faculdade de medicina ufpel - sargs · the immune system is maintained in a carefully regulated...
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FACULDADE DE MEDICINA UFPEL CENTRO DE ENSINO E TREINAMENTO em ANESTESIOLOGIA
Prof. Dr. Gastão F. Duval Neto
OPIÓIDES e IMUNOSUPRESSÃO :
resultados das últimas pesquisas
2012 - JOSULBRA
TRIAL CLÍNICOS PROSPECTIVOS CONTROLADOS RANDOMIZADOS DUPLAMENTE ENCOBERTO
ESTUDOS PROSPECTIVOS DE COORTE
ESTUDOS DE CASO CONTROLE
SÉRIES DE CASOS
RELATO DE CASOS CLÍNICOS
REVISÃO SISTEMÁTICA
REVISÃO NARRATIVA
REVISÕES EM LADOS OPOSTOS DA FORÇA DE EVIDÊNCIAS
POSSIBILID
AD
E DA
AN
ÁLISE CRÍTICA
DO
TEXTO
ESTUDOS RETROSPECTIVOS COM “n” BAIXOS
BASES CIENTÍFICAS DA APRESENTAÇÃO
“MICRO METASTIZAÇÃO”
A IMPORTÂNCIA DO PROBLEMA
Excisão cirúrgica é a base do tratamento de tumores sólidos potencialmente curáveis. Doença metastática é a mais importante causa de morte relacionada com esse grupo de pacientes.
Anesthesia Patient Safety Foundation NEWSLETTERThe Official Journal of the Anesthesia Patient Safety Foundation Volume 23, No. 4, Circulation 84,122 Winter 2008-2009
Does Anesthetic Management Affect Cancer Outcome? Editor’s Note: This thought-provoking article by Dr. Durieux raises questions that have yet to be answered and perhaps expands our conventional view of patient safety.
O sistema imunológico funciona protegendo contra infecções e CANCER
A resposta ao estresse perioperatório afeta o sistema imunológico do paciente
DEVE SER ENTENDIDO PELO ANESTESIOLOGISTA QUE :
“A CIRURGIA ONCOLÓGICA FAVORECE A LIBERAÇÃO DE CÉLULAS CANCEROSAS DURANTE UM PERÍODO DE POTENCIAL IMUNOSUPRESSÃO, FAVORECENDO O FENÔMENO DE PRODUÇÃO DE METÁSTASES (micro metástases)”.
TÉCNICAS ANESTÉSICAS PODEM INFLUENCIAR ESSE PROCESSO
Anesthesia Patient Safety Foundation NEWSLETTER The Official Journal of the Anesthesia Patient Safety Foundation Volume 23, No. 4, Circulation 84,122 Winter 2008-2009
The immune system is maintained in a carefully regulated balance between the two polarised control arms, Th1 (cellular immunity) and Th2 (humoral immunity). In disease states the balance is skewed such that the immune picture of autoimmune disease patients, such as multiple sclerosis, rheumatoid arthritis and type I diabetes, have a Th1 bias, whereas cancer patients have a Th2 bias. Immunotherapy strategies aimed at boosting the immune system of cancer patients serve to enhance the dominant Th2 response that failed to eradicate the tumour. Therapeutic cancer vaccines need to be designed with an immunomodulatory mechanism which is capable of converting a resident Th2 dominant immune response in cancer patients to a Th1 dominant immune response.
RESPOSTA AO ESTRESSE E CÂNCER
DIMINUIÇÃO DA APOPTOSE CELULAR
RESPOSTA AO ESTRESSE E CÂNCER
Panel A: Immune-mediated tumour killing requires a Th1 microenvironment. In the presence of Th1 cytokines, tumours upregulate MHC Iand co-stimulatory molecules necessary for cytolytic T-cells (CTL) to recognise and kill the tumours. In addition, the inflammatory Th1 environment can non-specifically activate T-cells to kill tumours through FasL and TRAIL effector molecules. Panel B: Tumours condition the microenvironment to have a dominant Th2-bias as a strategy to escape immunemediated attack. In the presence of Th2 cytokines, tumours down-regulate MHC and co-stimulatory molecules, attract suppressor cells such as Treg and myeloid suppressors which suppress killer cell function. The Th2 environment down-regulates co-stimulatory molecules on APC which serves to anergise any Th1 cells that may infiltrate the tumour, whether as a natural immune response or through tumour vaccination strategies. Therefore, strategies to boost Th1 immunity alone are not sufficient to mediate anti-tumour immunity. Sustained Th1 cytokine production is required in the tumour microenvironment.
