Category: Infectious Disease

Antibiotics, With or Without Delay!

This is a trial addressing a practice to which I’m not opposed, and recommended by some other experts: delayed antibiotic prescribing. Delayed prescribing, providing patients with an antibiotic to fill “just in case they get worse”, has seemingly reasonable fundamental components. An encounter with a patient is a single snapshot in time, frequently without a clear picture of the ongoing clinical course. Early bacterial illness may not be clearly apparent as infection, with subsequent days bringing the diagnosis into clearer focus. In the interests of respecting patients’ time and healthcare resource utilization, why not provide a provisional antibiotic prescription to be filled by the patient if they self-assess clinical worsening?

This specific delayed antibiotic prescribing trial was performed in children presenting with an acute, uncomplicated respiratory infection – which, by their inclusion criteria included acute otitis media, pharyngitis, rhinosinusitis, or acute bronchitis. These authors randomized 436 children to one of three arms: immediate antibiotics, delayed antibiotics, or no antibiotics. Parents whose children were enrolled in the delayed antibiotics arm were instructed to start the antibiotic if their children worsened or did not start feeling better within a few days to weeks, depending on the underlying illness at time of enrollment. The primary outcome for the trial was severity and duration of acute symptoms over the following month.

The good news – the trial was a “success”. Children randomized to the delayed antibiotics strategy reported similar numbers of symptom days as those randomized to the immediate antibiotics arm. Whether it was pharyngitis, otitis media, rhinosinusitis or bronchitis, children remained symptomatic – for 4 to 10 days – regardless of their treatment arm. Delayed antibiotic prescribing, then, was not clinically harmful with respect to the primary illness.

With respect to antibiotic use and adverse effects, within 30 days of enrolment nearly the entire immediate antibiotic arm used their prescriptions. In contrast, only 25% of those randomized to delayed antibiotics did so, along with 12% of those who had no antibiotic prescribed. As to be expected, those with fewer antibiotic exposures suffered fewer gastrointestinal side effects. Unscheduled primary care utilization was uncommon and similar across all treatment groups.

So, “success”!

Except for that other niggling, less-heralded study arm: the no antibiotics arm.

The authors conclude by saying “DAP compared to IAP led to greatly reduced antibiotic use and fewer gastrointestinal adverse effects associated with antibiotic intake.” While this is not untrue, the actual final conclusion might more appropriately be: “No practical advice can be provided regarding the appropriateness of a delayed antibiotic strategy, as this trial best demonstrates the no antibiotic strategy most likely the best choice.”

The entire premise of a delayed strategy is, in the context of clinical uncertainty, there is a substantial likelihood the underlying illness will ultimately require antibiotics for successful resolution. In this trial, the authors have selected a scenario where that is not the case – and, therefore, haven’t produced terribly generalizable information regarding delayed antibiotic prescribing strategies.

The authors have, at least, provided some useful insight into human behavior with respect to delayed antibiotics and the rate at which they are filled. But, mostly, they have best demonstrated, yet again, the vast majority of children evaluated for respiratory illnesses are best treated with supportive care and time, rather than antibiotics.

“Delayed Antibiotic Prescription for Children With Respiratory Infections: A Randomized Trial”
https://pediatrics.aappublications.org/content/early/2021/02/09/peds.2020-1323

Whirlwind COVID-19 Therapy Tour

Just a brief post collating some of the high-level evidence on therapies approved or under investigation for COVID-19. I’d written this up for another audience, and it could be obsolete as soon as I post – and hopefully mooted in just a few months!

Hydroxychloroquine:
No. What a farce.
https://www.nejm.org/doi/full/10.1056/NEJMoa2022926
https://www.nejm.org/doi/full/10.1056/NEJMoa2021801
https://www.nejm.org/doi/full/10.1056/NEJMoa2016638
https://www.nejm.org/doi/full/10.1056/nejmoa2019014

Remdesivir:
A controversial repurposing of an antiviral previously trialled against ebola. Consistent benefits have been difficult to replicate. ACTT-1 in the U.S. showed a small length-of-stay and mortality benefit, but SOLIDARITY by the WHO found none.
https://www.nejm.org/doi/full/10.1056/NEJMoa2007764
https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1

