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	Early Changes in the Small for Flow Syndrome
An Experimental Model


J.M. Asencioa, M.A. Steinera, J.L. G Sabridoa, J.A. L�pez Baenaa, J.P Ferreiroaa, A. Moralesa, P. Lozanoa,I. Peligrosb, J. Lasoc, M. Herreroc, C. Lisbonac, J.M. P�rez-Pe�ac, L. Olmedillac.

a. Department of General Surgery, b. Department of Pathological Anatomy, c. Department of Anesthesiology
Hospital General Universitario Gregorio Mara��n, Madrid, Spain.



Author contact:
Dr. Jos� Manuel Asencio Pascual
Address: c/o�donnell 6, Madrid 28009, Spain.
Phone: 0034 626948426
mail: jmasencio@gmail.com
Department of General Surgery III and Liver Trasplant Unit
Hospital General Universitario Gregorio Mara��n.




Abstract
Introduction. The aim of this experimental model is to describe the early hemodynamic and histological alterations after a hyperextended hepatectomy. The knowledge of these changes is important because the prevention of the early damages could prevent the development of the Small for Flow Syndrome.
Material and Methods. Sequential segmentectomies until completing the resection of 80% of the liver parenchyma were performed under general anesthesia in 13 Minipig. After each resection, histological samples were taken and the portal and arterial hepatic flow, the portal pressure, the pressure in the suprahepatic veins, the arterial pressure and the cardiac frequency were measured.
Results. The mean of the resected tissue was 79.8%. The portal pressure and flow per 100 gr. of the remnant parenchyma increased from 8,5 to 12 mmHg (p <0,01) and from 120 to 379 ml/min/100 gr. (p <0,01). The arterial flow decreased from 175 to 50 ml/min (p <0,001). The biopsies taken five minutes after each resection showed changes that evolve from interstitial edema and sinusoidal dilatation to periportal hemorrhage. The increase of the portosystemic pressure gradient is probably due to the damage in the microcirculation.
Conclusions. This hyperextended hepatectomy model reproduces the classical alterations of the Small for Flow Syndrome. The hemodynamic and histological changes observed are immediate, so the prevention of these changes must be performed perioperatively by modulating the flow and portal pressure. The intraoperative measurement of the flow and the portal pressure should be part of the therapeutical diagnostic algorithm in patients who undergo major hepatic resections.

Key Words: Small for Size Syndrome, Liver, Portal Flow, Portal Pressure, Hepatectomy, Small for Flow Syndrome. 










Introduction
During the last years pathophysiological similarities between Small for Size Syndrome (SFSS)1 and post-hepatectomy liver failure, have been described.2,3 The portal hyperperfusion has been placed as the main cause of histological damage that occurs with the use of small grafts and with hyperextended liver resections.4-8 Recently, we have describe the Small for Flow Syndrome (SFFS)1 as a more precise concept to characterize this situation with treatment implications.

We are celebrating the 50th anniversary of the first liver transplant performed by Starlz in 1963.9 During this period the liver transplant has evolved from being an experimental technique to become the treatment of choice of several liver diseases. The improvement of surgical and anesthetic techniques and of immunosuppression, have made the liver transplant a standardized and reliable technique. The good outcomes that were achieved have increased the number of patients waiting for a liver transplant. However, this has not been followed by an increase in the number of grafts, so this discrepancy has caused a rise in the waiting list and of the mortality within it.10,11

In order to increase the number of available grafts, different technical refinements such as the use of organs from a living donor, the partition into halves of an organ for two recipients and a dual transplant were developed.11-15

The Small for Size Syndrome has been described with the use of reduced grafts and in the living donor liver transplantation (LDLT) setting.16The occurrence of jaundice, coagulopathy and untreatable ascites is related to the discrepancy between the weight of the graft and that of the recipient. When this ratio (GWRW) is less than 0,8%, the incidence of SFSS increase.17,18 The role of the size in the etiology of the SFSS is being pushed into the background because of the importance which the portal pressure and hyperperfusion have acquired. Several groups have described the successful use of small grafts (GWRW <0,6%),19 with patients in whom the portal pressure is intraoperative controlled and modulated.20-25 This strategies are based in the SFFS concept1. 

