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1.
J Neurosurg ; : 1-7, 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34678766

RESUMO

OBJECTIVE: Awake craniotomies are often characterized by alternating asleep-awake-asleep periods. Preceding the awake phase, patients are weaned from anesthesia and mechanical ventilation. Although clinicians aim to minimize the time to awake for patient safety and operating room efficiency, in some patients, the time to awake exceeds 20 minutes. The goal of this study was to determine the average time to awake and the factors associated with prolonged time to awake (> 20 minutes) in patients undergoing awake craniotomy. METHODS: Records of patients who underwent awake craniotomy between 2003 and 2020 were evaluated. Time to awake was defined as the time between discontinuation of propofol and remifentanil infusion and the time of extubation. Patient and perioperative characteristics were explored as predictors for time to awake using logistic regression analyses. RESULTS: Data of 307 patients were analyzed. The median (IQR) time to awake was 13 (10-20) minutes and exceeded 20 minutes in 17% (95% CI 13%-21%) of the patients. In both univariate and multivariable analyses, increased age, nonsmoker status, and American Society of Anesthesiologists (ASA) class III versus II were associated with a time to awake exceeding 20 minutes. BMI, as well as the use of alcohol, drugs, dexamethasone, or antiepileptic agents, was not significantly associated with the time to awake. CONCLUSIONS: While most patients undergoing awake craniotomy are awake within a reasonable time frame after discontinuation of propofol and remifentanil infusion, time to awake exceeded 20 minutes in 17% of the patients. Increasing age, nonsmoker status, and higher ASA classification were found to be associated with a prolonged time to awake.

2.
Intensive Care Med Exp ; 9(1): 30, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34169407

RESUMO

BACKGROUND: Acute kidney injury is a severe complication following cardiopulmonary bypass (CPB) and is associated with capillary leakage and microcirculatory perfusion disturbances. CPB-induced thrombin release results in capillary hyperpermeability via activation of protease-activated receptor 1 (PAR1). We investigated whether aprotinin, which is thought to prevent thrombin from activating PAR1, preserves renal endothelial structure, reduces renal edema and preserves renal perfusion and reduces renal injury following CPB. METHODS: Rats were subjected to CPB after treatment with 33.000 KIU/kg aprotinin (n = 15) or PBS (n = 15) as control. A secondary dose of 33.000 KIU/kg aprotinin was given 60 min after initiation of CPB. Cremaster and renal microcirculatory perfusion were assessed using intravital microscopy and contrast echography before CPB and 10 and 60 min after weaning from CPB. Renal edema was determined by wet/dry weight ratio and renal endothelial structure by electron microscopy. Renal PAR1 gene and protein expression and markers of renal injury were determined. RESULTS: CPB reduced cremaster microcirculatory perfusion by 2.5-fold (15 (10-16) to 6 (2-10) perfused microvessels, p < 0.0001) and renal perfusion by 1.6-fold (202 (67-599) to 129 (31-292) au/sec, p = 0.03) in control animals. Both did not restore 60 min post-CPB. This was paralleled by increased plasma creatinine (p < 0.01), neutrophil gelatinase-associated lipocalin (NGAL; p = 0.003) and kidney injury molecule-1 (KIM-1; p < 0.01). Aprotinin treatment preserved cremaster microcirculatory perfusion following CPB (12 (7-15) vs. 6 (2-10) perfused microvessels, p = 0.002), but not renal perfusion (96 (35-313) vs. 129 (31-292) au/s, p > 0.9) compared to untreated rats. Aprotinin treatment reduced endothelial gap formation (0.5 ± 0.5 vs. 3.1 ± 1.4 gaps, p < 0.0001), kidney wet/dry weight ratio (4.6 ± 0.2 vs. 4.4 ± 0.2, p = 0.046), and fluid requirements (3.9 ± 3.3 vs. 7.5 ± 3.0 ml, p = 0.006) compared to untreated rats. In addition, aprotinin treatment reduced tubulointerstitial neutrophil influx by 1.7-fold compared to untreated rats (30.7 ± 22.1 vs. 53.2 ± 17.2 neutrophil influx/section, p = 0.009). No differences were observed in renal PAR1 expression and plasma creatinine, NGAL or KIM-1 between groups. CONCLUSIONS: Aprotinin did not improve renal perfusion nor reduce renal injury during the first hour following experimental CPB despite preservation of renal endothelial integrity and reduction of renal edema.

