The chain of survival and rehabilitation for sepsis: concepts and proposals for healthcare trajectory optimization.

This article describes the structures and processes involved in healthcare delivery for sepsis, from the prehospital setting until rehabilitation. Quality improvement initiatives in sepsis may reduce both morbidity and mortality. Positive outcomes are more likely when the following steps are optimized: early recognition, severity assessment, prehospital emergency medical system activation when available, early therapy (antimicrobials and hemodynamic optimization), early orientation to an adequate facility (emergency room, operating theater or intensive care unit), in-hospital organ failure resuscitation associated with source control, and finally a comprehensive rehabilitation program. Such a trajectory of care dedicated to sepsis amounts to a chain of survival and rehabilitation for sepsis. Implementation of this chain of survival and rehabilitation for sepsis requires full interconnection between each link. To date, despite regular international recommendations updates, the adherence to sepsis guidelines remains low leading to a considerable burden of the disease. Developing and optimizing such an integrated network could significantly reduce sepsis related mortality and morbidity.

Bothrops lanceolatus Envenoming in Martinique: A Historical Perspective of the Clinical Effectiveness of Bothrofav Antivenom Treatment.

Bothrofav, a monospecific antivenom, was introduced in June 1991 and has shown excellent effectiveness against life-threatening and thrombotic complications of Bothrops lanceolatus envenoming. Because of the reoccurrence of cerebral stroke events despite the timely administration of antivenom, new batches of Bothrofav were produced and introduced into clinical use in January 2011. This study's aim was to evaluate the effectiveness of Bothrofav generations at treating B. lanceolatus envenoming. During the first period of the study (2000-2010), 107 patients were treated with vials of antivenom produced in June 1991, while 282 envenomed patients were treated with vials of antivenom produced in January 2011 in the second study period (2011-2023). Despite timely antivenom administration, thrombotic complications reoccurred after an interval free of thrombotic events, and a timeframe analysis suggested that the clinical efficacy of Bothrofav declined after it reached its 10-year shelf-life. In of the case of an antivenom shortage due to the absence of regular batch production, no adverse effects were identified before the antivenom reached its 10-year shelf-life, which is beyond the accepted shelf-life for a liquid-formulation antivenom. While our study does not support the use of expired antivenom for potent, life-threatening B. lanceolatus envenoming, it can be a scientific message to public entities proving the necessity of new antivenom production for B. lanceolatus envenoming.

Addressing snakebite envenoming as a One Health issue in the Caribbean

The prevalence of snakebite envenoming and its understated impact on health and socioeconomic well-being in the Caribbean demand urgent attention. As a One Health challenge, this issue intersects human, animal, and environmental health, necessitating a multifaceted approach for comprehensive management. Despite the Caribbean’s rich biodiversity and cultural mosaic, there is a scarcity of data on the epidemiology and impact of snakebites in the region. This gap in knowledge, coupled with the absence of systematic records or survey-based studies, hampers the development of effective interventions. In countries such as Belize, Saint Lucia, and Trinidad and Tobago, among others, venomous snakes pose a significant threat, particularly to those in rural agricultural settings. Snakebite envenoming not only inflicts a direct health burden, evidenced by high rates of mortality and morbidity among humans, but also precipitates profound financial repercussions. The cost of clinical management for those affected and the loss of productivity due to long-term sequelae are considerable. Moreover, the impact on domestic animals, primarily livestock, translates into tangible economic losses for rural households, who rely on these animals for sustenance and income.

Central sleep apnea and exposure to ambient hydrogen sulfide emissions from massive strandings of decomposing sargassum in the Caribbean.

