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1.
Trials ; 21(1): 1005, 2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298149

RESUMO

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

2.
Clin Nutr ; 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33454128

RESUMO

BACKGROUND & AIMS: Hypophosphatemia (HypoP) is associated with organ dysfunction and mortality. Despite its potential severe consequences, HypoP remains poorly characterized in terms of real prevalence and timing of onset. The primary objective was to determine the prevalence of HypoP defined as blood phosphate <0.8 and < 0.65 mmol/l on one particular day at international level. METHODS: One-day point prevalence survey conducted by the Section of Metabolism, Endocrinology and Nutrition (MEN) of the European Society of Intensive Care Medicine (ESICM) during week 11-2020. RESULTS: In total, 56 adult and 4 paediatric ICUs, from 22 countries participated: 41 ICUs were mixed medico surgical, the 19 others being cardiac, medical or surgical. Phosphate measurements were performed daily in 21 ICUs, and 1-3 times per week in 39 ICUs. On D-Day 909 patients (883 adults) were present and 668/883 (75.7%) had serum/plasma phosphate determined, revealing a HypoP in 103 (15.4%) patients aged 62 [18 to 85] years. Of those, 49 patients presented phosphate <0.65 mmol/l: cases of hypophosphatemia were detected at any time of patient's ICU stay. No HypoP was observed in children. A treatment protocol existed only in 41.1% of adult ICUs, independently of ICU type, or size. Only 41/98 of the HypoP patients (29/41 of patients with phosphate <0.65 mmol/l) were receiving phosphate. CONCLUSION: HypoP is present at least in 15.4% of ICU patients, and may occur at any time during the ICU stay. The absence of phosphate repletion protocols in 60% of participating ICUs is an unexpected finding, and confirms the necessity for the development of ICU phosphate protocols and guidelines. CLINICALTRIALS IDENTIFIER: NCT04201899.

3.
Clin Microbiol Infect ; 22(6): 568.e9-568.e17, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27085724

RESUMO

There have been many studies pertaining to the management of herpetic meningoencephalitis (HME), but the majority of them have focussed on virologically unconfirmed cases or included only small sample sizes. We have conducted a multicentre study aimed at providing management strategies for HME. Overall, 501 adult patients with PCR-proven HME were included retrospectively from 35 referral centres in 10 countries; 496 patients were found to be eligible for the analysis. Cerebrospinal fluid (CSF) analysis using a PCR assay yielded herpes simplex virus (HSV)-1 DNA in 351 patients (70.8%), HSV-2 DNA in 83 patients (16.7%) and undefined HSV DNA type in 62 patients (12.5%). A total of 379 patients (76.4%) had at least one of the specified characteristics of encephalitis, and we placed these patients into the encephalitis presentation group. The remaining 117 patients (23.6%) had none of these findings, and these patients were placed in the nonencephalitis presentation group. Abnormalities suggestive of encephalitis were detected in magnetic resonance imaging (MRI) in 83.9% of the patients and in electroencephalography (EEG) in 91.0% of patients in the encephalitis presentation group. In the nonencephalitis presentation group, MRI and EEG data were suggestive of encephalitis in 33.3 and 61.9% of patients, respectively. However, the concomitant use of MRI and EEG indicated encephalitis in 96.3 and 87.5% of the cases with and without encephalitic clinical presentation, respectively. Considering the subtle nature of HME, CSF HSV PCR, EEG and MRI data should be collected for all patients with a central nervous system infection.


