Pathophysiological mechanisms and consequences of gut edema (Annika Reintam WSACS session ESA 2018 #EA18)

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

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

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

7. 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!

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

9. 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

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

11. 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

12. 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

13.  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

14. 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

15. 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

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

17. 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

18. 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

19. 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

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

21. 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.

22. 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

23. 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