Hypoxia evokes a sequence of raphe-pontomedullary network operations for inspiratory drive amplification and gasping.

Hypoxia can trigger a sequence of breathing-related behaviors, from augmentation to apneusis to apnea and gasping. Gasping is an autoresuscitative behavior that, via large tidal volumes and altered intrathoracic pressure, can enhance coronary perfusion, carotid blood flow, and sympathetic activity, and thereby coordinate cardiac and respiratory functions. We tested the hypotheses that hypoxia-evoked gasps are amplified through a disinhibitory microcircuit within the inspiratory neuron chain, and that this drive is distributed via an efference copy mechanism. This generates coordinated gasp-like discharges concurrently in other circuits of the raphe-pontomedullary respiratory network. Data were obtained from 6 decerebrate, vagotomized, neuromuscularly-blocked, and artificially ventilated adult cats. Arterial blood pressure, phrenic nerve activity, end-tidal CO2, and other parameters were monitored. Hypoxia was produced by ventilation with a gas mixture of 5% O2 in nitrogen. Neuron spike trains were recorded at multiple pontomedullary sites simultaneously and evaluated for firing rate modulations and short-time scale correlations indicative of functional connectivity. Experimental perturbations evoked reconfiguration of raphe-pontomedullary circuits during initial augmentation, apneusis and augmented bursts, apnea, and gasping. Functional connectivity, altered firing rates, efference copy of gasp drive, and coordinated incremental blood pressure increases support a distributed brain stem network model for amplification and broadcasting of inspiratory drive during autoresuscitative gasping. Gasping begins with a reduction in inhibition by expiratory neurons and an initial loss of inspiratory drive during hypoxic apnea, and culminates in autoresuscitative efforts.

The Unified Brain-Based Determination of Death Conceptually Justifies Death Determination in DCDD and NRP Protocols.

Organ donation after the circulatory determination of death requires the permanent cessation of circulation while organ donation after the brain determination of death requires the irreversible cessation of brain functions. The unified brain-based determination of death connects the brain and circulatory death criteria for circulatory death determination in organ donation as follows: permanent cessation of systemic circulation causes permanent cessation of brain circulation which causes permanent cessation of brain perfusion which causes permanent cessation of brain function. The relevant circulation that must cease in circulatory death determination is that to the brain. Eliminating brain circulation from the donor ECMO organ perfusion circuit in thoracoabdominal NRP protocols satisfies the unified brain-based determination of death but only if the complete cessation of brain circulation can be proved. Despite its medical and physiologic rationale, the unified brain-based determination of death remains inconsistent with the Uniform Determination of Death Act.

From flatline to lifeline: A scoping review of the Lazarus phenomenon.

BACKGROUND: The Lazarus phenomenon or autoresuscitation (autoROSC) is the return of spontaneous circulation (ROSC) after the termination of the cardiopulmonary resuscitation (CPR) efforts. PURPOSE: The purpose of the current scoping review is to present the available data in the literature regarding autoROSC. METHODS: We reviewed four scientific databases to identify all studies which reported autoROSC cases in patients who underwent CPR. We then extracted all information relevant to CPR and autoROSC. The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews. RESULTS: We identified 66 studies describing 76 autoROSC cases. The majority of cardiac arrests were in-hospital (44, 57.89%). Median time from termination of CPR to autoROSC was 5 min. Regarding the outcome, 52 (77.61%) patients died and 11 (14.47%) patients had intact neurological outcome. A higher mortality rate was identified in patients with respiratory comorbidities. Overall, 24 (31.58%) patients survived. CONCLUSION: AutoROSC is probably an under-reported event in the medical community. Healthcare professionals should be aware of the phenomenon and actively monitor for it, when appropriate.

Delayed Presentation of Spontaneous Shockable Rhythm After Death: Another Subtype of Lazarus Phenomenon?