3.
Intensive Care Med Exp ; 9(1): 23, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-33997943

RESUMO

BACKGROUND: Hemorrhagic shock is associated with acute kidney injury and increased mortality. Targeting the endothelial angiopoietin/Tie2 system, which regulates endothelial permeability, previously reduced hemorrhagic shock-induced vascular leakage. We hypothesized that as a consequence of vascular leakage, renal perfusion and function is impaired and that activating Tie2 restores renal perfusion and function. METHODS: Rats underwent 1 h of hemorrhagic shock and were treated with either vasculotide or PBS as control, followed by fluid resuscitation for 4 h. Microcirculatory perfusion was measured in the renal cortex and cremaster muscle using contrast echography and intravital microscopy, respectively. Changes in the angiopoietin/Tie2 system and renal injury markers were measured in plasma and on protein and mRNA level in renal tissue. Renal edema formation was determined by wet/dry weight ratios and renal structure by histological analysis. RESULTS: Hemorrhagic shock significantly decreased renal perfusion (240 ± 138 to 51 ± 40, p < 0.0001) and cremaster perfusion (12 ± 2 to 5 ± 2 perfused vessels, p < 0.0001) compared to baseline values. Fluid resuscitation partially restored both perfusion parameters, but both remained below baseline values (renal perfusion 120 ± 58, p = 0.08, cremaster perfusion 7 ± 2 perfused vessels, p < 0.0001 compared to baseline). Hemorrhagic shock increased circulating angiopoietin-1 (p < 0.0001), angiopoietin-2 (p < 0.0001) and soluble Tie2 (p = 0.05), of which angiopoietin-2 elevation was associated with renal edema formation (r = 0.81, p < 0.0001). Hemorrhagic shock induced renal injury, as assessed by increased levels of plasma neutrophil gelatinase-associated lipocalin (NGAL: p < 0.05), kidney injury marker-1 (KIM-1; p < 0.01) and creatinine (p < 0.05). Vasculotide did not improve renal perfusion (p > 0.9 at all time points) or reduce renal injury (NGAL p = 0.26, KIM-1 p = 0.78, creatinine p > 0.9, renal edema p = 0.08), but temporarily improved cremaster perfusion at 3 h following start of fluid resuscitation compared to untreated rats (resuscitation + 3 h: 11 ± 3 vs 8 ± 3 perfused vessels, p < 0.05). CONCLUSION: Hemorrhagic shock-induced renal impairment cannot be restored by standard fluid resuscitation, nor by activation of Tie2. Future treatment strategies should focus on reducing angiopoietin-2 levels or on activating Tie2 via an alternative strategy.

4.
Shock ; 56(6): 890-900, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33927137

RESUMO

BACKGROUND: Microvascular leakage is proposed as main contributor to disturbed microcirculatory perfusion following hemorrhagic shock and fluid resuscitation, leading to organ dysfunction and unfavorable outcome. Currently, no drugs are available to reduce or prevent microvascular leakage in clinical practice. We therefore aimed to provide an overview of therapeutic agents targeting microvascular leakage following experimental hemorrhagic shock and fluid resuscitation. METHODS: PubMed, EMBASE.com, and Cochrane Library were searched in January 2021 for preclinical studies of hemorrhagic shock using any therapeutic agent on top of standard fluid resuscitation. Primary outcome was vascular leakage, defined as edema, macromolecule extravasation, or glycocalyx degradation. Drugs were classified by targeting pathways and subgroup analyses were performed per organ. RESULTS: Forty-five studies, published between 1973 and 2020, fulfilled eligibility criteria. The included studies tested 54 different therapeutics mainly in pulmonary and intestinal vascular beds. Most studies induced trauma besides hemorrhagic shock. Forty-four therapeutics (81%) were found effective to reduce microvascular leakage, edema formation, or glycocalyx degradation in at least one organ. Targeting oxidative stress and apoptosis was the predominantly effective strategy (SMD: -2.18, CI [-3.21, -1.16], P < 0.0001). Vasoactive agents were found noneffective in reducing microvascular leakage (SMD: -0.86, CI [-3.07, 1.36], P = 0.45). CONCLUSION: Pharmacological modulation of pathways involved in cell metabolism, inflammation, endothelial barrier regulation, sex hormones and especially oxidative stress and apoptosis were effective in reducing microvascular leakage in experimental hemorrhagic shock with fluid resuscitation. Future studies should investigate whether targeting these pathways can restore microcirculatory perfusion and reduce organ injury following hemorrhagic shock. SYSTEMATIC REVIEW REGISTRATION NUMBER: CRD42018095432.


Assuntos
Hidratação/efeitos adversos , Microcirculação , Ressuscitação/métodos , Choque Hemorrágico/complicações , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/etiologia , Animais
5.
J Clin Med ; 10(3)2021 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530543

RESUMO

Obesity is a frequent comorbidity among patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Cardiac surgery with CPB impairs microcirculatory perfusion, which is associated with multiple organ failure. As microvascular function is frequently compromised in obese patients, we studied whether cardiac surgery with CPB has a more detrimental effect on microcirculatory perfusion in obese patients. Sublingual microcirculatory perfusion was measured with sidestream dark field (SDF) imaging in obese patients (body mass index ≥32 kg/m2; n = 14) without type II diabetes mellitus and in lean patients (BMI 20-25 kg/m2; n = 22) undergoing cardiac surgery with CPB. CPB reduced systolic blood pressure and mean arterial pressure more profoundly in lean compared with obese patients (SBP: 38% vs. 18%; MAP: 11% vs. 8%, p < 0.05), and both restored after weaning from CPB. No differences were present in intraoperative glucose, hematocrit, hemoglobin, lactate, and blood gas values between obese and lean patients. Microcirculatory perfusion did not differ between obese and lean patients the day before surgery. CPB decreased microcirculatory perfusion with 9% in both groups, but this was only significant in lean patients (p < 0.05). Three days following surgery, microcirculatory perfusion was restored in both groups. In conclusion, microcirculatory perfusion was equally disturbed during cardiac surgery with CPB in metabolically healthy obese patients compared to lean patients.

