Reference: Villar. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med 2020; 8: 267–76.
I know what you are thinking, “What gives? No COVID!” Well the two of you who read this are probably inundated with COVID info. So to give our brains a change I thought I would do a study that would DEFINITELY BE A HEADLINE if we weren’t COVID CRA. But just as DC gets overshadowed by Marvel so to this good (but slightly methodologically flawed) study may go unnoticed.
This study look at the utility of dexamethasone (dex) to treat MODERATE to SEVERE ARDS. I say this in bold because other trials didn’t have an entry criteria of a PaO2/FiO2 (“P/F” Ratio) of <200 (usually its worse like <150)…but this one did. Boy did they find a difference. The primary outcome was ventilator free days and they found that dex ALMOST halved this (7.5 vs 12.3)! Secondary outcomes (sloooowwww down those are hypothesis generating…quiet you, I want to be happy about something): All-cause mortality…halved!: (29 vs 50); ICU Mortality halved! (26 vs 43). Well not quite but pretty close. Now before we celebrate like its the end of social distancing* there are a TWO MAJOR FLAWS in the armor of this trial.
Flaw #1. Not only was it open label (the docs knew they were giving a steroid) but there WASN’T a placebo…what the what!!!! They state as follows:
“According to the ethical principles for medical research of the Declaration of Helsinki,19 the use of no placebo (no intervention) is acceptable when no proven intervention exists and when the patients who receive a placebo could be subjected to additional risks (eg, intravenous catheter-associated infections and interaction with other medications). The Spanish Agency of Drugs and Medical Devices and the referral Ethics Committee did not mandate a blinded design nor the administration of a placebo.”
“Although dexamethasone was not administered in a masked manner, the risk of assessment bias is very low because one of the outcomes of interest (mortality) is objective.”
Any who has ever been a patient or spent time as learner (and we are all learners) knows NOTHING is OBJECTIVE. The decision to take someone off the vent earlier COULD absolutely have been influenced.
Flaw #2: The trial was stopped short. The trial was calculated to have 317 parties with 157 in each arm but only ended up with 139 (+1) in each.
The trial was stopped at 88% enrollment due to low enrollment. Stopping a trial short can OVERESTIMATE the effect size.
A minor flaw in this study is that they also took less sick patients than other trials. As is the mantra with research “If it didn’t work, you didn’t give it early enough”…once again this was “right”.
Two good things they did correctly is look at new infections and hyperglycemia in both groups and found no difference.
That being said there looks like a signal here. Im sure when it comes down to it the GIANT changes seen here, they won’t pan out to be as big in real life but I bet there is something to giving dex to ARDS…at least I can hope. As an ER/ICU doc its another reason for me to give steroids… and you can’t spell stERoids without ER!
*I REALLY don’t like the term social distancing/isolation…we should call it “physical distancing/isolation”. We can stay in touch, without the touching!
THE BOTTOM LINE
A non-rebreather (NRB) mask ONLY delivers high FIO2 when the flow meter valve is opened fully and even then only gets to about 90%.
I find great joy in reading old literature. I’m pretty sure I would be camped out in a medical library if it weren’t for the interwebs, thank goodness I can do all this from home…For this installment of the basics we look at how much oxygen that non-rebreather (NRB) mask actually delivering.
First, we need to talk about what a non-rebreather does. It’s mostly in the name but it isn’t always intuitive as I see it often used incorrectly. A non-rebreather should not allow you to re-breathe; yes I know how silly that sounds. However, when the NRB is working correctly the reservoir should not deflate with inhalation otherwise you are rebreathing. The NRB has two one-way valves. One is between the reservoir and the mask to allow oxygen to flow into the mask when you breathe in but not when you breath out. The other is at the side of the mask and allows the exhaled air to escape to the world. Ideally, the 100% FIO2 (Fraction of Inspired oxygen) in the bag is inhaled and thus the patient gets 100% oxygen delivery. Unfortunately in the real world this does not happen. One important reason is most NRB’s only have the one one-way valve so the patient doesn’t suffocate if the wall oxygen were to fail. Also the mask may not fit as tightly so oxygen will escape from the mask further decreasing the FIO2. Finally, we use oxygen on sick patients who may have increased respiratory rates and abnormal tidal volumes. Thus the normal minute volume will be abnormal in a sick patient. The goal of preoxygenation is to get the nitrogen part of normal air washed out and replace it with oxygen so our blood will be “super-saturated” and we will have longer times of apnea without the oxygen saturation dropping while a patient is being intubated. Thus we would like as high as possible FIO2 going into the patient. Also we really cant tell what the PaO2 is from the pulse ox monitor because no correlation can be made once SaO2 is >98%.