Lazarus phenomenon was defined as spontaneous circulatory restoration after death. It is important because survival discharge is possible. A 44-year-old woman developed traumatic cardiac arrest. She was declared dead after 30 minutes of resuscitation. Suddenly, pulseless ventricular tachycardia was shown after 6 minutes of death declaration. Resuscitation with epinephrine injection was resumed but was terminated after 7 minutes, and she was declared dead once more. A case where an electrocardiography appears spontaneously should be classified as a subtype of the Lazarus phenomenon. If the transition from asystole to spontaneous shockable rhythm follows a mechanism similar to that of the Lazarus phenomenon, active resuscitation and monitoring for a period of time following death declaration should be considered.

Disparity in the effect of morphine on eupnea and gasping in anesthetized spontaneously breathing adult rats.

The goal of this study was to examine the effects of systemic morphine on the pattern and morphology of gasping breathing during respiratory autoresuscitation from transient anoxia. We hypothesized that systemic morphine levels sufficient to cause significant depression of eupnea would also cause depression of gasping breathing. Respiratory and cardiovascular variables were studied in 20 spontaneously breathing pentobarbital-anaesthetized adult male rats. Sham (saline) injections caused no significant change in resting respiratory or cardiovascular variables (n = 10 rats). Morphine, on the other hand, caused significant depression of eupneic breathing, with ventilation and peak inspiratory flow decreased by ∼30-60%, depending on the background condition (n = 10 rats). In contrast, morphine did not depress gasping breathing. Duration of primary apnea, time to restore eupnea, the number and amplitude of gasping breaths, average and maximum peak flows, and volume of gasping breaths were not significantly different postinjection in either condition. Blood pressures were all significantly lower following morphine injection at key time points in the process of autoresuscitation. Last, rate of successful recovery from anoxia was 80% in the morphine group (8/10 rats) compared with 100% (10/10 rats) in the sham group, postinjection. We conclude that the mechanisms and/or anatomic correlates underlying generation of gasping rhythm are distinct from those underlying eupnea, allowing gasping to remain robust to systemic morphine levels causing significant depression of eupnea. Morphine nevertheless decreases likelihood of recovery from transient anoxia, possibly as a result of decreased tissue perfusion pressures at critical time points during the process of respiratory autoresuscitation.

Partial Raphe Dysfunction in Neurotransmission Is Sufficient to Increase Mortality after Anoxic Exposures in Mice at a Critical Period in Postnatal Development.

Sudden infant death syndrome (SIDS) cases often have abnormalities of the brainstem raphe serotonergic (5-HT) system. We hypothesize that raphe dysfunction contributes to a failure to autoresuscitate from multiple hypoxic events, leading to SIDS. We studied autoresuscitation in two transgenic mouse models in which exocytic neurotransmitter release was impaired via conditional expression of the light chain from tetanus toxin (tox) in raphe neurons expressing serotonergic bacterial artificial chromosome drivers Pet1 or Slc6a4. These used recombinase drivers targeted different portions of medullary raphe serotonergic, tryptophan hydroxylase 2 (Tph2)(+) neurons by postnatal day (P) 5 through P12: approximately one-third in triple transgenic Pet1::Flpe, hßactin::cre, RC::PFtox mice; approximately three-fourths inSlc6a4::cre, RC::Ptox mice; with the first model capturing a near equal number of Pet1(+),Tph2(+) versus Pet1(+),Tph2(low or negative) raphe cells. At P5, P8, and P12, "silenced" mice and controls were exposed to five, ∼37 s bouts of anoxia. Mortality was 5-10 times greater in "silenced" pups compared with controls at P5 and P8 (p = 0.001) but not P12, with cumulative survival not differing between experimental transgenic models. "Silenced" pups that eventually died took longer to initiate gasping (p = 0.0001), recover heart rate (p = 0.0001), and recover eupneic breathing (p = 0.011) during the initial anoxic challenges. Variability indices for baseline breathing distinguished "silenced" from controls but did not predict mortality. We conclude that dysfunction of even a portion of the raphe, as observed in many SIDS cases, can impair ability to autoresuscitate at critical periods in postnatal development and that baseline indices of breathing variability can identify mice at risk. SIGNIFICANCE STATEMENT: Many sudden infant death syndrome (SIDS) cases exhibit a partial (∼26%) brainstem serotonin deficiency. Using recombinase drivers, we targeted different fractions of serotonergic and raphe neurons in mice for tetanus toxin light chain expression, which prevented vesicular neurotransmitter release. In one model, approximately one-third of medullary Tph2(+) neurons are silenced by postnatal (P) days 5 and 12, along with some Pet1(+),Tph2(low or negative) raphe cells; in the other, approximately three-fourths of medullary Tph2(+) neurons, also with some Tph2(low or negative) cells. Both models demonstrated excessive mortality to anoxia (a postulated SIDS stressor) at P5 and P8. We demonstrated fatal vulnerability to anoxic stress at a specific time in postnatal life induced by a partial defect in raphe function. This models features of SIDS.

