Perfluorocarbons for the treatment of decompression illness: how to bridge the gap between theory and practice

Abstract Decompression illness (DCI) is a complex clinical syndrome caused by supersaturation of respiratory gases in blood and tissues after abrupt reduction in ambient pressure. The resulting formation of gas bubbles combined with pulmonary barotrauma leads to venous and arterial gas embolism. Severity of DCI depends on the degree of direct tissue damage caused by growing bubbles or indirect cell injury by impaired oxygen transport, coagulopathy, endothelial dysfunction, and subsequent inflammatory processes. The standard therapy of DCI requires expensive and not ubiquitously accessible hyperbaric chambers, so there is an ongoing search for alternatives. In theory, perfluorocarbons (PFC) are ideal non-recompressive therapeutics, characterized by high solubility of gases. A dual mechanism allows capturing of excess nitrogen and delivery of additional oxygen. Since the 1980s, numerous animal studies have proven significant benefits concerning survival and reduction in DCI symptoms by intravenous application of emulsion-based PFC preparations. However, limited shelf-life, extended organ retention and severe side effects have prevented approval for human usage by regulatory authorities. These negative characteristics are mainly due to emulsifiers, which provide compatibility of PFC to the aqueous medium blood. The encapsulation of PFC with amphiphilic biopolymers, such as albumin, offers a new option to achieve the required biocompatibility avoiding toxic emulsifiers. Recent studies with PFC nanocapsules, which can also be used as artificial oxygen carriers, show promising results. This review summarizes the current state of research concerning DCI pathology and the therapeutic use of PFC including the new generation of non-emulsified formulations based on nanocapsules.

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Dysbarism

10.2310/em.4362 ◽

2015 ◽

Author(s):

Kris Lehnhardt

Keyword(s):

Inner Ear ◽

Medical Condition ◽

Ambient Pressure ◽

Oxygen Toxicity ◽

Signs And Symptoms ◽

Gas Mixtures ◽

Decompression Illness ◽

Pulmonary Barotrauma ◽

Gas Laws ◽

Inner Ear Barotrauma

Dysbarism is defined as any medical condition that arises as a result of changes in ambient pressure. This review describes dysbarism with a focus on the undersea environment. Conditions discussed in this review include middle and inner ear barotrauma, pulmonary barotrauma, immersion pulmonary edema, decompression illness, and gas toxicities. For each, assessment and stabilization, treatment and disposition, and outcomes are presented. Figures show the AQUARIUS habitat for saturation diving; the anatomy of the external, middle, and inner ear; the Teed classification; the paranasal sinuses; and an example of a recompression chamber. Tables list the types of diving, gas laws relevant to diving, units of underwater pressure, compositions of typical breathing gas mixtures, decompression illness risk factors, symptoms of decompression illness (in order of frequency), signs and symptoms of decompression illness based on body system, maximum recommended depth to reduce the risk of central nervous system oxygen toxicity for various breathing gas mixtures, and progression of nitrogen narcosis symptoms with increasing depth. This review contains 5 highly rendered figures, 9 tables, and 120 references.

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Cytokine adsorption is a promising tool in the therapy of hemophagocytic lymphohistiocytosis

The International Journal of Artificial Organs ◽

10.1177/0391398819857444 ◽

2019 ◽

Vol 42 (11) ◽

pp. 658-664 ◽

Cited By ~ 5

Author(s):

Silvius Frimmel ◽

Michael Hinz ◽

Jan Schipper ◽

Simon Bogdanow ◽

Steffen Mitzner ◽

...

Keyword(s):

Hemophagocytic Lymphohistiocytosis ◽

Animal Studies ◽

Marked Decrease ◽

Case Series ◽

Clinical Syndrome ◽

Porous Polymer ◽

Vasopressor Therapy ◽

Promising Tool ◽

Cytokine Levels ◽

Life Threatening

Hemophagocytic lymphohistiocytosis is a life-threatening clinical syndrome caused by severe hypercytokinemia brought on by a highly stimulated but ineffective immune response. Animal studies and case series have demonstrated that a reduction in blood cytokine levels achieved with an extracorporeal adsorption cartridge that contains blood-compatible porous polymer beads (CytoSorb®) can effectively attenuate the inflammatory response during sepsis and possibly improve outcomes. We report a case series of two patients in which three episodes of severe hemophagocytic lymphohistiocytosis triggered by infections with herpesviridae were treated successfully with cytokine adsorption. A marked decrease in interleukin-6 plasma levels and a stable or decreasing need of vasopressor therapy were the most significant results of this treatment. Importantly, treatment was safe and well-tolerated, without any adverse events.

