Anaesthesia, Pain, Intensive Care and Emergency - Part 5 pptx

ciency of the treatments appears to be tied to removal of inflammatory mediators, even though no difference in mortality between specific treatments has been confirmed in the literature. More specific approaches have been proposed, such as high-volume haemofil- tration and continuous plasma filtration [16, 17], in order to remove several pro- and anti-inflammatory mediators and to overcome the limitations of conventional continuous renal replacement therapy (CRRT) (i.e., low volume exchange and low sieving coefficients for sepsis-associated mediators). In order to improve the efficacy of a blood purification system in the critically ill septic patients, unselective adsorption onto a cartridge was added to plasma filtration and conventional diffusion/convection in a newly designed extracorpo- real device called coupled plasma filtration–adsorption (CPFA) (Fig. 1). CPFA is a specific method for the treatment of sepsis. The equipment it requires is as follows (Fig. 2): 1. A plasma-filter (polyethersulfone 0.45 m 2 with a cut-off of approx 800 kDa) 2. A haemofilter (polyethersulfone 1.4 m 2 ) 3. A cartridge (containing approximately 140 ml of hydrophobic styrenic resin) The kit is lodged in the Bellco ‘Lynda’ machine (Bellco, Mirandola, Italy). The treatment consists in separation of plasma from the whole blood with adsorption of the inflammatory mediators and cytokines from the plasma, and a subsequent purification step accomplished by way of a haemofilter. Fig. 1. The peak concentration hypothesis suggests that nonselective control of the peaks of inflammation and immunoparalysis may help to restore immunohomeostasis Plasma “bad molecules” “good molecules” UF out Reinfusate in 182 S. Livigni, M. Maio, G. Bertolini The life of the cartridge, as demonstrated by in vitro experiments, is 10 h, which corresponds to the mean expected treatment duration. In recent years resins and charcoals have been used because of their capacity and ability to remove toxic substances from blood, but the medical applications were often counterbalanced by safety concerns, such as leaching of metals, release of small microparticles and poor homogeneity and biocompatibility. Haemoper- fusion through ion/cation exchange resins was first proposed in 1948 for the treatment of renal failure, but several variations followed. Early experience and treatments were complicated by pyrogenic reactions, electrolyte disturbances and haemolysis. In fact, the use of more sophisticated technologies to coat resins reduces the problems that result from loss of efficiency, poor reproducibility and mixed out- comes. Extracorporeal applications require that resin is defined in terms of the chemical nature of the resin, particle size, porosity and surface area. Resins must be also tested for the release of microparticles, heavy metals and other toxic substances. The resin test is done in real conditions similar to those obtaining during a patient application. The optimisation of flow and column geometry is a parameter that also greatly influences adsorption efficacy. There is a balance between the volume of plasma being treated and the time plasma is in contact with the resin [18]. Using an experimental model of acute endotoxaemia in rabbits, Tetta et al. Fig. 2. Scheme of coupled plasma filtration–adsorption Infusion Haemofilter Cartridge Plasma Plasmafilter Plasma filtration in sepsis: a research protocol 183 studied whether nonselective adsorption from plasma of cytokines and other pro-inflammator y mediators known to be produced in excess during sepsis could reduce 72-h mortality. Cumulative survival was significantly impr oved in rabbits treated with CPFA, and cumulative su rviv al of the resin with the lipopolysaccha- ride (LPS) group was not significantly different from that of the control group (Fig. 3) [19]. Human studies are limited, but promising:Roncoetal.compared CPFA against haemodiafiltration by measuring homodynamic and immune responsiveness in ARF patients in septic shock. These authors observed that the haemodynamic was significantly better with the use of CPFA than with haemodiafiltration. They also observed significantly higher leucocyte responsiveness after CPFA treatment [20]. Another clinical study was conducted by Formica et al. The authors examined the effect of repeated applications of CPFA on haemodynamic response in septic