Thus we NEED to know the FIO2 of the non-rebreather going in. To figure this out we go back in time to 1991 while this might sound scary to go to a time period without iphones; we only have to be there long enough to see the article by Farias, Delivery of High Inspired Oxygen by Face Mask in the Journal of Critical Care. The recruited 5 healthy male volunteers and changed respiratory rates, tidal volumes and oxygen flow rates to see the effect on the FIO2 of a non-rebreather. Now here is the impressive part of the study “FIO, was measured from a catheter positioned through the nose so that its tip was in the pharynx”. The “catheter” was a 6Fr Foley that was inflated once in the oropharynx! These people volunteered for this? You sure they didn’t get paid something???? Yikes! This is why the old literature is entertaining! Anyway…. All wall oxygen comes through a flow valve with a little metal ball that measures the flow out. Normally, with a NRB the flow is set to 15L on the meter and sadly this is the highest the meter reads. So to test various flow rates they had to use their own flow meter and tested rates of 15, 20,30,40 and 60 L/min. They note, “by opening the valve fully on the flow meter, it was possible to attain an 02 flow of 60 L/min. “. At each flow rate the volunteers produced respiratory rates (RR) of 20, 30, and 40 breaths/min (brpm) and also varying tidal volumes (VT) of 500, 750, and 1000 mL. Normal tidal volume is around 500 ml or 7 ml/kg. For a normal RR of 20 and a “normal” VT of 500ml, when the flow was set to 15L the best FIO2 obtained was just shy of 60%. When the RR was 40 brpm and the VT was 1000 ml, this fell to 40% . The study notes, “When the O2 flow rate was increased to 60 L/min, the FIO2, remained at approximately [90%] despite increasing respiratory frequency and tidal volume.”
Hence, this is the reason I say crank that little knobby thing on the oxygen until it stops. Because only then are you getting 60 L/min of oxygen and only then, regardless of RR and VT, does one approximate FIO2 of 100%…well ok 90% but I’ll take it! The study also looks at ways to improve the masks by doing stuff to them but since I’m just using the NRB before I intubate I’ll be sufficiently happy with a 90% FIO2 to preoxygenate my patients besides I don’t need to look any crazier to the staff by making an art project out of the masks before I intubate someone…
Farias, E. et al. Delivery of high inspired oxygen by face mask Journal of Critical Care. Volume 6, Issue 3, September 1991, Pages 119-124.
There hasn’t been an update to the IDSA/ATS guidelines for CAP (community acquired pneumonia) since 2007 (I keep hearing they will be out soon). These guidelines recommend a macrolide antibiotic as first-line therapy for previously healthy patients who have no risk factors for drug-resistant S. pneumonia (SPN) infection (strong recommendation) and a combination of a macrolide and a beta-lactam for patients who require hospitalization but not in the ICU 1. In the last few years, concerns for macrolide resistance have been discussed (I’m looking at you EM-RAP). Paradoxically no real affects on clinical outcomes have been shown. Referred to as the aptly named in vivo-in vitro paradox2 there are divergent findings of macrolide resistance and clinical outcome. Lets talk amongst ourselves, shall we?