6.
Anesth Analg ; 131(6): 1708-1720, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33186159

RESUMO

During hyperinflammatory conditions that can occur in acute critical illness, such as shock or hypoperfusion, inflammatory mediators activate the endothelium, fueling a proinflammatory host-response as well as procoagulant processes. These changes result in shedding of the glycocalyx, endothelial hyperpermeability, edema formation, and lead to disturbed microcirculatory perfusion and organ failure. Different fluid strategies that are used in shock may have differential effects on endothelial integrity. Collectively, low protein content fluids seem to have negative effects on the endothelial glycocalyx, aggravating endothelial hyperpermeability, whereas fluids containing albumin or plasma proteins may be superior to normal saline in protecting the glycocalyx and endothelial barrier function. Targeting the endothelium may be a therapeutic strategy to limit organ failure, which hitherto has not received much attention. Treatment targets aimed at restoring the endothelium should focus on maintaining glycocalyx function and/or targeting coagulation pathways or specific endothelial receptors. Potential treatments could be supplementing glycocalyx constituents or inhibiting glycocalyx breakdown. In this review, we summarize mechanisms of endothelial dysfunction during acute critical illness, such as the systemic inflammatory response, shedding of the glycocalyx, endothelial activation, and activation of coagulation. In addition, this review focuses on the effects of different fluid strategies on endothelial permeability. Also, potential mechanisms for treatment options to reduce endothelial hyperpermeability with ensuing organ failure are evaluated. Future research is needed to elucidate these pathways and to translate these data to the first human safety and feasibility trials.


Assuntos
Estado Terminal/terapia , Endotélio Vascular/metabolismo , Microcirculação/fisiologia , Insuficiência de Múltiplos Órgãos/metabolismo , Insuficiência de Múltiplos Órgãos/prevenção & controle , Doença Aguda , Endotélio Vascular/patologia , Hidratação/métodos , Glicocálix/metabolismo , Glicocálix/patologia , Humanos , Insuficiência de Múltiplos Órgãos/patologia , Escores de Disfunção Orgânica
7.
Microcirculation ; 27(8): e12650, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32688443

RESUMO

OBJECTIVE: Microcirculatory perfusion disturbances following hemorrhagic shock and fluid resuscitation contribute to multiple organ dysfunction and mortality. Standard fluid resuscitation is insufficient to restore microcirculatory perfusion; however, additional therapies are lacking. We conducted a systematic search to provide an overview of potential non-fluid-based therapeutic interventions to restore microcirculatory perfusion following hemorrhagic shock. METHODS: A structured search of PubMed, EMBASE, and Cochrane Library was performed in March 2020. Animal studies needed to report at least one parameter of microcirculatory flow (perfusion, red blood cell velocity, functional capillary density). RESULTS: The search identified 1269 records of which 48 fulfilled all eligibility criteria. In total, 62 drugs were tested of which 29 were able to restore microcirculatory perfusion. Particularly, complement inhibitors (75% of drugs tested successfully restored blood flow), endothelial barrier modulators (100% successful), antioxidants (66% successful), drugs targeting cell metabolism (83% successful), and sex hormones (75% successful) restored microcirculatory perfusion. Other drugs consisted of attenuation of inflammation (100% not successful), vasoactive agents (68% not successful), and steroid hormones (75% not successful). CONCLUSION: Improving mitochondrial function, inhibition of complement inhibition, and reducing microvascular leakage via restoration of endothelial barrier function seem beneficial to restore microcirculatory perfusion following hemorrhagic shock and fluid resuscitation.


Assuntos
Hidratação , Microcirculação , Ressuscitação , Choque Hemorrágico , Animais , Modelos Animais de Doenças , Humanos , Choque Hemorrágico/fisiopatologia , Choque Hemorrágico/terapia
8.
Crit Care ; 24(1): 218, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404120

RESUMO

BACKGROUND: Microcirculatory perfusion disturbances are associated with increased morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Technological advancements made it possible to monitor sublingual microcirculatory perfusion over time. The goal of this review is to provide an overview of the course of alterations in sublingual microcirculatory perfusion following CPB. The secondary goal is to identify which parameter of sublingual microcirculatory perfusion is most profoundly affected by CPB. METHODS: PubMed and Embase databases were systematically searched according to PRISMA guidelines and as registered in PROSPERO. Studies that reported sublingual microcirculatory perfusion measurements before and after onset of CPB in adult patients undergoing cardiac surgery were included. The primary outcome was sublingual microcirculatory perfusion, represented by functional capillary density (FCD), perfused vessel density (PVD), total vessel density (TVD), proportion of perfused vessels (PPV), and microvascular flow index (MFI). RESULTS: The search identified 277 studies, of which 19 fulfilled all eligibility criteria. Initiation of CPB had a profound effect on FCD, PVD, or PPV. Seventeen studies (89%) reported one or more of these parameters, and in 11 of those studies (65%), there was a significant decrease in these parameters during cardiac surgery; the other 6 studies (35%) reported no effect. In 29% of the studies, FCD, PVD, or PPV normalized by the end of cardiac surgery, and in 24% percent of the studies, this effect lasted at least 24 h. There was no clear effect of CPB on TVD and a mixed effect on MFI. CONCLUSION: CPB during cardiac surgery impaired sublingual microcirculatory perfusion as reflected by reduced FCD, PVD, and PPV. Four studies reported this effect at least 24 h after surgery. Further research is warranted to conclude on the duration of CPB-induced microcirculatory perfusion disturbances and the relationship with clinical outcome. TRIAL REGISTRATION: PROSPERO, CRD42019127798.


