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2016 EDIZIONI MINERVA MEDICA


Online version at http://www.minervamedica.it Minerva Anestesiologica 2016 July;82(7):777-84

REVIEW

Mean arterial pressure target


in patients with septic shock
Franois BELONCLE 1, 2, Peter RADERMACHER 3, Claude GUERIN 4, Pierre ASFAR 1, 2 *

1Dpartement de Ranimation Mdicale et de Mdecine Hyperbare, Centre Hospitalier Universitaire dAngers,

Angers, France; 2Laboratoire de Biologie Neurovasculaire et Mitochondriale Intgre, Institut MITOVASC, CNRS
UMR 6214 - INSERM U1083, Universit Angers, PRES LUNAM, Angers, France; 3Institut fr Ansthesiologische
Pathophysiologie und Verfahrensentwicklung, Universittsklinikum, Ulm, Germany; 4Service de Ranimation
Mdicale, Hpital de la Croix Rousse, Hospices Civils de Lyon, Universit de Lyon, and INSERM 955, France
*Corresponding author: Pierre Asfar, Dpartement de Ranimation Mdicale et de Mdecine Hyperbare, Centre Hospitalier Univer-
sitaire, 4 rue Larrey, F-49 933 Angers Cedex 9, France. E-mail: piasfar@chu-angers.fr

ABSTRACT
In patients with septic shock, a mean arterial pressure higher than 65 mmHg is recommended by the Surviving Sepsis
Campaign Guidelines. However, a precise mean arterial pressure target has not been delineated. The aim of this paper
was to review the physiological rationale and clinical evidence for increasing mean arterial pressure in septic shock. A
mean arterial pressure level lower than renal autoregulatory threshold may lead to renal dysfunction. However, adjusting
macrocirculation objectives in particular after the early phase of septic shock may not correct established microcircula-
tion impairments. Moreover, sympathetic over-stimulation due to high doses of vasopressor (needed to achieve high
mean arterial pressure targets) may be associated with numerous harmful effects. Observational and small short term
interventional studies did not provide a definitive answer to this question but suggested that a high mean arterial pressure
(around 75-85 mmHg) may prevent acute kidney injury in some patients. The SEPSISPAM Trial, a large prospective,
randomized, controlled study, compared the targets of High (i.e. 80 to 85 mm Hg) versus Low (i.e. 65 to 70 mm Hg) mean
arterial pressure in patients with septic shock. The mortality was not different in the two groups. However in patients
with chronic hypertension, there were significantly less renal failure in the high mean arterial pressure group than the low
mean arterial pressure group.
(Cite this article as: Beloncle F, Radermacher P, Guerin C, Asfar P. Mean arterial pressure target in patients with septic shock.
Minerva Anestesiol 2016;82:777-84)
Key words: Shock - Sepsis - Arterial pressure - Critical care - Vasoconstrictor agents - Acute kidney injury.

S eptic shock combines decreased systemic


vascular resistance (SVR), hypovolemia,
impaired microcirculation and, frequently,
septic shock as it is used for defining both
the entity and the therapeutic goals. Rivers
et al. introduced the concept of early goal-
or other proprietary information of the Publisher.

depressed myocardial systolic and diastolic directed therapy (EGDT) in septic shock.
function,1 which ultimately leads to an im- Targeting MAP of at least 65 mmHg was one
balance between oxygen delivery and de- goal for the hemodynamic support in asso-
mand. The initial treatment of septic shock ciation with central venous pressure (CVP)
primary aims at correcting this imbalance. 8-12 mmHg, diuresis of at least 0.5 mL/
Mean arterial pressure (MAP) is one of the kg/h and central venous oxygen saturation
hemodynamic targets to ensure an adequate (ScvO2) greater than 70%. MAP is a macro-
perfusion pressure.2 It is a key variable in scopic variable that depends on the product

