Search

Cancer is amenable to low-cost treatments, given that it has a significant metabolic component, which can be affected through diet and lifestyle change at minimal cost. The Warburg hypothesis states that cancer cells have an altered cell metabolism towards anaerobic glycolysis. Given this metabolic reprogramming in cancer cells, it is possible to target cancers metabolically by depriving them of glucose. In addition to dietary and lifestyle modifications which work on tumors metabolically, there are a panoply of nutritional supplements and repurposed drugs associated with cancer prevention and better treatment outcomes. These interventions and their evidentiary basis are covered in the latter half of this review to guide future cancer treatment.

In December 2019, coronavirus disease 2019 (COVID-19), a severe respiratory illness caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of "what was working and what wasn't working", the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and non-antiviral co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro , pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically., Competing Interests: The authors declare that there is no conflict of interest., (Copyright 2022, Kory et al.)

Background: The relationship between computed tomography (CT) and prognosis of patients with COVID-19 pneumonia remains unclear. We hypothesized that the Ichikado CT score, obtained in the first 24 h of hospital admission, is an independent predictor for all-cause mortality during hospitalization in patients with COVID-19 pneumonia., Methods: Single-center retrospective cohort study of patients with confirmed COVID-19 pneumonia admitted at our institution between March 20th, 2020 and October 31st, 2020. Patients were enrolled if, within 24 h of admission, a chest CT scan, an arterial blood gas, a complete blood count, and a basic metabolic panel were performed. Two independent radiologists, who were blinded to clinical data, retrospectively evaluated the chest CT scans following a previously described qualitative and quantitative CT scoring system. The primary outcome was all-cause in-hospital mortality or survival to hospital discharge. Secondary outcomes were new requirements for invasive mechanical ventilation and hospital length of stay. Cox regression models were used to test the association between potential independent predictors and all-cause mortality., Results: Two hundred thirty-five patients, 197 survivors and 38 nonsurvivors, were studied. The median Ichikado CT score for nonsurvivors was significantly higher than survivors (P < 0.001). An Ichikado CT score of more than 172 enabled prediction of mortality, with a sensitivity of 84.2% and a specificity of 79.7%. Multivariate analysis identified Ichikado CT score (HR, 7.772; 95% CI, 3.164-19.095; P < 0.001), together with age (HR, 1.030; 95% CI, 1.030-1.060; P = 0.043), as independent predictors of all-cause in-hospital mortality., Conclusions: Ichikado CT score is an independent predictor of both requiring invasive mechanical ventilation and all-cause mortality in patients hospitalized with COVID-19 pneumonia. Further prospective evaluation is necessary to confirm these findings., Trial Registration: The WCG institutional review board approved this retrospective study and patient consent was waived due to its non-interventional nature (Identifier: 20210799)., (© 2021. The Author(s).)

Acute lung injury (ALI) leading to acute respiratory distress syndrome is the major cause of COVID-19 lethality. Cell entry of SARS-CoV-2 occurs via the interaction between its surface spike protein (SP) and angiotensin-converting enzyme-2 (ACE2). It is unknown if the viral spike protein alone is capable of altering lung vascular permeability in the lungs or producing lung injury in vivo. To that end, we intratracheally instilled the S1 subunit of SARS-CoV-2 spike protein (S1SP) in K18-hACE2 transgenic mice that overexpress human ACE2 and examined signs of COVID-19-associated lung injury 72 h later. Controls included K18-hACE2 mice that received saline or the intact SP and wild-type (WT) mice that received S1SP. K18-hACE2 mice instilled with S1SP exhibited a decline in body weight, dramatically increased white blood cells and protein concentrations in bronchoalveolar lavage fluid (BALF), upregulation of multiple inflammatory cytokines in BALF and serum, histological evidence of lung injury, and activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways in the lung. K18-hACE2 mice that received either saline or SP exhibited little or no evidence of lung injury. WT mice that received S1SP exhibited a milder form of COVID-19 symptoms, compared with the K18-hACE2 mice. Furthermore, S1SP, but not SP, decreased cultured human pulmonary microvascular transendothelial resistance (TER) and barrier function. This is the first demonstration of a COVID-19-like response by an essential virus-encoded protein by SARS-CoV-2 in vivo. This model of COVID-19-induced ALI may assist in the investigation of new therapeutic approaches for the management of COVID-19 and other coronaviruses.

