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  • Review
  • Open Access

Extracorporeal membrane oxygenation (ECMO) and the acute respiratory distress syndrome (ARDS): a systematic review of pre-clinical models

  • 1, 2, 10Email authorView ORCID ID profile,
  • 1, 3,
  • 1, 4,
  • 1, 5,
  • 1, 6,
  • 7,
  • 1, 2,
  • 8, 9,
  • 10,
  • 11,
  • 1, 2,
  • and
Intensive Care Medicine Experimental20197:18

https://doi.org/10.1186/s40635-019-0232-7

  • Received: 14 January 2019
  • Accepted: 3 March 2019
  • Published:

Abstract

Objectives

Extracorporeal membrane oxygenation (ECMO) is an increasingly accepted means of supporting those with severe acute respiratory distress syndrome (ARDS). Given the high mortality associated with ARDS, numerous animal models have been developed to support translational research. Where ARDS is combined with ECMO, models are less well characterized. Therefore, we conducted a systematic literature review of animal models combining features of experimental ARDS with ECMO to better understand this situation.

Data sources

MEDLINE and Embase were searched between January 1996 and December 2018.

Study selection

Inclusion criteria: animal models combining features of experimental ARDS with ECMO. Exclusion criteria: clinical studies, abstracts, studies in which the model of ARDS and ECMO has been reported previously, and studies not employing veno-venous, veno-arterial, or central ECMO.

Data extraction

Data were extracted to fully characterize models. Variables related to four key features: (1) study design, (2) animals and their peri-experimental care, (3) models of ARDS and mechanical ventilation, and (4) ECMO and its intra-experimental management.

Data synthesis

Seventeen models of ARDS and ECMO were identified. Twelve were published after 2009. All were performed in large animals, the majority (n = 10) in pigs. The median number of animals included in each study was 17 (12–24), with a median study duration of 8 h (5–24). Oleic acid infusion was the commonest means of inducing ARDS. Most models employed peripheral veno-venous ECMO (n = 12). The reporting of supportive measures and the practice of mechanical ventilation were highly variable. Descriptions of ECMO equipment and its management were more complete.

Conclusion

A limited number of models combine the features of experimental ARDS with ECMO. Among those that do, there is significant heterogeneity in both design and reporting. There is a need to standardize the reporting of pre-clinical studies in this area and to develop best practice in their design.

Keywords

  • Extracorporeal membrane oxygenation
  • Acute respiratory distress syndrome
  • Animal models
  • Pre-clinical models
  • Systematic review

Introduction

In recent years, the use of extracorporeal membrane oxygenation in patients with acute respiratory distress syndrome (ARDS) has grown substantially [1]. ECMO is now an accepted technique for temporarily supporting those with severe ARDS whose condition is refractory to conventional management [2, 3]. Despite advances in our understanding of the pathophysiology of ARDS, mortality among patients remains high, with only a modest improvement over the last decade [4]. A contributing factor may be the failure to successfully translate a proven therapeutic strategy for the treatment of ARDS [5]. Substantial effort has been devoted to this endeavor, and correspondingly numerous animal models of ARDS have been developed to assist in the investigation and translation of novel interventions [6]. As the use of ECMO in ARDS matures, it will become increasingly important to evaluate candidate ARDS therapies in the unique context of extracorporeal circulation [7]. Likewise, interventions primarily associated with ECMO require established pre-clinical models to facilitate progress toward clinical trials. There are fewer well-characterized models which combine experimental ARDS with ECMO than ARDS alone. To better understand existing animal models of ARDS and ECMO, we have undertaken a systematic review of studies reporting novel models in animals. A systematic appreciation of animal models which include the use of ECMO will allow us to identify current limitations, establish areas for innovation and improvement, and will assist in the creation of a minimum data set for pre-clinical ECMO studies.

Materials and methods

Design

A systematic review protocol was constructed in advance and published on the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) website (https://issuu.com/radboudumc/docs/animal_models_of_acute_respiratory_?e=28355229/48256411). The protocol addresses the requirements of the Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) statement [8]. The published protocol was amended after publication to remove the requirement for papers to be published in English. A native language speaker was identified to translate those not appearing in English.

Search strategy

We searched the MEDLINE (via PubMed) and Embase (via Ovid SP) indexed online databases from January 1996 to December 2018. The search strategy was designed in conjunction with a trained medical librarian (see Additional file 1 for the full search strategy). The filters used to identify animal studies were those previously described and validated by de Vries et al. [9] and Hooijmans et al. [10]. Citations were collected in a reference management software program (EndNote™, Clarivate Analytics, PA, USA).