Macrolide resistance is a thing! But the clinical studies don’t yet support the concerns of the in vitro findings of resistance. The IDSA/ATS guidelines have not been updated since 2009 and its still OK to use macrolide monotherapy when high levels of strep pneumo resistance are unlikely. So what to do? If I’m worried about compliance I’ll still prescribe OUTPATIENT azithromycin alone (especially if I feel atypicals are the cause and at least until new IDSA guidelines come out). If I am at all “worried” I will add in a beta-lactam. For HOSPITALIZED PATIENTS OR SEVERE DISEASE NEVER USE AZITHROMYCIN ALONE. RESISTANCE MAY BE ANNOYING BUT ITS NOT YET FUTILE
I’m not disagreeing with macrolide resistance in general, I just don’t think it’s futile to use these even as monotherapy in CAP. Typically Azithromycin resistance is defined as an MIC >2 μg/mL) and sometimes very high resistance levels are seen. However there seems to be disparate results between MIC’s and clinical cure rates. I think the misperception is best seen in Zhanel’s article 3on clinical cure rates. This study looked at community acquired respiratory infections (CARTI) and azithromycin resistance in streptococcus pneumoniae. Overall if you look at the study there was about a 10% difference in clinical cure rate in those treated with azithromycin for ALL respiratory tract infections. HOWEVER, in this group they included the following as CARTI: acute otitis media (sometimes air comes out of my ear when I sneeze but I don’t think its part of the respiratory tract!), CAP, acute bacterial exacerbations of chronic bronchitis and acute bacterial sinusitis. They found 1127 patients with CARTI of which they found 29% (112/388) of subjects with SPN had AZ-R. Overall, clinical cure rates in CARTI subjects treated with azithromycin were higher for in AZ-S (89.4%) versus AZ-R (78.6%; P=0.003). BUT if you look at CAP alone for AZ-S vs AZ-R the failure rates were 3/52 vs 2/27 (p=0.986) and the cure rates were 49/52 (94%) vs 25/27 (93%), respectively. These are small numbers true so lets look at some more studies.
In this study by Yanagihara4 they looked at a 3 (Three??? Yes three) day course of azithromycin in adults with mild to moderately severe CAP, and to determine whether in vitro macrolide resistance in of SPNis related to clinical failure. A good clinical response was defined as improvement of 3 of the 4 following outcomes: 1) resolution of fever 2) resolution of wbc’s, 3) improvement of CRP and 4) improvement of CXR findings. They found a good response in 13/17 (76%) and an ineffective response in 4/17 (23%). Strangely, 6 of 7 patients in whom high-level resistance was documented (MICs >256 μg/mL) showed good clinical responses. If you look at CAP alone for AZ-S vs. AZ-R the failure rates were 0/2 vs. 4/12 and the cure rates were 2/2 vs. 8/12, respectively.
In this study, Kohno5 looked at moderate-to-severe community-acquired pneumonia. They found that despite mostly having AZ-R strains in Japan, clinical efficacy and bacterial eradication were achieved in 10 of 11 patients. If we combine these 3 studies (not a great meta-analysis I know…) for AZ-R then you would have 43/50 (86%) good responses and 7/50 (14%) poor responses and this is in places with the highest rates of resistance… 6
Lastly, in this study by Cilloniz7 looked at outcomes in AZ-S vs. AZ-R. They found 30-day mortality in AZ-S to be 32/493 (6%) vs. AZ-R 9/133 (7%, p=0.93) and ICU admission to be 140/493 (28%) vs. 32/133 (24%, p=0.29).
Indeed there is some thought that macrolide antibiotics have additional properties than just their bacteriostatic/bacteriocidal properties. Some studies8 suggest that macrolides have anti-inflammatory properties and prevent the production of pro-inflammatory mediators and cytokines. This recent study of lowered mortality in CAP would agree with a reduction of all cause in hospital mortality and a 10% difference (not statistically significant) in 30-day mortality. Here, Arnold et al.9 looked at 549 patients with CAP and bacteremia where 247 (45%) were treated with a macrolide and 302 (55%) were not. The unadjusted 30-day mortality was 18.4% in the macrolide group, and 29.6% in the non-macrolide group (RR=0.81, CI 0.50–1.33; P = 0.41). Unadjusted in-hospital all-cause mortality was 7.3% in the macrolide group, and 18.9% in the non-macrolide group (RR= 0.54, CI 0.30–0.98; P = 0.043).