BACKGROUND: Sargassum invasion of Caribbean and American shorelines is a recurring environmental hazard. Potential health effects of long-term chronic exposure to sargassum gaseous emissions, notably hydrogen sulfide (H2S), are overlooked. H2S plays an important role in neurotransmission and is involved in generating and transmitting respiratory rhythm. Central sleep apnea (CSA) has been attributed to the depression of respiratory centers. OBJECTIVE: Evaluate the effects of exposure to sargassum-H2S on CSA. METHODS: This study, set in the Caribbean, describes the clinical and polysomnographic characteristics of individuals living and/or working in areas impacted by sargassum strandings, in comparison with non-exposed subjects. Environmental exposure was estimated by the closest ground H2S sensor. Multivariate linear regression was applied to analyze CSA changes according to cumulative H2S exposure over time. Effects of air pollution and other sargassum toxic compounds (NH3) on CSA were also controlled. RESULTS: Among the 685 study patients, 27 % were living and/or working in sargassum impacted areas. Compared with non-exposed patients, exposed ones had similar sleep apnea syndrome risk factors, but had increased levels of CSA events (expressed as absolute number or % of total sleep apnea). Multivariate regression retained only male gender and mean H2S concentration over a 6-month exposure period as independent predictors of an increase in CSA events. A minimal exposure length of 1 month generated a significant rise in CSA events, with the latter increasing proportionally with a cumulative increase in H2S concentration over time. CONCLUSION: This pioneer work highlights a potential effect of sargassum-H2S on the central nervous system, notably on the modulation of the activity of the brain's respiratory control center. These observations, jointly with previous studies from our group, constitute a body of evidence strongly supporting a deleterious effect of sargassum-H2S on the health of individuals chronically exposed to low to moderate concentration levels over time.

Increased Binding of von Willebrand Factor to Sub-Endothelial Collagen May Facilitate Thrombotic Events Complicating Bothrops lanceolatus Envenomation in Humans.

Consumption coagulopathy and hemorrhagic syndrome exacerbated by blood anticoagulability remain the most important causes of lethality associated with Bothrops snake envenomation. Bothrops venom also engages platelet aggregation on the injured endothelium via von Willebrand factor (vWF) interactions. Besides platelet aggregation, some Bothrops venom toxins may induce qualitative thrombopathy, which has been in part related to the inhibition of vWF activation. We tested whether B. lanceolatus venom impaired vWF to collagen(s) binding (vWF:CB) activity. Experiments were performed with B. lanceolatus crude venom, in the presence or absence of Bothrofav, a monospecific B. lanceolatus antivenom. Venom of B. lanceolatus fully inhibited vWF to collagen type I and III binding, suggesting venom interactions with the vWF A3 domain. In contrast, B. lanceolatus venom increased vWF to collagen type VI binding, suggesting the enhancement of vWF binding to collagen at the vWF A1 domain. Hence, B. lanceolatus venom exhibited contrasting in vitro effects in terms of the adhesive properties of vWF to collagen. On the other hand, the antivenom Bothrofav reversed the inhibitory effects of B. lanceolatus venom on vWF collagen binding activity. In light of the respective distribution of collagen type III and collagen type VI in perivascular connective tissue and the sub-endothelium, a putative association between an increase in vWF:CB activity for collagen type VI and the onset of thrombotic events in human B. lanceolatus envenomation might be considered.

Risk Stratification in Transthyretin Cardiac Amyloidosis: The Added Value of Lung Spirometry.

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized disease that often results in heart failure and death. Traditionally, biological staging systems are used to stratify disease severity. Reduced aerobic capacity has recently been described as useful in identifying higher risk of cardiovascular events and death. Assessment of lung volume via simple spirometry might also hold prognostic relevance. We aimed to assess the combined prognostic value of spirometry, cardiopulmonary exercise testing (CPET) and biomarker staging in ATTR-CA patients in a multi-parametric approach. We retrospectively reviewed patient records with pulmonary function and CPET testing. Patients were followed until study endpoint (MACE: composite of heart-failure-related hospitalization and all-cause death) or censure (1 April 2022). In total, 82 patients were enrolled. Median follow-up was 9 months with 31 (38%) MACE. Impaired peak VO2 and forced vital capacity (FVC) were independent predictors of MACE-free survival, with peak VO2 < 50% and FVC < 70% defining the highest risk group (HR 26, 95% CI: 5-142, mean survival: 15 months) compared to patients with the lowest risk (peak VO2 ≥ 50% and FVC ≥ 70%). Combined peak VO2, FVC and ATTR biomarker staging significantly improved MACE prediction by 35% compared to ATTR staging alone, with 67% patients reassigned a higher risk category (p < 0.01). In conclusion, combining functional and biological markers might synergistically improve risk stratification in ATTR-CA. Integrating simple, non-invasive and easily applicable CPET and spirometry in the routine management of ATTR-CA patients might prove useful for improved risk prediction, optimized monitoring and timely introduction of newer-generation therapies.

