and estimated that for
every major adverse event there were 29 minor ones and
300 non-injury accidents (near-misses). If similar
proportions relate to health care, latent failures represent
a tremendous opportunity to improve patient safety.
Even though errors of omission outnumber errors of
commission by two to one,
3
organisations respond more
readily to errors of commissionfor example, by
addressing the risk of administering highly concentrated
potassium solutions intravenously while overlooking
failure to correct hypokalaemia, which affects 20% of
inpatients and promotes life-threatening cardiac
Challenges in the care of the acutely ill
J F Bion, J E Heffner
Health care providers, hospital administrators, and politicians face competing challenges to reduce clinical errors,
control expenditure, increase access and throughput, and improve quality of care. The safe management of the
acutely ill inpatient presents particular difficulties. In the first of five Lancet articles on this topic we discuss patients
safety in the acute hospital. We also present a framework in which responsibility for improvement and better
integration of care can be considered at the level of patient, local environment, hospital, and health care system; and
the other four papers in the series will examine in greater detail methods for measuring, monitoring, and improving
inpatient safety.
Inpatient safety I
Search strategy
We focused our review on patients safety and the
management of the acutely ill hospital patient. To retrieve
information about the health care environment, we also
searched for publications about health care organisation and
emergency services. We used MEDLINE, EMBASE, and
Google, to access government publications and grey
literature, using singly and in paired combination the terms
safety, medical error, postoperative complications,
emergency medical services, critical care, and intensive care.
We discussed the themes extracted from this process with
other authors in the series and with professional colleagues
worldwide.
For personal use. Only reproduce with permission from The Lancet publishing Group.
of the public in the USA, 50% believed that suspension of
licences to practise would be an effective way to prevent
clinical error.
10
Substantial cultural differences also seem
to exist between medical disciplines
33
and between
countries
34,35
in attitudes to error. A reduction in
professional authority might have contributed to a
lessening of physicians sense of personal responsibility for
the duration of their patients care. Methods for reducing
error need to take into account changing doctor-patient
relationships and cultural differences.
Comparisons with industry
The safety and error-prevention record for health care
services is often compared unfavourably with that of
aviation, banking, chemicals, manufacturing, and military
services in peacetime, the best of which have highly
developed strategies to protect workers and clients. These
strategies include a safety culture that emphasises the
importance of safe practices, commitment of management
to safety, and non-punitive and simplified reporting of
errors with feedback of error analyses. Aviation has
focused on the importance of working in teams, and
lessons learned from crew resource management are
starting to be applied to health care.
36
Industries with successful safety records emphasise
standardisation of practices combined with flexibility to
address unique circumstances. They also invest in safety
training and research. This strategy has resulted in
substantial reductions in errors and adverse outcomes,
with some industries reporting no serious workforce
injuries for many years. The IOM has adopted the
viewpoint of groups that study high reliability
organisations (nuclear aircraft carriers, nuclear power
plants, and air-traffic control) that successful systems
engineering for high levels of safety is achievable.
3739
Health services have, therefore, been encouraged to
align their safety efforts with those of industry
40
and aim for
an error rate of less than 34 per million events.
41
This is
known as six sigma quality because it lies outside six
SDs of a normal distribution. Anaesthesia has made
substantial contributions to patients safety through
concerted efforts by practitioners and equipment
manufacturers to standardise processes. The IOM report
1
states that deaths attributable to anaesthesia have fallen to
54 per million, which approaches five sigma, although the
validity of the data that support this observation has been
questioned.
42
The persistence of a steady rate of fatalities in
aviation
22
or road transport
43
despite increased traffic
volume suggests that benefits of safety efforts could be
counterbalanced by competing risk factors, such as high
throughput, seriously ill patients, and complex
interventions.
Although industrial experience provides valuable insight
into potential solutions for clinical errors, the extent to
which it applies to health care remains uncertain. Health
care is characterised by highly complex processes, unique
problems and needs of individual patients, loosely knit
teams, multiple outcome measures, incomplete evidence
for many health care decisions, and varying layers of
responsibility. In hospitals, unpredictable workloads and
uncertainty about individual patients outcomes are
additional factors. A more appropriate industrial analogy
for safe care of the acutely ill patient would be the armed
forces contending with the uncertainties of warfare,
friendly fire, and collateral damage, a distinction which
governments seem willing to apply to safety of military
personnel.
44
Health services should learn from other
industries but they need models that address the unique
challenges of the acute hospital setting.
THE LANCET Vol 363 March 20, 2004 www.thelancet.com 971
arrhythmias.
15
Health services need to find novel ways of
avoiding errors of omission. Routine necropsy provides
one opportunity for identifying diagnostic and therapeutic
errors but they are less common than they used to be.
16
Although a systems approach has improved safety in the
aerospace and airline industries by identifying and
correcting latent errors, systems engineering remains
largely untested in health care.
17
Definitions
Disagreement exists not only about the precise scale of
medical error,
1821
the degree of public disclosure required
to stimulate safer medical practices,
10
and the extent to
which errors can be eliminated in complex systems,
22
but
also about the terminology.
17,23
The IOM used an
outcomes-based definition: the failure of a planned
action to be completed as intended or the use of a wrong
plan to achieve an aim.
1
Others define error as latent
failures at the systems level that include human,
organisational, and technical constraints on
performance,
24
whether there are adverse consequences or
not. Lumpers include any instance of underuse,
overuse, or misuse of medical care
23
whereas splitters
confine the definition to failed processes that have been
proved to cause adverse outcomes.
17
These competing taxonomies mesh poorly with the
definitions of health care quality on which efforts to
improve organisational performance are based.
2529
Definitions of quality incorporate concepts of causation,
attribution, preventability, and near-misses, which are
absent from definitions of medical error. Communication
is hampered too; so is research; and the identification and
correction of unsafe practices before an adverse event
occurs are delayed. The medical errors movement has yet
to take full advantage of the principles of outcomes
research. For instance, no investigators have
comprehensively and prospectively looked at the
frequency of clinical errors using a priori definitions to
establish causative links between errors and outcomes.
17
Most of the studies used for the IOM report were not
designed primarily to detect errors, assessors were not
masked to outcomes, and the reliability of the measures
were not provided. Because trained investigators have
poor interobserver agreement in identifying clinical errors
from medical record reviews,
21,30
clinicians justifiably
expect prospective, masked, outcome-based studies to
determine the dimensions of the problem, identify
methods for correcting it, and describe the quality of
acute care.
31
Cultural context
The causes of error are diverse, often complex, and rarely
attributable to single actions, events, or individuals. The
causes are usually rooted in unsafe systems rather than
individual caregivers. The final common pathway,
however, is the interaction between practitioner and
patient. This relation has undergone a profound change in
the past 50 years. Previously paternalistic, personal,
trusting, limited in therapeutic potency and low in
expectation of results, patient-clinician interactions have
become more equal, transparent, team-based, and
contractual. Patients want doctors to communicate more
effectively and devote more time to them. Treatments
have become more effective and have a correspondingly
greater capacity to harm if misused.
32
Increasingly, the public expects medical services to
deliver the anticipated results, and on time, and if the
outcome is not as anticipated, a culprit must be sought
and retribution exacted. In a telephone survey of members
INPATIENT SAFETY I
For personal use. Only reproduce with permission from The Lancet publishing Group.