CONCENTRAÇÃO DE CITOCININAS REGULAM A RELAÇÃO ENTRE IMUNIDADE, INFLAMAÇÃO E CÂNCER
CITOCININAS
FORMAÇÃO DE METÁSTASES
A sua anestesia pode ter influência na evolução normal da doença básica ?
Morfina modifica a sinalização genética de céls. Gliais em pacientes portadores de virus HIV-1 (Câncer ?)
The -Opioid Receptor in Cancer Progression Is There a Direct Effect? Frances E. Lennon, Ph.D -
Indirect Effects of μ-Opioids on Cancer Progression Suppression of natural killer (NK) cell activity – efeito dose dependente
Inhibits production of proinflammatory cytokines by monocytes Experimental effects without of clinical evidence
Direct Effects of μ-Opioids on Tumor Progression
MOR mediates the main clinical effects of opioids, including analgesia, but also mediates secondary effects such as addiction, respiratory depression,
and constipation
Effect of μ-Opioids on Angiogenesis
The -Opioid Receptor in Cancer Progression Is There a Direct Effect? Frances E. Lennon, Ph.D -
PRO ANGIOGENIC EFFECT
Smith T J et al. JCO 2002;20:4040-4049
©2002 by American Society of Clinical Oncology
Randomized Clinical Trial of an Implantable Drug Delivery System Compared With Comprehensive Medical Management for Refractory Cancer Pain: Impact on Pain, Drug-Related Toxicity, and Survival
Randomized Clinical Trial of an Implantable Drug Delivery System Compared With Comprehensive Medical Management for Refractory Cancer Pain: Impact on Pain, Drug-Related Toxicity, and Survival Thomas J. Smithnd - October 1, 2002 vol. 20 no. 19 4040-4049
Schematic diagram representing the mechanism(s) by which methylnaltrexone inhibits angiogenesis. Vascular endothelial growth factor (VEGF) binding to VEGF receptors induces Src activation, Src-mediated Akt, RhoA, and mammalian target of rapamycin (mTOR) activation and consequent endothelial cell proliferation, migration, and actin cytoskeletal reorganization required for angiogenesis. Methylnaltrexone (MNTX) inhibits the -opioid receptor (MOR) and promotes tyrosine phosphatase activity, leading to Src inactivation.This promotes Akt, RhoA, and mTOR inactivation and consequent inhibition of angiogenesis.
INCREASE MORPHINE ACTIVITY
Structure shown is based on canonical μ-opioid receptor (MOR) sequence (Uniprot ref P35372-1). Seven-transmembrane domain topology demonstrating extracellular, transmembrane, and intracellular domains are numbered. Reported single-nucleotide polymorphisms are highlighted in red, and the lipidation site is shown in green
EVIDENCE THAT STRESS AND SURGICAL INTERVENTIONS PROMOTE TUMORDEVELOPMENT BY SUPPRESSING NATURAL KILLER CELL ACTIVITY
Int. J. Cancer: 80, 880–888 (1999)
RESPOSTAS SISTÊMICAS AO ESTÍMULO CIRÚRGICO
ACELERAÇÃO DO PROCESSO DE “METASTIZAÇÃO”
RESPOSTA AO ESTRESSE E CÂNCER
Controle da Resposta Imunológica sobre MICRO METASTIZAÇÃO TUMORAL
CONTOLE DA IMUNIDADE
Linfócitos tipo TNK -T(natural killers)Células dentríticasMacrófafos
CELULAR INFLAMATÓRIA ANGIOGÊNESE
InterferonInterleucinas : ϒ IL 12 Células Helper (Th 1) Células Helper (Th 2)
Fatores : IL 6, 8 e 1β ciclooxigenase 2 NO FNT Insulina
Citocininas Th 2 diminuem a imunidade tumoral por inibirem a atividade das Th1.
A ativação β adrenérgica suprime a atividade NK promovendo a metastização.
Níveis baixos de NK perioperatório são associados a elevação de mortalidade p/ metastização tumoral.
A neo formação vascular eleva as possibilidades de metastização tumoral.
Guy Shakhar and Shamgar Ben-Eliyahu 1998;160;3251-3258
In Vivo b-Adrenergic Stimulation Suppresses Natural Killer Activity and Compromises Resistance to Tumor Metastasis in Rats
Número de células NK por micro/litro de sangue em 10 min, 20 min, 40 min, 1h, 3h, 5h e 18 h após a injeção s.c. de 1 mg/kg do MP. Tempo 0 refere-se a linha de base números NK (animais não tratados). O asterisco indica uma diferença significativa (<0.01) da linha de base.
metaproterenol (MP), CETAMINA ?