Study selection

Study selection occurred in two phases. Firstly, abstracts and citations were independently screened for relevance by two authors (JM and NB). Discrepancies were resolved by reference to a third author (MM). Articles were excluded on the following basis: (1) if they were not performed in animals, (2) if they did not involve the use of ECMO, or (3) if they did not include a model of ARDS. The full text of articles deemed relevant was retrieved. There were no language restrictions. Articles not published in English were translated by a native speaker. In the second phase, full-text articles were independently reviewed (JM, NB) and excluded if (1) they did not report an animal model, (2) they did not use veno-venous, veno-arterial, or central ECMO, (3) they did not include a model of ARDS, (4) they were in abstract format, or (5) if the same model of ARDS and ECMO had been reported in a previous publication. Disagreements were resolved by a third author (MM). The reference lists of screened studies were reviewed to identify publications not found by the original search strategy.

Study characteristics and data abstraction

Included studies were jointly reviewed by JM, NB, and VB. Data were extracted using a pre-piloted data extraction form (Additional file 2). Disagreements were resolved by reference to a senior member of the team. Descriptive data for each study were abstracted including the title, author(s), year of publication, and journal title. Detailed data were identified in relation to four major categories:
  1. 1.

    Study design. The aim(s) and hypothesis of the study was recorded, as were elements related to study design, such as randomization procedures, blinding, the use of sub-groups, and sample size.

     
  2. 2.

    Animals and their peri-experimental care. This included information on the species, strain, age, weight, and gender of the animals used in experiments. Additional data were abstracted on anesthesia, monitoring, fluid management, intra-experimental drug administration, and euthanasia.

     
  3. 3.

    Models of ARDS and mechanical ventilation. Details were extracted on the means of inducing experimental ARDS and on the definition of ARDS applied in each study. Additional data were extracted to assess mechanical ventilation practices before and during ECMO.

     
  4. 4.

    Models of ECMO and its intra-experimental management. Data were recorded on the mode of ECMO employed, devices used, the method and configuration of cannulation, priming, flow rates, pump speeds, sweep gas settings, anticoagulation practices, and the duration of extracorporeal support.

     

Studies published after 2011 were assessed for compliance with the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines [11].

Data synthesis and analysis

Data were tabulated for ease of comparison. Summary statistics were used as appropriate. Given the heterogeneous nature of included studies and the aim of this review, to characterize and assess the quality of the models rather than the study outcomes, no attempt was made at meta-analysis.

Results

A total of 370 unique citations were identified in our search. Of these, 44 passed the first phase of screening and had full-text articles retrieved. After secondary screening, 17 articles met the inclusion criteria and were included in the final analysis [1228]. Figure 1 shows the PRISMA flow diagram for study inclusion and exclusion.
Fig. 1
Fig. 1

PRSIMA flow diagram for inclusion and exclusion criteria

Description of included studies

An overview of included studies is included in Table 1. More than two thirds (n = 12) were published after 2009. Most studies were conducted in Europe (n = 5) and Asia (n = 5), followed by North America (n = 4), South America (n = 2), and Australasia (n = 1). The purpose of studies varied but included physiological studies (n = 6), technology evaluations (n = 5), and interventional trials (n = 5). All studies were conducted in large animals, the majority in pigs (n = 10), followed by sheep (n = 6) and a single canine study. No small animal models met the inclusion criteria. The median number of animals studied was 17 (12–24), with the largest two studies using 30 animals. The median duration of included studies was 8 (5–24) hours, with two studies, both in pigs, reporting recovery and follow-up of 7 and 14 days, respectively [26].
Table 1

Description of studies included in the systematic review

Study

Year

Species

Study type

Number

ARDS model type

ECMO configuration

Study duration (hours)

Kim et al. [18]

2004

Dog

Technology evaluation

16

Oleic acid

VA (central)

2

Araos et al. [12]

2016

Pig

Model development

18

Saline lavage + injurious ventilation

VV

24

Wang et al. [28]

2016

Pig

Interventional

28

LPS infusion

VV

24 + 14-day recovery

Ni et al. [23]

2015

Pig

Physiological

30

Blunt injury

VV

24

Pilarczyk et al. [25]

2015

Pig

Technology evaluation

14

Saline lavage

VV

8

Park et al. [24]

2013

Pig

Physiological

5

Saline lavage + fecal peritonitis

VV

Unclear

Kopp et al. [20]

2011

Pig

Technology evaluation

6

Hypoxia

VV

4

Song et al. [26]

2010

Pig

Interventional

28

LPS infusion

VV

24 + 7-day recovery

Kopp et al. [21]

