J Clin Monit Comput (2013) 27:215–221 DOI 10.1007/s10877-013-9432-y
ORIGINAL RESEARCH
StO2 guided early resuscitation in subjects with severe sepsis or septic shock: a pilot randomised trial Olivier Nardi • Andrea Polito • Je´roˆme Aboab • Gwenhael Colin • Virginie Maxime • Bernard Clair • Diane Friedman • David Orlikowski • Tarek Sharshar Djillali Annane
•
Received: 15 September 2012 / Accepted: 12 January 2013 / Published online: 5 February 2013 Ó Springer Science+Business Media New York 2013
Abstract The scientific community has agreed upon developing accurate monitoring of tissue perfusion and oxygenation to improve the management of subjects with sepsis. This pilot study aimed to investigate the feasibility of targeting tissue oxygen saturation (StO2) in addition to the currently recommended resuscitation goals, central venous pressure, mean arterial pressure and central venous oxygen saturation, in patients with severe sepsis or septic shock. A pilot, single-centre, randomised, non-blinded trial recruited 30 subjects with severe sepsis upon intensive care unit admission at an academic medical centre in France. Subjects were randomly assigned to a 6 h resuscitation strategy following the Surviving Sepsis Campaign guidelines with
For commentary, please refer Paul A. van Beest and Thomas W. L. Scheeren (doi:10.1007/s10877-013-9438-5).
Electronic supplementary material The online version of this article (doi:10.1007/s10877-013-9432-y) contains supplementary material, which is available to authorized users. O. Nardi (&) A. Polito J. Aboab G. Colin V. Maxime B. Clair D. Friedman D. Orlikowski T. Sharshar D. Annane General Intensive Care Unit, Raymond Poincare´ Hospital (AP-HP), 104 boulevard Raymond Poincare´, 92380 Garches, France e-mail:
[email protected] O. Nardi A. Polito J. Aboab V. Maxime T. Sharshar D. Annane Laboratory of Neuroendocrine Response to Sepsis (EA4342), University of Versailles SQY, 104 boulevard Raymond Poincare´, Garches, France D. Orlikowski D. Annane Centre for Clinical Research and Innovative Technologies (CIC-IT805), INSERM, 104 boulevard Raymond Poincare´, Garches, France
(experimental) or without (control) StO2. StO2 was measured over several muscles (masseter, deltoid and pectoral or thenar muscles), and a StO2 above 80 % over at least 2 muscles was the therapeutic goal. The primary outcome was evaluated as follows: 7-day mortality or worsening of SOFA score between day 7 and study onset, i.e., DSOFA [ 0). Thirty subjects were included in the study over a period of 40 weeks. Fifteen subjects were included in each group. Monitoring of StO2 over three areas was performed in the experimental group. However, measures over the pectoral muscle provided poor results. At study day 7, there were 5/15 (33.3 %) subjects who died or had a DSOFA [ 0 in the experimental arm and 4/15 (26.6 %) who died or had a DSOFA [0 in the control arm (p = 1.00). This pilot study was the first randomised controlled trial using an algorithm derived from the SSC recommendations, which included StO2 as a treatment goal. However, the protocol showed no clear trend for or against targeting StO2. Keywords Near infrared spectroscopy StO2 Severe sepsis Randomised controlled trial
1 Background Non-invasive evaluation of the ratio of oxyhaemoglobin to total haemoglobin of skeletal muscle (Tissue Oxygen Saturation or Skeletal Muscle Tissue Oxygenation: StO2) using near infrared spectroscopy (NIRS) has gained much attention among physicians, particularly for the management of subjects with trauma or elective surgery but also for those with severe sepsis or septic shock [1, 2]. Observational studies in critically ill subjects with sepsis have been performed, demonstrating an association between low StO2 and worse clinical outcome [3–8]. During sepsis, low StO2 may
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be related to microcirculatory perfusion alterations [9]. According to international guidelines on sepsis, the effects of haemodynamic support should be assessed by monitoring a combination of parameters of global and regional perfusion, and treatment should be implemented following standardised goal-oriented algorithms [10, 11]. A task bundle to fulfil during the first 6 h of management of severe sepsis and septic shock (6 h resuscitation bundle) following such an algorithm has been created by the Surviving Sepsis Campaign, an international performance improvement program targeting severe sepsis [11]. This algorithm includes goals such as systemic arterial pressure, central venous pressure and central venous oxygen saturation but no evaluation of regional perfusion. Some studies have shown that treatments included in this algorithm may impact microcirculation [12–15], and one study showed that patients with low StO2 status at the end of early goal-directed therapy (EGDT) using this algorithm have a worse clinical outcome [6]. Some patients with low StO2 status at the end of EGDT may benefit from treatment intensification. An algorithm including StO2 may help identify these patients and guide treatment. The impact on clinical outcome is uncertain. The aim of this pilot clinical trial was to assess the feasibility of adding StO2 to the various haemodynamic variables included as targets in the algorithm recommended by the Surviving Sepsis Campaign (SSC).