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Histopathological Evaluation of Contrast-Induced Acute Kidney Injury Rodent Models

BioMed Research International ◽

10.1155/2016/3763250 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 21

Author(s):

Norbert Kiss ◽

Péter Hamar

Keyword(s):

Acute Kidney Injury ◽

Animal Studies ◽

Renal Damage ◽

Cell Injury ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Rodent Models ◽

Histologic Appearance ◽

Rats And Mice ◽

To Receive

Contrast-induced acute kidney injury (CI-AKI) can occur in 3–25% of patients receiving radiocontrast material (RCM) despite appropriate preventive measures. Often patients with an atherosclerotic vasculature have to receive large doses of RCM. Thus, animal studies to uncover the exact pathomechanism of CI-AKI are needed. Sensitive and specific histologic end-points are lacking; thus in the present review we summarize the histologic appearance of different rodent models of CI-AKI. Single injection of RCM causes overt renal damage only in rabbits. Rats and mice need an additional insult to the kidney to establish a clinically manifest CI-AKI. In this review we demonstrate that the concentrating ability of the kidney may be responsible for species differences in sensitivity to CI-AKI. The most commonly held theory about the pathomechanism of CI-AKI is tubular cell injury due to medullary hypoxia. Thus, the most common additional insult in rats and mice is some kind of ischemia. The histologic appearance is tubular epithelial cell (TEC) damage; however severe TEC damage is only seen if RCM is combined by additional ischemia. TEC vacuolization is the first sign of CI-AKI, as it is a consequence of RCM pinocytosis and lysosomal fusion; however it is not sensitive as it does not correlate with renal function and is not specific as other forms of TEC damage also cause vacuolization. In conclusion, histopathology alone is insufficient and functional parameters and molecular biomarkers are needed to closely monitor CI-AKI in rodent experiments.

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Pathophysiology and management of depth-related disorders

10.1093/med/9780199600830.003.0351 ◽

2016 ◽

Author(s):

Peter Radermacher ◽

Claus-Martin Muth

Keyword(s):

Hyperbaric Oxygen ◽

Decompression Sickness ◽

Specific Treatment ◽

Decompression Illness ◽

Gas Embolism ◽

Hyperbaric Oxygen Treatment ◽

Pulmonary Barotrauma ◽

Oxygen Treatment ◽

Technical Issues ◽

Vascular Obstruction

Decompression illness comprises decompression sickness resulting from tissue inert gas super-saturation and pulmonary barotraumas due to alveolar or airway over-distension. Gas bubbles can cause vascular obstruction or tissue compression, resulting in tissue ischaemia and oedema. Interactions between the blood–gas interface and the endothelium will result in further tissue damage, and trigger an inflammatory cascade with capillary leakage and haemoconcentration. Decompression illness may mimic any other emergency pathology and any emergency coinciding with decompression is ‘due to’ decompression. Pulmonary barotrauma-induced arterial gas embolism and decompression sickness can be discriminated according to the onset of symptoms, with gas embolism predominantly developing within a few minutes after or even during decompression. Specific treatment consists of hyperbaric oxygen treatment, using several empirically-derived hyperbaric oxygen treatment schedules. Currently, there is no recognized pharmacological treatment, but fluid resuscitation is useful to counteract haemoconcentration and dehydration. Early treatment initiation is mandatory, and certain technical issues must be considered for the management of critically-ill patients in a hyperbaric chamber.

