Sepsis-induced organ failure is associated with high morbidity and mortality rates. The onset of an exaggerated host response to microbial invasion and/or trauma, is believed to be the primary cause of excessive inflammation and the subsequent tissue hypoperfusion observed in patients with severe sepsis. In our mouse model of sepsis induced by cecal ligation and perforation (CLP), symptoms indicative of the disease, including diarrhea, increased ventilation and persistent hypothermia, are present at six hours after the surgery (T6). In the untreated CLP mice, mortality occurs starting at T15. As induced hypothermia has shown to exert immunomodulatory effects, this study is aimed at assessing its potential in attenuating inflammation and improving survival in experimental sepsis. Our data has shown that deep hypothermia initiated at T6, by means of cold chamber-induced cooling, prolongs survival. Plasma cytokine quantification by enzyme-linked immunosorbent assays (ELISA) also reveals that induced deep hypothermia reduces tumour necrosis factor(TNF)-α and interleukin (IL)-6 production in untreated CLP mice. In contrast, induced moderate hypothermia does not have such effect. Antibiotic (cefotaxime) and saline resuscitation initiated immediately following CLP ensures survival. However, when these supportive treatments are initiated at T6, >50% mortality is observed in the CLP mice with or without induced hypothermia. In summary, this preliminary study provides proof for a downregulated inflammatory response mediated by external cooling. However, to achieve a survival benefit, treatment strategies in addition to cooling and antibiotics may be required.

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Žmogaus organizmas yra linkęs aklimuotis ir prie besikartojančių šilumos ir prie besikartojančių šalčio stimulų (Michael, 2001). Tai sukelia skirtingus fiziologinius atsakus organizme. Žmogaus organizmas aklimuodamasis šilumai siekia sušvelninti šilumos sukeltą fiziologinį stresą, ir pagerinti šiluminį komfortą bei treniravimosi galimybes. Aklimacija yra sukeliama pakartotinių šilumos stimulų, kurie sukelia pakankamą stresą, galintį pakelti odos ir vidines temperatūras, padidinti prakaitavimą. Dažniausiai aklimacija kasdien pasikartojantiems šilumos stimulams atsiranda per pirmas 4 dienas ir galutinai susiformuoja per 3 savaites. Šilumos aklimacijos sukelti požymiai – žemesnė vidinė temperatūra, padidėjęs prakaitavimas ir odos kraujotaka, sumažėjusi metabolinė medžiagų apykaita, sumažėjęs širdies ir kraujagyslių sistemai sukeliamas krūvis, pagerėjęs skysčių balansas ir padidėjusi šiluminė tolerancija (Michael ir kt., 2001). Šiais laikais profesinė ir rekreacinė veikla šaltomis oro sąlygomis yra gana dažna. Šalčio poveikis sukelia termoreguliacijos atsakus, kurie pasireiškia elgesiu arba fiziologiniais pokyčiais, kad išlaikytų šiluminę pusiausvyrą- padidėjusia metabolinė šilumos gamyba drebant arba vazokonstrikcija- sumažėjusiu šilumos atidavimu. Šie fiziologiniai atsakai priklauso nuo asmens individualių savybių- amžiaus, kūno sudėjimo, bendro prisitaikymo šalčiui. Stiprus šalčio stimulas gali sukelti medicinines traumas ar net mirtį (Launay, 2009). Aklimacija šalčiui yra... [toliau žr. visą tekstą] / Human body tends to acclimate to repeated heat or cold stimulus (Michael, 2001). This leads to different physiological responses in the body. During acclimation to heat the body seeks to soften heat-induced physiological stress, to improve thermal comfort and increase training opportunities. Acclimation is induced by repeated heat stimuli that cause sufficient stress, that can raise skin and core temperature, increase sweating. Usually the acclimation to daily repeated heat stimuli occurs within the first 4 days and finally forms during 3 weeks. Heat acclimation causes symptoms such as lower core temperature, increased sweating and skin blood circulation, decreased metabolism, decreased stress for cardiovascular system, improved fluid balance and increased thermal tolerance (Michael et al., 2001). Nowadays, professional and recreational activities in cold weather conditions are quite common. Cold exposures cause thermoregulatory responses that affects behaviour or physiological changes to maintain thermal balance- increased metabolic heat production while shivering, or vasoconstriction- reduced heating. These physiological responses depend on the person’s individual characteristics- age, body composition and general adaptation to cold. A strong cold stimulus can cause medical injuries or even death (Launey, 2009). Acclimation to cold is classified into several categories- metabolic, insulation, hypothermic and intermediate versions (Bittel, 1992). Acclimation to cold may... [to full text]