Polyphenolic compounds of Phyllanthus amarus Schum & Thonn. (1827) and diabetes-related activity of an aqueous extract as affected by in vitro gastrointestinal digestion.

ETHNOPHARMACOLOGICAL RELEVANCE: Extracts of the aerial part of Phyllanthus amarus have been extensively used in several countries to cure diabetes. No data is available on the impact of gastrointestinal digestion of such crude extracts on their antidiabetic activity. AIM OF THE STUDY: The aim of this study was to identify active fractions and compounds of fresh aerial parts of P. amarus extracted by an infusion method that are responsible for antidiabetic effects occurring at the level of glucose homeostasis. MATERIALS AND METHODS: An aqueous extract was obtained by an infusion method and its polyphenolic composition was analysed by reverse phase UPLC-DAD-MS. The influence of in vitro gastrointestinal digestion was evaluated both on the chemical composition and on the antidiabetic effect of P. amarus infusion extract using glucose-6-phosphatase enzyme inhibition and stimulation of glucose uptake. RESULTS: Analysis of the chemical composition of the crude extract revealed the presence of polysaccharides and various families of polyphenols such as phenolic acids, tannins, flavonoids and lignans. After simulated digestion, the total content of polyphenols decreased by about 95%. Caffeoylglucaric acid derivates and lignans exhibited strong stimulation of glucose uptake similar to metformin with an increase of 35.62 ± 6.14% and 34.74 ± 5.33% respectively. Moreover, corilagin, geraniin, the enriched polysaccharides fraction and the bioaccessible fraction showed strong anti-hyperglycemic activity with about 39-62% of glucose-6-phosphatase inhibition. CONCLUSION: Caffeoylglucaric acid isomers, tannin acalyphidin M1 and lignan demethyleneniranthin were reported for the first time in the species. After in vitro gastroinstestinal digestion, the composition of the extract changed. The dialyzed fraction showed strong glucose-6-phosphatase inhibition.

The ventilatory component of the muscle metaboreflex is overstimulated in transthyretin cardiac amyloidosis patients with poor aerobic capacity.

Background: The exercise pressor reflex, i.e., metabo- and mechano-reflex, partially regulates the control of ventilation and cardiovascular function during exercise. Abnormal exercise pressor reflex response has been associated with exaggerated ventilatory drive, sympathovagal imbalance and exercise limitation in chronic heart failure patients. Whether metaboreflex is over-activated and participate to poor aerobic capacity in patients with hereditary transthyretin cardiac amyloidosis (CA-TTR) is unknown. Methods: Twenty-two CA-TTR patients (aged 76 ± 7, 68% male) with the V122I (p.Val142Ile) transthyretin underwent a thorough evaluation including heart rate variability metrics, electrochemical skin conductance (ESC), physical function cardiopulmonary exercise testing, and muscle metaboreflex assessment. Eleven control subjects were chosen for muscle metaboreflex assessment. Results: Age-matched controls (n = 11) and CA-TTR patients (n = 22) had similar metaboreflex sensitivity for heart rate, stroke volume, cardiac index and mean systemic arterial pressure. Compared with age-matched controls, metaboreflex sensitivity for systemic vascular resistance (-18.64% ± 6.91% vs 3.14% ± 23.35%) and minute-ventilation responses (-9.65% ± 14.83% vs 11.84% ± 23.1%) was markedly increased in CA-TTR patients. Values of ESC displayed positive correlations with stroke volume (r = 0.53, p = 0.011) and cardiac index (r = 0.51, p = 0.015) components of metaboreflex sensitivity, an inverse correlation with systemic vascular resistance (r = -0.55, p = 0.008) and a trend with mean arterial (r = -0.42, p = 0.052) components of metaboreflex sensitivity. Peak aerobic capacity (peak VO2%) displayed an inverse correlation with the ventilation component of metaboreflex sensitivity (r = -0.62, p = 0.015). Conclusion: Consistent with the "muscle hypothesis" in heart failure, it is proposed that deterioration of skeletal muscle function in hereditary CA-TTR patients may activate muscle metaboreflex, leading to an increase in ventilation and sensation of breathlessness, the perception of fatigue, and overall sympathetic activation.

