IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE

IMMUNOLOGICAL MECHANISMS OF EXTRACORPOREAL PHOTOPHERESIS IN CUTANEOUS T CELL LYMPHOMA AND GRAFT VERSUS HOST DISEASE Publication No.___________ Lisa Harn-Ging Shiue, B.S. Supervisory Professor: Madeleine Duvic, M.D. Extracorporeal photopheresis (ECP) is an effective, low-risk immunomodulating therapy for leukemic cutaneous T cell lymphoma (L-CTCL) and graft versus host disease (GVHD), but whether the mechanism(s) of action in these two diseases is (are) identical or different is unclear. To determine the effects of ECP in vivo, we studied regulatory T cells (T-regs), cytotoxic T lymphocytes (CTLs), and dendritic cells (DCs) by immunofluorescence flow cytometry in 18 L-CTCL and 11 GVHD patients before and after ECP at Day 2, 1 month, 3 months, and 6 months. In this study, ECP was effective in 12/18 L-CTCL patients with a 66.7% overall response rate (ORR) and 6/11 GVHD patients with a 54.5% ORR. Prior to ECP, the percentages of CD4+Foxp3+ T cells in 9 L-CTCL patients were either lower (L-CTCL-Low, n=2) or higher (L-CTCL-High, n=7) than normal. Five of the 7 GVHD patients had high percentages of CD4+Foxp3+ T cells (GVHD-High). Six of 7 L-CTCL-High patients had >80% CD4+Foxp3+ T cells which were correlated with tumor cells, and were responders. Both L-CTCL-High and GVHD-High patients had decreased percentages of CD4+Foxp3+ and CD4+Foxp3+CD25- T cells after 3 months of treatment. CD4+Foxp3+CD25+ T cells increased in GVHD-High patients but decreased in L-CTCL-High patients after 3 months of ECP. In addition, numbers of CTLs were abnormal. We confirmed that numbers of CTLs were low in L-CTCL patients, but high in GVHD patients prior to ECP. After ECP, CTLs increased after 1 month in 4/6 L-CTCL patients whereas CTLs decreased after 6 months in 3/3 GVHD patients. Myeloid (mDCs) and plasmacytoid DCs (pDCs) were also low at baseline in L-CTCL and GVHD patients confirming the DC defect. After 6 months of ECP, numbers and percentages of mDCs and pDCs increased in L-CTCL and GVHD. MDCs were favorably increased in 8/12 L-CTCL responders whereas pDCs were favorably increased in GVHD patients. These data suggest that ECP is favorably modulating the DC subsets. In L-CTCL patients, the mDCs may orchestrate Th1 cell responses to overcome immune suppression and facilitate disease regression. However, in GVHD patients, ECP is favorably down-regulating the immune system and may be facilitating immune tolerance to auto-or allo-antigens. In both L-CTCL and GVHD patients, DCs are modulated, but the T cell responses orchestrated by the DCs are different, suggesting that ECP modulates depending on the immune milieu. _______________

Economic evaluation and randomised controlled trial of extracorporeal membrane oxygenation: UK collaborative trial

Objective: To compare the resource implications and short term outcomes of extracorporeal membrane oxygenation and conventional management for term babies with severe respiratory failure.

Capgras syndrome: a clinical manifestation of watershed cerebral infarct complicating the use of extracorporeal membrane oxygenation

Ischaemic cerebral accidents are frequent following extracorporeal membrane oxygenation (ECMO), especially after fixing the reinjection cannula in the right primitive carotid artery, which leads to an interruption in downstream flow. We describe a rare and unusual symptom of cerebral ischaemic accident that is known as Capgras syndrome. This feature is interesting because it may be documented by computed tomography (CT) scan and particular electroencephalography signals. It appears that our observation represents the first documented case of Capgras syndrome complicating ECMO. This incident emphasizes the potential hazards associated with right common artery ligature for venoarterial extracorporeal membrane oxygenation (VAECMO). In addition, it shows that this psychiatric symptom (that has been interpreted psychodynamically for many years) can have an organic basis, which should be studied.

