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Article ; Online: Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways.

Bickler, Philip E

2020 Volume 12, Issue 2

Abstract: The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the ... ...

Abstract	The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, inflammation, coagulopathy, cell/organ injury, and disruption of homeostatic mechanisms of normal physiology. In this review, we describe how snakebite is not only a condition mediated directly by venom, but by the amplification of signals dysregulating inflammation, coagulation, neurotransmission, and cell survival. Although venom proteins are diverse, the majority of important pathologic events following envenoming follow from a small group of enzyme-like activities and the actions of small toxic peptides. This review focuses on two of the most important enzymatic activities: snake venom phospholipases (svPLA
MeSH term(s)	Animals ; Blood Coagulation ; Humans ; Inflammation/metabolism ; Metalloproteases/metabolism ; Phospholipases A2, Secretory/metabolism ; Reptilian Proteins/metabolism ; Signal Transduction ; Snake Venoms/chemistry ; Snake Venoms/enzymology ; Snake Venoms/toxicity
Chemical Substances	Reptilian Proteins ; Snake Venoms ; Phospholipases A2, Secretory (EC 3.1.1.4) ; Metalloproteases (EC 3.4.-)
Language	English
Publishing date	2020-01-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518395-3
ISSN	2072-6651 ; 2072-6651
ISSN (online)	2072-6651
ISSN	2072-6651
DOI	10.3390/toxins12020068
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Neuromuscular Weakness and Paralysis Produced by Snakebite Envenoming: Mechanisms and Proposed Standards for Clinical Assessment.

Bickler, Philip E / Abouyannis, Michael / Bhalla, Ashish / Lewin, Matthew R

Toxins

2023 Volume 15, Issue 1

Abstract: Respiratory and airway-protective muscle weakness caused by the blockade of neuromuscular transmission is a major cause of early mortality from snakebite envenoming (SBE). Once weakness is manifest, antivenom appears to be of limited effectiveness in ... ...

Abstract	Respiratory and airway-protective muscle weakness caused by the blockade of neuromuscular transmission is a major cause of early mortality from snakebite envenoming (SBE). Once weakness is manifest, antivenom appears to be of limited effectiveness in improving neuromuscular function. Herein, we review the topic of venom-induced neuromuscular blockade and consider the utility of adopting clinical management methods originally developed for the safe use of neuromuscular blocking agents by anesthesiologists in operating rooms and critical care units. Failure to quantify neuromuscular weakness in SBE is predicted to cause the same significant morbidity that is associated with failure to do so in the context of using a clinical neuromuscular block in surgery and critical care. The quantitative monitoring of a neuromuscular block, and an understanding of its neurophysiological characteristics, enables an objective measurement of weakness that may otherwise be overlooked by traditional clinical examination at the bedside. This is important for the initial assessment and the monitoring of recovery from neurotoxic envenoming. Adopting these methods will also be critical to the conduct of future clinical trials of toxin-inhibiting drugs and antivenoms being tested for the reversal of venom-induced neuromuscular block.
MeSH term(s)	Humans ; Snake Bites/therapy ; Snake Bites/drug therapy ; Paralysis/drug therapy ; Neuromuscular Blockade/methods ; Neuromuscular Blocking Agents/therapeutic use ; Antivenins/therapeutic use
Chemical Substances	Neuromuscular Blocking Agents ; Antivenins
Language	English
Publishing date	2023-01-06
Publishing country	Switzerland
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518395-3
ISSN	2072-6651 ; 2072-6651
ISSN (online)	2072-6651
ISSN	2072-6651
DOI	10.3390/toxins15010049
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Article ; Online: Amplification of Snake Venom Toxicity by Endogenous Signaling Pathways

