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A cocktail solution for the ex vivo preservation and perfusion of the lung; Shehata solution

Mohamed S. A. Mohamed

Deutz-Kalker Str. 118, 50679 Cologne, Germany

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

DOI: 10.15761/TiT.1000212

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Abstract

The importance of lung transplantation is increasing, being the practical solution for the end stage pulmonary failure. ex vivo graft preservation is an essential step in the transplantation surgery that consists of hypothermic preservation and or normothermic perfusion.

There are many preservation solutions that are used for the ex vivo lung preservation and are commercially available or institutionally used. Based on the clinical results, the effective preservation determines the clinical outcome of the transplantation surgery.

Despite the great progress in the development of the preservation solutions, there is a continuous interest at further development in order to achieve the perfectionism of the technique. This paper describes an innovative solution to be used for the hypothermic graft preservation and the ex vivo lung perfusion, trying to apply the advantages of the other solutions, while avoiding any disadvantages, based on the translational medical knowledge.

Keywords

ex vivo lung perfusion, lung graft preservation, lung transplant, preservation solution

Introduction

Lung transplantation is the sole hope for the patients of end-stage pulmonary diseases. As the availabilty of the grafts is not enough to meet the requirements, the ex vivo lung perfusion (EVLP) technique was developed to recruit marginal grafts [1].

The practice of lung transplantation involves the surgical retrieval of the donor graft, followed by cold static preservation (till transplantation in the case of standard grafts) and ex vivo perfusion (in the case of marginal grafts) [2].

There are many solutions that have been developed and used for each of the two stages. For example, Celsoir and Perfadex solutions that are commonly used for the cold static preservation of the graft, and the Steen and Organ Care System solutions that are commonly used for the normothermic ex vivo perfusion. Nevertheless, there are other solutions that were developed for institutional and or commercial utilization [3].

State of the art

There are many preservation solutions that are available either in the market or for the institutional use. EuroCollins (EC) solution was initially the solution of choice until it was replaced in 1988 by the University of Wisconsin (UW) solution [4], whose high viscosity has been involved in organ dysfunction, leading to the development of other solutions including Celsior (CEL) and histidine tryptophan ketoglutarate (HTK) [5].

Due to its unique metabolic requirements and the unique physiology, special solutions, such as Perfadex (PER), are particularly designed for the lung. All solutions consist of several composite elements, which have some advantages and disadvantages (Table 1).

Table 1. Characteristics of some lung preservation solutions. All units are in mmol / L, unless otherwise stated. Abbreviations: EC, Euro Collins; UW, University of Wisconsin; HTK, histidine-tryptophan ketoglutarates; CEL, Celsior; PER, Perfadex; LactoB, lactobionate; HES, hydroxyethyl starch; Phos, phosphates; Bicarb, bicarbonates; GSH, glutathione; Trp, tryptophan; Α-KG, ketoglutarates. Source; J Thorac Dis. 2014 Aug; 6 (8): 1143-1149. Doi: 10.3978 / j.issn.2072-1439.2014.05.14

Solution

EC

UW

CEL

HTK

PER

Colloid Component

Glucose

LactoB, raffinose, HES

LactoB, mannitol

Mannitol

Dextran

Puffer

Phos, bicarb

Phos

Histidine

Histidine

Phos

Antioxidans

 

AlloP, GSH

GSH, mannitol

Trp, mannitol

 

Osmolarity (mOsm/L)

375

330

320

310

292

Glucose

180

 

 

 

5

Na+

10

25

100

15

138

K+

115

120

15

10

6

Ca2+

 

 

0.25

0.02

 

Mg2+

 

5

13

4

0.8

Cl-

15

20

 

32

142

Other Components

 

 

 

α-KG

SO42- 0.8 Dextran 40 g/L

Previously, high K+ preservation solutions were used that were associated with pulmonary vascular spasms and increased production of reactive oxygen species. Low potassium (dextran) solutions are currently widespread and are associated with better clinical outcomes.

Although 2 studies have confirmed Celsior's ability to provide similar clinical results to those of the Perfadex solution, with additional trends towards better survival and less incidence of chronic lung allograft dysfunction, especially with longer ischemic periods, Perfadex remains the most widely used preservation solution in most lung transplant centers [6,7].

In addition to the hypothermic preservation solutions, there are other solutions that are specifically used for the normothermic ex vivo graft perfusion, mostly Organ Care System and Steen solutions. The later is a colloidal solution that resembles the extracellular fluid (low K+), and contains albumin and dextran 40 to provide colloidal activity and endothelial protection [8].

What is the need for a new preservation solution?

