British Journal of Anaesthesia 112 (6): 1015–23 (2014) Advance Access publication 28 November 2013 . doi:10.1093/bja/aet375

Does the type of fluid affect rapidity of shock reversal in an anaesthetized-piglet model of near-fatal controlled haemorrhage? A randomized study C. Roger 1,3, L. Muller 1,3*, P. Deras 1, G. Louart1,3, E. Nouvellon 2, N. Molinari 4, L. Goret 3, J. C. Gris 2,3, J. Ripart 1,3, J. E. de La Coussaye 1,3 and J. Y. Lefrant 1,3 1

Department of Anesthesiology, Emergency and Critical Care Medicine and 2 Haematology Laboratory, Nimes University Hospital, Place du Pr Debre´, Nıˆmes 30029, France 3 Research team EA2992, Montpellier 1 University, Chemin du Carreau de Lanes, Nimes, France 4 Department of Biostatistics, UMR 729 MISTEA, Montpellier University Hospital, Avenue Gaston Giraud, Montpellier 34093, France

Editor’s key points † Optimal fluid strategies after haemorrhage remain a debated topic. † Using piglets the speed of shock reversal was compared using lactated Ringer’s solution compared with hydroxyethyl starch (HES). † Baseline arterial pressure was restored much faster with HES and required less fluid.

Background. The optimal resuscitation fluid for the early treatment of severe bleeding patients remains highly debated. The objective of this experimental study was to compare the rapidity of shock reversal with lactated Ringer (LR) or hydroxyethyl starch (HES) 130/0.4 at the early phase of controlled haemorrhagic shock. To assess the influence of vascular permeability in this model, we measured plasma vascular endothelial growth factor (VEGF) levels during the experiment. Methods. Thirty-six anaesthetized and mechanically ventilated piglets were bled (,30 ml kg21) to hold mean arterial pressure (MAP) at 40 mm Hg for more than 30 min and were resuscitated in two randomized groups: LR (n¼14) or HES (n¼14) at 1 ml kg21 min21 until MAP reached its baseline value of +10%. MAP was maintained at its baseline value for 1 h. The time and fluid volume necessary to restore the baseline MAP value were measured. Results. The time to restore the baseline MAP value of +10% was significantly lower in the HES group (P,0.001). During the initial resuscitation phase, the infused volume was 279 (119) ml in the HES group and 1011 (561) ml in the LR group (P,0.0001). During the stabilization phase, the infused volume was 119 (124) ml in the HES group and 541 (506) ml in the LR group. Biological data and plasma VEGF levels were similar between the groups. Conclusions. Restoration of MAP was four times faster with HES than with LR in the early phase of controlled haemorrhagic shock. However, there was no evidence of increased vascular permeability. Keywords: bleeding; laboratory animal model; resuscitation; shock Accepted for publication: 4 September 2013

Rapid fluid administration is the first therapeutic step in the management of severely bleeding patients in order to restore circulatory stability.1 Controversy remains regarding the choice of fluids for shock resuscitation.2 3 Given that colloids such as hydroxyethyl starch (HES) are more likely to be maintained in the intravascular space, they could theoretically be more efficient at expanding the circulating volume. Therefore, physicians commonly use HES for hypovolaemia resuscitation, shock resuscitation, or both.4 – 7 However, in severe sepsis, HES has been associated with renal dysfunction, increased mortality, or both.8 – 10 In addition, the crystalloids to colloids required volume ratio reported in large randomized studies was close to 1:1 questioning the plasma volume expansion effect of HES.2 11 – 14 During haemorrhage, the superiority of colloids

compared with crystalloids remains unresolved.15 16 In penetrating trauma, James and colleagues17 have reported a colloid to crystalloid ratio of 1:1.5 associated with improvements in renal function and lactate clearance. Many factors could influence the distribution of administered fluids such as the volume status of the patient, vascular tone, and capillary leak.18 19 After i.v. infusion, a fluid is first distributed into the intravascular space before diffusing to the extravascular space.20 This diffusion can vary under different conditions. Indeed, Drobin and Hahn21 have shown that the worse the hypovolaemia, the greater the circulating blood volume expansion of lactated Ringer (LR) in volunteers, because of a reduction in the elimination rate constant. Anaesthetic drugs also modify fluid shifts between compartments.22

& The Author [2013]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: [email protected]

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* Corresponding author: Department of Anesthesiology, Emergency and Critical Care Medicine, Nimes University Hospital, Place du Pr Debre´, Nıˆmes 30029, France. E-mail: [email protected]

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Methods This study was designed as a prospective randomized unblinded trial in a piglet model. The Animal Care and Use Committee Languedoc-Roussillon (CEEA-LR-12013) approved the protocol and all experiments were performed in an authorized animal research laboratory. All facilities and transport comply with current legal requirements.