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in the study while in the emergency department. The time window for inclusion was less than 8 h from the recognition of the first sign of hypoperfusion. Subjects younger than 18 years, pregnant women, brain dead patients, and those with the decision to withhold or withdraw life-supporting treatments were not eligible. 2.3 Randomisation The computer-generated randomisation list was provided by an independent statistician. Allocation concealment was guaranteed using sealed opaque envelopes containing the treatment arm. 2.4 Interventions
We conducted a pilot, single-centre, randomised, nonblinded trial. This study was conducted to prepare a larger multicentric study (NCT00167596). The protocol was approved by the Comite´ de Protection des Personnes at Saint-Germain en Laye, France. Written informed consent was obtained prior to randomisation from subjects or subjects’ next of kin, as appropriate. When a patient was unable to consent a priori deferred consent was recorded.
In the control arm, subjects were managed following an algorithm adapted from the Surviving Sepsis Campaign guidelines [17]. Briefly, subjects received 500 ml of crystalloids or colloids every 30 min until central venous pressure (CVP) was between 8 and 12 mm Hg. Then, if the mean blood pressure (MBP) remained lower than 65 mm Hg, vasopressor therapy (norepinephrine or epinephrine) was initiated and titrated to raise the MBP to 65–80 mm Hg. Then, if central venous oxygen saturation (ScvO2) was lower than 70 % and hematocrit was lower than 30 %, packed red blood cells were transfused. If the ScvO2 was lower than 70 % and hematocrit was higher than 30 %, dobutamine was initiated at a dose of 2.5 lg/kg/min and titrated by incremental steps of 2.5 lg/kg/min every 30 min until the ScvO2 level was of 70 % or higher or up to a maximum infusion rate of 20 lg/kg/min. Dobutamine infusion rate was kept constant as soon as all haemodynamic goals were achieved and decreased if heart rate rose above 120 bpm. In the StO2 arm, in addition to optimisation of CVP, MBP and ScvO2, StO2 were increased to 80 % or higher in at least 2 muscular sites, applying the aforementioned algorithm (Fig. 1). That precipitated using transfusion and/or dobutamine infusion to increase StO2.
