Month: January 2020

Put an End to Routine Chest Tubes

If you’ve watched any television or cinema, you’ve probably seen a violent encounter or two leading to a puncture wound to the chest. The affected party is usually worse for the wear. The suffering is real.

So, if there were a way – if you suffered a pneumothorax – to forgo such an invasion of the thoracic cavity, would you? The U.S. and European guidelines regarding the necessity of such a procedure are not in agreement, and include both chest tube placement and aspiration as options. However, neither explore another option – no intervention. Now, that paradigm may be dramatically altered.

This is a rather simple trial: spontaneous pneumothorax of moderate-to-large (32% or greater, by the Collins method) would be randomized to intervention or conservative management. By intervention, patients would undergo placement of a small-bore chest tube with subsequent observation and discharge or hospital admission as necessary. By conservative, patients were observed in the Emergency Department and discharged unless worsening as defined in the study protocol. The primary outcome was full lung expansion 8 weeks after randomization, with a non-inferiority margin of -9% percentage points.

There were 316 patients randomized, and 25 of the 162 randomized to the conservative management arm underwent an intervention owing to worsening symptoms during initial observation. The remaining cases represented those assessed for outcomes at 8 weeks.

Short story: Success – full expansion in 98.5% with intervention and 94.4% with conservative management.

Long story: If patients with missing data after 56 days were imputed as treatment failures, because more of those in the conservative management arm were lost to follow-up, these data are potentially fallible.

So, this clearly indicates conservative management is probably the preferred course, recognizing a significant number will require an intervention due to early progression. The risk difference is uncertain – or “fragile” – enough the uncertainty regarding management strategies should be shared with patients, in that there could yet be an undefined disadvantage to conservative management. However, it is probably the case patients who did not undergo a drainage procedure and did not return for follow-up were asymptomatic and functioning well. The available data on long-term follow-up even better reinforces the case for conservative management, as need for additional surgical procedures and 12-month recurrences all favored the conservative arm.

These data do not address whether aspiration as an initial strategy has any value, whether in short-term functional improvement or similar long-term outcomes. Considering how well the conservative management cohort did, however, it may ultimately be challenging to show a specific advantage to adding an aspiration procedure. This may perhaps be addressed by future trials.

“Conservative versus Interventional Treatment for Spontaneous Pneumothorax”

https://www.nejm.org/doi/full/10.1056/NEJMoa1910775

IV Contrast, Unleashed

“The putative risk of administering modern intravenous iodinated contrast media in patients with reduced kidney function has been overstated.”

What a glorious lead sentence to the summary of this most recent guideline, a product of the American College of Radiology and the National Kidney Foundation. Historically, there has been great concern – including delay or exclusion of imaging – regarding the potential for acute kidney injury from intravenous contrast media in advanced imaging. However, a variety of recent different pieces of evidence have led to changes in perspective. This lovely guideline summarizes the data and issues a panoply of clarifications and recommendations regarding its use.

The most important distinction this guideline makes is between contrast-associated AKI and contrast-induced AKI. CA-AKI, as the authors note, is quite common – but is a rather a product of the underlying medical illness rather than the administration of IV contrast. CI-AKI, the attributable injury associated with IV contrast, is much harder to reliably observe. As noted in this article, summarizing mostly observational data sets, tweezing out the actual risk of harm from IV contrast media is challenging.

This guideline bundles together a whole list of concise questions and answers with regard to which patients may be at risk, the reliability of those estimates of risk, and what – if any – prophylaxis could be considered. Effectively – and the authors use many more words to clarify individual scenarios – the uncertainty regarding the safety of IV contrast begins to creep in around an eGFR of 30mL/Min/1.73m2. It should be noted this is related to a paucity of data, rather than a known observable risk. The authors recommendation, however, is not to exclude these patients from imaging, but rather to prompt a conversation between the referring professional and the radiologist to discuss the risks and benefits of IV contrast. Certainly life-threatening illnesses may require imaging, thus the careful weighing of risks versus benefits, and in these areas of uncertainly, additional cognitive consideration is reasonable.

With regard to prophylaxis against CI-AKI, the authors also make eminently reasonable statements saline volume expansion could be considered if clinically tolerated. The authors note this recommendation is based rather on observations of the utility of volume expansion for treating CA-AKI rather than CI-AKI, specifically, but likely represents a reasonable clinical practice.

In all, these guidelines quite nicely represent the uncertainly regarding harms from IV contrast administration, and, absent known harms from contrast, the potential harms from exclusion of IV contrast. As with most clinical problems, additional prospective research is critical to better inform practice.

“Use of Intravenous Iodinated Contrast Media in Patients with Kidney Disease: Consensus Statements from the American College of Radiology and the National Kidney Foundation”
https://pubs.rsna.org/doi/10.1148/radiol.2019192094

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