Assuntos
Ponte Cardiopulmonar/efeitos adversos , Microcirculação/fisiologia , Perfusão/normas , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias
9.
Clin Hemorheol Microcirc ; 75(2): 121-133, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929146

RESUMO

BACKGROUND: Endothelial hyperpermeability is suggested to play a role in the development of microcirculatory perfusion disturbances and organ failure following hemorrhagic shock, but evidence is limited. OBJECTIVE: To study the effect of plasma from traumatic hemorrhagic shock patients on in vitro endothelial barrier function. METHODS: Plasma from traumatic hemorrhagic shock patients was obtained at the emergency department (ED), the intensive care unit (ICU), 24 h after ICU admission and from controls (n = 8). Sublingual microcirculatory perfusion was measured using incident dark field videomicroscopy at matching time points. Using electric cell-substrate impedance sensing, the effects of plasma exposure on in vitro endothelial barrier function of human endothelial cells were assessed. RESULTS: Plasma from traumatic hemorrhagic shock patients collected at ED admission induced a 19% loss of in vitro endothelial resistance compared to plasma from controls (p < 0.001). This loss was due to reduced cell-cell contacts (p < 0.01). Plasma withdrawn at later time points did not affect endothelial barrier function (p > 0.99). Interestingly, in vitro endothelial resistance showed a positive association with in vivo microcirculatory perfusion (r = 0.56, p < 0.01). CONCLUSIONS: Plasma from traumatic hemorrhagic shock patients obtained following ED admission, but not at later stages, induced in vitro endothelial hyperpermeability. This coincided with in vivo microcirculatory perfusion disturbances.


Assuntos
Células Endoteliais/fisiologia , Adulto , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Choque Hemorrágico/fisiopatologia , Adulto Jovem
10.
J Crit Care ; 56: 63-72, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31855708

RESUMO

PURPOSE: To compare the effectiveness of different types of pharmacological agents to reduce organ specific edema following cardiopulmonary bypass (CPB). METHODS: Pubmed, Embase.com and Cochrane were searched for studies administrating a pharmacological agent before CPB. Primary outcome was postoperative edema. RESULTS: Forty-four studies (clinical n = 6, preclinical n = 38) fulfilled eligibility criteria. Steroids were used in most clinical studies (n = 5, 83%) and reduced postoperative edema in 4 studies, however heterogeneity precluded meta-analysis. In preclinical studies, a total of 31 different drugs were tested of which 20 (65%) reduced edema in at least one organ. Particularly neutrophil inhibitors, and modulators of coagulation or endothelial barrier reduced pulmonary edema (SMD -2.77 [-3.93, -1.61]; -1.29 [-2.12, -0.46], -2.33 [-4.69, 0.03], respectively) compared to no treatment. Reducing renal (SMD -0.91 [CI -1.65 to -0.18]), intestinal (SMD -1.98 [CI -3.92 to -0.04]) or myocardial (SMD -1.95 [CI -3.91 to -0.01]) edema following CPB required specific modulators of endothelial barrier. CONCLUSION: Overall, neutrophil inhibitors and direct modulators of endothelial barrier (PAR1, Tie2 signaling) most effectively reduced edema following CPB, in particular pulmonary edema. Future research should focus on a combination of these strategies to reduce edema and assess the effect on organ function and outcome following CPB.


Assuntos
Ponte Cardiopulmonar/efeitos adversos , Edema/tratamento farmacológico , Edema/prevenção & controle , Antioxidantes/uso terapêutico , Capilares , Pesquisa Comparativa da Efetividade , Endotélio Vascular/metabolismo , Humanos , Neutrófilos/metabolismo , Permeabilidade , Período Pós-Operatório , Resultado do Tratamento
11.
J Cardiothorac Vasc Anesth ; 34(4): 912-919, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31787433

