Bo Løfgren

Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes.

Aims/hypothesisThe prevalence of Type 2 diabetes mellitus is increasing worldwide with obese diabetic patients constituting the majority of this population. Type 2 diabetes is associated with increased morbidity and mortality after acute myocardial infarction. Previous experimental studies of ischaemia-reperfusion tolerance in diabetes have only been performed in animal models of Type 1 diabetes mellitus, yielding conflicting data. The aim of the present study was to characterise and compare the tolerance to ischaemia and effects of ischaemic preconditioning (IPC) in hearts from obese Zucker diabetic fatty (ZDF) and lean Goto-Kakizaki (GK) Type 2 diabetic rats, using non-obese Zucker and Wistar rats as respective controls.MethodsThe two rat strains were divided into 8 groups. The ZDF study (n=47) consisted of: Control −IPC, Control +IPC, ZDF −IPC and ZDF +IPC. The GK study (n=38) consisted of: Control −IPC, Control +IPC, GK −IPC and GK +IPC. Hearts, which were studied in a Langendorff preparation perfused with Krebs-Henseleit buffer, were subjected or not to IPC (+IPC, −IPC) before 50 minutes of regional ischaemia and 120 minutes reperfusion.ResultsIschaemic reperfusion injury was smaller in obese (p<0.05) and lean (p<0.05) Type 2 diabetic animals than in their respective control animals. IPC reduced ischaemic reperfusion injury during reperfusion in non-diabetic control rats (p<0.01), but failed to protect hearts from both diabetic animal models. Post-ischaemic haemodynamic recovery was impaired in the ZDF rats compared to both control and GK rats (p<0.05).Conclusions/interpretationIschaemic preconditioning does not protect hearts from obese or lean Type 2 diabetic animals. However, the susceptibility of the Type 2 diabetic myocardium to ischaemic damage is lower than in non-diabetic hearts. The method described here could be used as a tool to study the pathogenesis of increased cardiovascular morbidity and mortality in Type 2 diabetes.

Part 3: Adult Basic Life Support and Automated External Defibrillation: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations

This review comprises the most extensive literature search and evidence evaluation to date on the most important international BLS interventions, diagnostics, and prognostic factors for cardiac arrest victims. It reemphasizes that the critical lifesaving steps of BLS are (1) prevention, (2) immediate recognition and activation of the emergency response system, (3) early high-quality CPR, and (4) rapid defibrillation for shockable rhythms. Highlights in prevention indicate the rational and judicious deployment of search-and-rescue operations in drowning victims and the importance of education on opioid-associated emergencies. Other 2015 highlights in recognition and activation include the critical role of dispatcher recognition and dispatch-assisted chest compressions, which has been demonstrated in multiple international jurisdictions with consistent improvements in cardiac arrest survival. Similar to the 2010 ILCOR BLS treatment recommendations, the importance of high quality was reemphasized across all measures of CPR quality: rate, depth, recoil, and minimal chest compression pauses, with a universal understanding that we all should be providing chest compressions to all victims of cardiac arrest. This review continued to focus on the interface of BLS sequencing and ensuring high-quality CPR with other important BLS interventions, such as ventilation and defibrillation. In addition, this consensus statement highlights the importance of EMS systems, which employ bundles of care focusing on providing high-quality chest compressions while extricating the patient from the scene to the next level of care. Highlights in defibrillation indicate the global importance of increasing the number of sites with public-access defibrillation programs. Whereas the 2010 ILCOR Consensus on Science provided important direction for the “what” in resuscitation (ie, what to do), the 2015 consensus has begun with the GRADE methodology to provide direction for the quality of resuscitation. We hope that resuscitation councils and other stakeholders will be able to translate this body of knowledge of international consensus statements to build their own effective resuscitation guidelines.

