a b s t r a c t

Objective: This study aimed to compare 2 fluid infusion rates of lactated Ringer (LR) and hydroxyethyl starch (HES) 130/0.4 on hemodynamic restoration at the early phase of controlled hemorrhagic shock.

Methods: Fifty-six anesthetized and ventilated piglets were bled until mean arterial pressure (MAP) reached 40 mm Hg. Controlled hemorrhage was maintained for 30 minutes. After this period, 4 resuscitation groups were studied (n = 14 for each group): HES infused at 1 or 4 mL/kg per minute or LR1 infused at 1 or 4 mL/kg per minute until baseline MAP was restored. Hemodynamic assessment using PiCCO monitoring and biological data were collected.

Results: Time to restore baseline MAP +-10% was significantly lower in LR4 group (11 +- 11 minutes) compared to LR1 group (41 +- 25 minutes) (P = .0004). Time to restore baseline MAP +-10% was significantly lower in HES4 group (4 +- 3 minutes) compared to HES1 (11 +- 4 minutes) (P = .0003). Time to restore baseline MAP +-10% was significantly lower with HES vs LR whatever the infusion rate.

No statistically significant difference was observed in cardiac output, central venous saturation, extravascular lung water, and arterial lactate between 4 and 1 mL/kg per minute groups.

Conclusions: In this controlled hemorrhagic shock model, a faster infusion rate (4 vs 1 mL/kg per minute) signif- icantly decreased the time for restoring baseline MAP, regardless of the type of infused fluid. The time for MAP restoration was significantly shorter for HES as compared to LR whatever the fluid infusion rate.

(C) 2016

Introduction

Despite large prevention programs around the world, severe injuries remain a major cause of death, greater than large pandemic infectious diseases [1]. massive hemorrhage and Neurologic injuries are the 2 main causes of death [2,3]. Even if early aggressive transfusion strategies are a key issue of severe bleeding management [4,5], fluid infusion re- mains the first therapeutic step, especially in prehospital settings [6]. However, infusion of large crystalloids volumes was shown to be asso- ciated with increased complications and mortality rates [4,7,8]. Damage control resuscitation is an emerging concept based on early transfusion and reduction of crystalloids [9-11]. If the link between the use of high fluid infusion rate, hemodynamic instability and need for emergent sur- gery was demonstrated, the optimal fluid infusion rate remains unclear

? Funding: This study was funded by public grants obtained from Physiology Depart- ment, EA 2992, Faculte de Medecine de Nimes, Universite Montpellier 1, Boulevard Kennedy 30,029 Nimes, France.

* Corresponding author.

E-mail address: [email protected] (L. Muller).

[12]. In recent guidelines, no precise recommendation on fluid infusion rate during severe hemorrhage was mentioned [13]. Previous studies have reported the effects of fluid administration rates on plasma dilu- tion in volunteers by applying principles similar to those used in phar- macokinetics [14-16]. Mathematical models suggested that high infusion rates (N 80 mL/kg per hour) of crystalloids may not increase ef- fectiveness of fluid resuscitation in acute hemorrhage model and could induce a higher transfer of fluid from plasma to interstitium [17]. Inter- stitial edema due to high crystalloid infused volume is associated with poor outcomes [8,9,18]. Some studies suggested that high infusion rates could be deleterious as compared to low infusion rates [19-21], whereas other study did not show any benefit of different infusion rates [22]. In controlled hemorrhage, the infusion rate used could also have a different impact. Such conflicting results suggest that additional studies are needed to investigate the impact of fluid infusion rate on re- suscitation target, especially arterial pressure restoration and global he- modynamics. The role of the type of fluid is also debated. Arterial colloids are no longer recommended in critically ill patients with septic shock because of lack of superiority over crystalloids, increased renal toxicity, and increased mortality [23,24]. These deleterious effects of

http://dx.doi.org/10.1016/j.ajem.2016.05.019

0735-6757/(C) 2016

colloids are not demonstrated in nonseptic patients, and some studies suggest a better hemodynamic efficacy of artificial colloids over crystal- loids during hemorrhage [25-28].

The primary objective of the present study was to compare the time needed to restore mean arterial pressure (MAP) at 2 different infusion rates (1 vs 4 mL/kg per minute) in a model of controlled hemorrhage in anesthetized piglets. The second objective was to assess if infusion rates could differently affect the ability of lactated Ringer (LR) and hydroxyethyl starch 130/0.4 (HES) to restore MAP.

Materials and methods

This study was conducted as a prospective trial in a piglet model. The Animal Care and Use Committee approved the protocol, and all experi- ments were performed in an authorized animal research laboratory. All facilities and transport comply with current legal requirements.

