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JOURNAL CLUB – JANUARY 2022

Updated: Nov 3, 2023

Journal Club Podcast for January 2022

Prof Peter Cameron Dr Divya Karna Dr Eanna Mac Suibhne

Editor: Dr David McCreary


Welcome to the Journal Club Podcast for January 2022. You can listen to the podcast above and have a read at our summary below, courtesy of our senior registrar for research, Dr Eanna Mac Suibhne.


This month I was joined by Professor Peter Cameron, Academic Director for the Alfred Emergency and Trauma Centre and Emergency Physician Dr Divya Karna.


This month in our Journal Club we reviewed a couple of papers from the COVID-sphere. The first reviews cardiac side-effects of COVID infection & vaccination and the second the use of fluvoxamine for the treatment of COVID infection (spoiler alert, it’s probably not that helpful, despite what the authors say).


Fear not, we also looked at two non-COVID papers: we discuss a paper assessing closed reduction vs open fixation of distal radius fractures and then the latest iteration of the surviving sepsis guidelines.


As always, have a look at the papers yourself and draw your own conclusions but, for a snap shot of what we thought, read on!


PAPER 1: RISKS OF MYOCARDITIS, PERICARDITIS, AND CARDIAC ARRHYTHMIAS ASSOCIATED WITH COVID-19 VACCINATION OR SARS-COV-2 INFECTION

READ IT HERE


CLINICAL QUESTION: Does vaccination lead to increased rates of cardiac events, specifically myocarditis/pericarditis/cardiac arrhythmia?

FINDINGS Of the 38,615,491 vaccinated individuals included in the study, 1,615 (0.004%) were admitted to hospital with, or died from, myocarditis at any time in the study period. Similarly, 0.004% were admitted to hospital with, or died from, pericarditis and 1% with cardiac arrhythmia. There was no evidence of an increase in the risk of pericarditis or cardiac arrhythmias following vaccination, except in the 1–28days following a second dose of the mRNA-1273 vaccine. In the same population, there was a greater risk of myocarditis, pericarditis and cardiac arrhythmia following SARS-CoV-2 infection. The increased risk of myocarditis after vaccination was higher in persons aged under 40 years. Extra myocarditis events were estimated to be between 1 and 10 per million persons in the month following vaccination, which was substantially lower than the 40 extra events per million persons observed following SARS-CoV-2 infection.

AUTHORS' CONCLUSIONS Vaccination for SARS-CoV-2 in adults was associated with a small increase in the risk of myocarditis within a week of receiving the first dose of both adenovirus and mRNA vaccines, and after the second dose of both mRNA vaccines. By contrast, SARS-CoV-2 infection was associated with a substantial increase in the risk of hospitalization or death from myocarditis, pericarditis and cardiac arrhythmia.

JOURNAL CLUB THOUGHTS This was a big study conducted in the UK which was an ideal location given that the three vaccinations were rolled out at speed and scale and the large sample size facilitated the study to be powered to investigate and detect the chosen outcomes. All this is obviously very topical and it’s useful to have this data to hand which is reassuring to the public. One of the main take-homes should be that if you don’t want to get myocarditis or pericarditis - get vaccinated. The researchers relied on hospital admission codes and death certification to define their outcome measures, as opposed to standard investigations such as imaging or biopsy and so cannot determine accurately which patients had myocarditis or pericarditis. This is problematic in interpreting the results and affects the internal validity of the study. The observation that the risk of myo- and pericarditis is much greater following Covid-19 disease than it is after Covid-19 vaccination is not new information, but this paper supports and confirms this.

PAPER 2: VOLAR PLATE FIXATION VERSUS CAST IMMOBILIZATION IN ACCEPTABLY REDUCED INTRA-ARTICULAR DISTAL RADIAL FRACTURES A RANDOMIZED CONTROLLED TRIAL

READ IT HERE


CLINICAL QUESTION:

Do functional outcomes differ between volar plate fixation and cast immobilization in a series of adult patients with displaced and acceptably reduced intra-articular distal radius fracture?