patients with and without renal failure.In this long-term study, theauthors showed CPFA to be a safe and feasible treatment leading to significant improvements in haemodynamic stability, vasopressor requirement, pulmonary function, and 28- and 90-day survival (Fig. 4). The 28-day survival rate was 90%, which was quite unexpected considering an APACHE II-predicted mortality of about 40% for these patients [21]. On the grounds of these experiences it was also expected that early therapy would hamper the inflammatory cascade. In the light of these remarks, GiViTI decided to launch a collaborative rando- mised controlled trial for formal evaluation of the efficacy and clinical safety of CPFA in septic shock. The main study objective is to clarify whether the implemen- tation of CPFA in addition to the current clinical practice can reduce mortality of septic shock patients in ICU. The second objective of the study is to determin e Fig. 3. Coupled plasma filtration–adsorption in a rabbit model of endotoxic shock 184 S. Livigni, M. Maio, G. Bertolini whether CPFA can reduce the incidence of organ dysfunction and length of stay. The study will involve Italian, adult, generalICUs affiliated to theGiViTIgroup, in which CPFA is regularly used in the treatment of septic shock. The study is restricted to ICUs that, based on the promising but still incomplete evidence available,havealready introduced CPFAintotheir routine practice.In other words, we ask the staff at these centres to use CPFA within a research programme that will yield information on the real efficacy of the treatment. All patients who are admitted to the ICU in septic shock or who develop septic shock while in the ICU will be eligible. The definition used for septic shock is that provided by the international literature [22, 23]. Patients will be considered eligible for the study only if it will be possible to initiate CPFA in less than 6 h either from admission to the ICU for patients admitted in septic shock, or from the diagnosis of septic shock for the others. There are some exclusion criteria that make patients not eligible for the study; these concern age, pregnancy, cerebral coma, metastatic cancer, cardiopulmonary resuscitation, life expectancy, etc. Eligible patients will be identified upon admis- sion or during the stay in the ICU and randomised. Patients randomised to the control arm will be treated according to the current clinical practice in the ICU. Patients randomised to the experimental arm will also be treated according to the ICU’s current clinical practice, but with the addition of CPFA. The CPFA treatment will be applied intermittently (10 consecutive hours fol- lowed by a 14-h break or CVVH for patients with renal failure) for 5 days following randomisation. The cartridge must be changed after 10 h; previous experience has shown saturation of the resin after this. The clinical follow-up starts on the day of randomisation and finishes at Fig. 4. Trend in mean arterial pressure (MAP) throughout the first ten sessions (each point is the mean of the measure at that time for all patients). Statistical significance is related to the difference between all 100 pre- vs posttreatment measurements Plasma filtration in sepsis: a research protocol 185 discharge from the ICU. During the ICU stay, information on compliance with the four A-level recommendations of the Surviving Sepsis Campaign [24], and the daily SOFA score (Sequential Organ Failure Assessment) [25] will be recorded. The vital status will be recorded at ICU discharge, at hospital discharge and at 90 days from randomisation. For patients transferred to other hospitals, “vital status at hospital discharge” will be intended as the vital status at discharge from the latest hospital in which the patients stayed. In agreement with the study rationale, lower mortality is expected in patients treated with CPFA than in patients treated according to standard practice only. In the light of these considerations, the following primary and secondary end-points were chosen: · Mortality at hospital discharge. For patients transferred to other hospitals, it will be intended as mortality at the discharge from the latest hospital in which the patients stayed. · Mortality within 90 days of randomisation. With this end-point it will be possible to evaluate whether a possible benefit obtained in the short term (hospital discharge) is maintained