P2X7 receptor blockade reduces pyroptotic inflammation and promotes phagocytosis in Vibrio vulnificus infection.

Vibrio vulnificus, a gram-negative bacterium, causes serious wound infections and septicemia. Once it develops into early phase sepsis, hyperinflammatory immune responses result in poor prognosis in patients. The present study aimed to examine the possible underlying pathogenic mechanism and explore potential agents that could protect against V. vulnificus cytotoxicity. Here, we report that infection of mouse macrophages with V. vulnificus triggers antiphagocytic effects and pyroptotic inflammation via ATP-mediated purinergic P2X7 receptor (P2X7R) signaling. V. vulnificus promoted P2X7-dependent nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 translocation, modulating the expression of the inflammasome sensor NLR family pyrin domain containing 3 (NLRP3), adaptor apoptosis-associated speck-like protein containing a card (ASC), and pyroptotic protein gasdermin D (GSDMD) in mouse macrophages. V. vulnificus induced the NLRP3/caspase-1 inflammasome signaling complex expression that drives GSDMD transmembrane pore formation and secretion of interleukin (IL)-1ß, IL-18, and macrophage inflammatory protein-2 (MIP-2). This effect was blocked by P2X7R antagonists, indicating that the P2X7R mediates GSDMD-related pyroptotic inflammation in macrophages through the NF-κB/NLRP3/caspase-1 signaling pathway. Furthermore, blockade of P2X7R reduced V. vulnificus-colony-forming units in the spleen, immune cell infiltration into the skin and lung tissues, and serum concentrations of IL-1ß, IL-18, and MIP-2 in mice. These results indicate that P2X7R plays a vital role in mediating phagocytosis by macrophages and pyroptotic inflammation during V. vulnificus infection and provides new opportunities for therapeutic intervention in bacterial infections.

Impact of a targeted temperature management quality improvement project on survival and neurologic outcomes in cardiac arrest patients.

BACKGROUND: Targeted temperature management (TTM) is recommended for postresuscitation care of patients with sudden cardiac arrest (SCA) and its implementation remains challenging. This study aimed to evaluate the newly designed Quality Improvement Project (QIP) to improve the quality of TTM and outcomes of patients with SCA. METHODS: Patients who experienced out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) with return of spontaneous circulation (ROSC) and were treated in our hospital between January 2017 and December 2019 were enrolled retrospectively. All included patients received QIP intervention initiated as follows: (1) Protocols and standard operating procedures were created for TTM; (2) shared decision-making was documented; (3) job training instruction was created; and 4) lean medical management was implemented. RESULTS: Among 248 included patients, the postintervention group (n = 104) had shorter duration of ROSC to TTM than the preintervention group (n = 144) (356 vs 540 minutes, p = 0.042); better survival rate (39.4% vs 27.1%, p = 0.04), and neurologic performance (25.0% vs 17.4%, p < 0.001). After propensity score matching (PSM), patients who received TTM (n = 48 ) had better neurologic performance than those without TTM (n = 48) (25.1% vs 18.8%, p < 0.001). OHCA (odds ratio [OR] = 2.705, 95% CI: 1.657-4.416), age >60 (OR = 2.154, 95% CI: 1.428-3.244), female (OR = 1.404, 95% CI: 1.005-1.962), and diabetes mellitus (OR = 1.429, 95% CI: 1.019-2.005) were negative predictors of survival; while TTM (OR = 0.431, 95% CI: 0.266-0.699) and bystander cardiopulmonary resuscitation (CPR) (OR=0.589, 95% CI: 0.35-0.99) were positive predictors. Age >60 (OR= 2.292, 95% CI: 1.58-3.323) and OHCA (OR= 2.928, 95% CI: 1.858-4.616) were negative predictors of favorable neurologic outcomes; while bystander CPR (OR=0.572, 95% CI: 0.355-0.922) and TTM (OR=0.457, 95% CI: 0.296-0.705) were positive predictors. CONCLUSION: A new QIP with defined protocols, documented shared decision-making, and medical management guidelines improves TTM execution, duration from ROSC to TTM , survival, and neurologic outcomes of cardiac arrest patients.

