International Journal of Clinical Medicine, 2012, 3, 407-410
http://dx.doi.org/10.4236/ijcm.2012.35076 Published Online September 2012 (http://www.SciRP.org/journal/ijcm)
1
Effect of Higher Mean Arterial Pressure with
Norepinephrine on Tissue Oxygenation and Perfusion in
Patients of Septic Shock
Sandeep Sharma, Mridula Pawar, Mohandeep Kaur, Nidhi Srivastava, Saurav Mustafi
Department of Anaesthesiology and Intensive Care, PGIMER Dr. Ram Manohar Hospital, New Delhi, India.
Received May 28th, 2012; revised June 26th, 2012; accepted July 9th, 2012
ABSTRACT
The current survival sepsis guideline proposes the use of vasopressors and fluid resuscitation to maintain the mean arte-
rial pressure (MAP) ≥ 65 mmHg. Titrating catecholamine infusion to achieve higher MAP has been demonstrated to
improve tissue oxygenation, microcirculation, renal function and overall outcome of the patient in some studies and
literature on actual hemodynamic goals is scarce. AIM: To study the influence of two MAP on tissue oxygenation and
perfusion parameters in patients of septic shock on norepinephrine infusion. SUBJECT AND MATERIALS: Forty adult
patients with the diagnosis of septic shock were enrolled. In all patients norepinephrine was titrated to first stabilize the
MAP at 65 ± 5 mmHg (Set I), followed by MAP of 85 ± 5 mmHg (Set II). Heart rate (HR), Central venous oxygen satu-
ration (SCVO2), Transcutaneous partial pressure of oxygen (PtcO2) by TCM 400/TINA (using miniature Clark electrode),
Arterial partial pressure of oxygen(PaO2), PtO2/PaO2 ratio, Urine output and Serum Base deficit were recorded in each
Set after 2 hr of stabilization. RESULTS: There was a significant increase in transcutaneous partial pressure of oxygen
PtcO2 (p < 0.0001), PtO2/PaO2 (p < 0.0001), SCVO2 (p < 0.0001), urine output (p < 0.006) on increasing the MAP from
65 mmHg to 85 mmHg. Serum base deficit also improved (p < 0.0001). CONCLUSION: Higher MAP with norepi-
nephrine is associated with better perfusion, oxygenation parameters in patients with established septic shock. These
findings suggest that there is improvement in tissue oxygenation parameters using escalating doses of norepinephrine to
achieve higher MAP without inherent adverse effect.
Keywords: Mean Arterial Pressure; Norepinephrine; Septic Shock; Tissue Oxygenation
1. Introduction
Despite many advances in understanding of pathophysi-
ology of septic shock and its management, the mortality
remains unacceptably high. In the year 1992 American
College of Chest Physicians/Society of Critical Care
Medicine consensus conference defined the septic shock
as follows “···sepsis induced hypotension (systolic BP <
90 mmHg or reduction of ≥40 mmHg from baseline)
despite adequate fluid resuscitation along with presence
of perfusion abnormalities that may include but not lim-
ited to lactic acidosis, oliguria or an acute alteration in
mental status” [1].
The current survival sepsis guideline in 2008 advo-
cates the use of vasopressors and fluid resuscitation to
maintain the mean arterial pressure (MAP) ≥ 65 mmHg.
The recommended end points with regards to MAP to
maintain tissue oxygenation and organ perfusion remain
controversial and ranges from 60 mmHg (auto regulatory
threshold below which organ blood flows become line-
arly dependent on perfusion pressure) to 90 mmHg. In
septic shock this autoregulatory threshold shifts to a
higher level. It can therefore be speculated that therapy
should be aimed at providing an adequate organ perfu-
sion pressure that is higher than the commonly targeted
or achieved in the treatment of septic patients [2]. It is
important to titrate the optimal dose of potent inotropic
agents as both inadequate and excessive dosages can
have deleterious consequences. Moreover the benefit of
titrating catecholamine infusion to higher level has been
demonstrated in a few studies [3-5] but not in others
[2,6-8].