afterwards. · Proportion of patientswhodevelopone, two, three andfour new organ failures during their ICU stay. A new organ failureis defined asachangein SOFA score from 0, 1 or 2 to 3 or 4 in any of the systems considered [26]. This end-point will determine whether CPFA can reduce the risk that organ failures will develop. · Days not spent in the ICU during the first 30 days after randomisation. With this end-point it will be possible to determine whether CPFA can reduce the complexity of these patients’ care. Data previously published by GiViTI show a hospital mortality rate of 63% in septic shock patients. The study is designed to reveal a 25% relative improvement in hospital mortality with the use of CPFA. For it to have a power of 80% to find out such a difference with 5% type I error, it is necessary to enrol 155 subjects in each arm. Increasing this estimate by approximately 5% to prevent possible pro- blems in compliance with the protocol yields a number of patients needed of 330. This sample allows detection of a 29% difference with a power of 90%. The trial will be m onitored with the Bayesian approach. As known, the Bayesian approach combines a prior distribution and the gathering of the experimental evidence into a posterior distribution. The posterior distribution will be the basis on which to decide wh ether to interrupt the trial or not. Hence, this analysis requires a probabilistic formalisation of two conflicting hypothe- ses: one sceptical and one enthusiastic. The trial wi ll be interrupted earlier than planned when the patient’s benefit is achieved (i.e., demonstration of treatment efficacy), when sceptics are convinced of the treatment efficacy or, in other words, when the posterior distribution deriving from a prior sceptical hypothesis ac- knowledges the achieved benefit. Conversely, the trial will be interrupted earlier than planned in case of treatment’s futility (i.e., demonstration that the treatment is futile) when a prior enthusiasti c approach is curbed by the treatment useless- ness or, in other word s, when the posterior distribution deriving from a prior 186 S. Livigni, M. Maio, G. Bertolini enthusiastic hypothesis acknowledges the unchanged conditions. Before enrolment, all patients will be given information on the study’s objec- tives, procedures and correlated risks. If any patient is not able to give consent, the instructions provided by the International Commission on Harmonisation will be followed (ICH Guideline for Good Clinical Practice). We consider thatthistrial is extremely important, to prove the effectiveness of this technique in decreasing morbidity and mortality in septic shock. If we obtain a positive result we can conclude that sepsis can be treated by bloodpurificationtechnology,buteven ifwe do not,the studywillstill beimportant because its result will modify the current clinical practice in ICUs. The trial has been registered with both the ClinicalTrials.gov (identifier NCT00332371) and the ISRCTN (24534559) registries. References 1. Friedman G,Silva E,Vincent JL (1998) Hasmortality of septic shockchanged withtime? Crit Care Med 26:2078–2086 2. Wheeler AP, Bernard GR(1999) Treating patients with sepsis. N EnglJ Med340:207–214 3. USA National Vital Statistics Report (2001) 49:6 4. Rossi C, BertoliniG(2005) Pro gettoMargherita (thesis).(Rapporto 2004)Sestante,Bergamo 5. Alberti C, Brun-Buisson C, Burchardi H et al (2002) Epidemiology of sepsis and infectionin ICUpatientsfroman internationalmulticentrecohortstudy.IntensiveCare Med 28(2):108–121 6. Liano G, Pascual J (1996) Acute renal failure. Madrid Acute Renal Failure Study Group. Lancet 17:347–349 7. Rangel-Frausto MS, Pittet D, Costigan M (1995) The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA 273:117–123 8. Bellomo R, Ronco C (1998) Indications and criteria for initiating renal replacement therapy in the intensive care unit. Kidney Int 53[Suppl 66]:S106–S109 9. Kellum JA, Johnson JP, Kramer D et al (1998) Diffusive vs convective therapy: effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome. Crit Care Med 26:1995–2000 10. