Gut edema in acute illness is not yet sufficiently studied and existing knowledge is largely based on experimental animal studies or small studies in healthy volunteers. However, increasing evidence confirms that gut edema impairs intestinal motility and healing of bowel anastomoses, being therefore an important contributor to outcome. Current presentation focuses mainly on the role of fluids in development of intestinal edema.

1. Pathophysiological mechanisms and
consequences of gut edema
Annika Reintam Blaser
Tartu, Estonia
Lucerne, Switzerland

2. Disclosures
 I have received
 honoraria for advisory board participation from Fresenius, Nestlé
and Nutricia
 consultancy and speaker fees from Fresenius and Nestlé
 study grant (to University of Tartu) from Fresenius
 I am
 a member of Executive Committee of WSACS
 Chair of the Clinical Trials Working Group of WSACS

3. Gut edema in the literature
Search Query Items found
1 ((bowel edema[Title/Abstract]) OR
gut edema[Title/Abstract]) OR
intestinal edema[Title/Abstract]
202

4. WATER TARGET SIGN = Enhanced mucosal (muscularis mucosae) and
muscular layer with the edematous submucosa in between
Palmquist S et al. Clin Case Rep. 2017; 5(5): 707–710

6. Sometimes no enhancement
Sometimes distended bowel = bowel wall thinner

7. Gut edema
Tissue hypoperfusion
Capillary leak
Fluid resuscitation
Mesenterial venous
congestion

8. Mechanisms 1
Trigger Pathophysiology Models to study
Ischemia-
reperfusion
- Tissue damage
- Cytokine release
- Increased vascular
permeability (to proteins)
Occlusion of superior mesenteric
artery (30-60 min)
1. Modified after: Shah SK et al. J Surg Res. 2011; 166(1): 120–130
2. Nessim C et al. J Surg Res. 2013 Aug;183(2):567-73
Hypoproteinemia
(large volume fluid
resuscitation)
Decreased oncotic
intravascular pressure
Older studies (“nutritional
edema”): plasmapheresis
Newer studies: impact of fluid
resuscitation on anastomoses 2
Venous congestion
(large volume fluid
resuscitation, intra-
abdominal
hypertension)
Increased intravenous
hydrostatic pressure
Partial ligation of superior
mesenteric vein ( -> venous
pressure ca 20 mmHg)
Edema takes >12 hrs to clear
No ischemia-reperfusion!

9. Verbrugge FH. JACC 2013; 62(6):485–95

10. Lymphangiogenesis
 Promoting lymphangiogenesis by vascular endothelial growth
factor-C (VEGF-C) aggravated intestinal edema
Wang XL et al. Brazilian Journal of Medical and Biological Research 2016; 49(5): e4738

11. Smooth muscular edema
Lautenschläger I et al. PLoS ONE 2015; 10(3): e0120802
platelet-activating factor (PAF)-
induced intestinal injury
normal

12. Consequences
of gut edema
 Impaired GI motility -> ileus
 Ileus -> edema due to lymphostasis (valve-less lymph vessels 2)
 Damaged barrier integrity -> sepsis?
 increased cell stretch, altered cytoskeleton -> inflammation
 Edema activates a mechanotransductive signaling cascade
 Longitudinal stretch = very similar pathway
 Bowel stretched to 120% of original length for 2 hours 3
 Impaired absorption of nutrients?
 Impaired healing of anastomoses
1. Shah SK et al. Neurogastroenterol Motil. 2010; 22(10): 1132–e290
2. Unthank JL et al. Am J Physiol. 1988; 254:G389–398
3. Shah SK et al. Surgery. 2010 June ; 147(6): 772–779
Basal contractile activity in mice 1

13. Fluids
 High-volume fluids cause edema and impair intestinal
contractility similarly to peritonitis or endotoxemia
Gorrasi J et al. Shock. 2017 Dec 14. doi: 10.1097/SHK.0000000000001088. [Epub ahead of print]
Young J et al. Math Biosciences 262 (2015): 206-213
. Acetylcholine doseresponse. Values are presented as mean and SEM. Acetylcholine
ct: p < 0.001, acetylcholine dose–group interaction: p=0.030. KB, Krebs buffer.
Acetylcholine-induced jejunal
contractility
Pigs
High-volume = 20 mL/kg/h
• 15 ml/kg/h Ringer's lactate
• 5 ml/kg/hr HES 130/04, 6%
Moderate volume =
10 mL/kg/h Ringer's lactate
Acetylcholine has to reach the postsynaptic membrane of intestinal smooth
muscular cells = longer distance with edema (30-60 nm instead of 15-30 nm?) 2