Assuntos
Encefalite por Herpes Simples/diagnóstico , Encefalite por Herpes Simples/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Líquido Cefalorraquidiano/virologia , DNA Viral/análise , DNA Viral/genética , Testes Diagnósticos de Rotina , Eletroencefalografia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Adulto Jovem
4.
Intensive Care Med ; 41(9): 1648-57, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26156107

RESUMO

PURPOSE: Studies on recovery from acute kidney injury (AKI) in ICU patients yield variable results. We assessed the impact of different recovery definitions, of different exclusion criteria, and of imputing missing baseline creatinine on AKI recovery in a heterogeneous ICU population. METHODS: Secondary analysis of the EPaNIC database. Recovery of kidney function in patients who developed AKI in ICU was assessed at hospital discharge. We studied recovery rates of different AKI stages with different definitions of recovery after inclusion or exclusion of non-survivors and in patients with or without chronic kidney disease (CKD). In addition, the impact of imputing missing baseline creatinine was investigated. RESULTS: A total of 1310 AKI patients were studied of which 977 were discharged alive from hospital. Rate of complete recovery (absence of KDIGO criteria) was markedly higher in survivors than in all AKI patients (79.5 vs 67.0%), especially for more severe forms of AKI. For patients with CKD, only the need for renal replacement therapy worsened kidney outcome as compared with no-CKD patients. Using stricter definitions of complete recovery significantly reduced its occurrence. New or worsening CKD occurred in 30% of AKI survivors. In no-CKD patients with available baseline creatinine, using an imputed baseline did not affect recovery. Patients with unavailable baseline creatinine were different from those with known baseline and revealed different recovery patterns. CONCLUSION: These results indicate the need for rigorous description of AKI severity, the included population, definitions, and baseline creatinine handling in reports on AKI recovery.


Assuntos
Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/terapia , Lesão Renal Aguda/sangue , Idoso , Fatores de Confusão Epidemiológicos , Creatinina/sangue , Estado Terminal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão
5.
Intensive Care Med ; 40(11): 1709-17, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25266132

RESUMO

PURPOSE: To quantify the error in evaluating recovery from acute kidney injury (AKI) with estimated GFR (eGFR) in relation to ICU stay. METHODS: Secondary analysis performed on the database of the EPaNIC trial. In a cohort of patients who developed AKI during ICU stay we compared eGFR with measured creatinine clearance (Clcr) at ICU discharge. Recovery of kidney function was assessed by comparison with baseline eGFR and the accuracy of eGFR to detect "potential CKD status" defined by Clcr was quantified. The same analysis was performed in subgroups with different ICU stay. Multivariate regression was performed to determine independent predictors of the eGFR-Clcr difference. RESULTS: A total of 757 patients were included. The bias (limits of agreement (LOA)) between eGFR and Clcr at ICU discharge related to ICU stay, increasing from +1.3 (-37.4/+40) ml/min/1.73 m(2) in patients with short stay to +34.7 (-54.4/+123.8) ml/min/1.73 m(2) in patients with ICU stay of more than 14 days. This resulted in a significantly different incidence of complete recovery with the two evaluation methods and reduced sensitivity to detect "potential CKD status" with eGFR in patients with prolonged ICU stay. Independent predictors of the bias included creatinine excretion on the last day in ICU, baseline eGFR, ICU stay, gender, and age. CONCLUSION: Compared to Clcr, discharge eGFR results in overestimation of renal recovery in patients with prolonged ICU stay and in reduced accuracy of "CKD staging". Since age, gender and race do not change during ICU stay the same conclusion can be drawn with regard to plasma creatinine.


Assuntos
Lesão Renal Aguda/fisiopatologia , Lesão Renal Aguda/terapia , Creatinina/urina , Taxa de Filtração Glomerular/fisiologia , Unidades de Terapia Intensiva , Avaliação de Resultados em Cuidados de Saúde , Idoso , Feminino , Humanos , Testes de Função Renal/métodos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Resultado do Tratamento
6.
Horm Metab Res ; 45(12): 862-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23950035