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348(2):138–150 11. Annane D, Bellissant E, Cavaillon J-M (2005) Septic shock. Lancet 365:63–78 12. Singh S, Evans TW (2006) Organ dysfunction during sepsis. Intensive Care Med 32(3):349–360 13. Mira JP, Cariou A, Grall F et al (1999) Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA 282:561–568 14. Godin PJ, Buchman TG (1996) Uncoupling of biological oscillators: a complementary hypothesis concerning the pathogenesis of multiple organ dysfunction syndrome. Crit Care Med 24:1107–1116 15. Wheeler AP, Bernard GR (1999) Treating patients with severe sepsis. N Engl J Med 340:207–214 16. Ronco C,Brendolan A,Bellomo et al (2004)The Rationalefor ExtracorporealTherapies in Sepsis. Adv Sepsis 4(1):2–10 Plasma filtration in sepsis: a research protocol 187 17. Bellomo R, Baldwin I, Cole L et al (1988) Preliminary experience with high volume hemofiltration in human septic shock. Kidney Int 53:182–185 18. Brendolan A, Ronco C, Ricci Z et al (2004) Coupled plasma filtration adsorption: rationale, technical development and early clinical experience sepsis, kidney and multiple organ dysfunction. Contrib Nephrol 144:376–386 19. Tetta C, Gianotti L, Cavaillon JM et al(2000) Continuous plasmafiltration coupled with sorbent adsorption in a rabbit model of endotoxic shock. Crit Care Med 28:1526–1533 20. Ronco C, Brendolan A, Lonnemann G et al (2002) A pilot study on coupled plasma filtration with adsorption in septic shock. Crit Care Med 30:1250–1255 21. Formica M, Olivieri C, Livigni S et al (2003) Hemodynamic response to coupled plasmafiltration–adsorption in human septic shock. Intensive Care Med 29(5):703–708 22. Levy MM, Fink MP, Marshall JC et al (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS Inter- national Sepsis Definition Conference. Intensive Care Med 29(4):530–538 23. Bone RC, Balk RA, Cerra FB et al (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101(6):1644–1655 24. Dellinger RP, Carlet JM, Masur H et al (2004). Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med 30(4):536–555 25. Vincent JL, de Mendonca A, Cantraine F et al (1998) Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicen- ter, prospective study. Working Group on “Sepsis-related Problems” of the European Society of Intensive Care Medicine. Crit Care Med 26(11):1793–1800 26. Iapichino G, Radrizzani D, Bertolini G et al (2001), Daily classification of the level of care. A method to describe clinical course of illness, use of resources and quality of intensive care assistance. Intensive Care Med 27(1):131–136 188 S. Livigni, M. Maio, G. Bertolini HIGHLIGHTS ON CIRCULATORY FAILURE, CPR AND TRAUMA The cell in shock M.M. MORALES,H.PETRS-SILVA ‘Cellular homeostasis’ is any of the processes involved in the maintenance of an internal equilibrium within a cell or between a cell and its external environment. The physical and biochemical parameters of physiological equilibrium conducive to eukaryotic cell function include availability and maintenance of nutrients, oxygenation, temperature, pH, and osmolality, but exposure to conditions when these parameters are outside the physiological ranges is considered to cause stress to the cell, leading to macromolecular damage. Many types of environmental stress have been shown to cause deleterious changes in cells, including osmotic stress [1], thermal stress [2], heavy metal stress [3], ionising radiation [4], baric stress [5], oxidative stress [6], chemical genotoxin stress [7], mechanical injury stress [8] and hypoxia/ischaemia [9]. As a reaction to the threat of macromolecular damage from sudden environ- mental change or frequent fluctuations in environmental factors, the cell induces a stress response. This response has been described as an evolutionarily highly conserved mechanism of cellular protection [10]. The endpoints of stress events include quick responses, such as protein modifications (e.g. protein phosphoryla- tion) [11], changes in Ca 2+ concentrations [12], and slow responses, such as protein chaperoning and repair, transcriptional regulation, removal of damage proteins, DNA and chromatin stabilisation and repair, cell-cycle control, cell proliferation and apoptosis [13]. Cells respond to multiple opposing signals simultaneously, and the decision on whether to die or survive will depend on the intensity of the stress signal. An extreme condition of stress represents a cell in shock. The cells have a few tools for reversing shock before it goes too far. But all too often shock is so devastating, because the dose of stress exceeds the cell’s capacity for maintaining integrity, that the cellular tools are driven to induce the death of the cell [14–16]. This process is physiological, since it serves to avoid the genesis