Cerebral Microembolization During Aortic Valve Replacement Using Minimally Invasive or Conventional Extracorporeal Circulation: A Randomized Trial.

To compare intraoperative cerebral microembolic load between minimally invasive extracorporeal circulation (MiECC) and conventional extracorporeal circulation (CECC) during isolated surgical aortic valve replacement (SAVR), we conducted a randomized trial in patients undergoing primary elective SAVR at a tertiary referral hospital. The primary outcome was the procedural phase-related rate of high-intensity transient signals (HITS) on transcranial Doppler ultrasound. HITS rate was used as a surrogate of cerebral microembolism in pre-defined procedural phases in SAVR using MiECC or CECC with (+F) or without (-F) an oxygenator with integrated arterial filter. Forty-eight patients were randomized in a 1:1 ratio to MiECC or CECC. Due to intraprocedural Doppler signal loss (n = 3), 45 patients were included in final analysis. MiECC perfusion regimen showed a significantly increased HITS rate compared to CECC (by a factor of 1.75; 95% confidence interval, 1.19-2.56). This was due to different HITS rates in procedural phases from aortic cross-clamping until declamping [phase 4] (P = 0.01), and from aortic declamping until stop of extracorporeal perfusion [phase 5] (P = 0.05). Post hoc analysis revealed that MiECC-F generated a higher HITS rate than CECC+F (P = 0.005), CECC-F (P = 0.05) in phase 4, and CECC-F (P = 0.03) in phase 5, respectively. In open-heart surgery, MiECC is not superior to CECC with regard to gaseous cerebral microembolism. When using MiECC for SAVR, the use of oxygenators with integrated arterial line filter appears highly advisable. Only with this precaution, MiECC confers a cerebral microembolic load comparable to CECC during this type of open heart surgery.

Bivalirudin for Alternative Anticoagulation in Extracorporeal Membrane Oxygenation: A Systematic Review.

BACKGROUND Extracorporeal membrane oxygenation (ECMO) offers therapeutic options in refractory respiratory and/or cardiac failure. Systemic anticoagulation with heparin is routinely administered. However, in patients with heparin-induced thrombocytopenia or heparin resistance, the direct thrombin inhibitor bivalirudin is a valid option and has been increasingly used for ECMO anticoagulation. We aimed at evaluating its safety and its optimal dosing for ECMO. METHODS Systematic web-based literature search of PubMed and EMBASE performed via National Health Service Library Evidence and manually, updated until January 30, 2016. RESULTS The search revealed 8 publications relevant to the topic (5 case reports). In total, 58 patients (24 pediatrics) were reported (18 received heparin as control groups). Bivalirudin was used with or without loading dose, followed by infusion at different ranges (lowest 0.1-0.2 mg/kg/h without loading dose; highest 0.5 mg/kg/h after loading dose). The strategies for monitoring anticoagulation and optimal targets were dissimilar (activated partial thromboplastin time 45-60 seconds to 42-88 seconds; activated clotting time 180-200 seconds to 200-220 seconds; thromboelastography in 1 study). CONCLUSION Bivalirudin loading dose was not always used; infusion range and anticoagulation targets were different. In this systematic review, we discuss the reasons for this variability. Larger studies are needed to establish the optimal approach with the use of bivalirudin for ECMO.

Extracorporeal circuit for Panton-Valentine leukocidin-producing Staphylococcus aureus necrotizing pneumonia [Traitement par ECMO d'une pneumopathie nécrosante à Staphylococcus aureus producteur de la leucocidine de Panton-Valentine]

