Mark Coburn

A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery

BACKGROUND Remote ischemic preconditioning (RIPC) is reported to reduce biomarkers of ischemic and reperfusion injury in patients undergoing cardiac surgery, but uncertainty about clinical outcomes remains. METHODS We conducted a prospective, double-blind, multicenter, randomized, controlled trial involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol. The trial compared upper-limb RIPC with a sham intervention. The primary end point was a composite of death, myocardial infarction, stroke, or acute renal failure up to the time of hospital discharge. Secondary end points included the occurrence of any individual component of the primary end point by day 90. RESULTS A total of 1403 patients underwent randomization. The full analysis set comprised 1385 patients (692 in the RIPC group and 693 in the sham-RIPC group). There was no significant between-group difference in the rate of the composite primary end point (99 patients [14.3%] in the RIPC group and 101 [14.6%] in the sham-RIPC group, P=0.89) or of any of the individual components: death (9 patients [1.3%] and 4 [0.6%], respectively; P=0.21), myocardial infarction (47 [6.8%] and 63 [9.1%], P=0.12), stroke (14 [2.0%] and 15 [2.2%], P=0.79), and acute renal failure (42 [6.1%] and 35 [5.1%], P=0.45). The results were similar in the per-protocol analysis. No treatment effect was found in any subgroup analysis. No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release, the duration of mechanical ventilation, the length of stay in the intensive care unit or the hospital, new onset of atrial fibrillation, and the incidence of postoperative delirium. No RIPC-related adverse events were observed. CONCLUSIONS Upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery. (Funded by the German Research Foundation; RIPHeart ClinicalTrials.gov number, NCT01067703.).

The neuroprotective effects of xenon and helium in an in vitro model of traumatic brain injury.

Objectives: The “inert” gas xenon has been shown to be an effective neuroprotectant in a variety of in vitro and in vivo models of neuronal injury. We examined its neuroprotective properties in an in vitro model of traumatic brain injury. Design: Controlled laboratory study. Setting: Academic research laboratory. Subjects: Organotypic hippocampal brain slices from mice pups. Interventions: The cultured brain slices were subjected to a focal mechanical trauma, and injury was monitored in the presence and absence of inert gases at normal and elevated pressures and under both normothermic and hypothermic conditions. Measurements and Main Results: Neuronal injury was quantified using propidium iodide, which becomes fluorescent only when it enters injured cells. Low pressures of both helium and xenon were effective neuroprotectants when applied in addition to 1 atm of air. Moreover, both gases were effective at normal pressures when they replaced nitrogen in a gas mixture. Conclusions: The inert gases helium and xenon are effective neuroprotectants in a model for traumatic brain injury, and this novel treatment warrants further investigation. Xenon was particularly effective at reducing the secondary injury that developed following the initial trauma and could be administered at least 3 hrs postinjury with only a small reduction in efficacy.

Argon: neuroprotection in in vitro models of cerebral ischemia and traumatic brain injury.

IntroductionRecently, it has been shown in several experimental settings that the noble gases xenon and helium have neuroprotective properties. In this study we tested the hypothesis that the noble gas argon has a neuroprotective potential as well. Since traumatic brain injury and stroke are widespread and generate an enormous economic and social burden, we investigated the possible neuroprotective effect in in vitro models of traumatic brain injury and cerebral ischemia.MethodsOrganotypic hippocampal slice cultures from mice pups were subjected to either oxygen-glucose deprivation or to a focal mechanical trauma and subsequently treated with three different concentrations (25, 50 and 74%) of argon immediately after trauma or with a two-or-three-hour delay. After 72 hours of incubation tissue injury assessment was performed using propidium iodide, a staining agent that becomes fluorescent when it diffuses into damaged cells via disintegrated cell membranes.ResultsWe could show argons neuroprotective effects at different concentrations when applied directly after oxygen-glucose deprivation or trauma. Even three hours after application, argon was still neuroprotective.ConclusionsArgon showed a neuroprotective effect in both in vitro models of oxygen-glucose deprivation and traumatic brain injury. Our promising results justify further in vivo animal research.