972 THE LANCET Vol 363 March 20, 2004 www.thelancet.com
Error and environment
Although most large safety studies have been in acute care
settings, few distinguish between elective admissions and
emergency admissions or emergencies during planned
treatment. Elective admissions and procedures have well-
defined care pathways which facilitate analysis of
deviations; emergencies tend to be less predictable. In our
view emergency care needs to be seen as a separate entity
with a focus on patients safety that cuts across disciplines
and departments. In view of the pressures to accelerate
patient throughput, improved safety will also require better
integration of community health care with discharge
planning, especially since preventable adverse events might
affect 6% of patients after hospital discharge.
45
Error in acute care
The risk of adverse events is higher for patients admitted to
emergency departments
3, 4648
and general medical wards
than for those admitted for elective surgery.
4,49
Clinical
errors most commonly affect the elderly,
3
who account for
most emergency admissions
50
and have the highest risk
from emergency surgery.
51
The risk of error increases when
such care is provided, as it often is, by inexperienced
clinicians and unsupervised trainees.
5254
The risk of an
adverse event increases by about 6% per day for patients
admitted as emergencies ,
55
and is especially high for those
needing lifesaving invasive interventions.
46
Critical illness increases the opportunity for clinical
error
5659
because of the complexity of patients problems
and the frequency of invasive interventions. The intensity
of monitoring in critical care units means that errors are
more likely to be detected. Iatrogenic complications are a
common cause of admission to intensive care,
60
and
previously suboptimal care is associated with an increased
mortality in the intensive care unit.
61
Cardiopulmonary
arrest in hospital is frequently preceded by warning signs
62
and can be prevented by interventions to identify and
manage patients earlier.
63
Premature discharge from
intensive care is associated with increased in-hospital
mortality.
64
These factors confirm the need for a systems
approach to error prevention.
Effect of case-mix
The greater risk of clinical errors in emergency admissions
is especially alarming because of the increasing demand for
emergency care.
65,66
In the USA, emergency admissions
constitute more than a third of all hospital admissions,
41% of admissions of children, and 55% of admissions of
patients older than 80 years. 54% have at least one
comorbid condition and a third have two or more.
67
Age
and comorbid disease add to the risk of adverse events
68
either from limited physiological reserve or because of
exposure to more interventions. In the UK, about 60% of
hospital admissions are emergencies, and the proportion
has been increasing yearly by 21% since 1989, when data
were first collated. For patients older than 65 years, the
annual increase is 33%.
69
Changes in service provision
In many developed countries the need for emergency
services has been growing in parallel with pressures to
reduce length of stay and numbers of beds.
70
For example,
day-cases account for an increasing proportion of elective
admissions. In the UK, the number of National Health
Service beds fell from 480000 in 1948 to 190000 in 1998,
throughput and occupancy have increased, and length of
stay has shortened.
69
Many regions in the USA have
shortages of beds and face the need to replace old
hospitals, and increasingly crowded emergency depart-
ments have a statutory obligation to provide care for the
46 million Americans who carry no health insurance.
These pressures can represent a substantial hindrance to
efforts to improve safety.
Poor integration of acute hospital services can also
contribute to error. Market forces in the USA promote
competition between neighbouring facilities, often
resulting in redundant services. In the UK, however, a
desire for convenient local access causes acute hospitals to
proliferate, preventing economies of scale when nearby
hospitals replicate specialist services, a tension reflected in
abrupt changes in governmental planning.
71
This lack of
integration dilutes professional experience, including
operative procedures, and lowers competency and quality
of outcomes.
Working hours
To provide safe acute care means employing adequate
numbers of trained staff, which is increasingly difficult in
the European Union because the Working Time Directive,
from August, 2004, limits the working hours for trainee
doctors to 56 per week and to an average of 48 for all
employees by 2009. Work is defined as required to be
present at the health centre regardless of the activities
being undertaken. This ruling has important implications
for out-of-hours and emergency care
72
since being asleep in
an on-call bedroom will still count as work. In the USA,
resident physicians in training have, since July, 2003, been
limited to an average of 80 h a week.
73
Comparison of the
effects of the European and American regulations should
prove useful, in view of evidence that fatigue from long
hours of work impairs patient safety.
74
Concerns have been expressed that these constraints
may adversely affect training and acquisition of skills.
75
They will certainly strain services in countries that have a
physician shortage. It will not be possible to train enough
extra doctors in the UK to fill the gap created by the
European directive before 2015. Reliance on non-
physician care-givers may improve the delivery of
preventive medicine and enhance performance of specific
tasks but does not seem to improve acute care.
76
Moreover,
the worldwide shortage of nurses
77
restricts the large-scale
transfer of traditional physician duties. A more
constructive approach for maintenance of patients safety
in acute care would be to focus on models of team-working
rather than transferring work to other groups.
Discontinuities in patient care
Hospital medicine has become increasingly compart-
mentalised, with blurred borders of responsibility and
multiple transitions (hand offs) between different health
care providers and teams.
78
The benefits of reduced fatigue
from restricted hours of work for medical staff may be
offset by the discontinuities in care and personal isolation
caused by shift-working, the greater risk of communication
failures, and constraints on the delivery of clinical
education. A clinical vignette illustrates the problems
(panel).
This patient did not have just one illness and nor did she
have a distinct medical error that resulted in a well-defined
adverse event. She had several comorbidities, was exposed
to high-risk interventions with known side-effects, and was
treated in an acute care environment with insufficient
safeguards against clinical error. Potentially avoidable
adverse events were caused by faulty actions and inactions,
suboptimal training, poor supervision, and inadequate
service provision at local and national levels. However,
establishing a root-cause would be difficult because of the
varied, diffuse, and overlapping failures.
INPATIENT SAFETY I
For personal use. Only reproduce with permission from The Lancet publishing Group.
summary of some of these issues. The next four articles in
this Lancet series will go into more detail, looking at the
monitoring of and improvements in safety for the acute
inpatient, both from a local and a systems standpoint.
Resources and organisation
Emergency departments
Safe emergency care needs prompt access to initial
treatment for life-threatening emergencies, and hospitals
cannot provide that if their emergency departments are
overloaded by medical problems that could have been
managed by a family practitioner or a pharmacist. Patients
cannot obtain prompt treatment without either adequate
local facilities or an efficient ambulance service. In large
hospitals, parallel provision of primary and secondary care
within the emergency department improves efficiency and
focuses resources on sicker patients. Small and rural acute
hospitals will need local solutions to professional staffing
that include shared management of the emergency
department by community practitioners, consultation
available via telemedicine links, and appropriately staffed
rapid transport to take more seriously ill patients to better-
equipped centres. This hub-and-spoke integration is well-
accepted for paediatric emergency care.
82,83
Appropriate
investment in training and career structures will also be
needed to encourage practitionersmedical and non-
medicalto develop team-based approaches to
emergency care as a method for reducing errors and
improving quality.
84,85
Models for delivering acute care
Future clinicians who provide core services in the acute
hospital setting will need new skill sets, which will be
transdisciplinary and especially suited to the range of
health care needs of hospital patients. Physicians, nurses,
pharmacists, and other health-care providers will develop
team-based models of care that avoid gaps in knowledge
and services. These gaps constitute an important risk for
patient safety.
86
Essential skill sets will draw on
anaesthesia, internal medicine, surgery, accident and
emergency medicine, basic sciences, and ethics whereas
behavioural competencies will learn from aviation and
crew resource management.