Sepsis-induced organ failure is associated with high morbidity and mortality rates. The onset of an exaggerated host response to microbial invasion and/or trauma, is believed to be the primary cause of excessive inflammation and the subsequent tissue hypoperfusion observed in patients with severe sepsis. In our mouse model of sepsis induced by cecal ligation and perforation (CLP), symptoms indicative of the disease, including diarrhea, increased ventilation and persistent hypothermia, are present at six hours after the surgery (T6). In the untreated CLP mice, mortality occurs starting at T15. As induced hypothermia has shown to exert immunomodulatory effects, this study is aimed at assessing its potential in attenuating inflammation and improving survival in experimental sepsis. Our data has shown that deep hypothermia initiated at T6, by means of cold chamber-induced cooling, prolongs survival. Plasma cytokine quantification by enzyme-linked immunosorbent assays (ELISA) also reveals that induced deep hypothermia reduces tumour necrosis factor(TNF)-α and interleukin (IL)-6 production in untreated CLP mice. In contrast, induced moderate hypothermia does not have such effect. Antibiotic (cefotaxime) and saline resuscitation initiated immediately following CLP ensures survival. However, when these supportive treatments are initiated at T6, >50% mortality is observed in the CLP mice with or without induced hypothermia. In summary, this preliminary study provides proof for a downregulated inflammatory response mediated by external cooling. However, to achieve a survival benefit, treatment strategies in addition to cooling and antibiotics may be required.

Os resultados sobre o tempo adequado da exclusão vascular total do fígado(EVTF) para a realização de hepatectomias continuam sendo discutidos. Dados favoráveis têm sido descritos, quando se associa a EVTF com a perfusão de solução hipotérmica, porém a comparação entre estas técnicas ainda não foi descrita. Este estudo tem como objetivo comparar os resultados da ressecção hepática com EVTF, realizada sob hipotermia(solução de preservação hipotérmica in situ), com aqueles obtidos quando se realiza esta ressecção com EVTF com tempo de isquemia menor que 60 minutos, e naqueles com tempo de isquemia maior ou igual a 60 minutos. Para tanto, foram analisados, como parâmetros, a função renal e hepática, morbidade, e mortalidade pós-operatórias nos três grupos mencionados,buscando-se determinar valores preditivos para indicação das técnicas. PACIENTES E MÉTODO. Foram estudados 81 pacientes submetidos à ressecção hepática. Estes pacientes foram divididos em três grupos. Trinta e quatro pacientes com EVTF menor do que 60 minutos (EVTF < 60’), 19 pacientes com EVTF maior ou igual a 60 minutos (EVTF &#8805; 60’), e 28 pacientes nos quais a perfusão hipotérmica in situ (EVTFHIPOT) foi realizada. Os valores das transaminases hepáticas (ASAT e ALAT), Bilirrubinas totais, creatinina, e tempo de protrombina foram registrados. Também foram verificados os índices de morbidade e de mortalidade pós-operatórias nos três grupos. RESULTADOS. O valor máximo no pós-operatório das enzimas hepáticas - ASAT e ALAT foram significativamente menores (p < 0.05) no grupo EVTFHIPOT (535 + 361 U/L e 436 + 427 U/L), quando comparados aos outros grupos - EVTF<60’(988 + 798 U/L; 844 + 733 U/L), EVTF>60’ (1583 + 984 U/L; 1082 + 842 U/L). No grupo EVTFHIPOT, os valores máximos das bilirrubinas (6,5 + 2,5 mg/dl),creatinina (1,2 + 0,7 mg/dl), e o número de complicações por paciente (1,2 + 1) foram semelhantes aos do grupo EVTF<60’’ (5,5 + 7,8; 1,3 + 1; e 0,7 + 1 respectivamente), e significativamente menores que os do grupo EVTF > 60’(12,8 + 11,8; 2,3 + 2,3, e 2,3 + 1,2). A mortalidade hospitalar foi de 1/34, 2/19 e 2/28 nos grupos EVTF < 60’, EVTF > 60’, e EVTFHIPOT, respectivamente,sem diferença estatística. CONCLUSÕES. Quando comparadas as técnicas clássicas de exclusão vascular do fígado,de qualquer duração, com aquela na qual se realizou a perfusão hipotérmica do fígado, conclui-se que, nesta última, os pacientes toleraram melhor a isquemia. Deve-se enfatizar que, na EVTF com hipotermia, existe melhor preservação da função hepática, melhor preservação da função renal, e menores índices de morbidade, quando comparada com a EVTF>60’’ sem hipotermia. Os fatores preditivos de EVTF por mais de 60 minutos auxiliam na adoção da opção pelo resfriamento hepático. / OBJECTIVE. To compare the results of liver resection performed under in situ hypothermic perfusion vs standard total vascular exclusion (TVE) of the liver < 60 minutes and &#8805; 60 minutes in terms of liver tolerance, liver and renal functions, postoperative morbidity and mortality. SUMMARY BACGROUND DATA. The safe duration of TVE is still debated. Promising results have been reported