2.2 Participants
2.5 ScvO2 and StO2 recording
Subjects with suspected or confirmed source of infection were considered for enrolment in the study if they were 18 years of age or older, admitted to the intensive care unit (ICU) at an academic medical centre in France (Raymond Poincare´ Hospital, Garches), had two or more Systemic Immune Response Syndrome criteria [16], and one of the following signs of hypoperfusion: (1) systolic blood pressure of 90 mmHg or less; (2) arterial lactates of 4 mmol/l or more; (3) mottled skin; (4) urine output of less than 30 ml/h for at least 1 h; and (5) mental confusion. All subjects had received some form of care prior to inclusion
All subjects had an arterial line placed in the radial or femoral artery and a catheter in the superior vena cava. ScvO2 (ABL 720; Radiometer, Brønshøj, Denmark) and StO2 were recorded at baseline (H0), H2, H4, H6 and H24 following randomisation. StO2 was recorded using an InSpectraTM Tissue Spectrometer (InSpectraTM 325 StO2 Tissue Oxygenation Monitor, Hutchinson Technology Inc, MN, USA) and a 25 mm depth probe placed over the left masseter muscle (Masseter-StO2) of the left deltoid muscle (Deltoid-StO2) and right pectoral muscle (Pectoral-StO2) (11 subjects) or the left thenar eminence (Thenar-StO2)
2 Materials and methods 2.1 Study design
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Patient with severe sepsis or septic shock
CVP > 8 mmHg CVP
Fluid challenge with 500 ml crystalloids or colloids until CVP above 8 mmHg or 12 mmHg if mechanically ventilated
No
Yes
Norepinephrine, epinephrine or dopamine centrally administered
MBP > 65 mmHg
No
Yes No
ScvO2 > 70%
Ht > 30%
Yes Yes
Experimental group
Transfusion of packed red blood cells
No
Administration of a dobutamine infusion (2.5 µg·kg -1·min-1 steps up to a maximum of 20 µg·kg 1 ·min-1). Check CVP and MBP before each adjustment.
Goal achieved, maintain monitoring
Yes
StO2>80% on at least 2 sites
Yes
No
Fig. 1 Haemodynamic treatment algorithm
(4 subjects). Measurement of the thenar-StO2 ipsilateral to a radial arterial line was allowed. StO2 was read after 2 min of recording, and then, probe was skipped to the next muscular area in the following order: masseter muscle, deltoid muscle and pectoral muscle or thenar muscle. Calibration of the spectrometer was performed once before monitoring, as recommended by the manufacturer. Adhesive shields over masseter (15 subjects), deltoid (15 subjects) and pectoral (11 subjects) or thenar (4 subjects) muscles were kept in place throughout the duration of the
experiments. StO2 was recorded only in the experimental arm to ensure that controls were managed without taking into account StO2 values. 2.6 Data collection and follow-up At hospital and ICU admission, we systematically recorded patients’ locations prior to ICU admission (community, hospital, long term care facility), co-morbid conditions and the SOFA score [18], type and dose of any intervention,
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routine laboratory data, arterial blood lactates, and cultures of samples collected at any suspected site of infection. Subjects were followed up to 28 days following randomisation. During the first 24 h, we recorded the type and dose of any intervention and ScvO2 at H0, H2, H4, H6 and H24 from randomisation. In the experimental arm, we also recorded StO2 values at the same timepoints. The SOFA score was recorded daily from randomisation to study day 7. Subjects’ vital status was recorded at study day 28 upon ICU and hospital discharge. 2.7 Endpoints The primary outcome was a composite endpoint: mortality at day 7 or a worsening of the SOFA score as defined by a difference between study day 7 and baseline SOFA [ 0 (DSOFA [ 0). Secondary endpoints were mortality at 28 days, ICU or hospital discharge, or variation in SOFA scores from randomisation to study day 7. 2.8 Statistical analysis No formal sample size was calculated for this pilot study. We planned to include 30 subjects, with 15 subjects in each group. We performed an intent-to-treat analysis. Continuous variables were described as the means and standard deviations or the median and interquartile range when appropriate. Categorical variables were expressed as numbers and percentages. Comparisons for the primary outcome for any categorical variables were performed using Fisher’s exact test. Wilcoxon matched-pairs signedranks test was used when appropriate. All tests were twosided, and a p value of 5 % or less was required for statistical significance.
