Michael J. Emery

Considerations for improving survival from out-of-hospital cardiac arrest

Since the implementation of a paramedic system in Seattle, yearly survival rates from out-of-hospital cardiac arrest due to ventricular fibrillation have averaged 25% without any significant increase over the years. Outcome for cardiac arrest associated with other rhythms has been poor: when asystole was the first rhythm recorded, only 1% of patients survived; when electromechanical dissociation was initially present, only 6% survived. For cases of electromechanical dissociation, neither the type of rhythm nor the rate appear to influence outcome. Survival from ventricular fibrillation can be improved by shortening the delay to initiation of CPR and to defibrillation. When outcome in 244 witnessed arrests was related to the times to beginning CPR and to initial defibrillation, mortality increased 3% each minute until CPR was begun and 4% a minute until the first shock was delivered. New strategies that minimize delays appear to have the greatest promise for improving survival after cardiac arrest.

Blast exposure causes early and persistent aberrant phospho- and cleaved-tau expression in a murine model of mild blast-induced traumatic brain injury

Mild traumatic brain injury (mTBI) is considered the signature injury of combat veterans that have served during the wars in Iraq and Afghanistan. This prevalence of mTBI is due in part to the common exposure to high explosive blasts in combat zones. In addition to the threats of blunt impact trauma caused by flying objects and the head itself being propelled against objects, the primary blast overpressure (BOP) generated by high explosives is capable of injuring the brain. Compared to other means of causing TBI, the pathophysiology of mild-to-moderate BOP is less well understood. To study the consequences of BOP exposure in mice, we employed a well-established approach using a compressed gas-driven shock tube that recapitulates battlefield-relevant open-field BOP. We found that 24 hours post-blast a single mild BOP provoked elevation of multiple phospho- and cleaved-tau species in neurons, as well as elevating manganese superoxide-dismutase (MnSOD or SOD2) levels, a cellular response to oxidative stress. In hippocampus, aberrant tau species persisted for at least 30 days post-exposure, while SOD2 levels returned to sham control levels. These findings suggest that elevated phospho- and cleaved-tau species may be among the initiating pathologic processes induced by mild blast exposure. These findings may have important implications for efforts to prevent blast-induced insults to the brain from progressing into long-term neurodegenerative disease processes.

Lung Volume Reduction by Bronchoscopic Administration of Steam

RATIONALEnAt present, bronchoscopic approaches to lung volume reduction (LVR) create airway obstruction to achieve parenchyma collapse, avoiding many risks of surgical LVR. However, LVR by these methods is limited by temporary or incomplete collapse and/or residual atelectatic and scarred tissue volumes. Heat-induced ablation of lung tissue is currently under investigation as an alternative LVR methodology.nnnOBJECTIVESnWe hypothesized that bronchoscopic steam injection can produce safe and effective LVR, and explored potential mechanisms for the effects.nnnMETHODSnSteam treatments were applied bilaterally to six cranial lobe segments of large dogs. For series 1, 14 dogs received one of three target heat dose levels (1, 4, or 8 cal · ml⁻¹ segment volume), and then 3 months of follow-up including pulmonary function testing and monitoring for complications. For series 2, 12 dogs received a single target dose (4 cal · ml⁻¹) or sham, similar follow-up, and then assessment of lobar mass, volume, and blood flow. Vapor content of series 2 steam was 40% greater than for series 1 (similar heat dose) to attempt more peripheral heat delivery.nnnMEASUREMENTS AND MAIN RESULTSnNineteen of 20 treatment animals survived with minimal evidence of serious risks or reduced pulmonary function testing volumes, but 1 died from pneumothorax 5 days post-treatment. Postmortem processing of animals that survived as planned revealed obvious dose-dependent lobe reductions, additional evidence of risks, and blood flow reduction that occurred immediately post-treatment.nnnCONCLUSIONSnBronchoscopic administration of steam is a potentially safe means to achieve LVR, but substantial risks are present and further research is recommended.

Ventilation heterogeneity is increased in hypocapnic dogs but not pigs.

Hypocapnia increases ventilation/perfusion (VA/Q) heterogeneity in dogs, possibly by adversely affecting distribution of ventilation through its effects on collateral ventilation. Because pigs lack collateral ventilation, we compared the effects of hypocapnia on ventilation heterogeneity in pentobarbital-anesthetized, mechanically-ventilated dogs and pigs. Simultaneous multiple breath washouts of helium and nitrogen were used to assess the uniformity of the ventilation distribution by the phase III (SnIII) method. Ventilation heterogeneity was partitioned into two components, e.g. convective-dependent inhomogeneity (cdi) and diffusive-convective-dependent inhomogeneity (dcdi). Pulmonary gas exchange was also measured in pigs by the multiple inert gas elimination technique. Ventilation heterogeneity was increased (P < 0.01) in hypocapnic dogs. Inspiration of CO2 decreased ventilation heterogeneity by decreasing dcdi (P < 0.01). In contrast, ventilation heterogeneity was not increased in hypocapnic pigs. However, hypocapnia increased VA/Q heterogeneity by 18% (P < 0.05) in pigs. We conclude that hypocapnia increases ventilation heterogeneity in dogs but not in pigs, most likely related to an interspecies difference in collateral ventilation.

Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

Background: Nitrite (NO2 −) is a physiologic source of nitric oxide and protects against ischemia-reperfusion injuries. We hypothesized that nitrite would be protective in a rat model of ventilator-induced lung injury and sought to determine if nitrite protection is mediated by enzymic catalytic reduction to nitric oxide. Methods: Rats were anesthetized and mechanically ventilated. Group 1 had low tidal volume ventilation (LVT) (6 ml/kg and 2 cm H2O positive end-expiratory pressure; n = 10); group 2 had high tidal volume ventilation (HVT) (2 h of 35 cm H2O inspiratory peak pressure and 0 cm H2O positive end-expiratory pressure; n = 14); groups 3–5: HVT with sodium nitrite (NaNO2) pretreatment (0.25, 2.5, 25 &mgr;mol/kg IV; n = 6–8); group 6: HVT + NaNO2 + nitric oxide scavenger 2-(4-carboxyphenyl)-4,5dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3oxide(n = 6); group 7: HVT + NaNO2 + nitric oxide synthase inhibitor N&ohgr;-nitro-L-arginine methyl ester (n = 7); and group 8: HVT + NaNO2 + xanthine oxidoreductase inhibitor allopurinol (n = 6). Injury assessment included physiologic measurements (gas exchange, lung compliance, lung edema formation, vascular perfusion pressures) with histologic and biochemical correlates of lung injury and protection. Results: Injurious ventilation caused statistically significant injury in untreated animals. NaNO2 pretreatment mitigated the gas exchange deterioration, lung edema formation, and histologic injury with maximal protection at 2.5 &mgr;mol/kg. Decreasing nitric oxide bioavailability by nitric oxide scavenging, nitric oxide synthase inhibition, or xanthine oxidoreductase inhibition abolished the protection by NaNO2. Conclusions: Nitrite confers protection against ventilator-induced lung injury in rats. Catalytic reduction to nitric oxide and mitigation of ventilator-induced lung injury is dependent on both xanthine oxidoreductase and nitric oxide synthases.

Axonal degeneration in the Trembler-j mouse demonstrated by stimulated single-fiber electromyography.

The Trembler‐j (Tr‐j) mouse is a naturally occurring mutant with a point mutation in the peripheral myelin protein‐22 gene causing severe peripheral nerve demyelination. It is a genetically homologous murine model for Charcot–Marie–Tooth disease type 1A (CMT 1A). Our prior pilot studies using stimulated single‐fiber needle electromyograpy (SSFEMG) showed increased jitter in 60‐day‐old Tr‐j mice compared to age‐matched, wildtype animals. The aim of this study was to better elucidate the etiology of increased jitter in Tr‐j mice and test the following hypotheses: (1) the increased jitter in Tr‐j mice is due to turnover of endplates secondary to axonal degeneration with reinnervation and not to conduction block secondary to demyelination of motor nerve axons; and (2) aging Tr‐j mice demonstrate increased jitter and fiber density compared with younger mutant mice due to progressive motor axon loss. SSFEMG studies performed on 60‐ and 140‐day‐old mice indicated that average mean consecutive difference (MCD) and fiber density estimates (FDE) were significantly increased in Tr‐j mice at both ages compared to age‐matched wildtypes. FDE also increased substantially in older mutant mice. Intraperitoneal neostigmine injections produced significant reductions in average MCD in Tr‐j mice, suggesting that impaired neuromuscular transmission is an early pathologic feature in these mice and likely reflects distal axonal degeneration. Our findings corroborate our prior pilot study, although in a much larger number of animals across a wider age span. Our study also indicates that SSFEMG, performed in a serial fashion, is a useful, noninvasive method of detecting progressive axon loss in this murine model of CMT 1A. This technique may be a valuable tool to study the affects of genetic or pharmaceutical interventions in murine models of peripheral neuropathy. Muscle Nerve, 2007

Regional creatine kinase, adenylate kinase, and lactate dehydrogenase in normal canine brain.