Antioxidant Activities of Natural Compounds from Caribbean Plants to Enhance Diabetic Wound Healing.

Diabetic wound healing is a global medical challenge. Several studies showed that delayed healing in diabetic patients is multifactorial. Nevertheless, there is evidence that excessive production of ROS and impaired ROS detoxification in diabetes are the main cause of chronic wounds. Indeed, increased ROS promotes the expression and activity of metalloproteinase, resulting in a high proteolytic state in the wound with significant destruction of the extracellular matrix, which leads to a stop in the repair process. In addition, ROS accumulation increases NLRP3 inflammasome activation and macrophage hyperpolarization in the M1 pro-inflammatory phenotype. Oxidative stress increases the activation of NETosis. This leads to an elevated pro-inflammatory state in the wound and prevents the resolution of inflammation, an essential step for wound healing. The use of medicinal plants and natural compounds can improve diabetic wound healing by directly targeting oxidative stress and the transcription factor Nrf2 involved in the antioxidant response or the mechanisms impacted by the elevation of ROS such as NLRP3 inflammasome, the polarization of macrophages, and expression or activation of metalloproteinases. This study of the diabetic pro-healing activity of nine plants found in the Caribbean highlights, more particularly, the role of five polyphenolic compounds. At the end of this review, research perspectives are presented.

Bothrops (Fer-de-lance) snakebites in the French departments of the Americas (Martinique and Guyana): Clinical and experimental studies and treatment by immunotherapy.

Snakebite envenomation is a relevant medical hazard in French Guiana and Martinique, two French territories in the Americas. All snakebite envenomations in Martinique are inflicted by the endemic viperid species Bothrops lanceolatus, whereas Bothrops atrox is responsible for the majority of snakebites in French Guiana, although other venomous snake species also occur in this South American territory. This review summarizes some of the key aspects of the natural history of these species, as well as of their venom composition, the main clinical manifestations of envenomations, and their treatment by antivenoms. B. atrox venom induces the typical set of clinical manifestations characteristic of Bothrops sp. venoms, i.e., local tissue damage and systemic alterations associated with coagulopathies, hemorrhage, hemodynamic alterations, and acute kidney injury. In the case of B. lanceolatus venom, in addition to some typical features of bothropic envenomation, a unique and severe thrombotic effect occurs in some patients. The pathogenesis of this effect remains unknown but may be related to the action of venom components and inflammatory mediators on endothelial cells in the vasculature. A monospecific antivenom has been successfully used in Martinique to treat envenomations by B. lanceolatus. In the case of French Guiana, a polyvalent antivenom has been used for some years, but it is necessary to assess the preclinical and clinical efficacy against viperid venoms in this country of other antivenoms manufactured in the Americas.

Inflammation and Oxidative Stress in Snakebite Envenomation: A Brief Descriptive Review and Clinical Implications.

Snakebite envenoming is a pathological condition which may occur in response to the injection of venom. Snake venoms contain a complex mixture of biologically active molecules which are responsible for a broad spectrum of clinical manifestations, ranging from local tissue injuries to fatal complications. Snake venom administration commonly provokes local tissue injury often associated with systemic effects, including neurotoxic and cardiotoxic manifestations, bleeding, acute kidney injury, and rhabdomyolysis. An important spectrum of pathogenesis of snake envenomation is the generation of reactive oxygen species (ROS), which can directly provoke tissue damage and also potentiate the deleterious consequences of inflammation at the bite site. Snake venom components known to induce oxidative stress include phospholipases A2, metalloproteinases, three-finger toxins, and L-amino acid oxidase. Clear evidence is mounting suggesting that inflammation and oxidative stress participate in the destructive effects of envenoming, including acute renal failure, tissue necrosis, and unusual susceptibility to bleed (hemorrhage), mostly due to hypocoagulability, neuro/cardio toxicity, and myonecrosis. Impaired regulation of oxidative stress may also set the stage for secondary/long-term complications of snakebite envenomation such as musculoskeletal disabilities. Some aspects of natural antioxidant therapeutic options are discussed in this review.

Determinants of ventilatory inefficiency in transthyretin cardiac amyloidosis: The role of excessive ventilatory drive.