According to the current surgical practice, the reported results, using various preservation solutions are promising, with the ability of EVLP to convert the non-acceptable grafts into acceptable in rates between 87-97%. However, these conversion rates are the result of careful consideration of the grafts to be subjected to reconditioning, where the more aggressive is the strategy, the lower is the conversion rate [9].

To increase the quality of the ex vivo graft preservation, and to provide the ability for more aggressive graft recruitment, the following solution is introduced (Table 2).

Table 2. Characteristics of Shehata lung preservation solution. The solution is to be supplemented with 500 mg methylprednisolone, 500 mg imipenem/ cilastatin and 3000 IU heparin, and to be used for both graft perfusion and static preservation.

Ingredient

Recommended Dose

Sucrose

0.5 M

Sodium

135 – 145 mmol/L

Glucose

100 – 120 mg/dL

Potassium

3.5 to 5.5 mEq/L

Phosphate

1.0 mmol/l

Calcium

2.2 mmol/l

Magnesium

1.7–2.2 mg/dL

Human serum albumin

50 g/L

Carbonate

29 mmol/L

Chloride

100 mEq

Vitamin C

0.5 g/L

Glutathion

1500 mg/L

Insulin

200 pmol/L

Pinacidil

0.25 – 0.3 mg/L

Infliximab

3 - 5 mg/L

Distilled water

Dissolvent

pH

7.4

The innovation in this solution

This solution aims to provide better reconditioning of the lung grafts that have extended criteria, in order to increase the available donor pool. The current available solutions have achieved success with grafts that meet the standard or border-line criteria, however, the grafts with extended criteria require additive care [3,4].

The electrolytes levels of the solution are based to resemble the physiological serum levels. Sucrose is added to provide colloidal force and stablization of the cellular membranes.10 Human serum albumin is included to provide oncotic pressure that helps the resolution of the pulmonary edema. Glucose adds to the actions of sucrose and albumin, in addition to provide nutrition.

The main injury during graft ischemia - reperfusion is mediated by the increased production of reactive oxygen species (ROS), the inhibition of the ATP-sensitive K+ channels (both are involved in the activation of the graft inflammasomes, hence, the increased production of interleukins 1ß, 18 & 6), and the increased production of TNFα.11 Glutathion and vitamin C provide potent antioxidant function, antagonizing ROS [12]. Vitamin C and Pinacidil activate the ATP-sensitive K+ channels [11,13]. In addition, infliximab antagonizes TNFα [11]. All together have the potential to significantly oppose and attenuate the ischemic reperfusion injury.

The Na+/K+ ATPase is inhibited by hypoxia and cold preservation, and the absence of shear stress during ischemia is associated with impaired functions of K+ channels, cell membrane depolarization, increased activity of nicotinamide-adenine-dinucleotide phosphate oxidase and xanthine oxidase enzymes, and impaired mitochondrial activity, leading to the increased production of ROS that activate protein kinase C-ζ, starting a sequence of phosphorylation-ubiquitination-recognition-endocytosis-degradation of Na+/K+ ATPase [14].

Insulin interferes with that sequence of events through the activation and recruitment of Na+/K+ ATPase, the induction of Na+/K+ ATPase, and the inhibition of K+ efflux channels. As Na+/K+ ATPase is also essential for the syncronized action of Na+ transport, insulin supplementation during cold static graft preservation, as well as during ex vivo perfusion, could be useful for glucose utilization, ATP production, Na+/K+ ATPase activation, inhibition of K+ efflux, and clearance of alveolar edema [14]

Conflicts of interest

The intellectual properties and the solution included and described in this manuscript belong solely to the author. All rights are registered and protected under the author's name. Reproduction or use of any of the included intellectual properties requires the written permission of the author. No funding was provided for the development of this work. The author welcomes funding cooperation for experimental and clinical studies.

