RESUMO
BACKGROUND: Remote ischemic preconditioning (RIPC) has been suggested to protect against certain forms of organ injury after cardiac surgery. Previously, we reported the main results of RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study, a multicenter trial randomizing 1403 cardiac surgery patients receiving either RIPC or sham-RIPC. METHODS AND RESULTS: In this follow-up paper, we present 1-year follow-up of the composite primary end point and its individual components (all-cause mortality, myocardial infarction, stroke and acute renal failure), in a sub-group of patients, intraoperative myocardial dysfunction assessed by transesophageal echocardiography and the incidence of postoperative neurocognitive dysfunction 5 to 7 days and 3 months after surgery. RIPC neither showed any beneficial effect on the 1-year composite primary end point (RIPC versus sham-RIPC 16.4% versus 16.9%) and its individual components (all-cause mortality [3.4% versus 2.5%], myocardial infarction [7.0% versus 9.4%], stroke [2.2% versus 3.1%], acute renal failure [7.0% versus 5.7%]) nor improved intraoperative myocardial dysfunction or incidence of postoperative neurocognitive dysfunction 5 to 7 days (67 [47.5%] versus 71 [53.8%] patients) and 3 months after surgery (17 [27.9%] versus 18 [27.7%] patients), respectively. CONCLUSIONS: Similar to our main study, RIPC had no effect on intraoperative myocardial dysfunction, neurocognitive function and long-term outcome in cardiac surgery patients undergoing propofol anesthesia. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01067703.
Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cognição , Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/epidemiologia , Traumatismo por Reperfusão Miocárdica/epidemiologia , Transtornos Neurocognitivos/epidemiologia , Anestésicos Intravenosos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Método Duplo-Cego , Ecocardiografia Transesofagiana , Alemanha/epidemiologia , Humanos , Incidência , Precondicionamento Isquêmico Miocárdico/efeitos adversos , Precondicionamento Isquêmico Miocárdico/mortalidade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/diagnóstico por imagem , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Transtornos Neurocognitivos/diagnóstico , Transtornos Neurocognitivos/prevenção & controle , Transtornos Neurocognitivos/psicologia , Testes Neuropsicológicos , Propofol/efeitos adversos , Estudos Prospectivos , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: The impact of remote ischaemic preconditioning (RIPC) on major clinical outcomes in patients undergoing cardiovascular surgery remains controversial. We systematically reviewed the available evidence to evaluate the potential benefits of RIPC in such patients. METHODS: PubMed, Embase, and Cochrane Library databases were searched for relevant randomised controlled trials (RCTs) conducted between January 2006 and March 2016. The pooled population of patients who underwent cardiovascular surgery was divided into the RIPC and control groups. Trial sequential analysis was applied to judge data reliability. The pooled relative risks (RRs) with 95% confidence intervals (CIs) between the groups were calculated for all-cause mortality, major adverse cardiovascular and cerebral events (MACCEs), myocardial infarction (MI), and renal failure. RESULTS: RIPC was not associated with improvement in all-cause mortality (RR, 1.04; 95%CI, 0.82-1.31; I2=26%; P>0.05) or MACCE incidence (RR, 0.90; 95%CI, 0.71-1.14; I2=40%; P>0.05) after cardiovascular surgery, and both results were assessed by trial sequential analysis as sufficient and conclusive. Nevertheless, RIPC was associated with a significantly lower incidence of MI (RR, 0.87; 95%CI, 0.76-1.00; I2=13%; P≤0.05). However, after excluding a study that had a high contribution to heterogeneity, RIPC was associated with increased rates of renal failure (RR, 1.53; 95%CI, 1.12-2.10; I2=5%; P≤0.05). CONCLUSIONS: In patients undergoing cardiovascular surgery, RIPC reduced the risk for postoperative MI, but not that for MACCEs or all-cause mortality, a discrepancy likely related to the higher rate of renal failure associated with RIPC.