Dexamethasone:
The best reliable evidence for benefit so far, with face validity in treating inflammation-mediated lung disfunction. For “moderate to severe” COVID-19, which is effectively anyone with hypoxia requiring supplemental oxygen.
https://www.nejm.org/doi/full/10.1056/NEJMoa2021436

Convalescent plasma:
Over 250,000 people in the U.S. have been treated with plasma donated by persons recovered from COVID-19. However, minimal evidence of efficacy exists. It certainly does not work in the very ill, but is still being explored in those early in the disease process.
https://www.nejm.org/doi/full/10.1056/NEJMoa2031304

Bamlanivimab:
This is the Eli Lilly neutralizing antibody, approved for emergency use in the U.S. This is a monoclonal antibody to the SARS-CoV-2 spike protein. Interestingly, this product failed in ACTIV-3, hospitalized inpatients. The interim results leading to FDA approval are from BLAZE-1, preventing deterioration of mild disease at high-risk for progression.
https://www.fda.gov/media/143603/download

Casirivimab plus imdevimab:
This is the Regeneron “antibody cocktail” given to President Trump. These are both monoclonal antibodies to different, non-overlapping domains of the SARS-CoV-2 spike protein. These are also similarly targeted at high-risk outpatients with mild disease with the goal of preventing progression.
https://www.fda.gov/media/143892/download

JAK (Janus kinase) inhibitor:
Baricitinib is approved as second-line therapy for moderate-to-severe rheumatoid arthritis. Per FDA EUA data, this conferred mortality benefit when given in tandem with remdesivir in ACTT-2. However, few patients in this trial received steroids, limiting generalizability.
https://www.fda.gov/media/143823/download

Tocilizumab:
This is an IL-6 inhibitor currently approved for moderate-to-severe rheumatoid arthritis. Mixed results have been observed with tocilizumab, and current use is primarily as a salvage in the mechanically ventilated. However, there is not much face validity for its effectiveness when added to dexamethasone.
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2772187
https://www.nejm.org/doi/full/10.1056/NEJMoa2028836

Ivermectin:
Antiparasitic agent theorized to reduce severity of COVID-19 through inhibition of viral protein transport. Widely used in the developing world due to its availability and low cost; virtually no useful data available.
https://journal.chestnet.org/article/S0012-3692(20)34898-4/fulltext
https://www.researchsquare.com/article/rs-109670/v1

Lopinavir and rotonavir:
Antiviral combination therapy typically used for HIV-1. No clinical benefit detected in the RECOVERY trial, and adverse effects led to discontinuation in other trials.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32013-4/fulltext
https://www.nejm.org/doi/full/10.1056/NEJMoa2001282

The NIH also features fairly good tables of agents under ongoing evaluation, if you’re interested in seeing more extensive summaries of evidence for each:
https://www.covid19treatmentguidelines.nih.gov/tables/table-2/
https://www.covid19treatmentguidelines.nih.gov/tables/table-3a/

The Futility of Mask Wearing?

The parade of COVID-19 papers is relentless enough (fluvoxamine, anyone?) it’s almost impossible to try and keep up, but this one is a little different. This trial, rather than just another inflammatory mediator striving for its day in the sun, tries to inform something we can all do every day: wear a mask.

So, this is the mask trial everyone’s been talking about – in which 4,862 patients completed a study where the intervention arm was given 50 masks and asked to wear them outside the home. The primary outcome at 1 month was SARS-CoV-2 infection, as measured by seroconversion, PCR, or hospital clinical diagnosis.

At the end of the day, this was a “negative” trial – there was no statistically significant difference in SARS-CoV-2 infection between the mask (1.8%) and control (2.1%) participants. C’est la vie.

While the findings of this trial are being covered by news outlets in a variety of ways, the more important takeaways from this research are what it does not show:

  • It does not show masks are ineffective for preventing the wearer from becoming infected with SARS-CoV-2. The 95% confidence interval for the between group difference is -1.2 to 0.4 percentage points. This can be strictly interpreted, in a frequentist sense, to indicate a range of possible true effect sizes from this study. Most of these true effect sizes favor the intervention, but, most likely not to the effect size meeting the authors’ definition of a clinically meaningful difference.
  • It does not have invalid results because of imperfect adherence with mask use. Research results need to be applicable to the world in which we live. A pragmatic trial taking into account individual behaviors reflects (and likely even overstates) their typical real-world use, and this can greatly inform public policy.
  • It does not, finally, inform any aspect of current mask recommendations, which are designed, primarily, to prevent the wearer from spreading infection. This is why surgeons wear masks while operating – it isn’t for their own protection, but for the patient.