Eupnea, tachypnea, and autoresuscitation in a closed-loop respiratory control model.

How sensory information influences the dynamics of rhythm generation varies across systems, and general principles for understanding this aspect of motor control are lacking. Determining the origin of respiratory rhythm generation is challenging because the mechanisms in a central circuit considered in isolation may be different from those in the intact organism. We analyze a closed-loop respiratory control model incorporating a central pattern generator (CPG), the Butera-Rinzel-Smith (BRS) model, together with lung mechanics, oxygen handling, and chemosensory components. We show that 1) embedding the BRS model neuron in a control loop creates a bistable system; 2) although closed-loop and open-loop (isolated) CPG systems both support eupnea-like bursting activity, they do so via distinct mechanisms; 3) chemosensory feedback in the closed loop improves robustness to variable metabolic demand; 4) the BRS model conductances provide an autoresuscitation mechanism for recovery from transient interruption of chemosensory feedback; and 5) the in vitro brain stem CPG slice responds to hypoxia with transient bursting that is qualitatively similar to in silico autoresuscitation. Bistability of bursting and tonic spiking in the closed-loop system corresponds to coexistence of eupnea-like breathing, with normal minute ventilation and blood oxygen level and a tachypnea-like state, with pathologically reduced minute ventilation and critically low blood oxygen. Disruption of the normal breathing rhythm, through either imposition of hypoxia or interruption of chemosensory feedback, can push the system from the eupneic state into the tachypneic state. We use geometric singular perturbation theory to analyze the system dynamics at the boundary separating eupnea-like and tachypnea-like outcomes.NEW & NOTEWORTHY A common challenge facing rhythmic biological processes is the adaptive regulation of central pattern generator (CPG) activity in response to sensory feedback. We apply dynamical systems tools to understand several properties of a closed-loop respiratory control model, including the coexistence of normal and pathological breathing, robustness to changes in metabolic demand, spontaneous autoresuscitation in response to hypoxia, and the distinct mechanisms that underlie rhythmogenesis in the intact control circuit vs. the isolated, open-loop CPG.

Isocitrate supplementation promotes breathing generation, gasping, and autoresuscitation in neonatal mice.

Breathing is a vital function generated and controlled by a brainstem neural network, which is able to adjust its function to fit different metabolic demands. For instance, the pre-Bötzinger complex (preBötC) can respond to low oxygen availability (hypoxia) by an initial increase in rhythm frequency followed by a decrease in respiratory efforts that leads to gasping generation. Gasping is essential for autoresuscitation, which has motivated studies of the cellular mechanisms involved in these processes. Hypoxia has different effects on enzymes that participate in the Krebs cycle. In particular, aconitase is downregulated, whereas isocitrate dehydrogenase is unaffected or upregulated under hypoxic conditions. We hypothesized that the application of isocitrate, the product of aconitase and the substrate of isocitrate dehydrogenase as well as an alternative metabolic substrate, might enhance breathing and render it more resistant to hypoxic insult. We tested the effects of isocitrate applied on brainstem slices containing the preBötC as well as its central effects in vivo using plethysmography. Our results show that isocitrate increases the frequency of fictive eupnea and fictive gasping produced by the preBötC in vitro. Moreover, isocitrate increases the amplitude of ventilation in vivo in normoxia, increases ventilation during gasping, and favors autoresuscitation when animals were subjected to asphyxiation. In conclusion, we have found that isocitrate improves ventilation under both normoxic and hypoxic conditions through a mechanism that involves the preBötC and possibly other respiratory neural networks. Thus, isocitrate would be useful to avoid the failure of gasping generation and autoresuscitation in pathological conditions.