Assuntos
Procedimentos Cirúrgicos Cardiovasculares/tendências , Precondicionamento Isquêmico Miocárdico/tendências , Complicações Pós-Operatórias/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Procedimentos Cirúrgicos Cardiovasculares/efeitos adversos , Procedimentos Cirúrgicos Cardiovasculares/mortalidade , Humanos , Precondicionamento Isquêmico Miocárdico/métodos , Precondicionamento Isquêmico Miocárdico/mortalidade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/mortalidade , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: Sildenafil has strong cardiac preconditioning properties in animal studies and has a safe side-effect profile in children. Therefore, we evaluated the application of Sildenafil preconditioning to reduce myocardial ischaemia/reperfusion injury in children undergoing surgical ventricular septal defect (VSD) closure. METHODS: This is a randomized, double-blind study. Children (1-17 years) undergoing VSD closure were randomized into three groups: placebo (Control group), preconditioning with 0.06 mg/kg (Sild-L group) and 0.6 mg/kg Sildenafil (Sild-H group). PRIMARY ENDPOINT: troponin release. CK-MB, Troponin I, inflammatory response (IL-6 and TNF-α), bypass and ventilation weaning times, inotropy score and echocardiographic function were assessed. Data expressed as median (range), and a value of P < 0.05 was considered significant. RESULTS: Thirty-nine patients were studied (13/group). Aortic cross-clamp time was similar [27 (18-85) and 27 (12-39) min] in the Control and Sild-L groups, respectively, but significantly longer [39 (20-96) min] in the Sild-H group when compared with the Control group. Area under the curve of CK-MB release was 1105 (620-1855) h ng/ml in the Control group, 1672 (564-2767) h ng/ml in the Sild-L group and was significantly higher in the Sild-H group [1695 (1252-3377) h ng/ml] when compared with the Control group. There were no significant differences in inflammatory response markers, cardiopulmonary bypass and ventilation weaning times, inotropy scores and echocardiographic function between the groups. CONCLUSIONS: In this small study, Sildenafil failed to reduce myocardial injury in children undergoing cardiac surgery, nor does it alter cardiac function, inotropic needs or postoperative course. A subclinical increase in cardiac enzyme release after Sildenafil preconditioning cannot be excluded. CLINICAL TRIALS REGISTRY: CTRI/2014/03/004468.
Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Precondicionamento Isquêmico Miocárdico/efeitos adversos , Precondicionamento Isquêmico Miocárdico/métodos , Citrato de Sildenafila/uso terapêutico , Adolescente , Pressão Sanguínea/efeitos dos fármacos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Procedimentos Cirúrgicos Cardíacos/estatística & dados numéricos , Criança , Pré-Escolar , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Cardiopatias Congênitas/cirurgia , Humanos , Lactente , Precondicionamento Isquêmico Miocárdico/mortalidade , Precondicionamento Isquêmico Miocárdico/estatística & dados numéricos , Masculino , Citrato de Sildenafila/administração & dosagem , Citrato de Sildenafila/farmacologiaRESUMO
AIMS: Remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction increases myocardial salvage. We investigated the effect of remote ischaemic conditioning on long-term clinical outcome. METHODS AND RESULTS: From February 2007 to November 2008, 333 patients with a suspected first acute ST-elevation myocardial infarction were randomized to receive primary percutaneous coronary intervention with (n = 166) or without (n = 167) remote ischaemic conditioning (intermittent arm ischaemia through four cycles of 5-min inflation followed by 5-min deflation of a blood-pressure cuff). Patient follow-up extended from the randomization date until an outcome, emigration or January 2012 (median follow-up = 3.8 years). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE)-a composite of all-cause mortality, myocardial infarction, readmission for heart failure, and ischaemic stroke/transient ischaemic attack. The individual components of the primary endpoint comprised the secondary endpoints. Outcomes were obtained from Danish nationwide medical registries and validated by medical record review and contact to patients' general practitioner. In the per-protocol analysis of 251 patient fulfilling trial criteria, MACCE occurred for 17 (13.5%) patients in the intervention group compared with 32 (25.6%) patients in the control group, yielding a hazard ratio (HR) of 0.49 (95% confidence interval: 0.27-0.89, P = 0.018). The HR for all-cause mortality was 0.32 (95% confidence interval: 0.12-0.88, P = 0.027). Although lower precision, the HRs were also directionally lower for all other secondary endpoints. CONCLUSION: Remote ischaemic conditioning before primary percutaneous coronary intervention seemed to improve long-term clinical outcomes in patients with ST-elevation myocardial infarction.
