Revisiting resistant hypertension: a comprehensive review.

Resistant hypertension (RHT) is typically defined as blood pressure that remains above guideline-directed targets despite the use of three anti-hypertensives, usually including a diuretic, at optimal or maximally tolerated doses. It is generally estimated to affect 10-30% of those diagnosed with hypertension, though the true incidence might be lower after one factor in the prevalence of non-adherence. Risk factors for its development include diabetes, obesity and other adverse lifestyle factors, and a diagnosis of RHT confers a greater risk of adverse cardiovascular outcomes, such as stroke, heart failure and mortality. It is essential to exclude pseudoresistance and secondary hypertension and to ensure non-pharmacologic management is optimised prior to consideration of fourth-line anti-hypertensive agents or advanced interventions, such as device therapies. In this review, we will cover the different definitions of RHT, along with the importance of careful diagnosis and management strategies, and discuss newer agents and research needs.

Higher- versus Lower-Dose Corticosteroids for Severe to Critical COVID-19: A Systematic Review and Dose-Response Meta-analysis.

Rationale: Corticosteroids are standard of care for patients with severe coronavirus disease (COVID-19). However, the optimal dose is uncertain. Objectives: To compare higher doses of corticosteroids with lower doses in patients with COVID-19. Methods: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, MedRxiv, and Web of Science from inception to August 1, 2022, for trials that randomized patients with severe-to-critical COVID-19 to corticosteroids, standard care, or placebo. Reviewers, working in duplicate, screened references, extracted data, and assessed risk of bias using a modified version of the Cochrane risk of bias 2.0 tool. We performed a dose-response meta-analysis and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess the certainty of evidence. We present our results both in relative risk and absolute risk difference per 1,000, with 95% confidence intervals (CIs). Results: We included 20 trials, with 10,155 patients. We show that, compared with lower-dose corticosteroids, higher-dose corticosteroids probably reduce mortality (absolute risk difference, 14 fewer deaths per 1,000 [95% CI, 26 fewer to 2 fewer]; moderate certainty) and may reduce the need for mechanical ventilation (absolute risk difference, 11.6 fewer per 1,000 [95% CI, 23.2 fewer to 6.9 more]; low certainty). The effect of corticosteroids on nosocomial infections is uncertain (16.7 fewer infections per 1,000 [95% CI, 5.4 fewer to 25.0 fewer]; very low certainty). Conclusions: Relatively higher doses of corticosteroids may be beneficial in patients with severe-to-critical COVID-19 and may not increase the risk of nosocomial infections.

Management of Intermittent Hemodialysis in the Critically Ill Patient.

Intermittent hemodialysis remains a cornerstone of extracorporeal KRT in the intensive care unit, either as a first-line therapy for AKI or a second-line therapy when patients transition from a continuous or prolonged intermittent therapy. Intermittent hemodialysis is usually provided 3 days per week in this setting on the basis that no clinical benefits have been demonstrated with more frequent hemodialysis. This should not detract from the importance of continually assessing and refining the hemodialysis prescription (including the need for extra treatments) according to dynamic changes in extracellular volume and other parameters, and ensuring that an adequate dose of hemodialysis is being delivered to the patient. Compared with other KRT modalities, the cardinal challenge encountered during intermittent hemodialysis is hemodynamic instability. This phenomenon occurs when reductions in intravascular volume, as a consequence of ultrafiltration and/or osmotic shifts, outpace compensatory plasma refilling from the extravascular space. Myocardial stunning, triggered by intermittent hemodialysis, and independent of ultrafiltration, may also contribute. The hemodynamic effect of intermittent hemodialysis is likely magnified in patients who are critically ill due to an inability to mount sufficient compensatory physiologic responses in the context of multiorgan dysfunction. Of the many interventions that have undergone testing to mitigate hemodynamic instability related to KRT, the best evidence exists for cooling the dialysate and raising the dialysate sodium concentration. Unfortunately, the evidence supporting routine use of these and other interventions is weak owing to poor study quality and limited sample sizes. Intermittent hemodialysis will continue to be an important and commonly used KRT modality for AKI in patients with critical illness, especially in jurisdictions where resources are limited. There is an urgent need to harmonize the definition of hemodynamic instability related to KRT in clinical trials and robustly test strategies to combat it in this vulnerable patient population.