Neuroprotective effects of argon in an in vivo model of transient middle cerebral artery occlusion in rats.

Objective: The neuroprotective effects of the noble gas xenon are well known. Argon, in contrast to xenon, is abundant, inexpensive, and therefore widely applicable. In this study, we analyzed the possible neuroprotective role of argon in an in vivo rat model of acute focal cerebral ischemia. Design: Controlled laboratory study. Setting: Academic research laboratory. Subjects: Male adult Sprague-Dawley rats. Interventions: Twenty-two rats underwent 2 hrs of transient middle cerebral artery occlusion using the endoluminal thread model. One hr after transient middle cerebral artery occlusion induction, spontaneously breathing rats received either 50 vol % argon/50 vol % O2 (argon group, n = 11) or 50 vol % N2/50 vol % O2 (control group, n = 11) for 1 hr through a face mask. Twenty-four hrs after reperfusion, rats were neurologically and behaviorally tested and euthanized. Rat brains were stained with 2,3,5-triphenyltetrazolium chloride and infarct volumes determined by planimetry. Measurements and Main Results: After 2 hrs of transient middle cerebral artery occlusion in the rat, we found in the argon group a significant reduction in the overall (p = .004) and after subdivision in the cortical (p = .007) and the basal ganglia (p = .02) infarct volumes. Argon treatment resulted in a significant improvement of the composite adverse outcome (p = .034). However, there was no advantage in acute survival 24 hrs after transient middle cerebral artery occlusion (p = .361). Conclusion: We were able to demonstrate argons neuroprotective effects in an in vivo experimental rat model of acute focal cerebral ischemia. Animals breathing spontaneously 50 vol % argon 1 hr after induction of transient middle cerebral artery occlusion for 1 hr by face mask showed significantly reduced infarct volumes and composite adverse outcomes.

Xenon reduces neurohistopathological damage and improves the early neurological deficit after cardiac arrest in pigs.

Objective:Treatment options to ameliorate brain damage following cardiopulmonary resuscitation from cardiac arrest are limited. Design:In a porcine model, we evaluated the effects of xenon treatment on neuropathologic and functional outcomes after cardiopulmonary resuscitation. Setting:Prospective, randomized laboratory animal study. Subjects:Male pigs. Interventions:Following successful resuscitation from 8 mins of cardiac arrest and 5 mins of cardiopulmonary resuscitation, 24 pigs were randomized to one of three groups receiving either 70% xenon for 1 or 5 hrs or untreated controls receiving 70% nitrogen. Measurements and Main Results:Gas exchange, hemodynamics, and lactate and glucose levels were measured at baseline and in the postresuscitation period. On four postoperative days, neurocognitive and overall neurologic deficits were assessed before day 5, when the brains were harvested for histologic analysis of predefined regions using a semiquantitative score (0–10% = 1, 10–20% = 2, 20–50% = 3, 50–80% = 4, 80–100% = 5). No differences in gas exchange, hemodynamics, or lactate and glucose levels were observed among the groups. Animals exposed to 1 and 5 hrs of xenon showed significantly reduced scores for necrotic neurons in the putamen (1.25 ± 0.5 and 1.25 ± 0.5 vs. 2.5 ± 1.2; p < 0.05), accompanied by significantly lesser scores for perivascular inflammation in putamen (0.8 ± 0.5 and 1.1 ± 0.8 vs. 2.1 ± 1.1; p < 0.05) and caudate nucleus (1.0 ± 0.8 and 0.6 ± 0.7 vs. 2.0 ± 1.1; p < 0.05). This resulted in improved neurocognitive and neurologic function on day 1 to 3 after cardiopulmonary resuscitation in xenon-treated animals. Conclusions:In this experimental study of cardiac arrest-induced neurologic damage, xenon conferred neurohistopathologic protection, translating in transiently improved functional outcome.