National audience

ECMO : the clinician’s view

Background: Extra corporeal membrane oxygenation (ECMO) is a complex rescue therapy used to provide cardiac and/or respiratory support for critically ill patients who have failed maximal conventional medical management. ECMO is based on a modified cardiopulmonary bypass (CPB) circuit, and can provide cardiopulmonary support for up-to several months. It can be used in a veno venous configuration for isolated respiratory failure, (VV-ECMO), or in a veno arterial configuration (VA-ECMO) where support is necessary for cardiac +/- respiratory failure. The ECMO circuit consists of five main components: large bore cannulae (access cannulae) for drainage of the venous system, and return cannulae to either the venous (in VV-ECMO) or arterial (in VA ECMO) system. An oxygenator, with a vast surface area of hollow filaments, allows addition of oxygen and removal of carbon dioxide; a centrifugal blood pump allows propulsion of blood through the circuit at upto 10 L/minute; a control module and a thermoregulatory unit, which allows for exact temperature control of the extra corporeal blood. Methods: The first successful use of ECMO for ARDS in adults occurred in 1972, and its use has become more commonplace over the last 30 years, supported by the improvement in design and biocompatibility of the equipment, which has reduced the morbidity associated with this modality. Whilst the use of ECMO in neonatal population has been supported by numerous studies, the evidence upon which ECMO was integrated into adult practice was substantially less robust. Results: Recent data, including the CESAR study (Conventional Ventilatory Support versus Extra corporeal membrane oxygenation for Severe Respiratory failure) has added a degree of evidence to the role of ECMO in such a patient population. The CESAR study analysed 180 patients, and confirmed that ECMO was associated with an improved rate of survival. More recently, ECMO has been utilized in numerous situations within the critical care area, including support in high-risk percutaneous interventions in cardiac catheter lab; the operating room, emergency department, as well in specialized inter-hospital retrieval services. The increased understanding of the risk:benefit profile of ECMO, along with a reduction in morbidity associated with its use will doubtless lead to a substantial rise in the utilisation of this modality. As with all extra-corporeal circuits, ECMO opposes the basic premises of the mammalian inflammation and coagulation cascade where blood comes into foreign circulation, both these cascades are activated. Anti-coagulation is readily dealt with through use of agents such as heparin, but the inflammatory excess, whilst less macroscopically obvious, continues un-abated. Platelet consumption and neutrophil activation occur rapidly, and the clinician is faced with balancing the need of anticoagulation for the circuit, against haemostasis in an acutely bleeding patient. Alterations in pharmacokinetics may result in inadequate levels of disease modifying therapeutics, such as antibiotics, hence paradoxically delaying recovery from conditions such as pneumonia. Key elements of nutrition and the innate immune system maysimilarly be affected. Summary: This presentation will discuss the basic features of ECMO to the nonspecialist, and review the clinical conundrum faced by the team treating these most complex cases.

Fully Bayesian experimental design for pharmacokinetic studies

Utility functions in Bayesian experimental design are usually based on the posterior distribution. When the posterior is found by simulation, it must be sampled from for each future data set drawn from the prior predictive distribution. Many thousands of posterior distributions are often required. A popular technique in the Bayesian experimental design literature to rapidly obtain samples from the posterior is importance sampling, using the prior as the importance distribution. However, importance sampling will tend to break down if there is a reasonable number of experimental observations and/or the model parameter is high dimensional. In this paper we explore the use of Laplace approximations in the design setting to overcome this drawback. Furthermore, we consider using the Laplace approximation to form the importance distribution to obtain a more efficient importance distribution than the prior. The methodology is motivated by a pharmacokinetic study which investigates the effect of extracorporeal membrane oxygenation on the pharmacokinetics of antibiotics in sheep. The design problem is to find 10 near optimal plasma sampling times which produce precise estimates of pharmacokinetic model parameters/measures of interest. We consider several different utility functions of interest in these studies, which involve the posterior distribution of parameter functions.

