Impact of liberal versus conservative saturation targets on gas exchange indices in COVID-19 related acute respiratory distress syndrome: a physiological study

ABSTRACT

Objective:

To compare gas exchange indices behavior by using liberal versus conservative oxygenation targets in patients with moderate to severe acute respiratory distress syndrome secondary to COVID-19 under invasive mechanical ventilation. We also assessed the influence of high FiO₂ on respiratory system mechanics.

Methods:

We prospectively included consecutive patients aged over 18 years old with a diagnosis of COVID-19 and moderate-severe acute respiratory distress syndrome. For each patient, we randomly applied two FiO₂ protocols to achieve SpO₂ 88% - 92% or 96%. We assessed oxygenation indices and respiratory system mechanics.

Results:

We enrolled 15 patients. All the oxygenation indices were significantly affected by the FiO₂ strategy (p < 0.05) selected. The PaO₂/FiO₂ deteriorated, PA-aO₂ increased and Pa/AO₂ decreased significantly when using FiO₂ to achieve SpO₂ 96%. Conversely, the functional shunt fraction was reduced. Respiratory mechanics were not affected by the FiO₂ strategy.

Conclusion:

A strategy aimed at liberal oxygenation targets significantly deteriorated gas exchange indices, except for functional shunt, in COVID-19-related acute respiratory distress syndrome. The respiratory system mechanics were not altered by the FiO₂ strategy.

Clinical Trials Register: NCT04486729.

Keywords:
COVID-19; Respiratory distress syndrome; Respiration; artificial; Oxygenation; Pulmonary gas exchange; Respiratory mechanics

RESUMO

Objetivo:

Comparar o comportamento dos índices de troca gasosa conforme o uso de alvos de oxigenação liberais em comparação a conservadores em pacientes com síndrome do desconforto respiratório agudo moderada a grave secundária à COVID-19 e em uso de ventilação mecânica; avaliar a influência da FiO₂ elevada na mecânica do sistema respiratório.

Métodos:

Foram incluídos prospectivamente pacientes consecutivos com idades acima de 18 anos, diagnóstico de COVID-19 e síndrome do desconforto respiratório agudo moderada e grave. Para cada paciente, aplicou-se aleatoriamente dois protocolos de FiO₂ para obter SpO₂ de 88% a 92% ou 96%. Avaliaram-se os índices de oxigenação e a mecânica do sistema respiratório.

Resultados:

Foram incluídos 15 pacientes. Todos seus índices foram significantemente afetados pela estratégia de FiO₂ (p < 0,05). A proporção PaO₂/FiO₂ deteriorou, o PA-aO₂ aumentou e o Pa/AO₂ diminuiu significantemente com a utilização de FiO₂ para obter SpO₂ 96%. Opostamente, a fração de shunt funcional foi reduzida. A mecânica respiratória não foi afetada pela estratégia de FiO₂.

Conclusão:

Uma estratégia com alvos liberais de oxigenação deteriorou significantemente os índices de troca gasosa, com exceção do shunt funcional, em pacientes com síndrome do desconforto respiratório agudo relacionada à COVID-19. A mecânica do sistema respiratório não foi alterada pela estratégia de FiO₂.

Registro Clinical Trials: NCT04486729.

Descritores:
COVID-19; Síndrome do desconforto respiratório; Respiração artificial; Oxigenação; Troca gasosa pulmonar; Mecânica respiratória

INTRODUCTION

The novel infection caused by coronavirus-19 (COVID-19) has been recently recognized and has spread throughout China and most countries around the world. Almost 25 million people were infected worldwide by August 27, 2020, and the number of deaths has risen to more than 820,000.(¹)

Approximately 85% of COVID-19-infected patients admitted to the intensive care unit (ICU) develop severe acute respiratory syndrome (SARS-CoV-2).(²) However, despite meeting acute respiratory distress syndrome (ARDS) criteria, the pathophysiological features and clinical course of SARS-CoV-2 may differ substantially from those of classical ARDS.(³,⁴)

According to the Berlin definition, the severity of ARDS is determined by the degree of gas exchange compromise.(³) Consequently, the quantification of oxygenation indices is considered mandatory. In particular, the quotient of partial pressure of oxygen and fraction of inspired oxygen (PaO₂/FiO₂) is the oxygenation index most widely used in daily clinical practice due to its availability and ease of interpretation. Furthermore, the PaO₂/FiO₂ value is a determinant to guide the implementation of rescue therapies such as high positive end expiratory pressure (PEEP), neuromuscular blocking agents,(⁵) prone positioning(⁶) or extracorporeal membrane oxygenation.(⁷) However, the PEEP level, the stabilization time after adjusting ventilatory settings, the time after ARDS onset and the FiO₂ selected when obtaining arterial blood gases have all been shown to significantly influence the PaO₂/FiO₂ value.(⁸)