2010

Pig

Technology evaluation

24

Saline lavage

VV

24

Henderson et al. [16]

2004

Pig

Interventional

24

Oleic acid

VA

8

Dembinski et al. [13]

2003

Pig

Technology evaluation

12

Saline lavage

VV

6

Kocyildrim et al. [19]

2017

Sheep

Interventional

11

LPS infusion

VV

4

Hou et al. [17]

2015

Sheep

Physiological

20

Hypoxia

VA (central)

unclear

Langer et al. [22]

2014

Sheep

Physiological

11

Oleic acid

VV

22

Shekar et al. [14]

2012

Sheep

Physiological

17

Smoke inhalation

VV

2–24

Totapally et al. [27]

2004

Sheep

Physiological

17

Saline lavage + HCL acid instillation

VA

6

Germann et al. [15]

1997

Sheep

Interventional

30

Oleic acid

VV (central)

5

LPS lipopolysaccharide, HCL hydrochloric acid, VA veno-arterial, VV veno-venous

Animals and their peri-experimental care

A summary of the peri-experimental care of animals is provided in Table 2. More than half (n = 9) of studies used exclusively female animals, while five did not report gender. The age of the animals was inconsistently documented, with 10 studies omitting this detail. The majority of investigators used total intravenous anesthesia (n = 14), including the two studies that involved recovery from anesthesia [26, 28]. Ketamine was the most commonly used anesthetic, with a maintenance dose range between 5 and 10 mg/kg/h. Inhalational anesthesia was used in two studies [16, 19]. Only four studies reported a protocolized approach to cardiovascular support [12, 24, 25, 27], while six studies provided data on cumulative fluid balance.
Table 2

Details of anesthetic, airway, and fluid management

Study

Age

Weight (kg)

Gender

Airway

Anesthesia

Paralysis

Fluid therapy

 

Induction

Maintenance

 

Type

Rate/volume

Dogs

 Kim et al. [18]

 

20–25

       

Pigs

 Araos et al. [12]

 

30 ± 5

 

ETT

Ketamine, midazolam, fentanyl

Ketamine, midazolam, fentanyl

Atricurium

Crystalloid

2 mL/kg/h

 Wang et al. [28]

4–6 weeks

7–8

F

ETT

Ketamine, diazepam

Ketamine, diazepam

   

 Ni et al. [23]

Juvenile

30 ± 5

M + F

Trach

Ketamine, diazepam

Ketamine, diazepam

 

Crystalloid

3 mL/kg/h

 Pilarczyk et al. [25]

 

57–62

F

ETT

Ketamine, azaperone

Propofol, midazolam, fentanyl

 

Crystalloid

3 mL/kg/h

 Park et al. [24]

 

79–81

F

 

Thiopentone

Midazolam, fentanyl

Pancuronium

Crystalloid

3 mL/kg/h

 Kopp et al. [20]

 

37 ± 1

F

ETT

Ketamine, thiopentone, azaperone

Thiopentone, fentanyl

 

Crystalloid + HES

 

 Song et al. [26]

4–5 weeks

9–14

M

ETT

Ketamine

Ketamine, fentanyl

 

Crystalloid

 

 Kopp et al. [21]

 

45 ± 6

F

ETT

Ketamine, thiopentone, azaperone

Thiopentone, fentanyl

 

Crystalloid + HES

 

 Henderson et al. [16]

Juvenile

7.7–15.0

 

ETT

Isoflurane

Isoflurane, fentanyl

 

Crystalloid

 

 Dembinski et al. [13]

 

37 ± 3

F

ETT

Thiopentone, ketamine, azaperone

Thiopentone, fentanyl

 

HES

 

Sheep

 Kocyildrim et al. [19]

 

36.5–65

 

ETT

Ketamine

Isoflurane

 

Crystalloid

1 mL/kg/h

 Hou et al. [17]

2 years

40 ± 5

M

ETT

Propofol

Sufentanil

Atricurium

  

 Langer et al. [22]

 

45 ± 6

F

Trach

Isoflurane, tiletamine-zolazepam, buprenorphine

Midazolam, buprenorphine

 

Crystalloid

150–200 mL/h

 Shekar et al. [14]

1–3 years

4–50

F

Trach

Alfaxalone, midazolam

Ketamine, alfaxalone, midazolam, buprenorphine

 

Crystalloid

2 mL/kg/h

 Totapally et al. [27]

2–6 weeks

3.6–12.7

 

Trach

Ketamine

Ketamine

Vecuronium

Crystalloid

5 mL/kg/h

 Germann et al. [15]

 

35–40

F

  

Thiopentone

    