Animal preparation Thirty-six piglets weighing 20–31 kg were included. Animals were fasted overnight with free access to water. The piglets were pre-medicated with i.m. injection of ketamine 10 mg kg21, atropine 0.05 mg kg21, and midazolam 1 mg kg21. Anaesthesia was induced with a bolus dose of propofol (4 mg kg21) and cisatracurium (0.25 mg kg21) via an ear vein. Anaesthesia was maintained with propofol (8 mg kg21 h21) and neuromuscular block was achieved with cisatracurium (0.5 mg kg21 h21). Animals’ lungs were ventilated after surgical tracheostomy (6.5 tracheal tube Tycow, Atlanta, GA, USA), with an inspired fraction of oxygen of 0.21, a tidal volume of 8 ml kg21, and a positive end-expiratory pressure of 5 cm H2O (Servo 900Cw ventilator, Siemens, Solna, Sweden). A similar anaesthetic management protocol was shown to be stable over a 2-h period in piglets.23 Once the piglets were anaesthetized, a left cervical downward cut was performed and a 7 French double-lumen catheter was inserted through the internal jugular vein into the right atrium. The central venous line was used to monitor central venous pressure (CVP), to sample venous blood gases and to inject cold boluses for transpulmonary thermodilution. A 5 French arterial catheter with an integrated thermistor tip was inserted through the femoral artery (PiCCOw; Pulsion Medical Systems, Munich, Germany) into the descending aorta for continuous arterial pressure monitoring, arterial blood sampling,

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and cardiac output (CO) transpulmonary thermodilution measurement. The femoral vein was also cannulated with an 8.5 French catheter (Arroww; Arrow International, Inc., Cleveland, OH, USA) for blood withdrawal and for the administration of resuscitation fluids. All pressure-measuring catheters were connected to transducers (PiCCOw plus, Pulsion) for continuous recording of systemic arterial pressure, heart rate (HR), and temperature.

Experimental protocol and times of measurements The duration of the protocol was 2 h (Fig. 1). Haemorrhage was initiated by withdrawing venous blood through the femoral venous catheter at 2 ml kg21 min21 until a mean arterial pressure (MAP) of 40 mm Hg was reached (35% total blood volume or 30 ml kg21). Blood withdrawn was collected in a bag containing a solution of sodium citrate to prevent coagulation and to allow an autologous transfusion if necessary for the following phase. During the next 30 min, MAP was maintained between 35 and 45 mm Hg by additional blood withdrawal or reinfusion of the shed blood as described in similar controlled haemorrhage models.24 Twenty-eight piglets were randomly allocated using sealed envelopes into two groups based on the type of infused fluid: LR group (n¼14) was resuscitated with LR solution and the HES group (n¼14) received 6% HES 130/0.4 (Voluvenw; Fresenius Kabi, Se`vres, France). Fluid was infused at 1 ml kg21 min21 until MAP reached the baseline value of +10%. The time needed to restore MAP +10% was recorded. We also studied two additional groups of piglets with the same protocol as the others except for the resuscitation phase: a transfusion group (n¼4) received blood by autologous transfusion for shock resuscitation and a control group (n¼4) received no fluid resuscitation. MAP was maintained at its baseline value +10% by additional fluid infusion according to the allocated group for a further hour then all animals were killed using i.v. thiopental infusion (2 g). During the experiment, the following parameters were measured: (1) Haemodynamic parameters at T0, T1, T2, T3, and T4: CVP, systolic, and diastolic arterial pressure, MAP, HR, CO by transpulmonary thermodilution, global end-diastolic volume (GEDV), extravascular lung water (EVLW), and pulse pressure variation (PPV) by pulse contour analysis. (2) Biological parameters at T0, T2, and T4: arterial blood gases, haemoglobin, venous oxygen saturation, Na+, Cl2, Ca2+, lactate, creatinine, haemoglobin, and albumin.