Combination therapy of iPSC-derived conditioned medium with ceftriaxone alleviates bacteria-induced lung injury by targeting the NLRP3 inflammasome.

The lung is the first and most frequent organ to fail among sepsis patients. The mortality rate of sepsis-related acute lung injury (ALI) is high. Despite appropriate antimicrobial therapy, no treatment strategies are available for sepsis-induced ALI. Stem cell-mediated paracrine signaling is a potential treatment method for various diseases. This study aimed to examine the effects of induced pluripotent stem cell-derived conditioned medium (iPSC-CM) combined with antibiotics on ALI in a rat model of Escherichia coli-induced sepsis. Rats were administered either iPSC-CM or the vehicle (saline) with antibiotics (ceftriaxone). After 72 h, liquid biopsy, bronchoalveolar lavage fluid (BALF), and tissues were harvested for analysis. Survival rates were observed for up to 3 days. Furthermore, we examined the effects of iPSC-CM on cytokine production, metalloproteinase 9 (MMP-9) expression, and NLRP3-ASC interaction in RAW264.7 cells stimulated with lipopolysaccharide/interferon-γ (LPS/IFN-γ). Combined treatment of iPSC-CM with antibiotics significantly improved survival in E. coli-infected rats (p = 0.0006). iPSC-CM ameliorated E. coli-induced infiltration of macrophages, reducing the number of cells in BALF, and suppressing interleukin (IL)-1ß, MIP-2, IL-6, and MMP-9 messenger RNA in lung sections. iPSC-CM treatment attenuated NLRP3 expression and inhibited NLRP3 inflammasome activation by disrupting NLRP3-mediated ASC complex formation in LPS/IFN-γ-primed RAW264.7 cells. This study reveals the mechanisms underlying iPSC-CM-conferred anti-inflammatory activity in ALI through the attenuation of macrophage recruitment to the lung, thus inactivating NLRP3 inflammasomes in macrophages. iPSC-CM therapy may be a useful adjuvant treatment to reduce sepsis-related mortality by ameliorating ALI.

Sarcopenia is associated with mortality in non-critical elderly patients visiting the emergency department.

Introduction: Geriatric syndrome (GS) increases risk of disability and mortality in older adults. Sarcopenia is a predominant illness of GS and accelerate its progression. This study aimed to investigate associations between mortality, emergency department (ED) re-visits and GS-related illnesses among older adults who visited the ED. Method: This retrospective observational study enrolled elderly patients who visited the ED in our hospital between January 2018 and October 2020. Patients were evaluated for potential sarcopenia, which was defined by both low handgrip strength and calf circumference. Follow-up was at least 6 months. Data of age, gender, mortality, ED re-visits, and GS-related illnesses were collected and analyzed for associations. Results: A total of 273 older adults aged 74 years or older were included, of whom 194 were diagnosed with possible sarcopenia. Older adults with possible sarcopenia also had significantly lower body mass index (BMI); a higher proportion needed assistance with daily activities; more had malnutrition, frailty, and history of falls (all p < 0.001) and acute decline in activities of daily living (p = 0.027). Multivariate analysis showed that possible sarcopenia [adjusted hazard ratio, aHR): 9.89, 95% confidence interval (CI): 1.17-83.81, p = 0.036], living in residential institutions (aHR: 2.85, 95% CI: 1.08-7.50, p = 0.034), and frailty (aHR: 7.30, 95% CI: 1.20-44.62, p = 0.031) were associated with mortality. Aged over 85 years (adjusted odds ratio: 2.44, 95% CI: 1.25-4.80, p = 0.02) was associated with ED re-visits. Conclusion: Sarcopenia is associated with mortality among older adults who visit ED. Initial screening for sarcopenia and relevant risk factors among older adults in the ED may help with early intervention for those at high-risk and may improve their prognosis.

Effects of epinephrine on heart rate variability and cytokines in a rat sepsis model.