ETT endotracheal tube, Trach tracheostomy, HES hydroxyethyl starch

Models of ARDS and mechanical ventilation

A summary of the means of inducing experimental ARDS in studies is contained in Table 1. A range of ARDS models are described, including oleic acid (OA) infusion (n = 4), lipopolysaccharide (LPS) infusion (n = 3), saline lavage (n = 3), hypoxia (n = 2), blunt injury (n = 1), and smoke inhalation (n = 1). Three further studies combined saline lavage with a secondary injury. Definitions of experimental ARDS were varied and not universally reported (Table 3). Likewise, mechanical ventilatory practices, both before and during ECMO, were incompletely described (Table 4).
Table 3

Detailed methods of inducing experimental ARDS and definitions of injury

Study

Detailed injury methods

Definition of injury (experimental ARDS)

Kim et al. [18]

0.1 mL/kg i.v. OA over 30 min

P/F < 150 mmHg

Araos et al. [12]

Saline lavage (30 mL/kg at 39 °C) × 4 (2 prone, 2 supine) and 2 h of injurious ventilation (inspiratory pressure 40 cmH2O, PEEP 0 cmH2O, FiO2 1.0, RR 10)

P/F < 250 mmHg

Wang et al. [28]

18–20 μg/kg i.v. E. coli LPS within 1 h

P/F ≤ 300 mmHg and 30% decrease in dynamic compliance from baseline

Ni et al. [23]

Blunt injury (free fall 0.45 kg weight from 1-m column) to each lateral chest wall (ribs 6–9) and hemorrhage to MAP 40 ± 5 mmHg for 2 h followed by crystalloid/autologous blood resuscitation

Not stated

Pilarczyk et al. [25]

Saline lavage (1000 mL bilaterally at 37 °C) repeated every 60 mins until injury achieved

PaO2 < 100 mmHg for > 1 h

Park et al. [24]

Saline lavage (1000 mL at 37 °C) repeated until injury achieved and fecal peritonitis (1 g/kg injection of feces into peritoneal cavity)

P/F < 50 mmHg

Kopp et al. [20]

Hypoxia (FiO2 reduced to achieve hypoxic inspiratory gas mixture)

SaO2 < 85%

Song et al. [26]

18–20 μg/kg i.v. E. coli LPS within 1 h

P/F ≤ 300 mmHg and 30% decrease in dynamic compliance from baseline

Kopp et al. [21]

Saline lavage (40 mL/kg) repeated until injury achieved

P/F < 100 mmHg

Henderson et al. [16]

0.2 mL/kg i.v. OA over 30 mins

P/F < 125 mmHg or HR < 60 bpm and/or reduction MAP > 50% from baseline

Dembinski et al. [13]

Saline lavage (40 mL/kg at 37 °C) repeated until injury achieved

PaO2 < 100 mmHg for > 1 h

Kocyildrim et al. [19]

3.5 μg/kg i.v. E. coli LPS over 30 mins

Not stated

Hou et al. [17]

Hypoxia (discontinuation of mechanical ventilation)

Not stated

Langer et al. [22]

0.1–0.15 mL/kg i.v. OA

P/F < 200 mmHg

Shekar et al. [14]

Smoke inhalation (10–12 mL/kg Vt breaths of cotton smoke, first cycle 12 breaths, then cycles of 8 breaths) repeated until injury achieved

Carboxyhemaglobin 45–50%

Totapally et al. [27]

Saline lavage (mL/kg) repeated × 3 and 2.5 mL/kg i.t. 0.1 N HCL

Not stated

Germann et al. [15]

0.5 mL/kg i.v. OA over 15 mins

LIS > 2.5

OA oleic acid, i.v. intravenous, PEEP positive end expiratory pressure, FiO2 inspired fraction of oxygen, P/F ratio of arterial partial pressure of oxygen to inspired fraction of oxygen, LPS lipopolysaccharide, MAP mean arterial pressure, PaO2 arterial partial pressure of oxygen, bpm beats per minute, Vt tidal volume, HCL hydrochloric acid

Table 4

Details of ventilatory management before and during ECMO

Study

Ventilator strategy

Gas exchange targets

Before ECMO

During ECMO

Before ECMO

During ECMO

Mode

Vt

PEEP

RR

FiO2

Mode

Vt

PEEP

RR

FiO2

PaO2

SpO2

PaCO2

PaO2

SpO2

PaCO2

 

mL/kg

cmH2O

b/min

  

mL/kg

cmH2O

b/min

 

mmHg

 

mmHg

mmHg

 

mmHg

Dogs

 Kim et al. [18]

    

0.4

     