86
Critical care medicine
illustrates this development. Intensivists (ie, intensive care
specialists) have become the general practitioners of acute
care. They have adopted multidisciplinary collaboration,
contributed to systems management within intensive care,
and emphasised intervention at the first signs of clinical
instability. Integrative models with well-organised systems
within intensive care units have reduced mortality,
87
and
the appointment of intensivists is a key recommendation
of the Leapfrog Group in the USA for improving hospital
safety.
88
In the USA, acute hospital care has been developed into
a professional track termed hospital medicine practised by
the hospitalist.
89
Australian hospitals have extended
intensive care services and personnel into hospital wards
by creating medical emergency teams.
90
The UK has
outreach care provided by critical-care-trained nurses for
patients admitted to the wards.
91
Such outreach detects
early signs of clinical deterioration and improves
communication between ward admitting teams and staff
in intensive care units.
92,93
Although there are no
comparative data to favour one model over another,
studies suggest that early intervention might reduce
cardiac arrest rates,
63,94
though there is also the risk that
the point of death could merely be shifted to the ICU.
63
Better integration should also extend into post-hospital
recovery. We are only just beginning to identify the safety
THE LANCET Vol 363 March 20, 2004 www.thelancet.com 973
Vincent and colleagues
79,80
have developed a structured
approach for analysis of such episodes, combining the
factors that affect clinical practice with Reasons
81
organisational model of error. We have adapted this
model, bringing in elements from the quality literature
(table), as a method for assessment safe care of the acutely
ill patient.
Responding to the challenge
Our perspective is that safety and reliability are the most
important components of quality in health care and that
services need extensive restructuring to achieve an
acceptable level of these characteristics of high quality
care. The restructuring demands a systems approach. In
the panel, we identify deficiencies in resources and
organisation, processes and delivery of care, monitoring,
clinical competence, communication, continuity of care,
therapeutic interventions including prescribing, leadership
and governance, and patient empowerment. We classify
these deficiencies as occurring at the four levels of patient,
microsystem, organisation, and environment, a
classification that allows consideration of quality and
safety issues from different perspectives. What follows is a
INPATIENT SAFETY I
A 56-year-old woman was admitted on a Saturday evening to
a university teaching hospital with progressive malaise,
diffuse abdominal pain, and diarrhoea 1 week after
chemotherapy for breast cancer. 10 years previously she had
had cancer in the other breast and had undergone
mastectomy with radiotherapy. She was on warfarin for an
axillary vein thrombosis caused by a Hickman catheter and
had a history of penicillin allergy. She was apyrexial,
tachypnoeic, hypotensive, and oliguric; total leucocyte count
of less than 0110
3
/L
3
, platelets 7010
3
/L
3
, serum
creatinine 170 mol/L, and international normalised ratio
62. Blood culture produced gram-negative rods within 12 h.
She was treated by the resident medical staff in the
emergency unit with piperacillin and gentamicin, inadequate
intravenous fluids, parenteral non-steroidal anti-inflammatory
analgesics, and diuretics. She had a head injury after falling
unobserved from the commode where she had been placed
by the nursing assistants, who then sat her in a chair despite
a documented systolic blood pressure of 70 mm Hg. There
were only two trained nurses on duty for this 28-bed ward.
She was eventually seen by a consultant 24 h after
admission, and was referred to intensive care in neutropenic
septic shock with multiple organ failure.
Because no bed was immediately available in the intensive
care unit, mechanical ventilation and cardiovascular support
were started in the ward. Preparations for transfer to another
hospital were cancelled when an appropriate bed did become
free. Shortly after admission she developed a transient rash
that was attributed to piperacillin, already discontinued. A CT
scan showed a small subdural haematoma that did not need
intervention other than correction of the coagulopathy. Renal
replacement treatment was needed. During her 4 weeks in
intensive care, she developed a ventilator-associated
pneumonia and became colonised with meticillin-resistant
Staphylococcus aureus. After being discharged to the ward,
she developed bacteraemia from a central venous catheter
that had been left in place several days longer than intended
and needed a brief re-admission to intensive care.
She returned home 2 months later, weak but able to look
after herself. Her husband confided that he was surprised by
the contrast between the quality of care in the intensive care
unit compared with that on the ward.
For personal use. Only reproduce with permission from The Lancet publishing Group.
974 THE LANCET Vol 363 March 20, 2004 www.thelancet.com
issues of post-discharge care,
45
though we know that the
physical consequences of critical illness persist.
95
Processes and delivery of care
Providing evidence-based interventions in a coordinated
and prompt manner to patients with complex health
problems defies the human abilities of inpatient
practitioners. With over 30000 new publications entering
the MEDLINE database each month, clinicians need
knowledge pathfinders to assist their decision-making. Safe
care of patients will need greater reliance on clinical
pathways, clinical practice guidelines, and decision support
tools. No longer physician-centric, transdisciplinary
teams will undertake their clinical responsibilities in an
integrated manner using guidelines and protocols. A team
approach using treatment algorithms has achieved more
rapid weaning of ventilator-dependent patients compared
with physician-dependent approaches.
96
Clinical practice
guidelines, adapted to the local clinical setting, increase the
likelihood of desired health-care outcomes.
97
Information management and communication
Failures of communication between health-care providers
and between clinicians and patients are common causes of
error and litigation. Training in communication skills will
be especially important for multidisciplinary teams
functioning in rapid-paced inpatient settings. The electronic
medical record and computerised physician order entry
(prescription system) offer opportunities to provide
clinicians with an electronic platform that embeds decision
support and knowledge resources to promote best practice.
Computerised prescribing should improve patient safety by
reducing documentation and by warning of potential drug
interactions, contraindications, dosing adjustments, and
allergies. Evidence is emerging for benefits from error
reduction and improved decision making,
98,99
and computer-
assisted record keeping and prescribing are among the
interventions recommended by the Leapfrog Group.
88
Information technology does need staged bottom-up
development, pilot testing, and appropriate implemen-
tation into existing hospital cultures. Greater dependency
on computerised systems creates new safety issues when
the system fails.
100
However, health services for the most
part still depend on the oral transmission of information
supported by handwritten records. It does seem logical to
build on the progress with computerised prescribing, and
develop an electronic patient record with modules for
investigations, diagnosis, interventions, and outcomes.
Monitoring and analysis
Early warning systems
Traditional monitoring in the acute hospital often
identifies adverse events only after they occur. Reactive
systems, based on instructions to call a doctor if there are
major changes in vital signs, should be replaced by
proactive monitoring to identify early changes and
empower ward staff to call for help and initiate further
investigation to prevent or limit the magnitude of adverse
events.
92,93,101
Adverse event and error monitoring
Adverse event reporting is essential for improving patient
safety but current methods are unsatisfactory.
102
Major
events may be more reliably reported, but near-misses are
likely to be ignored, deferred, or forgotten in the
pressured environment of clinical work. Barriers include
cumbersome and non-standardised paper formats; a
litigious culture that deters open reporting and discussion;
difficulty with identifying and reporting errors of
omission; a long interval between intervention and
adverse outcome (for example, nosocomial infection);
deficiencies in information synthesis, analysis, and
feedback; and failure of institutions to address
improvements in processes of care. Whether incident
reporting should be process or outcomes based remains
unclear.