A Critical Evaluation of the MARS Treatment in Finland

The Molecular Adsorbent Recirculating System (MARS) is an extracorporeal albumin dialysis device which is used in the treatment of liver failure patients. This treatment was first utilized in Finland in 2001, and since then, over 200 patients have been treated. The aim of this thesis was to evaluate the impact of the MARS treatment on patient outcome, the clinical and biochemical variables, as well as on the psychological and economic aspects of the treatment in Finland. This thesis encompasses 195 MARS-treated patients (including patients with acute liver failure (ALF), acute-on-chronic liver failure (AOCLF) and graft failure), and a historical control group of 46 ALF patients who did not undergo MARS. All patients received a similar standard medical therapy at the same intensive care unit. The baseline data (demographics, laboratory and clinical variables) and MARS treatment-related and health-related quality-of-life data were recorded before and after treatment. The direct medical costs were determined for a period of 3.5 years.Additionally, the outcome of patients (survival, native liver recovery and need for liver transplantation) and survival predicting factors were investigated. In the outcome analysis, for the MARS-treated ALF patients, their 6-month survival (75% vs. 61%, P=0.07) and their native liver recovery rate (49% vs. 17%, P<0.001) were higher, and their need for transplantations was lower (29% vs. 57%, P= 0.001) than for the historical controls. However, the etiological distribution of the ALF patients referred to our unit has changed considerably over the past decade and the percentage of patients with a more favorable prognosis has increased. The etiology of liver failure was the most important predictor of the outcome. Other survival predicting factors in ALF included hepatic encephalopathy, the coagulation factors and the liver enzyme levels prior to MARS treatment. In terms of prognosis, the MARS treatment of the cirrhotic AOCLF patient seems meaningful only when the patient is eligible for transplantation. The MARS treatment appears to halt the progression of encephalopathy and reduce the blood concentration of neuroactive amino acids, albumin-bound and water-soluble toxins. In general, the effects of the MARS treatment seem to stabilize the patients, thus allowing additional time either for the native liver to recover, or for the patients to endure the prolonged waiting for transplantation. Furthermore, for the ALF patients, the MARS treatment appeared to be less costly and more cost-efficient than the standard medical therapy alone. In conclusion, the MARS treatment appears to have a beneficial effect on the patient outcome in ALF and in those AOCLF patients who can be bridged to transplantation.

Monitorización avanzada en el posoperatorio de las cardiopatías congénitas : motorización hemodinámica avanzada en el posoperatorio de cardiopatías congénitas mediante termodilución transpulmonar y espectroscopia cercana al infrarrojo

196 p. : graf.

Avaliação da função endotelial microvascular, da rigidez arterial e da resposta inflamatória sistêmica em pacientes submetidos a cirurgia cardíaca com circulação extracorpórea

A Cirurgia de Revascularização do Miocárdio, realizada com o auxílio da Circulação Extracorpórea, está associada a alterações importantes na microcirculação e na produção e circulação de citocinas e marcadores inflamatórios. No presente estudo, foram avaliados 23 pacientes com indicação de Revascularização do Miocárdio, no dia do procedimento e 7 e 28 dias após a cirurgia. A microcirculação cutânea, enquanto reflexo da microcirculação coronariana, foi estudada através da hiperemia térmica e/ ou reativa pós oclusiva e da iontoforese de substâncias vasoativas por mecanismos dependentes e independentes do endotélio. A rigidez arterial foi aferida através da análise da onda de pulso digital. Foi avaliado ainda o impacto da doença e do procedimento cirúrgico sobre a produção e circulação sérica de citocinas e marcadores inflamatórios, tais como: PCR-HS, nitrito/ nitrato, IL-6, Il-7, IL-8, IL-10, IFN-γ, TNF-α e G-CSF. Foi observada uma tendência à redução da vasodilatação da microcirculação cutânea após a administração de doses acumulativas de acetilcolina (endotélio dependente) através da iontoforese de 7 e 28 dias após o procedimento cirúrgico. A hiperemia térmica foi mais pronunciada na avaliação basal do que aos 7 e 28 dias. A hiperemia reativa pós oclusiva não demonstrou alterações 7 dias após o procedimento. Aos 28 dias, houve um aumento da condutância microvascular cutânea. Quando avaliada a vasodilatação endotélio-independente (nitroprussiato de sódio), observamos aumento do fluxo microvascular cutâneo diretamente proporcional à carga/ dose aplicada, sem diferenças nos valores obtidos no basal e 7 e 28 dias após o procedimento. A rigidez arterial não apresentou alterações. A análise dos fatores inflamatórios e das citocinas demonstrou aumento marcante da IL-6 e da IL-8 após 7 dias do procedimento cirúrgico, com retorno parcial aos níveis basais da IL-6 e total da IL-8 após 28 dias. O IFN-γ, TNF-α e G-CSF apenas apresentaram níveis detectáveis na avaliação basal e IL-7 e IL-10 não demonstraram alterações significativas nos tempos avaliados. A PCR-HS demonstrou níveis mais elevados após 7 dias e retorno parcial aos níveis basais após 28 dias. O nitrito/ nitrato, após 7 dias, apresentou leve queda em sua concentração plasmática. Concluímos que a pequena diferença entre o valores obtidos entre o basal e após 7 dias do procedimento cirúrgico com a iontoforese de acetilcolina resulta em minimização do impacto endotelial e um valor constante deste dado após 28 dias, sugere recomposição fisiológica completa. Este resultado foi semelhante com a análise da hiperemia térmica e reativa pós oclusiva. As interleucinas IL-6 e IL-8, bem como a PCR-HS apresentaram comportamento correlacionável, refletindo a cinética inflamatória. A rigidez arterial não demonstrou alterações.