The Comparative Effectiveness of Vasoactive Treatments for Hepatorenal Syndrome: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Hepatorenal syndrome (HRS) is associated with high rates of morbidity and mortality. Evidence examining commonly used drug treatments remains uncertain. We assessed the comparative effectiveness of inpatient treatments for HRS by performing a network meta-analysis of randomized clinical trials (RCTs). DATA SOURCES: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process & Other Non-Indexed Citations, Scopus, and Web of Science from inception. STUDY SELECTION AND DATA EXTRACTION: Pairs of reviewers independently identified eligible RCTs that enrolled patients with type 1 or 2 HRS. Pairs of reviewers independently extracted data. DATA SYNTHESIS: We assessed risk of bias using the Cochrane tool for RCTs and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. Our main outcomes are all-cause mortality, HRS reversal, and serious adverse events. Of 3,079 citations, we included 26 RCTs examining 1,736 patients. Based on pooled analysis, terlipressin increases HRS reversal compared with placebo (142 reversals per 1,000 [95% CI, >87.7 to >210.9]; high certainty). Norepinephrine (112.7 reversals per 1,000 [95% CI, 52.6 to >192.3]) may increase HRS reversal compared with placebo (low certainty). The effect of midodrine+octreotide (67.8 reversals per 1,000 [95% CI, <2.8 to >177.4]; very low) on HRS reversal is uncertain. Terlipressin may reduce mortality compared with placebo (93.7 fewer deaths [95% CI, 168.7 to <12.5]; low certainty). Terlipressin probably increases the risk of serious adverse events compared with placebo (20.4 more events per 1,000 [95% CI, <5.1 to >51]; moderate certainty). CONCLUSIONS: Terlipressin increases HRS reversal compared with placebo. Terlipressin may reduce mortality. Until access to terlipressin improves, initial norepinephrine administration may be more appropriate than initial trial with midodrine+octreotide. Our review has the potential to inform future guideline and practice in the treatment of HRS.

Medical treatments for idiopathic pulmonary fibrosis: a systematic review and network meta-analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied IPF drug treatments. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov from inception to 2 April 2021. We included randomised controlled trials (RCTs) for adult patients with IPF receiving one or more of 22 drug treatments. Pairs of reviewers independently identified randomised trials that compared one or more of the target medical treatments in patients with IPF. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analysis. We calculated pooled relative risk (RR) ratios and presented direct or network estimates with 95% credibility intervals (95% CI), within the GRADE framework. RESULTS: We identified 48 (10 326 patients) eligible studies for analysis. Nintedanib [RR 0.69 (0.44 to 1.1), pirfenidone [RR 0.63 (0.37 to 1.09); direct estimate), and sildenafil [RR (0.44 (0.16 to 1.09)] probably reduce mortality (all moderate certainty). Nintedanib (2.92% (1.51 to 4.14)), nintedanib+sildenafil (157 mL (-88.35 to 411.12)), pirfenidone (2.47% (-0.1 to 5)), pamrevlumab (4.3% (0.5 to 8.1)) and pentraxin (2.74% (1 to 4.83)) probably reduce decline of overall forced vital capacity (all moderate certainty). Only sildenafil probably reduces acute exacerbation and hospitalisations (moderate certainty). Corticosteroids+azathioprine+N-acetylcysteine increased risk of serious adverse events versus placebo (high certainty). CONCLUSION AND RELEVANCE: Future guidelines should consider sildenafil for IPF and further research needs to be done on promising IPF treatments such as pamrevlumab and pentraxin as phase 3 trials are completed.

Isolated Penile Calciphylaxis Diagnosed by Ultrasound Imaging in a New Dialysis Patient: A Case Report.

RATIONALE: The recognition of calciphylaxis often eludes practitioners because of its multiple ambiguous presentations. It classically targets areas of the body dense with adipose tissue. A heightened suspicion for the disorder is therefore required in the case of penile calciphylaxis, given its unconventional location. The diagnosis of calciphylaxis is also challenging as the gold standard for diagnosis is biopsy which can often yield equivocal results. Unfortunately, in penile calciphylaxis, the utility of biopsies is further debated due to their potential to precipitate new lesions and their decreased sensitivity due to the limited depth of tissue that can be sampled. For these reasons, it is important that practitioners recognize other accessible and accurate investigative tools which can aid in their diagnosis. PRESENTING CONCERNS OF THE PATIENT: We present the case of a 49-year-old man who presented to the emergency room with penile pain in the context of known chronic kidney disease secondary to diabetic nephropathy. The pain had been present for about a week, was exquisitely tender, and was initially associated with a faint violaceous lesion. This gentleman had just recently initiated peritoneal dialysis and had no other lesions on his body. DIAGNOSIS: His pain was determined by ultrasound and plain radiograph to be secondary to calciphylaxis after two biopsies were nondiagnostic. INTERVENTIONS: The patient had already made changes to his diet to reduce phosphate and calcium intake, and had been on phosphate-lowering therapy with both calcium and phosphate being within their respective target range. Following his diagnosis, this patient was promptly converted from peritoneal dialysis to hemodialysis with sodium thiosulphate and initiated hyperbaric oxygen therapy. This patient continues to be followed by nephrology and urology specialists.