In clinical practice at the bedside, FiO₂ selection is based on pulse oximeter saturation (SpO₂). The most relevant ARDS clinical trials published in the last two decades set FiO₂ to obtain a SpO₂ between 88 - 95%.(⁵-⁷,⁹) However, some controversies exist regarding the benefits and harms of liberal versus conservative oxygenation approaches in patients with classical ARDS during controlled mechanical ventilation.(¹⁰,¹¹) In this setting, the surviving sepsis campaign recently recommended a SpO₂ between 92% and 96% in ARDS caused by COVID-19.(²) Considering the particular pathophysiological features of SARS-CoV-2, FiO₂ selection may considerably impact the oxygenation indices and affect clinical decisions. Furthermore, high concentrations of oxygen might alter the respiratory system mechanics through reabsorption atelectasis formation and augment the stress applied over the lung, thus promoting ventilator-induced lung injury.

The aim of this study was to compare gas exchange indices behavior by using liberal versus conservative oxygenation targets in patients with moderate to severe ARDS secondary to COVID-19 under invasive mechanical ventilation. Second, we assessed the influence of high FiO₂ on respiratory system mechanics to evaluate the impact of reabsorption atelectasis on lung stress.

METHODS

We conducted a prospective physiological study in the ICU of Sanatorio Anchorena San Martín. The local Review Board approved the protocol (committee’s reference number: 16/2020), and all of the patients’ next of kin signed informed consent forms. This is a preliminary report of clinicaltrial.gov NCT number: NCT04486729.

We included all consecutive patients admitted to our ICU aged over 18 years old with a confirmed diagnosis of COVID-19 (positive polymerase chain reaction through nasopharyngeal swab) and moderate to severe ARDS according to the Berlin definition.(³) Other inclusion criteria were invasive mechanical ventilation requirement for less than 72 hours before enrollment and the need of neuromuscular blocking agents by medical decision. Based on previous physiological studies with similar methodologies and designs, we planned to include a sample size of 15 patients.(¹²) The exclusion criteria were hemodynamic instability despite fluid resuscitation and vasopressor support, previous diagnosis of chronic obstructive pulmonary disease, no drained pneumothorax, intracranial hypertension, pregnancy, thoracic chest wall abnormalities, bronchopleural fistula and contraindications to esophageal catheter insertion.

Baseline characteristics and laboratory analysis of all patients were retrieved from our electronic clinical records. We collected the variables age, sex, number of days under invasive mechanical ventilation, Simplified Acute Physiology Score II (SAPS II) at admission, ARDS severity and sequential organ failure assessment (SOFA) score the day of enrollment.

Respiratory mechanics

We evaluated respiratory system mechanics using a specific device and software (Fluxmed, MBMed®, Buenos Aires, Argentina) connected to a personal computer. The flow (F) and volume (Vol) were measured with a flow sensor provided by the manufacturer that was correctly calibrated. We inserted an esophageal balloon (MBMed® VA-A-008, nonlatex) 7 cm in length filled with 0.5mL of air. The correct position in the lower third of the esophagus was confirmed by the presence of cardiac artifacts and the occlusion test as previously described elsewhere.(¹³) We performed end inspiratory and end expiratory occlusions of at least two seconds, and we evaluated the following variables: plateau pressure (P_plat), driving airway pressure (∆P_aw), inspiratory esophageal pressure (P_es insp), expiratory esophageal pressure (Pes exp), driving esophageal pressure (∆P_es), inspiratory transpulmonary pressure using the direct method (P_L-direct insp), expiratory transpulmonary pressure (P_L exp), driving transpulmonary pressure (∆P_L) and inspiratory transpulmonary pressure using the elastance-derived method (P_L-elas insp) using the formula:

$${\text{P}}_{\text{L-elas}}\text{insp}=\text{Plateau pressure x (lung elastance/respiratory system elastance).}$$