RESUMO

OBJECTIVE: Heparin biocompatible coating frequently is used to reduce inflammation and blood coagulation during cardiopulmonary bypass (CPB) in cardiac surgery. Whether heparin coating is protective or damaging to the vascular endothelium is unclear. The authors investigated whether heparin-coated (HC) circuits are associated with better preservation of microcirculatory perfusion and glycocalyx dimensions compared with nonheparin phosphorylcholine-coated (PC) circuits. DESIGN: Prospective, randomized blinded study. SETTING: Tertiary university hospital. PARTICIPANTS: A total of 26 adults undergoing elective coronary artery bypass graft surgery with CPB. INTERVENTIONS: PC (n = 13) versus HC circuits (n = 13). MEASUREMENTS AND MAIN RESULTS: Sublingual microcirculatory perfusion was measured before, during, and after CPB using sidestream dark field imaging and analyzed for perfused vessel density and perfused boundary region, an inverse parameter for glycocalyx dimensions. Onset of CPB was associated with an increase in perfused boundary region in the PC group that continued until the third postoperative day (2.0 ± 0.2 to 2.5 ± 0.2 µm; p = 0.018). This was paralleled by increased plasma syndecan-1 levels in the PC group. Contrastingly, both parameters remained unaltered in the HC group compared with baseline levels. CPB decreased perfused vessel density in both groups (CPB v pre-CPB: PC: 17 ± 2 to 13 ± 2 mm/mm2, p = 0.006; HC: 16 ± 2 to 11 ± 2 mm/mm2, p = 0.003) and remained equally altered in the first 3 postoperative days. CONCLUSION: The use of an HC circuit is associated with better preservation of the endothelial glycocalyx compared with PC circuits, whereas microcirculatory perfusion was disturbed equally in both groups. Hence, CPB-induced microcirculatory perfusion disturbances seem to be coating independent.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Fosforilcolina , Adulto , Ponte Cardiopulmonar , Heparina , Humanos , Microcirculação , Estudos Prospectivos
12.
Crit Care ; 23(1): 117, 2019 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975180

RESUMO

BACKGROUND: Endothelial hyperpermeability following cardiopulmonary bypass (CPB) contributes to microcirculatory perfusion disturbances and postoperative complications after cardiac surgery. We investigated the postoperative course of renal and pulmonary endothelial barrier function and the association with microcirculatory perfusion and angiopoietin-2 levels in patients after CPB. METHODS: Clinical data, sublingual microcirculatory data, and plasma samples were collected from patients undergoing coronary artery bypass graft surgery with CPB (n = 17) before and at several time points up to 72 h after CPB. Renal and pulmonary microvascular endothelial cells were incubated with patient plasma, and in vitro endothelial barrier function was assessed using electric cell-substrate impedance sensing. Plasma levels of angiopoietin-1,-2, and soluble Tie2 were measured, and the association with in vitro endothelial barrier function and in vivo microcirculatory perfusion was determined. RESULTS: A plasma-induced reduction of renal and pulmonary endothelial barrier function was observed in all samples taken within the first three postoperative days (P < 0.001 for all time points vs. pre-CPB). Angiopoietin-2 and soluble Tie2 levels increased within 72 h after CPB (5.7 ± 4.4 vs. 1.7 ± 0.4 ng/ml, P < 0.0001; 16.3 ± 4.7 vs. 11.9 ± 1.9 ng/ml, P = 0.018, vs. pre-CPB), whereas angiopoietin-1 remained stable. Interestingly, reduced in vitro renal and pulmonary endothelial barrier moderately correlated with reduced in vivo microcirculatory perfusion after CPB (r = 0.47, P = 0.005; r = 0.79, P < 0.001). In addition, increased angiopoietin-2 levels moderately correlated with reduced in vitro renal and pulmonary endothelial barrier (r = - 0.46, P < 0.001; r = - 0.40, P = 0.005) and reduced in vivo microcirculatory perfusion (r = - 0.43, P = 0.01; r = - 0.41, P = 0.03). CONCLUSIONS: CPB is associated with an impairment of in vitro endothelial barrier function that continues in the first postoperative days and correlates with reduced postoperative microcirculatory perfusion and increased circulating angiopoietin-2 levels. These results suggest that angiopoietin-2 is a biomarker for postoperative endothelial hyperpermeability, which may contribute to delayed recovery of microcirculatory perfusion after CPB. TRIAL REGISTRATION: NTR4212 .


Assuntos
Ponte Cardiopulmonar/efeitos adversos , Células Endoteliais/fisiologia , Microcirculação/fisiologia , Idoso , Angiopoietina-1/análise , Angiopoietina-1/sangue , Angiopoietina-2/análise , Angiopoietina-2/sangue , Biomarcadores/análise , Biomarcadores/sangue , Ponte Cardiopulmonar/métodos , Células Endoteliais/metabolismo , Feminino , Humanos , Rim/irrigação sanguínea , Rim/fisiopatologia , Pulmão/irrigação sanguínea , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Receptor TIE-2/análise , Receptor TIE-2/sangue
13.
Anesthesiology ; 128(2): 361-374, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28968277