OUTCOMES: At the time of publication there has been no amputation of the appendage although there has been presumably permanent loss of function. TEACHING POINTS: This case should reinforce the high index of suspicion needed to make a timely diagnosis of calciphylaxis, and the broad variety of ways in which the disorder may present. The findings advocate for the utility of alternative diagnostic modalities, including imaging with plain radiograph and ultrasound, for calciphylaxis diagnosis. JUSTIFICATION: Les multiples présentations cliniques de la calciphylaxie, une affection qui cible habituellement des régions du corps denses en tissu adipeux, font en sorte que sa détection échappe fréquemment aux praticiens. La calciphylaxie pénienne, en raison de son emplacement inhabituel, devrait faire l'objet d'une suspicion clinique accrue. La calciphylaxie est en outre difficile à diagnostiquer puisque la biopsie, l'étalon-or pour sa détection, mène souvent à des résultats équivoques. Dans le cas de la calciphylaxie pénienne, la pertinence de la biopsie fait d'autant plus débat puisqu'elle est susceptible de précipiter de nouvelles lésions et qu'elle présente une sensibilité réduite compte tenu de la profondeur limitée des tissus pouvant être obtenus. Il est donc important que les praticiens connaissent d'autres outils d'investigation accessibles et plus précis pouvant les aider dans leur diagnostic. PRÉSENTATION DU CAS: Nous présentons le cas d'un homme de 49 ans s'étant présenté aux urgences avec une douleur au pénis. Le patient était connu pour une insuffisance rénale chronique découlant d'une néphropathie diabétique. La douleur, initialement associée à une lésion légèrement violacée, était présente depuis environ une semaine et le membre était extrêmement sensible. Le patient venait tout juste d'amorcer des traitements de dialyze péritonéale et ne présentait aucune autre lésion sur le corps. DIAGNOSTIC: Après deux biopsies non diagnostiques, une échographie et une radiographie standard ont permis d'associer la douleur à la calciphylaxie. INTERVENTIONS: Le patient avait déjà apporté des changements à son alimentation afin de réduire son apport en phosphore et en calcium, et recevait déjà un traitement de chélateur de phosphate. Les taux de calcium et de phosphore se situaient dans leur plage cible respective. À la suite du diagnostic, le patient est rapidement passé de la dialyze péritonéale à l'hémodialyse, a été traité avec du thiosulfate de sodium et a entrepris une oxygénothérapie hyperbare. Le patient continue d'être suivi par des spécialistes en néphrologie et en urologie. RÉSULTATS: Au moment de la publication, le patient n'avait toujours pas subi d'amputation, malgré une vraisemblable perte de fonction permanente. ENSEIGNEMENTS TIRÉS: Ce cas devrait renforcer l'indice élevé de suspicion qui est nécessaire pour poser rapidement un diagnostic de calciphylaxie, en plus de montrer les très nombreuses présentations cliniques de ce trouble. Ces résultats plaident en faveur de modalités alternatives pour le diagnostic de la calciphylaxie, notamment le recours à l'échographie et à la radiographie standard.

Incidence and Outcomes of Acute Kidney Injury in Patients Admitted to Hospital With COVID-19: A Retrospective Cohort Study.