Part 4: Advanced life support

The International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support (ALS) Task Force performed detailed systematic reviews based on the recommendations of the Institute of Medicine of the National Academies1 and using the methodological approach proposed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Working Group.2 Questions to be addressed (using the PICO [population, intervention, comparator, outcome] format)3 were prioritized by ALS Task Force members (by voting). Prioritization criteria included awareness of significant new data and new controversies or questions about practice. Questions about topics no longer relevant to contemporary practice or where little new research has occurred were given lower priority. The ALS Task Force prioritized 42 PICO questions for review. With the assistance of information specialists, a detailed search for relevant articles was performed in each of 3 online databases (PubMed, Embase, and the Cochrane Library). By using detailed inclusion and exclusion criteria, articles were screened for further evaluation. The reviewers for each question created a reconciled risk of bias assessment for each of the included studies, using state-of-the-art tools: Cochrane for randomized controlled trials (RCTs),4 Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 for studies of diagnostic accuracy,5 and GRADE for observational studies that inform both therapy and prognosis questions.6 GRADE evidence profile tables7 were then created to facilitate an evaluation of the evidence in support of each of the critical and important outcomes. The quality of the evidence (or confidence in the estimate of the effect) was categorized as high, moderate, low, or very low,8 based on the study methodologies and the 5 core GRADE domains of risk of bias, inconsistency, indirectness, imprecision, and other considerations (including publication bias).9 These evidence profile tables were then used to create a …

Part 3: Adult Basic Life Support and Automated External Defibrillation

This Part of the 2015 International Consensus on Cardiopul monary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC) Science With Treatment Recommendations (CoSTR) presents the consensus on science and treatment recommendations for adult basic life support (BLS) and automated external defibrillation (AED). After the publication of the 2010 CoSTR, the Adult BLS Task Force developed review questions in PICO (population, intervention, comparator, outcome) format.1 This resulted in the generation of 36 PICO questions for systematic reviews. The task force discussed the topics and then voted to prioritize the most important questions to be tackled in 2015. From the pool of 36 questions, 14 were rated low priority and were deferred from this round of evidence evaluation. Two new questions were submitted by task force members, and 1 was submitted via the public portal. Two of these (BLS 856 and BLS 891) were taken forward for evidence review. The third question (368: Foreign-Body Airway Obstruction) was deferred after a preliminary review of the evidence failed to identify compelling evidence that would alter the treatment recommendations made when the topic was last reviewed in 2005.2 Each task force performed a systematic review using detailed inclusion and exclusion criteria, based on the recommendations of the Institute of Medicine of the National Academies.3 With the assistance of information specialists, a detailed search for relevant articles was performed in each of 3 online databases (PubMed, Embase, and the Cochrane Library). Reviewers were unable to identify any relevant evidence for 3 questions (BLS 811, BLS 373, and BLS 348), and the evidence review was not completed in time for a further question (BLS 370). A revised PICO question was developed for the opioid question (BLS 891). The task force reviewed 23 PICO questions for the …

Metformin Induces Cardioprotection against Ischaemia/Reperfusion Injury in the Rat Heart 24 Hours after Administration

The UK Prospective Diabetes Study demonstrated that the hypoglycaemic drug metformin is associated with a reduction in cardiovascular events in a group of obese type 2 diabetes patients. The energy sensing enzyme AMP-activated protein kinase (AMPK) has been indicated to play an important protective role in the ischaemic heart and is activated by metformin. The aim of this study was to determine whether a single dose of metformin protects the myocardium against experimentally induced ischaemia 24 hr after the administration, and furthermore to determine whether a single dose of metformin results in an acute increase in myocardial AMPK activity. Wistar rats were given either a single oral dose of metformin (250 mg/kg body weight), or a single oral dose of saline. After 24 hr, the hearts were Langendorff-perfused and subjected to 45 min. of coronary artery occlusion. Infarct size was determined by staining with triphenyltetrazoliumchloride (TTC) and Evans Blue and expressed as a percentage of the risk zone (IS/AAR %). Isoform specific AMPK activity was measured 2 hr after administration of metformin or saline. Infarct size was significantly reduced in the metformin treated (I/R: 19.9 +/- 3.9%versus 36.7 +/- 3.6%, P < 0.01, n = 8-14) compared to the control group. A single oral dose of metformin resulted in an approximately ~2-fold increase in AMPK-alpha2 activity 2 hr after administration (P < 0.015, n = 10). In conclusion, a single dose of metformin results in an acute increase in myocardial AMPK activity measured 2 hr after administration and induces a significant reduction in myocardial infarct size 24 hr after metformin administration. Increased AMPK activity may be an important signal mediator involved in the mechanisms behind the cardioprotective effects afforded by metformin.