Catecholamines have both anti-inflammatory and vasoactive properties. A decreased cardiac response to catecholamines has been associated with a high risk of death in sepsis and septic shock. The aim of this study was to investigate the effects of epinephrine (EPI) on heart rate variability (HRV) and autonomic balance, as well as cytokine levels, in a rat sepsis model. Thirty-six male Sprague-Dawley rats were assigned to 4 experimental groups and 2 control groups of 6 rats each. The rats in the experimental groups were inoculated with a lipopolysaccharide (LPS, endotoxin) to establish a sepsis model. Group A received only LPS; group B received LPS, antecedent EPI and the nonselective ß-blocker propranolol; group C received LPS and antecedent EPI; and group D received LPS, antecedent EPI and the selective ß1-blocker esmolol. One control group received EPI and the other received saline placebo. Heart rate variability (HRV) was analyzed and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) levels were measured. Measurements were carried out at baseline, at 0 hour after EPI infusion, and at 0.5, 2, and 4 hours after LPS inoculation. There were significant differences in HRV and cytokine levels between the groups, indicating that LPS infusion caused autonomic imbalance. Antecedent EPI significantly decreased the level of TNF-α in group C compared with group A in which TNF-α level peaked at 2 hours and then declined. Propranolol (group B) but not esmolol (group D) administration resulted in elevated TNF-α levels, comparable to those observed in group A. In conclusion, antecedent administration of EPI in a rat sepsis model inhibits the production of TNF-α possibly via the ß2-adrenoceptor.

Aichi Virus Induces Antiviral Host Defense in Primary Murine Intestinal Epithelial Cells.

The picornavirus Aichi virus (AiV) is a non-enveloped RNA virus that causes acute gastroenteritis symptoms, such as diarrhea, abdominal pain, nausea, vomiting, and fever. Antiviral host defense involves the fast response of type I interferon (IFN) and the secretion of inflammatory cytokines against pathogens. However, the intestinal inflammatory and antiviral response to AiV infection is poorly understood. This study evaluated the antiviral activity of intestinal epithelial cells (IECs), which form a single-cell layer separating the bowel wall from pathogens. Isolated primary mouse IECs were subjected to AiV infection and virion production, inducing the mRNA expression of type I/type III IFNs and inflammatory cytokines. The mechanism involved induced the expression of phospho-IFN regulatory factor 3 and mitochondrial antiviral-signaling protein of type I IFN signaling. These findings were also observed in AiV-infected human colon carcinoma cells. In summary, a viral productive and pathogenic infection of AiV in primary murine IECs is validated.

Emergency department overcrowding: Quality improvement in a Taiwan Medical Center.

BACKGROUND/PURPOSE: Overcrowding of hospital emergency departments (ED) is a worldwide health problem. The Taiwan Joint Commission on Hospital Accreditation has stressed the importance of finding solutions to overcrowding, including, reducing the number of patients with >48 h stay in the ED. Moreover, the Ministry of Health and Welfare aims at transferring non-critical patients to district or regional hospitals. We report the results of our Quality Improvement Project (QIP) on ED overcrowding, especially focusing on reducing length of stay (LOS) in ED. METHODS: For QIP, the following 3 action plans were initiated: 1) Changing the choice architecture of patients' willingness to transfer from opt-in to opt-out; 2) increasing the turnover rate of beds and daily monitoring of the number of free beds for boarding ED patients; 3) reevaluation of patients with a LOS of >32 h after the morning shift. RESULTS: Transfer rates increased minimally after implementation of this project, but the sample size was too small to achieve statistical significance. No significant increase was observed in the number of free medical beds, but discharge rates after 12 pm decreased significantly (p < 0.001). The proportion of over 48 h LOSs decreased from 4.9% to 3.7% before and after QIP implementation, respectively (p < 0.001). CONCLUSION: Patients with LOS of >32 h were reevaluated first. After QIP, the proportion of LOSs of >48 h dropped significantly. Changing the choice architecture may require further systemic effort and a longer observation duration. Higher-level administrators will need to formulate a more comprehensive bed management plan to speed up the turnover rate of free inpatient beds.