FINDINGS

Patients aged 18 and 75 years with a displaced, intra-articular fracture of the distal radius which had been successfully reduced were randomised to either operative fixation within 2 weeks of their injury or to nonoperative management in cast immobilisation for 4 to 5 weeks. The primary outcome here was difference in Patient-Rated Wrist Evaluation (PRWE) score at one year and this was found to favour the operative intervention group. Of note the prespecified clinically significant difference of 14 points was only found up to 6 months of followup and while there remained a statistically significant difference in the groups at 12 months, this no longer met the clinically significant criteria with a difference of 7 points favouring the operative group. Secondary outcomes included a clinical evaluation of range of motion and grip strength, superior in the operative group at 6 weeks but not at subsequent follow-ups. 13 non-operative patients (28%) had subsequent surgery due to displacement or malunion observed during the follow-up period.


AUTHORS' CONCLUSIONS

Adult patients with an acceptably reduced intra-articular distal radial fracture had better functional outcomes during 12 months when treated operatively instead of nonoperatively. Additionally, a subsequent surgery rate of 28% in the nonoperative group was found. Due to rising health-care costs, it has become increasingly important to provide effective care with good functional outcomes. The authors recommended surgery for patients with these fractures.


JOURNAL CLUB THOUGHTS

This study indicates ORIF improves early functional status without meaningful differences after a year and is logical, as ORIF allows for earlier mobilization and more rapid return to function. The 28% surgery rate in the non-operative group would indicate that early Ortho outpatient follow-up or referral at presenting episode is worthwhile to consider operative intervention. Even in less dependent patients, early ortho follow-up following initial reduction and immobilization is indicated to identify those at higher risk of malunion and re-evaluate the reduction status.


PAPER 3: EFFECT OF EARLY TREATMENT WITH FLUVOXAMINE ON RISK OF EMERGENCY CARE AND HOSPITALISATION AMONG PATIENTS WITH COVID-19: THE TOGETHER RANDOMISED, PLATFORM CLINICAL TRIAL

READ IT HERE


CLINICAL QUESTION:

Does outpatient treatment with fluvoxamine when compared to placebo prevent either extended emergency room observation or hospitalization due to COVID-19?


FINDINGS

This was a placebo-controlled, double-blind, randomised trial performed at 11 outpatient clinical sites in Brazil. Patients were randomly assigned to fluvoxamine at a dose of 100 mg twice a day for 10 days or corresponding placebo starting directly after randomisation. The primary outcome was a composite endpoint of admission to hospital due to COVID-19-related illness, or observation in the emergency department for more than 6 hours due to COVID-19-related illness, within 28 days of randomisation.


In the fluvoxamine group, 11% of participants had a primary outcome event compared with 16% in the placebo group. Hospitalisations were not statistically different between the groups (10% vs 13%, p=0.1). There was a statistically significant difference in the number of patients who were observed in the emergency department for 6 hours (1% vs 5%, p=0.0001). There was no difference in viral clearance at day 7, mechanical ventilation, number of days ventilated, or number of days hospitalized. 84 participants stopped fluvoxamine and 64 participants stopped placebo owing to issues of tolerability. The difference was statistically significant.


AUTHORS' CONCLUSIONS

Treatment with fluvoxamine (100 mg twice daily for 10 days) among high-risk outpatients with early diagnosed COVID-19, reduced the need for extended emergency room observation or hospitalisation.


JOURNAL CLUB THOUGHTS

There were a few issues identified with this paper that limit our confidence in the results. In terms of generalisability, the study was only performed in unvaccinated patients. These results may not be generalisable to vaccinated patients. Less relevant now in countries with over 90% vaccination rates, which most countries are heading towards and limits the applicability of these results in other settings.  The composite outcome that was used also raises questions, particularly the 6-hour observation in the ED being counted as a negative outcome. Also, the difference in primary outcome was driven by ED visits, not hospitalisations. In usual cases patients deemed safe to be discharged directly from the ED would typically be counted as a positive outcome so it's unclear why the authors used this measure. The authors also made alterations to the primary outcome changing from >12hrs to >6hrs. It is unclear from the paper when this was changed (i.e. before or after data analysis). With a positive result on a RCT, the knee jerk reaction is to jump on a treatment, however replication is the key to science, and no treatment should become standard based on a single RCT. The authors' conclusions are a bit misleading.