Transcutaneous partial pressure of oxygen (PtcO2) is
used as a non-invasive technique to monitor tissue oxy-
genation and perfusion and early detector of shock and
outcome [9]. Because PtcO2 reflects regional PO2, it
changes in response to both regional perfusion and to
global hemodynamic derangements [10]. When arterial
partial pressure (PaO2) remains constant, a decrease in
PtcO2 is probably due to changes in perfusion.

Effect of Higher Mean Arterial Pressure with Norepinephrine on Tissue Oxygenation
and Perfusion in Patients of Septic Shock
408
Hence, this single centre interventional study was
planned to evaluate tissue oxygenation at two sets of
mean arterial pressure of 65 mmHg and 85 mmHg (main-
tained with norepinephrine) in patients of septic shock,
using transcutaneous partial pressure of oxygen.
2. Material and Methods
After Institutional Review Board (IRB) approval and
written informed consent, this single centre prospective
interventional study was conducted in 40 adult patients
of either sex admitted in Multidisciplinary Intensive Care
Unit (ICU) with the diagnosis of septic shock2 (systolic
BP < 90 mmHg or 40 mmHg less than patients normal
BP for at least 1 hr after adequate fluid resuscitation) or
those who develop septic shock during their stay in ICU.
Patients with acute myocardial ischemia, acute ar-
rhythmia, pregnancy, diabetes, hypertension, peripheral
vascular disease, those requiring inotrope agents other
than norepinephrine and those on Renal Replacement
Therapy (RRT) were excluded from the study.
Baseline values of heart rate (HR), Invasive Blood
Pressure (IBP), Percent oxygen saturation of haemoglo-
bin (SpO2), Electrocardiography (ECG), Central Venous
Pressure and Urine output in last one hour were recorded
in all patients. The clinical management of each patient
was determined by clinical staff in accordance with care
bundles based on the current Survival Sepsis Guidelines.
No therapy was given during the study period that
might influence the hemodynamics of the patient like
hemofilteration, diuretics, other catecholamines etc.
After adequate fluid resuscitation (CVP = 8 - 12
mmHg in spontaneously breathing and 12 - 15 mmHg in
mechanically ventilated patients) norepinephrine was
started in all the patients. Patients acted as self control.
First the NE infusion was titrated and stabilized at SET I
pressures and then at Set II pressures as mentioned be-
low.
SET I-Norepinephrine was titrated to achieve a MAP
of 65 ± 5 mmHg.
SET II-Norepinephrine infusion was titrated to achieve
MAP of 85 ± 5 mmHg.
After stabilizing the patient for two hours on above
mentioned MAP, transcutaneous partial pressure of oxy-
gen (PtcO2), PaO2, PtcO2/PaO2 ratio, Superior Vena Cava
oxygen saturation (SCVO2), Heart rate (HR), Urine output
(ml/hr) and Serum Base deficit were recorded.
After recording these variables the clinical manage-
ment of the patient was continued as per determined by
the clinical staff in accordance with the care bundles
based on current survival sepsis guidelines.
Data was presented as mean (SD) where normally dis-
tributed. p < 0.05 was taken as significant. Paired t-test
was applied for comparing the changes in HR, SCVO2,
PtcO2, PaO2, PtcO2/PaO2 ratio and urine output. Changes in
base deficit were analyzed by wilcoxon signrank test.
3. Results
This single Centre prospective interventional study was
conducted in 40 adult patients with septic shock with a
mean age of 44.65yr (15 - 64 yr) of which 27 were male
and 13 were female. Since, the patients acted as self-
control the baseline demographic characteristics were
same. (Table 1). Mean baseline SOFA score in our pa-
tients was 7.7 with a range of 5 - 11. Probable source of
sepsis was abdominal in 67.5% of patients. There was
statistically significant increase in transcutaneous partial
pressure of oxygen PtcO2 (p < 0.0001), PtcO2/PaO2 ratio (p
< 0.0001), ScvO2 (p < 0.0001), Urine output (p < 0.006)
and Serum base deficit (p < 0.0001) on increasing the
MAP from 65 mmHg to 85 mmHg. There was a signifi-
cant fall in Heart Rate on increasing the MAP to 85 ± 5
mmHg (Table 2).