Idiopathic Pulmonary Arterial Hypertension Was Diagnosed Initially by the Computed Tomographic Angiogram.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease with non-specific signs and symptoms. A 50-year-old woman with IPAH presented to the emergency department (ED) with a complaint of episodic dyspnea that had persisted for the previous two months. Based on the fi ndings of the initial chest computed tomographic angiography conducted in the ED, we suspected pulmonary hypertension. IPAH was eventually confi rmed following a series of investigations, including right heart catheterization. The history of this interesting case is reported with a review of the relevant literature.

Disseminated Nocardiosis with Lung, Liver and Spleen Abscesses in Sweet Syndrome: A Case Report.

Hepatic abscesses are rarely encountered in disseminated nocardia infections. We report a rare case of idiopathic Sweet syndrome (SS) who responded well to steroid therapy. However, he developed multiple abscesses in the lung, liver and spleen after 6 months of systemic steroid therapy. The culture result from liver abscess and sputum was diagnostic of disseminiated nocardiosis. Intravenous sulfamethoxazole/trimethoprim was given and follow-up computed tomography (CT) scan revealed resolution of abscess. To conclude, nocardiosis should be suspected as a likely cause of lung, liver and spleen abscesses in patients undergoing long-term steroid treatment. A high index of clinical suspicion in patients with defects in cell-mediated immunity and prompt management by appropriate image studies are needed to prevent delay in diagnosis.

A rare but potentially lethal case of tuberculous aortic aneurysm presenting with repeated attacks of abdominal pain.

Tuberculous aortic aneurysm is an extremely rare disease with a high mortality rate. The clinical features of this condition are highly variable, ranging from asymptomatic with or without constitutional symptoms, abdominal pain to frank rupture, bleeding and shock. We herein report the case of a 56-year-old man with a large tuberculous mycotic aneurysm in the abdominal aorta with an initial presentation of repeated attacks of abdominal pain lasting for several months. Due to the vague nature of the initial symptoms, tuberculous aortic aneurysms may take several months to diagnose. This case highlights the importance of having a high index of suspicion and providing timely surgery for this rare but potentially lethal disease.

Recurrent Hypokalemic Periodic Paralysis Unmasks Sjogren Syndrome without Sicca Symptoms.

Hypokalemic Periodic Paralysis (HPP) may occur as a rare complication of Sjogren Syndrome (SS) and Renal Tubular Acidosis (RTA). A 64-year male patient came with HPP, and was later diagnosed with distal RTA. The patient, who had no xerostomia and xerophthalmia, was diagnosed with primary SS from serologic and histologic findings of minor salivary gland biopsy. The patient recovered after potassium replacement therapy. Renal biopsy was also performed and revealed evidence of tubulointerstitial nephritis. Corticosteroids were administered and there was no recurrence of HPP during a 4-year follow-up period. The case highlights the significance of acute hypokalemia management in emergency department as it can unmask SS even if the SS is not associated with sicca symptoms. Hypokalemic paralysis associated with normal anion gap metabolic acidosis should prompt toward the diagnosis of SS.

Hepatic angiosarcoma may have fair survival nowadays.

Hepatic angiosarcoma (HAS) is rare but often fatal. A review of literature in 1979 found that only 3% of the 70 patients lived for more than 2 years, but the survival might have been improved over the years. We conducted a retrospective study and reviewed the medical records of patients who visited a teaching hospital in Taiwan from January 2000 to August 2010 and had pathological proof of HAS. In addition, we conducted a review of literature and compared those who survived for 2 years or more to those who did not. Of the 3503 patients with primary liver cancer we identified, 9 had HAS, of whom 3 (33.3%) survived for 2 years or more. One survived for 24 months without surgical resection, and the other two received surgery with postoperative chemotherapy and were still alive 32 and 37 months later, respectively. Through reviewing literature, we identified 3 more patients in Taiwan who had survived for 2 years or more. One survived for 42 months without surgical resection, the other two received segmentectomy with postoperative chemotherapy or radiotherapy. We also identified 8 such cases outside Taiwan, including 1 who received chemotherapy without surgery and survived for 53 months. None of the differences in the clinical characteristics between those who had and had not survived for 2 years or more reached statistical significance. In conclusion, we believe the combination of surgery and adjuvant chemotherapy may be able to achieve long-term survival in some HAS patients nowadays, and it is even possible to achieve fair survival using chemotherapy alone.

