Trial Information

The Influence of Two Different Hepatectomy Methods on Transection Speed and Chemokine Release From the Liver

Many different techniques of parenchymal transection are used in hepatic surgery. In a
systematic review, there were no significant differences in morbidity (including bile leak),
mortality, routine markers of liver parenchymal injury or dysfunction and length of hospital
stay irrespective of the method used for parenchymal transection. This Cochrane review
analyzed studies comparing the following transection devices: CUSA (cavitron ultrasound
surgical aspirator) versus clamp-crush (two trials); radiofrequency dissecting sealer versus
clamp-crush (two trials); sharp dissection versus clamp-crush technique (one trial); and
hydrojet versus CUSA (one trial). The clamp-crush technique appeared to have the lowest
blood loss and lowest transfusion requirements compared to the other techniques.

However, even in specialized centers morbidity and mortality rates of hepatic resections are
still in the range of 45% and 3% respectively and uncertainty persists regarding the optimal
technique of transection. Local experience seems to be the most important factor for the
choice of the transection method. An innovative technique is stapler hepatectomy using
Covidien Endo-Gia™ Ultra Handle Short Staplers and Endo Gia™ TRI staple 60mm or 45 mm
AVM/AMT loading units (Covidien). A randomized controlled trial (CRUNSH trial) to evaluate
the intraoperative blood loss of stapler hepatectomy compared to the clamp-crushing
technique is currently under way.

The CUSA technique is well established in many centers including ours with excellent
morbidity and mortality rates. However, it has been shown that CUSA has a longer transection
speed than the clamp-crush technique (with vascular occlusion). The investigators of the
CRUNSH trial hypothesize that stapler hepatectomy technique might also be comparable or more
favorable to clamp-crushing regarding transection time with the advantage of avoiding
vascular occlusion. Therefore stapler hepatectomy should also be faster than CUSA.

It has been shown that the release of cytokines, chemokines, and stress hormones correlates
with postoperative infection and organ dysfunction. Chemokines are critically involved in
the process of leukocyte recruitment and activation in the liver. Major surgery causes
inflammation reflected in the production of pro-inflammatory cytokines. In various studies
IL-6, for instance, was a valid predictor for post-operative sepsis, complications or
mortality. Besides, the levels of these cytokines are expected to correlate with the degree
of surgical trauma. Therefore differences in cytokine levels between the two study groups
will be assessed, including pro- (INF-γ, IL-1β, IL-5, IL-6, IL12p70, TNFα) and
anti-inflammatory (IL-4, IL-10, IL-13) cytokines.

Monocyte chemotactic protein-1 (MCP-1) production is elevated in Kupffer cells following
ischemia / reperfusion in response to free radicals and neutrophil elastase, as well as in
animal oxidative liver injury models (e.g. carbon tetrachloride) Macrophage inflammatory
protein-3-alpha (MIP3-alpha) is constitutively expressed in the liver. It is strongly
chemotactic for cytokine-stimulated neutrophils, immature dendritic cells and
memory/effector T and B lymphocytes by utilizing chemokine receptor (CCR) 6.

sCD163 (soluble haemoglobin scavenger receptor) is a novel marker of activated macrophages,
like neopterin it can be determined in serum or plasma.

The effect of the transection speed in respect to chemokine release has never been
investigated. The investigators hypothesize that a shorter transection time leads to a
reduced release of these molecules potentially resulting in improved postoperative outcome.

Additionally the interaction between adaptive and innate immunity plays a significant role
in liver ischemia-reperfusion (I/R) injury. Notably, activation of T cells in the absence of
TCR ligation seems to be a predominant factor in the initial phase of I/R injury. Therefore
as a pilot study, peripheral T cell subsets (including naïve T cells, effector and central
memory T cells, regulatory T cells, early activated T cells) will be determined by flow
cytometry in a subgroup of study patients (i.e. patients undergoing hepatic resection for
other than oncological reasons).

The supposedly slower technique of CUSA resection shall therefore be compared with the novel
technique of stapler hepatectomy.