150–250

 

35–45

   

Pigs

 Araos et al. [12]

VC

10

5

16–18

1.0

VC

10

5

nPaCO2

   

35–50

  

30–50

 Wang et al. [28]

PC

7–9

0

30

0.21–0.30

PC

7–9

2–4

20–25

0.3–0.5

     

35–45

 Ni et al. [23]

     

VC

8

5

15

0.5

      

 Pilarczyk et al. [25]

PC

6

5

15

1.0

           

 Park et al. [24]

 

8

5

nPaCO2

1.0

  

VAR

   

94–96

35–45

VAR

VAR

VAR

 Kopp et al. [20]

   

nPaCO2

1.0

    

0.2

      

 Song et al. [26]

PC

7–9

0

30

0.21–0.35

PC

 

2–4

10–30

0.21–0.5

> 60

 

35–45

> 60

 

35–45

 Kopp et al. [21]

 

10

5

nPaCO2

1.0

PC

6–8

8

 

VAR

  

NORM

60–80

 

NORM

 Henderson et al. [16]

 

10–15

5

10

0.4

       

NORM

200–300

 

35–45

 Dembinski et al. [13]

VC

8

5

nPaCO2

1.0

       

NORM

   

Sheep

 Kocyildrim et al. [19]

 

10

 

12–15

0.6

 

6–7

5

10–12

0.21

  

35–40

   

 Hou et al. [17]

 

6–8

 

16–18

  

6–8

 

16–18

       

 Langer et al. [22]

CPAP

VAR

8

VAR

0.5

CPAP

VAR

8

VAR

0.5

     

VAR

 Shekar et al. [14]

     

VC

4–6

10

6

0.21

      

 Totapally et al. [27]

 

7

4

nPaCO2

1

CMV

  

VAR

   

35–45

  

35–45

 Germann et al. [15]

PC

 

0–10

 

0.3–0.7

     

> 70

     

Vt tidal volume, PEEP positive end expiratory pressure, RR respiratory rate, FiO2 inspired fraction of oxygen, PaO2 arterial partial pressure of oxygen, SpO2 peripheral oxygen saturation, PaCO2 arterial partial pressure of carbon dioxide, nPaCO2 to maintain PaCO2 in normal range, VC volume controlled, PC pressure controlled, CPAP continuous positive airway pressure, NORM to ‘normal range’, VAR varied

Models of ECMO and its intra-experimental management

Most studies performed veno-venous ECMO (n = 13). A summary of ECMO models and the management of ECMO during experiments are provided in Table 5. In most cases (n = 14), cannulation was peripheral, with three studies performing surgical cutdown [17, 25, 28]. There were a wide variety of cannulation configurations among studies. Few studies described a means of confirming cannula positioning, although peripheral ultrasonography [17, 24], intracardiac sonography [14], and a pressure guided method [22, 29] were reported. A range of commercial and experimental pumps and oxygenators were used. The constituents of priming solutions were described in less than half of the studies (n = 8) but included saline [12, 13, 24], lactated Ringers (LR) [25], albumin and saline [16], hydroxyethyl starch (HES) and LR [21], Voluven and LR [23], and Plasmalyte-148 and albumin [14]. The use of heparin as an anticoagulant was ubiquitous.
Table 5

Details of ECMO management

Study

ECMO type

ECMO equipment

ECMO settings

Anticoagulation

Mode

Configuration

Pump

Oxygenator

Cannula size (Fr)

A-R

Flow

Sweep gas

FiO2

Type

ACT target (s)

Dogs

 Kim et al. [18]

VAc

RA–Ao

Multiple

Multiple

23–19

1.2–2 L/min

1.8–2 L/min

0.6

  

Pigs

 Araos et al. [12]

VV

EJV–EJV

Medtronic Bioconsole 540

Medos HILTE 2400LT

23 dual-lumen

65 mL/kg/min

65 mL/kg/min

 

Heparin

180–220

 Wang et al. [28]

VV

EJV–FV

Maquet Jostra

Medos HILTE 2400LT

12–8

70–80 mL/kg/min

 

1.0

Heparin

180–220

 Ni et al. [23]

VV

FV–IJV

Maquet Rotaflow

Maquet Quadrox D

14–14

50 mL/kg/min

50 mL/kg/min

1.0

Heparin

180–220

 Pilarczyk et al. [25]

VV

FV–EJV

Multiple

Multiple

23–21

2.4–2.8 L/min

3 L/min

 

Heparin

180–220

 Park et al. [24]

VV

FV - EVJ

Maquet Rotaflow

Maquet Quadrox D

20/21–20/21

0.5–3 L/min

2:1–1:2 BF:GF

 