Philip E. Bickler

Toxins, Vol 12, Iss 2, p

2020 Volume 68

Abstract	The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, inflammation, coagulopathy, cell/organ injury, and disruption of homeostatic mechanisms of normal physiology. In this review, we describe how snakebite is not only a condition mediated directly by venom, but by the amplification of signals dysregulating inflammation, coagulation, neurotransmission, and cell survival. Although venom proteins are diverse, the majority of important pathologic events following envenoming follow from a small group of enzyme-like activities and the actions of small toxic peptides. This review focuses on two of the most important enzymatic activities: snake venom phospholipases (svPLA 2 ) and snake venom metalloproteases (svMP). These two enzyme classes are adept at enabling venom to recruit homologous endogenous signaling systems with sufficient magnitude and duration to produce and amplify cell injury beyond what would be expected from the direct impact of a whole venom dose. This magnification produces many of the most acutely important consequences of envenoming as well as chronic sequelae. Snake venom PLA 2 s and MPs enzymes recruit prey analogs of similar activity. The transduction mechanisms that recruit endogenous responses include arachidonic acid, intracellular calcium, cytokines, bioactive peptides, and possibly dimerization of venom and prey protein homologs. Despite years of investigation, the precise mechanism of svPLA 2 -induced neuromuscular paralysis remains incomplete. Based on recent studies, paralysis results from a self-amplifying cycle of endogenous PLA 2 activation, arachidonic acid, increases in intracellular Ca 2+ and nicotinic receptor deactivation. When prolonged, synaptic suppression supports the degeneration of the synapse. ...
Keywords	phospholipase a2 ; metalloprotease ; snake venom ; intracellular signaling ; neuromuscular paralysis ; intracellular calcium ; Medicine ; R
Subject code	616
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Enough Information to Evaluate Clinical Monitors?

Bickler, Philip E

Anesthesia and analgesia

2016 Volume 123, Issue 1, Page(s) 254–255

Language	English
Publishing date	2016-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0000000000001342
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Article ; Online: John W. Severinghaus, M.D., 1922 to 2021.

Bickler, Philip E / Hornbein, Thomas / Saidman, Lawrence J

Anesthesiology

2021 Volume 135, Issue 4, Page(s) 555–557

MeSH term(s)	Anesthesiologists/history ; Anesthesiology/history ; History, 20th Century ; History, 21st Century ; Humans ; Translational Medical Research/history
Language	English
Publishing date	2021-09-27
Publishing country	United States
Document type	Biography ; Editorial ; Historical Article
ZDB-ID	269-0
ISSN	1528-1175 ; 0003-3022
ISSN (online)	1528-1175
ISSN	0003-3022
DOI	10.1097/ALN.0000000000003927
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Article ; Online: Neuromuscular Weakness and Paralysis Produced by Snakebite Envenoming

Philip E. Bickler / Michael Abouyannis / Ashish Bhalla / Matthew R. Lewin

Toxins, Vol 15, Iss 49, p

Mechanisms and Proposed Standards for Clinical Assessment

2023 Volume 49

Abstract	Respiratory and airway-protective muscle weakness caused by the blockade of neuromuscular transmission is a major cause of early mortality from snakebite envenoming (SBE). Once weakness is manifest, antivenom appears to be of limited effectiveness in improving neuromuscular function. Herein, we review the topic of venom-induced neuromuscular blockade and consider the utility of adopting clinical management methods originally developed for the safe use of neuromuscular blocking agents by anesthesiologists in operating rooms and critical care units. Failure to quantify neuromuscular weakness in SBE is predicted to cause the same significant morbidity that is associated with failure to do so in the context of using a clinical neuromuscular block in surgery and critical care. The quantitative monitoring of a neuromuscular block, and an understanding of its neurophysiological characteristics, enables an objective measurement of weakness that may otherwise be overlooked by traditional clinical examination at the bedside. This is important for the initial assessment and the monitoring of recovery from neurotoxic envenoming. Adopting these methods will also be critical to the conduct of future clinical trials of toxin-inhibiting drugs and antivenoms being tested for the reversal of venom-induced neuromuscular block.
Keywords	snakebite ; neurotoxin ; anesthesia ; paralysis ; weakness ; presynaptic ; Medicine ; R
Subject code	610
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Accuracy of Samsung Smartphone Integrated Pulse Oximetry Meets Full FDA Clearance Standards for Clinical Use.