The respiratory system elastance (Ers), chest wall elastance (Ecw) and lung elastance (E_L) were calculated with the following formulas:

$$\begin{array}{rl}& \text{ Ers }=\mathrm{\Delta }\mathrm{P}\mathrm{a}\mathrm{w}/\mathrm{\Delta }\mathrm{V}\mathrm{o}\mathrm{l}(\text{ Expired volume in }\mathrm{L});\\ & {\mathrm{E}}_{\mathrm{c}\mathrm{w}}=\mathrm{\Delta }\mathrm{P}\mathrm{e}\mathrm{s}/\mathrm{\Delta }\mathrm{Vol}(\mathrm{L});\\ & \mathrm{E}\mathrm{L}=\mathrm{\Delta }{\mathrm{P}}_{\mathrm{L}}/\mathrm{\Delta }\mathrm{Vol}(\mathrm{L}).\end{array}$$

Oxygenation indices

The PaO₂/FiO₂ index was calculated as PaO₂ (mmHg)/FiO₂.(¹⁴) To calculate other oxygenation indices, we used the equation of partial pressure of alveolar oxygen (PAO₂) = ((Pbarometric - PvH₂O) x FiO₂) - PCO₂/RQ,(¹⁴) where Patm is the barometric pressure expressed in mmHg (760), PvH₂O is the partial pressure of water steam expressed in mmHg (47), PaCO₂ is the partial pressure of arterial carbon dioxide and RQ is the respiratory quotient (0.8). Once PAO₂ was obtained, we calculated the indices alveolar-arterial oxygen pressure gradient (PA-aO₂) and the quotient arterial/alveolar pressure of oxygen (Pa/AO₂).

The functional shunt fraction was calculated based on venous admixture determination, considering central venous oxygen saturation (ScVO₂) as an acceptable surrogate for mixed venous oxygen saturation: Qs/Qt = (CcO₂ - CaO₂)/(CcO₂/CvO₂), where CaO₂, CvO₂, and CcO₂ are the arterial, venous and capillary oxygen contents, respectively.(¹⁴) When available, mixed venous blood was obtained from a Swan Ganz catheter.

Procedure

All patients were deeply sedated with propofol and fentanyl and paralyzed with atracurium. The subjects were ventilated in semirecumbent position in volume control mode with a tidal volume 6mL/kg of predicted body weight, square flow waveform with 0.3 seconds of end inspiratory pause, respiratory rate between 15 - 35 breaths per minute, aiming to achieve a pH between 7.20 - 7.45. The PEEP value was 5cmH₂O.

We randomly applied two different FiO₂ strategies to each patient: one strategy to achieve a liberal (96%) SpO₂ and one to obtain a conservative (88 - 92%) SpO₂, both periods evaluated on the same day. For randomization, we used the software available on the randomization.com website, and we used closed opaque envelopes. Each phase lasted 10 minutes, based on the study carried out by Cakar et al., in which they showed that 5 minutes was enough time to achieve a stable PaO₂ level.(¹⁵) After the end of each period, we obtained arterial and mixed venous blood samples and monitored the respiratory system mechanics. We did not use a washout period between each phase because of aspects related to the viability and safety of the patients included. Considering the critical status of our sample and the wide variety of factors that could affect arterial oxygenation (including basic care such as mobilization, aspiration of secretions, positional changes), extending the time of measurements would have led to limiting these interventions for longer periods of time, affecting the standard of care in our unit and the patient´s clinical status.

Statistical analysis

Data are expressed as the mean ± standard deviation (SD) and number (percentage), as appropriate. The Shapiro-Wilk test was used to test normality. One sample Student`s t-test was used to assess the statistical significance of the difference between the two conditions when the data were normally distributed; otherwise, the Wilcoxon test was used. The results with a two-tailed p ≤ 0.05 were considered statistically significant. The statistical analysis was performed with R 4.0.3 (R Foundation for Statistical Computing - www.rproject.org) and the ggplot2 package.

RESULTS

We enrolled 15 patients. The mean age was 55.6 years old, and 73.3% of patients were men with SAPS II 32 and SOFA 6.2 at admission (Table 1). Three subjects were classified as severe ARDS, and twelve were classified as having moderate ARDS. The median (interquartile range) of days between intubation and enrollment was 1 (1 - 3). The liberal oxygenation phase could not be completed in one patient due to desaturation despite using FiO₂ 1.

The mean ± SD FiO₂ and SpO₂ for liberal and conservative oxygenation targets were 0.80 ± 0.19 and 96% ± 1 and 0.40 ± 0.13 and 89% ± 3, respectively.