of tumours and genetic instability of organisms [17]. Chapter 18 Cellular stressors Heat shock and the heart shock proteins Ashburner and Bonner wrote the first review on the induction of gene activity by heat shock 27 years ago, describing how immediately after an increase in tempera- ture all cells increase production of a certain class of molecules called heat shock proteins [18]. Subsequent studies have revealed that the same response takes place when cells are subjected to a wide variety of environmental insults, such as toxic metals [19], alcohols [20], and many metabolic insults [21]. Similar changes in gene expression provide a rapid and direct mechanism of cellular defence against so many different stress-induced damage that the term ‘heat shock response’ has been replaced by the more general term ‘stress response’, and the associated products are now referred to as stress proteins [22, 23]. Many stress proteins are also expressed in normal cells with the same function, such as control of protein synthesis, folding, and translocation into organelles [24]. And after cells have been exposed to a stress, these proteins are required to recognise unfolded proteins and either target them for removal, prevent their aggregation or assist in their refolding into their native, functional state. Five molecular chape- rones represent the minimal stress proteome: DnaK/HSP70, DnaJ/HSP40, GrpE, HSP60, and peptidyl-prolyl isomerase (cylophilin). The proteins involved in cellu- lar stress responses are the most highly conserved of all organisms [10]. In biology, chaperones are specific proteins that have the function of assisting other proteins in achieving proper folding. They were discovered as heat shock proteins, that is, proteins expressed in heat shock conditions. The reason for this behaviour is that protein folding is severely affected by heat, and chaperones therefore act to coun- teract the potential damage. Although most proteins can fold in the absence of chaperones, for a minority their presence is an absolute requirement. Recent analysis has revealed that stress, rather than simply imposing destruc- tive forces, leads to subtle changes in macromolecular structures, which result in a redirection of the cell energy to allow the synthesis of heat shock proteins, which themselves function in restoring homeostasis [25]. Cells that produce high levels of stress proteins are better able to survive the stress damage than cells that do not [26]. The major inducible heatshock protein is HSP70.The binding activity ofHSP70 itself is involved in the regulation of apoptosis, where it may associate with pro-apoptotic proteins, thereby keeping these proteins in the inactive state, or play a part in the proteasome-mediated degradation of apoptosis-regulatory proteins [27]. However after a severe stress, when repair turns out to be impossible HSP 70 is involved in activation of the apoptotic programme and, in the extreme case, of cellular necrosis [28]. 192 M.M. Morales, H. Petrs-Silva [...]... of JIK (c-Jun-N-terminal-inhibitory kinase), and TNF-receptor-associated factor 2 (TRAF2) TRAF2 activates c-Jun N-terminal protein kinase (JNK) and downstream proapoptotic kinases, such as apoptosis-signalling kinase 1 (ASK1), finally directing the activation of mitochondrial apoptotic protease-activating factor-1 (Apaf-1)-dependent caspase [46] The mechanism underlying apoptosis via IRE1-JNK signalling... (20 05) Persistent cerebral microcirculatory blood flow after onset of cardiac arrest Crit Care Med 33(12) Suppl A100:173 34 Lewis CM, Weil MH (1969) Hemodynamic spectrum of vasopressor and vasodilator drug JAMA 208:139 1-1 398 35 Standards and guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC) (1986) JAMA 255 :290 5- 2 989 36 Guidelines for cardiopulmonary resuscitation and emergency. .. 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Dellinger RP, Carlet JM, Masur H et al (2004). Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Med 30(4) :53 6 55 5 25. Vincent. cas- pase-12 and PERK/CHOP. Under chronic ER stress, inositol requiring-1 (IRE1),an ER-resident transmem- brane protein kinase, is activated, leading to the recruitment of JIK (c-Jun-N-ter- minal-inhibitory. 118(11):2 652 –2 656 5. Somero GN (1992) Adaptations to high hydrostatic pressure. Annu Rev Physiol 54 :55 7 57 7 6. Butler D, Bahr BA (2006) Oxidative stress and lysosomes: CNS-related consequences and