Animal preparation

Fifty-six male 3-month-old piglets weighing 25 to 30 kg were includ- ed in the study. Animals were fasted overnight with free access to water. The animals were prepared as previously reported. Briefly, the piglets were premedicated with Intramuscular injection of ketamine 10 mg/kg, atropine 0.05 mg/kg, and midazolam 1 mg/kg. Anesthesia was induced with a bolus dose of propofol (4 mg/kg) and cisatracurium (0.25 mg/kg) via an ear vein. Anesthesia was maintained with propofol (8 mg/kg per hour), and Neuromuscular blockade was achieved with cisatracurium (0.5 mg/kg per hour). Animals were ventilated after surgi- cal tracheotomy (6.5 endotracheal tube Tyco) with an inspired fraction of oxygen of 0.21, a tidal volume of 8 mL/kg, and a positive end-expiratory pressure of 5 cm H₂O (Servo 900C ventilator; Siemens, Solna, Sweden).

Once the piglets were anesthetized, a left cervical downward cut was performed, and a 7F double-lumen catheter was inserted through the internal jugular vein into the right atrium. The Central venous line was used for central venous pressure monitoring, venous blood gazes sampling, and cold Bolus injections for cardiac output (CO) mea- surement by transpulmonary thermodilution method. A 5F arterial catheter with an integrated thermistor tip was inserted through the femoral artery (PiCCO; Pulsion Medical Systems, Munich, Germany) into the descending aorta for continuous arterial blood pressure

MAP

monitoring, arterial blood sampling, and CO measurement. The femoral vein was also cannulated with an 8.5F catheter (Arrow; Arrow interna- tional, Inc) for blood withdrawal and for the administration of resuscita- tion fluids. All pressure-measuring catheters were connected to transducers (PiCCO plus; Pulsion) for continuous recording of systemic arterial pressure, heart rate (HR), and temperature.

Experimental protocol and times of measurements

The protocol was divided into 4 phases (Fig. 1).

At baseline (T₀), measurements of hemodynamic and biological pa- rameters were performed. Hemorrhage was initiated by withdrawing venous blood through the femoral venous catheter at 2 mL/kg per min- ute until a MAP of 40 mm Hg was reached (~45% total blood volume or

~30 mL/kg). At the time of a 40 mm Hg MAP value could be read on the monitor (T₁), CO was measured by transpulmonary thermodilution. Withdrawn blood was collected in a bag containing a solution of sodium citrate to prevent coagulation and to allow an autotransfusion if neces- sary for the following phase. During the following 30 minutes, MAP was maintained between 35 and 45 mm Hg by additional blood withdrawal or reinfusion of the shed blood. At the end of this phase (T₂), hemody- namic parameters were measured, and blood samples were collected. Fifty-six piglets were divided into 4 groups based on the administration rate of infused fluid: LR1 group (n = 14) was resuscitated with LR at a 1 mL/kg per minute infusion rate; LR4 group (n = 14), with LR at a 4 mL/kg per minute infusion rate; HES1 group (n = 14), with 6% HES 130/0.4 (Voluven; Fresenius Kabi, France) at a 1 mL/kg per minute infu- sion rate; and HES4 group (n = 14), with 6% HES 130/0.4 at a 4 mL/kg per minute infusion rate. The choice between LR and HES was random- ized. To respect the 3Rs rule of the use of animals in research and to re- duce the number of animals, we used collected data of the piglets resuscitated at 1 mL/kg per minute in our previous study, and we added 2 groups: HES4 and LR4 submitted to the strict similar protocol. The overall experiment for the 4 groups was performed during the same and short period (from April 2011 to June 2012) and under strictly same experimental conditions. The allocated fluid was infused until MAP reached the baseline value +-10%. At this point (T₃), hemodynamic parameters including CO by thermodilution were measured. During the following hour, MAP was maintained at its baseline value +-10% by ad- ditional fluid infusion according to the allocated group when necessary.

baseline MAP

Fluid loading

– HES1 }1 ml.kg-1.min-1

– LR1

– HES4 }4 ml.kg-1.min-1

– LR4

Blood withdrawal

2 ml.kg-1.min-1

1 hour

30 minutes

HAEMORRHAGIC PHASE

Additional fluid loading

if necessary

Autotransfusion or

blood withdrawal

STABILIZATION PHASE

RESUSCITATION PHASE

maintenance phase

40 mmHg

Time

T0 T1 T2 T3 T4

Fig. 1. Study design.

Table 1

Hemodynamic data at baseline (T₀), during hemorrhagic shock (T₂), and after fluid resuscitation (T₄) in HES1, HES4, LR1, and LR4 groups