14.  crystalloids preferred for initial resuscitation 2
 balanced cristalloids
 synthetic colloids associated with renal dysfunction
 natural colloids (e.g. albumin) could be considered
Figure 1: Body water compartments. The ability of a solution to expand the plasm
volume is dependent on the volume of distribution of the solute, so that wh
colloids are mainly distributed in the intravascular compartment, dextro
containing solutions are distributed through the total body water and hence have
limited and transient volume expanding capacity. Isotonic sodium-containi
crystalloids are distributed throughout the extracellular space and in practice t
efficiency of these solutions to expand the plasma volume is only 20-25%, t
remainder being sequestered in the interstitial space.
1. British Consensus Guidelines on Intravenous Fluid
Therapy for Adult Surgical Patients, 2009
2. Perel P, Roberts I. Cochrane 2011;3: CD000567

15. Liberal vs restrictive fluids (and salt)
 Restrictive (maintained BW) vs. liberal fluids in elective GI surgery 1
 earlier return of bowel function
 Patients with increased risk of complications after major abdominal surgery 2
 Restrictive fluids: more surgical site infections, acute kidney injury and RRT
 Hypertonic saline reducing edema formation? 3
 Less fluids, but more hypernatremia 4
 Positive sodium (and water) balance after elective colonic surgery (>3L and 154
mmol; <2 L and 77 mmol) 5
 slower gastric emptying and passage of stool
 4% albumin vs. 0.9% sodium chloride (SAFE study) 6
 no changes in ICU stay, hospital stay, MV or renal-replacement therapy
1. Brandstrup B et al. Ann Surg 2003; 238 (5):641-648
2. Myles PS et al. NEJM 2018, May 10, doi: 10.1056/NEJMoa1801601
3. Shah SK et al. J Surg Res. 2011; 166(1): 120–130
4. Shrum B et al. Cochrane Database Syst Rev. 2016;(6):CD005576
5. Lobo D et al. Lancet. 2002 May 25;359(9320):1812-8
6. Finfer S et al. N Engl J Med 2004; 350:2247-2256

16. Balanced crystalloids vs saline
Shaw et al. Critical Care 2015; 19:334
Propensity-matched retrospective cohort study in patients with SIRS criteria 1
Favors
balanced
Favors
0.9% saline

17. Transudate formation
Zausig YA. Crit Care. 2013; 17(5): R203
Guinea pigs hearts perfused with 1% albumin buffer
Then diluted with artificial solutions

18. Colloid vs crystalloid
 Volunteers: 1 L of fluid over 1 hour 1
 Escaped from the intravascular space at the end of infusions
 68% of 0.9% saline
 21% of gelatine (Gelofusine)
 16% of HES 130/04, 6% (Voluven)
1. Lobo DN et al. Crit Care Med. 2010 38(2):464-470
2. Hahn RG, Lyons G. Eur J Anaesthesiol. 2016 Jul; 33(7): 475–482
 A model with effect of different elimination half-lives 2

19. Different infusion rates
Hahn RG. Biology of Sex Differences 2016;7:54
Hahn RG et al. Acta Anaesthesiol Scand. 2016;60(5):569-78
The return of Ringer's acetate from the peripheral fluid compartment to the
plasma was slower with high than with low infusion rates

20. Infusion rate and amount
Simulations based on 10 volunteers 1
A: Ringer’s acetate solution is infused 3:1 after
900 mL of blood was withdrawn from male
volunteers
B: less (slower) Ringer to reach euvolemia
1. Hahn RG. Anaesth Intensive Ther 2014; 46 (5): 342–349
2. Jacob M et al. Crit Care 2012;16(3):R86
10 Volunteers: 1L of blood simultaneously
replaced by 3 L of Ringer’s lactate 2
• hypovolemia (80% of RL escaped)
• intertitial edema of 2 liters ?
• 20% albumin (250 ml) solution restored

21. Patients ≠ volunteers
Hahn RG, Lyons G. Eur J Anaesthesiol. 2016; 33(7): 475–482

22. Concomitant arterial blood pressure
Hahn RG. Anaesthesiology Intensive Therapy 2014; 46 (5): 342–349
Li Y et al. Acta Anaesthesiol Scand 2007; 51: 880−887.

23. Concomitant venous pressure
Moore-Olufemi SD et al. J Trauma 2005;58:264-270
Rats
HTN = mesenteric venous
hypertension through partial
occlusion of the superior
mesenteric vein

24. Summary
 Gut edema in ICU patients occurs due to
 ischemia-reperfusion injury
 decreased oncotic pressure (hypoproteinemia, fluids)
 increased hydrostatic pressure (fluids ± venous hypertension/IAH)
 Tissue damage and inflammation
 Magnitude of the edema depends also on
 type, amount, timing and rate of resuscitation fluids
 possibly of concomitant arterial pressure
 Edema activates similar pathways as mechanic longitudinal stretch
 Edema has relevant effect on bowel motility
 Similar to peritonitis or endotoxemia