following TVE associated with hypothermic perfusion of the liver with durations of up to several hours. The two techniques have not been compared so far. PATIENTS AND METHODS.The study population includes 81 consecutive liver resections under TVE < 60 minutes (group TVE < 60’ , 34 patients), &#8805; 60 minutes (group TVE &#8805; 60’, 19 patients) and in situ hypothermic perfusion (group TVEHYPOTH , 28 patients). Liver tolerance (peaks of transaminases), liver and kidney function (peak of bilirubin, minimum prothrombin time and peak of creatinine), morbidity and inhospital mortality were compared within the 3 groups. RESULTS. The postoperative peaks of ASAT and ALAT were significantly lower (p < 0.05) in group TVE HYPOTH (535 + 361 U/L and 436 + 427 U/L) compared to the groups TVE<60’ (988 + 798 U/L; 844 + 733 U/L) and TVE&#8805;60’ (1583 + 984 U/L; 1082 + 842 U/L). In the group TVE HYPOTH , the peaks of bilirubin (6,5 + 2,5 mg/dl), creatinine (1,2 + 0,7 mg/dl), and the number of complications per patient (1,2 + 1) were comparable to those of the group TVE<60’ (5,5 + 7,8; 1,3 + 1; e 0,7 + 1 respectively) and significantly lower to those of the group TVE&#8805;60’ (12,8 + 11,8; 2,3 + 2,3, e 2,3 + 1,2). In hospital mortality rates were 1/34, 2/19 and 2/28 for the groups TVE < 60’ , TVE &#8805; 60’ , and TVEHYPOTH respectively and were comparable. On multivariate analysis, the size of the tumor, portal vein embolization and a planned vascular reconstruction werem significantly predictive of TVE &#8805; 60 minutes. CONCLUSIONS. Compared to standard TVE of any duration, hypothermic perfusion of the liver is associated with a better tolerance to ischemia. In addition, compared to TVE &#8805; 60 minutes, it is associated with better postoperative liver and renal functions, and a lower morbidity. Predictive factors for TVE &#8805; 60 minutes may help to indicate hypothermic perfusion of the liver.

Bakgrund: Hypotermi innebär en kärntemperatur under 36 °C och är en vanlig komplikation under perioperativa förloppet. Vid anestesi störs kroppens normala fysiologiska temperatureglering. Hypotermi kan leda till flertalet allvarliga komplikationer som kan orsaka ett lidande för patienten samt en ökad kostnad för samhället. Trots att forskning länge visat att preventiva åtgärder minskar risken för hypotermi kvarstår problemet. Syfte: Syftet är att identifiera preoperativa aktiva värmebevarande metoder och vilken effekt dessa har på att minska risken för perioperativ hypotermi hos den vuxna patienten. Metod: En systematisk litteraturstudie valdes som metod för att besvara syftet. Sökningar genomfördes i CINAHL, PubMed och Web of Science. Totalt 19 kvantitativa artiklar inkluderades och data extraherades genom en extraktionsmall. Resultat: Resultatet är sammanfattat i två huvudkategorier, preoperativa aktiva värmebevarande metoder och effekten av preoperativ aktiv värmning på patientens perioperativa temperatur. Fem olika värmebevarande metoder identifierades. Resultatet visar att preoperativa aktiva värmemetoder har en positiv effekt på att minska uppkomst av hypotermi under det perioperativa förloppet. Slutsats: Perioperativ hypotermi kan förebyggas genom ökad medvetenhet hos vårdpersonal kring problemet och genom aktiva värmebevarande metoder under det perioperativa förloppet. / Background: Hypothermia means a core temperature below 36 ° C and is a common complication during the perioperative process. In the event of anesthesia, the body's normal physiological temperature control is disturbed. Hypothermia can lead to a number of serious complications that can cause a patient suffering and an increased cost for society. Although research has long shown that preventive efforts reduce the risk of hypothermia, the problem persists. Aim: The aim is to identify preoperative active heat-saving methods and the effect they have on reducing the risk of perioperative hypothermia in the adult patient. Method: A systematic literature study was chosen as a method of answering the purpose. Searches were conducted in CINAHL, PubMed and Web of Science. A total of 19 quantitative scientific articles were included and data extracted by an extraction template. Result: The result is summarized in two main categories, preoperative active heat-saving methods and the effect of preoperative active warming at the patient's perioperative temperature. Five different heat-saving methods were identified. The result shows that preoperative active heat methods have a positive effect on reducing the appearance of hypothermia during the perioperative process. Conclusion: Perioperative hypothermia can be prevented through increased awareness of healthcare professionals around the problem and through active heat-saving methods during the perioperative process.