	HES1 group, n = 14	HES4 group, n = 14	LR1 group, n = 14	LR4 group, n = 14	Overall P values
CVP (mm Hg)
T0	6 +- 6	4 +- 2	6 +- 5	4 +- 1	.45
T1	1 +- 0	1 +- 0	6 +- 7	1 +- 0	.35
T2	2 +- 4	5 +- 3	3 +- 5	1 +- 1	.52
T3	4 +- 4	4 +- 3	6 +- 5	4 +- 2	.3
T4	5 +- 4	5 +- 3	5 +- 4	5 +- 1	.61
P value (T4 vs T2) CO (L/min) T0	.08 2.8 +- 0.7	.0005 3.1 +- 0.8	.01 2.8 +- 0.8	b.0001 3.3 +- 1	.3
T1	3.2 +- 4.8	2.5 +- 2.2	3.2 +- 4.5	2.0 +- 1.5	.8
T2	1.2 +- 0.4	1.3 +- 0.3	1.2 +- 0.3	1.2 +- 0.3	.5
T3	3.3 +- 1.2	3.8 +- 1.6	3.2 +- 1.1	4.1 +- 1.7	.4
T4 P value (T4 vs T2) HR (beats per minute)	3.2 +- 1.4 b.0001	3.7 +- 1.3 b.0001	2.8 +- 0.8 b.0001	3.5 +- 0.8 b.0001	.08
T0	137 +- 30	128 +- 27	129 +- 18	129 +- 24	.7
T1	211 +- 60	217 +- 44	195 +- 50	239 +- 65	.1
T2	188 +- 18	182 +- 30	184 +- 22	189 +- 21	.98
T3	179 +- 31	149 +- 33	164 +- 36	163 +- 25	.2
T4	177 +- 41	132 +- 28a	160 +- 43	151 +- 35	.04
P value (T4 vs T2) stroke volume variation (%) T0	.5 20 +- 8	.0002 19 +- 7	.09 17 +- 6	.004 14 +- 6	.1
T1	32 +- 4	29 +- 5	33 +- 5	31 +- 4	.3
T2	27 +- 7	22 +- 4	23 +- 5	21 +- 5	.5
T3	20 +- 4	16 +- 8	19 +- 7	15 +- 5	.1
T4	20 +- 5	17 +- 8	19 +- 5	17 +- 6	.2
P value (T4 vs T2) GEDV (mL) T0	.6 333 +- 104	.07 334 +- 55	.04 306 +- 83	.03 369 +- 77	.2
T1	188 +- 31	156 +- 36	191 +- 29	177 +- 37	.05
T2	210 +- 44	226 +- 59	179 +- 42	209 +- 34	.07
T3	285 +- 69	364 +- 80	292 +- 73	349 +- 64	.2
T4	284 +- 66	373 +- 83	266 +- 64	328 +- 56	.006
P value (T4 vs T2) EVLW (mL) T0	.001 251 +- 66	b.0001 224 +- 61	.0007 215 +- 49	b.0001 249 +- 47	.4
T1	232 +- 63	243 +- 43	197 +- 55	234 +- 33	.07
T2	211 +- 75	262 +- 85	188 +- 51	245 +- 58	.04
T3	241 +- 69	274 +- 77a	227 +- 47	250 +- 54	.007
T4	242 +- 66	269 +- 48	221 +- 54	251 +- 41	.2
P value (T4 vs T2)	.6	.2	.1	.7

For multiple group comparison, we used the Kruskal-Wallis test. Pairwise comparisons used the Mann-Whitney rank sum test with Bonferroni correction.

^a HES1 vs HES4 (P b .0125).

After the 1-hour stabilization phase (T₄), the last hemodynamic assess- ments were performed, and blood samples were collected. Then, all an- imals were euthanized using intravenous solution of thiopental (2 grams).

The following parameters were measured during the experiment:

• Hemodynamic parameters measured at T₀, T₁, T₂, T₃, and T₄: MAP, HR, CVP, CO, global end-diastolic volume (GEDV), extravas- cular lung water (EVLW) by transpulmonary thermodilution method, and stroke volume variation by pulse contour analysis.

• Biological parameters measured at T₀, T₂, and T₄: arterial blood gases, hemoglobin venous oxygen saturation, Na⁺, K⁺, Cl^–, Ca²⁺, lactate, creatinine, and hemoglobin.

  Statistical analysis

  Statistical analysis was performed using R (version 2.13.2) statistical software. Data are expressed in median values (with interquartile range) or mean values (+-SD) according to variable distribution for quantitative parameters and in absolute values and percentages for qualitative parameters. Statistical significance of differences was stud- ied by the Kruskal-Wallis test for nonparametric variables. P b .05 was considered as statistically significant. Pairwise comparisons were performed with Mann-Whitney U test followed by the Bonferroni

  correction (for pairwise comparisons, differences were considered sig- nificant at P b .0125). A sample size of 14 piglets in each group was cal- culated to give 80% power to detect a 1:4 ratio of fluid volumes required to restore baseline MAP value at1 mL/kg per minute compared to 4 mL/kg per minute infusion rates.

