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.
- ARDS vs. pseudoARDS: failure of the Berlin definition (2018)
- Defining ARDS and recruitability, with implications for COVID-19
- 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