Most vertebrates can synthesize vitamin C with synthesis increasing during stress. Humans, however, have lost the ability to synthesize vitamin C. Vitamin C is an important anti-oxidant and an enzyme ...cofactor for many important biological reactions. Sepsis results in the overwhelming production of reactive oxygen species with widespread endothelial, cellular and mitochondrial injury leading to progressive organ failure. Sepsis is associated with an acute deficiency of vitamin C. In experimental sepsis models, intravenous vitamin C reduces organ injury and improves survival. In addition, emerging evidence suggests that the combination of vitamin C, corticosteroids and thiamine may act synergistically to reverse sepsis induced organ dysfunction. These findings are supported by a recent observational study. Randomized controlled trials are underway to investigate this novel approach to the treatment of sepsis.
Stress hyperglycemia is common in critically ill patients and appears to be a marker of disease severity. Furthermore, both the admission as well as the mean glucose level during the hospital stay is ...strongly associated with patient outcomes. Clinicians, researchers and policy makers have assumed this association to be causal with the widespread adoption of protocols and programs for tight in-hospital glycemic control. However, a critical appraisal of the literature has demonstrated that attempts at tight glycemic control in both ICU and non-ICU patients do not improve health care outcomes. We suggest that hyperglycemia and insulin resistance in the setting of acute illness is an evolutionarily preserved adaptive responsive that increases the host's chances of survival. Furthermore, attempts to interfere with this exceedingly complex multi-system adaptive response may be harmful. This paper reviews the pathophysiology of stress hyperglycemia and insulin resistance and the protective role of stress hyperglycemia during acute illness.
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.
Despite a previous meta-analysis that concluded that central venous pressure should not be used to make clinical decisions regarding fluid management, central venous pressure continues to be ...recommended for this purpose.
To perform an updated meta-analysis incorporating recent studies that investigated indices predictive of fluid responsiveness. A priori subgroup analysis was planned according to the location where the study was performed (ICU or operating room).
MEDLINE, EMBASE, Cochrane Register of Controlled Trials, and citation review of relevant primary and review articles.
Clinical trials that reported the correlation coefficient or area under the receiver operating characteristic curve (AUC) between the central venous pressure and change in cardiac performance following an intervention that altered cardiac preload. From 191 articles screened, 43 studies met our inclusion criteria and were included for data extraction. The studies included human adult subjects, and included healthy controls (n = 1) and ICU (n = 22) and operating room (n = 20) patients.
Data were abstracted on study characteristics, patient population, baseline central venous pressure, the correlation coefficient, and/or the AUC between central venous pressure and change in stroke volume index/cardiac index and the percentage of fluid responders. Meta-analytic techniques were used to summarize the data.
Overall 57% ± 13% of patients were fluid responders. The summary AUC was 0.56 (95% CI, 0.54-0.58) with no heterogenicity between studies. The summary AUC was 0.56 (95% CI, 0.52-0.60) for those studies done in the ICU and 0.56 (95% CI, 0.54-0.58) for those done in the operating room. The summary correlation coefficient between the baseline central venous pressure and change in stroke volume index/cardiac index was 0.18 (95% CI, 0.1-0.25), being 0.28 (95% CI, 0.16-0.40) in the ICU patients, and 0.11 (95% CI, 0.02-0.21) in the operating room patients.
There are no data to support the widespread practice of using central venous pressure to guide fluid therapy. This approach to fluid resuscitation should be abandoned.
Patients who have had an unprovoked deep venous thrombosis (DVT) or pulmonary embolus (PE) are at a high risk for recurrent venous thromboembolism (VTE). Extended "life-long" anticoagulation has been ...recommended in these patients. However, the risk benefit ratio of this approach is controversial and the role of the direct oral anticoagulants (DOACs) and aspirin is unclear. Furthermore, in some patients with a "weak provoking factor" there is clinical equipoise regarding continuation or cessation of anticoagulant therapy after treatment of the acute VTE event.
A systematic review and meta-analysis to determine the risks (major bleeding) and benefits (recurrent VTE and mortality) of extended anticoagulation with vitamin k antagonists (VKA), DOACs and aspirin in patients with an unprovoked VTE and in those patients with clinical equipoise regarding continuation or cessation of anticoagulant therapy. In addition, we sought to determine the risk of recurrent VTE events once extended anti-thrombotic therapy was discontinued.
MEDLINE, Cochrane Register of Controlled Trials, citation review of relevant primary and review articles.
Randomized placebo-controlled trials (RCTs) that compared the risk of recurrent VTE in patients with an unprovoked DVT or PE who had been treated for at least 3 months with a VKA or a DOAC and were then randomized to receive an oral anti-thrombotic agent or placebo for at least 6 additional months. We included studies that included patients in whom clinical equipoise existed regarding the continuation or cessation of anticoagulant therapy.
Independent extraction of articles by both authors using predefined data fields, including study quality indicators. Data were abstracted on study size, study setting, initial event (DVT or PE), percentage of patients where the initial VTE event was unprovoked, the number of recurrent VTE events, major bleeds and mortality during the period of extended anticoagulation in the active treatment and placebo arms. In addition, we recorded the event rate once extended treatment was stopped. Meta-analytic techniques were used to summarize the data. Studies were grouped according to the type of anti-thrombotic agent.