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Arterial Gas Embolism and Decompression Sickness

Physiology ◽

10.1152/nips.01370.2001 ◽

2002 ◽

Vol 17 (2) ◽

pp. 77-81 ◽

Cited By ~ 4

Author(s):

Tom S. Neuman

Keyword(s):

Gas Phase ◽

Decompression Sickness ◽

Ambient Pressure ◽

The Body ◽

Pulmonary Vasculature ◽

Gas Embolism ◽

Pulmonary Barotrauma ◽

Arterial Gas Embolism ◽

Underlying Pathophysiology

Decompression sickness occurs when a sufficiently large gas phase forms within the tissues of the body after a reduction in ambient pressure. Arterial gas embolism occurs secondary to pulmonary barotrauma when gas is forced into the pulmonary vasculature. Although they may clinically present in a similar fashion, the underlying pathophysiology of the two conditions is quite different.

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Animal Models of OCD

10.1093/med/9780190228163.003.0029 ◽

2017 ◽

Author(s):

Christopher Pittenger ◽

Stephanie Dulawa ◽

Summer L. Thompson

Keyword(s):

Animal Models ◽

Animal Studies ◽

Mammalian Species ◽

Clinical Syndrome ◽

Model Systems ◽

Clinical Aspects ◽

Brain Anatomy ◽

Subjective Report ◽

Compulsive Disorder ◽

Animal Modeling

Obsessive-compulsive disorder and related conditions are characterized by demonstrable alterations in brain function, and aspects of these may, in principle, be recapitulated and studied in animals. However, the relationship between animal models and the clinical syndrome is complex. Many clinical aspects of OCD, especially those that can only be evaluated by subjective report, cannot be assessed in an animal. As a result, some discount the utility of animal modeling of OCD altogether. However, conservation of both genes and brain anatomy across mammalian species supports the opposite perspective, that key aspects of the pathophysiology of OCD and related disorders can be recapitulated in animals, and thus fruitfully studied in model systems. This introductory chapter addresses these issues, seeking to identify both the strengths and the limitations of animal studies as contributors to our understanding of OCD. This discussion provides a framework for the more specific material about particular animal models presented in this section.

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Uneven distribution of Purkinje cell injury in the cerebellar vermis of term neonates with hypoxic-ischemic encephalopathy

10.1101/2020.04.15.043018 ◽

2020 ◽

Author(s):

K.V. Annink ◽

I.C.E. van Leeuwen ◽

N.E. van der Aa ◽

T. Alderliesten ◽

F. Groenendaal ◽

...

Keyword(s):

Animal Studies ◽

Cell Injury ◽

Cerebellar Vermis ◽

Hypoxic Ischemic Encephalopathy ◽

Rank Test ◽

Posterior Lobe ◽

Term Neonates ◽

Paired Samples ◽

Significant Difference ◽

Ischemic Encephalopathy

ABSTRACTIntroductionIn term neonates with hypoxic-ischemic encephalopathy (HIE), cerebellar injury is becoming more and more acknowledged. Animal studies demonstrated that Purkinje cells (PCs) are especially vulnerable for hypoxic-ischemic injury. In neonates, however, the extent and pattern of PC injury has not been investigated. The aim of this study was to determine the distribution of PC injury in the cerebellar vermis of term born neonates with HIE.MethodsTerm born neonates with HIE that underwent post-mortem autopsy of the cerebellar vermis were included. Haematoxylin & Eosin (H&E) stained sections of the vermis were used to determine total PC count and morphology (normal, abnormal or non-classified) at the bases and crown of the folia and of the lobules in both the anterior and posterior lobes. Differences in PC count and PC morphology between the anterior and posterior lobe and between the bases and crown were calculated using the paired samples T-test or Wilcoxon-signed rank test.ResultsThe total number of PCs were significantly higher at the crown compared to the bases (p<0.001) irrespective of the precise location. Besides, PCs at the bases more often had an abnormal morphology. No significant difference between the total number of PCs in the anterior and posterior lobe was observed.ConclusionThe abnormal PC count and morphology in term neonates with HIE resembles supratentorial ulegyria.