Background: After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials., Areas of Uncertainty: The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses., Data Sources: Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns., Therapeutic Advances: A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns., Conclusions: Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly reduced risks of contracting COVID-19 with the regular use of ivermectin. Finally, the many examples of ivermectin distribution campaigns leading to rapid population-wide decreases in morbidity and mortality indicate that an oral agent effective in all phases of COVID-19 has been identified., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Studies reported to date suggest that men with COVID-19 have more severe disease and worse outcomes when compared with women. The explanation for this finding is not entirely clear. The goal of this study was to compare clinical characteristics, inflammatory biomarkers and clinical outcome between men and women. This retrospective study included patients with COVID-19 admitted to 10 Virginia hospitals from January 1, 2020, to June 15, 2020. Demographic data, comorbidities, and inflammatory markers, including C reactive protein (CRP), D-dimer, ferritin, and the neutrophil:lymphocyte ratio, as well as patient outcomes, were compared between men and women. During the study period, 701 patients with PCR-confirmed COVID-19 infection were admitted. The patient's mean age was 61±17 years. There were 370 men (52.8%). There was no difference in age, racial distribution, and comorbidities in the male patients compared with the female patients. However, both the baseline and peak levels of CRP and ferritin were significantly higher in men as compared with women. While the baseline D-dimer was similar between the sexes, men had a significantly higher maximal D-dimer. Men had evidence of greater disease severity, with a significantly greater admission to the intensive care unit and borderline higher hospital mortality. Our study supports the observation that COVID-19 causes more severe disease in men. The greater disease severity in men was not due to the effect of age or comorbidities; however, in keeping with experimental studies, men had evidence of a heightened inflammatory response, likely contributing to disease severity., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

A before-after-before direct comparison between catheters lined with chlorhexidine and silver sulfadiazine (CHSS) versus silver ionotrophes (SI) with a primary objective of comparison of rate of central-line-associated infection (CLABSI) in three 10-month windows. The CHSS catheters were associated with a lower rate of CLABSI.

Introduction: COVID-19 disease progresses through a number of distinct phases. The management of each phase is unique and specific. The pulmonary phase of COVID-19 is characterized by an organizing pneumonia with profound immune dysregulation, activation of clotting, and a severe microvascular injury culminating in severe hypoxemia. The core treatment strategy to manage the pulmonary phase includes the combination of methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+ protocol). The rationale for the MATH+ protocol is reviewed in this paper., Areas Covered: We provide an overview on the pathophysiological changes occurring in patients with COVID-19 respiratory failure and a treatment strategy to reverse these changes thereby preventing progressive lung injury and death., Expert Opinion: While there is no single 'Silver Bullet' to cure COVID-19, we believe that the severely disturbed pathological processes leading to respiratory failure in patients with COVID-19 organizing pneumonia will respond to the combination of Methylprednisone, Ascorbic acid, Thiamine, and full anticoagulation with Heparin (MATH+ protocol).We believe that it is no longer ethically acceptable to limit management to 'supportive care' alone, in the face of effective, safe, and inexpensive medications that can effectively treat this disease and thereby reduce the risk of complications and death.