The comparisons between oxygenation indices obtained with liberal versus conservative oxygenation targets are presented in figure 1. All of the indices were significantly affected by FiO₂ selection. The PaO₂/FiO₂ deteriorated (FiO₂ liberal; mean = 140.9 ± 34.0, FiO₂ conservative; mean = 165 ± 54.4; p = 0.015), PA-aO₂ increased (FiO₂ liberal; mean = 397.5 ± 133; FiO₂ conservative; mean = 190.4 ± 139.7; p < 0.001) and Pa/AO₂ decreased (FiO₂ liberal; mean = 0.22 ± 0.06; FiO₂ conservative; mean = 0.31 ± 0.13; p = 0.002) significantly by using FiO₂ to achieve SpO₂ 96%. Conversely, the functional shunt fraction was reduced (FiO₂ liberal; mean = 0.40 ± 0.08, FiO₂ conservative; mean = 0.45 ± 0.13; p = 0.040).

Table 1
Baseline characteristics of the patients

Variables
Demographic variables
Female sex	4/15
Age	55.6 ± 9.4
APACHE II	13.1 ± 5
SAPS II	32 (10.8)
Respiratory variables
Tidal volume (mL/kg)	6.1 ± 0.4
PEEP (cmH2O)	10.9 (10.5 - 12.5)
FiO2	0.45 (0.35 - 0.52)
Airway driving pressure (cmH2O)	10.5 (9.55 - 11.6)
Gas exchange
PaO2/FiO2	147.4 (125.5 - 179)
Functional Qs/Qt	0.34 ± 0.11
Moderate ARDS, n/total	12/15
ICU mortality, (n/total)	6/15

₂₂₂

The variables related to the respiratory mechanics are presented in table 2. There were no significant changes in mechanical variables between the conservative and liberal SpO₂ strategies.

DISCUSSION

Our findings show that adopting a liberal SpO₂ target considerably affects the oxygenation indices, which may have implications not only in severity stratification of ARDS but also in the clinical decision-making process.

A proper stabilization time and standardized ventilatory settings have been shown to improve the severity stratification in classical ARDS.(⁶) Villar et al. found that selecting an FiO₂ of 0.5 with the aim of achieving an SpO₂ not less than 88% allows to better identify patients at risk of death in comparison with higher fractions of inspired oxygen.(⁸) In patients with a high percentage of shunt and low ventilation/perfusion (V/Q) units, increasing the oxygen supply significantly affects the gas exchange indices due to the marginal effect on PaO₂ of higher concentrations of PAO₂.(¹⁶) Indeed, perfused and ventilated alveoli present limited capacity to increase CaO₂, as explained by the classic behavior of the hemoglobin dissociation curve. Hence, deterioration in PA-aO₂ and Pa/AO₂ is somewhat expected considering that theoretical PAO₂ will rise in the same proportion that FiO₂ is changed (provided that PaCO₂ is constant), but PO₂ will not because deoxygenated blood leaving low V/Q units will mix with oxygenated blood coming from normal V/Q units.(¹⁷) The patients included in our study presented a 40% functional shunt average, which explains why, even in COVID-19, where pathophysiological features may differ from classical ARDS, the application of high oxygen concentrations affected the gas exchange indices in a similar way to previous descriptions.(¹⁴,¹⁶,¹⁸)

Figura 1
Oxygenation indices behavior with liberal and conservative oxygenation strategies.

The LOCO II trial recently found survival benefits at 90 days and fewer mesenteric ischemic events approaching a liberal oxygenation strategy in typical ARDS. The control group received lower PEEP and considerably less prone positioning trials, which could be explained by the fact that both interventions were decided based on the PaO₂/FiO₂ value.(¹¹) Our study suggests that using liberal SpO₂ strategies may increase the need of rescue therapies to treat the refractory hypoxemia consequences of a remarkable deterioration of the PaO₂/FiO₂ index in this context. In our study, three patients changed their severity of ARDS from moderate to mild, and other three subjects increased their PaO₂/FiO₂ above 150mmHg only by using a lower FiO₂, a situation that has been reported previously in non-COVID-19-related ARDS.(¹⁸) Moreover, only two patients required less than 0.6 FiO₂ to achieve at least an SpO₂ of 96%, which should warns about the adverse effects of exposing the alveolar gas barrier to high concentrations of oxygen for long periods of time.