Background and objective: Along with impaired aerobic capacity, increased slope of the relationship between ventilation (VE) and pulmonary CO2 output (VCO2), i.e., VE-VCO2 slope is a common finding in patients with cardiac amyloidosis (CA), which suggests ventilatory inefficiency. Little is known about mechanisms leading to ventilatory inefficiency in CA patients. The purpose of this investigation was to examine the factors that underlie the abnormal ventilatory efficiency in transthyretin hereditary CA patients, such as excessive ventilatory drive, inability of pulmonary blood flow to increase adequately during exercise and excessive sympathetic stimulation, which are known mechanisms of VE-VCO2 slope increase. Methods: In this single-center retrospective observational study, consecutive patients (n = 41) with known familial transthyretin amyloidosis p.Val142Ile mutation carriers with confirmed cardiac phenotype were included. Results: Compared with CA patients without ventilatory inefficiency (VE-VCO2 slope < 36), patients with ventilatory inefficiency (VE-VCO2 slope ≥ 36) had increased inter-ventricular septum thickness, lower VO2 peak along with hyperventilation, and prolonged post-exercise heart rate recovery. By multivariate analysis, only excess of minute-ventilation at anaerobic threshold (ß = 0.127; p = 0.011) remained an independent predictor of ventilatory inefficiency. Conclusion: Our data suggest that high ventilatory stimulation during exercise leading to hyperventilation is the main determinant of ventilatory inefficiency in hereditary transthyretin cardiac amyloidosis patients. This novel finding helps to better understand the mechanism of exercise intolerance in these patients where physiological limitation may be related to both heart dysfunction and abnormal pulmonary response.

Acute Rubigine® Poisoning in Martinique a French Overseas Department of America: Clinical Characteristics and Prognostic Factors.

Rubigine® is an anti-rust stain remover containing fluorides which is believed to have been the cause of many deaths in Martinique. However, after the modification of its composition in 2006, serious poisoning from old formulas containing fluorides persisted. Our main objective was to determine the clinical characteristics and prognostic factors of these intoxications. Methods: Any patient admitted to the Martinique University Hospital for acute Rubigine® poisoning was included from 1 January 2000 to 31 December 2016. Usual demographic and clinical data were collected and comparisons between surviving and deceased patients made using a univariate analysis and logistic regression. Results: Fifty-five patients were included (mean age: 43 years; sex ratio M/F: 1.1), and the main clinical characteristics were: changes in electrocardiogram (ECG) (80%), digestive system disorders (75%), and neurological disorders (12%). The main features linked to death were the presence of hydrofluoric acid (p < 0.0001), age over 55 years (p = 0.01), hypocalcemia after the initial intravenous calcium supplementation (p = 0.0003), diarrhea (p < 0.0001), hypersialorrhea (p < 0.0001), myocardial excitability (p < 0.0001), and state of shock (p < 0.0001). Three patients required circulatory support by venous-arterial ECMO. Mortality was 10.9%. Conclusions: Rubigine® poisoning is responsible for significant morbidity and mortality. Fortunately, its incidence as well as mortality has sharply decreased in Martinique thanks to the measures taken by the French state. This retrospective work nevertheless shows that acute intoxication by the old formula of Rubigine® remains the main factor of poor prognosis.

Clinical Characteristics of Ciguatera Poisoning in Martinique, French West Indies-A Case Series.

Ciguatera poisoning (CP) is one of the most common causes worldwide of marine poisoning associated with fish consumption from tropical areas. Its incidence is underreported. CP cases seem to increase with grouped cases reported during summer. Exposure to ciguatoxins, toxins responsible for CP with sodium-channel agonistic, voltage-gated potassium channel blocking, cholinergic, and adrenergic activities, may result in a large spectrum of manifestations. We aimed to describe the clinical characteristics, management, and outcome of CP in Martinique, French West Indies. We conducted an observational retrospective single-center study during six years (October 2012 to September 2018) including all CP patients managed by the prehospital medical services, admitted to the university hospital emergency department, or declared to the regional health agency. A total of 149 CP patients (81 females/63 males; median age, 46 years (interquartile range, 34-61)) were included. Acute features consisted in general (91%; mainly, myalgia pruritus, and asthenia), gastrointestinal (90%; mainly diarrhea, abdominal pain, and nausea), neurological (72%; mainly, paresthesia, dysgeusia, and impairment of hot/cold feeling), and cardiovascular manifestations (22%; bradycardia, hypotension, and heart conduction disorders). Management was supportive. No patient died but symptoms persisted in 40% of the 77 patients with follow-up at day 15. CP was mainly attributed to the ingestion of trevallies (59%), snappers (13%), and king mackerels (8%) with collective contaminations (71%). Unusual fish (tuna, salmon, and spider conchs) were suspected in rare cases. Ingestion of trevallies was associated with significantly higher persistent symptoms (odds ratio, 3.00; 95% confidence interval, (1.20-8.00); p = 0.03). CP incidence was 0.67 cases per 10,000 patient-years in Martinique over the study period. To conclude, CP represents an increasing public health issue in Martinique, as is the case in other Caribbean islands. Patients present usual but possibly life-threatening features. Outcome is excellent despite frequently prolonged manifestations.