Dexmedetomidine is neuroprotective in an in vitro model for traumatic brain injury

BackgroundThe α2-adrenoreceptor agonist dexmedetomidine is known to provide neuroprotection under ischemic conditions. In this study we investigated whether dexmedetomidine has a protective effect in an in vitro model for traumatic brain injury.MethodsOrganotypic hippocampal slice cultures were subjected to a focal mechanical trauma and then exposed to varying concentrations of dexmedetomidine. After 72 h cell injury was assessed using propidium iodide. In addition, the effects of delayed dexmedetomidine application, of hypothermia and canonical signalling pathway inhibitors were examined.ResultsDexmedetomidine showed a protective effect on traumatically injured hippocampal cells with a maximum effect at a dosage of 1 μM. This effect was partially reversed by the simultaneous administration of the ERK inhibitor PD98059.ConclusionIn this TBI model dexmedetomidine had a significant neuroprotective effect. Our results indicate that activation of ERK might be involved in mediating this effect.

Performance of cardiac output measurement derived from arterial pressure waveform analysis in patients requiring high-dose vasopressor therapy

BACKGROUND Arterial pressure waveform analysis of cardiac output (APCO) without external calibration (FloTrac/Vigileo™) is critically dependent upon computation of vascular tone that has necessitated several refinements of the underlying software algorithms. We hypothesized that changes in vascular tone induced by high-dose vasopressor therapy affect the accuracy of APCO measurements independently of the FloTrac software version. METHODS In this prospective observational study, we assessed the validity of uncalibrated APCO measurements compared with transpulmonary thermodilution cardiac output (TPCO) measurements in 24 patients undergoing vasopressor therapy for the treatment of cerebral vasospasm after subarachnoid haemorrhage. RESULTS Patients received vasoactive support with [mean (sd)] 0.53 (0.46) µg kg(-1) min(-1) norepinephrine resulting in mean arterial pressure of 104 (14) mm Hg and mean systemic vascular resistance of 943 (248) dyn s(-1) cm(-5). Cardiac output (CO) data pairs (158) were obtained simultaneously by APCO and TPCO measurements. TPCO ranged from 5.2 to 14.3 litre min(-1), and APCO from 4.1 to 13.7 litre min(-1). Bias and limits of agreement were 0.9 and 2.5 litre min(-1), resulting in an overall percentage error of 29.6% for 68 data pairs analysed with the second-generation FloTrac(®) software and 27.9% for 90 data pairs analysed with the third-generation software. Precision of the reference technique was 2.6%, while APCO measurements yielded a precision of 29.5% and 27.9% for the second- and the third-generation software, respectively. For both software versions, bias (TPCO-APCO) correlated inversely with systemic vascular resistance. CONCLUSIONS In neurosurgical patients requiring high-dose vasopressor support, precision of uncalibrated CO measurements depended on systemic vascular resistance. Introduction of the third software algorithm did not improve the insufficient precision (>20%) for APCO measurements observed with the second software version.

Effects of different fibrinogen concentrations on blood loss and coagulation parameters in a pig model of coagulopathy with blunt liver injury

IntroductionThe early application of fibrinogen could potentially reverse haemodilution-induced coagulopathy, although the impact of varying concentrations of fibrinogen to reverse dilutional coagulopathy has not been studied in vivo. We postulated that fibrinogen concentration is correlated with blood loss in a pig model of coagulopathy with blunt liver injury.MethodsCoagulopathy was induced in 18 anaesthetized pigs (32 ± 1.6 kg body weight) by replacing 80% of blood volume with hydroxyethylstarch 130/0.4 and Ringers lactated solution, and re-transfusion of erythrocytes. Animals were randomly assigned to receive either 70 mg kg-1 (F-70) or 200 mg kg-1 (F-200) fibrinogen or placebo before inducing blunt liver injury using a force of 225 ± 26 Newton. Haemodynamics, coagulation parameters and blood loss were monitored for 2 hours. After death, histological examination of internal organs was performed to assess the presence of emboli and the equality of liver injury.ResultsPlasma dilution caused severe coagulopathy. Measured by thromboelastography fibrinogen restored coagulation dose-dependently. Total blood loss was significantly lower and survival better in both fibrinogen groups as compared to controls (P < 0.05). Between the F-70 (1317 ± 113 ml) and the F-200 group (1155 ± 232 ml) no significant difference in total blood loss could be observed, despite improved coagulation parameters in the F-200 group (P < 0.05). Microscopy revealed even injury pattern and no (micro) thrombi for either group.ConclusionsRestoring fibrinogen with 70 or 200 mg kg-1 after severe dilutional coagulopathy safely improved coagulation and attenuated blood loss after experimental blunt liver trauma. The higher dosage of fibrinogen was not associated with a further reduction in blood loss.