There are two major mechanisms mediating resistance to macrolides. The ermB gene encodes a methyltransferase that causes ribosomal methylation resulting in a phenotype that reduces susceptibility to macrolides (and lincosamide FYI). This mechanism results in the highest macrolide resistance. The second mechanisms is the mefA gene which codes for an antibiotic efflux pump removing the drug from the SPN. Macrolides are concentrated intra-cellularly, and this is thought to result in increased drug delivery to the site of infection, and exposure to high concentrations of drug following phagocytosis, which may overcome low level resistance6 . Possibly high-level resistance may be clinically relevant , however that was not exactly the case in the above Yanagihara study.
So in summary, macrolide resistance is definitely real. However, there really does not seem to be a huge affect clinically when azithromycin resistance is encountered. Furthermore, Azithromycin resistance is probably more likely in its uses other than CAP, like otitis media and sinusitis (and other infections I don’t treat with antibiotics). So how do we use this information? Well I would NEVER use macrolides alone for hospitalized patients. I still believe that for hospitalized patients macrolides and beta-lactams are the way to go. In fact, I like to add azithromycin to even my ICU patients just in case there is something magical about the macrolides. For outpatient management of mild CAP I think there is still a role for macrolide monotherapy. We all know that compliance is not great with patients and I feel in mild disease I’d rather they take 1 once a day antibiotic rather than have to add in a beta-lactam and have them not take it.
- Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44 Suppl 2, S27-72.
- Bishai W. The in vivo-in vitro paradox in pneumococcal respiratory tract infections. J Antimicrob Chemother 2002; 49, 433-436.
- Zhanel GG, Wolter KD, Calciu C et al. Clinical cure rates in subjects treated with azithromycin for community-acquired respiratory tract infections caused by azithromycin-susceptible or azithromycin-resistant Streptococcus pneumoniae: analysis of Phase 3 clinical trial data. J Antimicrob Chemother 2014; 69, 2835-2840.
- Yanagihara K, Izumikawa K, Higa F et al. Efficacy of Azithromycin in the Treatment of Community-acquired Pneumonia, Including Patients with Macrolide-Resistant Streptococcus pneumoniae Infection. Internal Medicine 2009; 48, 527-535.
- Kohno S, Tateda K, Kadota J et al. Contradiction between in vitro and clinical outcome: intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia. J Infect Chemother 2014; 20, 199-207.
- Cheng AC, Jenney AWJ. Macrolide resistance in pneumococci-is it relevant. Pneumonia (Nathan) 2016; 8, 10.
- Cilloniz C, Albert RK, Liapikou A et al. The Effect of Macrolide Resistance on the Presentation and Outcome of Patients Hospitalized for Streptococcus pneumoniae Pneumonia. Am J Respir Crit Care Med 2015; 191, 1265-1272.
- Ianaro A, Ialenti A, Maffia P et al. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther 2000; 292, 156-163.
- Arnold FW, Lopardo G, Wiemken TL et al. Macrolide therapy is associated with lower mortality in community-acquired bacteraemic pneumonia. Respir Med 2018; 140, 115-121.
QUICK HIT ARTICLE
Effect of a Low vs. Intermediate Tidal Volume Strategy on Ventilator-Free Days in Intensive Care Unit Patients Without ARDS: A Randomized Clinical Trial. Writing Group for the PReVENT Investigators . Simonis. JAMA. 2018; 320(18):1872-1880
All right pop quiz, hotshot. Altered patient gets intubated in the ED. He’s almost to the ICU. The RT asks you for vent settings. What do you do Jack. What do you do …
TAKE HOME MESSAGE
In this somewhat blinded RCT of low (4-6 ml/kg) versus intermediate (10 ml/kg) in patients WITHOUT ARDS for the composite primary outcome of number of ventilator-free days AND alive at day 28, there was not difference between the 2 groups. Setting your tidal volume anywhere less than or equal to 10 is probably fine in the patients without ARDS/Lung issues.