None of the patient developed tachycardia, arrhyth-
mias, myocardial ischemia, signs of excessive vasocon-
striction or any other adverse effect that could be attrib-
uted to the intervention.
Table 1. Baseline patient characteristics.
AGE (yr) 44.65 (15 - 64)
GENDER (M/F) 27/13
Time from onset of sepsis (days)2.4 (1.37)
Mortality 21 deaths (52.5%)
Probable Source of Infection Frequency (%)
Respiratory 13 (30)
Abdominal
26 (67.5)
Soft tissue 1 (2.5)
SOFA Score 7.7 (5 - 11)
Table 2. Hemodynamic and Perfusion parameters in the
two groups.
ParameterMAP 65MAP 85p value
Heart rate (/min)105.75 ± 17.27101.1± 15.58≤0.0001
ScvO2 (%)73.23 ± 4.0075.11 ± 3.98≤0.0001
PtcO2 (mmHg)35.75 ± 8.4041.57 ± 11.42≤0.0001
PaO2 (mmHg)109.11 ± 23.58106.77 ± 23.310.0186
PtcO2/PaO20.337 ± 0.0840.3987 ± 0.11≤0.0001
Urine output‡ (mL/hr)43.5 ± 18.7050.2 ± 27.110.0068
Base deficit† (meq/L)5.25 ± 2.294.65 ± 2.39≤0.0001
Mean (SD). p value < 0.05 is taken as significant. Paired t test applied.
‡normal distribution of data seen with Shapiro wilk test. †Wilcoxon signrank
test applies.

Effect of Higher Mean Arterial Pressure with Norepinephrine on Tissue Oxygenation
and Perfusion in Patients of Septic Shock
409
The rise in PtcO2 on increasing the mean arterial pres-
sure from 65 mmHg to 85 mmHg is less as the time from
onset septic shock increases (Figure 1). It can be seen
that as the duration of septic shock increases the response
to increasing MAP is less or none at all. The time inter-
val from the onset of septic shock to the start of our study
varied from 1 - 6 days with mean of 2.4 days. 40 percent
of patients (16) were included at day 2 of septic shock
(Figure 2).
4. Discussion
Septic shock is a life threatening complication of infec-
tion. Besides treatment of sepsis, hemodynamic man-
agement of the patient is mandatory to improve oxygen
supply to tissues. Depending on the cardiac function,
blood volume expansion and/or inotropic drugs are indi-
cated. When fluid administration fails to restore adequate
arterial pressure and organ perfusion, therapy with vaso-
pressor agent is initiated [11].
1 day 2 days 3 days 4 days 5 days 6 days
Time from onset of Septic Shock
- - - mean transcutaneous partial pressure of oxygen at 65 ± 5 mmH
g
—
mean transcutaneous partial pressure of oxygen at 85 ± 5 mmH
g
50
40
30
20
10
0
M
ean
P
tc
O
2
Mean PtcO2 at 65 ± 5 mmHg (broken line) and 85 ± 5 mmHg (solid line)
with respect to Time from onset of septic shock. As duration of septic shock
increases, rise in mean PtcO2 decreases on increasing MAP.
Figure 1. Relation of change in mean PtcO2 for two sets of
MAP to the time from onset of Septic Shock.
1 day 2 days 3 days 4 days 5 days 6 days
frequency
Distribution of time from the onset of Septic Shock
18
16
14
12
10
8
6
4
2
0
11
16
5
3 4
1
X-axis: Time from onset of septic shock; Y-axis: Number of patients. Num-
ber of patients with respect to Time from onset of septic shock.
