There has been considerable speculation in the literature regarding the physiology of intubated patients with COVID, but little actual data. A fresh study describing the physiology of intubated patients at Massachusetts General Hospital and Beth Israel offers to finally answer some questions.
This is a retrospective case series involving 66 patients intubated during March 11-30. Hospital treatment guidelines recommended the following:
- High-flow nasal cannula or non-invasive ventilation were not supposed to be used.
- Volume-cycled ventilation was favored with a target tidal volume below 6 cc/kg ideal body weight.
- Early prone ventilation was promoted for patients with a P/F ratio <200.
- PEEP was titrated per institutional protocols in a variety of ways (including the use of the lower PEEP / higher FiO2 ARDSnet table, titration by best compliance, or esophageal manometry).
General description of patients & outcomes
Without the ability to use noninvasive respiratory support, a strategy of early intubation was utilized. Almost all patients were intubated on the day of hospital admission.
Proning was used in 47% of patients, neuromuscular blockade in 42%, inhaled pulmonary vasodilators in 27%, and ECMO in 5%. Nearly all patients received azithromycin and hydroxychloroquine, with 26% also receiving remdesivir and 8% receiving steroids.
62% of patients were extubated following a median duration of ventilation of 16 days (interquartile range 10-21 days). 21% of patients received a tracheostomy, and 17% of patients died.
85% of patients initially met the Berlin definition of ARDS.
There has been a persistent debate about whether or not COVID patients have ARDS.
This study used the Berlin definition of ARDS, which is the standard definition. This definition is based upon the following criteria:
- Acute deterioration in respiratory status within <1 week.
- Bilateral opacities on chest imaging (not fully explained by effusions, atelectasis, or nodules).
- Respiratory failure not fully explained by cardiac failure or volume overload.
- PaO2/FiO2 ratio < 300 mm.
As discussed before, the Berlin definition of ARDS is horrifically broad and clinically useless. Nearly any intubated patient with acute bilateral parenchymal lung disease will meet this definition. Therefore, having ARDS based on this definition means almost nothing. No study has ever utilized the Berlin definition of ARDS as a trigger for any specific intervention – so the presence of ARDS doesn’t have any immediate clinical implication.
On ICU admission, only 85% of intubated COVID patients met the Berlin definition of ARDS. This is less than I would have expected. 97% of patients had bilateral opacities. Thus, the main reason that some patients failed to meet the definition of ARDS was that ten patients had a PaO2/FiO2 ratio >300 on the day of admission:
This is shockingly good oxygenation for patients who were just intubated due to hypoxemic respiratory failure. For example, a patient with P/F of >300 might be expected to achieve a PaO2 of >60 mm on only 21% FiO2. Such good oxygenation may partially be explained by their early-intubation scheme (with intubation of patients whose oxygenation really wasn’t very poor). However, the most likely explanation is probably that positive pressure ventilation caused immediate lung recruitment on the ventilator, with immediate improvements in the P/F ratio.
So yes, most patients intubated with COVID meet the Berlin criteria for ARDS. However, meeting this definition has no evidence-based clinical implications.
Many patients had pseudoARDS
PseudoARDS is defined as patients whose P/F ratio increases above 150 after 12-24 hours of optimization on mechanical ventilation (without proning). PseudoARDS is clinically relevant, because these patients don’t meet the Proseva trial’s indication for proning.1
Most patients in this series appeared to have pseudoARDS. The P/F ratio improved considerably over the first day on ventilation. By day #2, nearly all patients had a P/F ratio above 150 (red box below).
One limitation to this conclusion is that 47% of patients were proned (without indication of exactly when this happened). Thus, some of the improvement in oxygenation on day #2 likely resulted from proning (which would not meet the definition of pseudoARDS).
Patients with COVID-19 seem to have substantial problems with atelectasis and favorable responses to positive pressure ventilation (e.g. noninvasive CPAP). Much of the improvements seen between Day #1 and Day #2 could have reflected gradual recruitment in response to intubation with PEEP. These centers often used a low PEEP scale (with an average initial PEEP of 10 cm), so it’s conceivable that even greater improvements in P/F ratio might have been seen with a higher levels of PEEP.