  Results

  Fifty-six animals were included. We compared HES at 1 mL/kg per minute infusion rate (HES1) (n = 14; weight, 26 [4]), to HES at 4 mL/kg per minute infusion rate (HES4) (n = 14; weight, 27 [2]) and LR at 1 mL/kg per minute infusion rate (LR1) (n = 14; weight, 26 [4]) to LR at 4 mL/kg per minute infusion rate (LR4) (n = 14; weight, 29 [1]). To reduce the number of animals used, we added 2 groups of 14 piglets re- suscitated with HES or LR at 4 mL/kg per minute infusion rate and submit- ted to the strict similar protocol design. Targeted MAP of 40 mm Hg was successfully achieved and maintained for 30 minutes in all groups (Table 1). The volume of hemorrhage was similar between groups: 32 +- 10 mL/kg (LR1), 32 +- 8 mL/kg (LR4), 31 mL/kg +- 10 mL/kg (HES1), and 32 +- 9 mL/kg (HES4) (P, nonsignificant). None of the studied piglets needed blood autotransfusion during the hemorrhage phase. He- modynamics and biological data are given in Tables 1 and 2, respectively. Time to restore baseline MAP +-10% was significantly lower in LR4 group (11 +- 11 minutes) compared to LR1 group (41 +- 25 minutes)

  Table 2

  Biological data at baseline (T₀), during hemorrhagic shock (T₂), and after fluid resuscitation (T₄) in HES1, HES4, LR1, and LR4 groups

  Variables	HES1, n = 14	HES4, n = 14	LR1, n = 14	LR4, n = 14	Overall P values
  Arterial lactate (mmol/L)
  T0	3.2 +- 2.8	2.6 +- 1	2.8 +- 2.3	4.2 +- 3.6	.5
  T2	6.9 +- 4.1	4.8 +- 1.8	5.3 +- 1.9	6.2 +- 3.1	.7
  T4	3.7 +- 2.9	2.6 +- 1.3	3.6 +- 2.2	5.5 +- 2.8c	.008
  P value (T4 vs T2) Central venous saturation (%) T0	.02 69 +- 15	.001 70 +- 15	.03 65 +- 18	.5 64 +- 17	.9
  T2	40 +- 16	27 +- 8	37 +- 13	42 +- 21	.2
  T4	63 +- 16	68 +- 10	59 +- 15	65 +- 17	.4
  P value (T4 vs T2) Hemoglobin (g/dL)	.006	b.0001	.002	.009
  T0	10,3 +- 0.8	10.4 +- 1	10.9 +- 1.6	10 +- 1.5	.9
  T2	9.8 +- 1.3	9.4 +- 2.1	9.4 +- 1.1	9.4 +- 2.1	.5
  T4	7.2 +- 1.6	6.1 +- 1.5	7.6 +- 1.5	6.4 +- 1.7	.07
  P value (T4 vs T2) arterial pH T0	.0004 7.40 +- 0.07	.0003 7.39 +- 0.04	.0008 7.40 +- 0.11	.0008 7.36 +- 0.10	.7
  T2	7.32 +- 0.15	7.40 +- 0.08	7.38 +- 0.12	7.33 +- 0.09	.3
  T4	7.41 +- 0.08	7.41 +- 0.08	7.46 +- 0.12	7.35 +- 0.12	.7
  P value (T4 vs T2) PaO2/FIO2 (mm Hg) T0	.2 374 +- 78	.4 427 +- 104	.1 363 +- 97	.4 379 +- 121	.4
  T2	373 +- 67	438 +- 86	393 +- 69	490 +- 151	.046
  T4	422 +- 81	515 +- 109	459 +- 97	464 +- 106	.23
  P value (T4 vs T2) Plasma HCO3- (mmol/L) T0	b.0001 29.6 +- 3.9	.08 30.6 +- 2.7	b.0001 30.2 +- 2.6	.9 28.2 +- 3.7	.1
  T2	24.6 +- 5.2	27.9 +- 3.1	26.2 +- 3.5	25.3 +- 3.6	.2
  T4	29.6 +- 4.6	31.2 +- 2.4c	29.7 +- 3.3	26.7 +- 3.1	.01
  P value (T4 vs T2) Plasma Na+ (mmol/L)	.3	.003	.02	.2
  T0	137 +- 3	138 +- 3	138 +- 2	137 +- 2	.99
  T2	136 +- 3	136 +- 3	137 +- 2	136 +- 2	.5
  T4	137 +- 2	137 +- 2	137 +- 2	137 +- 2	.9
  P value (T4 vs T2) Plasma Cl– (mmol/L)	.4	.05	.7	.07
  T0	101 +- 3	100 +- 2	101 +- 2	100 +- 1	.5
  T2	101 +- 3	100 +- 2	102 +- 2	100 +- 1	.1
  T4	103 +- 3	102 +- 2	103 +- 3	102 +- 2	.5
  P value (T4 vs T2) Plasma Ca2+ (mmol/L)	.1	.005	.2	.01
  T0	2.4 +- 0.2	2.5 +- 0.2	2.4 +- 0.2	2.4 +- 0.2	.5
  T2	2.4 +- 0.2	2.5 +- 0.2	2.4 +- 0.2	2.3 +- 0.2	.4
  T4	2.1 +- 0.3	2.1 +- 0.2	2.2 +- 0.2	2.2 +- 0.2	.3
  P value (T4 vs T2) Plasma K+ (mmol/L)	.01	.0003	.07	.07
  T0	4.3 +- 0.4	4.2 +- 0.3	4.5 +- 0.5	4.2 +- 0.5	.5
  T2	5.5 +- 1.2	5.2 +- 0.8	5.1 +- 1.1	5.4 +- 1.6	.8
  T4	4.0 +- 0.4	3.8 +- 0.3	4.3 +- 0.4	4,2 +- 0,6	.03
  P value (T4 vs T2) Plasma creatinine (umol/L) T0	b.0001 67 +- 7	b.0001 74 +- 13	.01 69 +- 9	.004 76 +- 15	.2
  T2	89 +- 13	95 +- 15	90 +- 15	97 +- 24	.6
  T4	71 +- 8	75 +- 12	66 +- 8	73 +- 13	.2
  P value (T4 vs T2)	.001	.0003	b.0001	.003

