Effect of Higher Mean Arterial Pressure with Norepinephrine on Tissue Oxygenation and Perfusion in Patients of Septic Shock

doi:10.4236/ijcm.2012.35076

Paper Menu >>

Journal Menu >>

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)

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.

Email: [email protected]

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

—

mean transcutaneous partial pressure of oxygen at 85 ± 5 mmH

ean

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

3 4

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.

REFERENCES

[1] ACCP/SCCM, “Definitions of Sepsis and Organ Failure

and Guidelines for the Use of Innovative Therapies in

Sepsis,” Critical Care Medicine, Vol. 20, 1992, pp. 864-

874. doi:10.1097/00003246-199206000-00025

[2] A. Bourgoin, M. Leone, A. Delmas, F. Garnice, J. Al-

banese and C. Martin, “Effect of Increasing MAP in Pa-

tient with Septic Shock: Effect on Oxygen Variables and

Renal Functions. Critical Care Medicine, Vol. 33, 2005,

pp. 780-786. doi:10.1097/01.CCM.0000157788.20591.23

[3] S. Jhanji, S. Stirling, N. Patel, C. Hinds and R. Pearse,

“The Effect of Increasing Doses of Norepinephrine on

Tissue Oxygenation and Microvascular Flow in Patients

with Septic Shock,” Critical Care Medicine, Vol. 37, No.

6, 2009, pp. 1961-1966.

doi:10.1097/CCM.0b013e3181a00a1c

[4] K. G. Barry, R. I. Mazze and F. D. Schwartz, “Prevention

of Surgical Oligouria Renal Hemodynamic Suppression

by Sustained Hydration,” New England Journal of Medi-

cine, Vol. 270, No. 26, 1964, pp. 1371-1377.

[5] C. Martin, L. Papazian, G. Perrin, et al., “Norepinephrine

or Dopamine for Treatment of Hyperdynamic Septic

Shock?” Chest, Vol. 103, No. 6, 1993, pp. 1826-1831.

[6] D. Ledoux, M. E. Astiz, C. M. Carpati and E. Rackow,

“Effects of Perfusion Pressure on Tissue Perfusion in

Septic Shock,” Critical Care Medicine, Vol. 28, No. 8,

2000, pp. 2729-2732.

doi:10.1097/00003246-200008000-00007

[7] T. Venzi, J. Romand, D. Bergener, M. Svensson, P. M.

Suter and A. Aneman, “Norepinephrine Induced Blood

Pressure Increase to Pre-Shock Level Worsens Regional

Flow Distribution in Porcine Septic Shock Model,”

Critical Care, Vol. 4, No. S1, 2000, p. 48.

doi:10.1186/cc768

[8] A. Dublin, M. Pozo, C. A. Casabella, F. Palizas, G.

Murias, C. Ince, et al., “Increasing Arterial Blood Pres-

sure with Norepinephrine Does Not Improve Microcircu-

latory Blood Flow: A Prospective Study,” Critical Care,

Vol. 13, No. 3, 2009, pp. 1-8.

[9] M. Yu, S. Y. Morita, S. R. Daniel, et al., “Transcutaneous

Pressure of O2 A Noninvasive and Early Detector of Pe-

ripheral Shock and Outcome,” SHOCK, Vol. 26, 2006,

450-456. doi:10.1097/01.shk.0000228798.18174.6a

[10] R. S. Irwin and J. M. Rippe’s, “Intensive Care Med,” 6th

Edition, Lippincott William & Wilkin, Vol. 12, 2008, pp.

249-250.

[11] R. P. Dellinger, “Cardiovascular Management of Septic

Shock,” Critical Care Medicine, Vol. 31, No. 3, 2003, pp.

946-953.

[12] R. Bellomo and D. Giantomasso, “Noradrenaline and the

Kidney: Friends or Foes?” Critical Care, Vol. 5, No. 6,

2001, pp. 294-298.

[13] S. Deruddre, G. Cheisson, J. Mazoit, E. Vicout, D. Ben-

hamou and J, Duranteau, “Renal Arterial Resistance in

Septic Shock—Effect of Increasing MAP with Norepi-

nephine on Renal Resistive Index with Droppler Ultra-

sound,” Intensive Care Medicine, Vol. 33, No. 9, 2007,

pp. 1557-1562.