Background-Mild hypothermia improves outcome when induced after cardiac arrest in humans. Recent studies in both dogs and mice suggest that induction of mild hypothermia during cardiopulmonary resuscitation (CPR) greatly enhances its efficacy. In this study, we evaluate the time window for the beneficial effect of intra-arrest cooling in the setting of prolonged CPR in a clinically relevant large-animal model. Methods and Results-Seventeen dogs had ventricular fibrillation cardiac arrest no flow of 3 minutes, followed by 7 minutes of CPR basic life support and 50 minutes of advanced life support. In the early hypothermia group (nϭ9), mild hypothermia (34°C) was induced with an intravenous fluid bolus flush and venovenous blood shunt cooling after 10 minutes of ventricular fibrillation. In the delayed hypothermia group (nϭ8), hypothermia was induced at ventricular fibrillation 20 minutes. After 60 minutes of ventricular fibrillation, restoration of spontaneous circulation was achieved with cardiopulmonary bypass for 4 hours, and intensive care was given for 96 hours. In the early hypothermia group, 7 of 9 dogs survived to 96 hours, 5 with good neurological outcome. In contrast, 7 of 8 dogs in the delayed hypothermia group died within 37 hours with multiple organ failure (Pϭ0.012). Conclusions-Early application of mild hypothermia with cold saline during prolonged CPR enables intact survival. Delay in the induction of mild hypothermia in this setting markedly reduces its efficacy. Our data suggest that if mild hypothermia is used during CPR, it should be applied as early as possible. Key Words: cardiopulmonary resuscitation Ⅲ cooling Ⅲ heart arrest Ⅲ hypothermia Ⅲ resuscitation A fter successful resuscitation from cardiac arrest (CA), hypothermia has been shown in several experimental studies to improve cerebral outcome. [1][2][3][4][5] On the basis of recent clinical studies, therapeutic mild hypothermia is recommended by the American Heart Association and the International Liaison Committee on Resuscitation for Unconscious Survivors of CA. 6,7 Despite a relatively late and slow surface cooling technique, these clinical trials in Europe and Australia documented neurological benefits with mild hypothermia in survivors of out-of-hospital CA. 8,9 Because evidence exists that a delay in cooling negates the beneficial effect of mild hypothermia, 4,10 some have suggested that hypothermia should be initiated as soon as possible after resuscitation or, preferably, during cardiopulmonary resuscitation (CPR) attempts. 5,10 In a recent study of CA in mice, application of mild hypothermia during CPR was shown to enhance outcome compared with its application after restoration of spontaneous circulation (ROSC). 11 Similarly, in a clinically relevant study of prolonged ventricular fibrillation (VF) in dogs, we documented that mild or moderate hypothermia Clinical Perspective p 2696induced during 40 minutes of CPR attempts preserves organ viability and significantly improves outcome. 12 Intact survival was achieved despite 40 mi...

BackgroundEvidence of the clinical safety of endothelin receptor antagonists (ERAs) is limited and derived mainly from individual trials; therefore, we conducted a meta‐analysis.Methods and ResultsAfter systematic searches of the Medline, Embase, and Cochrane Library databases and the ClinicalTrials.gov website, randomized controlled trials with patients receiving ERAs (bosentan, macitentan, or ambrisentan) in at least 1 treatment group were included. All reported adverse events of ERAs were evaluated. Summary relative risks and 95% CIs were calculated using random‐ or fixed‐effects models according to between‐study heterogeneity. In total, 24 randomized trials including 4894 patients met the inclusion criteria. Meta‐analysis showed that the incidence of abnormal liver function (7.91% versus 2.84%; risk ratio [RR] 2.38, 95% CI 1.36–4.18), peripheral edema (14.36% versus 9.68%; RR 1.44, 95% CI 1.20–1.74), and anemia (6.23% versus 2.44%; RR 2.69, 95% CI 1.78–4.07) was significantly higher in the ERA group compared with placebo. In comparisons of individual ERAs with placebo, bosentan (RR 3.78, 95% CI 2.42–5.91) but not macitentan (RR 1.17, 95% CI 0.42–3.31) significantly increased the risk of abnormal liver function, whereas ambrisentan (RR 0.06, 95% CI 0.01–0.45) significantly decreased that risk. Bosentan (RR 1.47, 95% CI 1.06–2.03) and ambrisentan (RR 2.02, 95% CI 1.40–2.91) but not macitentan (RR 1.08, 95% CI 0.81–1.46) significantly increased the risk of peripheral edema. Bosentan (RR 3.09, 95% CI 1.52–6.30) and macitentan (RR 2.63, 95% CI 1.54–4.47) but not ambrisentan (RR 1.30, 95% CI 0.20–8.48) significantly increased the risk of anemia. ERAs were not found to increase other reported adverse events compared with placebo.ConclusionsThe present meta‐analysis showed that the main adverse effects of treatment with ERAs were hepatic transaminitis (bosentan), peripheral edema (bosentan and ambrisentan), and anemia (bosentan and macitentan).