Parathyroidectomy improves cardiovascular outcome in nondiabetic dialysis patients with secondary hyperparathyroidism.

OBJECTIVE: Secondary hyperparathyroidism and its associated abnormalities in mineral metabolism and haemodynamic changes increase the cardiovascular risk in patients with end-stage renal disease (ESRD). Our objective was to determine the association of parathyroidectomy (PTX) with major cardiovascular events in nondiabetic dialysis patients with severe secondary hyperparathyroidism (SHPTH). DESIGN AND PATIENTS: We performed a cohort study with fifty-three nondiabetic ESRD patients who were treated with maintenance haemodialysis and who had intact parathyroid hormone (PTH) levels > 800 pg/ml. Participants received either only medical therapy or medical therapy and total PTX with autotransplantation for SHPTH. MEASUREMENTS: We evaluated the associations between PTX and major cardiovascular events including death, cerebrovascular accident and myocardial infarction. The biochemical and haemodynamic changes associated with PTX were measured. RESULTS: During the mean follow-up of 72 months, twenty-three patients received only medical treatment (medical group) while thirty patients underwent PTX in addition to medical treatment (PTX group). The two groups were comparable in respect of baseline characteristics. PTX group was found to be associated with a reduced incidence of major cardiovascular events (P = 0·021). A multiple Cox regression analysis showed that the variable significantly associated with major cardiovascular events was treatment modality (medical therapy vs medical therapy and parathyroidectomy, hazard ratio = 26·12, 95% CI = 1·30-526·27, P = 0·033). Blood pressure, haemoglobin, alkaline phosphatase, calcium, phosphate and calcium × phosphate product significantly improved after PTX. CONCLUSIONS: PTX was associated with better cardiovascular outcome in nondiabetic dialysis patients with severe SHPTH.

The role of autonomic nervous system function in hypothermia-mediated sepsis protection.

OBJECTIVE: The objective of this study is to determine whether hypothermia will lessen decreases in heart rate variability and improve outcome in a rat model of sepsis. METHODS: Thirty-six male Sprague-Dawley rats were randomized into 3 groups: control, low sepsis, and high sepsis groups. These groups were each subdivided into a normothermia (37°C) (n = 6) and a hypothermia group (34°C) (n = 6). Cyclophosphamide (100 mg/kg) was administered 5 days before Staphylococcus aureus injection to produce conditions in which sepsis could be induced reliably. Hypothermic rats received temperature reduction for 1 hour post injection. Electrocardiogram was recorded before, after, and 1 day after staphylococcal injection, and the low frequency, high frequency (HF), and LF/HF ratio measurements of heart rate variability and the frequencies of arrhythmia were recorded. The effects of time, sepsis severity, and hypothermia on these variables were analyzed using a multivariate generalized estimation equation mode. RESULTS: Four deaths occurred in the normothermic group, and none, in the hypothermic group. Sepsis of both low and high severity increased low frequency and HF 1 day after sepsis induction. Hypothermia significantly decreased HF in low, but not high sepsis severity. CONCLUSIONS: Hypothermia decreased mortality in septic rats. The influence of hypothermia on HF depended on the severity of the sepsis.

Influence of age on heart rate variability during therapeutic hypothermia in a rat model.