In December 2019, COVID-19, a severe respiratory illness caused by the new coronavirus SARS-CoV-2 (COVID-19) emerged in Wuhan, China. The greatest impact that COVID-19 had was on intensive care units (ICUs), given that approximately 20% of hospitalized cases developed acute respiratory failure (ARF) requiring ICU admission. Based on the assumption that COVID-19 represented a viral pneumonia and no anti-coronaviral therapy existed, nearly all national and international health care societies' recommended "supportive care only" avoiding other therapies outside of randomized controlled trials, with a specific prohibition against the use of corticosteroids in treatment. However, early studies of COVID-19-associated ARF reported inexplicably high mortality rates, with frequent prolonged durations of mechanical ventilation (MV), even from centers expert in such supportive care strategies. These reports led the authors to form a clinical expert panel called the Front-Line COVID-19 Critical Care Alliance (www.flccc.net). The panel collaboratively reviewed the emerging clinical, radiographic, and pathological reports of COVID-19 while initiating multiple discussions among a wide clinical network of front-line clinical ICU experts from initial outbreak areas in China, Italy, and New York. Based on the shared early impressions of " what was working and what wasn't working, " the increasing medical journal publications and the rapidly accumulating personal clinical experiences with COVID-19 patients, a treatment protocol was created for the hospitalized patients based on the core therapies of methylprednisolone, ascorbic acid, thiamine, heparin and co-interventions (MATH+). This manuscript reviews the scientific and clinical rationale behind MATH+ based on published in-vitro, pre-clinical, and clinical data in support of each medicine, with a special emphasis of studies supporting their use in the treatment of patients with viral syndromes and COVID-19 specifically. The review concludes with a comparison of published multi-national mortality data with MATH+ center outcomes.

COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-inflammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.

There are limited proven therapies for COVID-19. Vitamin C's antioxidant, anti-inflammatory and immunomodulating effects make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19. This literature review focuses on vitamin C deficiency in respiratory infections, including COVID-19, and the mechanisms of action in infectious disease, including support of the stress response, its role in preventing and treating colds and pneumonia, and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2-8 g/day) may reduce the incidence and duration of respiratory infections and intravenous vitamin C (6-24 g/day) has been shown to reduce mortality, intensive care unit (ICU) and hospital stays, and time on mechanical ventilation for severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and the frequency of vitamin C deficiency in respiratory infections, it may be worthwhile testing patients' vitamin C status and treating them accordingly with intravenous administration within ICUs and oral administration in hospitalised persons with COVID-19.

Background: The COVID-19 pandemic has placed an enormous and growing burden on the population and health infrastructure, warranting innovative ways to mitigate risk of contracting and developing severe forms of this disease. A growing body of literature raises the issue of vitamin C and vitamin D as a risk-assessment tool, and therapeutic option, in COVID-19., Objective: The objective of this pilot study was to measure serum vitamin C and vitamin D levels in a cohort of patients with critical COVID-19 illness in our community hospital ICU, correlate with other illness risk factors (age, BMI, HgbA1c, smoking status), generate hypotheses, and suggest further therapeutic intervention studies., Method: This pilot study included all 21 critically ill COVID-19 patients hospitalized in May 2020 in the ICU of North Suburban Medical Center, Thornton, Colorado, in whose care the principal investigator (C.A.) was involved. We measured patients' serum vitamin C and vitamin D levels, and standard risk factors like age, BMI, HbA1c, and smoking status. Variables in this study were gauged using descriptive statistics., Results: Of 21 critically ill COVID-19 patients (15 males and 6 females, 17 Hispanic and 4 Caucasian, of median age 61 years, range 20-94), there were 11 survivors.Serum levels of vitamin C and vitamin D were low in most of our critically ill COVID-19 ICU patients.Older age and low vitamin C level appeared co-dependent risk factors for mortality from COVID-19 in our sample.Insulin resistance and obesity were prevalent in our small cohort, but smoking was not., Conclusion: Our pilot study found low serum levels of vitamin C and vitamin D in most of our critically ill COVID-19 ICU patients. Older age and low vitamin C level appeared co-dependent risk factors for mortality. Many were also insulin-resistant or diabetic, overweight or obese, known as independent risk factors for low vitamin C and vitamin D levels, and for COVID-19.These findings suggest the need to further explore whether caring for COVID-19 patients ought to routinely include measuring and correcting serum vitamin C and vitamin D levels, and whether treating critically ill COVID-19 warrants acute parenteral vitamin C and vitamin D replacement., Competing Interests: The authors of this paper have had no conflicts of interest in conducting and publishing this research., (© 2020 The Authors.)