VEGF measurements VEGF is an endothelial cell-specific growth factor. It appears to be a key regulator of vascular permeability and has been implicated in several pathophysiological situations such as angiogenesis, retinopathy, tumour growth, and wound healing. In septic shock, high levels of VEGF were reported, correlated

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Finally, increased vascular permeability as a result of inflammation could influence fluid distribution and could minimize differences between crystalloids and colloids in terms of plasma volume expansion. On the contrary, in situations without increased vascular permeability, colloids could be a better plasma expander, especially in terms of the rapidity of blood volume restoration. To the best of our knowledge, the rapidity of shock reversal with crystalloids or colloids has never been compared at the initial phase of haemorrhagic shock resuscitation. We hypothesized that initial administration of HES for rapid fluid resuscitation may provide a faster and greater plasma volume expansion effect compared with LR during the early phase of severe haemorrhage. To assess vascular permeability in this model, we measured plasma vascular endothelial growth factor (VEGF) levels during the experiment. Therefore, the aim of the present study was to compare time and volume of HES 130/0.4 needed to restore haemodynamics vs LR at the initial phase of a controlled haemorrhage model in anaesthetized and ventilated piglets.

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Rapidity of shock reversal

Haemorrhagic phase

Resuscitation phase

Maintenance phase

Stabilization phase

30 min

MAP

1h

Autotransfusion or Blood withdrawal

40

Fluid resuscitation

T1

-HES -LR -Blood 1 ml kg–1 min–1

T2

T3

T4

Fig 1 Study design.

with prognosis.25 26 Therefore, VEGF concentrations were measured during the experiment to assess the pathological capillary leak in this model. Blood samples for VEGF analyses were collected in citrated tubes at T0, T2, and T4. Blood was centrifuged twice at 1000 g for 15 min at 248C and plasma was stored at 2808C until VEGF analysis. VEGF concentrations were measured singly using a commercial enzyme-linked immunosorbent assay (ELISA) (Quantikinew ELISA, R&D Systems, Abingdon, UK). All measurements were done in accordance with the manufacturers’ instructions.

Statistical analysis Statistical analysis was performed using the R software (version 2.13.2). Data are presented as median and interquartile range for non-normally distributed variables, absolute values, and percentage for categorical variables, or mean and standard deviation (SD) for normally distributed variables. All analyses were performed on an intention-to-treat basis. A per-protocol analysis was also performed. The statistical significance of differences was studied by one-way analysis of variance for parametric data and the Kruskal –Wallis test for non-parametric data (two-tailed tests). Because of repeated measures (T0, T2, and T4), we used a linear mixed-effects model to estimate the differences in biological data and haemodynamic parameters between the four groups over time. All P-values were two-tailed and P,0.05 was considered statistically significant. A sample size of 14 piglets in each group was calculated to give 80% power to detect a 1:3 ratio of colloids to crystalloids needed to restore the baseline MAP

value as reported in previous studies at a 5% significance level.27 28

Results Twenty-eight animals were randomly allocated to the HES group [n¼14, weight¼26 (3) kg] or to the LR group [n¼14, weight¼27 (3) kg]. Two animals in the HES group died during the haemorrhagic phase before fluid resuscitation. However, their data were included in the intention-to-treat statistical analysis. Targeted MAP of 40 mm Hg was successfully achieved and maintained for 30 min in all groups. The induced haemorrhagic shock had marked effects on haemodynamics with no significant differences between the groups (Table 1). The volume of haemorrhage was similar between the groups. The time necessary to restore the baseline MAP value of +10% was significantly lower in the HES group (P,0.001; Fig. 2). In the blood transfusion group, the volume of blood reinfused was 389 (221) ml [i.e. 0.5-fold the shed blood volume (P¼0.0145 compared to LR and P¼0.67 compared to HES)]. Less blood was infused in the HES group compared with the LR group (P,0.0001; Fig. 3), corresponding to 0.3- and 1.2-fold the shed blood volume for the HES and LR groups, respectively. In order to maintain the baseline MAP value +10% for 1 h, less fluid was infused in the HES group than in the LR group corresponding to 4.5-fold greater volume in the LR group than in the HES group (P¼0.04; Fig. 3). Biological data at all times of measurements are given in Table 2. Plasma VEGF levels were similar in all groups at baseline and remained similar throughout the experiment with no difference between groups (Supplementary Fig. S4). The results of