There are also additional points to make regarding the right censoring of outcomes. Patients received their final testing kits at one month, but sensitivity limitations inherent to both PCR and lateral flow immunoassays could have missed infections present at time of final testing. This would have the effect of attenuating the observed effect size. Other limitations of these tests are clearly applicable, but their inaccuracies ought to be evenly distributed between groups. Many others have also pointed out issues with study attrition, and its inevitable effect on outcomes.

Lastly, a fair bit of discussion on Twitter pertains to whether this study ought to have been published at all, considering it may be disseminated with headlines lacking the nuance of the study findings. I certainly do not have a problem with letting light shine upon data, and it being the responsibility of authors and editors to educate through their contextual presentation. I would also go as far to say if this trial had been clearly positive (instead of just inconclusive based on their sample and power), it would have been potentially a strong motivator for mask use. We should be wary of the scientific harms of publication bias and encourage the completion and dissemination of “negative” studies.

“Effectiveness of Adding a Mask Recommendation to Other Public Health Measures to Prevent SARS-CoV-2 Infection in Danish Mask Wearers: A Randomized Controlled Trial”
https://www.acpjournals.org/doi/10.7326/M20-6817

Covid-19 is EVERYWHERE

That lede encapsulates the underlying subtext of the most recent New England Journal of Medicine publication regarding the spread of coronavirus. This article is very simple, and – importantly – very limited.

These authors from Columbia University in New York, New York, simply supply a short research letter describing their experience screening pregnant patients for SARS-CoV-2 infection at their obstetrical intake prior to delivery. Between March 22nd and April 4th, there were 215 women who delivered at New York-Presbyterian and Columbia University Irving. Four were febrile and symptomatic at admission and all tested positive. However, an additional 29 patients who were not experiencing symptoms of Covid-19 also tested positive by nasophargyneal swab and RT-PCR. Thus, the big freak out: 15% of this convenience sample were asymptomatic at time of diagnosis.

Many important limitations may preclude its generalizability to clinical practice and public health policy:

  • New York was in the midst of a substantial outbreak during sampling, with certainly higher background prevalence than most communities.
  • Full follow-up was not completed to determine whether the “asymptomatic” patients were truly “asymptomatic” or actually “presymptomatic”. Truly asymptomatic infection would imply vastly larger pools of infected and/or recovered citizens. This would drive down case-fatality rates and contribute to “herd immunity”. Presymptomatic infection is distinctly different, however, as these patients would be reflected in our current methods of (under)counting cases.
  • Pregnant women are not representative of the general populace, neither in their overall immune system physiology, nor with respect to the frequency with which they leave the home and access healthcare systems during a high-risk period.
  • It’s simply a convenience sample of 215 patients, diminishing the precision of their measurements.

The big takeaway here mostly has implications for testing. In areas with high prevalence of circulating infection – particularly circulating, undetected infection – routine screening at hospital admission should probably be performed. Right now, that is basically everywhere – so, in the interests in protecting healthcare workers and staff, all patients being admitted to the hospital ought to be screened, if possible. The other implication is reinforcement of our larger testing needs, and the already-known risks of presymptomatic viral shedding. Contact tracing and testing will be critical to stamping out local flare ups of disease – and we will need millions more tests than we currently perform.

“Universal Screening for SARS-CoV-2 in Women Admitted for Delivery”
https://www.nejm.org/doi/full/10.1056/NEJMc2009316

Update on Hydroxychloroquine and Azithromycin

It’s the French team from Marseille again – with more data on hydroxychloroquine and azithromycin.

You may remember them from the first, tiny uncontrolled trial featuring hydroxychloroquine monotherapy, and then combination therapy with hydroxychloroquine and azithromycin, with “untreated patients from another center” as their negative controls. This trial, with its grand total of 36 patients has been touted as a miraculous success – as opposed to a small 30 patient trial in China that was unrevealing.

Now we have 80 patients – but worse, still, it is even without any sort of controlled comparison, let alone a randomized, controlled comparison. Minimal enrollment criteria are noted in the publication, but they do note 6 patients are a carryover from their first study. It appears all patients receiving treatment for at least 3 days and received at least 6 days of follow-up were included in the analysis.