Background: The global burden of death due to sepsis is considerable. Early diagnosis is essential to improve the outcome of this deadly syndrome. Yet, the diagnosis of sepsis is fraught with difficulties. Patients with blood stream infection (BSI) are at an increased risk of complications and death. The aim of this study was to determine the diagnostic accuracy of four readily available biomarkers to diagnose BSI in patients with suspected sepsis., Methods: In this retrospective, observational, Electronic Medical Record based study we compared the accuracy of procalcitonin (PCT), serum lactate concentration, total white blood cell (WBC) count and the neutrophil-lymphocyte count ratio (NLCR) to diagnose BSI in adult patients presenting to hospital with suspected sepsis. Based on the blood culture results patients were classified into 1 of the following 5 groups: i) negative blood cultures, ii) positive for a bacterial pathogen, iii) positive for a potential pathogen, iv) fungal pathogen and v) potential contaminant. Group 2 was further divided into Gram -ve and Gram +ve pathogens. Receiver operating characteristic (ROC) curves were constructed to compare the diagnostic performance of the biomarkers., Results: There were 1767 discreet patient admissions. The median PCT concentration differed significantly across blood culture groups (p < 0.0001). The highest median PCT concentration was observed in patients with a Gram-negative pathogen (17.1 ng/mL; IQR 3.6-49.7) and the lowest PCT in patients with negative blood cultures (0.6 ng/mL; IQR 0.2-2.8). The AUROC was 0.83 (0.79-0.86) for PCT, 0.68 (0.64-0.72) for the NLCR, 0.55 (0.51-0.60) for lactate concentration and 0.52 (0.48-0.57) for the WBC count. The AUROC for PCT was significantly greater than that of the NLCR (p < 0.0001). A PCT less than 0.5 ng/mL had a negative predictive value of 95% for excluding BSI. The best cut-off value of PCT for predicting BSI was 1.5 ng/ml., Conclusion: Our results suggest that PCT of less than 0.5 ng/mL may be an effective screening tool to exclude BSI as the cause of sepsis, while the diagnosis of BSI should be considered in patients with a PCT above this threshold. The total WBC count and blood lactate concentration may not be reliable biomarkers for the diagnosis of BSI. The NLCR may be a useful screening test for BSI when PCT assays are not available., Competing Interests: Declaration of Competing Interest None of the authors has any competing interests in the manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents an emergent global threat which is straining worldwide healthcare capacity. As of May 27th, the disease caused by SARS-CoV-2 (COVID-19) has resulted in more than 340,000 deaths worldwide, with 100,000 deaths in the US alone. It is imperative to study and develop pharmacological treatments suitable for the prevention and treatment of COVID-19. Ascorbic acid is a crucial vitamin necessary for the correct functioning of the immune system. It plays a role in stress response and has shown promising results when administered to the critically ill. Quercetin is a well-known flavonoid whose antiviral properties have been investigated in numerous studies. There is evidence that vitamin C and quercetin co-administration exerts a synergistic antiviral action due to overlapping antiviral and immunomodulatory properties and the capacity of ascorbate to recycle quercetin, increasing its efficacy. Safe, cheap interventions which have a sound biological rationale should be prioritized for experimental use in the current context of a global health pandemic. We present the current evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients as an adjunct to promising pharmacological agents such as Remdesivir or convalescent plasma., (Copyright © 2020 Colunga Biancatelli, Berrill, Catravas and Marik.)