Eventos cardíacos decorrentes da infusão contínua de cloridrato de amiodarona: implicações para o enfermeiro

O objeto de estudo são os eventos cardíacos resultantes da infusão contínua de cloridrato de amiodarona em pacientes que evoluíram com fibrilação atrial em pós-operatório de cirurgia cardíaca. Os objetivos foram descrever as características dos pacientes que receberam infusão contínua de cloridrato de amidoarona, apresentar a prevalência de bradicardia e hipotensão encontrada nos pacientes que receberam infusão contínua de cloridrato de amiodarona e discutir as implicações dos achados para a prática dos enfermeiros a partir da prevalência encontrada de bradicardia e hipotensão decorrente da infusão contínua desta substância. Trata-se de um estudo transversal, retrospectivo, documental, por meio de análise de prontuários e avaliação quantitativa dos mesmos. Desenvolvida em uma unidade de pós-operatório de cirurgia cardíaca em um hospital universitário pertencente à rede sentinela no município do Rio de Janeiro. Foi considerado hipotensão em presença de PAS menor que 90 mmHg e bradicardia em presença de frequência cardíaca menor que 60 bpm. As variáveis que caracterizavam a população do estudo e as aferições de pressão arterial e frequência cardíaca foram transcritas para um instrumento de coleta de dados dos anos de 2010 e 2011, gerando 1782 horas de infusão contínua de cloridrato de amiodarona em 27 pacientes cirúrgicos (10,50%). Tratou-se de uma população predominantemente feminina, com idade a cima de 60 anos, período de internação superior a uma semana, apresentava hipertensão arterial prévia (59,26%), era portadora de fibrilação atrial (55,56%) e o diagnóstico cirúrgico de revascularização do miocárdio com circulação extracorpórea foi predominante (70,37%). Os dados mostram que 85,19% dos pacientes eram portadores de pelo menos um fator de risco, 70,37% apresentavam dois fatores de risco e 55,55% apresentavam três fatores de risco para desenvolver fibrilação atrial no pós-operatório de cirurgia cardíaca. Foi encontrada uma prevalência de 85,19% pacientes que apresentaram bradicardia, 66,67% apresentaram hipotensão e 59,26% apresentaram tanto bradicardia como hipotensão. Foram 160 episódios de bradicardia com 6,40 episódios por paciente e 77 episódios de hipotensão com 4,2 por paciente. A bradicardia ocorreu principalmente entre 48 e 72 horas do inicio da infusão. Já a hipotensão aumentou progressivamente nas primeiras 48 horas de infusão. Na presença de bradicardia a intervenção mais frequente foi redução da vazão de amiodarona já na presença de hipotensão, a manutenção de infusão de noradrenalina foi a conduta mais regular. Como estratégia de melhoria para segurança do paciente, foram elaboradas condutas como método de barreira para prevenção de eventos adversos como a bradicardia e hipotensão. Os principais cuidados de enfermagem a serem implementados pelo enfermeiro foram o levantamento de fatores de risco para a fibrilação atrial, a detecção da fibrilação atrial, a manutenção de monitorização cardíaca contínua, aferição horária do ritmo cardíaco e o controle da frequência cardíaca e pressão arterial, objetivando intervir precocemente em presença de hipotensão ou bradicardia.