Browne, Sara H / Bernstein, Mike / Bickler, Philip E

medRxiv : the preprint server for health sciences

2021

Abstract: Background: Pulse oximetry is used as an assessment tool to gauge the severity of COVID-19 infection and identify patients at risk of poor outcomes.: Methods: The accuracy of integrated pulse oximetry in the Samsung 9 smartphone during stable ... ...

Abstract	Background: Pulse oximetry is used as an assessment tool to gauge the severity of COVID-19 infection and identify patients at risk of poor outcomes. Methods: The accuracy of integrated pulse oximetry in the Samsung 9 smartphone during stable arterial oxygen saturations (SaO Findings: The RMSD of the over 257 data points based on blood sample analysis obtained from 12 human volunteers tested was 2.6%. Interpretation: Evaluation of the smartphone pulse oximeter performance is within requirements of <3.5% RMSD blood oxygen saturation (SpO
Language	English
Publishing date	2021-02-18
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.02.17.21249755
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Article ; Online: Pulse Oximeter Bias and Inequities in Retrospective Studies--Now What?

Moore, Kelvin L / Gudelunas, Koa / Lipnick, Michael S / Bickler, Philip E / Hendrickson, Carolyn M

Respiratory care

2022 Volume 67, Issue 12, Page(s) 1633–1636

MeSH term(s)	Humans ; Retrospective Studies ; Oximetry ; Oxygen
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2022-11-25
Publishing country	United States
Document type	Editorial ; Comment
ZDB-ID	603252-7
ISSN	1943-3654 ; 0098-9142 ; 0020-1324
ISSN (online)	1943-3654
ISSN	0098-9142 ; 0020-1324
DOI	10.4187/respcare.10654
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Article ; Online: Low Perfusion and Missed Diagnosis of Hypoxemia by Pulse Oximetry in Darkly Pigmented Skin: A Prospective Study.

Gudelunas, M Koa / Lipnick, Michael / Hendrickson, Carolyn / Vanderburg, Sky / Okunlola, Bunmi / Auchus, Isabella / Feiner, John R / Bickler, Philip E

Anesthesia and analgesia

2023 Volume 138, Issue 3, Page(s) 552–561

Abstract: Background: Retrospective clinical trials of pulse oximeter accuracy report more frequent missed diagnoses of hypoxemia in hospitalized Black patients than White patients, differences that may contribute to racial disparities in health and health care. ... ...