INPATIENT SAFETY I
Level
Patient Microsystem Organisation Environment
Resources and organisational Equity Outreach, medical emergency Evidence-based resource Patients safety agencies
structures Access teams, hospitalists management Clinical networks
Patient safety officer at Interhospital transport
hospital board level systems
Health-care funding
Processes and delivery of care Competence Transdisciplinary team-working Mapping the patient Primary and secondary care
Compassion Policies, protocols and journey linkages
Timeliness procedures Admission, Best practice guidelines
Computerised prescribing discharge, and transfers
Infection control
Information management and Electronic patient records Continuity of care and information Responsiveness National framework
communication including prescribing transfer Intranet access Workplace-based access linking safety, clinical
(computerised patient to information practice and training
order entry, CPOE) Collaborative planning
Monitoring and analysis tools Severity of illness and Audit and PSDA cycles, including Adverse event monitoring Benchmarking
early warning systems errors of omission Consumer surveys Target indicators
Questionnaires, feedback Adverse event reporting and Staff sickness and Serious adverse
Patient-centred outcomes near-misses turnover rates event databanks
Failure mode and effects Observational databases,
analysis standardised mortality ratios
Root cause analysis Control charts
Competence, training, Advance directives Workplace-based training and Investment in and Integrated transdisciplinary
education, and behaviour Public education in assessment of knowledge, skills, appointment of appropriately competency-based training
healthcare outcomes attitudes, and behaviour skilled staff at undergraduate and
postgraduate level
Governance Empowerment through Local leadership and responsibility Culture of safety and Professional self-regulation
education, participation for individual patient outcomes learning Continuing professional
and transparency Collaborative management development
in the front-line Hospital accreditation
PSDA=patient self-determination act.
Conceptual framework for evaluating safe care of the acutely ill patient
For personal use. Only reproduce with permission from The Lancet publishing Group.
Health care providers cannot be passive in this process
but must lead it, if they are to show patients that they are
worthy of public trust, and they must lead by example and
from the front. This in turn requires commitment from
the public, from politicians and from administrators to
provide an infrastructure that facilitates safe care and to
support those responsible for delivering it.
Conflict of interest statement
None declared.
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Hospitals need data collection systems that allow
providers to enter information anonymously and easily.
Intranet-based online systems with automated analysis
and reporting to directors of patient safety and hospital
executives should improve institutional responsiveness.
103
Collation of institutional data by regulatory or
governmental agencies should make it easier to detect
patterns and recommend improvements. The US
University Health System Consortium has an internet-
based reporting system; the Joint Committee on
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voluntary reporting of sentinel events; and four agencies
within the US Department of Health and Human Services
are integrating their data systems on clinical errors or
adverse events. These developments will increase the
pressure for public disclosure of patient safety records but
such data must accurately reflect the quality of care and
the hospitals case-mix. So far, no such data collection
systems exist.
Competency-based training
Many of our proposals need investment in new ways of
training health care personnel. Traditional teaching has
been specialty-based. Evidence of the trainees success in
making the transition to independent practitioner has
rested on the completion of training of the required
duration followed by a formal examination. This model
has not facilitated horizontal integration of trainees across
disciplines, and it has inhibited the sharing of knowledge
and skills, and impeded collaboration and team building.
The focus on knowledge assessment also produces a
barrier between the curriculum and desirable educational
outcomes. This is now starting to change with the
development of competency-based training.
Competency-based training replaces time-based
training. The process of defining areas of competence and
mapping it to the core curriculum promotes integration of
common elements across specialties. Patients safety will
become one such core competency. The UK has a
competency-based training programme for multidisci-
plinary intensive-care medicine,
104
and proposals are being
developed for a similar approach across Europe. The US
Accreditation Council for Graduate Medical Education
has also restructured postgraduate medical education
around competency-based outcomes.
The same educational principles must be applied in the
undergraduate setting but undergraduate curricula
remain largely silent on patients safety.
105
One method by
which undergraduates can learn the basic principles of
patients safety and team-working in acute care is by
provision of transdisciplinary peer-led tuition in
resuscitation and emergency care, training senior students
to act as tutors and role models in multidisciplinary
groups.
106
Governance: taking responsibility for change
To achieve improvements in acute patient safety in the
current climate and across different health care systems
will take many years, but the process has started. Classen
103
proposes four evolutionary stages: building awareness;
development of organisational learning; proactive
management of risk; and establishment and maintenance
of high reliability organisations.
104
Progress through these
stages will need a multiplicity of approaches, from step-
change at a local level to strategic planning at national and
international levels. It will also need the establishment of
common goals and shared responsibilities as we build
partnerships between the public, practitioners, politicians,
administrators, insurers, and educators.
INPATIENT SAFETY I
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INPATIENT SAFETY I
Predicting Fluid Responsiveness in ICU
Patients*
A Critical Analysis of the Evidence
Frederic Michard, MD, PhD; and Jean-Louis Teboul, MD, PhD
Study objective: To identify and critically review the published peer-reviewed, English-language
studies investigating predictive factors of fluid responsiveness in ICU patients.
Design: Studies were collected by doing a search in MEDLINE (from 1966) and scanning the
reference lists of the articles. Studies were selected according to the following criteria: volume
expansion performed in critically ill patients, patients classified in two groups (responders and
nonresponders) according to the effects of volume expansion on stroke volume or on cardiac
output, and comparison of responder and nonresponder patients characteristics before volume
expansion.
Results: Twelve studies were analyzed in which the parameters tested were as follows: (1) static
indicators of cardiac preload (right atrial pressure [RAP], pulmonary artery occlusion pressure
[PAOP], right ventricular end-diastolic volume [RVEDV], and left ventricular end-diastolic area
[LVEDA]); and (2) dynamic parameters (inspiratory decrease in RAP [RAP], expiratory decrease
in arterial systolic pressure [down], respiratory changes in pulse pressure [PP], and respiratory
changes in aortic blood velocity [Vpeak]). Before fluid infusion, RAP, PAOP, RVEDV, and
LVEDA were not significantly lower in responders than in nonresponders in three of five studies,
in seven of nine studies, in four of six studies, and in one of three studies, respectively. When a
significant difference was found, no threshold value could discriminate responders and nonre-
sponders. Before fluid infusion, RAP, down, PP, and Vpeak were significantly higher in
responders, and a threshold value predicted fluid responsiveness with high positive (77 to 95%)
and negative (81 to 100%) predictive values.
Conclusion: Dynamic parameters should be used preferentially to static parameters to predict
fluid responsiveness in ICU patients. (CHEST 2002; 121:20002008)
Key words: arterial pressure; cardiac output; cardiac preload; fluid responsiveness; left ventricular end-diastolic area;
pulmonary artery occlusion pressure; right atrial pressure; right ventricular end-diastolic volume; stroke volume; volume
expansion
Abbreviations: down expiratory decrease in arterial systolic pressure; LVEDA left ventricular end-diastolic area;
PAOP pulmonary artery occlusion pressure; PEEP positive end-expiratory pressure; PP respiratory changes in
arterial pulse pressure; RAP right atrial pressure; RAP inspiratory decrease in right atrial pressure;
RVEDV right ventricular end-diastolic volume; Vpeak respiratory changes in aortic peak velocity
V
olume expansion is frequently used in critically ill
patients to improve hemodynamics. Because of
the positive relationship between ventricular end-
diastolic volume and stroke volume,
1
the expected
hemodynamic response to volume expansion is an
increase in right ventricular end-diastolic volume
(RVEDV), left ventricular end-diastolic volume,
stroke volume, and cardiac output. The increase in
end-diastolic volume as a result of fluid therapy
depends on the partitioning of the fluid into the
different cardiovascular compliances organized in
*From the Medical ICU, CHU de Bice tre, Assistance Publique-
Ho pitaux de Paris, Le Kremlin-Bice tre, Universite Paris XI,
France.