O efeito de aumento das doses de MP sobre a retenção de pulmão de células de tumor MADB106 radiolabeled em ratos normais ou NK-esgotado. Valores são expressos como uma porcentagem do valor de controlo relevantes (±SEM). O nível absoluto de retenção de tumor de pulmão em grupos de controle foi 223 vezes maior nos ratos NK-empobrecido do que em ratos normais (não mostrados). O asterisco indica um desvio significativo (α < 0,0001) o valor do controle (100%).
Guy Shakhar and Shamgar Ben-Eliyahu 1998;160;3251-3258
In Vivo b-Adrenergic Stimulation Suppresses Natural Killer Activity and Compromises Resistance to Tumor Metastasis in Rats
O β BLOQUEIO PODE ELEVAR A RESITÊNCIA A METASTIZAÇÃO TUMORAL
Técnicas regionais, tais como anestesia epidural ou espinal, através do bloqueio neural aferentes por anestésico local, profundamente inibem a resposta ao estresse metabólico e hormonal.
A concentração da citocinina pro –inflamatórias IL-6 foi aumentada em pacientes após a anestesia espinhal com nenhum aumento dos níveis de Th1 citocina IFN-gama e nenhuma elevação de citocininas como IL-10 e IL-4, que são associados com o de tipo 2 (Th2) - como a resposta imune.
A anesthesia na raque resulta em menos imunossupressão, ou seja, mantém o número de células Th1, estimulando assim a imunidade celular.
Neuropeptide Y Y1 receptors mediate morphine- induced reductions of natural killer cell activity
Collectively, these findings demonstrate that NPY Y1 receptors mediate morphine's suppressive effect on NK activity and further suggest that opioid-induced increases in nucleus accumbens D1 receptor activation inhibit splenic NK activity via NPY released
from the sympathetic nervous system
SAUER - Volume 177, 18-26, August 2006
LINHAS DE PESQUISA
Epidemiológica Clínica Weckermann D, Polzer B, Ragg T, et al: Perioperative activation of disseminated tumor
cells in bone marrow of patients with prostate cancer. J ClinOncol 27:1549-1556, 2009
Durieux ME: Does anesthetic management affect cancer outcome? http:// www.apsf.org/assets/Documents/winter2009.pdf
Biki B, Mascha E, Moriarty DC, et al: Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: A retrospective analysis. Anesthesiology 109:180-187, 2008
Exadaktylos AK, Bugy DJ, Moriarty DC, et al: Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 105:660-664, 2006
Sessler DI, Ben-Eliyahu S, Mascha EJ, et al: Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter randomized trial. Contemp Clin Trials 29:517-526, 2008
Recorrência de tumores malígnos
MAMA PRÓSTATA CÓLON
Resultados de Pesquisa em Cobaios
Anestesia Regional na Raque ( subaracnóide/epidural)
Diminuí as necessidades de anestésicos inalatórios e venosos OPIÓIDES AMBOS DIMINUEM A ATIVIDADE DE KILLER CELLS
Os OPIÓIDES quando administrados por via medular - em pequenas doses NÃO EXERCEM EFEITOS IMUNOSSUPRESSIVOS
A analgesia epidural bloqueia efetivamente as respostas neuro-endócrino- metabólicas (diminuindo catecolamninas circulantes) DIMINUINDO A REDUÇÃO DE
KILLER CELLS CIRCULANTES
Ben-Eliyahu S. Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain 2001;90:191-9.
The Novel Role of the Mu Opioid Receptor in LungCancer Progression: A Laboratory Investigation
Clique para editar os estilos do texto mestreSegundo nível
Terceiro nívelQuarto nível
Quinto nível
Efeito Pro-Angiogênico dos receptores opióides mu ativados
2011 112:558-567
The Novel Role of the Mu Opioid Receptor in LungCancer Progression: A Laboratory Investigation
Clique para editar os estilos do texto mestreSegundo nível
Terceiro nívelQuarto nível
Quinto nível
2011 112:558-567
NALTREXONA
Combined Spinal and General Anesthesia Attenuates Liver Metastasis by Preserving Th1/Th2 Cytokine Balance Wada, Hiroki M.D. – 2007; 106: 499
RATOS
Resultados de Pesquisa em Humanos
Estudos epidemiológicos retrospectivosCirurgia Oncológica x Anestesia Regional
Can Anesthetic Technique for Primary Breast Cancer Surgery Affect Recurrence or Metastasis?