La méthode de préservation d’organes la plus utilisée actuellement en transplantation rénale est la conservation statique en hypothermie. Cependant, ce mode de conservation induit des dommages inhérents aux lésions du syndrome d’ischémie/reperfusion (I/R). Cette étude a eu pour objectif d’identifier de nouvelles conditions de préservation des greffons, afin de limiter les lésions d’I/R, en modulant la température de conservation ou par ajout d’un transporteur d’oxygène. Nous avons utilisé deux modèles : in vitro avec des cellules endothéliales et in vivo en autotransplantation rénale chez le porc.Les résultats ont confirmé les effets délétères de la conservation à 4°C contrairement à des conservations à 19°C, 27°C et surtout 32°C, permettant d’obtenir une activité métabolique, une viabilité et une intégrité cellulaire supérieures ainsi qu’une diminution des marqueurs de l’inflammation et du stress oxydant. Nous avons aussi démontré les bénéfices d'un nouveau transporteur d’oxygène, M101, dans deux des solutions de conservation les plus utilisés, UW et HTK. L'utilisation de M101 en conservation statique permet une meilleure reprise de fonction à court terme et une réduction de la fibrose, cause principale de la perte du greffon. Enfin, nous avons montré une conservation des bénéfices de M101 à des doses réduites et déterminé que cette protection était due à une multifonctionnalité de la molécule, combinant un transporteur d’oxygène, une activité superoxyde dismutase et une taille importante (permettant de réguler la pression oncotique). Ce travail a montré de nouvelles pistes de réflexion vers une préservation, et donc une qualité, supérieure des organes à transplanter. / The most used preservation method in renal transplantation is hypothermic cold storage (CS). However, this method induces damages inherent to the ischemia/ reperfusion (I /R) syndrome.My study was aimed at identifying new grafts preservation conditions, to limit I/R damage, by varying storage temperature or by adding an oxygen carrier.We used two models: in vitro with endothelial cells and in vivo in pig renal autotransplantation. The results confirmed the deleterious effects of 4°C storage in contrast to conservations at 19°C, 27°C and above 32°C, resulting in improved metabolic activity, cellular viability and integrity as well as a significant reduction in markers of inflammation and oxidative stress. Then we demonstrated the benefits of a new oxygen carrier, M101, in the two most used preservation solutions, UW and HTK. Indeed, use of M101 in CS protocols improved short-term function recovery and reduced fibrosis development, main cause of graft loss. Finally, we have shown that the benefits of M101 were preserved at lower doses and we determined that this protection was due to a multifunctionality of the molecule, combining oxygen transport, superoxyde dismutase activity and a large size (regulating oncotic pressure). This work permitted the uncovering of new concepts towards improved organ preservation and quality for transplantation.