  For multiple group comparison, we used the Kruskal-Wallis test. Pairwise comparisons used the Mann-Whitney rank sum test with Bonferroni correction.

  ^aLR1 vs LR4 (P b .0125).

  ^bHES1 vs HES4 (P b .0125).

  ^c HES4 vs LR4 (P b .0125).

  (P = .0004). Time to restore baseline MAP +-10% was significantly lower in HES4 group (4 +- 3 minutes) compared to HES1 (11 +- 4 minutes) (P =

  .0003) (Fig. 2A). Time to restore baseline MAP +-10% was significantly lower with HES vs LR regardless of the infusion rate (Fig. 2A).

  The total volume of infused fluid during the experiment was 398 +- 229 mL (HES1) vs 543 +- 399 mL (HES4) (P = .34) and 1551 +- 607 mL

  (LR1) vs 2145 +- 1133 mL (LR4) (P = .23). The volume needed to restore baseline MAP was significantly lower in HES1 compared to LR1 group (P b .0001) and lower in HES 4 compared to LR 4 group (P = .01) (Fig. 2B).

  For the resuscitation phase, the volume of infused fluid to restore the baseline MAP +-10% was not statistically different between the HES1 and the HES4 groups (280 +- 119 mL vs 440 +- 396 mL; P = .22) and be- tween LR1 and LR4 groups (1011 +- 515 mL vs 1356 +- 1319 mL; P =

  .83) (Fig. 2C).

  For the stabilization phase, we did not find statistically significant difference between HES1 and HES4 groups (119 +- 124 mL vs 104 +- 160 mL; P = .43) and between LR1 and LR4 groups (541 +- 506 mL vs 790 +- 770 mL; P = .49) (Fig. 2D).

  Fig. 2. InfusED volumes and time needed during the resuscitation and stabilization phases in HES1, HES4, LR1, and LR4 groups. A, Time needed to restore MAP during resuscitation phase. B, Total fluid volumes. C, Resuscitation phase fluid volumes. D, Stabilization phase fluid volumes. Data are expressed as box plots: the top of the box represents the 75th percentile, the bottom of the box represents the 25th percentile, and the line in the middle of the box represents the median value. The lines that extend out of the top and bottom of the box represent the 90th and 10th percentiles.

  Discussion

  In this Experimental model of controlled hemorrhage, high infusion rate (4 mL/kg per minute) is associated with a quicker restoration of MAP than lower infusion rate (1 mL/kg per minute) regardless of the type of infused fluid. High infusion rate did not significantly alter CO, EVLW, or arterial lactate.

  Our study is the first study focusing on the influence of fluid infusion rate on arterial pressure restoration in a controlled hemorrhagic shock. The present study shows that high infusions rates are associated with a more rapid MAP restoration. Surprisingly, this was not associated with significant differences in CO, GEDV, lactate, or SvO₂. This suggests that a more rapid MAP restoration is not associated in this model with a greater restoration of blood volume or tissue perfusion. Moreover, in the present study, the 4 times faster infusion rate of both LR and HES did not reduce the volume of fluid required to restore baseline MAP

  +-10% (Fig. 2). These findings imply that the faster restoration of MAP, observed in the high infusion rates groups, is not due only to a Volume expansion effect. As infused volumes are similar, whereas baseline MAP value is reached earlier, we could hypothesized that high infusion rates (4 mL/kg per minute) increase peripheral vascular resistances more than low infusion rates (1 mL/kg per minute).

  Conversely, it was previously demonstrated that hemorrhagic shock induces vascular hyporeactivity after blood loss ~30% of total blood vol- ume [29]. In case of rapid fluid infusion, a transient and Rapid increase of intravascular volume could lead to an improved vascular tone response. Another explanation could be that during high infusion rates, fluid dis- tribution between the intravascular and interstitial space has been modulated by the rapidity of fluid loading [30].

