ARTICLE IN PRESS

Journal of Critical Care (2009) xx, xxx–xxx

Hemodynamic effects of recombinant human activated

protein C in patients with septic shock☆
Baltasar Sanchez MDa , Enrique Piacentini MDa,⁎, Vittorio Pradella MDb ,
Mariano Mignini MDc , Juan Nava MDa
a
Intensive Care Unit, Hospital Mútua deTerrassa, Terrassa, Spain
b
Intensive Care Unit “Bozza” Ospedale Ca' Granda Niguarda, Milan, Italy
c
Medical Department, Eli Lilly Italy & Co. Critical Care, Sesto Fiorentino, Italy

Keywords:
Abstract
Septic shock;
Purpose: The aim of this study is to examine the effects of recombinant human activated protein C
Recombinant human
(rhAPC) on hemodynamic parameters in patients with septic shock.
activated protein C;
Methods: This is a retrospective study of 2 university-hospital critical care units. Patients with septic shock
Cardiovascular
with pulmonary artery catheterization or transthoracic thermodilution monitoring were studied. We
dysfunction;
matched patients with septic shock with at least 2 organ failures (18 treated with rhAPC and 18 controls) on
Mean arterial pressure
sex, age, sequential organ failure assessment (SOFA), Acute Physiology and Chronic Health Evaluation
(APACHE) II, and sepsis etiology. We recorded norepinephrine dose and hemodynamic parameters at
baseline and 24, 36, and 48 hours after the real or theoretical start of rhAPC treatment.
Results: Mean arterial pressure remained stable in both groups. In rhAPC patients, norepinephrine
requirements, initially higher than in controls, were significantly lower at 48 hours, and stroke volume at
24 and 48 hours improved (P b .05).
Conclusion: Recombinant human activated protein C use correlated with improved hemodynamic
parameters and decreased norepinephrine requirements. The retrospective nature of the study limits the
strength of these findings.
© 2009 Published by Elsevier Inc.

1. Introduction
Severe sepsis, a generalized inflammatory and procoagu-
lant host response to infection, occurs in approximately
☆
Conflicts of interests: Dr Baltasar Sanchez, Dr Enrique Piacentini, Dr
Vittorio Pradella, and Dr Juan Nava declare that they have no competing
interests. Dr Mariano Mignini is a full-time employee and has stocks and
stock options of Eli Lilly Italy & Co.
⁎ Corresponding author. Tel.: +34 93 726 5050; fax: +34 93 726 5006.
E-mail address: enpiache@yahoo.com.ar (E. Piacentini).
751 000 cases per year in the United States [1]. Despite
technical advances in critical care, mortality from severe
sepsis remained unchanged until the Recombinant Human
Activated Protein C (rhAPC) Worldwide Evaluation in
Severe Sepsis (PROWESS) trial [2]. The new Surviving
Sepsis Campaign Guidelines suggest the use of rhAPC with
grade 2B evidence [3]. Nevertheless, the use of rhAPC
remains controversial [4].
Sepsis has been described as a hyperdynamic state. Under
conditions of adequate volume resuscitation, profoundly
reduced systemic vascular resistance leads to a concomitant

0883-9441/$ – see front matter © 2009 Published by Elsevier Inc.

doi:10.1016/j.jcrc.2009.06.046
 ARTICLE IN PRESS
2 B. Sanchez et al.