Background: Copper-oxide-impregnated linens and hard surfaces within the hospital environment have emerged as a novel technology to reduce environmental contamination and thereby potentially reduce the risk of healthcare-associated infections (HCAIs)., Methods: This was a two-phase study. Phase 1 was a prospective, cluster-randomized, cross-over clinical trial in which one pod (eight beds) of our general ICU (GICU) utilized copper-oxide-impregnated linens whereas the other pod (eight beds) used standard hospital linens. Phase 2 was a two-year before-after study, following the relocation of three ICUs into a new ICU tower in which all the hard surfaces were treated with copper oxide (in addition to copper-impregnated linens). HCAIs were recorded using the National Healthcare Safety Network definitions., Findings: A total of 1282 patients were enrolled in phase 1. There was no difference in the rate of HCAI between the patients who received standard compared with copper oxide linen. In phase 2 there was a significant reduction in the number of infections due to Clostridioides difficile (2.4 per 1000 vs 0.7 per 1000 patient-days; incidence rate ratio: 3.3; 95% confidence interval: 1.4-8.7; P = 0.002) but no difference in the rate of central-line-associated bloodstream infections nor of catheter-associated urinary tract infections., Conclusion: Copper-oxide-impregnated linens alone had no effect on the rate of HCAI. Our data suggest that copper-oxide-treated hard surfaces reduced the rate of infections due to C. difficile; however, important confounders cannot be excluded., (Copyright © 2020 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

The coronavirus, COVID-19, has infected hundreds of thousands and killed tens of thousands of individuals worldwide. This highly infectious condition continues to ravage the world population and has yet to reach it peak infective rate in some countries. Many conventional drugs including hydroxychloroquine/chloroquine, lopinavir, remdesivir, etc., have been repurposed as treatments for this often deadly disease, but there is no specifically-designed effective drug available; also, the drugs mentioned have significant side effects and their efficacy is unknown. New drugs and vaccines are being designed as COVID-19 treatment, but their development and testing will require months to years. Time is not a luxury that this crisis has. Thus, there is a serious unmet need for the identification of currently-available and safe molecules which can be used to slow or treat COVID-19 disease. Here, we suggest melatonin be given consideration for prophylactic use or treatment alone or in combination with other drugs. Melatonin's multiple actions as an anti-inflammatory, anti-oxidant, and anti-viral (against other viruses) make it a reasonable choice for use. Melatonin is readily available, can be easily synthesized in large quantities, is inexpensive, has a very high safety profile and can be easily self-administered. Melatonin is endogenously-produced molecule in small amounts with its production diminishing with increased age. Under the current critical conditions, large doses of melatonin alone or in combination with currently-recommended drugs, e.g., hydroxychloroquine/chloroquine, to resist COVID-19 infection would seem judicious., (Copyright © 2020 Reiter, Abreu-Gonzalez, Marik and Dominguez-Rodriguez.)

Background: Optimal fluid therapy in the perioperative and critical care settings depends on understanding the underlying cardiovascular physiology and individualizing assessment of the dynamic patient state., Methods: The Perioperative Quality Initiative (POQI-5) consensus conference brought together an international team of multidisciplinary experts to survey and evaluate the literature on the physiology of volume responsiveness and perioperative fluid management. The group used a modified Delphi method to develop consensus statements applicable to the physiologically based management of intravenous fluid therapy in the perioperative setting., Discussion: We discussed the clinical and physiological evidence underlying fluid responsiveness and venous capacitance as relevant factors in fluid management and developed consensus statements with clinical implications for a broad group of clinicians involved in intravenous fluid therapy. Two key concepts emerged as follows: (1) The ultimate goal of fluid therapy and hemodynamic management is to support the conditions that enable normal cellular metabolic function in order to produce optimal patient outcomes, and (2) optimal fluid and hemodynamic management is dependent on an understanding of the relationship between pressure, volume, and flow in a dynamic system which is distensible with variable elastance and capacitance properties., Competing Interests: Competing interestsGSM - none; DAK - grant funding and travel reimbursement for Cheetah Medical, Advisory Board and speaker honoraria for Pulsion Medical Systems; PEM - advisory board and research funding from Baxter; NS - none ; DL - none; JW – none; DBM – none; DC - Speakers Bureau for Edwards Lifesciences, Medtronic; JL – none; TW – none; KM – none; MLNGM – xxx; TMW – none; DM – consultant for Edwards Lifesciences and Siemens Healthineers; CHEI – none; MWM – none; HH – none; MPWG – research funding from Sphere Medical Ltd (UK) and Pharmacosmos Ltd (UK), advisory board of Sphere Medical Ltd.; MGM - University Chair Sponsor at UCL by Smiths Medical, Director Evidence Based Perioperative Medicine (EBPOM) Community Interest Company (CiC), Director Medinspire Ltd (Patent holder “QUENCH”), Paid consultant for Edwards Lifesciences and Baxter; TJG - Consultant for Acacia, Edwards Lifesciences, Mallinckrodt, Medtronic and Merck; TEM – research funding and consultant for Edwards Lifesciences., (© The Author(s) 2020.)