3 Results 3.1 Subjects From July 2005 to March 2006 (40 weeks), 30 subjects were included in the study. Fifteen subjects were randomised to the experimental arm and 15 subjects to the control arm. Subject characteristics at baseline are displayed in Table 1. Overall, the two treatment arms were well balanced for demographic data and severity of illness. The lung was the most common source of infection (67 %). A pathogen was identified in 70 % of cases, and 20 % of subjects had positive blood cultures. At baseline, ScvO2 was lower than 70 % in 11 subjects (5 in the experimental arm and 6 in the control arm) (Table 2). In the experimental group, the mean thenar-StO2 was 86 %. Over the other muscular areas, mean StO2 values were lower than
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80 %, and values were lower than 80 % in 47–60 % of subjects (Table 2). Among the 10 subjects with ScvO2 above 70 % at baseline in the experimental group, only 4 subjects had StO2 above 80 % over at least 2 areas. None of the subjects of the experimental group with ScvO2 below 70 % at baseline had StO2 above 80 % over at least 2 areas. 3.2 Primary endpoint At study day 7, 5/15 (33.3 %) subjects died (n = 3) or had a DSOFA [ 0 (n = 2) in the experimental arm, and 4/15 (26.6 %) died (n = 2) or had a DSOFA [ 0 (n = 2) in the control arm (p = 1.00) (Table 3). 3.3 Secondary endpoints and other results There were 5/15 (33.3 %) and 4/15 (26.6 %) deaths by 28 days in the experimental and control arms, respectively. Similarly, there was no difference between groups for mortality at ICU discharge, mortality at hospital discharge and mean length of stay in the ICU (Table 3). During the first 6 h of resuscitation, the mean ScvO2 remained above 70 % in both groups, and the number of subjects with a ScvO2 lower than 70 % decreased over time in both groups (Table 2). At H6, there were no significant differences between groups in ScvO2 variation (p = 0.63) (Table 2). In the experimental arm, the proportion of subjects with StO2 lower than 80 % at H0 decreased from 47 to 20 % for masseter-StO2, from 60 to 30 % for deltoid-StO2, and from 60 to 47 % for pectoral-StO2; however, none of these decreases was statistically significant after a paired Wilcoxon sign rank test (p = 0.5 for Masseter-StO2, p = 1 for Deltoid-StO2, and p = 0.4 for Pectoral-StO2). The StO2 therapeutic objective was to obtain at least two muscular sites above 80 %. At baseline, four patients fulfilled this criterion and maintained at least two sites with StO2 above 80 % until H6. One patient with only masseter-StO2 above 80 % at baseline fulfilled the StO2 objective at H2 due to an increase in deltoid-StO2 from 77 to 81 %. At H4, this patient’s deltoid-StO2 decreased below 80 % until H24. During the first 6 h of management, subjects in the experimental arm were more likely to be initiated on dobutamine; however, this trend was not statistically significant (p = 0.16) (Table 4), and at day 2, no patient was given dobutamine in either group (Table 5 additional material).
4 Discussion This study is the first prospective randomised trial of NIRS-derived StO2-guided resuscitation in subjects with
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Table 1 Primary characteristics of 30 patients with severe sepsis or septic shock (mean ± SD, unless otherwise specified) All patients (N = 30)
Experimental arm (N = 15)
Control arm (N = 15)
p value
Age (year)
61.5 ± 15
59 ± 15
63 ± 15
0.4
Gender male, n (%)
21 (70)
11 (73)
10 (67)
0.7
Weight (kg)
70 ± 18
68 ± 21
72 ± 15
0.5
Height (cm)
170 ± 10
168 ± 8
172 ± 8
0.12
1
19 (63)
10 (67)
9 (60)
2 3
9 (30) 2 (7)
3 (20) 2 (13)
6 (40) 0 (0)
A
12 (40)
6 (40)
6 (40)
B
9 (30)
4 (27)
5 (33)
C
6 (20)
3 (20)
3 (20)
D
3 (10)
2 (13)
1 (7)
SAPS II
48 ± 23
43 ± 18
52 ± 27
0.3
SOFA score at ICU admission
7.5 ± 4
7±3
8±4
0.6