This study was a randomized clinical trial conducted at ICUs of 6 hospitals in the Netherlands. The trial did utilize concealed allocation and intention to treat analysis. The trial enrolled patients who received invasive ventilation just before or after admission to the ICU and who were expected to be intubated for more than 24 hours. Patients were to be randomized within 1 hour of initiation of ventilation in the ICU. Exclusion criteria were the presence of ARDS, strictly following the criteria of the Berlin Definition for ARDS. Patients were randomized in a 1:1 ratio to a low or intermediate tidal volume ventilation strategy group. Patients assigned to the low tidal volume group started at a tidal volume of 6 mL/kg predicted body weight (PBW) and received either volume-controlled or pressure support ventilation. Tidal volume was then decreased by 1 mL/kg PBW every hour to a minimum of 4 mL/kg PBW. With pressure support ventilation, the lowest level of pressure support was used to reach the target tidal volume with a minimum of 5 cm H2O. If tidal volume increased more than 8 mL/kg PBW with the minimum pressure support, this was to be accepted.
Patients assigned to the intermediate tidal volume group started at a tidal volume of 10 mL/kg PBW using a volume-controlled ventilation mode. If the plateau pressure exceeded 25 cm H2O, tidal volume was decreased in increments of 1 mL/kg PBW per hour. Additional use of analgesia, sedation or muscle relaxants, with the purpose of allowing the assigned ventilation strategy, was not permitted.
The primary (composite) outcome(s) was the number of ventilator-free days AND alive at day 28, defined as the number of days that a patient was alive and free from invasive ventilation. Secondary outcomes included ICU and hospital length of stay; ICU, hospital, and 28- and 90-day mortality; and the occurrence of pulmonary complications, including the development of new ARDS, ventilator-associated pneumonia, severe atelectasis, and pneumothorax. Mortality at day 28 was not included as a secondary outcome in the original protocol but was subsequently added in the updated protocol. A sample size of 952 patients (476 per group) was estimated to have 80% statistical power to show a difference of 1 ventilator-free day at day 28 allowing for a 20% dropout rate. In a pre-specified exploratory analysis, the effects of the intervention on the primary outcome were investigated in subgroups: with vs. without pneumonia; with vs. without sepsis; PaO2/FiO2 less than or equal to 200 vs. greater than 200, etc.
Between September 1, 2014, and August 20, 2017, 3695 patients were screened. More than 80% of the patients were admitted to the ICU for a medical reason. The most frequent reason for invasive ventilation was cardiac arrest.
The median time between the start of ventilation and randomization was 0.88 hours (IQR, 0.36-2.01). During the first 3 days of ventilation, tidal volumes and airway pressures were significantly different among the groups. Plateau and driving pressure were lower and respiratory rate was higher in the low tidal volume group than in the intermediate tidal volume group, while minute ventilation and PEEP did not differ significantly between groups.
For the primary outcome there was no difference between the two groups. Patients in both groups had a median of 21 ventilator-free days (mean difference, –0.27 [95% CI −1.74 to 1.19]; P = .71). There was no significant difference in ANY of the secondary outcomes nor in any of the subgroups. The differences on day 3 were only in the respiratory variables. In the low tidal volume the groups had a higher paCO2 (42 vs. 38), more patients with a pH <7.25 (7 vs. 1), and more respiratory acidosis (17 vs. 8). The driving pressure (Plateau minus the PEEP, which some argue as the value most consistent with barotrauma) was lower in the Low TV group vs. Intermediate (11 vs. 14).
Thus it would seem on its face that there may be no differences between low TV and intermediate TV for patients without ARDS. This may be due to the fact that we aren’t talking low vs. high TV but intermediate TV. There were some respiratory parameters such as more acidosis and lower driving pressures in the low TV group but for both groups the driving pressure was under 15 which some would say is the “safe” range. Of note respiratory rate was not elevated and the minute ventilation was not different suggesting that the VT may not have been that different. Overall there is a range of TV’s that are probably fine for the patient
Doshi. P. High-Velocity Nasal Insufflation in the Treatment of Respiratory Failure: A Randomized Clinical Trial. Ann Emerg Med. 2018;72:73-83.