Large volume fluid resuscitation is currently viewed as the cornerstone of the treatment of septic shock. The surviving sepsis campaign (SSC) guidelines provide a strong recommendation to rapidly administer a minimum of 30 mL/kg crystalloid solution intravenously in all patients with septic shock and those with elevated blood lactate levels. However, there is no credible evidence to support this recommendation. In fact, recent findings from experimental, observational and randomized clinical trials demonstrate improved outcomes with a more restrictive approach to fluid resuscitation. Accumulating evidence suggests that aggressive fluid resuscitation is harmful. Paradoxically, excess fluid administration may worsen shock. In this review, we critically evaluate the scientific evidence for a weight-based fluid resuscitation approach. Furthermore, the potential mechanisms and consequences of harm associated with fluid resuscitation are discussed. Finally, we recommend an individualized, conservative and physiologic guided approach to fluid resuscitation., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Sepsis affects 30 million people worldwide, leading to 6 million deaths every year (WHO), and despite decades of research, novel initiatives are drastically needed. According to the current literature, oxidative imbalance and mitochondrial dysfunction are common features of septic patients that can cause multiorgan failure and death. Melatonin, alongside its traditionally accepted role as the master hormonal regulator of the circadian rhythm, is a promising adjunctive drug for sepsis through its anti-inflammatory, antiapoptotic and powerful antioxidant properties. Several animal models of sepsis have demonstrated that melatonin can prevent multiorgan dysfunction and improve survival through restoring mitochondrial electron transport chain (ETC) function, inhibiting nitric oxide synthesis and reducing cytokine production. The purpose of this article is to review the current evidence for the role of melatonin in sepsis, review its pharmacokinetic profile and virtual absence of side effects. While clinical data is limited, we propose the adjunctive use of melatonin is patients with severe sepsis and septic shock., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

The stress response is a preserved evolutionary response that functions to enhance the survival of the species. In mammals, the stress response is characterized by activation of the HPA axis and sympathoadrenal system (SAS) as well as the increased synthesis and secretion of vitamin C. Cortisol, catecholamines, and vitamin C act synergistically to increase hemodynamic reserve, maintain immune function and protect the host against excessive oxidant injury. Humans (and anthropoid apes) have lost the ability to synthesize vitamin C and therefore have an impaired stress response. The inability to produce vitamin C has serious implications in septic humans. Treatment with vitamin C appears to restore the stress response and improve the survival of stressed humans., Competing Interests: Conflicts of Interest: The author has no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