Initial assessment and treatment with the Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach

The Airway, Breathing, Circulation, Disability, Exposure (ABCDE) approach is applicable in all clinical emergencies for immediate assessment and treatment. The approach is widely accepted by experts in emergency medicine and likely improves outcomes by helping health care professionals focusing on the most life-threatening clinical problems. In an acute setting, high-quality ABCDE skills among all treating team members can save valuable time and improve team performance. Dissemination of knowledge and skills related to the ABCDE approach are therefore needed. This paper offers a practical “how-to” description of the ABCDE approach.

Mouth-to-mouth ventilation is superior to mouth-to-pocket mask and bag-valve-mask ventilation during lifeguard CPR: A randomized study

AIM The quality of cardiopulmonary resuscitation (CPR) is a crucial determinant of outcome following cardiac arrest. Interruptions in chest compressions are detrimental. We aimed to compare the effect of mouth-to-mouth ventilation (MMV), mouth-to-pocket mask ventilation (MPV) and bag-valve-mask ventilation (BMV) on the quality of CPR. MATERIALS AND METHODS Surf lifeguards in active service were included in the study. Each surf lifeguard was randomized to perform three sessions of single-rescuer CPR using each of the three ventilation techniques (MMV, MPV and BMV) separated by 5 min of rest. Data were obtained from a resuscitation manikin and video recordings. RESULTS A total of 60 surf lifeguards were included (67% male, 33% female, mean age 25 years). Interruptions in chest compressions were significantly reduced by MMV (8.9 ± 1.6 s) when compared to MPV (10.7 ± 3.0 s, P < 0.001) and BMV (12.5 ± 3.5s, P < 0.001). Significantly more effective ventilations (visible chest rise) were delivered using MMV (91%) when compared to MPV (79%, P < 0.001) and BMV (59%, P < 0.001). The inspiratory time was longer during MMV (0.7 ± 0.2 s) and MPV (0.7 ± 0.2s, P < 0.001 for both) compared to BMV (0.5 ± 0.2s). Tidal volumes were significantly lower using BMV (0.4 ± 0.2L) compared to MMV (0.6 ± 0.2L, P < 0.001) and MPV (0.6 ± 0.3 L, P < 0.001), whereas no differences were observed when comparing MMV and MPV. CONCLUSION MMV reduces interruptions in chest compressions and produces a higher proportion of effective ventilations during lifeguard CPR. This suggests that CPR quality is improved using MMV compared to MPV and BMV.

Amino acid transamination is crucial for ischaemic cardioprotection in normal and preconditioned isolated rat hearts – focus on l‐glutamate

We have found that cardioprotection by l‐glutamate mimics protection by classical ischaemic preconditioning (IPC). We investigated whether the effect of IPC involves amino acid transamination and whether IPC modulates myocardial glutamate metabolism. In a glucose‐perfused, isolated rat heart model subjected to 40 min global no‐flow ischaemia and 120 min reperfusion, the effects of IPC (2 cycles of 5 min ischaemia and 5 min reperfusion) and continuous glutamate (20 mm) administration during reperfusion on infarct size and haemodynamic recovery were studied. The effect of inhibiting amino acid transamination was evaluated by adding the amino acid transaminase inhibitor amino‐oxyacetate (AOA; 0.025 mm) during reperfusion. Changes in coronary effluent, interstitial (microdialysis) and intracellular glutamate ([GLUT]i) concentrations were measured. Ischaemic preconditioning and postischaemic glutamate administration reduced infarct size to the same extent (41 and 40%, respectively; P < 0.05 for both), without showing an additive effect. Amino‐oxyacetate abolished infarct reduction by IPC and glutamate, and increased infarct size in both control and IPC hearts in a dose‐dependent manner. Ischaemic preconditioning increased [GLUT]i before ischaemia (P < 0.01) and decreased the release of glutamate during the first 10 min of reperfusion (P= 0.03). A twofold reduction in [GLUT]i from the preischaemic state to 45 min of reperfusion (P= 0.0001) suggested increased postischaemic glutamate utilization in IPC hearts. While IPC and AOA changed haemodynamics in accordance with infarct size, glutamate decreased haemodynamic recovery despite reduced infarct size. In conclusion, ischaemic cardioprotection of the normal and IPC‐protected heart depends on amino acid transamination and activity of the malate–aspartate shuttle during reperfusion. Underlying mechanisms of IPC include myocardial glutamate metabolism.