BACKGROUND: The incidence of acute kidney injury (AKI) in patients with COVID-19 and its association with mortality and disease severity is understudied in the Canadian population. OBJECTIVE: To determine the incidence of AKI in a cohort of patients with COVID-19 admitted to medicine and intensive care unit (ICU) wards, its association with in-hospital mortality, and disease severity. Our aim was to stratify these outcomes by out-of-hospital AKI and in-hospital AKI. DESIGN: Retrospective cohort study from a registry of patients with COVID-19. SETTING: Three community and 3 academic hospitals. PATIENTS: A total of 815 patients admitted to hospital with COVID-19 between March 4, 2020, and April 23, 2021. MEASUREMENTS: Stage of AKI, ICU admission, mechanical ventilation, and in-hospital mortality. METHODS: We classified AKI by comparing highest to lowest recorded serum creatinine in hospital and staged AKI based on the Kidney Disease: Improving Global Outcomes (KDIGO) system. We calculated the unadjusted and adjusted odds ratio for the stage of AKI and the outcomes of ICU admission, mechanical ventilation, and in-hospital mortality. RESULTS: Of the 815 patients registered, 439 (53.9%) developed AKI, 253 (57.6%) presented with AKI, and 186 (42.4%) developed AKI in-hospital. The odds of ICU admission, mechanical ventilation, and death increased as the AKI stage worsened. Stage 3 AKI that occurred during hospitalization increased the odds of death (odds ratio [OR] = 7.87 [4.35, 14.23]). Stage 3 AKI that occurred prior to hospitalization carried an increased odds of death (OR = 5.28 [2.60, 10.73]). LIMITATIONS: Observational study with small sample size limits precision of estimates. Lack of nonhospitalized patients with COVID-19 and hospitalized patients without COVID-19 as controls limits causal inferences. CONCLUSIONS: Acute kidney injury, whether it occurs prior to or after hospitalization, is associated with a high risk of poor outcomes in patients with COVID-19. Routine assessment of kidney function in patients with COVID-19 may improve risk stratification. TRIAL REGISTRATION: The study was not registered on a publicly accessible registry because it did not involve any health care intervention on human participants.

Inflammatory biomarkers as independent prognosticators of 28-day mortality for COVID-19 patients admitted to general medicine or ICU wards: a retrospective cohort study.

Inflammatory biomarkers may be associated with disease severity and increased mortality in COVID-19 patients but have not been studied in North American populations. We sought to determine whether a set of commonly ordered inflammatory biomarkers can predict 28-day mortality. We analyzed a multi-centered (four) COVID-19 registry cohort from March 4th to December 7th, 2020. This cohort included COVID-19-positive patients admitted to medical wards or intensive care units. Patients presenting to the emergency department for COVID-19 symptoms and then subsequently discharged were also included. We performed Cox-regression analysis to measure whether commonly used biomarkers were associated with an increased 28-day mortality. Of 336 COVID-19-positive patients, 267 required hospital admission, and 69 were seen in the emergency room and discharged. The median age was 63 years (IQR 80-50) and the female-to-male ratio was 49:51. Derivation of internally validated cut-offs suggested that C-reactive protein ≥ 78.4 mg/L, neutrophil-to-lymphocyte ratio ≥ 6.1, lymphocyte-to-white blood cell ratio < 0.127, and a modified Glasgow prognostic score equal to 2 vs. 1 or 0 were associated with the highest increased risk of 28-day mortality. We provide early estimates of cut-off values for inflammatory biomarkers and indices measured at the time of admission that may be useful to clinicians for predicting 28-day mortality in North American COVID-19 patients.

Evaluating the endometabolic and bone health effects of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukaemia: a systematic review protocol.

INTRODUCTION: Chronic Myeloid Leukaemia (CML) constitutes 15% of new adult leukaemia cases as well as 2%-3% of leukaemia in children under 15% and 9% of leukaemias in adolescents 15-19 years of age annually. The introduction of Tyrosine Kinase Inhibitors (TKI) therapy has dramatically improved survival in these patients, yet the off-target effects of this treatment may have long-term health impacts on CML survivors. The risk of adverse health outcomes is especially important in children, where TKI exposure may occur during critical windows of growth and puberty, and patients require treatment for prolonged periods of time. The aim of this systematic review protocol is to report on the methods used to conduct a systematic review to investigate the endometabolic and bone health effects of TKI therapy in CML. METHODS AND ANALYSIS: Searches will be conducted in the Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE from inception on August 1st, 2019. Searches may be updated while performing the systematic review to ensure new evidence is included if applicable. Grey literature search will include ClinicalTrials.gov and ProQuest Dissertations and Theses A&I. We will perform a meta-analysis if there are at least two studies reporting similar populations, interventions, methods and tracking the same outcome measures. The studies should also have similar age and sex distributions. ETHICS AND DISSEMINATION: As this is a systematic review protocol, it does not include patient data; therefore, Research Ethics Board approval is not indicated. The systematic review will be published in a peer-reviewed journal and presented at international conferences. PROSPERO REGISTRATION NUMBER: CRD42018091175.