Manuscript received June 4, 2001; revision accepted December
19, 2001.
Correspondence to: Frederic Michard, MD, PhD, Service de
Reanimation Medicale, CHU de Bicetre, Universite Paris XI, 78,
rue du General Leclerc, 94275 Le Kremlin Bicetre cedex, France;
e-mail: f.michard@wanadoo.fr
critical care review
2000 Critical Care Reviews
series. The increase in stroke volume as a result of
end-diastolic volume increase depends on ventricu-
lar function since a decrease in ventricular contrac-
tility decreases the slope of the relationship between
end-diastolic volume and stroke volume.
1
Therefore,
only 40 to 72% of critically ill patients have been
shown to respond to volume expansion by a signifi-
cant increase in stroke volume or cardiac output in
studies
213
designed to examine fluid responsiveness.
This finding emphasizes the need for predictive
factors of fluid responsiveness in order to select
patients who might benefit from volume expansion
and to avoid ineffective or even deleterious volume
expansion (worsening in gas exchange, hemodilu-
tion) in nonresponder patients, in whom inotropic
and/or vasopressor support should preferentially be
used.
Bedside indicators of ventricular preload have
been proposed as predictors of fluid responsive-
ness.
24,69,1113
In this regard, a postal survey in
Germany showed that right atrial pressure (RAP)
and pulmonary artery occlusion pressure (PAOP) are
used by a majority of ICU physicians when deciding
to administer fluid,
14
and several recommendations
support the use of cardiac filling pressures in order
to guide fluid therapy in critically ill patients.
15,16
Other bedside indicators of ventricular preload,
namely RVEDV and left ventricular end-diastolic
area (LVEDA), have also been tested as predictors of
the hemodynamic effects of volume expansion in
critically ill patients.
24,69,11,13
The respiratory changes in RAP, arterial pressure,
and aortic blood velocity, assumed to be dynamic
indicators of the sensitivity of the heart to changes in
preload induced by changes in pleural pressure, have
also been proposed to predict fluid responsiveness in
critically ill patients.
5,9,10,12,13
Therefore, the aim of
the present study was to analyze the clinical studies
investigating predictive factors of fluid responsive-
ness in critically ill patients in order to assess the
value of each parameter tested.
Materials and Methods
Selection of Studies To Be Evaluated
We collected studies investigating the predictive factors of
fluid responsiveness in critically ill patients by doing a search in
MEDLINE (from 1966). Studies were selected according to the
following criteria: volume expansion performed in critically ill
patients, patients classified in two groups (responders and non-
responders) according to the effects of volume expansion on
stroke volume or on cardiac output, and comparison of responder
and nonresponder patients characteristics before volume expan-
sion. The reference lists of the selected articles were scanned for
additional studies. Of the 12 included studies,
213
11 studies were
identified from the electronic database and 1 study was identified
from reference tracing.
5
The main characteristics of these studies
are presented in Table 1.
Parameters Tested as Predictors of Fluid Responsiveness
Ten studies have investigated the value of ventricular
preload indicators in predicting fluid responsiveness. The
parameters tested were RAP in five studies,
24,8,12
PAOP in
nine studies,
24,69,11,12
RVEDV in six studies,
24,68
and
Table 1Main Characteristics of Clinical Studies Investigating the Predictive Factors of Fluid Responsiveness in
ICU Patients*
Source
Patients,
No.
FC,
No.
Fluid
Infused
Volume
Infused, mL
Speed of
FC, min
Definition of
Response
Rate of
Response, % Parameters Tested
Calvin et al
2
28 28 5% Alb 250 2030 SV 0% 71 RAP, PAOP, RVEDV
Schneider et al
3
18 18 FFP 500 30 SV 0% 72 RAP, PAOP, RVEDV
Reuse et al
4
41 41 4.5% Alb 300 30 CO 0% 63 RAP, PAOP, RVEDV
Magder et al
5
33 33 9% NaCl 100950 CO 250 52 RAP
mL/min
Diebel et al
6
15 22 R. lactate 300500 CO 10% 59 PAOP, RVEDV
Colloids 500
Diebel et al
7
32 65 R. lactate 300500 CO 20% 40 PAOP, RVEDV
Wagner and 25 36 9% NaCl 938 480 7120 SV 10% 56 RAP, PAOP, RVEDV
Leatherman
8
5% Alb, FFP 574 187
Tavernier et al
9
15 35 HES 500 30 SV 15% 60 PAOP, LVEDA, down
Magder and Lagonidis
10
29 29 25% Alb 100 15 CO 250 45 RAP
9% NaCl 150400 mL/min
Tousignant et al
11
40 40 HES 500 15 SV 20% 40 PAOP, LVEDA
Michard et al
12
40 40 HES 500 30 CO 15% 40 RAP, PAOP, PP
Feissel et al
13
19 19 HES 8 mL/kg 30 CO 15% 53 LVEDA, Vpeak
Total 334 406 52
*FC fluid challenge; Alb serum albumin; FFP fresh frozen plasma; NaCl serum saline solution; R. lactate Ringers lactate;
HES hydroxyethylstarch; SV volume expansion-induced changes in stroke volume; CO volume expansion-induced changes in cardiac
output.
www.chestjournal.org CHEST / 121 / 6 / JUNE, 2002 2001
LVEDA in three studies
9,11,13
(Table 1). In all studies, the RAP
and PAOP were measured at end-expiration without ventilator
disconnection or removal of positive end-expiratory pressure
(PEEP). In four studies,
4,68
RVEDV was calculated from the
measurement of right ventricular ejection fraction and cardiac
output by using a fast-response thermistor pulmonary artery
catheter as follows: RVEDV (cardiac output/heart rate)/
right ventricular ejection fraction. In two other studies,
2,3
RVEDV was evaluated by cardiac scintigraphy. LVEDA was
measured by transesophageal echocardiography using the
transgastric short-axis view of the left ventricle.
9,11,13
Five studies have investigated the value of dynamic parameters
in predicting fluid responsiveness. These parameters were the
inspiratory decrease in RAP (RAP) in two studies,
5,10
the
expiratory decrease in arterial systolic pressure (down) in one
study,
9
the respiratory changes in arterial pulse pressure (PP) in
one study,
12
and the respiratory changes in aortic blood velocity
(Vpeak) in one study
13
(Table 1). The RAP was calculated as
the difference between the expiratory and the inspiratory
RAP.
5,10
The down was calculated as the difference between
the value of the systolic pressure during an end-expiratory pause
and the minimal value of systolic pressure over a single respira-
tory cycle.
9
The PP was calculated as the difference between
the maximal and the minimal value of pulse pressure over a single
respiratory cycle, divided by the mean of the two values, and
expressed as a percentage.
12
The Vpeak was calculated as the
difference between the maximal and minimal peak velocity of
aortic blood flow over a single respiratory cycle, divided by the
mean of the two values, and expressed as a percentage.
13
Aortic
blood flow was measured by a pulsed-wave Doppler echocardio-
graphic beam at the level of the aortic valve.