The standard treatment protocol is 200mg hydroxychloroquine three times a day, along with a typical 500mg/250mg azithromycin 5 day course. Those with pneumonia and NEWS scores ≥5 received ceftriaxone, as well.

There’s almost no point in mentioning a “primary outcome”, but effectively a good outcome is alive and discharged. Data were collected on viral culture Ct value (the number of amplification cycles required to obtain a positive result).

Overall, 65 of 80 (81.3%) improved and were discharged. One patient was admitted to the ICU and died on day 7 after initiation of treatment. Others have had waxing and waning clinical course in the hospital. Viral culture results, unsurprisingly, mirrored clinical improvement.

The authors infuriatingly suggest: “We believe other teams should urgently evaluate this cost-effective therapeutic strategy.” It is close to unethical to call for others to investigate these agents when they clearly have the means to do so themselves.

The lack of a control group renders these results uninterpretable. Further, the mention in results of “six days of follow-up” for analysis suggests survivorship bias. For a treatment already in widespread use (and misuse), we remain woefully underinformed regarding its true effectiveness and clinical utility.

“Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 COVID-19 patients with at least a six-day follow up: an observational study”
https://www.mediterranee-infection.com/wp-content/uploads/2020/03/COVID-IHU-2-1.pdf

#COVID19

As you may have noticed, the global pandemic is consuming a bit of attention these days.

I’ve been putting most of my efforts into rapid-response threads to new literature and preprints on Twitter: @emlitofnote. You can follow along there as we try to rapidly titrate and disseminate effective strategies for dealing with this scourge.

I hope we will all return to normalcy in due time.

Potpourri

Just a quick-hit collection of articles I’ve wanted to highlight/catalogue for future reference, but couldn’t find the time for deep dives into each:

Shared Decision Making in Patients With Suspected Uncomplicated Ureterolithiasis: A Decision Aid Development Study.
For this common clinical scenario in the Emergency Department, the authors have developed a patient-facing packet to facilitate shared decision-making. However, more important than the product, is the process these authors have described for its creation. A similar roadmap could be followed to address similar opportunities in your department.

Reduction of Inappropriate Antibiotic Use and Improved Outcomes by Implementation of an Algorithm-Based Clinical Guideline for Nonpurulent Skin and Soft Tissue Infections.
Amazing – using the correct antibiotics reduces treatment failures and, likewise, treatment failures necessitating admission to the hospital. This is an effort-intensive intervention featuring provider education and individual prescribing feedback, but, given the limitations, can be considered a change management success. Whether this can be replicated at your institution will depend on many cultural factors.

Utility of INR For Prediction of Delayed Intracranial Hemorrhage Among Warfarin Users with Head Injury.
Here’s a topic with a ton of practice variation – do you admit patients with closed head injury on anticoagulation for observation? This retrospective review of those patients just on warfarin tries to make the case patients with INR <2 are safe for discharge, whereas those with higher scores are not. Again, however, the yield of observation is somewhere south of 1% in their entire therapeutic cohort, making it truly challenging to find the inflection point of value. Another opportunity for shared decision-making?

Performance of Novel High-Sensitivity Cardiac Troponin I Assays for 0/1-Hour and 0/2- to 3-Hour Evaluations for Acute Myocardial Infarction: Results From the HIGH-US Study.
A detailed look at high-sensitivity Troponin I rule-in/rule-out algorithms suggests a 0/1-hour strategy is similar to a 0/3-hour strategy. Overall, while the disposition of patients is likely to be more rapid from the 0/1 hour strategy, a greater proportion of patients ultimately fall into the “intermediate” zone requiring further observation and diagnostics. Certainly, combinations of hsTnI and other risk-stratification instruments ought to mean the majority of patients with straightforward chest pain presentations may be discharged from the Emergency Department.

Randomized Clinical Trial of IV Acetaminophen as an Adjunct to IV Hydromorphone for Acute Severe Pain in Emergency Department Patients.
In this trial, patients receiving hydromorphone were randomized to receive adjunctive treatment with IV acetaminophen or placebo. With 159 patients, they found advantages to the multi-modal approach favoring the addition of acetaminophen – but the confidence interval for their primary outcome crossed unity by 0.01. The authors conclude this is a negative trial, but it rather seems to me there’s certainly no harm in adding acetaminophen (it need not be IV) – adding it likely has a favorable effect, even if the effect size may not be large.

