Preload Dependence Indices to Titrate Volume Expansion During Septic Shock

A Randomized Controlled Trial

Jean-Christophe Richard; Frédérique Bayle; Gael Bourdin; Véronique Leray; Sophie Debord; Bertrand Delannoy; Alina Cividjian Stoian; Florent Wallet; Hodane Yonis; Claude Guerin

Disclosures

Crit Care. 2015;19(5)

Abstract and Introduction

Abstract

Introduction In septic shock, pulse pressure or cardiac output variation during passive leg raising are preload dependence indices reliable at predicting fluid responsiveness. Therefore, they may help to identify those patients who need intravascular volume expansion, while avoiding unnecessary fluid administration in the other patients. However, whether their use improves septic shock prognosis remains unknown. The aim of this study was to assess the clinical benefits of using preload dependence indices to titrate intravascular fluids during septic shock.

Methods In a single-center randomized controlled trial, 60 septic shock patients were allocated to preload dependence indices-guided (preload dependence group) or central venous pressure-guided (control group) intravascular volume expansion with 30 patients in each group. The primary end point was time to shock resolution, defined by vasopressor weaning.

Results There was no significant difference in time to shock resolution between groups (median (interquartile range) 2.0 (1.2 to 3.1) versus 2.3 (1.4 to 5.6) days in control and preload dependence groups, respectively). The daily amount of fluids administered for intravascular volume expansion was higher in the control than in the preload dependence group (917 (639 to 1,511) versus 383 (211 to 604) mL, P = 0.01), and the same held true for red cell transfusions (178 (82 to 304) versus 103 (0 to 183) mL, P = 0.04). Physiologic variable values did not change over time between groups, except for plasma lactate (time over group interaction, P <0.01). Mortality was not significantly different between groups (23% in the preload dependence group versus 47% in the control group, P = 0.10). Intravascular volume expansion was lower in the preload dependence group for patients with lower simplified acute physiology score II (SAPS II), and the opposite was found for patients in the upper two SAPS II quartiles. The amount of intravascular volume expansion did not change across the quartiles of severity in the control group, but steadily increased with severity in the preload dependence group.

Conclusions In patients with septic shock, titrating intravascular volume expansion with preload dependence indices did not change time to shock resolution, but resulted in less daily fluids intake, including red blood cells, without worsening patient outcome.

Introduction

Fluid administration is the first-line component of hemodynamic support in septic shock treatment.^[1] Preload optimization is a major issue in the treatment of these patients. However, observational studies found a strong association between intensive care unit (ICU) mortality and positive fluid balance,^[2,3] suggesting that aggressive fluid resuscitation may be harmful. While several hemodynamic algorithms have been evaluated in randomized controlled trials during the first hours of septic shock resuscitation,^[4–7] the evidence is relatively scarce regarding the practical modalities of fluid administration some hours later. A substantial amount of physiological studies^[8,9] have demonstrated that static preload indices (such as central venous pressure (CVP)) may not be reliable to assess fluid responsiveness (cardiac output change in response to fluid administration), especially in septic patients. In contrast, dynamic preload indices such as pulse pressure variation (PPV) or stroke volume change during passive leg raising (PLR) are highly reliable to assess fluid responsiveness,^[10,11] should validity conditions for PPV accuracy be met. Driving intravascular volume expansion with dynamic preload indices should avoid unnecessary fluid administration, preventing pulmonary side effects, and select fluid-responsive patients. As a result, oxygen delivery should be optimized and organ failure shortened. However, while several studies have demonstrated a beneficial effect of volume expansion driven by preload dependence indices in the perioperative context,^[12–15] none has been performed in septic shock patients.

We conducted an exploratory randomized controlled study to explore whether preload dependence-driven fluid management in ICU patients with septic shock would reduce the duration of cardiovascular failure, as compared to CVP-driven fluid management.