In a systematic series of studies in dogs, the rapid induction of profound cerebral hypothermia (tympanic temperature 10 degrees C) by aortic flush of cold saline immediately after the start of exsanguination cardiac arrest-which rarely can be resuscitated effectively with current methods-can achieve survival without functional or histologic brain damage, after cardiac arrest no-flow of 60 or 90 mins and possibly 120 mins. The use of additional preservation strategies should be pursued in the 120-min arrest model.

Objective Resuscitation of hemorrhagic hypotension after traumatic brain injury (TBI) is challenging. A hemoglobin (Hb)-based oxygen carrier (HBOC) may offer advantages. The novel therapeutic HBOC, polynitroxylated pegylated Hb (PNPH) may represent a neuroprotective HBOC for TBI resuscitation. Hypotheses 1) PNPH is a unique non-neurotoxic HBOC in neuronal culture and is neuroprotective in in vitro neuronal injury models. 2) Resuscitation with PNPH would require less volume to restore mean arterial blood pressure (MAP) than lactated Ringer’s (LR) or Hextend (HEX) and confer neuroprotection in a mouse model of TBI plus hemorrhagic hypotension. Design Prospective randomized controlled experimental study. Setting University center. Measurements and Main Results In rat primary cortical neuron cultures, control bovine Hb was neurotoxic (LDH release; MTT assay) at concentrations from 12.5 to 0.625µM, while polyethylene-glycol (Peg)-conjugated Hb showed intermediate toxicity. PNPH was not neurotoxic (p<0.05 vs bovine Hb and Peg-Hb; all concentrations). PNPH conferred neuroprotection in in vitro neuronal injury (glutamate/glycine exposure and neuronal stretch), as assessed via LDH, and MTT all p<0.05 vs control. C57BL6 mice received controlled cortical impact followed by hemorrhagic hypotension (2mL/100g, MAP ~35–40 mmHg) for 90 min. Mice were resuscitated (MAP >50 mmHg for 30 min) with LR, HEX, or PNPH, then shed blood was re-infused. MAPs, resuscitation volumes, blood gasses, glucose and lactate were recorded. Brain sections at 7d were examined via H&E and Fluoro-Jade C (FJC, identifying dying neurons) staining in CA1 and CA3 hippocampus. Resuscitation with PNPH or HEX required less volume than LR (both p<0.05). PNPH but not HEX improved MAP vs. LR (p<0.05). Mice resuscitated with PNPH had fewer FJC+ neurons in CA1 vs. HEX and LR, and CA3 vs. HEX (p<0.05). Conclusion PNPH is a novel neuroprotective HBOC in vitro and in vivo that may offer unique advantages for TBI resuscitation.

ConspectusThe human body is a complex network of molecules, organelles, cells, tissues, and organs: an uncountable number of interactions and transformations interconnect all the system’s components. In addition to these biochemical components, biophysical components, such as pressure, flow, and morphology, and the location of all of these interactions play an important role in the human body. Technical difficulties have frequently limited researchers from observing cellular biology as it occurs within the human body, but some state-of-the-art analytical techniques have revealed distinct cellular behaviors that occur only in the context of the interactions. These types of findings have inspired bioanalytical chemists to provide new tools to better understand these cellular behaviors and interactions.What blocks us from understanding critical biological interactions in the human body? Conventional approaches are often too naïve to provide realistic data and in vivo whole animal studies give complex results that may or may not be relevant for humans. Microfluidics offers an opportunity to bridge these two extremes: while these studies will not model the complexity of the in vivo human system, they can control the complexity so researchers can examine critical factors of interest carefully and quantitatively. In addition, the use of human cells, such as cells isolated from donated blood, captures human-relevant data and limits the use of animals in research. In addition, researchers can adapt these systems easily and cost-effectively to a variety of high-end signal transduction mechanisms, facilitating high-throughput studies that are also spatially, temporally, or chemically resolved. These strengths should allow microfluidic platforms to reveal critical parameters in the human body and provide insights that will help with the translation of pharmacological advances to clinical trials.In this Account, we describe selected microfluidic innovations within the last 5 years that focus on modeling both biophysical and biochemical interactions in cellular communication, such as flow and cell–cell networks. We also describe more advanced systems that mimic higher level biological networks, such as organ on-a-chip and animal on-a-chip models. Since the first papers in the early 1990s, interest in the bioanalytical use of microfluidics has grown significantly. Advances in micro-/nanofabrication technology have allowed researchers to produce miniaturized, biocompatible assay platforms suitable for microfluidic studies in biochemistry and chemical biology. Well-designed microfluidic platforms can achieve quick, in vitro analyses on pico- and femtoliter volume samples that are temporally, spatially, and chemically resolved. In addition, controlled cell culture techniques using a microfluidic platform have produced biomimetic systems that allow researchers to replicate and monitor physiological interactions. Pioneering work has successfully created cell–fluid, cell–cell, cell–tissue, tissue–tissue, even organ-like level interfa...