The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients

Objective:The trace elements selenium, copper, and zinc are essential for maintaining the oxidative balance. A depletion of antioxidative trace elements has been observed in critically ill patients and is associated with the development of multiorgan dysfunction and an increased mortality. Cardiac surgery using cardiopulmonary bypass provokes ischemia-reperfusion-mediated oxidative stress. We hypothesized that an intraoperative decrease of circulating trace elements may be involved in this response. Design:Prospective observational clinical study. Setting:University hospital cardiothoracic operation theater and intensive care unit. Patients:Sixty patients (age 65 ± 14 yrs) undergoing cardiac surgery with the use of cardiopulmonary bypass. Measurements and Main Results:Whole blood concentrations of selenium, copper, and zinc were measured after induction of anesthesia and 1 hr after admission to the intensive care unit. All patients were separated in a priori defined subgroups according to the development of no organ failure, single organ failure, and ≥2 organ failures in the postoperative period. Results:Fifty patients exhibited a significant selenium deficiency already before surgery, whereas copper and zinc concentrations were within the reference range.In all patients, blood levels of selenium, copper, and zinc were significantly reduced after end of surgery when compared to preoperative values (selenium: 89.05 ± 12.65 to 70.84 ± 10.46 &mgr;g/L; zinc: 5.15 ± 0.68 to 4.19 ± 0.73 mg/L; copper: 0.86 ± 0.15 to 0.65 ± 0.14 mg/L; p < .001).During their intensive care unit stay, 17 patients were free from any organ failure, while 31 patients developed single-organ failure and 12 patients multiple organ failure.Multilogistic regression analysis showed that selenium concentrations at end of surgery were independently associated with the postoperative occurrence of multiorgan failure (p = .0026, odds ratio 0.8479, 95% confidence interval 0.7617 to 0.9440). Conclusions:Cardiac surgery using cardiopulmonary bypass resulted in a profound intraoperative decrease of whole blood levels of antioxidant trace elements. Low selenium concentrations at end of surgery were an independent predictor for the postoperative development of multiorgan failure.

Propofol: neuroprotection in an in vitro model of traumatic brain injury.

IntroductionThe anaesthetic agent propofol (2,6-diisopropylphenol) has been shown to be an effective neuroprotective agent in different in vitro models of brain injury induced by oxygen and glucose deprivation. We examined its neuroprotective properties in an in vitro model of traumatic brain injury.MethodsIn this controlled laboratory study organotypic hippocampal brain-slice cultures were gained from six- to eight-day-old mice pups. After 14 days in culture, hippocampal brain slices were subjected to a focal mechanical trauma and subsequently treated with different molar concentrations of propofol under both normo- and hypothermic conditions. After 72 hours of incubation, tissue injury assessment was performed using propidium iodide (PI), a staining agent that becomes fluorescent only when it enters damaged cells via perforated cell membranes. Inside the cell, PI forms a fluorescent complex with nuclear DNA.ResultsA dose-dependent reduction of both total and secondary tissue injury could be observed in the presence of propofol under both normo- and hypothermic conditions. This effect was further amplified when the slices were incubated at 32°C after trauma.ConclusionsWhen used in combination, the dose-dependent neuroprotective effect of propofol is additive to the neuroprotective effect of hypothermia in an in vitro model of traumatic brain injury.