Gattinoni’s L-phenotype & H-phenotype model is disproven.
Gattinoni et al. has suggested the existence of two different phenotypes of COVID.2–5 According to this model, patients present initially with the “L-phenotype” which is marked by normal lung compliance and low recruitability. Over time, lung injury may cause this to progress to the “H-phenotype” which is marked by low compliance and high recruitability. This model is supported by nearly no actual evidence. Remarkably, this speculative model has led Gattinoni et al. to recommend that patients with COVID be ventilated initially with low levels of PEEP (<10 cm) and high tidal volumes (7-9 cc/kg) – a management strategy which flies in the face of decades of research on hypoxemic respiratory failure.3
The Boston data disproves Gattinoni’s dichotomanious model, by demonstrating that the respiratory compliance of patients is actually low beginning on Day #1 (figure below; a normal compliance might be roughly 50-80 ml/cm). Please note that patients presented early (after a median illness duration of 7 days) and were intubated promptly. Thus, these mechanics should be an excellent representation of early COVID respiratory failure.
Another argument against Gattinoni’s model is lack of change in compliance over five days on ventilation (above). This data from Boston is entirely compatible with a prior series from Seattle, which likewise demonstrated low compliance on the ventilator beginning day #1 and no decrease in compliance over time (if anything, the opposite trend may have occurred):6
Similarly, a recent study involving 10 patients found no correlation between recruitability and duration of mechanical ventilation.7
Positive response to prone ventilation
Prone ventilation was utilized in 47% of patients. Proning caused improvements in oxygenation (from a median P/F ratio of 150 to 232). Among 31 patients who were proned, 12 received concurrent neuromuscular blockade. Thus:
- Prone ventilation does improve oxygenation (although proning is unnecessary in most patients).
- Prone ventilation can often be safely performed without paralysis.
So, how should we ventilate patients with COVID-19?
The short answer is that we should ventilate these patients the same way we have always ventilated patients with ARDS.
- Traditional ARDSnet ventilation is an evidence-based and solid approach to these patients (including variations with slightly higher or lower amounts of PEEP, or personalized PEEP).
- Early APRV ventilation is also evidence-based and might be preferable at centers with experience in this mode.8 APRV may be more likely to recruit lung tissue early, thereby avoiding a need for proning +/- paralysis (potentially minimizing sedative requirements and reducing time on the ventilator).
- Prone ventilation is effective. Furthermore, many patients appear to tolerate proning without paralysis.
- Patients who are intubated with COVID will nearly always meet the Berlin definition of ARDS. However, this is a very broad definition, so satisfying it has no immediate clinical implications.
- Many patients with COVID will have improvements in P/F ratio to >150 within one day of intubation (i.e., pseudoARDS). Patients whose P/F ratio increases over 150 simply due to ventilator optimization are less likely to benefit from proning.
- COVID patients have low compliance very early in the disease process, disproving Gattinoni’s H/L hypothesis.
- Patients with COVID should be ventilated in the same fashion as we have always ventilated patients with ARDS. At most centers, this will consist of low tidal-volume ventilation with ample amounts of PEEP (either based on a PEEP table or personalized titration). APRV is another evidence-based technique which is attractive, for centers with adequate expertise.
- “New” ventilatory strategies which fly in the face of existing evidence should be avoided (e.g. using unusually low levels of PEEP and high tidal volumes). Many of these strategies aren’t truly new – they’ve actually been disproven years ago.