Glucocorticoids (GC) in all its various forms and formulations are likely one of the most commonly used pharmacologic agents in medicine. Their use can be profoundly therapeutic but are also associated with a myriad of acute and chronic side effects. It is fairly well-accepted in the medical community that GC can be life-saving when used in critically ill patients with severe exacerbations of asthma and chronic obstructive pulmonary disease, HIV-associated pneumocystosis, and systemic vasculitides. However, the adjunctive role of GC is much more controversial in acute respiratory distress syndrome (ARDS), septic shock, community-acquired pneumonia, and several other serious medical conditions. Despite such controversies, GC should at least be considered for patients with fulminant manifestations of the following conditions as there is equipoise to indicate that GC may improve outcome with acceptable risks: (i) severe ARDS with refractory hypoxemia despite one to two weeks of state-of-the-art management, (ii) recalcitrant, vasopressor-dependent septic shock, (iii) non-influenza, severe community-acquired pneumonia, and (iv) severe alcoholic hepatitis. The bases for these controversies is likely due to both host factors (e.g., differences in GC resistance and susceptibility to adverse effects) and different phenotypes of any one disease state; e.g., different pathogenesis and pathogens under the rubric of "sepsis." Elucidation of better biomarkers to determine the underlying pathogenic phenotype will significantly advance our understanding and prediction of which critically ill patients will benefit from GC and who would experience a deleterious effect from its use., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The use of lactate as a marker of the severity of circulatory shock was popularized by Dr. Weil in the 1970's. Dr. Weil promoted the idea that blood lactate concentration increased in circulatory shock due to anaerobic metabolism following decreased oxygen delivery. This concept becomes entrenched with 1992 ACCP/SCCM consensus conference definition of sepsis. Since then, the central role of lactate in the definition and management of septic shock has only been expanded and become more ingrained. This review will discuss the wisdom of such an approach, an updated model describing the origins of hyperlactatemia in sepsis, and how such improvements in our knowledge of the underlying physiology should change our approach to resuscitation in patients presenting with septic shock., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2020 Journal of Thoracic Disease. All rights reserved.)

We present the case of a 33-year-old woman with no significant past medical history who was admitted to an outside hospital for the abrupt onset of fevers, malaise and a diffuse mucocutaneous rash. Her constellation of symptoms and presentation were most consistent with a diagnosis of Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome secondary to ibuprofen exposure. Her rash continued to worsen and she was transferred to our medical intensive care unit (ICU), where broad-spectrum antibiotics were discontinued and she was treated with supportive care as well as 'low-dose' intravenous hydrocortisone, ascorbic acid (vitamin C) and thiamine (HAT therapy). After starting this therapy, the patient demonstrated a dramatic response with rapid improvement of her cutaneous and mucosal lesions. She was tolerating a diet provided by the hospital on day 4 and was discharged from the ICU a few days later., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Hookah is a single-stemmed or multistemmed instrument for vaporizing and smoking flavored tobacco, whose smoke is passed through a water basin before inhalation. The use of hookah dates back centuries and is believed to have originated in India during the reign of Akbar the Great or the Safavid dynasty of Persia. Outside its native region, hookah smoking has gained popularity throughout the world, especially among younger people. There is generally a misconception among hookah users that it is less addictive than combustible cigarette smoking and that there is little to no nicotine content in hookah, with some even believing that certain additives impart health benefits. Although studies investigating the health hazards of hookah are rather limited, the inhaled smoke contains large quantities of nicotine, tar, carbon monoxide, polyaromatic hydrocarbons, heterocyclic compounds, carboxylic compounds, and various inorganic compounds such as heavy metals, all of which are found in combustible cigarette smoking. Regular hookah use is associated with an increased risk of obstructive lung disease as well as lung cancer and malignancies of the head and neck. This narrative review summarizes the available data on the health hazards of hookah, with an emphasis on pulmonary complications. Increased knowledge and awareness of hookah smoking among healthcare providers can potentially lead to better patient education and identification of at-risk populations.

Purpose of Review: Shock, best defined as acute circulatory failure is classified into four major groups, namely hypovolemic, cardiogenic, obstructive, and distributive (vasodilatory). The purpose of this review is to provide a practical approach to fluid optimization in patients with the four types of shock., Recent Findings: Large-volume fluid resuscitation has traditionally been regarded as the cornerstone of resuscitation of shocked patients. However, in many instances, aggressive fluid resuscitation may be harmful, increasing morbidity and mortality., Summary: We believe that the approach to fluid therapy must be individualized based on the cause of shock as well as the patient's major diagnosis, comorbidities and hemodynamic and respiratory status. A conservative, physiologically guided approach to fluid resuscitation likely improves patient outcomes.