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Blood withdrawal 2 ml kg–1 min–1

T0

Additional fluid loading if necessary

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Table 1 Haemodynamic data at baseline (T0), during haemorrhagic shock (T2), and after fluid resuscitation (T4) in HES, LR, blood, and control groups. Data are expressed as mean (SD). HES, hydroxyethyl starch; LR, lactated Ringer LR group (n514)

Blood group (n54)

Control group (n54)

MAP (mm Hg) T0

86 (9)

89 (12)

93 (17)

100 (9)

T2

39 (4)

40 (4)

43 (3)

37 (5)

T4

87 (14)

80 (16)

94 (11)

45 (25)

CO (litre min

21

)

T0

2.8 (0.6)

2.8 (0.8)

2.6 (0.5)

3.1 (0.7)

T2

1.2 (0.4)

1.2 (0.3)

1.0 (0.4)

0.9 (0.4)

T4

3.2 (1.4)

2.8 (0.8)

2.1 (0.8)

1.9 (0.4)

T0

5 (4)

4 (4)

7 (2)

5 (4)

T2

1 (3)

2 (4)

5 (2)

1 (4)

T4

4 (3)

4 (3)

6 (2)

4 (0)

HR (beats min21)

60

40

20

HES group

T0

137 (30)

129 (18)

131 (63)

136 (5)

T2

188 (18)

184 (22)

179 (69)

196 (25)

T4

177 (41)

160 (43)

149 (56)

187 (38)

PPV (%) T0

21 (7)

19 (6)

20 (2)

13 (4)

T2

32 (5)

32 (3)

33 (6)

27 (12)

T4

22 (7)

24 (7)

22 (5)

35 (0)

GEDV (ml) T0

333 (104)

306 (83)

334 (72)

388 (31)

T2

210 (45)

179 (42)

219 (64)

200 (12)

T4

285 (66)

266 (64)

318 (76)

212 (4)

EVLW (ml) T0

251 (66)

215 (49)

232 (45)

250 (21)

T2

211 (78)

188 (51)

242 (47)

233 (21)

T4

242 (66)

221 (54)

238 (13)

219 (22)

the per-protocol analysis confirmed the results of the intention-to-treat analysis.

Discussion In the present study comparing the plasma volume expansion effects of HES 130/0.4 vs LR at the initial phase of a severe controlled haemorrhage in mechanically ventilated and sedated piglets, the time to reach the predefined MAP was four times quicker with HES than LR. After MAP restoration, the volume of HES needed for the stabilization phase was much less than the volume of LR needed. Finally, as VEGF was not significantly increased in both groups, this model confirms that, at the early phase of haemorrhage, altered vascular permeability does not interfere with fluid efficacy. The choice of fluids for shock resuscitation remains highly controversial. Given that 75% of crystalloids leave the intravascular space, detrimental effects of large crystalloid volumes were reported, leading to a higher rate of complications and mortality during severe haemorrhage.29 30 Colloids have

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80

LR group

Fig 2 Time to restore initial MAP value +10% during resuscitation phase. Data are expressed as box plots showing median, interquartile, and full range. The circle represents extreme values.