RESUMO

Prolonged critically ill patients present with distinct alterations in calcium and bone metabolism. Circulating bone formation markers are reduced and bone resorption markers are substantially elevated, indicating an uncoupling between osteoclast and osteoblast activity, possibly resulting in pronounced bone loss, impaired traumatic or surgical fracture healing, and osteoporosis. In addition, we have previously shown that increased circulating osteoclast precursors in critically ill patients result in increased osteoclastogenesis in vitro, possibly through FcγRIII signaling. In the current study, we investigated the effects of sustained critical illness on bone metabolism at the tissue level in a standardized rabbit model of prolonged (7 days), burn injury-induced critical illness. This in vivo model showed a reduction in serum ionized calcium and osteocalcin levels, as is seen in humans. Trabecular area, bone mineral content, and -density were decreased in sick rabbits [by 43% (p<0.01), 31% (p<0.01), and 29% (p<0.05), respectively], as was the trabecular gene expression of osteoblast and angiogenesis markers, indicating decreased bone formation and impaired vascularization. There was no change in the expression of osteoclast differentiation markers from the canonical RANK/RANKL/OPG pathway, however, there was an increase in expression of markers from the non-canonical, immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway, FcγRIII, and DAP12 (148% and 59%, respectively; p<0.01). The current study has shown a detrimental effect of prolonged critical illness on trabecular bone integrity, possibly explained by reduced osteoblast differentiation and angiogenesis, coupled with increased osteoclastogenesis signaling that may be mediated via the non-canonical immunoreceptor tyrosine-based activation motif signaling pathway.


Assuntos
Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Estado Terminal , Motivo de Ativação do Imunorreceptor Baseado em Tirosina , Animais , Biomarcadores/metabolismo , Reabsorção Óssea/sangue , Reabsorção Óssea/genética , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Cálcio/sangue , Regulação da Expressão Gênica , Humanos , Íons/sangue , Masculino , Neovascularização Fisiológica/genética , Osteocalcina/sangue , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteogênese/genética , Coelhos , Transdução de Sinais
7.
Horm Metab Res ; 45(4): 277-82, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23093461

RESUMO

Prolonged critical illness is hallmarked by striking alterations in the somatrope, thyrotrope, and lactotrope axes, the severity of which is associated with the risk of morbidity and mortality. The exact role of the pituitary gland in these alterations is unknown. We studied the impact of sustained critical illness on pituitary morphology and hormone production in a standardized rabbit model of prolonged (7 days) burn injury-induced critical illness. In healthy and prolonged critically ill rabbits, we determined pituitary weight, size, morphology and orientation of the somatrope, lactotrope and thyrotrope cells and the pituitary expression of GH, PRL, and TSH at gene and protein level. The weight of the pituitary gland was unaltered by 7 days of critical illness. Also, spatial orientation and morphology of the GH, PRL, and TSH producing cells remained normal. In prolonged critically ill rabbits GH mRNA levels were higher and PRL mRNA levels were lower than in healthy controls, whereas TSH mRNA was not affected. The sizes of GH, PRL, or TSH producing cells and the pituitary content of GH, PRL, and TSH proteins were unaltered. In conclusion, in this rabbit model of prolonged critical illness, the morphology of the pituitary gland and the pituitary GH, PRL, and TSH content was normal. The alterations in pituitary hormone mRNA levels with sustained critical illness are compatible with altered hypothalamic and peripheral regulation of pituitary hormone release as previously suggested indirectly by responses to exogenous releasing factors.


Assuntos
Queimaduras/metabolismo , Queimaduras/patologia , Regulação da Expressão Gênica , Adeno-Hipófise/metabolismo , Adeno-Hipófise/patologia , Hormônios Hipofisários/biossíntese , Animais , Estado Terminal , RNA Mensageiro/biossíntese , Coelhos , Fatores de Tempo
9.
Bioorg Med Chem Lett ; 9(21): 3159-64, 1999 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-10560744

RESUMO

Short-chain 3-fluoro-(dihydro)ceramide analogues are synthesized from L-serine using diethylaminosulfur trifluoride (DAST) as fluorinating agent. The apoptogenic activity of these compounds was measured in three different cell lines and compared with their hydroxylated counterparts.