13
Results
There were 406 fluid challenges in 334 patients
(Table 1). Most of the patients were septic (55%) and
receiving mechanical ventilation (84%). The decision
of volume expansion was based on criteria listed in
Table 2. Fluid administration was performed using
colloid solutions (albumin, fresh frozen plasma, or
hydroxyethylstarch) in 253 instances, and crystalloid
solutions (serum saline solution or Ringers lactate)
in 153 instances (Table 1). In nine studies, the volume
infused was predetermined and ranged from 250 to
500 mL for colloids and from 300 to 500 mL for
crystalloids (Table 1). In two studies,
5,10
volume infu-
sion was performed until a rise in RAP 2 mm Hg
was obtained; hence, the volume of serum saline
solution infused varied from 100 to 950 mL. In
another study,
8
fluid was administered until a rise
in PAOP 3 mm Hg was obtained. In this case,
the volume infused was 938 480 mL for serum
saline solution and 574 187 mL for 5% albumin
or fresh frozen plasma. The speeds of fluid infusion are
reported in Table 1. In all studies but one,
9
hemo-
dynamic measurements were performed just before
and immediately at the end of fluid infusion.
The hemodynamic response to volume expansion
was defined by an increase in stroke volume in five
studies and in cardiac output in seven studies (Table
1). The values of stroke volume or cardiac output
increase used to define responder and nonresponder
patients are presented in Table 1.
RAP
Before volume expansion, RAP was not signifi-
cantly lower in responders than in nonresponders in
three of five studies
2,4,12
(Fig 1). The two remaining
studies
3,8
reported a lower value of baseline RAP in
Table 2Criteria Used to Decide Volume Expansion*
Source Criteria
Calvin et al
2
Cardiac index 3.5 L/min/m
2
and PAOP 12 mm Hg in septic and trauma patients
Cardiac index 2.5 L/min/m
2
and PAOP 20 mm Hg in acutely ill patients with a defined cardiac cause
Schneider et al
3
Systematic infusion in patients with septic shock
Reuse et al
4
Systolic BP 90 mm Hg or cardiac index 2.5 L/min/m
2
or heart rate 120/min or decreased urine
output ( 25 mL/h)
Magder et al
5
Clinical impression that the cardiac output was inadequate for tissue needs and would respond to volume
loading
Diebel et al
6
Oliguria (urine output 30 mL/h) or hypotension or in an attempt to optimize oxygen delivery
Diebel et al
7
In an attempt to increase oxygen delivery to 600 mL/min/m
2
or to reach a plateau in the oxygen
consumption-delivery relationship
Wagner and Leatherman
8
One or more clinical conditions that suggested the possibility of inadequate preload: hypotension ( 100
mm Hg), oliguria ( 30 mL/h), tachycardia ( 100/min), lactic acidosis, cool extremities, vasopressor
wean, azotemia
Tavernier et al
9
Sepsis-induced hypotension (systolic BP 90 mm Hg or its reduction by 40 mm Hg from usual values)
Magder and Lagonidis
10
As part of routine testing to assess cardiac filling status if PAOP 18 mm Hg
Tousignant et al
11
PAOP 20 mm Hg or inotropic support or low urine output and adequate gas exchange
Michard et al
12
Systolic BP 90 mm Hg or the need of vasoactive drugs (dopamine 5 g/kg/min or norepinephrine)
and PAOP 18 mm Hg and Pao
2
/Fio
2
100 mm Hg
Feissel et al
13
Systematic infusion in septic shock patients with preserved left ventricular systolic function and Pao
2
/Fio
2
100 mm Hg
*Fio
2
fraction of inspired oxygen.
2002 Critical Care Reviews
responders than in nonresponders (Fig 1), and a
significant relationship between the baseline RAP
(r
2
0.20), and the increase in stroke volume in
response to volume expansion was reported by Wag-
ner and Leatherman.
8
However, the marked overlap
of individual RAP values did not allow the identifi-
cation of a RAP threshold value discriminating re-
sponders and nonresponders before fluid was admin-
istered.
PAOP
Before volume expansion, PAOP was not signifi-
cantly lower in responders than in nonresponders in
seven of nine studies
24,6,7,9,12
(Table 3). Three stud-
ies
6,8,11
reported a significant difference between the
baseline value of PAOP in responders and nonre-
sponders (Table 3). In the first study,
6
the mean
value of PAOP was significantly higher in responder
patients (14 7 mm Hg vs 7 2 mm Hg, p 0,01).
In contrast, the two other studies
8,11
reported a
significantly lower value of PAOP at baseline in
responders than in nonresponders (Table 3), and a
significant relationship between the baseline PAOP
(r
2
0.33) and the increase in stroke volume in
response to volume expansion was reported by Wag-
ner and Leatherman.
8
However, in none of these
studies, a PAOP cutoff value was proposed to predict
the hemodynamic response to volume expansion
before fluid was administered.
RVEDV
Before volume expansion, RVEDV index was not
significantly lower in responders than in nonre-
sponders in four of six studies
24,8
(Fig 2). In the two
remaining studies of Diebel et al,
6,7
RVEDV index
was significantly lower at baseline in responders than
in nonresponders (Fig 2), RVEDV index 90
mL/m
2
was associated with a high rate of response
(100% and 64%, respectively), and RVEDV index
138 mL/m
2
was associated with the lack of re-
sponse to volume expansion. However, when the
RVEDV index ranged from 90 to 138 mL/m
2
, no
threshold value was proposed to discriminate re-
sponder and nonresponder patients before volume
expansion. Moreover, another study
8
reported a
positive response to volume expansion in four of nine
patients with a RVEDV index 138 mL/m
2
, a lack
of response in three of nine patients despite a
RVEDV 90 mL/m
2
, and a significant but weak
relationship between the baseline RVEDV index
Figure 1. Mean RAP before volume expansion in responders and nonresponders.
Table 3PAOP Before Volume Expansion in
Responders and Nonresponders*
Source
PAOP, mm Hg
Responders Nonresponders
Calvin et al
2
8 1 7 2
Schneider et al
3
10 1 10 1
Reuse et al
4
10 4 10 3
Diebel et al
6
14 7 7 2
Diebel et al
7
16 6 15 5
Wagner and Leatherman
8
10 3 14 4
Tavernier et al
9
10 4 12 3
Tousignant et al
11
12 3 16 3
Michard et al
12
10 3 11 2
*Values are expressed as mean SD, except for the study of
Schneider et al
3
(mean SEM).
p 0.05 responders vs nonresponders.
www.chestjournal.org CHEST / 121 / 6 / JUNE, 2002 2003
(r
2
0.19) and the increase in stroke volume in
response to volume expansion.
LVEDA
In two studies,
9,11
the LVEDA before volume
expansion was significantly lower in responders than
in nonresponders (Table 4). In the study of Tav-
ernier et al,
9
a significant and negative relationship
(r
2
0.4, p 0.01) was also reported between the
baseline value of LVEDA index and the percentage
of increase in stroke volume in response to volume
expansion. However, using receiver operating char-
acteristic curve analysis, Tavernier et al
9
demon-
strated minimal value of LVEDA index to discrimi-
nate responder and nonresponder patients. In the
study of Tousignant et al,
11
a marked overlap of
baseline individual LVEDA values was observed so
that a given value of LVEDA could not be used to
predict the hemodynamic response to fluid infusion.