been considered to be four- to five-fold more effective than crystalloids in expanding blood volume.31 However, no survival benefit of colloids could be found in critically ill patients.9 32 A recent study has even reported increased 90-day mortality and a greater risk of renal impairment when using HES in patients with severe sepsis.11 Moreover, the dogma of superior plasma volume expansion with colloids has been challenged. Post hoc analyses of clinical studies have suggested that the volume-sparing effect of HES was smaller than that expected. Comparable resuscitation was achieved with considerably less crystalloid volumes than commonly suggested: less than two-fold the volume of colloids.10 – 12 14 Because of the lack of improvement in survival and the comparable plasma volume expansion effects associated with the risk of renal failure and platelet dysfunction, it was suggested that the use of colloids, especially HES, should be stopped in septic patients.6 11 The present study does not support the idea that crystalloids and colloids have comparable effects at the early phase of haemorrhagic shock resuscitation. We found that HES allowed restoration of predefined haemodynamic parameters four times quicker than LR. Indeed, the volume needed to restore MAP in the crystalloid group was four-fold greater than in the colloid group, because the fluid administration rate was equal, constant, and predefined in the two groups. Tetrastarch was about four-fold more effective than LR in maintaining intravascular fluid volume over time. Rapidity of intravascular loss reversal is a frequent argument reported by physicians for prescribing colloids,8 but the time needed to reverse shock is rarely reported. Fluid resuscitation studies have focused more on fluid volume rather than rapidity of shock reversal.10 11 14 However, the speed of shock reversal is

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CVP (mm Hg)

100 Time to restore initial MAP (min)

HES group (n514)

P = 0.0002

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P = 0.04

Resuscitation fluid volume (ml)

2000

1500

1000

500

HES group

LR group

1500

1000

500

HES group

LR group

Fig 3 Volumes of fluid perfused during resuscitation and stabilization phases. Data are expressed as box plots showing median, interquartile, and full range. Circles represent extreme values.

an important attribute of fluid efficacy. Persistent hypovolaemia compromises tissue oxygenation and worsens prognosis. Early goal-directed therapy studies have reported outcome improvements in patients with severe sepsis and high-risk surgical patients.33 – 35 Previous studies have also reported a faster time to initial recovery or faster lactate normalization with colloids in sepsis and trauma.12 13 17 There are several explanations with regard to the difference in crystalloid to colloid volume ratio reported in recent clinical studies and the results of this experimental study, that are in accordance with textbooks and older studies.27 28 36 (1) The volume efficacy of a fluid strongly depends on patients’ volaemic status. In a recent large cohort of patients in severe sepsis, the volume of HES 130/0.4 was similar to the volume of Ringer’s acetate during the first day of resuscitation with an increased risk of death at Day 90 in the HES group.11 One explanation could be the absence of severe absolute hypovolaemia in this study. Indeed, considering the baseline circulatory parameters, lactate values were low (2 mmol litre21), CVP was 10 mm Hg, and ScvO2 was 75%, suggesting moderate or no hypovolaemia. In the case of moderate or no hypovolaemia, capillary leak equally affects crystalloids and colloids. Hahn and colleagues21 have shown that LR shifts from the intravascular to extravascular space four-fold less after 900 ml blood removal. Similar results were shown with colloids. Several studies have confirmed that the plasma volume expansion of iso-oncotic colloids was 40% in cases of moderate hypovolaemia but reached .90% in cases of severe hypovolaemia.37 38 This can explain the similar efficacy of crystalloids and colloids in the absence of profound hypovolaemia. In our

experimental model, about one-third of the total blood volume was withdrawn, inducing profound hypovolaemia confirmed by tachycardia, severe hypotension and hyperlactacidaemia. High values of PPVs observed before haemorrhage were likely attributable to high (10 ml kg21) tidal volumes whereas the decrease of high PPV values during the resuscitation phase suggests that hypovolaemia partly induces higher PPV values at the end of the haemorrhagic phase. During hypovolaemia, the hydrostatic capillary pressure and lymphatic return are lower during normovolaemia, tending to reduce fluid shifting towards the interstitial space and leading to increased fluid efficacy. The present study clearly demonstrates that at the early phase of profound hypovolaemia, colloids are superior to crystalloids for reversing shock. (2) The explanation is that in the early phase of severe haemorrhage, there is probably no pathological capillary leak (Type 2 capillary leak because of increased vascular permeability). The present study focused on the first hour of haemorrhagic shock resuscitation. In this initial phase, our results highlight the absence of increased vascular permeability, as plasma VEGF levels were not increased during the experiment. In septic shock (a situation in which pathological capillary leak is quite constant), high levels of VEGF were reported, and correlated with prognosis.25 26 Furthermore, Thickett and colleagues39 have reported increased VEGF levels in plasma from subjects with acute respiratory distress syndrome. These findings suggest that an increase in plasma VEGF levels is associated with a systemic inflammatory response. A human study has shown that, 30 min after injury, plasma VEGF levels were not elevated (20–40 pg ml21),

