It is common knowledge that severe blood loss and traumatic injury can lead to a cascade of detrimental signaling events often resulting in mortality. 1,2,3,4,5 These signaling events can also lead to sepsis and/or multiple organ dysfunction (MOD). 6,7,8,9 It is critical then to investigate the causes of suppressed immune function and detrimental signaling cascades in order to develop more effective ways to help patients who suffer from traumatic injuries. 10 This fixed pressure Hemorrhagic Shock (HS) procedure, although technically challenging, is an excellent resource for investigation of these pathophysiologic conditions. 11,12,13 Advances in the assessment of biological systems, i.e. Systems Biology have enabled the scientific community to further understand complex physiologic networks and cellular communication patterns. 14 HemorrhagicShock has proven to be a vital tool for unveiling these cellular communication patterns as they relate to immune function. 15,16,17,18 This procedure can be mastered! This procedure can also be used as either a fixed volume or fixed pressure approach. We adapted this technique in the murine model to enhance research in innate and adaptive immune function. 19,20,21 Due to their small size HS in mice presents unique challenges. However due to the many available mouse strains, this species represents an unparalleled resource for the study of the biologic responses. The HS model is an important model for studying cellular communication patterns and the responses of systems such as hormonal and inflammatory mediator systems, and danger signals, i.e. DAMP and PAMP upregulation as it elicits distinct responses that differ from other forms of shock. 22,23,24,25 The development of transgenic murine strains and the induction of biologic agents to inhibit specific signaling have presented valuable opportunities to further elucidate our understanding of the up and down regulation of signal transduction after severe blood loss, i.e. HS and trauma 26,27,28,29,30 .There are numerous resuscitation methods (R) in association with HS and trauma. 31,32,33,34 A fixed volume resuscitation method of solely lactated ringer solution (LR), equal to three times the shed blood volume, is used in this model to study endogenous mechanisms such as remote organ injury and systemic inflammation. 35,36,38 This method of resuscitation is proven to be effective in evaluating the effects of HS and trauma 38,39 .

Traumatic injury is a significant cause of morbidity and mortality worldwide. Microcirculatory activation and injury from hemorrhage contributes to organ injury. Many adaptive responses occur within the microcirculatory beds to limit injury including up regulation of heme oxygenase (HO) enzymes, the rate limiting enzymes in the breakdown of heme to carbon monoxide (CO), iron, and biliverdin. Here we tested the hypothesis that CO abrogates trauma induced injury and inflammation protecting the microcirculatory beds. Methods. C57Bl/6 mice underwent sham operation or hemorrhagic shock to a mean arterial pressure of 25mmHg for 120 minutes. Mice were resuscitated with Lactated Ringer’s at 2X the volume of maximal shed blood. Mice were randomized to receive CO-releasing molecule (CO-RM) or inactive CO-RM at resuscitation. A cohort of mice was pretreated with tin protoporphyrin-IX (SnPP) to inhibit endogenous CO generation by heme oxygenases (HO). Primary mouse liver sinusoidal endothelial cells were cultured for in vitro experiments. Results. CO-RM protected against hemorrhagic shock/resuscitation (HS/R) organ injury and systemic inflammation and reduced hepatic sinusoidal endothelial injury. Inhibition of HO activity with SnPP exacerbated liver hepatic sinusoidal injury. HS/R in vivo or cytokine stimulation in vitro resulted in increased endothelial expression of adhesion molecules that was associated with decreased leukocyte adhesion in vivo and in vitro. Conclusions. HS/R is associated with endothelial injury. HO enzymes and CO are involved in part in diminishing this injury and may prove useful as a therapeutic adjunct that can be harnessed to protect against endothelial activation and damage.

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Objective The cellular injury that occurs in the setting of hemorrhagic shock and resuscitation (HS/R) affects all tissue types and can drive altered inflammatory responses. Resuscitative adjuncts hold the promise of decreasing such injury. Here we test the hypothesis that sodium nitrite (NaNO2), delivered as a nebulized solution via an inhalational route, protects against injury and inflammation from HS/R. Methods Mice underwent HS/R to a mean arterial pressure (MAP) of 20 or 25 mmHg. Mice were resuscitated with Lactated Ringers after 90–120 minutes of hypotension. Mice were randomized to receive nebulized NaNO2 via a flow through chamber (30mg in 5mL PBS). Pigs (30–35 kg) were anesthetized and bled to a MAP of 30–40 mmHg for 90 minutes, randomized to receive NaNO2 (11 mg in 2.5 mL PBS) nebulized into the ventilator circuit starting 60 minutes into the hypotensive period, followed by initial resuscitation with Hextend. Pigs had ongoing resuscitation and support for up to four hours. Hemodynamic data were collected continuously. Results NaNO2 limited organ injury and inflammation in murine hemorrhagic shock. A nitrate/nitrite depleted diet exacerbated organ injury, as well as mortality, and inhaled NaNO2 significantly reversed this effect. Furthermore, NaNO2 limited mitochondrial oxidant injury. In porcine HS/R, NaNO2 had no significant influence on shock induced hemodynamics. NaNO2 limited hypoxia/reoxia or HS/R-induced mitochondrial injury and promoted mitochondrial fusion. Conclusion NaNO2 may be a useful adjunct to shock resuscitation based on its limitation of mitochondrial injury.

This paper describes the equipment and techniques that were used for a high-pressure, high-temperature (HPHT) cleanout operation carried out on the Shearwater platform in the UK central North Sea with the support of a jackup drilling unit. The project involved intervention in three wells over a period of 9 months. The wells had been shut in for some time following production of reservoir solids. A hydraulic workover unit (HWU) was selected to clean out the production tubing to allow isolation barriers to be installed. In rig-assist mode, the HWU deploys pipe against surface pressure with the rig providing pipe-handling support. The paper details the planning and pre-engineering work that preceded offshore operations. Detailed planning and risk assessment were also required during operations because well conditions changed. Some equipment problems required a review of planned operations, and during an annual process plant shutdown, onshore tests were carried out before mobilization for the second phase of the intervention project. Modifications were required to the HWU to withstand the high buckling loads associated with snubbing against high pressure. Additionally, special downhole tooling was required to accommodate extreme well conditions. The paper discusses the development work involved and the subsequent performance of the equipment. Operating performance statistics and key lessons learned during the project are presented. Introduction The Shearwater field is located in the central North Sea in Block 22/30b, approximately 138 miles east of Aberdeen (Fig. 1). The field was discovered in 1988 and developed with dual platform facilities. The development consisted of a process, utilities, and quarters (PUQ) platform linked to a wellhead platform (WHP) by an 80-m (262-ft) bridge (Fig. 2). The platforms are installed in 90 m (297 ft) of water.