Heparin

1.5–2.5 × baseline

 Kopp et al. [20]

VV

FV–EJV

Experimental

Experimental

19–17

30–40% CO

2 L/min

 

Heparin

≥ 149

 Song et al. [26]

VV

EVJ–FV

Maquet Jostra

Medos HILTE 2400LT

14–12

70–80 mL/kg/min

2 L/min

1.0

Heparin

180–220

 Kopp et al. [21]

VV

FV – EVJ

Multiple

Multiple

Multiple

25–40% CO

3–6 L/min

 

Heparin

120–150

 Henderson et al. [16]

VA

EJV–CA

Stockert roller pump

 

8–10

100 mL/kg/min

  

Heparin

180–220

 Dembinski et al. [13]

VV

FV–FV

Medos DeltaStream

Medos HILTE 7000

17–15

30% CO

30% CO

1.0

Heparin

≥ 130

Sheep

 Kocyildrim et al. [19]

VV

SVC–PA

Thoratec Centrimag

Xenios iLA

24–24

1.2–1.4 L/min

  

Heparin

> 200

 Hou et al. [17]

VAc

Multiple

Maquet Rotaflow

Maquet Quadrox D

19–15

50 mL/kg/min

50 mL/kg/min

1.0

Heparin

180–220

 Langer et al. [22]

VV

EJV–EJV

Maquet Cardiohelp

Maquet HLS Set

23 dual-lumen

2 L/min

1–10 L/min

0.5–1.0

Heparin

> 160

 Shekar et al. [14]

VV

EJV–EJV

Maquet Rotaflow

Maquet Quadrox D

21–19

60–80 mL/kg/min

80% pump flow

1.0

Heparin

220–250

 Totapally et al. [27]

VA

IJV–CA

 

Medtronic Minimax

 

15% CO

1 L/min

1.0

Heparin

 

 Germann et al. [15]

VVc

IVC–SVC

Stockert roller pump

Medtronic Maxima+

 

2.5–3.5 L/min

 

0.21–1.0

  

Fr French, FiO2 inspired fraction of oxygen, A–R access–return, ACT activated clotting time, Vac central veno-arterial, RA right atrium, Ao aorta, VV veno-venous, EJV external jugular vein, FV femoral vein, IJV internal jugular vein, VA veno-arterial, CA carotid artery, SVC superior vena cava, PA pulmonary artery, VVc central veno-veno

ARRIVE compliance

No study published after 2011 explicitly referenced the ARRIVE standards or reported compliance with them.

Discussion

This systematic review provides the first detailed overview of animal models which combine features of experimental ARDS with ECMO. In doing so, we have demonstrated marked heterogeneity in both their design and reporting.

Animal models play a key role in research into ARDS and are well established in both small [30] and large animal species [31]. Given the complexity of the underlying pathophysiology, they are essential tools for deriving new mechanistic insights as well as establishing the efficacy and safety of novel interventions [32]. Their place in current ECMO research is less clear. Our study found no example of a contemporary small animal model combining features of ARDS and ECMO. This may reflect the inherent difficulties of replicating a clinically relevant extracorporeal circulation in a small animal species, although such models have been described in the absence of lung injury in rodents [33] and rabbits [34, 35]. While small animal models are limited by the inability to use clinical ECMO devices, differences in lung morphology [36], and variations in innate immunity [37], they offer several advantages. Studies involving small animal species are less resource intensive than those in large animals, can be conducted more quickly, may take advantage of varied genetic strains, and have the advantage of using multiple assays and imaging techniques not available in large animals.

All models identified by our study were conducted in large animals. These models may have advantages, which are generally the converse of the limitations seen in small animals. A feature of studies in our review is their relatively short duration, with only two models describing recovery and follow-up beyond 24 h [26]. This may be a result of the intensive and costly nature of large animal studies, although models supported for more than 24 h and/or those with the potential for recovery would be of benefit in addressing important research questions. In the context of ARDS and ECMO, models of greater duration would facilitate research into the proliferative phase of lung injury, allow investigators to explore lung recovery during ECMO, and could test approaches to weaning from extracorporeal support.