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Table 1. General characteristics at admission and inclusion
	Control (n = 30)	Preload dependence (n = 30)	P
Age (years)	64 [54–76]	65 [58–80]	0.38
Male gender	22 (73%)	21 (70%)	1
Admission category
Medical	27 (90%)	30 (100%)	0.24
Unscheduled surgery	3 (10%)	0 (0%)
Charlson score	3 [2–5]	3 [1–5]	0.74
Immunodeficiency*	9 (30%)	9 (30%)	1
SAPS II	56 [50–60]	57 [47–69]	0.55
SOFA score at inclusion	10 [9–12]	11 [9–13]	0.52
Time between hypotension and inclusion (H)	9 [5–11]	10 [6–11]	0.64
Time between ICU admission and inclusion (H)	8 [4–15]	6 [3–12]	0.55
Renal replacement therapy	6 (20%)	8 (27%)	0.76
Mechanical ventilation	26 (87%)	20 (67%)	0.13
Volume of IV fluids administered between hypotension and inclusion (L)	3.0 [2.5–4.0]	3.5 [2.5–4.4]	0.26
Type of infection
Community-acquired infection	23 (77%)	21 (70%)	0.77
Hospital-acquired infection	7 (23%)	9 (30%)
Infection site
Pulmonary	16 (53%)	18 (60%)	0.80
Intra-abdominal	5 (17%)	7 (23%)	0.75
Urinary tract	3 (10%)	6 (20%)	0.47
Catheter-related infection	1 (3%)	3 (10%)	0.61
Other	3 (10%)	4 (13%)	1
Positive blood cultures	15 (50%)	15 (50%)	1
Identification of causative pathogen	25 (83%)	27 (90%)	0.71
Causative pathogens
Enterobacteriaceae	13 (43%)	16 (53%)	0.61
Non-fermenting gram-negative bacilli	5 (17%)	3 (10%)	0.71
Other gram-negative bacilli	2 (7%)	4 (13%)	0.67
Staphylococci	6 (20%)	7 (23%)	1
Streptococci	2 (7%)	6 (20%)	0.25
Gram-positive bacilli	0 (0%)	1 (3%)	1
Enterococci	0 (0%)	1 (3%)	1
Gram-negative cocci	0 (0%)	1 (3%)	1
Fungi	0 (0%)	1 (3%)	1
Empirical antibiotic therapy
Adequate	24 (80%)	23 (77%)	0.42
Inadequate	1 (3%)	4 (13%)
Not applicable	5 (17%)	3 (10%)

Data are median [interquartile range] or number of patients (%). *immunodeficiency was considered in any of the following situations: chronic treatment with steroids or other immunosuppressive agents, chemotherapy within one month, infection with the human immunodeficiency virus, neutropenia below 0.5 G.L⁻¹, or past history of splenectomy. SAPS II, Simplified Acute Physiology Score II [20]; SOFA, Sequential Organ Failure Assessment score [21]; ICU, intensive care unit; IV, intravenous.

Table 2. Hemodynamic characteristics at inclusion
	Control (n = 30)	Preload dependence (n = 30)	P
Mean arterial pressure (mm Hg)	68 [64–75]	72 [68–82]	0.08
Central venous pressure (mm Hg)	9 [7–14]	10 [8–12]	0.67
Cardiac index (L.min⁻¹.m⁻²)	3.5 [2.7–4.7]	3.6 [2.9–4.8]	0.43
Hemoglobin (g.dL⁻¹)	9.8 [8.9–11.6]	10.6 [9.5–11.4]	0.57
Oxygen arterial transport (mL.min⁻¹.m⁻²)	414 [352–619]	468 [395–648]	0.14
ScvO₂ (%)	77 [74–83]	77 [72–84]	0.89
ScvO₂ < 70%	5 (17%)	6 (20%)	1
Extravascular lung water index (mL.kg⁻¹ PBW)	13 [10–16]	12 [10–16]	0.65
Lactate (mmol.L⁻¹)	2.7 [2.2–3.6]	2.9 [2.5–5.7]	0.32
Lactate above upper normal laboratory limit	22 (73%)	25 (83%)	0.53
Inotrope treatment	5 (17%)	6 (20%)	1
Vasopressor dose (μg.kg⁻¹.min⁻¹)	0.51 [0.26–1.05]	0.60 [0.34–1.14]	0.38

Data are median [interquartile range] or number of patients (%). ScvO₂, superior vena cava oxygenation saturation; PBW, predicted body weight.