Inhibition of the malate–aspartate shuttle by pre-ischaemic aminooxyacetate loading of the heart induces cardioprotection

AIMS Preserved mitochondrial function is essential for protection against ischaemia-reperfusion (IR) injury. The malate-aspartate (MA) shuttle constitutes the principal pathway for transport of reducing cytosolic equivalents for mitochondrial oxidation. We hypothesized that a transient shut-down of the MA-shuttle by aminooxyacetate (AOA) during ischaemia and early reperfusion modulates IR injury by mechanisms comparable to ischaemic preconditioning (IPC). METHODS AND RESULTS Isolated perfused rat hearts exposed to 40 min global no-flow ischaemia were studied in: (i) control, (ii) pre-ischaemic AOA (0.1 mM), (iii) IPC, and (iv) AOA+IPC hearts. IR injury was evaluated by infarct size and haemodynamic recovery. Tracer-estimated glucose oxidation and metabolic changes in glycogen, lactate, pyruvate, tricarboxylic acid (TCA) cycle intermediates, and ATP degradation products were measured. The effects of AOA on complex I respiration and reactive oxygen species (ROS) production were examined in isolated rabbit mitochondria. Treatment with AOA, IPC, or AOA+IPC induced significant infarct reduction; 28 ± 6, 30 ± 3, and 18 ± 1%, respectively, vs. 52 ± 5% of left ventricular (LV) mass for control (P < 0.01 for all). LV-developed pressure improved to 60 ± 3, 63 ± 5 and 53 ± 4 vs. 31 ± 5 mmHg (P < 0.01 for all) after 2 h reperfusion. Pre-ischaemic AOA administration inhibited glycolysis and increased glucose oxidation during post-ischaemic reperfusion similar to IPC, and suppressed complex I respiration and ROS production in the non-ischaemic heart. Changes in lactate, pyruvate, TCA intermediates, and ATP end products suggested an AOA inhibition of the MA-shuttle during late ischaemia and early reperfusion. CONCLUSION Inhibition of the MA-shuttle during ischaemia and early reperfusion is proposed as a mechanism to reduce IR injury.

L-glutamate and glutamine improve haemodynamic function and restore myocardial glycogen content during postischaemic reperfusion: A radioactive tracer study in the rat isolated heart.

1 l‐Glutamate and glutamine have been suggested to have cardioprotective effects. However, the issue is controversial and the metabolic mechanisms underlying a beneficial effect are not well understood. 2 In the present study we investigated the effects of l‐glutamate and glutamine on haemodynamic recovery, the rate of de novo glycogen synthesis and myocardial glucose uptake during postischaemic reperfusion. 3 . Hearts from male Wistar rats (250–300 g) were divided into three groups as follows: (i) control (n = 12); (ii) l‐glutamate (n = 12); and (iii) glutamine (n = 12). Hearts were mounted in a Langendorff preparation and perfused with oxygenated Krebs’–Henseleit solution at 80 mmHg and 37C. Global ischaemia for 20 min was followed by 15 min reperfusion, during which l‐glutamate (50 mmol/L) or glutamine (20 mmol/L) were administered. Left ventricular developed pressure (LVDP), de novo synthesis of glycogen using [14C]‐glucose and myocardial glucose uptake using d‐[2‐3H]‐glucose were measured. 4 l‐Glutamate and glutamine increased postischaemic LVDP (P < 0.01 vs control hearts for both). l‐Glutamate and glutamine increased de novo glycogen synthesis by 78% (P < 0.001) and 55% (P < 0.01), respectively. At the end of reperfusion, total myocardial glycogen content was increased by both l‐glutamate and glutamine (5.7 ± 0.3 and 6.2 ± 0.7 mmol/g wet weight, respectively; P < 0.05 and 0.01, respectively) compared with that in control hearts (3.6 ± 0.4 mmol/g wet weight). Neither l‐glutamate nor glutamine affected myocardial glucose uptake during reperfusion. 5 . Improved postischaemic haemodynamic recovery after l‐glutamate and glutamine supplementation during reperfusion is associated with increased de novo glycogen synthesis, suggesting a favourable modulation of intracellular myocardial carbohydrate metabolism.