elevation in cardiac index that obscures the myocardial At T0 and after 12 hours (T12), 24 hours (T24), 36 hours
dysfunction that also occurs [5]. In the 1980s, significant (T36), and 48 hours (T48), we recorded MAP, heart rate (HR),
reductions in both stroke volume (SV) and ejection fraction central venous pressure (CVP), SV, and norepinephrine doses.
in septic patients were observed despite normal total cardiac We calculated the multiorgan dysfunction (MOD) cardiovas-
output [6]. cular score [11] (the pressure-adjusted rate, calculated as the
Recently, echocardiographic studies demonstrated product of the HR and CVP, divided by MAP) at each point.
impaired left and right ventricular systolic and diastolic We also recorded antibiotic therapy, mechanical
function during the early phase of septic shock [7,8]. In ventilation, doses of dobutamine or epinephrine, CVP,
survivors, all abnormalities regressed, regardless of their volume of fluid loading, use of corticoids, and renal
severity [8]. replacement techniques.
Monnet et al [9] reported that administering rhAPC to Results are expressed as mean ± SD or median and
patients with septic shock improved hemodynamic para- interquartile range (IQR), accordingly their distribution. The
meters, and decreasing doses of norepinephrine were required 2 groups were compared using multivariate analysis of
to maintain mean arterial pressure (MAP). It is probable that variance for normally distributed variables, the Mann-
improvements in arterial pressure were correlated with Whitney U test for nonnormally distributed variables, and
improvements in myocardial performance, but the effect of the χ2 test for mortality. Differences with a P value less than
rhAPC on myocardial dysfunction in patients with septic .05 were considered statistically significant.
shock was not reported.
This study aimed to test the repercussions of rhAPC on
hemodynamic parameters in patients with septic shock, 3. Results
with special attention to cardiac SV. We hypothesized that
the use of rhAPC would improve sepsis-related myocar- Thirty-six patients were studied, 18 in each group: the
dial dysfunction. rhAPC group contained 12 cases of community-acquired
The preliminary results of this study were reported in pneumonia, 5 of peritonitis, and 1 of mediastinitis, and the
abstract form [10]. control group contained 12 cases of community-acquired
pneumonia, 5 of peritonitis, and 1 of purpura fulminans.
Patients' baseline characteristics are reported in Table 1, and
2. Patients and methods patients' baseline laboratory values are reported in Table 2;
there were no significant differences between rhAPC or
Using a retrospective case-control design, we selected 2 control patients in the 2 hospitals. All patients were
groups of patients in 2 university-hospital critical care units.
The institutional review boards at the 2 hospitals waived the
need for informed consent. Table 1 Main characteristics at T0 of patients treated with
The first group is composed of all consecutive patients rhAPC and control patients
with septic shock that received rhAPC and had undergone
pulmonary artery catheterization (10 patients) or transthor- rhAPC group Control
(n = 18) group (n = 18)
acic thermodilution catheter (PICCO) (8 patients) monitor-
ing before rhAPC infusion between December 2004 and APACHE II 28 ± 5 29 ± 5
July 2006. SOFA 12.4 ± 2.9 12.1 ± 2.3
The control group is composed of patients with septic shock No. of organ failures 3.7 ± 0.8 3.3 ± 0.8
who had undergone pulmonary artery catheterization (10 Age (y) 49 ± 15 56 ± 17
Sex (% male) 56 56
patients) or PICCO (8 patients) catheter monitoring between
Glycemia (mg/dL) 166 ± 52 154 ± 58
January 2002 and July 2004; none of these patients received Patients receiving 3 3
rhAPC because it was not yet commercially available. This dobutamine
control group was an exact one-to-one pair match with the Patients receiving 18 15
rhAPC group on criteria of sex, age, SOFA, APACHE II, corticosteroids
and sepsis etiology. We selected patients who survived at least Patients receiving 4 5
48 hours after the onset of the second organ failure. hemodialysis
In the rhAPC group, baseline (T0) was defined as the time % appropriate 100 100
that rhAPC infusion started. The time between the onset of antibiotic treatment
the second organ failure and T0 was recorded; we used the Tidal volume in 7.4 ± 1.5 6.9 ± 1.4
same time to calculate T0 in the control group (eg, if 12 hours MV (ml/kg)
PEEP (cmH2O) 8.3 ± 2.9 8.5 ± 3.1
elapsed between the onset of the second organ failure and the
start of rhAPC in a treatment case, then in the corresponding No significant differences between groups were found for any variable.
MV indicates mechanical ventilation; PEEP, positive end-expiratory
pair-match control case, we designated 12 hours after onset
pressure.
of the second organ failure as T0).
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Hemodynamic effects of rhAPC in patients with septic shock 3