Review article: Back to life from being declared dead in the Resus Bay: An integrative review of the phenomenon of autoresuscitation and learning for ED.

This is a literature review of ED autoresuscitation. The impetus for this review was a case which revealed a lack of understanding about Lazarus syndrome among ED staff. The primary objective was to see the proportion of cases who survived neurologically intact to discharge and the time frame when this occurred after death had been declared. A secondary outcome was to see whether these studies mention whether bedside echo was performed prior to deciding whether to terminate resuscitation. A systematic search of five databases was undertaken with keywords, 'autoresuscitation', 'cardiac arrest' and 'emergency department'. Articles published in the English language were selected for inclusion. No time frame was selected because of the low number of articles. A total of 240 articles were identified, that yielded 26 cases that were relevant and could be synthesised to create a discussion on the current clinical guidelines around resuscitation. Our analysis demonstrates that of the 11 survivors who were discharged neurologically intact, the average age was 42.9 years; otherwise, the average was 62.6 years. The majority (23/26) 88% auto-resuscitated within 10 min after being pronounced dead. Only five patients are mentioned as having had a bedside echo prior to deciding to cease efforts. Under-reporting of autoresuscitation is suspected because of fears of blame. Passive monitoring for 10 min after resuscitation is ceased, is recommended. There is need for more data on this phenomenon to help inform further research on the topic.

Lazarus Phenomenon or the Return from the Afterlife-What We Know about Auto Resuscitation.

Autoresuscitation is a phenomenon of the heart during which it can resume its spontaneous activity and generate circulation. It was described for the first time by K. Linko in 1982 as a recovery after discontinued cardiopulmonary resuscitation (CPR). J.G. Bray named the recovery from death the Lazarus phenomenon in 1993. It is based on a biblical story of Jesus' resurrection of Lazarus four days after confirmation of his death. Up to the end of 2022, 76 cases (coming from 27 countries) of spontaneous recovery after death were reported; among them, 10 occurred in children. The youngest patient was 9 months old, and the oldest was 97 years old. The longest resuscitation lasted 90 min, but the shortest was 6 min. Cardiac arrest occurred in and out of the hospital. The majority of the patients suffered from many diseases. In most cases of the Lazarus phenomenon, the observed rhythms at cardiac arrest were non-shockable (Asystole, PEA). Survival time after death ranged from minutes to hours, days, and even months. Six patients with the Lazarus phenomenon reached full recovery without neurological impairment. Some of the causes leading to autoresuscitation presented here are hyperventilation and alkalosis, auto-PEEP, delayed drug action, hypothermia, intoxication, metabolic disorders (hyperkalemia), and unobserved minimal vital signs. To avoid Lazarus Syndrome, it is recommended that the patient be monitored for 10 min after discontinuing CPR. Knowledge about this phenomenon should be disseminated in the medical community in order to improve the reporting of such cases. The probability of autoresuscitation among older people is possible.

Do we need standardized management after termination-of-resuscitation attempts? Autoresuscitation in a 67-year-old woman.