Assuntos
Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/terapia , Intervenção Coronária Percutânea/métodos , Causas de Morte , Terapia Combinada , Feminino , Seguimentos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/mortalidade , Humanos , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/mortalidade , Precondicionamento Isquêmico Miocárdico/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Traumatismo por Reperfusão Miocárdica/mortalidade , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Readmissão do Paciente , Intervenção Coronária Percutânea/mortalidade , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Resultado do TratamentoRESUMO
BACKGROUND: Ischemic postconditioning has been reported to reduce infarct size in patients with ST-segment-elevation myocardial infarction. However, cardioprotective effects of postconditioning have not been demonstrated in a large-scale trial. METHODS AND RESULTS: We performed a multicenter, prospective, randomized, open-label, blinded end-point trial. A total of 700 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction within 12 hours after symptom onset were randomly assigned to the postconditioning group or to the conventional primary PCI group in a 1:1 ratio. Postconditioning was performed immediately after restoration of coronary flow as follows: The angioplasty balloon was positioned at the culprit lesion and inflated 4 times for 1 minute with low-pressure (<6 atm) inflations, each separated by 1 minute of deflation. The primary end point was complete ST-segment resolution (percentage resolution of ST-segment elevation >70%) measured at 30 minutes after PCI. Complete ST-segment resolution occurred in 40.5% of patients in the postconditioning group and 41.5% of patients in the conventional PCI group (absolute difference, -1.0%; 95% confidence interval, -8.4 to 6.4; P=0.79). The rate of myocardial blush grade of 0 or 1 and the rate of major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis) at 30 days did not differ significantly between the postconditioning group and the conventional PCI group (17.2% versus 22.4% [P=0.20] and 4.3% versus 3.7% [P=0.70], respectively). CONCLUSION: Ischemic postconditioning did not improve myocardial reperfusion in patients with ST-segment-elevation myocardial infarction undergoing primary PCI with current standard practice.
Assuntos
Angioplastia Coronária com Balão/métodos , Pós-Condicionamento Isquêmico/métodos , Precondicionamento Isquêmico Miocárdico/métodos , Infarto do Miocárdio/terapia , Idoso , Angioplastia Coronária com Balão/mortalidade , Angiografia Coronária , Circulação Coronária , Reestenose Coronária/mortalidade , Trombose Coronária/mortalidade , Eletrocardiografia , Feminino , Humanos , Pós-Condicionamento Isquêmico/mortalidade , Precondicionamento Isquêmico Miocárdico/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Estudos Prospectivos , Stents , Resultado do TratamentoRESUMO
BACKGROUND: Remote ischaemic preconditioning has been associated with reduced risk of myocardial injury after coronary artery bypass graft (CABG) surgery. We investigated the safety and efficacy of this procedure. METHODS: Eligible patients were those scheduled to undergo elective isolated first-time CABG surgery under cold crystalloid cardioplegia and cardiopulmonary bypass at the West-German Heart Centre, Essen, Germany, between April, 2008, and October, 2012. Patients were prospectively randomised to receive remote ischaemic preconditioning (three cycles of 5 min ischaemia and 5 min reperfusion in the left upper arm after induction of anaesthesia) or no ischaemic preconditioning (control). The primary endpoint was myocardial injury, as reflected by the geometric mean area under the curve (AUC) for perioperative concentrations of cardiac troponin I (cTnI) in serum in the first 72 h after CABG. Mortality was the main safety endpoint. Analysis was done in intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov, number NCT01406678. FINDINGS: 329 patients were enrolled. Baseline characteristics and perioperative data did not differ between groups. cTnI AUC was 266 ng/mL over 72 h (95% CI 237-298) in the remote ischaemic preconditioning group and 321 ng/mL (287-360) in the control group. In the intention-to-treat population, the ratio of remote ischaemic preconditioning to control for cTnI AUC was 0·83 (95% CI 0·70-0·97, p=0·022). cTnI release remained lower in the per-protocol analysis (0·79, 0·66-0·94, p=0·001). All-cause mortality was assessed over 1·54 (SD 1·22) years and was lower with remote ischaemic preconditioning than without (ratio 0·27, 95% CI 0·08-0·98, p=0·046). INTERPRETATION: Remote ischaemic preconditioning provided perioperative myocardial protection and improved the prognosis of patients undergoing elective CABG surgery. FUNDING: German Research Foundation.