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BELONCLE MEAN ARTERIAL PRESSURE TARGET IN PATIENTS WITH SEPTIC SHOCK


This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
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of cardiac output (CO) and systemic vascular previous systemic hypertension and possibly
resistance (SVR). Therefore, CO should also even lower in patients in young patients with-
be used as a therapeutic goal during hemody- out cardiovascular comorbidity.
namic resuscitation and is indirectly assessed These recommendations are based on: i)
by using ScvO2 taken as a surrogate of CO. retrospective studies that assessed the relation-
However, CO is determined by preload, con- ship between MAP level and survival, a MAP
tractility and afterload and its optimization ranging from 60 to 65 mmHg being the most
should take into account each of them. The discriminative threshold value,6 and ii) short-
above mentioned target for MAP is the lower term studies of small sample size investigating
bound and, hence the upper bound is not well the effects of increments of MAP from 65 to
defined. Increasing MAP above this target 75 to 85 mmHg. The end points differed wide-
is a question that has been regularly asked, ly, based on improvement in kidney function,
with the rationale to improve tissue perfusion renal or skin or sublingual microcirculatory
and to take into account abnormalities in the blood flows.
autoregulation of regional blood flow in spe-
cific settings (diabetes mellitus, chronic hy-
Rationale for higher MAP levels:
pertension) and in specific organs (kidney).
pros and cons
For a given increase in MAP, higher organ
perfusion would occur if there is a linear Concept of autoregulation
relationship between these two variables
(MAP-dependent organ perfusion) or if the In the autoregulation zone of autoregu-
critical MAP below which organ perfusion lated organs, blood flow entering the organ is
starts to decrease is shifted to the right due to constant irrespective of the perfusion pressure
abnormal regional autoregulation. It is worth with a range of MAP values. Below or above
to note that previous attempts to increase CO this autoregulation zone, organ blow flow is
to supramaximal levels in ICU patients of directly dependent on perfusion pressure (Fig-
various settings were associated with worse ure 1). Autoregulation plays a major role in the
outcomes 34. Intuitively, it is unlikely that brain,7 heart 8 and kidney.9 Renal autoregula-
the single increase in MAP well above 65 tory threshold is higher than the cardiac or ce-
mmHg, an action set at the macroscopic level rebral one.10, 11 Therefore, it may be considered
of circulation, would be homogeneously dis- as a major resuscitation objective. If MAP lev-
tributed across the various regional circula- el is lower than renal autoregulatory threshold,
tory beds or affect those regional circulations renal blood flow may be lower than physi-
that would require more perfusion. The aim ological renal blood flow and, consequently,
of this paper is to review the physiological renal function may be altered. It is critical to
rationale and clinical evidence for increasing note that this renal autoregulatory threshold
MAP in patients with septic shock. is higher during chronic hypertension.12 Thus
patients with chronic hypertension may need
Recommendation of the Surviving higher MAP resuscitation target during sepsis
Sepsis Campaign Guidelines than patients without chronic hypertension.
Of note, this picture is likely to be altered
or other proprietary information of the Publisher.

During initial resuscitation, MAP higher by septic conditions. In rats, sepsis has been
than 65 mm Hg is recommended by the Sur- found to not impact renal blood flow over a
viving Sepsis Campaign Guidelines (grade large range of MAP suggesting that autoregu-
1C: High grade recommendation based on low lation may be conserved in sepsis.13 However,
level evidence) 5. However, according to these in a study using cine phase-contrast magnetic
recommendations, the optimal MAP should be resonance imaging in patients, renal blood
individualized as it may be higher in selected flow was lower in septic patients than in con-
patients such as those with atherosclerosis or trol healthy patients. Of note, in septic patients

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MEAN ARTERIAL PRESSURE TARGET IN PATIENTS WITH SEPTIC SHOCK BELONCLE


This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
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Organ blood flow Fluids Vasoactive agents