Abstract	Background: Retrospective clinical trials of pulse oximeter accuracy report more frequent missed diagnoses of hypoxemia in hospitalized Black patients than White patients, differences that may contribute to racial disparities in health and health care. Retrospective studies have limitations including mistiming of blood samples and oximeter readings, inconsistent use of functional versus fractional saturation, and self-reported race used as a surrogate for skin color. Our objective was to prospectively measure the contributions of skin pigmentation, perfusion index (PI), sex, and age on pulse oximeter errors in a laboratory setting. Methods: We enrolled 146 healthy subjects, including 25 with light skin (Fitzpatrick class I and II), 78 with medium (class III and IV), and 43 with dark (class V and VI) skin. We studied 2 pulse oximeters (Nellcor N-595 and Masimo Radical 7) in prevalent clinical use. We analyzed 9763 matched pulse oximeter readings (pulse oximeter measured functional saturation [Sp o2 ]) and arterial oxygen saturation (hemoximetry arterial functional oxygen saturation [Sa o2 ]) during stable hypoxemia (Sa o2 68%-100%). PI was measured as percent infrared light modulation by the pulse detected by the pulse oximeter probe, with low perfusion categorized as PI < 1%. The primary analysis was to assess the relationship between pulse oximeter bias (difference between Sa o2 and Sp o2 ) by skin pigment category in a multivariable mixed-effects model incorporating repeated-measures and different levels of Sa o2 and perfusion. Results: Skin pigment, PI, and degree of hypoxemia significantly contributed to errors (bias) in both pulse oximeters. For PI values of 1.0% to 1.5%, 0.5% to 1.0%, and <0.5%, the P value of the relationship to mean bias or median absolute bias was <.00001. In lightly pigmented subjects, only PI was associated with positive bias, whereas in medium and dark subjects bias increased with both low perfusion and degree of hypoxemia. Sex and age was not related to pulse oximeter bias. The combined frequency of missed diagnosis of hypoxemia (pulse oximeter readings 92%-96% when arterial oxygen saturation was <88%) in low perfusion conditions was 1.1% for light, 8.2% for medium, and 21.1% for dark skin. Conclusions: Low peripheral perfusion combined with darker skin pigmentation leads to clinically significant high-reading pulse oximeter errors and missed diagnoses of hypoxemia. Darkly pigmented skin and low perfusion states are likely the cause of racial differences in pulse oximeter performance in retrospective studies.
MeSH term(s)	Humans ; Prospective Studies ; Missed Diagnosis ; Retrospective Studies ; Oximetry ; Hypoxia/diagnosis ; Oxygen ; Perfusion
Chemical Substances	Oxygen (S88TT14065)
Language	English
Publishing date	2023-12-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0000000000006755
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Article ; Online: Accuracy of Smartphone Integrated Pulse Oximetry Meets Full FDA Clearance Standards for Clinical Use.

Browne, Sara H / Bernstein, Mike / Bickler, Philip E.

medRxiv

Abstract: Background: Pulse oximetry is used as an assessment tool to gauge the severity of COVID-19 infection and identify patients at risk of poor outcomes. The pandemic highlights the need for accurate pulse oximetry, particularly at home, as infection rates ... ...

Abstract	Background: Pulse oximetry is used as an assessment tool to gauge the severity of COVID-19 infection and identify patients at risk of poor outcomes. The pandemic highlights the need for accurate pulse oximetry, particularly at home, as infection rates increase in multiple global regions, including the UK, USA, and South Africa. Over 100 million Samsung smartphones containing dedicated biosensors (Maxim Integrated Inc, San Jose, CA) and preloaded Apps to perform pulse oximetry, are in use globally. We performed detailed in human hypoxia testing on the Samsung S9 smartphone to determine if this integrated hardware meets full FDA/ISO requirements for clinical pulse oximetry. Methods: The accuracy of integrated pulse oximetry in the Samsung 9+ smartphone during stable oxygen saturation (SaO2) between 70% and 100% was evaluated in 12 healthy subjects. Inspired oxygen, nitrogen, and carbon dioxide partial pressures were monitored and adjusted via a partial rebreathing circuit to achieve stable target SaO2 plateaus between 70% and 100%. Arterial blood samples were taken at each plateau, and saturation measured on each blood sample using ABL-90FLEX blood gas analyzer. Bias, calculated from smartphone readings minus the corresponding arterial blood sample, was reported as root mean square deviation (RMSD). Findings: The RMSD of the over 257 data points based on blood sample analysis obtained from 12 human volunteers tested was 2.6%. Interpretation: Evaluation of the smartphone pulse oximeter performance is within requirements of <3.5% RMSD blood oxygen saturation (SpO2) value for FDA/ISO clearance for clinical pulse oximetry. This is the first report of smartphone derived pulse oximetry measurements that meet full FDA/ISO accuracy certification requirements. Both Samsung S9 and S10 contain the same integrated pulse oximeter, thus over 100 million smartphones in current global circulation could be used to obtain clinically accurate spot SpO2 measurements to support at home assessment of COVID-19 patients.
Keywords	covid19
Language	English
Publishing date	2021-02-18
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2021.02.17.21249755
Database	COVID19

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