  Few studies investigated the influence of varied infusion rates on fluid hemodynamic effects during severe bleeding. In a moderate hem- orrhage volume kinetic model, crystalloid infusion rates exceeding 80 mL/kg per hour were associated with a higher fluid volume required to maintain blood volume as compared to infusion rates of 40 mL/kg per hour [17]. These results differ from the present study as we reported similar infused volumes for high and lower infusion rates. However, the goal to achieve differs as we chose mean arterial pressure as primary objective of fluid infusion, whereas Tatara et al [17] considered blood volume. We focused on arterial pressure as it is well established that systolic arterial pressure is a major clinical goal and the most common available parameter at the early phase of hemorrhagic shock [13,31-33]. It has been suggested that high infusion rate could be deleterious during severe uncontrolled hemorrhage [34]. Several animal studies confirmed that mortality increased with the increase of MAP [35,36]. Conversely, some studies reported a higher occurrence of deaths in hy- potensive treatment groups in multiple hemorrhage models, and prolonged hypotensive resuscitation induced increased mortality rate, persistent metabolic stress, and tissue hypoxia in a swine controlled hemorrhagic shock [35,37-39]. It was then demonstrated that targeting intermediate value of MAP during hemorrhage resuscitation was the best compromise between the risk of fatal hypovolemia and the risk of rebleeding associated with highest MAP level [40,41]. It could also be hypothesized that high infusion rate could be associated with excessive capillary leak, pulmonary edema, and mortality. The present report does not fully support this hypothesis. In LR1 and LR4 groups, the infused vol- ume according to animal body weight was 39 mL/kg (LR1 group) and 47 mL/kg (LR4 group). In a previous study, Svensen et al [42] showed that significant capillary leak was observed for crystalloid infused

  volume exceeding 50 mL/kg. As this critical value was not reached in the present study, it could explain why the rapidity of MAP restoration is greater with high infusion rates in LR group.

  As a second result, fluid infusion rate differently affects crystalloids and colloids. Quadrupling LR infusion rates increases 3.6-fold the rapid- ity of MAP restoration. In contrast, quadrupling HES infusion rate only increases 2.7-fold the rapidity of MAP restoration (Fig. 2). Several re- ports suggest that, after a critical infused volume, the hemodynamic ef- fect of a fluid was saturated and additional amounts of infused fluid only induce capillary leak and interstitial edema without favorable hemody- namic effects [16,42]. This phenomenon affects both crystalloids and colloids [16,42,43]. In the present study, high infusion rates of HES were associated with a significant increase in EVLW at T₃ (Table 1). This could mean that because HES has a better hemodynamic effect than LR, the threshold at which the maximal hemodynamic effect is reached is lower than LR. This could partially explain the differences be- tween LR and HES in the 2 different infusion regimens observed in the present study. Another explanation could be that HES and LR modulate differently the vascular reactivity. Indeed, in a rat hemorrhagic shock model, Liu et al [29] demonstrated that colloids improved the vascular hyporesponsiveness observed after hemorrhage better than crystal- loids. Therefore, HES could better restore vascular reactivity and con- tractility as the influence of administration rate on MAP restoration is less pronounced for HES than LR.

  In other causes of shock and/or hypovolemia, few studies investigat-

  ed the role of infusion rate on the ability of a given fluid to restore arte- rial pressure [17,44,45]. Ewaldsson and Hahn [30] assessed the effects of different fluid regimens before induction of Spinal anesthesia. They ob- served that a bolus injection of either Ringer or 1-kDa dextran did not change the decrease in arterial pressure after induction of spinal anes- thesia as compared to continuous infusion rates. In addition, Bark et al

  [44] recently reported no significant difference in plasma volume- expanding effect for the bolus and the continuous crystalloid groups in a septic rat model. Similarly, Bark et al reported a greater plasma vol- ume expansion with colloids (5% albumin, 6% HES 130/0.4, 4% gelatin, and 6% dextran 70) with a slow infusion rate especially for albumin in septic models of rat or guinea pigs [44,45].

  Limitations

• Any extrapolation to humans should be made with caution, as the short experiment period does not allow any conclusion about Long-term effects of fluids.
• The findings of the present study may not be extrapolated to trau-

ma patients as no direct tissue damage was induced in this model.

• The total blood volume was not measured by techniques involv- ing hemodilution, indicator dye dilution, or radioactive albumin escape rate [46-48].
• The infusion rates in the present study are higher compared to those used in the clinical practice. Indeed, 1 to 4 mL/kg per min- ute corresponds to infusion rates of 4 to 16 L/h for a 70-kg human. However, the study highlights that too aggressive resus- citation rates could not be efficient and indeed deleterious. We cannot exclude that an intermediate infusion rate (between 1 and 4 mL/kg per minute) would have been equally efficient to 4 mL/kg per minute.

Conclusion

In this controlled hemorrhagic shock model, a faster infusion rate (4 vs 1 mL/kg per minute) significantly decreased the time for restoring baseline MAP, regardless of the type of infused fluid. The time for MAP restoration was significantly shorter for HES as compared to LR whatev- er the fluid infusion rate. High infusion rates (4 mL/kg per minute) were not associated with a reduction of LR or HES infused volumes and did not alter CO, EVLW, or lactate.