RESUMO

BACKGROUND: Microcirculatory dysfunction is associated with multiple organ failure and unfavorable patient outcome. We investigated whether therapeutically targeting the endothelial angiopoietin/Tie2 system preserves microvascular integrity during hemorrhagic shock. METHODS: Rats were treated with the angiopoietin-1 mimetic vasculotide and subjected to hemorrhagic shock and fluid resuscitation. Microcirculatory perfusion and leakage were assessed with intravital microscopy (n = 7 per group) and Evans blue dye extravasation (n = 8 per group), respectively. The angiopoietin/Tie2 system was studied at protein and RNA level in plasma, kidneys, and lungs. RESULTS: Hemorrhagic shock significantly reduced continuously perfused capillaries (7 ± 2 vs. 11 ± 2) and increased nonperfused vessels (9 ± 3 vs. 5 ± 2) during hemorrhagic shock, which could not be restored by fluid resuscitation. Hemorrhagic shock increased circulating angiopoietin-2 and soluble Tie2 significantly, which associated with microcirculatory perfusion disturbances. Hemorrhagic shock significantly decreased Tie2 gene expression in kidneys and lungs and induced microvascular leakage in kidneys (19.7 ± 11.3 vs. 5.2 ± 3.0 µg/g) and lungs (16.1 ± 7.0 vs. 8.6 ± 2.7 µg/g). Vasculotide had no effect on hemodynamics and microcirculatory perfusion during hemorrhagic shock but restored microcirculatory perfusion during fluid resuscitation. Interestingly, vasculotide attenuated microvascular leakage in lungs (10.1 ± 3.3 µg/g) and significantly reduced the required amount of volume supplementation (1.3 ± 1.4 vs. 2.8 ± 1.5 ml). Furthermore, vasculotide posttreatment was also able to restore microcirculatory perfusion during fluid resuscitation. CONCLUSIONS: Targeting Tie2 restored microvascular leakage and microcirculatory perfusion and reduced fluid resuscitation requirements in an experimental model of hemorrhagic shock. Therefore, the angiopoietin/Tie2 system seems to be a promising target in restoring microvascular integrity and may reduce organ failure during hemorrhagic shock.


Assuntos
Hidratação/métodos , Microcirculação/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Choque Hemorrágico/fisiopatologia , Choque Hemorrágico/terapia , Animais , Modelos Animais de Doenças , Extravasamento de Materiais Terapêuticos e Diagnósticos/diagnóstico por imagem , Microscopia Intravital/métodos , Masculino , Ratos , Ratos Wistar , Choque Hemorrágico/diagnóstico por imagem , Resultado do Tratamento
14.
Am J Physiol Heart Circ Physiol ; 314(3): H381-H391, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29101165

RESUMO

Myocardial contrast echocardiography (MCE) offers the opportunity to study myocardial perfusion defects in mice in detail. The value of MCE compared with single-photon emission computed tomography, positron emission tomography, and computed tomography consists of high spatial resolution, the possibility of quantification of blood volume, and relatively low costs. Nevertheless, a number of technical and physiological aspects should be considered to ensure reproducibility among research groups. The aim of this overview is to describe technical aspects of MCE and the physiological parameters that influence myocardial perfusion data obtained with this technique. First, technical aspects of MCE discussed in this technical review are logarithmic compression of ultrasound data by ultrasound systems, saturation of the contrast signal, and acquisition of images during different phases of the cardiac cycle. Second, physiological aspects of myocardial perfusion that are affected by the experimental design are discussed, including the anesthesia regimen, systemic cardiovascular effects of vasoactive agents used, and fluctuations in body temperature that alter myocardial perfusion. When these technical and physiological aspects of MCE are taken into account and adequately standardized, MCE is an easily accessible technique for mice that can be used to study the control of myocardial perfusion by a wide range of factors.


Assuntos
Meios de Contraste/administração & dosagem , Ecocardiografia , Cardiopatias/diagnóstico por imagem , Coração/diagnóstico por imagem , Imagem de Perfusão do Miocárdio/métodos , Animais , Circulação Coronária , Modelos Animais de Doenças , Coração/fisiopatologia , Cardiopatias/fisiopatologia , Camundongos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
15.
J Diabetes Res ; 2017: 4126820, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28349068

RESUMO

Background. Type 2 diabetes mellitus (T2DM) increases the risk of myocardial ischemia, followed by increased perioperative risk of cardiovascular morbidity. We investigated whether reducing caloric intake reduces ischemic injury and myocardial dysfunction and affects the protective effects of the volatile anesthetic sevoflurane in diet-induced T2DM rats. Methods. Rats received a western (WD) or control diet (CD). Caloric intake was reduced by reversing WD-fed rats to CD. Myocardial function was determined with echocardiography. After 8 weeks of diet feeding, myocardial infarction was induced and the effect of sevoflurane was studied on myocardial function and ischemia/reperfusion injury. Results. WD-feeding resulted in a mild T2DM phenotype and myocardial dysfunction. Sevoflurane further impaired systolic function in WD-fed rats. Unexpectedly, WD-feeding reduced infarct size compared to CD-feeding. Sevoflurane reduced infarct size in CD-fed rats; however it enlarged infarct size in WD-fed rats. Caloric reduction restored myocardial dysfunction and the protective effect of sevoflurane against ischemia compared to WD-fed rats, whereas the protective effects of WD-feeding persisted. Conclusion. Caloric reduction restored the T2DM phenotype and myocardial function, while the cardioprotective properties of WD-feeding or sevoflurane persisted. Our data suggest that reducing caloric intake in T2DM might be a possible intervention to reduce perioperative risk of cardiovascular morbidity.