OBJECTIVES: To evaluate the effect of age on heart rate variability (HRV) in a rat model of therapeutic hypothermia. METHODS: Thirty-six male Sprague-Dawley rats (18 were 2 months old and 18 were 18 months old) were randomized into one of three groups: normothermia (37°C), mild hypothermia (34°C), and moderate hypothermia (31°C). An electrocardiogram (ECG) was recorded at baseline and continuously for 1h once the target core body temperature was reached. Various heart rate variability measurements were calculated. RESULTS: Significant effects of age were observed in respect to the ratio of standard deviation of all normal to normal R-R [NN] intervals (SDNN)/standard deviation of the differences between adjacent NN intervals (SD of delta NN) (P=0.037), low frequency (LF) power, normalized units (nu, %) (P<0.001), and the ratio of LF and high frequency (HF) (P<0.001). Significant effects of temperature were found in LF power and a significant body-temperature interaction was found in HF power. HF power was significantly lower in the young rats at mild and moderate hypothermic conditions. For the LF/HF, the ratio was significantly lower in the young animals compared to the older animals at normal body temperatures and during mild hypothermia. LF/HF increased significantly at both 34°C and 31°C in the young rats compared to the young rats at 37°C. In contrast, LF/HF was significantly lower in the older group of rats at 34°C and 31°C compared to the older group of rats maintained under normothermic conditions. CONCLUSIONS: This study noted that autonomic regulation determined via HRV, primarily the ratio of LF to HF, was different between different age groups. Additional studies on this topic are needed to achieve a more detailed understanding of therapeutic hypothermia.

Isolated pathogens and clinical outcomes of adult bacteremia in the emergency department: a retrospective study in a tertiary Referral Center.

BACKGROUND: Approximately two-thirds of the patients with severe sepsis or septic shock are first encountered in the emergency departments (EDs) of western countries, in which bacteremia is present in about 50% of patients with severe sepsis. The situation of bacteremia presenting to the EDs in Taiwan is not well documented. The objective of this study was to examine the epidemiology and microbiology of bacteremia in adult patients who visited the ED of a medical center in southern Taiwan. METHODS: A retrospective observational study of the epidemiology and microbiology of bacteremia was conducted in the ED of a medical center involving 6,137 adult patients and 13,903 blood cultures. RESULTS: A total of 831 consecutive patients with 890 episodes of bacteremia were obtained from January 1 to December 31, 2004, indicating a positive culture rate of 13.5% (1,872/13,903). Among these episodes, 525 (59%) were defined as true community-acquired infections followed by 263 (29.5%) as health care-associated infections and 102 (11.5%) as nosocomial infections. Of the 972 isolates, 289 (29.7%) were gram-positive species and 683 (70.3%) were gram-negative species. Urinary tract infections (32.2%, 287/890) were most common in these patients, with Escherichia coli (30.8%, 299/972) being the most common pathogen. Bacteremia caused by Staphylococcus aureus was more common in nosocomial than true community-acquired infections (31.3% vs. 12%) and had significantly higher possibility of resistance to methicillin in infections not purely acquired from community (odds ratio = 24.92; 95% confidence interval, 9.88-62.87). The overall crude mortality rate was 21% and nearly half of the mortalities occurred within 3 days of visiting the ED. All patients discharged inadvertently were uneventful (n = 65, two lost at follow-up). CONCLUSIONS: Categories of bacteremia acquisition was associated with different distribution of pathogens, antimicrobial resistance, and clinical outcome. Traditional classification might overestimate the problem of drug resistance in community-acquired infections. The concept of health care-associated infection should be introduced to avoid overemphasis of drug-resistant problem in true community-acquired infection.

The effects of lazaroid U-74389G in a rat sepsis model.

OBJECTIVE AND DESIGN: To examine the protective effects of a lazaroid, 21-aminosteroid U-74389G, in a rat septic shock model. MATERIALS OR SUBJECTS: Male Sprague-Dawley rats (n = 60) aged 6-8 months. TREATMENT: Groups were exposed to 500 cGy radiation followed by E. coli inoculation, and either placebo or lazaroid injection (10 mg/kg intraperitoneal) 5 days after irradiation. METHODS: Hemodynamic measurements, arterial blood gases, serum lactate, total antioxidative capacity, and cytokine levels were measured at specific time intervals. RESULTS: Treatment with the lazaroid U-74389G maintained cardiac output and mean aortic pressure. Lazaroid treatment also prevented the increase in serum lactate seen in placebo-treated rats. Cytokine serum levels in lazaroid-treated rats were not significantly different from those in placebo-treated rats at any time point. CONCLUSIONS: Lazaroid treatment of E. coli-inoculated septic animals lessens the hemodynamic deterioration seen in sepsis.

Epinephrine reduces cerebral perfusion during cardiopulmonary resuscitation.