Assuntos
Ponte de Artéria Coronária/métodos , Precondicionamento Isquêmico Miocárdico , Idoso , Ponte de Artéria Coronária/mortalidade , Doença das Coronárias/mortalidade , Doença das Coronárias/cirurgia , Feminino , Humanos , Precondicionamento Isquêmico Miocárdico/efeitos adversos , Precondicionamento Isquêmico Miocárdico/métodos , Precondicionamento Isquêmico Miocárdico/mortalidade , Masculino , Prognóstico , Fatores de Risco , Fatores de Tempo , Troponina I/sangueRESUMO
Numerous small trials have been conducted to confirm the existence of the ischaemic preconditioning (IP) mechanism in the human heart and to clarify whether it can be induced in a clinical situation. The effect on clinical end-points remains unclear. Most of the available trials reported some clinical outcomes. We performed a systematic review and meta-analysis in order to determine whether IP produces any clinical benefit in cardiac surgery. The systematic review identified 22 eligible trials containing 933 patients. All patients undergoing on-pump surgery also received cardioplegia or intermittent cross-clamp fibrillation (ICCF) with or without adjunctive cooling. IP was mainly performed after initiation of cardiopulmonary bypass, before any additional myocardial protection was initiated. Overall, IP was associated with significant reductions in ventricular arrhythmias (pooled odds ratio 0.11; 95% CI 0.04-0.29; p=0.001), inotrope requirements (pooled odds ratio 0.34; 95% CI 0.17-0.68; p=0.002) and intensive care unit stay (weighted mean difference -3h; 95% CI -4.6 to -1.5h; p=0.001). These effects persisted when the analyses were restricted to those patients receiving cardioplegia. The effect disappeared when the analyses were restricted to patients receiving ICCF. IP may provide additional myocardial protection over cardioplegia alone, but a large-scale clinical trial may be required to determine the role of IP with any certainty.
Assuntos
Ponte Cardiopulmonar/métodos , Parada Cardíaca Induzida/métodos , Precondicionamento Isquêmico Miocárdico/métodos , Ponte Cardiopulmonar/mortalidade , Feminino , Parada Cardíaca Induzida/mortalidade , Humanos , Precondicionamento Isquêmico Miocárdico/mortalidade , Masculino , Razão de Chances , Assistência Perioperatória/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
The aim of this study was to characterize the effect of increasing numbers of preconditioning cycles on the different branching patterns (bifurcation/trifurcation) of the coronary artery in the rabbit heart. Fifty-six NZW rabbits were assigned to a bifurcation group and subjected to 0, 1, 3, 5, or 7 (B0, B1, B3, B5, or B7 subgroup, respectively) cycles of preconditioning (PC) (5 min of regional ischemia plus 10 min of reperfusion/cycle) and this was followed by 45 min of sustained ischemia and 72 h of reperfusion; 16 rabbits were assigned to a trifurcation group and subjected to 0, 1, 3, or 5 (T0, T1, T3, or T5 subgroup, respectively) cycles of PC. The ratio of necrotic zone (NZ) to ischemic zone (IZ) was calculated. The bifurcation group showed higher mortality (28.6%) than the trifurcation group (0%). The volume of the ischemic zone (expressed as a percentage of volume of the left ventricle) and the volume of the necrotic zone were larger in the bifurcation group than in the trifurcation group. The ratio of the necrotic zone to the ischemic zone was significantly lower in the B5 and B7 subgroups than in the B0, B1, and B3 subgroups. In the trifurcation group, the ratio of the necrotic zone to the ischemic zone showed a diminishing tendency in the subgroups as the PC cycle number increased, but without statistical significance. Thus, in the trifurcation pattern of the rabbit coronary artery there could be little effect on preconditioning, but in the bifurcation pattern the number of preconditioning is recommended to be 5 to 7 cycles. In this regard, different branching patterns of the epicardial branching of the rabbit coronary artery should be considered when interpreting experimental results on ischemic preconditioning.