Effect of No Prehydration vs Sodium Bicarbonate Prehydration Prior to Contrast-Enhanced Computed Tomography in the Prevention of Postcontrast Acute Kidney Injury in Adults With Chronic Kidney Disease: The Kompas Randomized Clinical Trial.
In news surprising no one, another trial fails to show benefit of prehydration in staving off post-contrast exposure acute kidney injury. As seen on Twitter, rather than “contrast-induced nephropathy”, the clinical paradigm is effectively “contrast-adjacent nephropathy.” The impairment in renal function is associated with the underlying medical illness and not the exposure to IV contrast. Thus, no intervention – such as prehydration – can prevent such.

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.
This interesting observational study evaluated patients with a diagnosis of non-ST elevation acute coronary syndrome using coronary CT angiography prior to invasive coronary angiography. The good news: CT angiography was probably useful at excluding obstructive coronary disease. The bad news: nearly 70% of patients had a coronary stenosis identified on invasive angiography, so patient selection prior to CT angiography will be important to improve the value of using it as a screen to prevent invasive angiography.

Industry Payment to Vascular Neurologists: A 6-Year Analysis of the Open Payments Program From 2013 Through 2018.
As we watch our healthcare delivery system struggle and groan under the various strains and burdens, one of the culprits has always been the influence of pharmaceutical/device manufacturers targeting investments to improve uptake of their products. In this observational analysis of the OpenPayments database, these authors identified the recipients of financial support from the manufacturers of endovascular devices. About 16% of vascular neurologists received funding from industry, but over 75% could be identified as “influencers” – chiefs of staff, department chairs, or similar. Pharma et al should always be remembered they are serving the interests of owners and shareholders, and not patients and our healthcare system.

Happy VITAMINS Day!

After a couple years wandering in the wilderness after the Marik report, and a few small or unrevealing trials, we finally have our first RCT evidence regarding the use of thiamine, vitamin C, and steroids in sepsis: the VITAMINS trial.

In this trial, 216 patients with septic shock received hydrocortisone 50mg every six hours, and were then randomized to usual care or open-label vitamin C 1.5g every six hours plus thiamine 200mg every twelve hours. The primary outcome was time alive and free of vasopressor administration up to day 7, along with pre-specified secondary mortality outcomes. Important exclusions in the eligibility screening process included onset of septic shock >24 hours, imminent death, and use of study drugs for other reasons. Few differences between the two groups were observed at baseline, although the control arm had median lactate level of 3.3 at enrollment compared with 4.2 in the intervention arm.

The primary outcome was: no different, 122.1 hours with the intervention and 124.6 hours in the control arm. The secondary mortality outcomes: at 28 days, no different, 22.6% vs. 20.4%; at 90 days, no different, 28.6% vs 24.5%. The remaining secondary outcomes, including ventilation-free days, renal replacement, and acute kidney injury were no different, but there was a small different in SOFA scores at day 3 favoring the intervention. The authors appropriately caution this observed improvement in SOFA score should be interpreted at your peril, as its significance is not adjusted for multiple comparisons and subject to both competing risks from early death and early discharge from the ICU.

So, the pure frequentist conclusion: this trial, repeated, would provide an estimate containing the true effect size with bounds crossing unity most of the time. The Bayesian conclusion, accounting for the weak, positive, prior evidence: there is a low probability of the true effect being positive. If you were holding off adopting the addition of thiamine and vitamin C, this trial reinforces your skepticism. If you’ve already adopted thiamine and vitamin C, it is unlikely harms were caused, but it is now more likely than not these treatments are not resulting in benefit. Additional trials will report results capable of further clarifying these observations.

The accompanying editorial by Andre Kalil sums up the interpretation of these results in context beautifully:

“Given that other studies are forthcoming, there appears to be no immediate justification for adoption of high-dose vitamin C, alone or in combination, as a component of treatment for sepsis. Moreover, use of high-dose vitamin C in combination or alone “just in case” or as a “measure of last resort,” aside from providing no survival benefits, could have several other potential consequences, including diverting funding from needed research to examine sepsis mechanisms and diagnostics; stifling the development of other sepsis therapies; perpetuating false hopes for patients, families, and clinicians; and delaying proven lifesaving therapies such as prompt initiation of antibiotic therapy.”

“Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock”
https://jamanetwork.com/journals/jama/fullarticle/2759414

Tamiflu, Cure-All

Once upon a time in Europe, we find they are beset by a befuddling problem: no one uses oseltamivir.

“Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials.”

Ah, to have such problems.

These authors choose to address this dire problem in the most pragmatic fashion possible: rather than try to determine a subgroup of potential maximal benefit, just blindly give everyone oseltamivir in empiric fashion for influenza-like illness. It’s not what one would consider “high-value care”, but it certainly effectively eliminates the barriers to prescribing.

In this open-label trial, patients presenting with influenza-like illness to primary care were assigned to “usual care” or “usual care plus oseltamivir”. Across three influenza seasons, the authors recruited 3,266 participants across 15 countries in Europe. The outcomes were universally excellent: oseltamivir use decreased time to symptom resolution a mean of 1.02 days, effectively reducing mean suffering from 6.73 days to 5.71 days.

And, the better news, oseltamivir worked whether you had influenza or not – half the patients in the trial had confirmed influenza infection while half did not, and the hazard ratio for benefit was actually better [ed. not significantly so] in those who did not have influenza.

… and thus invalidates the entire trial as a giant placebo effect. The industry-funded authors of the most recent meta-analysis of industry-funded trials for the approval of oseltamivir said it best, after all:

“In the intention-to-treat-not infected population, the estimated time ratio was close to unity (time ratio 0·99, 95% CI 0·88–1·12; p=0·91), so only participants identified as influenza-infected benefited from oseltamivir.”

This trial does not show benefit to liberal oseltamivir use. There is no new indication hereby discovered regarding oseltamivir’s efficacy for non-influenza influenza-like viral illness – it simply shows people feel better when they get medicine (particularly when it is more expensive).

“Oseltamivir plus usual care versus usual care for influenza-like illness in primary care: an open-label, pragmatic, randomised controlled trial”
https://www.ncbi.nlm.nih.gov/pubmed/31839279

Sepsis Alerts Save Lives!

Not doctors, of course – the alerts.

This is one of those “we had to do it, so we studied it” sorts of evaluations because, as most of us have experienced, the decision to implement the sepsis alerts is not always driven by pent-up clinician demand.

The authors describe this as sort of “natural experiment”, where a phased or stepped roll-out allows for some presumption of control for unmeasured cultural and process confounders limiting pre-/post- studies. In this case, the decision was made to implement the “St John Sepsis Algorithm” developed by Cerner. This algorithm is composed of two alerts – one somewhat SIRS- or inflammation-based for “suspicion of sepsis”, and one with organ dysfunction for “suspicion of severe sepsis”. The “phased” part of the roll-out involved turning on the alerts first in the acute inpatient wards, then the Emergency Department, and then the specialty wards. Prior to being activated, however, the alert algorithm ran “silently” to create the comparison group of those for whom an alert would have been triggered.

The short summary:

  • In their inpatient wards, mortality among patients meeting alert criteria decreased from 6.4% to 5.1%.
  • In their Emergency Department, admitted patients meeting alert criteria were less likely to have a ≥7 day inpatient length-of-stay.
  • In their Emergency Departments, antibiotic administration of patients meeting alert criteria within 1 hour of the alert firing increased from 36.9% to 44.7%.

There are major problems here, of course, both intrinsic to their study design and otherwise. While it is a “multisite” study, there are only two hospitals involved. The “phased” implementation not the typical different-hospitals-at-different-times, but within each hospital. They report inpatient mortality changes without actually reporting any changes in clinician behavior between the pre- and post- phases, i.e., what did clinicians actually do in response to the alerts? Then, they look at timely antibiotic administration, but they do not look at general antibiotic volume or the various unintended consequences potentially associated with this alert. Did admission rates increase? Did percentages of discharged patients receiving intravenous antibiotics increase? Did clostridium difficle infection rates increase?

Absent the funding and infrastructure to better prospectively study these sorts of interventions, these “natural experiments” can be useful evidence. However, these authors do not seem to have taken an expansive enough view of their data with which to fully support an unquestioned conclusion of benefit to the alert intervention.

“Evaluating a digital sepsis alert in a London multisite hospital network: a natural experiment using electronic health record data”

https://academic.oup.com/jamia/advance-article/doi/10.1093/jamia/ocz186/5607431