Moreover, in another study,
13
responder and nonre-
sponder patients were not different with regard to
the baseline value of LVEDA index (10 4 cm
2
/m
2
vs 10 2 cm
2
/m
2
), and no significant relationship
(r
2
0.11, p 0.17) was observed between the
baseline value of LVEDA index and the percentage
of increase in cardiac index in response to volume
expansion.
RAP
In patients with spontaneous breathing activity,
two studies from Magder et al
5,10
demonstrated that
an inspiratory decrease in RAP 1 mm Hg pre-
dicted a positive response to volume expansion, with
positive predictive values of 77% and 84% and
negative predictive values of 81% and 93% (Table 5).
down
In sedated patients receiving mechanical ventila-
tion with sepsis-induced hypotension, one study
9
demonstrated that the down was significantly
greater (11 4 mm Hg vs 4 2 mm Hg,
p 0.0001) in responders than in nonresponders,
and that the down threshold value of 5 mm Hg was
able to discriminate responders and nonresponders
with a positive predictive value of 95% and a nega-
tive predictive value of 93% (Table 5). Moreover,
this study
9
reported a positive and good relationship
(r
2
0.58, p 0.001) between the baseline value of
down and the percentage of increase in stroke
volume in response to volume expansion.
Table 4LVEDA Before Volume Expansion in
Responders and Nonresponders*
Source
LVEDA, cm
2
/m
2
Responders Nonresponders
Tavernier et al
9
9 3 12 4
Tousignant et al
11
15 5 20 5
Feissel et al
13
10 4 10 2
*Data are presented as mean SD.
p 0.05 responders vs nonresponders.
Area expressed in centimeters squared.
Figure 2. Mean RVEDV index before volume expansion in responders and nonresponders.
2004 Critical Care Reviews
PP
In sedated patients receiving mechanical ventila-
tion with acute circulatory failure related to sepsis,
one study
12
demonstrated that PP was significantly
greater (24 9% vs 7 3%, p 0.001) in respond-
ers than in nonresponders, and that a PP threshold
value of 13% allowed discrimination between re-
sponder and nonresponder patients with a positive
predictive value of 94% and a negative predictive
value of 96% (Table 5). Moreover, in this study,
12
the
value of PP before fluid administration was signif-
icantly and closely correlated (r
2
0.85, p 0.001)
with the volume expansion-induced changes in car-
diac output, such that the higher PP at baseline, the
greater was the increase in cardiac output in re-
sponse to fluid infusion.
Vpeak
In sedated patients receiving mechanical ventila-
tion with septic shock, one study
13
demonstrated that
Vpeak was significantly greater (20 6% vs
10 3%, p 0.01) in responder patients than in
nonresponder patients, and that a Vpeak threshold
value of 12% allowed discrimination between re-
sponder and nonresponder patients with a positive
predictive value of 91% and a negative predictive
value of 100% (Table 5). Moreover, a positive and
tight linear correlation (r
2
0.83, p 0.001) was
found between the Vpeak before volume expansion
and the volume expansion-induced changes in car-
diac output.
Discussion
The present analysis emphasizes the minimal clin-
ical value of ventricular preload indicators and the
higher value of dynamic parameters (testing the
cardiovascular response to respiratory changes in
pleural pressure) in predicting fluid responsiveness
in critically ill patients. It has been suggested that a
beneficial hemodynamic effect of volume expansion
cannot be expected in critically ill patients with a
RAP 12 mm Hg
17
and/or a PAOP 12 mm Hg or
15 mm Hg.
15,18
In this regard, RAP and PAOP
have been reported to be lower in responders than in
nonresponder patients in two studies (Fig 1, Table
3). Moreover, a significant relationship between the
increase in stroke volume in response to volume
expansion and the baseline RAP (r
2
0.20) or the
baseline PAOP (r
2
0.33) was reported by Wagner
and Leatherman,
8
suggesting that the lower RAP or
PAOP before volume expansion, the greater the
increase in stroke volume in response to fluid infu-
sion. However, although statistically significant,
these relationships were weak because a given value
of RAP or of PAOP could not be used to discriminate
responders and nonresponders before fluid was ad-
ministered. Moreover, in all other clinical studies
(Fig 1, Table 3), no difference between responder
and nonresponder patients was observed with regard
to the baseline value of RAP and of PAOP, and no
relationship was reported between cardiac filling
pressures before volume expansion and the hemo-
dynamic response to volume expansion. Finally, it
must be noted that fluid infusion has been shown
to significantly increase cardiac output in some
critically ill patients with central venous pressures
15 mm Hg.
19
Two studies of Diebel et al
6,7
reported a lower
value of RVEDV index in responder than in non-
responder patients, and suggested that a beneficial
hemodynamic effect of volume expansion was likely
(rate of response 100% and 64%) when the RVEDV
index was below 90 mL/m
2
and very unlikely (rate
of response of 0%) when the RVEDV index was
138 mL/m
2
. However, when the RVEDV index
ranged from 90 to 138 mL/m
2
, no cutoff value could
be proposed to discriminate responder and nonre-
sponder patients. Moreover, Wagner and Leatherman
8
reported positive responses to volume expansion in
patients with a RVEDV index 138 mL/m
2
, and
the lack of response in patients with a RVEDV index
90 mL/m
2
. Finally, in four of six studies investigating
whether RVEDV could predict fluid responsiveness,
no significant difference was observed between re-
Table 5Positive and Negative Predictive Values of Dynamic Parameters
Source
Patients,
No.
Parameters
Tested
Best Threshold
Value
Positive
Predictive
Value, %
Negative
Predictive
Value, %
Magder et al
5
33 RAP 1 mm Hg 84 93
Tavernier et al
9
35 down 5 mm Hg 95 93
Magder and Lagonidis
10
29 RAP 1 mm Hg 77 81
Michard et al
12
40 PP 13% 94 96
Feissel et al
13
19 Vpeak 12% 91 100
www.chestjournal.org CHEST / 121 / 6 / JUNE, 2002 2005
sponders and nonresponders with regard to the base-
line value of RVEDV index (Fig 2).
The echocardiographic measurement of LVEDA
has been shown to reflect more accurately the left
ventricular preload when compared with PAOP,
20
and to improve the ability to detect changes in left
ventricular function caused by acute blood loss.
21
In
nine anesthetized mongrel dogs, Swenson et al
22
reported a significant relationship between baseline
LVEDA and changes in cardiac output induced by
IV fluid therapy, suggesting that LVEDA could be an
indicator of fluid responsiveness. In this regard,
LVEDA was found to be significantly lower in
responders than in nonresponders in two clinical
studies,
9,11
and a significant relationship between the
baseline LVEDA index and the changes in stroke
volume induced by volume expansion has also been
reported.
9
However, using receiver operating char-
acteristic curve analysis, Tavernier et al
9
demon-
strated in patients with sepsis-induced hypotension
the minimal value of a given LVEDA index value to
discriminate responders and nonresponders before
fluid was administered. Moreover, in the study of
Tousignant et al,
11
including medical-surgical ICU
patients, considerable overlap of baseline individual
values of LVEDA was observed between responders
and nonresponders, supporting the interpretation
that a specific LVEDA value cannot reliably predict
fluid responsiveness in an individual patient. Re-
cently, in patients with septic shock, Feissel et al
13
did not observe any difference between the mean
baseline value of LVEDA index in responders and
nonresponders, neither any relationship between the
baseline value of LVEDA index and the percentage
of change in cardiac index in response to volume
expansion.