To be or not to be, chocolate or vanilla, Bipap or High Flow… That is the question. In respiratory failure which modality is best for the distressed patient to prevent intubation. I’ve always thought that Bipap for CHF, High flow for everything else. This week we have a study that looked at this question…
This was a prospective multicenter RCT of high flow (HF) vs BiPAP in patients with respiratory distress. The “distress” was defined by clinician judgement at the time. The authors concluded this trial showed HF was non-inferior to BiPAP because of a difference of less than 15% of patients were intubated at 72 hours (7% vs 13%, respectively). However, it is a little more complicated than that. HF did have less intubations at 72 hours but it also had more patients fail that pathway and crossover to BiPAP than did in the BiPAP arm. I think a larger study that excluded CHF patients would be great. The bottom line is I still think BiPAP for CHF and high flow for all other respiratory distress. If you want the nitty gritty it’s below
The Dirty Details
Study Method: Prospective Multicenter, parallel group RCT of high flow and BIPAP in 5 centers in the US. A sample size of 204 patients (102 in each arm) was calculated such that a test of proportions with a .05 significance level and 90% power with a noninferiority margin for intubation of 15%. Analyses were based on an intention-to-treat
Study Population: >18 yo with clinical judgment of the treating clinician of acute respiratory failure requiring escalation to BIPAP.
Exclusion criteria: overdose, CV instability, end stage cancer, life expectancy less than 6 months, significant respiratory depression on presentation (e.g., drug overdose), Glasgow Coma Scale score less than 9, cardiac or respiratory arrest on presentation, need for emergency intubation, known or suspected cerebrovascular accident, known or suspected ST-segment elevation myocardial infarction, and patients with increased risk of pulmonary aspiration, agitation, or uncooperativeness.
Primary Outcome: The primary outcomes were treatment failure rate, defined as the need for intubation, and arm failure rate, defined as the decision for crossover to the alternate therapy, within 72 hours of initiation of assigned therapy. Failure of the assigned noninvasive ventilatory therapy was defined as failure to tolerate therapy, failure to oxygenate, failure to ventilate, failure to alleviate respiratory distress, or deteriorating medical status.
Hypothesis Generation: Secondary outcomes included evaluation of the ability of high-velocity nasal insufflation versus BiPAP to affect the degree and timing of changes of PCO2, pH, and other signs or symptoms of respiratory distress, including vital signs and perceived exertion scores reported by the patients.
Patients Enrolled: 228 patients from October 2014 to September 2016. 204 were enrolled in the trial, 24 patients randomized but not enrolled (You can’t do that, No soup for you!)
Demographics: APACHE II scores were similar in both (6.3 vs 6.5). Mean baseline PCO2 level was 53.4 mm Hg in the high-velocity nasal insufflation group and 58.7 mm Hg in the BiPAP group. The most common condition treated was COPD, both in terms of presenting condition (39%) and discharge diagnosis (26%). The second most common discharge diagnosis was acute decompensated heart failure (21%), followed by pneumonia (14%) and acute multifactorial hypoxic and hypercapnic respiratory failure (14%).
BIPAP Dose: High-velocity nasal insufflation was titrated to a mean flow rate of 30 L/min, BiPAP was titrated to mean settings of 13 cm H2O over 6 cm H2O
|Noninferiority=15% difference||High Flow||BiPAP|
|Intubation at 72hr*||7 (7%)||13(13%)|
|Mode Success||77 (74%)||83 (83%)|
|Mode Failure||27 (26%)||17 (17%)|
|Intubated||4 (4%)||11 (11%)|
|Crossed Over||23 (22%)||6 (6%)|
|Intubated after Cross over||3 (13%)||3 (50%)|
The Bottom Line
So essentially this trial would argue statistically that High Flow is non-inferior to BiPAP. However, it is a little more confusing than that. Starting with HF there were fewer overall intubations. However, there were more “failures” in the HF also where more people crossed over to BIPAP (were those the CHF patients?). Unfortunately, these are things we don’t know. So, I don’t think this will change my practice much as of now although I already do a fair amount of High Flow but I will still keep doing BiPAP in CHF until I see otherwise. From my clinical experience BiPAP works so well for CHF.