Assuntos
Restrição Calórica , Cardiotônicos/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Coração/efeitos dos fármacos , Éteres Metílicos/farmacologia , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Anestésicos Inalatórios/farmacologia , Animais , Dieta Ocidental , Ecocardiografia , Ingestão de Energia , Coração/fisiopatologia , Masculino , Isquemia Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos , Ratos Wistar , Sevoflurano
17.
Cardiovasc Diabetol ; 15(1): 135, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27651131

RESUMO

BACKGROUND: While most studies focus on cardiovascular morbidity following anesthesia and surgery in excessive obesity, it is unknown whether these intraoperative cardiovascular alterations also occur in milder forms of adiposity without type 2 diabetes and if insulin is a possible treatment to improve intraoperative myocardial performance. In this experimental study we investigated whether mild adiposity without metabolic alterations is already associated with cardiometabolic dysfunction during anesthesia, mechanical ventilation and surgery and whether these myocardial alterations can be neutralized by intraoperative insulin treatment. METHODS: Mice were fed a western (WD) or control diet (CD) for 4 weeks. After metabolic profiling, mice underwent general anesthesia, mechanical ventilation and surgery. Cardiac function was determined with echocardiography and left-ventricular pressure-volume analysis. Myocardial perfusion was determined with contrast-enhanced echocardiography. WD-fed mice were subsequently treated with insulin by hyperinsulinemic euglycemic clamping followed by the same measurements of cardiac function and perfusion. RESULTS: Western-type diet feeding led to a 13 % increase in bodyweight, (p < 0.0001) and increased adipose tissue mass, without metabolic alterations. Despite this mild phenotype, WD-fed mice had decreased systolic and diastolic function (end-systolic elastance was 2.0 ± 0.5 versus 4.1 ± 2.4 mmHg/µL, p = 0.01 and diastolic beta was 0.07 ± 0.03 versus 0.04 ± 0.01 mmHg/µL, p = 0.02) compared to CD-fed mice. Ventriculo-arterial coupling and myocardial perfusion were decreased by 48 % (p = 0.003) and 43 % (p = 0.03) respectively. Insulin treatment in WD-fed mice improved echo-derived systolic function (fractional shortening 42 ± 5 % to 46 ± 3, p = 0.05), likely due to decreased afterload, but there was no effect on load-independent measures of systolic function or myocardial perfusion. However, there was a trend towards improved diastolic function after insulin treatment (43 % improvement, p = 0.05) in WD-fed mice. CONCLUSIONS: Mild adiposity without metabolic alterations already affected cardiac function and perfusion during anesthesia, mechanical ventilation and surgery in mice. Intraoperative insulin may be beneficial to reduce afterload and enhance intraoperative ventricular relaxation, but not to improve ventricular contractility or myocardial perfusion.


Assuntos
Adiposidade , Cardiopatias/prevenção & controle , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Obesidade/complicações , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Anestesia Geral/efeitos adversos , Animais , Circulação Coronária/efeitos dos fármacos , Dieta Ocidental , Modelos Animais de Doenças , Esquema de Medicação , Ecocardiografia , Cardiopatias/diagnóstico por imagem , Cardiopatias/etiologia , Cardiopatias/fisiopatologia , Cuidados Intraoperatórios , Masculino , Metabolômica , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/fisiopatologia , Respiração Artificial/efeitos adversos , Índice de Gravidade de Doença , Função Ventricular Esquerda/efeitos dos fármacos , Pressão Ventricular/efeitos dos fármacos , Ganho de Peso
18.
PLoS One ; 11(7): e0157233, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27391645

RESUMO

BACKGROUND: Microvascular injury (MVI) after coronary ischemia-reperfusion is associated with high morbidity and mortality. Both ischemia and reperfusion are involved in MVI, but to what degree these phases contribute is unknown. Understanding the etiology is essential for the development of new potential therapies. METHODS AND FINDINGS: Rats were divided into 3 groups receiving either 30 minutes ischemia, 90 minutes ischemia or 30 minutes ischemia followed by 60 minutes reperfusion. Subsequently hearts were ex-vivo perfused in a Langendorff-model. Fluorescence and electron microscopy was used for analysis of capillary density, vascular permeability and ultrastructure. Most MVI was observed after 30 minutes ischemia followed by 60 minutes reperfusion. In comparison to the 30' and 90' ischemia group, wall thickness decreased (207.0±74 vs 407.8±75 and 407.5±71, p = 0.02). Endothelial nuclei in the 30'-60' group showed irreversible damage and decreased chromatin density variation (50.5±9.4, 35.4±7.1 and 23.7±3.8, p = 0.03). Cell junction density was lowest in the 30'-60' group (0.15±0.02 vs 2.5±0.6 and 1.8±0.7, p<0.01). Microsphere extravasation was increased in both the 90' ischemia and 30'-60' group. CONCLUSIONS: Ischemia alone for 90 minutes induces mild morphological changes to the coronary microcirculation, with increased vascular permeability. Ischemia for 30 minutes, followed by 60 minutes of reperfusion, induces massive MVI. This shows the direct consequences of reperfusion on the coronary microcirculation. These data imply that a therapeutic window exists to protect the microcirculation directly upon coronary revascularization.