Patients without Endothelial Leukocyte Blood flow


chronic hypertension permeability adhesion heterogeneity

Patients with
chronic hypertension Cardiac output Microvascular flow
Vascular resistances and
Organ flow redistribution Microvascular shunting
Autoregulation zone

MAP Macrocirculation Microcirculation

Figure 1.Autoregulation concept in patients with or with- Figure 2.Determinants of macrocirculation and microcir-
out chronic hypertension. In the autoregulation zone of au- culation dysfunction. Therapeutics (as fluids and vasoactive
toregulated organs (i.e. brain, heart and kidney) blood flow agents) may impact independently macrocirculation and mi-
entering the organ is constant irrespective of the perfusion crocirculation. The effect of vasoactive agents on microcir-
pressure. The organ autoregulatory threshold is higher in culation and the interaction between macrocirculation and
patient with chronic hypertension than in normotensive pa- microcirculation dysfunction remain unclear.
tients. MAP: mean arterial pressure.

MAP ranged between 70 and 100 mmHg sug- early non stabilized septic shock) remains to
gesting that autoregulation is not maintained be assessed.
(or autoregulation thresholds change) during Consequently, although adjusting hemody-
sepsis.14 namic objectives at the second phase of the
septic shock, when patients are hemodynami-
Relationship between systemic mean arterial cally stable, is unlikely to correct established
pressure and microcirculatory blood flow impairments of the microcirculation, targeting
high MAP levels in the early phase of septic
The relationship between systemic hemo- shock may allow preventing the development
dynamics and microcirculatory blood flow is of microcirculatory dysfunction.
complex (Figure 2).15 Sepsis is associated with
microcirculation alterations and tissue hypox- Specific effect of high vasopressor load
ia.16, 17
Increasing MAP level above 65 mmHg per Increasing MAP target to high levels nor-
se may not change microvascular perfusion. mally requires higher doses of vasopressor
Furthermore, microcirculation abnormalities agents. Norepinephrine is the most commonly
may persist whereas MAP is correct.17 Of note used vasopressor in septic patients. Norepi-
the timing of intervention may play a major nephrine primarily increases SVR (and thus
role: De Backer et al. reported improved mi- left ventricular afterload), and slightly increas-
crocirculation with fluids, in the early but not es cardiac output as a result of its -adrenergic
in the late phase of sepsis.18 agonist properties and -adrenergic effects on
Some authors propose to use vasodilators venous return.20 This latter effect 21 together
to try to improve microcirculation in patients with sepsis 22 might also result in increased
or other proprietary information of the Publisher.

with septic shock. However in patients with postcapillary venular pressure, which in turn
early-phase severe sepsis or septic shock, in- may decrease the pressure gradient from the
travenous nitroglycerin started after fulfillment artery to vein.
of systemic hemodynamic end points, did not Besides the possibly deleterious consequenc-
improve microcirculation assessed by sublin- es of excessive vasoconstriction, other effects
gual microcirculatory blood flow.19 Whether should be taken into account when addressing
this negative result was related to the timing the question of optimal vasopressor load. Sym-
of nitroglycerin infusion (i.e. late stabilized vs. pathetic over-stimulation (or adrenergic stress)

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BELONCLE MEAN ARTERIAL PRESSURE TARGET IN PATIENTS WITH SEPTIC SHOCK