As Peter comments, you can look up this and other such COVID trials on the National COVID-19 Clinical Evidence Taskforce website.


PAPER 4: SURVIVING SEPSIS CAMPAIGN: INTERNATIONAL GUIDELINES FOR MANAGEMENT OF SEPSIS AND SEPTIC SHOCK 2021.

READ IT HERE


The final topic we discussed this month was the recently published update to the international guidelines for the management of sepsis and septic shock from the Surviving Sepsis Campaign.


The guidelines summarised the evidence from the literature up to July 2019, and are composed of 6 parts as “screening and early treatment”, “infection”, “hemodynamic management”, “ventilation”, “additional therapies” and “long-term outcomes and goals of care”. There are a total of 93 items and 99 recommendations.


Sepsis care has changed significant in the last 20 years. You can find a full list of updates here.


The guys over at emDOCs.net have a nice summary of the guidelines and have a few selected ED-relevant points for consideration, including discussion of the evidence behind them:

For adults with septic shock, we suggest using capillary refill time to guide resuscitation as an adjunct to other measures of perfusion. Weak, low quality of evidence, NEW.
  • The ANDROMEDA SHOCK trial evaluated resuscitation using capillary refill time and found it to be more effective than a resuscitation strategy using lactate in reducing organ dysfunction.

    • You can hear Dave’s discussion of this study on the RCEMLearning Podcast here.

For patients with sepsis-induced hypoperfusion or septic shock we suggest that at least 30 mL/kg of IV crystalloid fluid should be given within the first 3 hr of resuscitation. Weak, low quality of evidence DOWNGRADE from Strong, low quality of evidence.
  • There are no prospective interventional studies looking at different volumes for the initial resuscitation of those with sepsis or septic shock. A retrospective study including ED adult patients with sepsis or septic shock found failure to receive 30 mL/kg of crystalloids was associated with higher mortality.

For adults with sepsis or septic shock, we suggest using balanced crystalloids instead of normal saline for resuscitation. Weak, low quality of evidence, CHANGED from weak recommendation, low quality of evidence.
  • The SMART and SALT ED trials support the use of balanced crystalloids, with a network meta-analysis demonstrating decreased mortality with balanced fluids

For adults with septic shock on vasopressors, we recommend an initial target mean arterial pressure (MAP) of 65 mm Hg over higher MAP targets. Strong, moderate-quality evidence.
  • An RCT evaluating patients in septic shock randomized to MAP targets of 65-70 mm Hg versus 80-85 mm Hg found no difference in mortality. There was reduced risk of renal replacement therapy in patients with chronic hypertension and higher rates of atrial fibrillation in the group randomized to the higher MAP target group.

For adults with septic shock, we suggest starting vasopressors peripherally to restore mean arterial pressure rather than delaying initiation until central venous access is secured. Weak, very low quality of evidence, NEW.
  • Vasopressors play an important role in treatment of septic shock. Peripheral administration of vasopressors is generally safe if infused in the antecubital fossa for a short period of time (< 6 hours). Peripheral infusion is associated with shorter time to administration and time to achieving a MAP > 65.

For adults with sepsis-induced hypoxemic respiratory failure, we suggest the use of high flow nasal oxygen (also known as HFNC) over non-invasive ventilation (NIV). Weak, low quality of evidence, NEW.
  • One RCT demonstrates improved 90-day survival with HFNC compared with NIV (OR 0.42, 95% CI 0.21-0.85), with more days from mechanical ventilation.


REFERENCES

  1. Patone M, Mei XW, Handunnetthi L, Dixon S, Zaccardi F, Shankar-Hari M, et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nat Med. 2021;1–13.

  2. Selles CA, Mulders MAM, Winkelhagen J, Eerten PV van, Goslings JC, Schep NWL, et al. Volar Plate Fixation Versus Cast Immobilization in Acceptably Reduced Intra-Articular Distal Radial Fractures: A Randomized Controlled Trial. J Bone Joint Surg. 2021;103(21):1963–9.

  3. Reis G, Moreira-Silva EA dos S, Silva DCM, Thabane L, Milagres AC, Ferreira TS, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. Lancet Global Heal. 2022;10(1):e42–51.

  4. Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063–143.

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