Likewise, the new chemotherapeuticals have changed the paradigm of the treatment of the liver metastasis so that the number of lesions, their condition of bilobarity and even their size, has been pushed into a second plane. Nowadays, the inability to get a remnant liver parenchyma greater than 30% of the initial total is considered to be a limiting factor of resectability.26-29 The development of techniques such as a two-stage hepatectomy, preoperative portal embolization, associating liver partition and portal vein ligation for staged hepatectomy (ALPPS)30 and the so called extreme liver surgery, manages to increase the number of patients with resectable liver lesions.31,32 Nevertheless, the increase of the resected liver volume sometimes makes it cross the safety threshold of 30%. As an aggravating factor, many of these patients undergo several cycles of preoperative chemotherapy and thus they tolerate worse the major liver resections.

During the last year, the communications of experiences of liver transection with portal ligature to accelerate the liver regeneration with early reoperation to complete the resection (ALPPS)30, have proliferated.33-35 Few works describing the liver hemodynamic changes in patients undergoing these �new� hyperextended resection techniques have been found in literature30.

The incidence of post-hepatectomy hepatic insufficiency (PHHI) puts the patients life at risk and is between 0,7 and 9,1%. The occurrence of hyperbilirubinemia, untreatable ascites and coagulopathy, usually end up with the appearance of systemic infection and the death of the patient.36,37

From a histological point of view, in both the SFFS, SFSS and the PHHI, similar changes in the structure of the hepatic lobe were described.3 Chronologically, first the occurrence of a sinusoidal dilatation is followed by a periportal hemorrhage with arterial vasospasm, and finally, the development of ischemic cholangitis.2

Currently, most groups agree that the pathophysiology of the PHHI, SFFS and SFSS,3  are similar, the portal hyperperfusiom and the decrease in the arterial flow being the cause of histological damage. The last two trigger the occurrence of the syndrome.2,8 In the case of liver trasplantation it is necessary to bear in mind the role played by the ischemia-reperfusion and its possible boost effect over the damage that causes the portal hyperperfusiom and the arterial vasoconstriction.

Many groups have agreed to unify both situations in the term SFSS, as they share etiology, pathophysiology, clinical and histological findings.2,3,38,39 The difference between the hepatic mass and the portal flow conform the main axis of damages that trigger the occurrence of the SFSS.1,4-8,23,24

In 2011 our team began the study of the SFSS on a large animal model for experimentation, considering that both situations are similar from the pathophysiological point of view. Therefore, from now onwards the term SFSS will be used in this work to refer both to the PHHI and the SFSS. We coined the SFFS concept as a more useful tool for diagnosing and treating the syndrome.1

The aim of this study is to analyze if the early histological and hemodynamic changes known in the SFFS would reproduce in a swine model of hyperextended hepatectomy. In our preliminary experience we developed this swine model of massive hepatectomy in which we sequentially performed the resection until we reached 80% of the resected liver parenchyma.

Materials and Methods
This acute experimental prospective study was held at the Experimental Surgery laboratory in the Gregorio Mara��n University General Hospital in Madrid, Spain. The working team is made up of surgeons and anesthesiologists of the Liver Transplant Unit as well as a pathologist with a vast dedication to hepatic surgery and transplant. Research Commission and the Ethics Committee of Animal Experimentation of our centre approved the study.

In order to characterize the early changes taking place in the SFFS, we studied 13 Minipig with an average weight of 39,15 kg. (22-50 kg.). A J-shaped incision to access the abdominal cavity was performed under general anesthesia induced by Fentanyl and Propofol. For the hemodynamic study, a Swanz-Ganz catheter in the suprahepatic vein and a pressure catheter in the portal vein were placed in order to measure the portal pressure (PP), the pressure in the suprahepatic vein (SHP), and to calculate the portosystemic pressure gradient. Jugular vein was dissected with open technique and a double-lumen catheter was inserted to liquids infusion.