BACKGROUND: Autoresuscitation is the phenomenon of spontaneous return of circulation after cessation of CPR, also known as the Lazarus phenomenon. Most of the evidence is based on case reports and a few systematic reviews. The occurrence of autoresuscitation may lead to self-reproach and dismay in affected emergency personnel and may rise questions about the correct procedure after terminating resuscitative efforts. In contrast to existing cardiac arrest guidelines there is no standardized approach to terminating resuscitative attempts. CASE: We report a case of out of hospital autoresuscitation in a 67-year-old female after 60 min of advanced cardiac life support. After shock refractory shockable rhythm, we recorded pulseless electrical activity and fixed pupils, consequently resuscitation was terminated. About 50 min later the patient surprisingly showed signs of life. Due to the suggestive history a coronary angiography was performed, showing severe coronary heart disease which necessitated surgical intervention. After ACBP surgery and intensive care followed by treatment on the cardiological ward, she was finally discharged to neurological rehabilitation. CONCLUSION: As already proposed by existing literature, there should be at least a 10-min interval of close monitoring after abandoning CPR. Transport of a deceased patient should only take place after secure signs of death can be detected. Further investigation is needed to determine which patients are most likely to benefit from an extended observation period. Our case reports highlights the difficulties in death declaration and the importance of close monitoring after abandoning CPR.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part I. Tissue-based evidence for serotonin receptor signaling abnormalities in cardiorespiratory- and arousal-related circuits.

The sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality in the United States, is typically associated with a sleep period. Previously, we showed evidence of serotonergic abnormalities in the medulla (e.g. altered serotonin (5-HT)1A receptor binding), in SIDS cases. In rodents, 5-HT2A/C receptor signaling contributes to arousal and autoresuscitation, protecting brain oxygen status during sleep. Nonetheless, the role of 5-HT2A/C receptors in the pathophysiology of SIDS is unclear. We hypothesize that in SIDS, 5-HT2A/C receptor binding is altered in medullary nuclei that are key for arousal and autoresuscitation. Here, we report altered 5-HT2A/C binding in several key medullary nuclei in SIDS cases (n = 58) compared to controls (n = 12). In some nuclei the reduced 5-HT2A/C and 5-HT1A binding overlapped, suggesting abnormal 5-HT receptor interactions. The data presented here (Part 1) suggest that a subset of SIDS is due in part to abnormal 5-HT2A/C and 5-HT1A signaling across multiple medullary nuclei vital for arousal and autoresuscitation. In Part II to follow, we highlight 8 medullary subnetworks with altered 5-HT receptor binding in SIDS. We propose the existence of an integrative brainstem network that fails to facilitate arousal and/or autoresuscitation in SIDS cases.

Lazarus Syndrome After Aortic Aneurysm Repair.

Introduction: Lazarus syndrome is defined as the spontaneous return of circulation after cessation of cardiopulmonary resuscitation (CPR). Though there have been multiple cases of Lazarus syndrome documented in the literature, it is a significantly underreported phenomenon with less than 100 cases reported in the literature since the first case in 1982. Case Presentation: After elective aortic aneurysm repair, an 88-year-old with a do-not-resuscitate directive had cardiac arrest, briefly showing post-mortem respiration and pulse. Despite resuscitation efforts including pharmacological intervention and CPR, he passed away within an hour. This case highlights complexities in end-of-life care and warrants exploration of post-mortem physiological responses. Conclusion: The Lazarus phenomenon, rare post-CPR circulation return, challenges resuscitation cessation. Our case, among the oldest, highlights extended monitoring necessity, especially in chronic obstructive pulmonary disease patients. Debate persists on monitoring duration after failed CPR, lacking established Lazarus syndrome prevention guidelines.

The Last Beat: Contemporary Ethical Controversies Surrounding Determination of Cardiopulmonary Death.

Part one of this series tracked the evolution of the death examination, noting its stability over the last century despite changing diagnostic and therapeutic technologies and social contexts. In part two, we discuss the practical and ethical debates surrounding the exact timing of death. Although the irreversible cessation of cardiopulmonary systems remains the most common criteria used for the determination of death, identification of the moment of irreversibility is imprecise. In most cases, this imprecision is not problematic, but, when the cessation of circulation is used to identify the time of organ procurement for transplantation, it becomes critical. The phenomenon of autoresuscitation highlights these issues because patients who meet all the criteria for circulatory death (sometimes for periods of observation well beyond the norm) apparently return to life. Were these patients resurrected (like Lazarus) or did we simply not wait long enough?