Exadaktylos, Aristomenis K. M.D. - 105(4), October 2006, pp 660-664
n - 129 Mastectomia com esvaziamento axilar
Resultados : Livre de Metástase x Metástase 94% (95% confidence interval, 87–100%) e 82% (74–91%) em 24 meses e 94% (87–100%) 77% (68–87%) at 36 meses , paravertebral e anestesia geral , respectivamente (P = 0.012).
Esses resultados sugerem que os bloqueios regionais no neuro eixo podem ser mais efetivos que a quimioterapia pós operatótia para evitar metástases
Resultados de Pesquisa em Humanos
Estudos epidemiológicos retrospectivosCirurgia Oncológica x Anestesia Regional
Can Anesthetic Technique for Primary Breast Cancer Surgery Affect Recurrence or Metastasis?
Exadaktylos, Aristomenis K. M.D. - 105(4), October 2006, pp 660-664
Resultados de Pesquisa em Humanos
Potential Influence of the Anesthetic Technique Used during Open Radical Prostatectomy on Prostate Cancer-related Outcome: A Retrospective Study
- 113(3), September 2010, pp 570-576 Wuethrich, Patrick Y. M.D.*
HR 0.45, P = 0.002
Resultados de Pesquisa em Humanos
Potential Influence of the Anesthetic Technique Used during Open Radical Prostatectomy on Prostate Cancer-related Outcome: A Retrospective Study
- 113(3), September 2010, pp 570-576 Wuethrich, Patrick Y. M.D.*
P = 0.19
CONCLUSÕES
A anestesia espinhal apresentou um menor nível de imunosupressão e uma menor correlação entre Th1/Th2 quando comparada com anestesia geral com opióides
Le Cras, Anna E. BSc, MSc Anesthesia & AnalgesiaIssue: Volume 87(6), December 1998, pp 1421-1425
Spinal but Not General Anesthesia Increases the Ratio of T Helper 1 to T Helper 2 Cell Subsets in Patients Undergoing Transurethral Resection of the ProstateLe Cras, Anna E. BSc, MSc; Galley, Helen F. PhD, FIMLS; Webster, Nigel R. PhD, FRCA, FRCP
Spinal anesthesia may result in less immunosuppression after surgery. We found that the ratio of T helper 1 to T helper 2 cells was higher in patients undergoing prostate surgery by spinal rather than general anesthesia. Th1 cells promote protective immune responses that may result in fewer postoperative infections and metastasis.
Follow-up data of 4329 patients on the Central Melanoma Registry of the German Dermatological Society were analysed. (RETROSPECTIVE STUDY)
Results :
General anaesthesia for primary excision of melanoma was associated with a decrease in the survival rate (relative risk 1.46, P < 0.0001).
This study revealed a slight but significantly increased risk of death for patients treated with general anaesthesia for the primary excision of melanoma.
Therefore local anaesthesia should be preferred for the treatment of primary melanoma.
2011; 342:d1491 doi: 10.1136/bmj.d1491 (Published 29 March 2011) Prof. Paul Myles
Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial ( PROSPECTIVE STUDY)
Use of epidural block in abdominal surgery for cancer is not associated with improved cancer-free survival.
Recurrence-free survival after cancer surgery by group (log rank P=0.61).
Myles P S et al. BMJ 2011;342:bmj.d1491
Recurrence-free survival after cancer surgery by group (log rank P=0.61)
Five year recurrence-free survival by subgroups.
Myles P S et al. BMJ 2011;342:bmj.d1491
©2011 by British Medical Journal Publishing Group
Effect of anaesthetic technique and other perioperativefactors on cancer recurrenceG. L. Snyder1,2*
FACULDADE DE MEDICINA UFPEL CENTRO DE ENSINO E TREINAMENTO em ANESTESIOLOGIA
Prof. Gastão F. Duval Neto
2012 - JOSULBRA
AGRADEÇO PELA SUA ATENÇÃO
FACULDADE DE MEDICINA UFPEL CENTRO DE ENSINO E TREINAMENTO em ANESTESIOLOGIA
Prof. Gastão F. Duval Neto
BLOQUEIOS EM PACIENTES ONCOLÓGICOS:
benefícios além da anestesia/analgesia
2011 - LASRA
BLOQUEIOS EM PACIENTES ONCOLÓGICOS:
benefícios além da anestesia/analgesia
2012 - JOSULBRA