Table 3. Fluid administration and fluid balance
	Control (n = 30)	Preload dependence (n = 30)	P
Intravascular volume expansion ITT (mL.day⁻¹)	986 [654–1,624]	446 [295–1,105]	0.04
Intravascular volume expansion PP (mL.day⁻¹)	917 [639–1,511]	383 [211–604]	0.01
RBC transfusion (mL.day⁻¹)	178 [82–304]	103 (0–183]	0.04
Other blood products (mL.day⁻¹)	0 [0–122]	0 [0–125]	0.76
Other fluids (mL.day⁻¹)	3151 [2,791–3,456]	2919 [2,533–3,368]	0.70
Fluid intake^* (mL.day⁻¹)	4096 [3,770–4,677]	3610 [2,982–4,560]	0.16
Diuresis (mL.day⁻¹)	2116 [368–3,212]	1854 [513–3,332]	0.95
Fluid output (mL.day⁻¹)	2550 [1,914–3,331]	2609 [2,079–3,202]	0.95
Fluid balance (mL.day⁻¹)	1749 [146–2,788]	888 [153–2,816]	0.68
Intravascular volume expansion/fluid intake (%)	23%	15%	0.04

Data are median [interquartile range] or number of patients (%). *total volume of fluids administered (intravascular volume expansion + blood products + other fluids). ITT, intention to treat; PP, per protocol; RBC, red blood cells.

Table 4. Study outcomes
	Control (n = 30)	Preload dependence (n = 30)	P
Time to shock resolution (days)	2.0 [1.2–3.1]	2.3 [1.4–5.6]	0.29
Ventilator-free days at day 28	8 [0–21]	14 [0–24]	0.35
Number of days with lactates above upper normal laboratory limit	1 [1–4]	2 [1–4]	0.14
Number of days with pulmonary edema (that is ELWI >10 ml.kg⁻¹ PBW)	4 [1–5]	4 [1–6]	0.94
Number of days with organ system failure (that is SOFA ≥6)	4 [3–5]	4 [2–8]	0.61
ICU length of stay (days)	10 [7–20]	14 [6–28]	0.55
In survivors	14 [9–28]	22 [6–28]	0.89
In non-survivors	8 [5–11]	5 [3–17]	0.85
Mortality at day 28	14 (47%)	7 (23%)	0.10

Data are median [interquartile range] or number of patients (%). ELWI, extravascular lung water index; ICU, intensive care unit; PBW, predicted body weight; SOFA, Sequential Organ Failure Assessment score [21].

Authors and Disclosures

Jean-Christophe Richard^1,2,3*, Frédérique Bayle¹, Gael Bourdin¹, Véronique Leray¹, Sophie Debord¹, Bertrand Delannoy¹, Alina Cividjian Stoian^1,2, Florent Wallet¹, Hodane Yonis^1,2 and Claude Guerin^1,2,3

¹Service de Réanimation Médicale, Hôpital De La Croix Rousse, Hospices Civils de Lyon, 103 Grande Rue de la Croix Rousse, Lyon, 69004, France. ²Université de Lyon, Université LYON I, 37 Rue du Repos, Lyon, 69007, France. ³CREATIS INSERM 1044 CNRS 5220, 20 Avenue Albert Einstein, Villeurbanne, 69621, France

*Correspondence
j-christophe.richard@chu-lyon.fr

Competing interests
The authors declare that they have no competing interests.

Authors' contributions
JCR made substantial contributions to the study design, acquisition, analysis, and interpretation of data; drafted the manuscript; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. FB made substantial contributions to acquisition and interpretation of data; revised the manuscript for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. GB made substantial contributions to acquisition and interpretation of data; revised the manuscript for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. VL made substantial contributions to acquisition and interpretation of data; revised the manuscript for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. SD made substantial contributions to acquisition and interpretation of data; revised the manuscript for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. BD made substantial contributions to acquisition and interpretation of data; revised the manuscript for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. AS made substantial contributions to acquisition and interpretation of data; revised the manuscript for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. FW made substantial contributions to acquisition and interpretation of data; revised the manuscript for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. HY made substantial contributions to acquisition and interpretation of data; revised the manuscript for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. CG made substantial contributions to the study design, analysis, and interpretation of data; revised the manuscript for important intellectual content; approved the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors read and approved the final version.