OBJECTIVE: Epinephrine has been the primary drug for cardiopulmonary resuscitation (CPR) for more than a century. The therapeutic rationale was to restore threshold levels of myocardial and cerebral blood flows by its alpha1 (alpha1) and alpha2 (alpha2)-adrenergic agonist vasopressor actions. On the basis of coincidental observations on changes in microvascular flow in the cerebral cortex, we hypothesized that epinephrine selectively decreases microvascular flow. DESIGN: Randomized prospective animal study. SETTING: University-affiliated research laboratory. SUBJECTS: Domestic pigs. INTERVENTIONS: Four groups of five male domestic pigs weighing 40 +/- 3 kg were investigated. After induction of anesthesia, endotracheal intubation was followed by mechanical ventilation. A frontoparietal bilateral craniotomy was created. Ventricular fibrillation was induced and untreated for 3 minutes before the start of precordial compression, mechanical ventilation, and attempted defibrillation. Animals were randomized to receive central venous injections during CPR of 1) placebo, 2) epinephrine, 3) epinephrine in which both alpha1- and beta (beta)-adrenergic effects were blocked by previous administration of prazosin and propranolol, and 4) epinephrine in which both alpha2- and beta-adrenergic effects were blocked by previous administration of yohimbine and propranolol. MEASUREMENTS AND MAIN RESULTS: Cerebral cortical microcirculatory blood flow (MBF) was measured with orthogonal polarization spectral imaging. Cerebral cortical carbon dioxide and oxygen tensions (Pbco2 and Pbo2) were concurrently measured using miniature tissue optical sensors. Each animal was resuscitated. No differences in the number of electrical shocks for defibrillation or in the duration of CPR preceding return of spontaneous circulation were observed. Yet when epinephrine induced increases in arterial pressure, it significantly decreased Pbo2 tension and increased Pbco2 tension. Epinephrine therefore significantly decreased MBF and increased indicators of cerebral ischemia. Reduced MBF and magnified brain tissue ischemia during and after cardiopulmonary resuscitation were traced to the alpha1-adrenergic agonist action of epinephrine. When the alpha2 effects of epinephrine were blocked, reduced MBF and tissue ischemia persisted. No differences in cardiac output, end tidal Pco2, arterial Po2 and Pco2, and brain temperature were observed before inducing cardiac arrest and following return of spontaneous circulation. CONCLUSIONS: In this model, epinephrine through its alpha1-agonist action had adverse effects on cerebral microvascular blood flow such as to increase the severity of cerebral ischemia during CPR.

Exclusion of a patient assessment interval and extension of the CPR interval both mitigate post-resuscitation myocardial dysfunction in a swine model of cardiac arrest.

AIM OF STUDY: Interruptions in cardiopulmonary resuscitation (CPR), particularly as guided by automated external defibrillators, have been implicated in poor survival from cardiac arrest. Interruptions of CPR may be reduced by eliminating repetition of shocks between periods of CPR, elimination of the interval for patient assessment before CPR, and extension of the periods of CPR. MATERIALS AND METHODS: The effects of exclusion of a 30s post-shock assessment interval prior to CPR and use of a longer interval (180s versus 90s) of CPR on resuscitation and post-resuscitation function were assessed in a factorial design using an established swine model of cardiac arrest. Repetitive shocks were excluded. Ventricular fibrillation was induced ischemically and maintained untreated for 5min. RESULTS: All subjects were resuscitated, 95% survived 3 days, and 97% of survivors had full neurological recovery. Exclusion of the assessment interval reduced the delay to first return of spontaneous circulation by 33.1s (P=0.004) and the delay to sustained resuscitation by 99.2s (P=0.004), reduced post-resuscitation ECG ST elevation by 0.12mV (P=0.03), and alleviated transient post-resuscitation ejection fraction reduction (P<0.0001). Extension of the CPR interval reduced transient post-resuscitation fractional area change impairment (P=0.003). CONCLUSIONS: Exclusion of an interval for assessment of airway, breathing and signs of circulation mitigates post-resuscitation dysfunction in a swine model of cardiac arrest. Extension of the period of CPR independently provides measurable, though less comprehensive, mitigation as well.