Therefore, all clinical studies have emphasized the
lack of value of ventricular preload indicators as
predictors of fluid responsiveness in critically ill
patients. Methodologic and physiologic reasons
could be advanced to explain these findings. First,
RAP, PAOP, RVEDV, and LVEDA are not always
accurate indicators of ventricular preload. Indeed,
RAP and PAOP have been shown to overestimate
transmural pressures in patients with external
23
or
intrinsic
24
PEEP. The PAOP is highly dependent on
left ventricular compliance,
25
which is frequently
decreased in ICU patients (sepsis, ischemic, or hy-
pertrophic cardiopathy). Because it is the transmural
pressures and not intracavitary pressures such as
RAP and PAOP that are related to end-diastolic
volumes via the chamber compliance, it is not sur-
prising that those surrogates bear little relationship
to fluid responsiveness. The evaluation of RVEDV
by thermodilution has been shown influenced by
tricuspid regurgitation,
26
which is frequently en-
countered in patients with pulmonary hypertension
(ARDS, mechanical ventilation with PEEP). The
estimation of the LVEDA by echocardiography does
not always accurately reflect left ventricular end-
diastolic volume
27
and hence LV preload. Second, in
case of right ventricular dysfunction, a beneficial
hemodynamic effect of volume expansion cannot be
expected, even in the case of low left ventricular
preload.
28
Third, knowing the preinfusion end-
diastolic volume tells little about the diastolic cham-
ber compliance. In this regard, hypovolemia can be
associated with a normal or high LVEDA value in
patients with dilated cardiopathy. Finally, two mat-
ters must be stressed: (1) the increase in end-
diastolic volume as a result of fluid therapy depends
on the partitioning of the fluid into the different
cardiovascular compliances organized in series, and
(2) the rise in stroke volume as a result of end-
diastolic volume increase depends on ventricular
function since a decrease in ventricular contractility
decreases the slope of the relationship between
end-diastolic volume and stroke volume.
1
Therefore,
a patient can be nonresponder to a fluid challenge
because of high venous compliance, low ventricular
compliance and/or ventricular dysfunction. In this
regard, it is not so surprising that bedside indicators
of cardiac chambers dimensions are not accurate
predictors of fluid responsiveness in ICU patients in
whom venous capacitance, ventricular compliance,
and contractility are frequently altered.
Assuming that respiratory changes in pleural pres-
sure induce greater changes in RAP when the right
ventricle is highly compliant than when it is poorly
compliant, Magder et al investigated whether the
inspiratory decrease in RAP could be used to predict
fluid responsiveness.
5,10
Two studies
5,10
demon-
strated that a positive response to volume expansion
was very likely in patients with an inspiratory de-
crease in RAP 1 mm Hg, while it was unlikely if
the inspiratory decrease in RAP was 1 mm Hg.
Unfortunately, most of ICU patients with acute
circulatory failure are sedated and receiving mechan-
ical ventilation, thus are unable to produce an in-
spiratory decrease in pleural pressure sufficient to
decrease the RAP.
10
In this condition, analysis of the
respiratory changes in left ventricular stroke volume
has been proposed to predict fluid responsiveness.
Indeed, by decreasing the venous return pressure
gradient, mechanical insufflation may decrease the
right ventricular filling,
29
and consequently the right
ventricular output if the right ventricle is sensitive to
changes in preload. In this condition, the following
decrease in left ventricular filling may also induce a
significant decrease in left ventricular output if the
left ventricle is sensitive to changes in preload.
Therefore, the magnitude of the respiratory changes
2006 Critical Care Reviews
in left ventricular stroke volume, which reflects the
sensitivity of the heart to changes in preload induced
by mechanical insufflation, has been proposed as a
predictor of fluid responsiveness. Because the arte-
rial pulse pressure (systolic minus diastolic pressure)
is directly proportional to left ventricular stroke
volume,
30
the respiratory changes in left ventricular
stroke volume have been shown reflected by changes
in pulse pressure.
31
Accordingly, the respiratory
changes in pulse pressure have been shown to
accurately predict fluid responsiveness in patients
receiving mechanical ventilation with acute circula-
tory failure related to sepsis.
12
The analysis of the
respiratory changes in systolic pressure has also been
proposed to assess fluid responsiveness. However,
the systolic pressure variation induced by mechanical
ventilation results not only from changes in aortic
transmural pressure (mainly related to changes in
left ventricular stroke volume), but also from
changes in extramural pressure (ie, from changes in
pleural pressure).
32,33
Therefore, the systolic pres-
sure variation is a less specific indicator of changes in
left ventricular stroke volume and hence a less
accurate predictor of fluid responsiveness than the
pulse pressure variation.
12
In this regard, it has been
proposed to discriminate the inspiratory increase in
systolic pressure (not necessarily due to a change in
left ventricular stroke volume) from the down,
which in contrast necessarily reflects a change in left
ventricular stroke volume.
34
Experimental and clin-
ical studies
34,35
have emphasized the influence of
volume status on down (hemorrhage increases
down, while volume expansion decreases down),
and Tavernier et al
9
demonstrated that down is an
accurate predictor of fluid responsiveness in septic
patients with hypotension.
The analysis of the arterial pressure waveform is
not possible in patients with cardiac arrhythmias.
36
Indeed, in this condition, the changes in arterial
pressure do not reflect the effects of mechanical
insufflation on left ventricular stroke volume. It must
be emphasized that the evaluation of down and of
PP requires invasive arterial pressure catheteriza-
tion. However, in shock states, estimation of BP
using a cuff is commonly inaccurate, and use of an
arterial cannula provides a more appropriate and
reproducible measurement of arterial pressure.
15
Interestingly, Feissel et al
13
have recently demon-
strated that Doppler echocardiographic imaging of
aortic blood velocity could be used to assess nonin-
vasively the respiratory changes in aortic blood ve-
locity and to predict fluid responsiveness in patients
with septic shock. It must be noted that down,
PP, and Vpeak have been shown to be accurate
predictors of fluid responsiveness in sedated patients
receiving mechanical ventilation with sepsis.
Whether they also predict fluid responsiveness in
nonsedated, spontaneously breathing patients with-
out sepsis remains to be determined.
It must be emphasized that various types and
volumes of fluid, speeds of fluid infusion, and defi-
nitions of responders to volume expansion have been
used in the studies analyzed (Table 1). This may have
a significant influence on the results and conclusions
of the studies. Indeed, the hemodynamic effects of
an hypertonic colloid infusion are expected to be
more dramatic than those of an equal volume of
isotonic crystalloid infusion. Because of intravascu-
lar-extravascular equilibration, the speed of volume
infusion should also greatly influence the hemody-
namic response, particularly in septic patients with
systemic capillary leakness. Moreover, because of
different definitions of responders from one study to
another, some patients considered as responders in
some studies, would have been considered as non-
responders in other studies. Unfortunately, because
individual data were not available in all but one
study, a comparison of the predictive value of each
parameter using the same definition of responders
was not possible. Finally, the predictive value of
dynamic parameters has been tested by only few
studies. Therefore, further studies are required to
confirm the high value of dynamic parameters in
discriminating responder and nonresponder patients
before fluid infusion. However, our analysis empha-
sizes the minimal value of static ventricular preload
parameters as predictors of fluid responsiveness and
strongly supports the use of the dynamic parameters
in the decision-making process concerning volume
expansion in critically ill patients.
ACKNOWLEDGMENT: The authors thank Dr. Denis Chemla
for helpful discussion.
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