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may be associated with numerous harmful ef- and more importantly the time spent under 65
fects such as diastolic dysfunction, tachyar- mmHg correlated to 30-day mortality.6 The best
rythmia, skeletal muscles damage (apoptosis), predictive MAP threshold for 30-day mortality
coagulopathy or endocrinological, immuno- was 65 mmHg. However, when drawing con-
logical and metabolic disturbances.23, 24 This clusions from these results caution is warrant-
extensive list of potential side effects related ed because of the strong association between
to norepinephrine (and other catecholamines) MAP level and disease severity. In a similarly
may explain the interest in vasopressin as alter- designed study including 274 patients with
native vasoactive drug. In addition, the asso- sepsis or septic shock, results were adjusted for
ciation of two different vasopressors (e.g. nor- disease severity (as assessed by the Simplified
epinephrine and vasopressin) could facilitate Acute Physiology Score (SAPS) II excluding
the reduction in some of these adverse effects Systolic arterial pressure).28 The hourly time
by using lower dose of each molecule. integral of MAP drops below 60 mmHg was
However, there is no clear relationship be- shown to be associated with mortality at day
tween norepinephrine dose, MAP and organ 28, and patients with one or more episodes of
dysfunction (in particular Acute Kidney Injury hypotension below 60 mmHg for at least 2 min-
[AKI]) or mortality rate. High norepinephrine utes had higher mortality at day 28 than patients
doses are associated with high mortality rate 25 without hypotension. Moreover, this study also
and high risk of AKI occurrence,26 but the MAP suggested that higher MAP level might prevent
level was not related to mortality in the Dnsers AKI. Indeed, the highest area under the ROC
Study 25 and a high MAP was associated with a curve to predict the need for renal replacement
low AKI occurrence in the Finnaki Study.26 therapy was obtained for the hourly time inte-
Unfortunately, so far a precise MAP target gral of MAP drops below 75 mmHg.
cannot be determined in septic shock because Using logistic regression models adjusted
patients are between a rock and a hard place for age, presence of chronic arterial hyperten-
for the above mentioned reasons. A 65 mmHg sion, disease severity at admission (SAPS II)
MAP target may not be sufficient for many pa- and vasopressor load in a post hoc analysis of
tients, and increasing the dose of vasopressors the control group including 290 patients with
to achieve a higher MAP carries the risk of ex- septic shock of a large randomized control
cessive peripheral vasoconstriction. Pragmati- Trial investigating the effects on mortality of
cally, the optimal MAP target (or the optimal LNMA, a nitric oxide inhibitor,30 Dnser et al.
vasopressor dose) corresponds to the optimal did not find any association between MAP (or
balance between these two risks. Of note, the MAP quartiles) and mortality or occurrence of
resuscitation strategy of fluid administration disease-related events.25 It is important to note
followed by early or delayed infusion of va- that the association between MAP and 28-day
soactive drugs may also influence prognosis.29 mortality or AKI was not affected by the age
or the presence of chronic arterial hyperten-
sion. However, a direct relation was found be-
Clinical studies
tween the mean vasopressor load and the mor-
Observational studies tality or the number of disease-related events.
In 217 patients with shock (including 59% of
or other proprietary information of the Publisher.

In two retrospective studies including sep- septic shock), the lower the average MAP over
sis patients, Varpula and Dnser used MAP 6 hours or 12 hours to 24 hours the higher the
recording to assess the time spent below dif- incidence of AKI at 72 hours only in patients
ferent thresholds of MAP during the first days with septic shock and AKI at 6 hours.31 In these
and correlated it to survival and organ dys- patients, MAP threshold from 72 to 82 mmHg
function.6, 28 was shown to allow the best prediction of AKI
In 111 patients with septic shock, the mean at 72 hours. There was no correlation between
MAP measured for the first 6 and 48 hours, MAP and AKI at H72 in the other patients.

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MEAN ARTERIAL PRESSURE TARGET IN PATIENTS WITH SEPTIC SHOCK BELONCLE


This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies
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Using the data prospectively collected in increase in cardiac output, an improvement in