Early air transport after thoracic surgery might be safe: A retrospective observational study in the French Caribbean.

Objective: The objective of this study was to determine the incidence of early air transport (EAT) morbidity after transpleural surgery. We compared our cohort with our patients not requiring air transport. Methods: This was a retrospective observational study, in the Thoracic and Cardiovascular Surgery Department of the University Hospital of Martinique over 40 months. We included all of the files (national and local database, and systematic postoperative consultation) of patients operated on for thoracic surgery or distinguished transpleural surgical intervention, whatever their geographical origin. Patients from another French department benefited from EAT. The complications were classified according to Clavien-Dindo before or after the EAT. Diagnostic criteria were chest pain, dyspnea, and abnormal chest radiograph. Continuous variables are presented as mean, median, and SDs. Discrete variables are presented as n (%). Results: Of 491 patients operated on, 315 were transpleural surgeries, and 99 patients benefited from EAT. There were 55% resections, a percent predicted of forced expiratory volume in 1 second, and an average preoperative Tiffeneau ratio of respectively, 86% and 78. One complication was found: a pneumothorax in an emphysematous patient, 15 days after the flight, who had an index of prolonged air leak >10. The mean time between surgery and flight was 7.2 days (σ = 4.5), and 3.3 days (σ = 2.9) between removal of the last drain and flight. The morbidity of EAT after transpleural surgery was 1%. The 2 cohorts of "EAT" and "Locals" patients were statistically comparable, particularly in morbidity. Conclusions: EAT appears to be safe after transpleural surgery, following usual criteria for hospital discharge. It would be interesting to study, on a larger scale, the effect of IPAL as an independent risk factor (in case of high IPAL > 10) as well as pathologies that modify transpleural pressures restrictive ventilatory defect.

Identification of von Willebrand factor D4 domain mutations in patients of Afro-Caribbean descent: In vitro characterization.

Background: Von Willebrand disease was diagnosed in two Afro-Caribbean patients and sequencing of the VWF gene (VWF) revealed the presence of multiple variants located throughout the gene, including variants located in the D4 domain of VWF: p.(Pro2145Thrfs*5) in one patient and p.(Cys2216Phefs*9) in the other patient. Interestingly, D4 variants have not been studied often. Objectives: Our goal was to characterize how the D4 variants p.(Pro2145Thrfs*5) and p.(Cys2216Phefs*9) influenced VWF biosynthesis/secretion and functions using in vitro assays. Methods: Recombinant VWF (rVWF), mutant or wild-type, was produced via transient transfection of the human embryonic kidney cell line 293T. The use of different tags for the wild-type and the mutant allele allowed us to distinguish between the two forms when measuring VWF antigen in medium and cell lysates. Binding of rVWF to its ligands, collagen, factor VIII, ADAMTS13, and platelet receptors was also investigated. Results: Homozygous expression of the p.(Cys2216Phefs*9)-rVWF mutation resulted in an almost complete intracellular retention of the protein. Heterozygous expression led to secretion of almost exclusively wild-type-rVWF, logically capable of normal interaction with the different ligands. In contrast, the p.(Pro2145Thrfs*5)-rVWF exhibited reduced binding to type III collagen and αIIbß3 integrin compared to wild-type-rVWF. Conclusions: We report two mutations of the D4 domains that induced combined qualitative and quantitative defects.