Table 2 Main laboratory values at T0 of patients treated with

rhAPC and control patients
rhAPC group Control group
(n = 18) (n = 18)
pH 7.31 ± 0.38 7.33 ± 0.43
PCO2 (mm Hg) 37 ± 7 36 ±7
Po2 (mm Hg) 86 ± 15 87 ± 16
Creatinine (mg/dL) 2.0 ± 0.8 1.9 ± 1.2
Na+ (Meq/L) 138 ± 6 141 ±8
K+ (Meq/L) 4.9 ± 0.9 4.7 ± 1.1
Prothrombin 81 ± 17 82 ± 17
time (%)
Platelets(/mm3) 209 400 ± 160 700 316 600 ± 202 600
Bilirubin (mg/dL) 1.45 ± 1.09 0.95 ± 0.42
No significant differences between groups were found for any variable. Fig. 2 Percent change from baseline in norepinephrine require-
ments in patients with septic shock treated with rhAPC and in
control patients throughout the study period. Data are shown as
mechanically ventilated at T0 and remained mechanically median and IQR.
ventilated throughout the study. The use of corticosteroids,
renal replacement techniques, and dobutamine or epinephr- (Fig. 2). The MOD cardiovascular score improved at T24 in
ine was similar in the 2 groups at all times. Fluid balance was the rhAPC group compared with the control group, achieving
positive and similar at T24 and at T48 in the 2 groups. Mean a significant difference at T48 (Fig. 3). In the rhAPC group,
arterial pressure increased in both groups (Fig. 1). The CVP SV improved (43.2 ± 7.1 mL at baseline, 55.3 ± 12.4 at T24,
remained unchanged in both groups (11 ± 5 mm Hg in the and 65.7 ± 10 mL at T48; P b .05 between baseline and T48),
rhAPC group and 11 ± 4 mm Hg in the control group at whereas in the control group, SV increased in the first 24
baseline, and 10 ± 4 mm Hg in the rhAPC group and 10 ± 3 hours but remained stable in the next observational period
mm Hg in the control group at T48). The HR decreased in (45.4 ± 8.1 mL at baseline, 55.1 ± 13.6 at T24, and 55.3 ± 9.1
both groups (107 ± 18 beats/min in the rhAPC group and mL at T48; not significant). At T48, SV was higher in the
116 ± 27 beats/min in the control group at baseline, and 92 ± rhAPC group than in the control group (P b .05) (Fig. 4).
22 beats/min in the rhAPC group and 90 ± 18 beats/min in In-hospital mortality was 16.7% in the rhAPC group and
the control group at T 48 ; P b .05). The need for 33.3% in the control group (P = .24).
norepinephrine decreased in the rhAPC group (0.67 μg
kg−1 min−1 [IQR, 0.25-0.97] at baseline, 0.53 μg kg−1 min−1
[IQR, 0.32-0.90] at T12, 0.43 μg kg−1 min−1 [IQR, 0.19-
0.79] at T24, and 0.20 μg kg−1 min−1 [IQR 0.0-0.35] at T48; 4. Discussion
P b .05 for each comparison) but remained stable throughout
the study in the control group (0.43 μg kg−1 min−1 [IQR We found that rhAPC improved the hemodynamic status
0.24-0.61] at baseline and 0.30 μg kg−1 min−1 [IQR, 0.16- of patients with septic shock, decreasing the norepinephrine
0.61] at T48; P = .35). At T48, norepinephrine dose was
lower in the rhAPC group than in the control group (P b .05)

Fig. 1 Mean arterial pressure in patients with septic shock treated Fig. 3 The MOD cardiovascular score in patients with septic
with rhAPC and in control patients throughout the study period. shock treated with rhAPC and in control patients throughout the
Data are shown as mean ± SD. study period. Data are shown as mean ± SD.
 ARTICLE IN PRESS
4 B. Sanchez et al.
Fig. 4 Stroke volume in patients with septic shock treated with
rhAPC and in control patients throughout the study period. Data are
shown as mean ± SD.
dosage required and improving MAP and SV. Our results
suggest that rhAPC treatment was associated with improve-
ments in both the vascular dysfunction and the myocardial
dysfunction induced by sepsis. These improvements
achieved statistical significance at 48 hours.
The PROWESS [2] study found that rhAPC reduces
mortality in patients with severe sepsis and septic shock but
did not report its effects on organ failure. Reporting on data
from the PROWESS trial, 2 studies observed that cardio-
vascular and respiratory dysfunction was corrected more
rapidly over the first 7 days in rhAPC-treated patients than in
placebo-treated patients [12,13].
Monnet et al [9] showed a decrease in the required
norepinephrine dosage but did not report any data on
myocardial function.
Various studies have addressed the prognostic value of
myocardial dysfunction in sepsis. Parker et al [6] reviewed
septic patients on initial presentation and at 24 hours to
determine prognostic indicators; they found that improve-
ments in systemic vascular resistance index and in cardiac
index at 24 hours were associated with survival. A recent
study confirms that left ventricular systolic dysfunction is
common in the acute phase of septic shock in fluid-loaded
patients on vasopressors and who also have left ventricular
diastolic dysfunction [8]. Interestingly, cardiac dysfunction
regressed in survivors [6,8].
We observed a reduction in the required dose of
norepinephrine and an improvement in SV over the first 24
hours of rhAPC treatment. A large prospective study
targeting patients with early and severe septic shock is
currently recording data about myocardial dysfunction [14].
The results of this trial, expected for July 2010 [15], might
reinforce and explain our findings.
5. Limitations of the study
Our study has several limitations; among which, the chief
is the retrospective nature of the study. However, we think
this design was appropriate for “proof of concept” about the
effects of rhAPC on myocardial performance. We must stress
that our study did not include patients who died in the first 24
hours after the onset of the second organ failure. Another
limitation is the 3-year difference in recruitment time of the 2
groups. This difference was unavoidable because all patients
with septic shock treated at our centers received rhAPC after
it was introduced in clinical practice. The time gap between
the 2 groups is not entirely “innocent”; many changes were
incorporated into sepsis treatment during this period [3].
Nevertheless, in our series, there were no differences in fluid
loading, administration of corticoids, mechanical ventilation
approach, or glucose control. Finally, although the trend
toward reduced mortality observed in the rhAPC group
might seem promising, the small sample precludes any
conclusions about mortality.
6. Conclusion
In this group of septic patients, the use of rhAPC was
correlated with improved hemodynamic parameters and
decreased vasopressor requirements.
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