References

1. Norton R, Kobusingye O. Injuries. N Engl J Med 2013;368:1723-30.
2. Evans JA, van Wessem KJ, McDougall D, Lee KA, Lyons T, Balogh ZJ. Epidemiology of traumatic deaths: comprehensive population-based assessment. World J Surg 2010; 34:158-63.
3. Di Saverio S, Gambale G, Coccolini F, Catena F, Giorgini E, Ansaloni L, et al. Changes in the outcomes of Severe trauma patients from 15-year experience in a Western Euro- pean trauma ICU of Emilia Romagna region (1996-2010). A population cross-sec- tional survey study. Langenbeck’s Arch Surg 2014;399:109-26.
4. Polderman KH, Varon J. Do not drown the patient: appropriate fluid management in critical illness. Am J Emerg Med 2015;33:448-50.
5. Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 2015; 313:471-82.
6. Yeguiayan JM, Garrigue D, Binquet C, Garrigue D, Jacquot C, Martin C, et al. Medical pre-hospital management reduces mortality in severe blunt trauma: a prospective Epidemiological study. Crit Care 2011;15:R34.
7. Gruen RL, Brohi K, Schreiber M, Balogh ZJ, Pitt V, Narayan M, et al. Haemorrhage con- trol in severely injured patients. Lancet 2012;380:1099-108.
8. Duchesne JC, Heaney J, Guidry C, McSwain Jr N, Meade P, Cohen M, et al. Diluting the benefits of Hemostatic resuscitation: a multi-institutional analysis. J Trauma Acute Care Surg 2013;75:76-82.
9. Kutcher ME, Kornblith LZ, Narayan R, Curd V, Daley AT, Redick BJ, et al. A paradigm shift in trauma resuscitation: evaluation of evolving massive transfusion practices. JAMA Surg 2013;148:834-40.
10. Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma 2007;62:307-10.
11. Shrestha B, Holcomb JB, Camp EA, Camp EA, Del Junco DJ, Cotton BA, et al. Damage- control resuscitation increases successful Nonoperative management rates and sur- vival after severe blunt liver injury. J Trauma Acute Care Surg 2015;78:336-41.
12. Mizushima Y, Tohira H, Mizobata Y, Matsuoka T, Yokota J. Fluid resuscitation of trau- ma patients: how fast is the optimal rate? Am J Emerg Med 2005;23:833-7.
13. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. Management of bleeding and coagulopathy following major trauma: an updated Eu- ropean guideline. Crit Care 2013;17:R76.
14. Hahn RG. Volume effect of Ringer’s solution in the blood during general anaesthesia. Eur J Anaesthesiol 1998;15:427-32.
15. Li Y, Zhu S, Hahn RG. The kinetics of Ringer’s solution in young and elderly patients during induction of general anesthesia with propofol and Epidural anesthesia with ropivacaine. Acta Anaesthesiol Scand 2007;51:880-7.
16. Hahn RG. Volume kinetics for infusion fluids. Anesthesiology 2010;113:470-81.
17. Tatara T, Tsunetoh T, Tashiro C. Crystalloid infusion rate during fluid resuscitation from acute haemorrhage. Br J Anaesth 2007;99:212-7.
18. Chappell D, Jacob M, Hofmann-Kiefer K, Conzen P, Rehm M. A rational approach to perioperative fluid management. Anesthesiology 2008;109:723-40.
19. Bruttig SP, O’Benar JD, Wade CE, Dubick MA. Benefit of slow infusion of hypertonic

    saline/dextran in swine with uncontrolled aortotomy hemorrhage. Shock 2005;24: 92-6.

    Stern SA, Kowalenko T, Younger J, Wang X, Dronen SC. Comparison of the effects of bolus vs. slow infusion of 7.5% NaCl/6% dextran-70 in a model of near-lethal uncon- trolled hemorrhage. Shock 2000;14:616-22.