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Rescue of a submerged convulsing diver

Undersea and Hyperbaric Medicine ◽

10.22462/04.06.2019.8 ◽

2019 ◽

pp. 154-157

Author(s):

Jan Risberg ◽

◽

Simon Phillips ◽

Keyword(s):

Animal Studies ◽

Face Mask ◽

Specific Recommendation ◽

Pulmonary Barotrauma ◽

Essential Step ◽

Underwater Environment ◽

Compressed Gas ◽

Clonic Seizures ◽

And Control ◽

The Military

In 2018, the Medical Panel of the NATO Underwater Diving Working Group (UDWG) discussed the question of the rescue and management of a submerged unresponsive compressed-gas diver. The Panel reviewed the 2012 recommendation by the UHMS Diving Committee with respect to the specific recommendation in a convulsing diver using a half-face mask and separate mouthpiece, to delay surfacing until the clonic phase had subsided if the mouthpiece was in place. There is a paucity of scientific, epidemiological, experimental and observational human studies to substantiate this guidance. Experimental animal studies suggest that the likelihood of a complete airway obstruction during an ongoing seizure is low and that there is a high likelihood of surviving pulmonary barotrauma caused by complete airway closure. Airway management and control is an essential step in the management of the unresponsive diver and would be challenging to achieve in the underwater environment. Even in the military setting, it will be difficult to provide sufficient training to enable divers to handle such a situation. In this very rare scenario it is considered that emergency guidelines should be clear, concise and easy to follow. The UDWG therefore recommends that all unconscious military divers in this situation should be rescued to surface without waiting for clonic seizures to subside. Training organizations for recreational and occupational divers should consider whether this guidance should be applied for civilian divers as well.

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Pulmonary barotrauma: assessment and investigation in divers

Undersea and Hyperbaric Medicine ◽

10.22462/04.06.2019.12 ◽

2019 ◽

pp. 189-196

Author(s):

Reza Ashrafi ◽

◽

Mark Turner ◽

Keyword(s):

Decompression Sickness ◽

Predisposing Factors ◽

Inert Gas ◽

Phase Identification ◽

Decompression Illness ◽

Pulmonary Barotrauma ◽

Initial Management ◽

Causative Mechanism ◽

Future Risk

Decompression illness (DCI) is an uncommon problem but can be significant in terms of morbidity and, very rarely, mortality. The mechanisms of DCI are pulmonary barotrauma and decompression sickness due to inert gas supersaturation. After the initial management phase, identification of predisposing factors is important to help advise divers regarding future risk and avoidance. Here we present four cases of DCI where pulmonary barotrauma was the likely causative mechanism. We highlight the important features in assessment for pulmonary barotrauma and advising divers on the risk of a recurrence.

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Perfluorocarbon-based oxygen carriers: from physics to physiology

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-020-02482-2 ◽

2020 ◽

Author(s):

Johannes Jägers ◽

Anna Wrobeln ◽

Katja B. Ferenz

Keyword(s):

Vascular System ◽

Cancer Therapeutics ◽

Blood Substitutes ◽

The Body ◽

Oxygen Carriers ◽

Body Experiences ◽

Diverse Application ◽

Physical Background ◽

Application Fields ◽

Respiratory Gases

Abstract Developing biocompatible, synthetic oxygen carriers is a consistently challenging task that researchers have been pursuing for decades. Perfluorocarbons (PFC) are fascinating compounds with a huge capacity to dissolve gases, where the respiratory gases are of special interest for current investigations. Although largely chemically and biologically inert, pure PFCs are not suitable for injection into the vascular system. Extensive research created stable PFC nano-emulsions that avoid (i) fast clearance from the blood and (ii) long organ retention time, which leads to undesired transient side effects. PFC-based oxygen carriers (PFOCs) show a variety of application fields, which are worthwhile to investigate. To understand the difficulties that challenge researchers in creating formulations for clinical applications, this review provides the physical background of PFCs’ properties and then illuminates the reasons for instabilities of PFC emulsions. By linking the unique properties of PFCs and PFOCs to physiology, it elaborates on the response, processing and dysregulation, which the body experiences through intravascular PFOCs. Thereby the reader will receive a scientific and easily comprehensible overview why PFOCs are precious tools for so many diverse application areas from cancer therapeutics to blood substitutes up to organ preservation and diving disease.

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