Lazarus phenomenon in trauma.

Lazarus phenomenon embodies auto-resuscitation, aka the return of spontaneous circulation following termination of cardiopulmonary resuscitation. Limited or no literature exists that describes auto-resuscitation in trauma. In the current report, we describe a case of an older woman that presented with poly-traumatic injuries following a motor vehicle collision. The aggressive resuscitation efforts failed, and the patient witnessed a pulseless electrical activity; however, nine-minutes after cessation of resuscitation efforts, the patient experienced auto-resuscitation. In addition to the sequel of events following the presentation, the report highlights the management dilemma and ethical implications relating to the observation period for auto-resuscitation in cases of donation after circulatory death, where the urgency to harvest the organs to ensure maximum viability is in direct opposition to ensuring enough time has elapsed to rule out auto-resuscitation. Guidelines on an appropriate period for observation in auto-resuscitation patients queued for organ donation are warranted, keeping in lieu viability of organs following death.

Autoresuscitation (Lazarus phenomenon) after termination of cardiopulmonary resuscitation - a scoping review.

BACKGROUND: Autoresuscitation describes the return of spontaneous circulation after termination of resuscitation (TOR) following cardiac arrest (CA). We aimed to identify phenomena that may lead to autoresuscitation and to provide guidance to reduce the likelihood of it occurring. MATERIALS AND METHODS: We conducted a literature search (Google Scholar, MEDLINE, PubMed) and a scoping review according to PRISMA-ScR guidelines of autoresuscitation cases where patients undergoing CPR recovered circulation spontaneously after TOR with the following criteria: 1) CA from any cause; 2) CPR for any length of time; 3) A point was reached when it was felt that the patient had died; 4) Staff declared the patient dead and stood back. No further interventions took place; 5) Later, vital signs were observed. 6) Vital signs were sustained for more than a few seconds, such that staff had to resume active care. RESULTS: Sixty-five patients with ROSC after TOR were identified in 53 articles (1982-2018), 18 (28%) made a full recovery. CONCLUSIONS: Almost a third made a full recovery after autoresuscitation. The following reasons for and recommendations to avoid autoresuscitation can be proposed: 1) In asystole with no reversible causes, resuscitation efforts should be continued for at least 20 min; 2) CPR should not be abandoned immediately after unsuccessful defibrillation, as transient asystole can occur after defibrillation; 3) Excessive ventilation during CPR may cause hyperinflation and should be avoided; 4) In refractory CA, resuscitation should not be terminated in the presence of any potentially-treatable cardiac rhythm; 5) After TOR, the casualty should be observed continuously and ECG monitored for at least 10 min.

Central serotonin and autoresuscitation capability in mammalian neonates.

Autoresuscitation is an important cardiorespiratory protective mechanism that allows neonatal mammals to recover from primary apnea. It begins with hypoxia-induced gasping and ends, if successful, with the recovery of rhythmic breathing and normal heart rate. Many factors influence the efficacy of autoresuscitation, including the availability of serotonin (5-HT) in the brain. Since the early 2000's, there has been mounting interest in the role of 5-HT in promoting autoresuscitation, driven in large part by the recognition that both failed autoresuscitation and a deficiency of central 5-HT correlate with Sudden Infant Death Syndrome in humans. Within this timeframe, newly developed animal models with a central 5-HT deficiency have examined experimentally the role of 5-HT in autoresuscitation capability. The purpose of this review is to discuss some of the methodological considerations associated with 5-HT-deficient animal models, to summarize major findings arising from their use, and to highlight several key issues related to 5-HT involvement in gasping and the autoresuscitation response.