A study of the artery pressure and the cardiac frequency was performed in the femoral artery with a PICCO( monitor (Pulsion Medical Systems AG, Munich, Germany). The measurement of the portal and the hepatic artery flow was carried out with a flowmeter (Transonic System Inc. Flow Meter T106, Ithaca, NY). Once the animal was monitored, sequential segmentectomies were performed in order from left to right until the completion of 80% of the liver parenchyma. (Figure 1) The data collection began after the anesthetic induction by the measurement of the base values of the suprahepatic pressure, the portal pressure, the portal flow (PF), the arterial flow (AF) and the systolic and diastolic arterial pressure (SAP and DAP).

The total hepatic flow was calculated by adding the arterial and the portal flow. To calculate the arterial and portal flow corrected by weight, the remnant weight after each resection was divided by 100 and was multiplied by the portal or arterial weight after each resection. The calculation of the percentage of the total hepatic flow (THF) that means the arterial or the portal flow, was obtained by the division of the arterial or portal flow after each segmentectomy by the THF after each resection, and multiplied by 100.

After obtaining the database, resection of the left lateral lobe (LLL), then the left medial lobe (LML), the right medial lobe (RML) and the right lateral lobe (RLL) were performed. After each segmentectomy, the hemodynamic data collection and the gathering of biopsies of the remnant parenchyma was performed 5 minutes after each resection. Each resected segment was weighed and after completion of the last taken resection and hemodynamic data, we proceeded to the sacrifice of the animal and the extraction of the remnant liver for weighing.

The Masson trichromic and the eosin hematoxylin techniques were used for the histological study.

The data were analyzed with the SSPS Statistical Program, 20 version for Mac. It was found that the variables analyzed were following a normal distribution using the Kolmogorov Smirnov test. The means of the hemodynamic variables of the base values were compared to the values at the end of the surgery using the Student�s t test for paired data.

Results

Of the 13 animals included in the study, 2 died at the beginning of the surgery because of anesthetic complications, 1 after the LML resection, and 2 died after the RML resection due to bleeding problems and gaseous embolism. The mean proportion of the remnant parenchyma after each resection was: LLL 79,2%; LML 60,93%; RML 35,8% and RLL 20,20% (Figure 2).

The hemodynamic results are represented as means and standard deviation in Table 1. At the end of the resection there is a loss of blood volume that conditions a non-significant decrease of the SAP and an increase of the cardiac frequency (CF) without variation of the central venous pressure (CVP).

At hepatic level, an increase of the PP associated with a decrease of the PF is produced. However, when studying the portal flow with regard to the weight of the remnant parenchyma it is noticed how, as the segmentectomies progress, an increase of the portal flow associated with the weight of the remnant parenchyma is produced. The relative portal flow undergoes an increase of 316%, passing from a base flow of 120 ml/min/100 gr to 379 ml/min/100 gr (p =0,004) after the last resection (Figure 3).

When analyzing the THF percentage provided by the PF it is seen how an increase from 83% to 91% (p =0,015) is produced. The arterial flow decreases progressively and more abruptly after the last resections. When studying its relation to the weight of the remnant liver it is seen that it keeps constant throughout the segmentectomies with a slight increase at the end . However, the percentage of the total hepatic flow provided by the arterial flow decreases from the base 16,9% to 8,9%  (p =0,015) at the end of the surgery.

The portal pressure increases proportionally to the reduction of the hepatic mass parallel to the increase in the gradient of portosystemic pressure, reflection of the portal hyperperfusion, which a reduced mass of sinusoids. In the tissue samples analyzed evolution is evident from interstitial edema, sinusoidal dilatation and hemorrhage are accentuated throughout surgery (Figure 4).

