Optimizing mean arterial pressure in septic shock: a critical reappraisal of the literature

Methods

Pubmed and Google Scholar were searched by using the key words ‘arterial pressure’,
‘septic shock’, and ‘norepinephrine’. The search was limited to studies published
between 1 January 2000 and 31 July 2014. Only randomized clinical trials, comparative
studies, and observational studies were analyzed; reviews and editorials were excluded
as were animal studies and studies published in languages other than English.

Results

We identified 12 studies; seven were comparative studies determining the effect of
different goals of blood pressure on outcome (Table 1) 18]-24], and five were observational studies (Table 2) analyzing hemodynamic variables in patients with septic shock to determine the influence
of arterial pressure on outcomes 1],2],25]-27]. The end-points were mortality, regional circulation, and microcirculation in four
1],2],24],25], five 18]-20],26],27], and three 21]-23] studies, respectively. Among the seven comparative studies, six studies included
fewer than 30 patients 18]-23]; one of the two randomized clinical trials included 776 patients 24]. Because of the relative weight of this latter study, it will likely have a larger
impact on future guidelines than the smaller studies. Nevertheless, the smaller studies
collected useful additional informative data that were not included in the large study.
Surprisingly, severity scores were similar in the different studies, although mortality
rates were highly variable, ranging from 17% to 76%.

Table 1. Studies comparing different levels of mean arterial pressure in septic shock

Table 2. Observational studies assessing the effect of mean arterial pressure on outcomes

Mean arterial pressure and macro-hemodynamics

MAP was increased from 65 to 85 mm Hg in six of the comparative studies 18]-20],22]-24] and to 60, 70, 80, and 90 mm Hg in one study 21]. Overall in the studies, the increase in MAP was achieved by a 1.7?±?0.4 ?g/kg per
minute increase in norepinephrine infusion. Heart rate was not affected by the increase
in norepinephrine infusion, but cardiac output increased. Because the increase in
MAP was greater than the increase in cardiac output, systemic vascular resistance
increased (Table 3). Mean pulmonary arterial pressure changed inconsistently.

Table 3. Hemodynamic variables for mean arterial pressure targets of 65 and 85 mm Hg

Effects on organ function

The effects on organ function of increasing MAP from 65 to 85 mm Hg were assessed
in two comparative studies 18],19], which included a total of 38 patients. The first study included 10 patients in whom
MAP was progressively increased to three levels (65, 75, and 85 mm Hg) 18]. In the second study, variables were measured at a MAP of 65 mm Hg and then the MAP
was either kept at 65 mm Hg or increased to 85 mm Hg 19]. The findings were consistent in the two studies and showed no differences in gastric
or renal circulations with the different MAP targets. In the three observational studies
that assessed the effect of different MAPs on organ function, a MAP of less than 75 mm
Hg was associated with development of AKI 1],26],27].

Deruddre and colleagues 20] prospectively studied the relationship between MAP and organ function, increasing
the MAP from 65 to 75 and 85 mm Hg by increasing the norepinephrine infusion rate
in 11 patients with septic shock. The renal resistive index measured by pulsed Doppler
in the interlobar renal arteries decreased and urine output increased when MAP was
increased from 65 to 75 mm Hg but not when MAP was increased from 75 to 85 mm Hg.
Creatinine clearance was unaffected.

The effects of mean arterial pressure on oxygen metabolism

Oxygen exchange was measured in five of the comparative studies 18],19],21]-23]. Increase in cardiac output was associated with an increase in oxygen delivery; whole
body oxygen uptake did not change. Plasma lactate levels were unaffected. The effects
of increasing MAP on mixed venous oxygen saturation or central venous oxygen saturation
were inconsistent: mixed venous oxygen saturation/central venous oxygen saturation
increased in three studies 18],20],21] and was unchanged in two studies 18],23]. This discrepancy may be due to several factors, including the preload of patients
and their cardiac function. The magnitude of change in oxygen variables did not appear
to be clinically relevant (Table 3).

Effects on the microcirculation

The effects of an increase in MAP on the microcirculation were variable. Using sidestream
darkfield (SDF) imaging, Dubin and colleagues 23] increased MAP to 65, 75, and 85 mm Hg and measured sublingual capillary microvascular
flow index or the proportion of perfused capillaries. In patients with septic shock,
increasing MAP improved microcirculatory variables in the patients with impaired microcirculation
at baseline. In contrast, the microcirculation was impaired when baseline conditions
were normal. This underlines the need for an individualized assessment. Using near-infrared
spectroscopy with vaso-occlusive tests, Thooft and colleagues 22] found that perfusion was slightly improved when MAP was increased from 75 to 85 mm
Hg but that it was impaired when MAP was decreased to 65 mm Hg. However, these effects
were quite variable from one patient to another. In a study using measurement of intra-cutaneous
oxygen partial pressure via a Clark electrode coupled with laser Doppler flowmetry,
Jhanji and colleagues 21] found that increase in MAP was accompanied by a significant increase in cutaneous
oxygen partial pressure and red blood cell flow, whereas the sublingual microcirculation
explored by SDF imaging was unaffected.

Effects on mortality

In two of the observational studies, MAP levels of less than 60 to 70 mm Hg were independent
determinants of mortality 1],2]. However, in a post hoc analysis, Dünser and colleagues 25] found no association between MAP and mortality.

In a large randomized clinical trial of 776 patients, Asfar and colleagues 24] compared the effects of low-target and high-target MAP on mortality. The study was
designed to show an absolute 10% difference in mortality at day 28, assuming a mortality
rate of 45%. The patients were allocated to protocols targeting MAPs of 65 to 70 mm
Hg or 80 to 85 mm Hg for 5 days. As expected, the doses of norepinephrine were higher
in the high-MAP target group than in the low-target group, but the cumulative fluid
balance was similar. The 28-day mortality rate was 35% in both groups. The only difference
was a higher rate of de novo atrial fibrillation in the high-target group (6.7% versus 2.8%, P?=?0.02). Chronic arterial hypertension was reported in 44% of patients, and in a
predefined stratum analysis of these patients, targeting a MAP of 80 to 85 mm Hg was
associated with better renal function (lower rate of serum creatinine doubling and
renal replacement therapy requirements). However, as also reported in one of the observational
studies 27], there was no clear relationship between mortality and AKI. Consequently, this finding
would suggest that targeting a MAP of 65 to 70 mm Hg or 80 to 85 mm Hg has similar
effects on survival in a heterogeneous population of patients with septic shock. Of
note, one limitation of this study 24] was that the actual MAP achieved in the low-target group was 75 mm Hg instead of
65 to 70 mm Hg.

Norepinephrine dosages and levels of mean arterial pressure

In the comparative studies, the doses of norepinephrine were increased by about 63%
in order to increase MAP from 65 to 85 mm Hg 18]-24]. Hence, patient management per se may have impacted outcomes in that not only was the level of MAP altered but also
the dosages of vasopressors. One of the observational studies analyzed the interactions
between MAP, norepinephrine load, and outcome 25]. The norepinephrine load was associated with mortality with a relative risk of 1.83
and a 95% confidence interval of between 1.40 and 2.38. This load was also associated
with several disease-related events, and these associations were independent of age,
prior history of hypertension, and co-morbidity. This study, therefore, suggests that
the norepinephrine load, rather than the MAP per se, was associated with impaired outcomes. This limitation, which is related to the
design of these studies, makes it difficult to differentiate between the effects of
blood pressure and those of norepinephrine.