Assuntos
Circulação Coronária , Coração/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Animais , Capilares , Comunicação Celular , Núcleo Celular/metabolismo , Cromatina/química , Modelos Animais de Doenças , Isquemia/fisiopatologia , Masculino , Microesferas , Reperfusão Miocárdica , Perfusão , Permeabilidade , Ratos , Ratos Wistar
19.
Am J Physiol Heart Circ Physiol ; 310(5): H550-8, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26747506

RESUMO

Although hemodilution is attributed as the main cause of microcirculatory impairment during cardiopulmonary bypass (CPB), this relationship has never been investigated. We investigated the distinct effects of hemodilution with or without CPB on microvascular perfusion and subsequent renal tissue injury in a rat model. Male Wistar rats (375-425 g) were anesthetized, prepared for cremaster muscle intravital microscopy, and subjected to CPB (n = 9), hemodilution alone (n = 9), or a sham procedure (n = 6). Microcirculatory recordings were performed at multiple time points and analyzed for perfusion characteristics. Kidney and lung tissue were investigated for mRNA expression for genes regulating inflammation and endothelial adhesion molecule expression. Renal injury was assessed with immunohistochemistry. Hematocrit levels dropped to 0.24 ± 0.03 l/l and 0.22 ± 0.02 l/l after onset of hemodilution with or without CPB. Microcirculatory perfusion remained unaltered in sham rats. Hemodilution alone induced a 13% decrease in perfused capillaries, after which recovery was observed. Onset of CPB reduced the perfused capillaries by 40% (9.2 ± 0.9 to 5.5 ± 1.5 perfused capillaries per microscope field; P < 0.001), and this reduction persisted throughout the experiment. Endothelial and inflammatory activation and renal histological injury were increased after CPB compared with hemodilution or sham procedure. Hemodilution leads to minor and transient disturbances in microcirculatory perfusion, which cannot fully explain impaired microcirculation following cardiopulmonary bypass. CPB led to increased renal injury and endothelial adhesion molecule expression in the kidney and lung compared with hemodilution. Our findings suggest that microcirculatory impairment during CPB may play a role in the development of kidney injury.


Assuntos
Injúria Renal Aguda/etiologia , Lesão Pulmonar Aguda/etiologia , Capilares/fisiopatologia , Ponte Cardiopulmonar/efeitos adversos , Hemodiluição/efeitos adversos , Rim/irrigação sanguínea , Microcirculação , Injúria Renal Aguda/genética , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Citocinas/genética , Citocinas/metabolismo , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Microscopia Intravital , Rim/metabolismo , Rim/patologia , Pulmão/irrigação sanguínea , Pulmão/metabolismo , Pulmão/patologia , Masculino , Modelos Animais , Ratos Wistar , Fatores de Tempo
20.
J Diabetes Res ; 2016: 5205631, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26824042

RESUMO

Preservation of myocardial perfusion during surgery is particularly important in patients with increased risk for perioperative complications, such as diabetes. Volatile anesthetics, like sevoflurane, have cardiodepressive effects and may aggravate cardiovascular complications. We investigated the effect of sevoflurane on myocardial perfusion and function in prediabetic rats. Rats were fed a western diet (WD; n = 18) or control diet (CD; n = 18) for 8 weeks and underwent (contrast) echocardiography to determine perfusion and function during baseline and sevoflurane exposure. Myocardial perfusion was estimated based on the product of microvascular filling velocity and blood volume. WD-feeding resulted in a prediabetic phenotype characterized by obesity, hyperinsulinemia, hyperlipidemia, glucose intolerance, and hyperglycemia. At baseline, WD-feeding impaired myocardial perfusion and systolic function compared to CD-feeding. Exposure of healthy rats to sevoflurane increased the microvascular filling velocity without altering myocardial perfusion but impaired systolic function. In prediabetic rats, sevoflurane did also not affect myocardial perfusion; however, it further impaired systolic function. Diet-induced prediabetes is associated with impaired myocardial perfusion and function in rats. While sevoflurane further impaired systolic function, it did not affect myocardial perfusion in prediabetic rats. Our findings suggest that sevoflurane anesthesia leads to uncoupling of myocardial perfusion and function, irrespective of the metabolic state.


Assuntos
Anestésicos Inalatórios/toxicidade , Circulação Coronária/efeitos dos fármacos , Dieta Ocidental , Éteres Metílicos/toxicidade , Microcirculação/efeitos dos fármacos , Estado Pré-Diabético/fisiopatologia , Disfunção Ventricular Esquerda/induzido quimicamente , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Ecocardiografia , Masculino , Imagem de Perfusão do Miocárdio/métodos , Fenótipo , Estado Pré-Diabético/sangue , Estado Pré-Diabético/etiologia , Ratos Wistar , Sevoflurano , Sístole , Fatores de Tempo , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologia
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