Background: At least a third of the world's population consumes alcohol regularly. Patients with alcohol use disorders (AUDs) are frequently hospitalized for both alcohol-related and unrelated medical conditions. It is well recognized that patients with an AUD are thiamine deficient with thiamine replacement therapy being considered the standard of care. However, the incidence of vitamin C deficiency in this patient population has been poorly defined., Methods: In this retrospective, observational study, we recorded the admission vitamin C level in patients with an AUD admitted to our medical intensive care unit (MICU) over a 1-year period. In addition, we recorded relevant clinical and laboratory data including the day 2 and day 3 vitamin C level following empiric treatment with vitamin C. Septic patients were excluded from this study., Results: Sixty-nine patients met the inclusion criteria for this study. The patients' mean age was 53 ± 14 years; 52 patients (75%) were males. Severe alcohol withdrawal syndrome was the commonest admitting diagnosis (46%). Eighteen patients (26%) had cirrhosis as the admitting diagnosis with 18 (13%) patients admitted due to alcohol/drug intoxication. Forty-six patients (67%) had evidence of acute alcoholic hepatitis. The mean admission vitamin C level was 17.0 ± 18.1 μmol/l (normal 40-60 μmol/l). Sixty-one (88%) patients had a level less than 40 μmol/l (subnormal) while 52 patients (75%) had hypovitaminosis C (level < 23 μmol/l). None of the variables recorded predicted the vitamin C level. Various vitamin C replacement dosing strategies were used. A 1.5-g loading dose, followed by 500-mg PO q 6, was effective in restoring blood levels to normal by day 2., Conclusion: Our results suggest that hypovitaminosis C is exceedingly common in patients with an AUD admitted to an intensive care unit and that all such patients should receive supplementation with vitamin C in addition to thiamine. Additional studies are required to confirm the findings of our observational study and to determine the optimal vitamin C dosing strategy.

Sepsis is a devastating disease that carries an enormous toll in terms of human suffering and lives lost. Over 100 novel pharmacologic agents that targeted specific molecules or pathways have failed to improve the outcome of sepsis. Preliminary data suggests that the combination of Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) may reduce organ failure and mortality in patients with sepsis and septic shock. HAT therapy is based on the concept that a combination of readily available, safe and cheap agents, which target multiple components of the host's response to an infectious agent, will synergistically restore the dysregulated immune response and thereby prevent organ failure and death. This paper reviews the rationale for HAT therapy with a focus on vitamin C.

Background: In general, patients with sepsis die from the host response to the infecting pathogen rather than from the infecting pathogen itself. Four patterns of death have been identified in sepsis, namely vasoplegic shock, single-organ respiratory failure (acute respiratory distress syndrome [ARDS]), multi-system organ failure (MSOF), and persistent MSOF with ongoing inflammation and immunosuppression with recurrent infections (persistent inflammation-immunosuppression and catabolism syndrome [PICS]). To improve the outcome of sepsis adjunctive therapies that modulate the immune system have been tested; these therapies that have targeted specific molecules or pathways have universally failed. Conclusion: We propose that the combination of hydrocortisone, intravenous ascorbic acid, and thiamine (HAT therapy), which synergistically targets multiple pathways, restores the dysregulated immune system and organ injury, and reduces the risk of death and organ failure following sepsis.

The combination of thiamine, ascorbic acid, and hydrocortisone has recently emerged as a potential adjunctive therapy to antibiotics, infectious source control, and supportive care for patients with sepsis and septic shock. In the present manuscript, we provide a comprehensive review of the pathophysiologic basis and supporting research for each element of the thiamine, ascorbic acid, and hydrocortisone drug combination in sepsis. In addition, we describe potential areas of synergy between these therapies and discuss the strengths/weaknesses of the two studies to date which have evaluated the drug combination in patients with severe infection. Finally, we describe the current state of current clinical practice as it relates to the thiamine, ascorbic acid, and hydrocortisone combination and present an overview of the randomized, placebo-controlled, multi-center Ascorbic acid, Corticosteroids, and Thiamine in Sepsis (ACTS) trial and other planned/ongoing randomized clinical trials.