Assuntos
Vasos Coronários/anatomia & histologia , Precondicionamento Isquêmico Miocárdico , Pericárdio/anatomia & histologia , Animais , Artérias/anatomia & histologia , Eletrocardiografia , Precondicionamento Isquêmico Miocárdico/métodos , Precondicionamento Isquêmico Miocárdico/mortalidade , Infarto do Miocárdio/patologia , Isquemia Miocárdica/etiologia , Isquemia Miocárdica/patologia , Miocárdio/patologia , Necrose , Coelhos , Medição de Risco , Fatores de TempoRESUMO
Brief periods of myocardial ischaemia preceding a subsequent more prolonged ischaemic period 24-72 h later confer protection against myocardial infarction ('delayed preconditioning' or the 'second window' of preconditioning). In the present study, we examined the effects of pharmacological modifiers of inducible nitric oxide synthase (iNOS) induction and activity on delayed protection conferred by ischaemic preconditioning 48 h later in an anaesthetized rabbit model of myocardial infarction. Rabbits underwent a myocardial preconditioning protocol (four 5 min coronary artery occlusions) or were sham-operated. Forty-eight hours later they were subjected to a sustained 30 min coronary occlusion and 120 min reperfusion. Infarct size was determined with triphenyltetrazolium staining. In rabbits receiving no pharmacological intervention, the percentage of myocardium infarcted within the risk zone was 43.9+5.0% in sham-operated animals and this was significantly reduced 48 h after ischaemic preconditioning with four 5 min coronary occlusions to 18.5+5.6% (P<0.01). Administration of the iNOS expression inhibitor dexamethasone (4 mg kg(-1) i.v) 60 min before ischaemic preconditioning completely blocked the infarct-limiting effect of ischaemic preconditioning (infarct size 48.6+/-6.1%). Furthermore, administration of aminoguanidine (300 mg kg(-1), s.c.), a relatively selective inhibitor of iNOS activity, 60 min before sustained ischaemia also abolished the delayed protection afforded by ischaemic preconditioning (infarct size 40.0+/-6.0%). Neither aminoguanidine nor dexamethasone per se had significant effect on myocardial infarct size. Myocardial risk zone volume during coronary ligation, a primary determinant of infarct size in this non-collateralized species, was not significantly different between intervention groups. There were no differences in systolic blood pressure, heart rate, arterial blood pH or rectal temperature between groups throughout the experimental period. These data provide pharmacological evidence that the induction of iNOS, following brief periods of coronary occlusion, is associated with increased myocardial tolerance to infarction 48 h later.
Assuntos
Precondicionamento Isquêmico Miocárdico , Infarto do Miocárdio/prevenção & controle , Óxido Nítrico Sintase/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Dexametasona/farmacologia , Indução Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Precondicionamento Isquêmico Miocárdico/mortalidade , Masculino , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase Tipo II , CoelhosRESUMO
Previous research has demonstrated that a transient increase in interstitial adenosine and subsequent activation of ATP-sensitive K+ (KATP) channels are involved in triggering ischemic preconditioning (PC), however, the role of adenosine in mediating the cardioprotection of hypoxic PC and that produced by KATP channel openers is less clear. Thus, the aim of the present study was to determine the role of adenosine in mediating the cardioprotective effects of PC produced by 5 min of ischemia, hypoxia, or by a 5-min intracoronary (i.c.) infusion of the KATP channel opener bimakalim (1 microgram/min). A single microdialysis probe was implanted into the midwall of the ischemic area for sampling of interstitial fluid adenosine and its breakdown products during the PC stimulus, prolonged occlusion (60 min) and during the first 30 min of the reperfusion (3 h) period. Ischemic, hypoxic and bimakalim pretreatment significantly reduced infarct size, 5.3 +/- 1.5; 8.9 +/- 2.5; 11.4 +/- 3.2, respectively, as compared to control: 27.3 +/- 6.5. Both ischemic and hypoxic PC produced similar and significant increases (0.56 +/- 0.13 mumol/l to 1.12 +/- 0.12 mumol/l and 1.32 mumol, control, ischemic and hypoxic PC, respectively) in dialysate adenosine concentration which persisted during the brief 10-min reperfusion period following PC. However, i.c. bimakalim resulted in a significant decrease in dialysate adenosine (0.56 +/- 0.13 mumol/l to 0.22 +/- 0.04 mumol/l) which persisted during the 10-min drug-free period. All three PC protocols resulted in similar decreases in dialysate adenosine, inosine and uric acid concentrations throughout the prolonged ischemic period as compared to control animals. In conclusion (1): PC produced by ischemia or hypoxia results in an increase in interstitial adenosine prior to a prolonged occlusion period; (2) the KATP channel agonist, bimakalim, significantly decreased interstitial adenosine prior to a prolonged occlusion period; (3) ischemic PC, hypoxic PC, and bimakalim pretreatment produced a similar reduction in interstitial adenosine and its breakdown products during the prolonged ischemic period. These results suggest that an increase in interstitial adenosine may be necessary for the initiation of the protective effect of ischemic and hypoxic PC but an increase in adenosine is not necessary for the cardioprotective effect of a direct opener of the KATP channel.