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Fluid volume during stabilization phase (ml)

P = 0.0145

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Table 2 Biological data at baseline (T0), during haemorrhagic shock (T2), and after fluid resuscitation (T4) in HES, LR, blood, and control groups. Data are expressed as mean (SD). HES, HES; LR, lactated Ringer Variables

HES group (n514)

LR group (n514)

Blood group (n54)

Control group (n54)

Arterial lactate (mmol litre21) T0

3.2 (2.8)

2.8 (2.3)

2.8 (1.5)

2.0 (0.3)

T2

6.9 (4.1)

5.3 (1.9)

4.9 (3.1)

6.3 (2.8)

T4

3.7 (2.9)

3.6 (2.2)

2.6 (1.2)

8.5 (4.0)

Central venous saturation (%) T0

69 (15)

65 (18)

70 (6)

54 (13)

T2

40 (16)

37 (13)

34 (11)

18 (3)

T4

63 (16)

59 (15)

64 (13)

42 (4)

T0

10.3 (0.8)

10.9 (1.6)

10.7 (1.2)

10.6 (0.9)

T2

9.8 (1.3)

9.4 (1.1)

9.9 (0.5)

9.0 (0.4)

T4

7.2 (1.6)

7.6 (1.5)

11.0 (1.5)

8.4 (0.9)

Haemoglobin (g dl21)

T0

7.40 (0.07)

7.40 (0.11)

7.41 (0.07)

7.39 (0.12)

T2

7.32 (0.15)

7.38 (0.12)

7.41 (0.06)

7.34 (0.16)

T4

7.41 (0.08)

7.46 (0.12)

7.43 (0.08)

7.35 (0.07)

T0

50 (10)

48 (13)

56 (5)

45 (14)

T2

50 (9)

52 (9)

62 (5)

48 (14)

T4

56 (11)

61 (13)

54 (5)

60 (9)

PaO2 /FIO2 (kPa)

21 ) Plasma HCO2 3 (mmol litre

T0

29.6 (3.9)

30.2 (2.6)

30.6 (0.9)

29.8 (1.5)

T2

24.6 (5.2)

26.2 (3.5)

27.1 (3.8)

24.0 (4.7)

T4

29.6 (4.6)

29.7 (3.3)

31.8 (3.0)

22.6 (3.5)

Plasma Na+ (mmol litre21) T0

137 (3)

138 (2)

139 (3)

138 (2)

T2

136 (3)

137 (2)

135 (4)

134 (2)

T4

137 (2)

137 (2)

138 (4)

136 (1)

Plasma Cl2 (mmol litre21) T0

101 (3)

101 (2)

102 (2)

102 (2)

T2

101 (3)

102 (2)

101 (1)

102 (3)

T4

103 (3)

103 (3)

100 (1)

103 (2)

Plasma Ca2+ (mmol litre21) T0

2.4 (0.2)

2.4 (0.2)

2.4 (0.2)

2.4 (0.1)

T2

2.4 (0.2)

2.4 (0.2)

2.3 (0.3)

2.3 (0.3)

T4

2.1 (0.3)

2.2 (0.2)

2.5 (0.2)

2.3 (0.4)

Plasma K+ (mmol litre21) T0

4.3 (0.4)

4.5 (0.5)

4.5 (0.4)

4.8 (1.1)

T2

5.5 (1.2)

5.1 (1.1)

4.9 (0.5)

6.2 (0.8)

T4

4.0 (0.4)

4.3 (0.4)

4.0 (0.4)

6.6 (2.9) 67 (9)

Plasma creatinine (mmol litre21) T0

67 (7)

69 (9)

65 (7)

T2

89 (13)

90 (15)

89 (13)

T4

71 (8)

66 (8)

74 (5)

105 (7)

T0

10 (2)

11 (2)

11 (2)

10 (3)

T2

9 (2)

9 (2)

9 (2)

8 (2)

T4

7 (2)

8 (2)

10 (3)

8 (2)

95 (14)

Albumin (g litre21)

similar to the results of our study.40 Furthermore, the low EVLW levels throughout the experiment confirm the absence of Type 2 capillary leak. This absence of