423 patients with severe sepsis from the large microcirculatory function (assessed by thenar
observational FINNAKI Study,32 time-adjust- muscle oxygen saturation, using near infra-
ed MAP under 73 mmHg was associated with red spectroscopy with serial vaso-occlusive
progression of AKI.27 Of note as in the study tests on the upper arm and sublingual micro-
by Badin et al.,31 results were not adjusted for circulation using sidestream dark field imag-
disease severity. ing in 6 patients), and a decrease in arterial
Beyond the classical limitations inherent lactate in comparison with a low MAP target
to the observational studies, it is important to (65 mmHg).35 Of note, the authors observed a
note that the close link between disease sever- large variability in microvascular response to
ity and MAP level may confound the interpre- MAP changes according to the patients sug-
tation of results. However, some of these stud- gesting that an individual adaptation of MAP
ies provide convincing arguments for a MAP level may be needed in patients with septic
target higher than 65 mmHg to prevent AKI in shock.
some septic patients. In 16 patients with septic shock, higher
oxygen delivery, cutaneous microvascular
Interventional studies flow, and tissue oxygenation using a variety
of methods to assess microvascular flow (cu-
To delineate an optimal MAP target in septic taneous tissue PtO2 measured by a Clark elec-
patients, some authors tried to assess the im- trode, cutaneous red blood cell flux assessed
pact of a modification of MAP level. The de- by laser Doppler flowmetry, and sublingual
signs of all of these studies were similar: an in- microvascular flow evaluated by sidestream
crease in vasopressor doses led to an increase darkfield imaging) were observed when
in MAP level over a short period of time. He- MAP was increased from 60 to 70, 80 and 90
modynamics, microcirculation or renal func- mmHg.36 However the increase in MAP did
tion were assessed after 30 minutes to 2 hours not impact sublingual microvascular flow ab-
at a delineated MAP level. normalities as in the study conducted by Du-
In 10 patients with septic shock, an increase bin et al.34
in MAP from 65 to 75 then to 85 mmHg for Finally, in a short term physiological study
less than 2 hours did not impact systemic oxy- including 11 patients with septic shock, an in-
gen metabolism, skin microcirculatory blood crease in MAP level from 65 to 75 mmHg for
flow (assessed by skin capillary blood flow 2 hours due to an increase in norepinephrine
and red blood cell velocity), urine output and doses was associated with an increase in uri-
splanchnic perfusion (assessed by gastric mu- nary output and a decrease in the renal resistive
cosal PCO2).33 Of note, many of the patients index measured by echography.37 However,
received dopamine and not norepinephrine as MAP changes from 75 to 85 mmHg did not
it is now recommended. impact these parameters. These results sug-
In 20 patients with septic shock, oxygen de- gest that a MAP target around 75 mmHg could
livery and consumption or serum lactate were correspond to the optimal balance between an
not impacted by an increase in MAP from 65 increase in perfusion pressure and excessive
to 75 or 85 mmHg, although an increase in vasoconstriction. Some authors suggest that re-
or other proprietary information of the Publisher.

cardiac index was observed when the norepi- nal resistive index could allow the clinicians to
nephrine infusion dose increased.34 Sublingual adjust this optimal MAP level for each patient.
capillary microvascular flow index and the Nevertheless, it is essential to note that changes
percent of perfused capillaries were not differ- of the renal resistive index depend on numer-
ent for the different MAP values. ous determinants and, hence, do not represent
In a study including 13 patients with septic only renal resistance or renal blood flow.38
shock, a high MAP target (85 mmHg for 30 In addition, impact of MAP level on hemo-
minutes) was shown to be associated with an dynamics, microcirculation and renal function

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BELONCLE MEAN ARTERIAL PRESSURE TARGET IN PATIENTS WITH SEPTIC SHOCK