related:
- ARDS vs. pseudoARDS: failure of the Berlin definition (2018)
- Defining ARDS and recruitability, with implications for COVID-19
Image credit: Photo by todd kent on Unsplash
references
- 1.Guérin C, Reignier J, Richard J, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159-2168. doi:10.1056/NEJMoa1214103
- 2.Gattinoni L, Chiumello D, Rossi S. COVID-19 pneumonia: ARDS or not? Crit Care. April 2020. doi:10.1186/s13054-020-02880-z
- 3.Marini JJ, Gattinoni L. Management of COVID-19 Respiratory Distress. JAMA. April 2020. doi:10.1001/jama.2020.6825
- 4.Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. Covid-19 Does Not Lead to a “Typical” Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. March 2020. doi:10.1164/rccm.202003-0817le
- 5.Gattinoni L, Chiumello D, Caironi P, et al. COVID-19 pneumonia: different respiratory treatments for different phenotypes? Intensive Care Med. April 2020. doi:10.1007/s00134-020-06033-2
- 6.Bhatraju P, Ghassemieh B, Nichols M, et al. Covid-19 in Critically Ill Patients in the Seattle Region – Case Series. N Engl J Med. March 2020. doi:10.1056/NEJMoa2004500
- 7.Mauri T, Spinelli E, Scotti E, et al. Potential for Lung Recruitment and Ventilation-Perfusion Mismatch in Patients With the Acute Respiratory Distress Syndrome From Coronavirus Disease 2019. Critical Care Medicine. April 2020:1. doi:10.1097/ccm.0000000000004386
- 8.Zhou Y, Jin X, Lv Y, et al. Early application of airway pressure release ventilation may reduce the duration of mechanical ventilation in acute respiratory distress syndrome. Intensive Care Med. 2017;43(11):1648-1659. doi:10.1007/s00134-017-4912-z
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Hi Josh. I’m an ICU trainee in Australia and enjoy your blog, e-book and podcast. I tend to agree with your conclusions here but would like to hear more of your thoughts on two points. Firstly a little push back on APRV being evidence based. Although i share your enthusiasm for this therapy I am not sure the evidence is not solid enough to call a base, As you point out in your initial blogpost on the trial, the Zhou paper you reference here has many issues. I was wondering about your thoughts on this summary review of that trial… Read more »
1) the Zhou paper isn’t perfect, but it’s a reasonably compelling RCT. I discussed it previously here: https://emcrit.org/pulmcrit/aprv/. There are lots of different ways to set APRV, so it’s not one homogenious thing. Fundamentally, APRV is reasonably similar to low tidal volume ventilation in many ways (in the Zhou trial, there was no significant difference in tidal volume between the conventional ventilation group vs. APRV group). The main point though is that APRV has been studied and utilized in ARDS for years. It’s not something that we just made up out of the blue to deal with COVID. 2) yeah… Read more »
Josh I usually agree with your interpretation of literature, or at least I appreciate your take on a lot of subjects even when I don’t agree. I really think this post is bit overstated. The data you mention is contrary to what Gattinoni described, however it’s a huge stretch to say it disproves the H/L phenotype theory (which we all know is not a true dichotomy but rather two opposite ends of a spectrum, with most patients falling somewhere in the middle). The lack of change in compliance over 5 days on the vent in the Boston paper is interesting;… Read more »
The amount of evidence required to disprove a theory depends on how well the theory was initially supported to begin with.
for example, the theory of gravity is supported by lots of evidence. so it would take an enormous amount of incontrovertible evidence to somehow disprove it.
Gattinoni’s theory is supported by almost no evidence. therefore, it doesn’t take much evidence to dispute it. It seems to me that all of the best available evidence argues *against* Gattinoni’s concepts – and there was never any solid evidence to support them in the first place.
I hope everyone is safe in this pandemic. I hope everything goes back to normal like before.