Respiratory sepsis, n (%)
20 (67)
12 (80)
8 (53)
McCabe category, n (%)
0.2
Knaus Class, n (%)
0.4
Type of pathogen, n (%)
0.2 0.7
Streptococcus pneumoniae
4 (13)
2 (13)
2 (13)
Staphylococcus aureus
6 (20)
3 (20)
3 (20)
Gram-positive-others
3 (10)
2 (13)
1 (7)
Gram-negative
7 (23)
3 (20)
4 (27)
Legionella pneumoniae Others
2 (7) 2 (7)
1 (7) 2 (13)
1 (7) 0 (0)
Unknown
7 (23)
3 (20)
4 (27)
Positive blood culture, n (%)
5 (20)
3 (20)
2 (13)
Corticosteroids treatment, n (%)
12 (40)
6 (40)
6 (40)
1
Activated protein C treatment, n (%)
6 (20)
2 (13)
4 (27)
0.8
severe sepsis or septic shock and the first study to consider multi-site StO2 measurements. There is no gold standard to evaluate microcirculation. Thus, it is not possible to compare StO2 with another test to evaluate its accuracy. We evaluated a clinical pathway including the StO2. Therefore, the present study did not evaluate performance of StO2 for the diagnosis of microcirculatory dysfunction but instead evaluated the downstream consequences of using StO2 on clinical outcome [19]. During the first 6 h of resuscitation, there was no significant variation in the experimental arm in the mean values of StO2, regardless of the recorded areas. Nevertheless, the number of subjects with masseterStO2 or deltoid-StO2 values lower than 80 % decreased over time. However, the objective was to increase StO2 above 80 % on at least two sites, and the number of patients fulfilling this criterion remained constant between H0 and H6 (n = 4). This may reflect a lack of impact of the treatment on StO2 but may also be due to a poor choice of monitored muscles. We recorded StO2 in different areas to obtain a broader evaluation of tissue oxygenation. StO2
0.9
measurements are influenced by adipose tissue thickness [20, 21]. In this study, we did not measure subcutaneous fat layer thickness. Nevertheless, pectoral-StO2 was lower than deltoid-StO2 or masseter-StO2, and there were more problems in obtaining a stable signal. Acquiring pectoralStO2 was impossible for 3/11 subjects, and 2 more subjects showed recordings below 10 %, which was not observed for other muscles. Additionally, we cannot rule out that pectoral-StO2 might be actually lower than masseter-StO2 or deltoid-StO2; differences in fat layer thickness may partially explain these findings. After evaluation of 11 patients in the experimental group, we abandoned the pectoral muscle site and replaced it by the thenar site. Thereafter, the 3 areas monitored were the masseter muscle, deltoid muscle and thenar muscle. Although only 4 subjects had thenar-StO2 measured, 2 subjects had thenarStO2 above 80 % from H0 to H6 and at least 2 sites with StO2 above 80 %. Therefore, we do not recommend recording pectoral-StO2 with currently available devices, this area will not be considered for the main study.
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Table 2 Primary haemodynamic and oxygenation variables (mean ± SD, unless otherwise specified. See detailed table in additional material) Experimental arm H0
H2
Control arm H4
H6
H24
H0
H2
H4
H6
H24
Mean blood pressure (mmHg)
79 ± 18
80 ± 23
83 ± 20
82 ± 14
79 ± 21
72 ± 14
74 ± 13
76 ± 18
89 ± 15
69 ± 27
Central venous pressure (mmHg) Heart rate (bpm)
10 ± 6
9±5
8±4
9±4
6±4
10 ± 5
14 ± 5
14 ± 6
12 ± 5
10 ± 6
103 ± 22
112 ± 26
105 ± 21
104 ± 19
102 ± 20
90 ± 17
89 ± 18
98 ± 19
96 ± 28
87 ± 46
Lactates (mmol/l)
4.0 ± 4.1
4.1 ± 4.9
4.2 ± 4.4
4.0 ± 5.5
3.2 ± 2.5
3.0 ± 2.2
3.1 ± 2.6
3.6 ± 2.9
2.1 ± 1.7
1.5 ± 1.1
PaO2/FiO2 (mmHg) ScvO2 (%)
170 ± 89
170 ± 100
181 ± 101
198 ± 113
165 ± 94
166 ± 92
226 ± 143
188 ± 70
191 ± 102
198 ± 79
70 ± 20
72 ± 17
77 ± 14
80 ± 5
72 ± 11
73 ± 7
76 ± 8
77 ± 11
77 ± 10
77 ± 7
MasseterStO2 (%)
79 ± 18
78 ± 22
81 ± 20
82 ± 15
75 ± 19
–
–
–
–
–
DeltoidStO2 (%)
70 ± 24
69 ± 23
79 ± 15
78 ± 18
62 ± 29
–
–
–
–
–
PectoralStO2 (%)
43 ± 33