BackgroundDynamic interspinous spacers, such as X-stop, Coflex, DIAM, and Aperius, are widely used for the treatment of lumbar spinal stenosis. However, controversy remains as to whether dynamic interspinous spacer use is superior to traditional decompressive surgery.MethodsMedline, Embase, Cochrane Library, and the Cochrane Controlled Trials Register were searched during August 2013. A track search was performed on February 27, 2014. Study was included in this review if it was: (1) a randomized controlled trial (RCT) or non-randomized prospective comparison study, (2) comparing the clinical outcomes for interspinous spacer use versus traditional decompressive surgery, (3) in a minimum of 30 patients, (4) with a follow-up duration of at least 12 months.ResultsTwo RCTs and three non-randomized prospective studies were included, with 204 patients in the interspinous spacer (IS) group and 217 patients in the traditional decompressive surgery (TDS) group. Pooled analysis showed no significant difference between the IS and TDS groups for low back pain (WMD: 1.2; 95% CI: −10.12, 12.53; P = 0.03; I2 = 66%), leg pain (WMD: 7.12; 95% CI: −3.88, 18.12; P = 0.02; I2 = 70%), ODI (WMD: 6.88; 95% CI: −14.92, 28.68; P = 0.03; I2 = 79%), RDQ (WMD: −1.30, 95% CI: −3.07, 0.47; P = 0.00; I2 = 0%), or complications (RR: 1.39; 95% CI: 0.61, 3.14; P = 0.23; I2 = 28%). The TDS group had a significantly lower incidence of reoperation (RR: 3.34; 95% CI: 1.77, 6.31; P = 0.60; I2 = 0%).ConclusionAlthough patients may obtain some benefits from interspinous spacers implanted through a minimally invasive technique, interspinous spacer use is associated with a higher incidence of reoperation and higher cost. The indications, risks, and benefits of using an interspinous process device should be carefully considered before surgery.

Hypotension after traumatic brain injury (TBI) worsens outcome. We published the first report of TBI plus hemorrhagic shock (HS) in mice using a volume-controlled approach and noted increased neuronal death. To rigorously control blood pressure during HS, a pressure-controlled HS model is required. Our hypothesis was that a brief, severe period of pressure-controlled HS after TBI in mice will exacerbate functional deficits and neuropathology versus TBI or HS alone. C57BL6 male mice were randomized into four groups (n = 10/group): sham, HS, controlled cortical impact (CCI), and CCI + HS. We used a pressure-controlled shock phase (mean arterial pressure [MAP] = 25-27 mm Hg for 35 min) and its treatment after mild to moderate CCI including, a 90 min pre-hospital phase, during which lactated Ringer's solution was given to maintain MAP > 70 mm Hg, and a hospital phase, when the shed blood was re-infused. On days 14-20, the mice were evaluated in the Morris water maze (MWM, hidden platform paradigm). On day 21, the lesion and hemispheric volumes were quantified. Neuropathology and hippocampal neuron counts (hematoxylin and eosin [H&E], Fluoro-Jade B, and NeuN) were evaluated in the mice (n = 60) at 24 h, 7 days, or 21 days (n = 5/group/time point). HS reduced MAP during the shock phase in the HS and CCI + HS groups ( p < 0.05). Fluid requirements during the pre-hospital phase were greatest in the CCI + HS group ( p < 0.05), and were increased in HS versus sham and CCI animals ( p < 0.05). MWM latency was increased on days 14 and 15 after CCI + HS ( p < 0.05). Swim speed and visible platform latency were impaired in the CCI + HS group ( p < 0.05). CCI + HS animals had increased contusion volume versus the CCI group ( p < 0.05). Hemispheric volume loss was increased 33.3% in the CCI + HS versus CCI group ( p < 0.05). CA1 cell loss was seen in CCI + HS and CCI animals at 24 h and 7 days ( p < 0.05). CA3 cell loss was seen after CCI + HS ( p < 0.05 at 24 h and 7 days). CA1 cell loss at 21 days was seen only in CCI + HS animals ( p < 0.05). Brief, severe, pressure-controlled HS after CCI produces robust functional deficits and exacerbates neuropathology versus CCI or HS alone.

Attenuated plaque was present in three-quarters of patients with AMI. The amount of attenuated plaque strongly correlated with no-reflow; the larger the attenuated plaque, the greater the likelihood of no-reflow. (Dual Arm Factorial Randomized Trial in Patients w/ST Segment Elevation AMI to Compare the Results of Using Anticoagulation With Either Unfractionated Heparin + Routine GP IIb/IIIa Inhibition or Bivalirudin + Bail-out GP IIb/IIIa Inhibition; and Primary Angioplasty with stent implantation with Either a Slow Rate-release Paclitaxel-eluting Stent [TAXUS™] or Uncoated Bare Metal Stent [EXPRESS2™]; NCT00433966).