I think patients were intubated prematurely without even trying high flow. The initial protocols of intubating patients requiring high flow is misguided based on fear of aerosolisation. These patients do well with non invasive ventilation as well. We intubate patients only if patients fail both.
agree
Dear Josh: Incredible review as always. I just do not find any advantage in using ARDS net table for setting PEEP levels. I believe an open lung strategy and PEEP titration with a recruitment manouver (incr-decr with PCV) would be a more physiologic strategy. Optimal PEEP levels could vary over time and titration to optimal compliance would be a protective and rational strategy. More over, lung ultrasound scores and CO2 GAP (especially if you have access to volumetric capnography) are other important tools we can use in order to individualize the best ventilatory settings for each patient and clinical context.… Read more »
Dear Josh: Thanks for sharing your thouhts and all you do to propel #FOAM forward. Have to push back on a couple of your comments: 1. The debate is not wether COVID patients meet the BERLIN criteria. As this paper shows and as many in practice have seen they often do when patients are sick and get intubated in the ICU. The observation made by Gattinoni simply states that there is a subset of patients that present with lung mechanic findings not typical to what we usually see in moderate to severe ARDS. 2. Yor are very ademant that this… Read more »
The burden of proof lies with those who are making new claims. Bold claims call for substantive supporting evidence. If H&L phenotypes exist, then it is incumbent upon Gattinoni et al to furnish evidence that they exist (and if they are as common as claimed, finding such evidence shouldn’t be difficult at all). As always, I’m fully open to reconsidering my position on the basis of new evidence.
agee 100% Gattinoni L and H is not 2 types, but a spectrum, and also what we have see in my ICU, menu has normal CSr/Cdy stille has the hallmarks of ARDS. see the paO2 go up when you turn down the peep the high tabel.
physiology applied to individual patient, is better than cook book medicine, as long as you you know the evidence and goals
Josh Farkas the work you do is top class !!!!!
Neonatologist here, following this as closely as one can from a laptop. I read the cohort study and Josh’s interpretation. Can anyone comment on the echo results and the response to inhaled pulmonary dilators? Neither of these are mentioned in the article.
Josh, I fully agree that you can’t go from a pathological pattern to a ventilatory strategy – this is an important concept for the trainees to grasp – especially when you probably haven’t fully delineated the pathology concerned. Before bedside ECHO became a tool of the intensivists, we only had a rather blinkered view of the issue of the lack of response to airway recruitment maneuvers. The full hemo-dynamic and pulmonary impact of increasing the MEAN AIRWAY PRESSURE could never be fully grasped and we were mostly in the rather treacherous territory of “educated guesses” and “assumptions”!. By focusing rather… Read more »
Almost forgot to add – if a patent Foramen Ovale is the reason for worsening hypoxemia in response to the usual recruitment maneuvers, proning would help, because anatomical studies have shown that in the prone posiition, there is a slight “shift” of the inter-atrial septum, causing a kind of ‘natural closure’ of the foramen – decreasing the right to left shunt. http://rc.rcjournal.com/content/early/2017/05/30/respcare.05512
Hi Josh
To intubate. or not to intimate?
That is the great question
And when?
Thanks for all of the fantastic work you do. I have learned a tremedous amount from your posts over the years. My specific question is regarding the last point in “the bullet” ; “New” vent strategies which could allow for low peep, high tidal volume. A) Do you agree with Amato regarding the concept of driving pressure as the major mechanism of ventilator induced lung injury? B) If you do, (a big if) and the patient’s compliance and oxygenation allow, (I won’t say “L” phenotype) do you think that there is harm associated with “high” (I guess more than 6… Read more »
Simple dude with a simple question: I’m seeing this described as endothelial vascular thrombosis. Yes? No?
Still seeking a fact check on this. On social media the hypothesis is attributed to someone named Não há, who might be a medical researcher in Italy. For definition of endothelial vascular thrombosis, does this pre-COVID article serve? https://journals.sagepub.com/doi/pdf/10.1177/0003319717732238
Dear Josh, Thank you for this fantastic insight on COVID-19 management. Like many others have stated I’d like to continue to try NPPV/NIV as this modality seems to help these patients and if we have the required PPE with a negative pressure room than there is no reason not to trial non-invasive therapies. As this new theory from Gattinoni et al seems like a decent theory and seems believable, I didn’t see any evidence that really back it up like you have stated as well. Does anyone support the use of PRVC? ASV? I think there might be a genetic… Read more »
Hey, It was amazing to go through your post, that was really so useful and informative!