Assuntos
Apoptose/efeitos dos fármacos , Ceramidas/síntese química , Compostos de Flúor/síntese química , Ceramidas/farmacologia , Dietilaminas/química , Flúor/química , Compostos de Flúor/farmacologia , Humanos , Linfócitos/efeitos dos fármacos , Células Tumorais Cultivadas
10.
Arch Androl ; 41(2): 103-14, 1998.
Artigo em Inglês | MEDLINE | ID: mdl-9730439

RESUMO

Sperm morphology has always been considered an important tool in evaluating a man's fertilizing potential. The objective of this multicentric study was to evaluate intra- and interindividual variability and between-laboratory variation using the same or different criteria of sperm morphology assessment. Semen samples were obtained from 20 males and 32 smears were made of all samples. Eighty coded smears (4 per patient) were sent to 8 laboratories for morphology assessment. The centers applied different classification systems (strict criteria, WHO 1987, Düsseldorf criteria) and participants were asked to analyze the 80 smears twice, with an interval of 1 week between each participant's two analyses. Intraclass correlations between repeats showed that sperm morphology can be assessed with acceptable within observer reproducibility. Expected increases in imprecision were observed up to coefficients of variation of >30% with decreasing morphology scores, regardless of the classification system used. Agreement in correct classification of samples as normal/abnormal was obtained in 80% of cases. Differences in reproducibility between slides may reflect an important source of heterogeneity due to smear preparation. These results emphasize the importance of external quality control systems to improve the value of sperm morphology assessments in the investigation of the male partner in a subfertile couple.


Assuntos
Espermatozoides/citologia , Fertilização In Vitro , Humanos , Laboratórios/normas , Masculino , Reprodutibilidade dos Testes
11.
Clin Chem ; 44(5): 939-43, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9590365

RESUMO

Creatine kinase (CK, EC 2.7.3.2) assays usually contain thiol-reducing compounds to restore the enzyme activity. In this study, we investigated the effect of endogenous extracellular glutathione on serum CK activity. We examined CK activity and glutathione concentrations in serum from 200 healthy subjects (107 males, 93 females) and 38 patients with multiple organ failure, muscle wasting, and low serum CK activity (<50 U/L) (24 males, 14 females). Muscle damage was further evaluated using serum myoglobin concentrations and aldolase activity. In the overall group, serum glutathione concentrations correlated with serum CK activity (r = 0.791) but not with myoglobin concentrations and aldolase activity. In patients with multiple organ failure, low serum CK activities were accompanied by extremely low serum glutathione concentrations (<0.5 ,micromol/L, P <0.001). Endogenous glutathione can be regarded as a CK-preserving agent during the lifetime of the enzyme in the circulation (22 h on average). Serum CK activity should be interpreted with caution in patients with liver disease and multiple organ failure. In these conditions, the loss of CK activity due to extracellular glutathione depletion cannot be restored by the presence of thiol-reducing compounds in the CK assays.


Assuntos
Creatina Quinase/sangue , Glutationa/sangue , Músculo Esquelético/enzimologia , Adulto , Idoso , Ensaios Enzimáticos Clínicos , Estabilidade Enzimática , Espaço Extracelular/metabolismo , Feminino , Frutose-Bifosfato Aldolase/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/patologia , Debilidade Muscular/diagnóstico , Debilidade Muscular/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/diagnóstico , Atrofia Muscular/patologia , Mioglobina/sangue , Oxirredução , Compostos de Sulfidrila/química
12.
Anesth Analg ; 85(1): 111-6, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9212132

RESUMO

We describe a novel supraclavicular approach to the brachial plexus. Designated as the intersternocleidomastoid technique, this new approach was tested in unembalmed cadavers. It was then applied for evaluation to 150 ASA grade I or II patients scheduled for elective surgery or physiotherapy of the upper limb or for treatment of reflex sympathetic dystrophy associated with painful shoulder. The new approach was easy to master because of a very simple surface landmark, i.e., the triangle formed by the sternocleidomastoid heads, which were visible and palpable in most patients studied (90%). The procedure was effective intraoperatively, providing satisfactory anesthesia in 140 patients (93%), partially satisfactory blocks in 6 (4%), and unsatisfactory blocks in only 4 (3%). The catheter entry point is cephalad enough not to obscure the surgical field on the shoulder. Catheter insertion was successful in 63 of 70 patients. Postoperative analgesia was provided for 48 h or more in 45 patients and for 24 h in 18 patients. Only minor complications were observed: asymptomatic phrenic nerve block in 89 patients (60%), transient Horner's syndrome in 15 (10%), transient recurrent laryngeal nerve blockade in 2, and misplacement of the catheter into the subclavian vein in 1 patient. No pneumothorax was observed.