Following acute stroke, creatine kinase and other enzymes are released into the cerebrospinal fluid and blood from injured brain tissue. To determine whether regional differences in brain enzyme activity might exist and therefore affect the amount of enzyme released, we quantified the levels of creatine kinase, adenylate kinase, and lactate dehydrogenase in 12 regions of normal canine brain (n = 4). Adenylate kinase activity varied the least among regions (49 +/- 7 units/g), followed by lactate dehydrogenase activity (122 +/- 28 units/g). The pattern for both adenylate kinase and lactate dehydrogenase was higher activity in predominantly gray matter areas, lower activity in white matter, and intermediate activity in mixed regions. The distribution of creatine kinase brain isoenzyme and mitochondrial creatine kinase in canine brain was less predictable, showing wider variations among regions (isoenzyme, 462 +/- 116 units/g; mitochondrial, 42 +/- 20 units/g). Even cerebral gray matter demonstrated substantial regional variations in creatine kinase brain isoenzyme, ranging from 606 units/g in the parietal cortex to 329 units/g in the temporal cortex. We conclude that the content of creatine kinase brain isoenzyme varies more than twofold among areas of brain. This regional variation may be important in the interpretation of creatine kinase brain isoenzyme measurements in cerebrospinal fluid and serum used to assess neurologic injury following stroke.

CO2 relaxation of the rat lung parenchymal strip

Evidence from liquid-filled rat lungs supported the presence of CO2-dependent, active relaxation of parenchyma under normoxia by unknown mechanisms (Emery et al., 2007). This response may improve matching of alveolar ventilation (V˙A) to perfusion (Q˙) by increasing compliance and V˙A in overperfused (high CO2) regions, and decrease V˙A in underperfused regions. Here, we have more directly studied CO2-dependent parenchymal relaxation and tested a hypothesized role for actin-myosin interaction in this effect. Lung parenchymal strips (∼1.5mm×1.5mm×15mm) from 16 rats were alternately exposed to normoxic hypocapnia ( [Formula: see text] ) or hypercapnia ( [Formula: see text] ). Seven specimens were used to construct length-tension curves, and nine were tested with and without the myosin blocker 2,3-butanedione monoxime (BDM). The results demonstrate substantial, reversible CO2-dependent changes in parenchyma strip recoil (up to 23%) and BDM eliminates this effect, supporting a potentially important role for parenchymal myosin in V˙A/Q˙ matching.

Ventilation and the Response to Hypercapnia after Morphine in Opioid-naive and Opioid-tolerant Rats.

Background:Opioid-related deaths are a leading cause of accidental death, with most occurring in patients receiving chronic pain therapy. Respiratory arrest is the usual cause of death, but mechanisms increasing that risk with increased length of treatment remain unclear. Repeated administration produces tolerance to opioid analgesia, prompting increased dosing, but depression of ventilation may not gain tolerance to the same degree. This study addresses differences in the degree to which chronic morphine (1) produces tolerance to ventilatory depression versus analgesia and (2) alters the magnitude and time course of ventilatory depression. Methods:Juvenile rats received subcutaneous morphine for 3 days (n = 116) or vehicle control (n = 119) and were then tested on day 4 following one of a range of morphine doses for (a) analgesia by paw withdraw from heat or (b) respiratory parameters by plethysmography–respirometry. Results:Rats receiving chronic morphine showed significant tolerance to morphine sedation and analgesia (five times increased ED50). When sedation was achieved for all animals in a dose group (lowest effective doses: opioid-tolerant, 15 mg/kg; opioid-naive, 3 mg/kg), the opioid-tolerant showed similar magnitudes of depressed ventilation (−41.4 ± 7.0%, mean ± SD) and hypercapnic response (−80.9 ± 15.7%) as found for morphine-naive (−35.5 ± 16.9% and −67.7 ± 15.1%, respectively). Ventilation recovered due to tidal volume without recovery of respiratory rate or hypercapnic sensitivity and more slowly in morphine-tolerant. Conclusions:In rats, gaining tolerance to morphine analgesia does not reduce ventilatory depression effects when sedated and may inhibit recovery of ventilation.

Gas exchange and regional redistribution of pulmonary blood flow during resuscitation of acute pulmonary bead embolization.

Acute pulmonary embolism (PE) was induced by injecting polystyrene beads into the right atrium of 18 anaesthetized dogs. The animals were resuscitated for 45 min with either Ringers Lactate (RL), norepinephrine (NE) or isoproterenol (IP). The multiple inert gas elimination technique (MIGET) was used to estimate the distributions of ventilation (V) and blood flow (Q) to different V/Q regions. Measurements were made prior to embolism, 10 min after PE and during the resuscitative phase. Microspheres with three different radioactive labels were also used to mark blood flow distribution to different lung regions in these three phases. The data show that cardiac output decreases after PE, while perfusion to shunt and low V/Q regions increases. Pulmonary blood flow heterogeneity, estimated from the MIGET data, is also increased after PE. Resuscitation by RL or NE consistently increases cardiac output but IP does so inconsistently and is associated with systemic hypotension. All three methods of resuscitation cause increases in perfusion to the shunt and low V/Q regions but no change in perfusion heterogeneity in the remaining V/Q units. Increases in regional blood flow during resuscitation occur preferentially in the less embolized areas. The concomitant increase in perfusion to shunt and low V/Q units suggests that increased perfusion to these less embolized regions results in further hypoxemia despite improvement in cardiac output.