Figure 2. Destribution of time from onset of sepsis.
Current survival sepsis guidelines for hemodynamic
support of adult patients with sepsis recommend that
vasopressor should be titrated to the minimum level re-
quired to provide an effective organ perfusion. The ade-
quate arterial pressure is the endpoint of vasopressor
therapy but does not always means adequate organ blood
flow. The precise level of mean arterial pressure required
to optimize tissue perfusion is still debated. Thus this
single center prospective interventional study was con-
ducted for comparative evaluation of tissue oxygenation
using transcutaneous partial pressure of oxygen at two
sets of mean arterial pressure of 65 mmHg and 85 mmHg
maintained on norepinephrine infusion in patients of sep-
tic shock.
The principal finding of this study is that the use of in-
cremental doses of norepinephrine to achieve higher
MAP was associated with increase in oxygenation and
perfusion parameters. In our study, tissue oxygenation
parameters namely PtcO2, PtcO2/PaO2 and SCVO2 im-
proved significantly at higher MAP. Since, PtcO2 is a di-
rect measure of microvascular flow, it can be inferred
that a higher MAP (85 mmHg) was associated with im-
provement in the tissue microcirculation and thus oxy-
genation. Jhanji S. et al. also found that titrating vaso-
pressors to achieve higher MAP is associated with in-
crease in global oxygen delivery, cutaneous microvascu-
lar flow and tissue oxygenation [3].
The perfusion parameters namely base deficit and
urine output also showed significant improvement at
higher MAP in our study. This improvement can be at-
tributed to improved organ perfusion at higher MAP.
Beneficial effects of higher doses of norepinephrine on
renal perfusion (GFR and urine output) has been well
documented [4,5,12]. Stephane Deruddre et al. have also
observed that on increasing the MAP from 65 to 75
mmHg with norepinephrine there was significant in-
crease in urine output and decrease in renal resistive in-
dex [13].
However there are studies with contrasting evidence
[2,6-8]. Amongst the most recent is the study by Aurelie
bourgoin et al. in 28 patients which showed that increas-
ing MAP from 65 mmHg to 85 mmHg with Norepineph-
rine neither affects metabolic variables nor improves
renal function [2]. However the patients included in this
study had severe form of septic shock (with 2 or more
organ failure) and were sicker whereas our study ex-
cluded the patients with comorbid conditions. This might
be the differentiating factor that can explain no im-
provement in tissue oxygenation and perfusion parame-
ters in his group of patients.
Ledoux et al. [6] found out that on increasing MAP
from 65 to 85 mm Hg with norepinephrine does not sig-
nificantly affect systemic O2 metabolism, skin microcir-

Effect of Higher Mean Arterial Pressure with Norepinephrine on Tissue Oxygenation
and Perfusion in Patients of Septic Shock
410
culation, urine output or splanchnic perfusion. However
the APACHE II score in his group of patients was 29 ±
2.1 which was more than in the study group of Aurelie
bourgoin et al. [2] which was 27 - 28 in this study. In
both studies the patient population belonged to a higher
severity-of-illness score compared to our study which
had a mean SOFA score of 7.7. Also the equilibration
period in this study was only 60 minutes which was
probably not sufficient to reflect changes in tissue oxy-
genation and perfusion parameters.
In the above mentioned studies the patients enrolled
were older, in mid sixties compared to our patients, with
mean age of 44 yr. Our results are applicable to younger
population with recent onset of septic shock (67.5% pa-
tients with onset within 2 days) and primarily abdominal
(65%) source of sepsis. This can be seen in Figure 1
which shows that as the duration of septic shock in-
creases, the rise in PtcO2 decreases with increase in MAP.
5. Conclusion
Higher MAP with norepinephrine is associated with im-
proved perfusion and oxygenation parameters in younger
age group with septic shock when NE therapy is insti-
tuted early in the course of disease. Further research is
required to know more about long term effects of higher
arterial pressure targets in these patients.
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