Regardless of species, models of experimental ARDS identified in this study were diverse. Previously, the American Thoracic Society (ATS) has attempted to standardize experimental ARDS by identifying core pathophysiological features which should be established in pre-clinical models [38]. In our review, few studies published after the ATS workshop report acknowledge these features or reported compliance. To increase the validity of studies, the presence or absence of these features should be evaluated during model development. Most commonly described means of inducing lung injury were described: saline lavage, oleic acid infusion, endotoxemia, acid aspiration, and smoke inhalation. Notably, we failed to identify a study which included the use of live bacteria, a method frequently employed in singular models of experimental ARDS [31]. Recent work, using latent class analysis (LCA), has identified stable ARDS phenotypes present in large clinical trial cohorts. These have been broadly represented as ‘hyper-’ or ‘hypo-inflammatory’, each group having distinct clinical and biological features. Importantly, sub-phenotypes also appear to have differing responses to treatment and variations in outcome [3941]. This work has implications for the design of pre-clinical studies. In our review, there is a preponderance toward models which likely induce ‘hypo-inflammatory’ ARDS, such as oleic acid infusion and saline lavage, both have which have been associated with a failure to induce pro-inflammatory cytokines or significant neutrophil influx to the lung [31]. In future, investigators should consider phenotypes when contemplating a method of injury. Regardless of the method of achieving experimental ARDS in animals, models that incorporate ECMO must also take account of the severity of the disease. Only four studies identified by our review targeted an injury which delivered a partial pressure of oxygen to inspired fraction of oxygen (P/F) ratio of less than 100 mmHg [13, 20, 24, 25]. No included study evaluated ventilatory pressures or the presence of acidosis as part of the definition of injury. Future models, particularly those used to assess interventions during ECMO, should aim to replicate clinically meaningful injury criteria such as those used for inclusion into large clinical trials [3].

The supportive care administered to animals in included studies was an area of significant variation. The choice of agent for the induction and maintenance of anesthesia differed between studies, although almost all employed a total intravenous approach. The influence of anesthesia on outcomes of interest should be considered during the design of a model, and this is particularly true in respect of inhalational agents where emerging evidence points toward a potential role in modifying the inflammatory response associated with ARDS [42]. Reassuringly, most models described combining anesthetic and analgesic infusions, commonly with the addition of fentanyl. Only four models reported the use of neuromuscular blockade [12, 17, 24, 27]. Ten of the models were reported after publication of the ACURASYS study, which reported an improvement in mortality among patients with severe ARDS receiving early paralysis [43]. While some models may seek to evaluate spontaneous breathing during ECMO, neuromuscular blockade should be considered a standard of care in severe ARDS and thus be replicated as a feature of a high fidelity pre-clinical model.

Mechanical ventilation practices, both before and after the institution of ECMO, were poorly described. Few studies instituted lung-protective ventilation prior to ECMO and many described using tidal volumes in excess of 8 mL/kg. Given the clear evidence for low tidal volume ventilation in ARDS [44], failure to implement this in pre-clinical models limits their validity. While the evidence supporting approaches to ventilation during ECMO is less well defined, only one model reported the use of an ultra-protective ventilatory strategy [14]. Levels of positive end-expiratory pressure (PEEP) during ECMO also appear low when compared with contemporary clinical practice [45]. Considering the importance of mechanical ventilation in ARDS and its ability to aggravate injury through ventilator-induced lung injury (VILI), models of ARDS and ECMO should at a minimum provide a detailed description of ventilatory practices.

In general, reporting of ECMO was more complete. All models provided a description of cannula configuration. In the future, investigators should use the Extracorporeal Life Support Organization Maastricht Treaty on ECMO nomenclature to ensure consistency and clarity [46]. As would be expected, models employed a variety of ECMO devices, many of which are in contemporary clinical use. While flow and sweep gas settings were well reported, few studies provided details on gas exchange targets during ECMO, with only 1 in 4 stating a target PaO2 and less than half providing a target PaCO2. Heparin was the anticoagulant of choice in every model that provided details of anticoagulation practice. Likewise, all but three studies provided target activated clotting time (ACT) ranges. The ubiquity of ACT may reflect the relatively short duration of included models and the requirement for a cost-effective bedside measure of coagulation. Anticoagulation targets varied between models, which may reflect continuing uncertainty as to the optimal clinical regime [47].

No study identified by this review, and published after 2011, explicitly referenced the ARRIVE guidelines for improving the reporting of animal studies [11]. This is perhaps not a feature limited to models of ARDS and ECMO, but instead reflects a wider issue with adherence despite widespread support for the standard [48]. While adherence to the ARRIVE standards (or similar) is likely to enhance the quality and reproducibility of published studies, there are many subject-specific domains (e.g., technical aspects of ECMO, mechanical ventilation practices) which are equally important but omitted by these higher-level guidelines. Several initiatives have attempted to address this in pre-clinical stroke models and more recently in sepsis. Here we have outlined what domains a minimum reporting standard for pre-clinical models of ARDS and ECMO may contain (Table 6).
Table 6