References

  1. Cypel M, Keshavjee S (2013) Strategies for safe donor expansion: donor management, donations after cardiac death, ex-vivo lung perfusion. Curr Opin Organ Transplant 18(5): 513-517.
  2. Cypel M, Yeung JC, Hirayama S, Rubacha M, Fischer S, et al. (2008) Technique for prolonged normothermic ex vivo lung perfusion. J Heart Lung Transplant 27: 1319-1325. [Crossref]
  3. Van Raemdonck D, Neyrinck A, Cypel M (2015) Ex-vivo lung perfusion. Transpl Int 28: 643-656. [Crossref]
  4. Mühlbacher F, Langer F, Mittermayer C (1999) Preservation solutions for transplantation. Transplant Proc 31: 2069-2070. [Crossref]
  5. Feng XN, Xu X, Zheng SS (2006) Current status and perspective of liver preservation solutions. Hepatobiliary Pancreat Dis Int 5: 490-494. [Crossref]
  6. Menezes AQ, Pego-Fernandes PM, Cardoso PF (2012) Comparison of Celsior and Perfadex lung preservation solutions in rat lungs subjected to 6 and 12 hours of ischemia using an ex-vivo lung perfusion system. Clinics (Sao Paulo) 67(11): 1309-1314.
  7. Gohrbandt B, Simon AR, Warnecke G (2015) Lung Preservation with Perfadex or Celsior in Clinical Transplantation: A Retrospective Single-Center Analysis of Outcomes. Transplantation 99(9): 1933-1939.
  8. Van Raemdonck D, Neyrinck A, Cypel M (2015) Ex-vivo lung perfusion. Transpl Int 28: 643-656. [Crossref]
  9. Sage E, Mussot S, T2021 Copyright OAT. All rights reserv transplantation from initially rejected donors after ex vivo lung reconditioning: the French experience. Eur J Cardiothorac Surg 46: 794-799. [Crossref]
  10. Ali Mohamed MS (2015) Slow cryopreservation is not superior to vitrification in human spermatozoa; an experimental controlled study. Iran J Reprod Med 13: 633-644. [Crossref]
  11. Mohamed MS (2015) Could Ex Vivo Lung Perfusion Be a Platform to Decrease the Incidence of Chronic Lung Allograft Dysfunction? Arch Med Res 46: 240-243. [Crossref]
  12. Mohamed MS (2014) Antagonizing reactive oxygen species during ex vivo lung perfusion. Am J Physiol Lung Cell Mol Physiol 307: L908. [Crossref]
  13. Mohamed MS (2016) Ascorbic Acid Supplementation During Ex Vivo Lung Perfusion. Exp Clin Transplant 14: 112-113. [Crossref]
  14. Mohamed MS (2016) Insulin Supplementation of the Lung Graft Cold Preservation Solution. Ann Thorac Surg 101: 411-412. [Crossref]

Editorial Information

Editor-in-Chief

Article Type

Research Article

Publication history

Received date: October 23, 2016
Accepted date: November 17, 2016
Published date: November 21, 2016

Copyright

© 2016 Mohamed MSA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Mohamed MSA (2016) A cocktail solution for the ex vivo preservation and perfusion of the lung; Shehata solution. Trends in Transplantation 1: DOI: 10.15761/TiT.1000212

Corresponding author

Mohamed S. A. Mohamed

Deutz-Kalker Str. 118, 50679 Cologne, Germany

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Table 1. Characteristics of some lung preservation solutions. All units are in mmol / L, unless otherwise stated. Abbreviations: EC, Euro Collins; UW, University of Wisconsin; HTK, histidine-tryptophan ketoglutarates; CEL, Celsior; PER, Perfadex; LactoB, lactobionate; HES, hydroxyethyl starch; Phos, phosphates; Bicarb, bicarbonates; GSH, glutathione; Trp, tryptophan; Α-KG, ketoglutarates. Source; J Thorac Dis. 2014 Aug; 6 (8): 1143-1149. Doi: 10.3978 / j.issn.2072-1439.2014.05.14

Solution

EC

UW

CEL

HTK

PER

Colloid Component

Glucose

LactoB, raffinose, HES

LactoB, mannitol

Mannitol

Dextran

Puffer

Phos, bicarb

Phos

Histidine

Histidine

Phos

Antioxidans

 

AlloP, GSH

GSH, mannitol

Trp, mannitol

 

Osmolarity (mOsm/L)

375

330

320

310

292

Glucose

180

 

 

 

5

Na+

10

25

100

15

138

K+

115

120

15

10

6

Ca2+

 

 

0.25

0.02

 

Mg2+

 

5

13

4

0.8

Cl-

15

20

 

32

142

Other Components

 

 

 

α-KG

SO42- 0.8 Dextran 40 g/L

Table 2. Characteristics of Shehata lung preservation solution. The solution is to be supplemented with 500 mg methylprednisolone, 500 mg imipenem/ cilastatin and 3000 IU heparin, and to be used for both graft perfusion and static preservation.

Ingredient

Recommended Dose

Sucrose

0.5 M

Sodium

135 – 145 mmol/L

Glucose

100 – 120 mg/dL

Potassium

3.5 to 5.5 mEq/L

Phosphate

1.0 mmol/l

Calcium

2.2 mmol/l

Magnesium

1.7–2.2 mg/dL

Human serum albumin

50 g/L

Carbonate

29 mmol/L

Chloride

100 mEq

Vitamin C

0.5 g/L

Glutathion

1500 mg/L

Insulin

200 pmol/L

Pinacidil

0.25 – 0.3 mg/L

Infliximab

3 - 5 mg/L

Distilled water

Dissolvent

pH

7.4