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Type 2 capillary leak at the early phase of haemorrhagic shock could increase the intravascular volume expansion of HES due to the absence of increased endothelial

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Arterial pH

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permeability to HES. However, at this early phase, crystalloids are still affected by physiological (Type 1) capillary leak given that perfused LR volumes in this study are higher than the shed blood volume. Type 1 capillary leak is only because of the absence of oncotic properties of crystalloids, which causes systematic capillary leak, usually at 20%.4 21 31 Short-term volume challenge studies have previously reported better plasma volume expansion with colloids in the first hour of hypovolaemic shock.27 41 This phenomenon at the initial phase of haemorrhage or hypotension could explain why physicians largely use HES in haemodynamically unstable patients.5 8

Within these limitations, we conclude that in this experimental model of controlled haemorrhage, HES was four times faster than LR in restoring MAP, and required four-fold less volume in the early phase of haemorrhagic shock. The plasma volume expansion after fluid administration was not accompanied by changes in VEGF permeability. The role of the different fluids in shock resuscitation should be reconsidered according to the severity of shock, and their theoretical intravascular volume expansion but also according to their kinetics.

Supplementary material Supplementary material is available at British Journal of Anaesthesia online.

Authors’ contributions C.R. participated in experimental design, animal preparation, executing experiments, data collection and analysis, and writing the manuscript. L.M. participated in study design, data analysis, data interpretation, and writing the manuscript. P.D. participated in experimental design, animal preparation, and data collection. G.L. participated in experimental design, animal preparation, supervision of experimental work, and data collection and analysis. E.N. participated in biological analysis, interpretation of the data, and helped to draft the manuscript. N.M. participated in data analysis and interpretation, assisted with statistics, and helped to draft the manuscript. L.G. participated in experimental design and supervision of experimental work. J.C.G. consulted on the experimental design, made a substantial contribution to the manuscript, and served as senior advisor. J.R. consulted on the experimental design, made a substantial contribution to the manuscript, and served as senior advisor. J.E.d.L.C. consulted on the experimental design, made a substantial contribution to the manuscript, and served as senior advisor. J.Y.L. participated in experimental design, data analysis and interpretation, helped to draft the manuscript, and served as senior advisor. All authors read and approved the final manuscript.

Acknowledgements The authors thank Joe¨lle Risson and Marc Granier for assistance during animal preparation and support during the experiments.

Declaration of interest None declared.

Funding This work was supported by academic grants, not by external sources.

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The present study confirms the hysteresis previously reported by Dalibon and colleagues.42 After blood withdrawal and complete retransfusion, MAP is significantly higher than the baseline value. In the blood group, the volume of blood needed to restore MAP was two-fold less than the blood volume withdrawn. Similarly, the colloid volume needed to correct MAP was three-fold less than the blood volume withdrawn. This cannot be interpreted as a hyperoncotic effect of tetrastarch, which is iso-oncotic, but rather a hysteresis effect.43 Most of haemorrhagic shock studies were designed with a predefined ratio of fluid to shed blood volume (3:1 for crystalloids and 1:1 for colloids) based on current anaesthesia and surgical textbooks.44 However, the results of this study and also previous studies reported lower ratios than that expected.24 41 These findings suggest changes in vascular properties between the haemorrhagic phase and the resuscitation phase. Effects of HES infusion could be both plasma volume expansion and changes in vessel wall properties such as compliance and resistance. However, this study does not allow us to distinguish between these two effects. Finally, no statistically significant acid –base or chloride difference was found between the groups. A hypothesis to explain these findings could be the volume of infused solutions. Indeed, even though HES is a saline-based solution, the volume of infused HES is low (219 ml) and not sufficient to induce hyperchloraemic acidosis. In addition, a recent study has shown that infusion of 2213 ml of LR’s solution induced at least a 1 mmol litre21 bicarbonate variation, but maintained the arterial pH unchanged.45 Our study has several limitations. First, this model of controlled haemorrhagic shock does not take into account associated traumatic injuries. Secondly, this model had a short observation period. We cannot extrapolate the present findings to the effects of survival or other outcomes. Furthermore, data from this piglet model should not be extrapolated to humans. Thirdly, as the present study was focused on the plasma volume expansion of HES and LR, the present findings cannot conclude on any potential metabolic adverse effects.

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