Proposed domains of a minimum reporting standard for pre-clinical studies of ARDS and ECMO

Domains

Example items

Notes

1. ARDS model and definition

Method of injury, including dosing and duration

Should be consistent with ATS report [38]

Description of validation

Operational definition of injury

2. Mechanical ventilation

Mode of ventilation

Target tidal volume

PEEP settings

Ventilatory strategy during ECMO

3. Supportive care

Use of neuromuscular blockade

Prone positioning

Fluid therapy–type and quantity

4. ECMO equipment

Pump and oxygenator make and model

Cannulae make and model

5. ECMO cannulation

Standard description of configuration

Should use Maastricht treaty nomenclature [46]

Method of cannulation

6. ECMO management

Flow targets

Gas exchange targets/sweep gas management

Anticoagulation strategy and targets

Limitations

Our review has several limitations. Firstly, despite each included study being the first description of a combined model of ARDS and ECMO, occasionally investigators used components of previous instances of experimental ARDS or ECMO in creating them. Where such studies were referenced, we made every attempt to retrieve relevant data. Secondly, no formal risk of bias assessment was undertaken as part of this review. While this limited our ability to assess the quality of included studies, the principal aim of our review was to identify and describe models. Finally, an arbitrary date was used to exclude historical models of ARDS and ECMO. This was pre-judged to allow consideration of models most likely to have contemporary clinical significance but may have excluded older models which remain viable.

Conclusion

A limited number of models combine the features of experimental ARDS with ECMO. Among those that exist, there is significant heterogeneity in both design and reporting. This creates difficulty in assessing results and in generalizing findings to clinical settings. There is a need to standardize the reporting of pre-clinical studies using in this area. This could be achieved by the introduction of a minimum data set for pre-clinical ECMO studies.

Abbreviations

ACT: 

Activated clotting time

Ao: 

Aorta

ARDS: 

Acute respiratory distress syndrome

Bpm: 

Beats per minute

CA: 

Carotid artery

CMV: 

Continuous mandatory ventilation

ECMO: 

Extracorporeal membrane oxygenation

EJV: 

External jugular vein

ETT: 

Endotracheal tube

FA: 

Femoral artery

FiO2

Inspired fraction of oxygen

Fr: 

French

FV: 

Femoral vein

HCL: 

Hydrochloric acid

HES: 

Hydroxyethyl starch

IJV: 

Internal jugular vein

LPS: 

Lipopolysaccharide

LR: 

Lactated Ringers

MAP: 

Mean arterial pressure

OA: 

Oleic acid

P/F: 

Ratio of arterial partial pressure of oxygen to inspired fraction of oxygen

PA: 

Pulmonary artery

PaCO2

Arterial partial pressure of carbon dioxide

PaO2

Arterial partial pressure of oxygen

PC: 

Pressure controlled

PEEP: 

Positive end-expiratory pressure

Rpm: 

Revolutions per minute

SpO2

Peripheral oxygen saturation

SVC: 

Superior vena cava

Trach: 

Tracheostomy

VA: 

veno-arterial

VC: 

Volume controlled

Vt: 

Tidal volume

VV: 

Veno-venous

Declarations

Acknowledgements

Not applicable.

Funding

JEM is supported by the National Health and Medical Research Council (NHMRC), Australia (APP1079421).

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its supplementary information files].

Authors’ contributions

JEM conceived and designed the systematic review. JEM, NB, and VvB conducted data screening and extraction. All authors participated in the drafting and critical revision of the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors’ Affiliations

(1)
Critical Care Research Group, The Prince Charles Hospital, Brisbane, 4035 QLD, Australia
(2)
Faculty of Medicine, University of Queensland, Brisbane, Australia
(3)
School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology, Brisbane, Australia
(4)
Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm, Sweden
(5)
Department of Internal Medicine II, Cardiology and Pneumology, University Medical Center Regensburg, Regensburg, Germany
(6)
Wellcome Trust Centre for Global Health Research, Imperial College London, London, UK
(7)
U.O.C. Anestesia e Rianimazione 1, IRCCS, Policlinico San Matteo Foundation, Pavia, Italy
(8)
Medical-Surgical Intensive Care Unit, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
(9)
Institute of Cardiometabolism and Nutrition, Sorbonne University, Paris, France
(10)
Wellcome-Wolfson Centre for Experimental Medicine, Queen’s University Belfast, Belfast, UK
(11)
Department of Cardiothoracic Surgery, Heart & Vascular Centre, Maastricht University Medical Hospital, Maastricht, Netherlands

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Copyright

© The Author(s). 2019

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