Discussion
This model of hyperextended liver resection in animals is reproducible and the data that can be obtained are clinically relevant. The aim of this study is to reproduce the early damages of the Small for Flow Syndrome.1 On the other hand, because it is an acute model, the clinical and analytical changes in the syndrome must be further studied with a survival model. After the resection of 80% of the liver parenchyma the hemodynamic changes to which the remnant is submitted and their histological reflex can certainly be studied with our model.39

In the clinical practice it is considered that a liver lesion is resectable when it is possible to preserve 25%-30% of healthy liver parenchyma, 30% if there is steatosis and more than 40% if it underwent several chemotherapy cycles.26-28,36,37 The knowledge of SFFS pathophysiology derived from our study is relevant, since intervening or modifying the mentioned portal hiperperfusion, there could be an increase of the number of patients whose lesions are considered liable of being resected.1,19

The modulation of the portal pressure allows the use of smaller grafts,19,23-25 which could result in an increase of the number of available grafts by dividing the organs for two adults. Besides, it permits the use of the left lobe for the transplant of a living donor, diminishing the risk that such donor is submitted to. 21,22

There are several experimental works in literature that relate the development of SSFS to a portal hyperperfusion. Most of these works are studies performed in experimental models of liver transplants.7,8 All the animals in our study show a portal flow with little variability until the end of the surgery, where it decreases significantly as a result of the increase of the resistance to the flow that is produced by decreasing the remnant sinusoidal mass. Nevertheless, when analyzing the portal flow as regards with the weight of the remnant liver, it is observed a marked increase of it until becoming more than threefold of the initial value. The increase of the portal flow regarding the available hepatic sinusoidal mass is responsible of the alterations in the hepatic microcirculation, determining an increase of the portosystemic pressure gradient with an almost immediate histological reflex.2,7,8,38,39 Thus in the biopsies taken five minutes after each resection it is seen a progressive increase of the interstitial edema and the sinusoidal dilatation, finally a perisinusoidal and periportal hemorrhage being produced. The reversible or irreversible character of these lesions should be studied with survival models and modulation of the flow and portal pressures.

The progressive decrease of the arterial flow and its decrease in the provision to the THF is well described in literature and it could be a consequence of the hepatic arterioportal buffer response, according to which by increasing the portal flow adenosin is washed in the Mall space producing a strong arterial vasoconstriction.40,41 These changes in the arterial flow can be responsible for the late ischemic cholangitis that makes up the SFFS,2 although in order to investigate this aspect, a study with animal survival should be performed, as it comprises part of the late findings of the SFFS.

The knowledge of pathophysiology of the SFFS is important in order to design the effective strategies to prevent its development.1 The perioperative portal modulation4-7,23 is relevant and must be studied with similar models with longer survival, in which hemodynamic, histological, biochemical and clinical changes are described. Prevention of the SFFS should be a perioperative strategy, from the selection of the anesthetics,42,43 to the intraoperative modulation of the portal flow with surgical maneuvers4,8 and drugs  described in literature.1, 44

Currently we are running a prospective study with survival where we analyze several ways to prevent the development of SFFS by modulating portal flow.


Conclusions

The experimental model of hyperextended hepatectomy reproduces the pathophysiologic mechanisms of the SFFS: an increase of portal flow/remnant liver ratio, a decrease of the arterial flow, and the typical hystopathological changes. 

As this changes develops very early after hepatectomy, prevention of SFFS should be a perioperative strategy.

Finally to modulate the portal hyperperfusion and hypertension we propose the systematic measurement of the portal flow and pressure as well as the arterial flow in those patients that require an extended liver resection.


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Table 1 and Figures:


Table1. Comparison of hemodynamics findings at baseline and after the final resection. 


Fig 1. Reconstruction of the sequential segmentectomies during the procedure. LLL left lateral lobe, LML left median lobe, RML right median lobe, RLL right lateral lobe.

Fig 2. Percentage of liver remnant after each resection.

Fig 3. Portal flow/100g evolution during the procedure.

Fig 4.  Histological findings analysed with hematoxilin eosin. Choppy arrow indicates the sinusoidal dilation. Black arrows indicate the interstitial hemorrhage. 

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