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was assessed in two short term randomized In addition, it should be noted that the actual
controlled studies. MAP level is often higher than the originally
In a small randomized prospective study, prescribed target. This clinical observation
cardiac index was higher in the high MAP may be explained by safety limits: relatively
group (85 mmHg) than in the low MAP group high MAP levels may avoid episodes of very
(65 mmHg).39 However arterial lactate, oxy- low MAP. Thus, in the large randomized con-
gen consumption and urine output, serum cre- trolled trials,41-46 MAP levels around 80 mmHg
atinine, and creatinine clearance were not dif- are frequent. In particular in the study by Riv-
ferent in both groups. ers et al comparing two strategies of care in pa-
And in a small, randomized study, 20 pa- tients with severe sepsis or septic shock (stan-
tients received either dopamine or norepi- dard therapy versus the Early Goal Directed
nephrine. Patients were evaluated at baseline Therapy [EGDT]), the mean MAP reached in
(MAP=65 mmHg and 63 mmHg in the norepi- the EGDT group, was 95 mmHg. The preva-
nephrine and dopamine group, respectively) lence of excessive vasoconstrictive detrimen-
and 3 hours after they achieved a MAP level tal events such as digital, or splanchnic isch-
higher than 75 mmHg with norepinephrine or emia does not seem to be particularly high in
dopamine infusion (MAP=87 mmHg in both these studies. Thus these large clinical trials
groups).40 Oxygen delivery and consumption provide the evidence that MAP levels higher
(determined by indirect calorimetry) increased than 65 mmHg are very often reached and are
in both groups. The gastric intramucosal pH not associated with overt side effects suggest-
(determined by gastric tonometry) increased ing excessive vasoconstriction. Of note, this
in the norepinephrine group but decreased in observation probably reflects routine practice.
the dopamine group.
Thus an optimal MAP level for every pa- Sepsispam
tient with septic shock cannot be delineated
by these studies. The timing of these studies The SEPSISPAM Trial, a prospective, ran-
(in particular the time from the beginning of domized, controlled study, was designed to an-
disease process (or ICU admission) to the in- swer the question of the optimal MAP target
clusion) is probably essential for interpreting in patients with septic shock 47. The trial com-
the results. In all of these small intervention- pared the targets of High (i.e. 80 to 85 mmHg)
al studies, most of the patients were enrolled versus Low (i.e. 65 to 70 mmHg) MAP in pa-
when they had already been hemodynamically tients with septic shock and enrolled early in
stabilized. These interventional studies are the course of septic shock, i.e. within 6 hours
summarized in Table I.33-39 after the start of vasopressors. The primary end

Table I.Small size short term studies.


Number Design of MAP titration
Study Measures Results
of patients in mmHg (duration)
Ledoux 33 10 65, 75, 85 (105) Hemo, tono, LD, renal function CI ns
Dubin 34 20 65, 75, 85 (30) Hemo, tono, CI, DO2 ns,
SDF Tono ns, SDF ns
Thooft 35 13 65, 75, 85 (30) Hemo, StO2, CI, StO2, SDF
or other proprietary information of the Publisher.

SDF
Jhanji 36 16 60, 70, 80, 90 (45) Hemo, PtO2, DO2,PtO2
LD, SDF LD, SDF ns
Deruddre 37 11 65, 75, 85 (120) Hemo, renal function, RRI 65-75 mmHg: urine output, RRI
Bourgoin 39 2x14 65 vs 85 (4 h) Hemo, renal function CI
Renal function ns
Hemo: hemodynamics; Tono: tonometry; CI: Cardiac Index; DO2: systemic O2 transport; LD: cutaneous microvascular Laser Doppler flow-
metry; PtO2: cutaneous tissue O2 tension measured using a Clark electrode; RRI: renal resistive index; SDF: sidestream dark field imaging; :
increase; : decrease; Ns: no significant change.

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MEAN ARTERIAL PRESSURE TARGET IN PATIENTS WITH SEPTIC SHOCK BELONCLE


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point was mortality, which differed neither at References


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Conflicts of interest.The authors certify that there is no conflict of interest with any financial organization regarding the material
discussed in the manuscript.
Article first published online: March 11, 2016. - Manuscript accepted: March 9, 2016. - Manuscript revised: January 15, 2016. -
Manuscript received: February 2, 2015.

784 Minerva Anestesiologica July 2016