Étude expérimentale de l'hypothermie ultra-rapide par ventilation liquide totale au cours de situations critiques d'ischémie-reperfusionL’ischémie-reperfusion est une situation rencontrée de façon pluri-quotidienne en anesthésie-réanimation. Sa prise en charge thérapeutique est limitée au traitement de la pathologie causale et à la suppléance des organes défaillants. Dans ce contexte, l’hypothermie possède des effets cyto- et organo-protecteurs pléiotropes, dont les bénéfices pourraient être pénalisés par des délais d’application trop longs. La ventilation liquide totale (VLT) hypotherme est une approche émergente, permettant de refroidir très rapidement un organisme. Elle consiste à ventiler les poumons avec des perfluorocarbones liquides, permettant d’assurer les échanges gazeux, tout en faisant varier la température de ces perfluorocarbones, et en utilisant le poumon comme bio-échangeur thermique.L’objectif de cette thèse était d’investiguer les effets de la VLT hypotherme au cours de la défaillance multi-viscérale dans des modèles d’ischémie-reperfusion systémique chez le lapin.Dans un premier travail, nous avons étudié un modèle d’ischémie-reperfusion par clampage de 30 minutes de l’aorte abdominale supra-cœliaque, suivi par 5 heures de reperfusion. Les animaux témoins développaient une défaillance multi-viscérale d’expression clinico-biologique sévère. Dans le groupe soumis à la VLT, cette stratégie permettait d’abaisser la température à 33°C en moins de 15 minutes, cible thermique maintenue pendant 75 minutes avant réchauffement. Les défaillances cardio-circulatoires, rénales et hépato-splanchniques étaient atténuées de façon pérenne, avec une protection d’autant plus puissante que la VLT était initiée tôt par rapport au clampage.Dans un second travail, nous nous sommes appuyés sur un modèle d’arrêt cardiaque en rythme non choquable par asphyxie, à l’origine d’une mortalité majeure de cause neurologique, et d’un syndrome post-arrêt cardiaque sévère. La VLT hypotherme offrait une neuro- et cardio-protection puissante, et une réduction du syndrome inflammatoire. L’hyperhémie cérébrale, la production d’espèces réactives de l’oxygène et l’augmentation de la perméabilité de la barrière hémato-encéphalique étaient également significativement réduits.Ces travaux démontrent qu’une hypothermie systémique ultra-rapide par VLT hypotherme atténue les effets délétères multi-viscéraux de l’ischémie-reperfusion. La brièveté de la fenêtre temporelle de protection suggère que la rapidité d’obtention de la cible thermique est un élément clef dans le bénéfice permis par cette approche. / Ultra-fast cooling with total liquid ventilation and ischemia-induced multi-organ failureIschemia and reperfusion injury is a major challenge in anesthesiology and critical care. Resolution of the underlying condition and organ replacement therapies are the cornerstone of the treatment. Hypothermia exhibits a myriad of protective effects, but delays of application may blunt its benefits. Ultra-fast cooling with total liquid ventilation (TLV) is an emerging strategy, which consists in lung ventilation with cold perflurocarbons and uses the lungs as a heat exchanger while maintaining normal gas exchanges. Our objective was to investigate the effects of TLV-induced cooling during multiorgan failure caused by systemic ischemia-reperfusion in rabbits.In a first study, the application of 30 minutes of supraceliac aortic cross-clamping followed by 300 minutes of reperfusion led to severe multiorgan failure in control animals. On the contrary, animals submitted to hypothermic TLV reached the temperature of 33°C within less than 15 minutes. Hypothermia was maintained during 75 minutes before rewarming. This brief period of hypothermic TLV attenuated biochemical and histological markers of multiorgan failure. Cardiovascular and liver dysfunctions were limited by this short period of hypothermic TLV, even when started after reperfusion. Conversely, acute kidney injury was limited only when hypothermia was started before reperfusion.In a second study, non-shockable cardiac arrest from respiratory cause was responsible for a high rate of mortality and a severe post-cardiac arrest syndrome. Hypothermic TLV had potent neuro- and cardio-protective effects, as well as reduced inflammatory syndrome. Early preservation of the blood-brain barrier integrity and cerebral hemodynamics as well as reduction in the immediate reactive oxygen species production in the brain, heart, and kidneys were also notable.These studies demonstrate that ultra-fast cooling by TLV alleviates the deleterious effects of ischemia-reperfusion. The optimal duration and timing of TLV-induced hypothermia for end-organ protection in hypoperfusion states remains to be determined.

Sepsis-induced organ failure is associated with high morbidity and mortality rates. The onset of an exaggerated host response to microbial invasion and/or trauma, is believed to be the primary cause of excessive inflammation and the subsequent tissue hypoperfusion observed in patients with severe sepsis. In our mouse model of sepsis induced by cecal ligation and perforation (CLP), symptoms indicative of the disease, including diarrhea, increased ventilation and persistent hypothermia, are present at six hours after the surgery (T6). In the untreated CLP mice, mortality occurs starting at T15. As induced hypothermia has shown to exert immunomodulatory effects, this study is aimed at assessing its potential in attenuating inflammation and improving survival in experimental sepsis. Our data has shown that deep hypothermia initiated at T6, by means of cold chamber-induced cooling, prolongs survival. Plasma cytokine quantification by enzyme-linked immunosorbent assays (ELISA) also reveals that induced deep hypothermia reduces tumour necrosis factor(TNF)-α and interleukin (IL)-6 production in untreated CLP mice. In contrast, induced moderate hypothermia does not have such effect. Antibiotic (cefotaxime) and saline resuscitation initiated immediately following CLP ensures survival. However, when these supportive treatments are initiated at T6, >50% mortality is observed in the CLP mice with or without induced hypothermia. In summary, this preliminary study provides proof for a downregulated inflammatory response mediated by external cooling. However, to achieve a survival benefit, treatment strategies in addition to cooling and antibiotics may be required.