Assuntos
Plexo Braquial , Bloqueio Nervoso/métodos , Adulto , Braço/cirurgia , Feminino , Humanos , Masculino , Bloqueio Nervoso/efeitos adversos , Dor/reabilitação , Manejo da Dor , Medição da Dor , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controle , Modalidades de Fisioterapia , Articulação do Ombro
14.
Ann Fr Anesth Reanim ; 15(2): 189-91, 1996.
Artigo em Francês | MEDLINE | ID: mdl-8734239

RESUMO

A toxic shock syndrome occurred after a femoral nail removal requiring revision surgery. After administration of suxamethonium (1 mg.kg-1), an apnoea prolonged over 45 minutes was observed. The trachea was extubated 105 minutes after suxamethonium administration. For the nail removal, two days before, the anaesthetic had been given by the same anaesthesiologist, with a similar protocol. Apnoea extended over 20 minutes. The day of the revision surgery, plasma cholinesterase activity was 410 UI.L-1 and reached 910 UI.L-1, 9 months later. Dibucaine number was 20 and fluorure number 17. The apnoea was in relation with a genetic plasma cholinesterase deficiency increased by the toxic shock syndrome. Shock and hepatic insufficiency were suspected to contribute to the decrease in plasma cholinesterase. Suxamethonium should be avoided in case of toxic shock syndrome.


Assuntos
Apneia/induzido quimicamente , Fármacos Neuromusculares Despolarizantes/efeitos adversos , Choque Séptico/complicações , Infecções Estafilocócicas/complicações , Succinilcolina/efeitos adversos , Adulto , Colinesterases/sangue , Colinesterases/metabolismo , Humanos , Masculino
18.
Can J Anaesth ; 35(3 ( Pt 1)): 242-8, 1988 May.
Artigo em Inglês | MEDLINE | ID: mdl-3383316

RESUMO

Sixteen patients (13-38 yr) undergoing spinal fusion for scoliosis under controlled hypotension were studied to determine the haemodynamic and neuroendocrine responses to IV dihydralazine (1.0 mg.kg-1) followed by 0.5 and 1 MAC of enflurane or isoflurane. Twenty minutes after dihydralazine administration mean arterial pressure (-20 per cent) and systemic vascular resistance (-50 per cent) decreased, and cardiac index (+57 per cent), heart rate (+37 per cent) and intrapulmonary shunt increased. Plasma renin activity and aldosterone and norepinephrine levels increased. Further decreases in mean arterial pressure and in systemic vascular resistance were observed when 0.5 MAC enflurane or isoflurane were added. With 1 MAC anaesthetic levels a further decrease in mean arterial pressure was observed in both groups, but pressure fell to a lower level with isoflurane than with enflurane (p less than 0.01). The reduction of arterial blood pressure to a level of 50-60 mmHg for three to four hours was easy to control and was free of complications. The preliminary IV administration of dihydralazine allowed a reduced volatile agent concentration which attenuated undesirable haemodynamic effects, in spite of renin and norepinephrine release, and permitted a rapid intraoperative awakening.


Assuntos
Anestésicos/administração & dosagem , Di-Hidralazina/administração & dosagem , Hidralazina/análogos & derivados , Hipotensão/induzido quimicamente , Adolescente , Adulto , Anestesia , Sinergismo Farmacológico , Enflurano/administração & dosagem , Feminino , Humanos , Isoflurano/administração & dosagem , Masculino , Escoliose/cirurgia , Fusão Vertebral
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