Referee 1's review (Juan Puyana):

Remarks for the authors
This is an elegant manuscript, well written and with a compelling story about the role of heart apoptosis as a possible explanation for HCC and a probable therapeutic intervention (IL-6) for it.
I recommend that the paper be accepted for publication but I believe the authors must deal with the issues explained below. They may choose to address some of these issues in the discussion and to provide detailed information about the resuscitation schemes used as described below.
My comments will focus mainly on the concepts of definition of HCC and the occurrence of the phenomenon of apoptosis in relation to resuscitation

1. The definition of HCC is difficult to find in the manuscript, it is given as a footnote on table one. HCC is a complex phenomenon that has NOT been uniformly reproduced by investigators working on this field. Each publication may come up with a different version of HCC and different set of circumstances leading to HCC. Therefore the authors need to clearly defined the parameters for HCC in the methods and delineate the physiologic characteristics and the natural course of the phenomenon. In there data HCC only occurs n 33% of the moderate hypotension group and in 67% of the severe hypotension group.
a. What happened to the other animals if they don't go in HCC?
b. How they differ from those who do developed HCC.

2. The authors clearly stated that HCC induced apoptosis ONLY occurs after resuscitation has been instituted, yet they do not specify how resuscitation is done. They refer the reader to two publications (7-8), although one can go search these publications; I believe this is insufficient because the very phenomenon in which the whole paper is centered on is perhaps related to the type of resuscitation rather than HCC. I recommend that a clear description of what the authors call resuscitation be given in the abstract and also be explained in detail in the methods
a. How much volume was given?
b. How long was it given for?
c. What types of crystaloides were used?
d. Was any more blood returned as part of the resuscitation scheme?

In fact this point is critical to discern whether the HCC induced apoptosis is not a function of the fluids used for resuscitation. It has been known for a while that lactated ringers may induce apoptosis in the liver (J Trauma. 2002 May;52(5):872-8) therefore this possibility needs to be addressed.
These same authors reporting on the effect of lactated Ringer and apoptosis have shown that apoptosis can be attenuated by changing the racemic forms of lactated ringers and most of the apoptosis appears to be related to the clinically used D Lactated isomer. (J Am Coll Surg. 2006 Jan;202(1):25-35. Epub 2005 Nov 10)

Have they used different resuscitation fluids to see if apoptosis in the heart is also attenuated or enhanced by the resuscitation fluids?

Finally and perhaps more on the philosophical realm, the authors should address the fact that HCC induced apoptosis does not occur at all in the unresuscitated group of animals, yet these animals were submitted to 50% shed blood return. One may argue that providing 50% of the blood back may be considered as a partial resuscitation although I realized that this blood is given in the setting of persistent hypotension so the question is what happens if IL6 is given at the end of this period before the conventional crystalloid fluid volume is given. On the other hand if we were to use other fluids "less" capable of inducing apoptosis would
IL-6 still has any therapeutic effect?

In the clinical world the very idea of returning shed blood is not existent; (in other words the Wiggers model is far from the clinical reality). It will be interesting to see if HCC apoptosis can be reproduced in uncontrolled hemorrhage model. Patients are immediately resuscitated as soon as they receive prehospital care on the field. Most recent data for Iraq suggest using minimal amounts of crystalloids and to provide whole blood or blood and FFP in a one to one ratio at the earliest possible time to prevent coagulopathy if so a large animal model of a more clinically relevant model of hemorrhage will need to be developed to best identify the time and sequence for IL-6 interventions with the purpose of protecting the heart from HCC.

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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.