46 ± 33
47 ± 33
45 ± 36
35 ± 34
–
–
–
–
–
ThenarStO2 (%)*
86 ± 11
77 ± 17
82 ± 13
83 ± 12
84 ± 8
–
–
–
–
–
* 4 patients Table 3 Outcomes All patients (N = 30)
Experimental arm (N = 15)
Control arm (N = 15)
p value
10 (33)
5 (33.3)
4 (26.6)
1
Primary outcome Death or DSOFA [ 0 at day 7 (%)
Secondary outcomes Death at day 28, n (%)
9 (27)
5 (33.3)
4 (26.6)
1
Death at ICU discharge
9 (27)
5 (33.3)
4 (26.6)
1
Death at hospital discharge
10 (33)
6 (40)
4 (26.6)
0.7
Mean length of stay (days)
21.5 ± 28
19 ± 32
23.5 ± 25
0.7
Fischer’s exact test or student’s t test when appropriate
We used the commonly accepted NIRS technology to measure StO2. An StO2 cut-off value of 80 % was considered the treatment goal in our study in accordance with recommendations of the manufacturer. This may be questionable. First, as mentioned above, we observed important variations in StO2 values according to the muscle for which StO2 was measured. Second, there is currently no clinical
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Table 4 Resuscitation therapies during the first 6 h (mean ± SD, unless otherwise specified) Experimental arm (N = 15)
Control arm (N = 15)
p value
Cumulative fluid loading (ml)
1,500 ± 894
1,363 ± 744
0.7
Number of patients transfused n (%)
4 (26.6)
5 (33.3)
1
Number of patients receiving dobutamine n (%)
5 (33)
1 (7)
0.17
evidence to set a cut-off value in patients with sepsis. Testing a different cut-off value of StO2 may be appropriate. However, in our study, 47 % of patients in the experimental group had a StO2 below 80 % at baseline. Only 5 patients had a masseter-StO2 below 70 %. Therefore, choosing a cut-off value of 70 % would have lessened the opportunity to treat further patients included in the experimental group and would have diminished the difference of management induced by StO2 measurement between the two groups. We opted for a multi-site approach in this study. In previous works, we found a statistically significant association between masseter-StO2 and ScvO2 [22]. In other fields, researchers found interesting results using
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masseter-StO2 [23, 24]. Furthermore, StO2 may vary by measurement site, and thenar-StO2, the most widely used site of measurement, may not be the most sensitive site for haemodynamic monitoring [25]. The correlation with ScvO2 is too moderate to be used as a surrogate [26]. Relying on a multi-site approach at this stage of development of the NIRS technique in septic patients may thus be more informative than a single-site approach. We did not perform a vascular occlusion test to compute desaturation and resaturation slopes. This test is feasible only when assessing thenar-StO2, whereas we favoured a multi-site approach. The rate of inclusions was low in this study (30 patients over 40 weeks). A multicentre study would be preferred to conduct a larger study. This pilot study allows no conclusion on the clinical benefit of targeting StO2 measured over three muscular sites (masseter, deltoid and pectoral or thenar muscles) in addition to currently recommended resuscitation goals in patients with severe sepsis or septic shock. None of the secondary endpoints were significantly different between the groups. This pilot study was underpowered to show any difference on clinical endpoints. However, the protocol showed no clear trend for or against targeting StO2. Acknowledgments Djillali Annane and Olivier Nardi designed the trial, performed the analyses, interpreted the data, and drafted the manuscript. All authors contributed to subject inclusions and followup, interpretation of the data and critical revision of the manuscript. Djillali Annane was the guarantor of the paper. Conflict of interest disclose.
The authors have no conflicts of interest to
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