20. Knoferl MW, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Do different rates of fluid resuscitation adversely or beneficially influence immune responses after trauma-hemorrhage? J Trauma 1999;46:23-33.
21. Lilly MP, Gala GJ, Carlson DE, et al. Saline resuscitation after fixed-volume hemor- rhage. Role of resuscitation volume and rate of infusion. Ann Surg 1992;216:161-71.
22. Haase N, Perner A, Hennings LI, Siegemund M, Lauridsen B, Wetterslev M, et al. Hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin in patients with sepsis: systematic review with meta-analysis and trial sequential analysis. BMJ 2013;346:f839.
23. Zarychanski R, Abou-Setta AM, Turgeon AF, Houston BL, McIntyre L, Marshall JC, et al. Association of hydroxyethyl starch administration with mortality and acute kidney injury in critically ill patients requiring volume resuscitation: a systematic re- view and meta-analysis. JAMA 2013;309:678-88.
24. Roger C, Muller L, Deras P, Louart G, Nouvellon E, Molinari N, et al. Does the type of fluid affect rapidity of shock reversal in an anaesthetized-piglet model of near-fatal controlled haemorrhage? A randomized study. Br J Anaesth 2014;112:1015-23.
25. He B, Xu B, Xu X, Li L, Ren R, Chen Z, et al. Hydroxyethyl starch versus other fluids for non-septic patients in the intensive care unit: a meta-analysis of randomized con- trolled trials. Crit Care 2015;19:92.
26. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declere AD, et al. Effects of fluid re- suscitation with colloids vs crystalloids on mortality in critically ill patients present- ing with hypovolemic shock: the CRISTAL randomized trial. JAMA 2013;310: 1809-17.
27. James MF, Michell WL, Joubert IA, et al. Resuscitation with hydroxyethyl starch im- proves renal function and Lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma). Br J Anaesth 2011;107:693-702.
28. Liu LM, Ward JA, Dubick MA. Effects of crystalloid and colloid resuscitation on hem- orrhage-induced vascular hyporesponsiveness to norepinephrine in the rat. J Trau- ma 2003;54:S159-68.
29. Ewaldsson CA, Hahn RG. Bolus injection of Ringer’s solution and dextran 1 kDa dur- ing induction of spinal anesthesia. Acta Anaesthesiol Scand 2005;49:152-9.
30. Edelman DA, White MT, Tyburski JG, Wilson RF. Post-traumatic hypotension: should systolic blood pressure of 90-109 mmHg be included? Shock 2007;27:134-8.
31. Eastridge BJ, Salinas J, McManus JG, Blackburn L, Bugler EM, Cooke WH, et al. Hypo- tension begins at 110 mm Hg: redefining “hypotension” with data. J Trauma 2007; 63:291-7 [discussion 297-299].
32. Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, et al. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med 2014;40:1795-815.
33. Bickell WH, Wall Jr MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994;331:1105-9.
34. Stern SA, Dronen SC, Birrer P, Wang X. Effect of blood pressure on hemorrhage vol- ume and survival in a near-fatal hemorrhage model incorporating a Vascular injury. Ann Emerg Med 1993;22:155-63.
35. Capone AC, Safar P, Stezoski W, Tisherman S, Peitzman AB. Improved outcome with fluid restriction in treatment of uncontrolled hemorrhagic shock. J Am Coll Surg 1995;180:49-56.
36. Rafie AD, Rath PA, Michell MW, Kirschner RA, Deyo DJ, Prough DS, et al. Hypotensive re- suscitation of multiple hemorrhages using crystalloid and colloids. Shock 2004;22:262-9.
37. Vaid SU, Shah A, Michell MW, Rafie AD, Deyo DJ, Prough DS, et al. Normotensive and hypotensive closed-loop resuscitation using 3.0% NaCl to treat multiple hemor- rhages in sheep. Crit Care Med 2006;34:1185-92.
38. Skarda DE, Mulier KE, George ME, Bellman GJ. Eight hours of hypotensive versus normotensive resuscitation in a porcine model of controlled hemorrhagic shock. Acad Emerg Med Off J Soc Acad Emerg Med 2008;15:845-52.
39. Burris D, Rhee P, Kaufmann C, Pikoulis E, Austin B, Eror A, et al. Controlled resuscita- tion for uncontrolled hemorrhagic shock. J Trauma 1999;46:216-23.
40. Mapstone J, Roberts I, Evans P. Fluid resuscitation strategies: a systematic review of animal trials. J Trauma 2003;55:571-89.
41. Svensen CH, Brauer KP, Hahn RG, Uchida T, Traber LD, Traber DL, et al. Elimina- tion rate constant describing clearance of infused fluid from plasma is indepen- dent of large infusion volumes of 0.9% saline in sheep. Anesthesiology 2004; 101:666-74.
42. Rehm M, Haller M, Orth V, Kreimeier U, Jacob M, Dressel H, et al. Changes in blood volume and hematocrit during acute preoperative volume loading with 5% albumin or 6% hetastarch solutions in patients before radical hysterectomy. Anesthesiology 2001;95:849-56.
43. Bark BP, Persson J, Grande PO. Importance of the infusion rate for the plasma expanding effect of 5% albumin, 6% HES 130/0.4, 4% gelatin, and 0.9% NaCl in the septic rat. Crit Care Med 2013;41:857-66.
44. Bark BP, Grande PO. Infusion rate and plasma volume expansion of dextran and al- bumin in the septic guinea pig. Acta Anaesthesiol Scand 2014;58:44-51.
45. Hahn RG. A haemoglobin dilution method (HDM) for estimation of blood volume variations during transurethral prostatic surgery. Acta Anaesthesiol Scand 1987; 31:572-8.
46. Hahn RG, Drobin D, Stahle L. Volume kinetics of Ringer’s solution in female volun- teers. Br J Anaesth 1997;78:144-8.
47. Margarson MP, Soni NC. Plasma volume measurement in septic patients using an al- bumin dilution technique: comparison with the standard radio-labelled albumin method. Intensive Care Med 2005;31:289-95.