Massive pulmonary embolism, sepsis, and ALI are the other main causes of acute pulmonary arterial hypertension (PAH) in the adult patient population.Preexisting pulmonary vascular and lung diseases, including Interstitial lung disease, chronic obstructive pulmonary disease and obstructive sleep apnea are other leading causes of chronic PAH.Whatever the cause, the management of critically ill patients with hemodynamically significant pulmonary hypertension remains challenging, especially in the field, away from equipped ICU and tertiary medical centers.We developed an innovative therapeutic approach by stimulation vagal nerve (VNS) which can be used in modulation vascular tone.Our study aims was focused to treat acute and chronic PAH in different animal model using VNS approach.A rodent model with PAH induced by hypoxia (FiO2 10%) for 3 weeks only (mild form of PAH) or hypoxia and Sugen together (Chronic form of PAH), were used.Continuous monitoring of the vital signs: Heart rate, EKG, oxygen saturation, breathing rate and both right ventricular pressure (RVP) and systemic pressure; were recorded using a computerized hemodynamic recording system.Continuous monitoring/stimulation of vagal nerve activity was established using a stimulation module controlled by the Acknowledge software (Biopac Systems).Stimulation was delivered using different matching stimulation parameters (current intensity Amplitude, pulse width htz, pulsing frequency, and pulsing duration).Our data showed that by using specific electric stimulation with specific parameters, we were able to target specific nerve fiber which can induce smooth muscle relaxation of the pulmonary vascular bed, followed a subsequent drop of RVP.Analysis of the data using beat to beat analysis showed that specific target for certain vagal nerve fibers can induce relaxation of contracted pulmonary vascular tree and significant drop of RVP, without any significant or marked change in systemic pressure, heart rate or breathing pattern (no apnea).Similar data was obtained using different murine animal models with wide range of PH severity and with variable degree of pulmonary vascular remodeling induced by Hypoxia and Sugen.We did also able to define a specific pattern of VNS (with a safe margin), which can trigger the vascular smooth muscle relaxation with none or minimal systemic or unwanted side effects (including hypotension, apnea and bradycardia).In conclusion, VNS is an innovative therapeutic modality which can be used in alleviating pulmonary pressure in animal model with variable degree and severity of PAH.Pre-clinical experiment on large animal model is warranted Neuromodulation as a New Strategy in Management of Pulmonary Hypertension

Background: Most clinical trials of sepsis treatment modalities fail at their primary objective of establishing superiority over placebo when added to background standard of care.While there is no definitive explanation for the high failure rate, it might be stated that our attempts to insert a new therapeutic agent into standard of care encounters severe problems with definition of exactly what stage is ongoing, and what are the criteria for progression or resolution from that time point onwards.Clearly there is need for a means of defining steps in the septic process that would apply to individuals, and to better define the course of sepsis in each patient after they are enrolled in a trial.Methods: For core model development, 30 septic patients were studied for time-related progression in relation to biomarkers, employing a Load Model in a neural net algorithm in MatLab.Causative bacterial infections were linked to primary infection sites.In order to minimize overparameterization, the model was allowed to estimate outputs using the best three input parameters.Bacterial load was tracked from origin using clinical and microbiologic data to provide an estimate at the start of sepsis.The bacterial load as well as clinical and laboratory parameters were model inputs with the output parameter being organ failures and/ or mortality.Results: At onset of sepsis, human bacterial load estimates ranged from between 10 8 and 10 11 CFU, which is consistent with inocula in animal models of sepsis.Sepsis proceeds to organ failures and mortality in a series of steps that are initially linked to bacterial load and inflammatory response, followed by coagulopathy, ischemia, oxygen deprivation in organs and tissues, and culminating in organ failures.The later stages of sepsis are all driven by metabolic parameters, and there seems to be little benefit to blocking inflammation at later stages.Substrate and oxygen deficiencies must be addressed first.Conclusion: Neural net progression models based on biomarkers and physiological markers are able to describe the evolution of sepsis to septic shock, organ failures, and provide some evidence that mortality may be a consequence of the stages of sepsis.Overall, these models appear useful to the task of sorting out organ failure endpoints and mechanisms in individual patients with sepsis progression across sepsis to septic shock.

IntroductionIn 2002, the Surviving Sepsis Campaign defi ned a strategy that aimed to reduce the high mortality due to sepsis.One point of this strategy was a recommendation to recognize that sepsis is a frequent cause of death and high economic costs in the pediatric intensive care unit.Knowledge of the disease is the fi rst step to impact it.There are few studies on pediatric sepsis epidemiology in the world and none in Colombia.Hypothesis The epidemiological features of Colombian children are diff erent from other countries.Methods We constructed a website where 14 intensive care units across the country reported in a prospective way the epidemiological features of children with sepsis using an electronic process [1].We asked for sociodemographics, microbiological data, sepsis classifi cation, complications, and outcome. ResultsWe collected 253 patients from March to May 2009.Fifty-fi ve percent of the cases were male and 45% were female; 53% were less than 1 year old.A total of 67.2% came from urban areas and 33% came from rural villages.Eighty-fi ve percent were very poor (score 1 and 2 over 6 used in Colombia as socioeconomic classifi cation).Forty-fi ve percent have governmentsupported insurance.In total, 23.72% of the population presented with sepsis; 30.04% with severe sepsis; and 46.5% with septic shock.The infection origin was respiratory in 54.55%, followed by abdominal in 17.39%.In 50.2% no cause was identifi ed.A total of 75.1% required mechanical ventilation.The mortality rate was 20.4%.Conclusions Sepsis, severe sepsis, or septic shock is a common diagnosis in Colombian intensive care units.The majority of pediatric patients are 2 years or younger and from the poorest communities.It aff ected males more.In the majority, the process starts in the respiratory system.We had diffi culty identifying the cause.The disease causes high mortality and cost for a developing society.We need a complete survey to fi nd a correct approach to the problem.Reference 1. Sepsis en Columbia [www.sepsisencolombia.com]P2 Randomized controlled trials are not designed to prove the safety of third-generation hydroxyethyl starch for resuscitation: results from a systematic review CS Hartog, M Kohl, K Reinhart

Macrophage cytokine production is inhibited by cholinergic signals transmitted via the vagus nerve, an α7 nicotinic acetylcholine receptor (α7nAChR) dependent pathway termed the “cholinergic anti‐inflammatory pathway” (Nature 420:853–9, 2002). Here we addressed the hypothesis that this pathway is capable of providing short‐term memory by downregulating macrophage responses to endotoxin for up to 48 hr. Vagus nerve stimulation (VNS) (5V, 2 ms, 1Hz, 2.5 min) in rats 24 h prior to endotoxin (LPS) significantly reduced serum TNF (sham =767 pg/ml; VNS =358 pg/ml, p<0.01); this effect persisted for 48 h (sham TNF = 1327; VNS TNF = 824, p<0.05). The molecular mechanism is attributable to α7nAChR signaling, because VNS fails to reduce TNF levels in α7nAChR KO mice. This molecular memory is recapitulated in cultured human macrophages pulsed with acetylcholine (ACh) (60 min pulse 24 h prior to LPS). LPS‐induced TNF release was reduced 54% as compared with vehicle controls (p<0.05); pulsing also significantly suppressed activation of NF‐κB (74%). Ach‐pulsing significantly altered the macrophage transcriptome response to endotoxin, indicating that vagus nerve signals “train” macrophages as a short‐term (48 hr) memory response. Evidence that discrete neural signals can mediate short‐term memory in macrophages via α7nAChR has surprising implications for understanding innate immunity. Supported in part by NIGMS.