Seven studies which enrolled 6778 patients met our inclusion criteria; two studies evaluated the extended use of Coumadin, three studies evaluated a DOAC and two studies evaluated the use of aspirin. The duration of followup varied from 6 to 37 months. In the Coumadin and aspirin studies 100% of the randomized patients had an unprovoked VTE, while in the DOAC studies between 73.5% and 93.2% of the VTE events were unprovoked. In the control group recurrent VTE occurred in 9.7% of patients compared to 2.8% in the active treatment group (OR 0.21; 95% CI 0.11-0.42, p<0.0001). VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with VKA and DOACs being significantly more effective than aspirin. Major bleeding events occurred in 12 patients in the control group (0.4%) and 25 of 3815 (0.6%) patients in the active treatment group (OR 1.64; 95% CI 0.69-3.90, NS). There were 39 (1.3%) deaths in control patients and 33 (0.9%) deaths in the anti-thrombotic group during the treatment period (OR 0.73; 95% CI 0.40-1.33, NS). Patients whose initial VTE event was a PE were more likely to have a recurrent PE than a DVT. The annualized event rate after discontinuation of extended antithrombotic therapy was 4.4% in the control group and 6.5% in the active treatment arm.
VKA, DOACs and aspirin significantly reduced the risk of recurrent VTE, with DOACs and VKA being more effective than aspirin. The decision regarding life-long anticoagulation following an unprovoked DVT or PE should depend on the patients' risk for recurrent PE as well as the patients' values and preferences.
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.
The diagnosis of adrenal failure and the indications for corticosteroid therapy in critically ill patients are controversial.
This controversy is fueled by the complexity of the issues and the ...paucity of data from high quality clinical trials. Nevertheless,
while the use of high-dose corticosteroids in patients with severe sepsis and ARDS failed to improve outcome and was associated
with increased complications, an extended course of stress-dose corticosteroids has been reported to increase the occurrence
of ventilator-free days and survival in select groups of ICU patients. These patients typically have an exaggerated proinflammatory
response. Until recently the exaggerated proinflammatory response that characterizes critically ill patients with systemic
inflammation has focused on suppression of the hypothalamic-pituitary-adrenal axis and adrenal failure. However, experimental
and clinical data suggest that glucocorticoid tissue resistance may also play an important role. This complex syndrome is
referred to as critical illness-related corticosteroid insufficiency (CIRCI) and is defined as inadequate corticosteroid activity
for the severity of the illness of a patient. The paper reviews cortisol physiology, CIRCI, and the role of corticosteroid
therapy in critically ill patients.
adrenal failure
ARDS
corticosteroid insufficiency
cortisol
critical illness
glucocorticoid receptor
sepsis
septic shock
systemic inflammatory response syndrome
The global burden of sepsis is estimated as 15 to 19 million cases annually, with a mortality rate approaching 60% in low-income countries.
In this retrospective before-after clinical study, we ...compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome.
There were 47 patients in both treatment and control groups, with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04-0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure. All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group (P < .001).
Our results suggest that the early use of intravenous vitamin C, together with corticosteroids and thiamine, are effective in preventing progressive organ dysfunction, including acute kidney injury, and in reducing the mortality of patients with severe sepsis and septic shock. Additional studies are required to confirm these preliminary findings.
Central venous pressure (CVP) is used almost universally to guide fluid therapy in hospitalized patients. Both historical and recent data suggest that this approach may be flawed.
A systematic review ...of the literature to determine the following: (1) the relationship between CVP and blood volume, (2) the ability of CVP to predict fluid responsiveness, and (3) the ability of the change in CVP (ΔCVP) to predict fluid responsiveness.
MEDLINE, Embase, Cochrane Register of Controlled Trials, and citation review of relevant primary and review articles.
Reported clinical trials that evaluated either the relationship between CVP and blood volume or reported the associated between CVP/ΔCVP and the change in stroke volume/cardiac index following a fluid challenge. From 213 articles screened, 24 studies met our inclusion criteria and were included for data extraction. The studies included human adult subjects, healthy control subjects, and ICU and operating room patients.
Data were abstracted on study design, study size, study setting, patient population, correlation coefficient between CVP and blood volume, correlation coefficient (or receive operator characteristic ROC) between CVP/ΔCVP and change in stroke index/cardiac index, percentage of patients who responded to a fluid challenge, and baseline CVP of the fluid responders and nonresponders. Metaanalytic techniques were used to pool data.
The 24 studies included 803 patients; 5 studies compared CVP with measured circulating blood volume, while 19 studies determined the relationship between CVP/ΔCVP and change in cardiac performance following a fluid challenge. The pooled correlation coefficient between CVP and measured blood volume was 0.16 (95% confidence interval CI, 0.03 to 0.28). Overall, 56 ± 16% of the patients included in this review responded to a fluid challenge. The pooled correlation coefficient between baseline CVP and change in stroke index/cardiac index was 0.18 (95% CI, 0.08 to 0.28). The pooled area under the ROC curve was 0.56 (95% CI, 0.51 to 0.61). The pooled correlation between ΔCVP and change in stroke index/cardiac index was 0.11 (95% CI, 0.015 to 0.21). Baseline CVP was 8.7 ± 2.32 mm Hg mean ± SD in the responders as compared to 9.7 ± 2.2 mm Hg in nonresponders (not significant).
This systematic review demonstrated a very poor relationship between CVP and blood volume as well as the inability of CVP/ΔCVP to predict the hemodynamic response to a fluid challenge. CVP should not be used to make clinical decisions regarding fluid management.
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.
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 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.
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.
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.
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