In conventional ARDS, atelectasis caused by superimposed pressure and lung volume reduction represent the main mechanisms of hypoxemia, showing a direct relationship between Qs/Qt and PaO₂/FiO₂ after adjusting for Crs.(¹⁹) The same reasoning does not hold completely true for COVID-19-related ARDS. Our initial hypothesis was that high FiO₂ would increase Qs/Qt secondary to reabsorption atelectasis and the reversal of hypoxic vasoconstriction.(²⁰) Our results showed the opposite, which could be explained by three potential reasons. First, respiratory system mechanics, in particular, lung stress (PL-elas insp and PL-direct insp) remained unchanged after increasing FiO₂, which might indicate that atelectasis formation was not significant, possibly due to the limited time of exposure as well as the use of FiO₂ lower than 100%. Second, the impairment of the normal mechanisms of hypoxemic vasoconstriction has been proposed as a possible cause to explain the profound hypoxemia in COVID-19 in the absence of significant alterations of respiratory mechanics;(²¹-²³) thus, increasing FiO₂ could not have had considerable effects on vasomotor tone. Third, an adequate evaluation of shunt fraction implies the application of FiO₂ 100%, a condition that was not accomplished because it was not the aim of our study. Setting FiO₂ < 100% not only assesses the real shunt fraction but also includes those units with a low V/Q ratio in the Qs/Qt calculation.(¹⁷) It is expected that increasing FiO₂ will ameliorate the influence of low V/Q units, making the true shunt fraction more visible. Grasso et al. found a high proportion of Qs/Qt (> 40%) when assessing functional shunt with an FiO₂ lower than 100%; when pure oxygen was used, the real shunt fraction was only 4%.(²⁴)

Table 2
Respiratory mechanics behavior with liberal and conservative oxygenation strategies

Variable	FiO2 conservative (T1)	FiO2 liberal (T2)	T1 - T2 (95%CI)	p value
ΔPaw	10.0 ± 1.5	9.9 ± 1.5	-0.1 (-0.2 - 0.4)	0.579
Pplat	16.1 ± 2.2	16.2 ± 2.3	-0.1 (-0.3 - 0.4)	0.682
ΔPL	8.1 ± 1.7	8.0 ± 1.8	0.1 (-0.4 - 0.7)	0.582
ΔPes	1.9 ± 0.9	1.9 ± 0.7	0.0 (-0.4 - 0.3)	0.258
PL exp	-3.2 ± 3.4	-2.6 ± 3.2	-0.2 (-0.3 - 0.6)	0.768
PL-elas insp	13.0 ± 2.6	13.1 ± 2.4	0.1 (-0.6 - 0.9)	0.741
PL-direct insp	4.7 ± 3.1	5.3 ± 3.1	0.4 (-0.3 - 1.1)	0.280
Ers	26.2 ± 6.2	25.4 ± 5.1	0.2 (-0.7 - 1.1)	0.598
EL	20.8 ± 5.5	20.4 ± 5.0	-0.4 (-0.9 - 1.8)	0.498
Ecw	5.3 ± 2.7	4.9 ± 2.1	-0.2 (-1.1 - 0.7)	0.620
EL/Ers	0.79 ± 0.08	0.80 ± 0.08	0.01(-0.03 - 0.04)	0.839

_{2awplatLesLL-elasL-directrsL}

Our study presents several limitations that must be addressed. First, the small number of patients enrolled in our study does not allow us to make conclusions regarding the best clinical strategy in terms of outcome benefits. On the other hand, cardiac output was not monitored during the protocol, and a reduction in the functional shunt when FiO₂ was increased might be a feasible consequence of the reduction in cardiac output secondary to improvement in CaO₂. Finally, all of the measurements were carried out with a PEEP of 5cmH₂O and the behavior of gas exchange indices when varying FiO₂ may be different with higher PEEP levels. However, this scenario is more physiologically attractive for assessing the effects of different FiO₂ values considering that low PEEP exacerbates the loss of lung volume and increases the proportion of low V/Q units and functional shunt and, thus, the possible activation of hypoxia-induced vasoconstriction.(²⁵) In addition, the Berlin definition of ARDS not only defines but also stratifies the severity of the condition using a level of PEEP equal to or greater than 5cmH2O.(³) In addition, several physiological studies have advocated using low PEEP levels to more accurately assess ARDS severity.(²⁵-²⁸) Higher levels of PEEP might mask the severity of the underlying lung injury and impact the assessment of lung recruitability, and, therefore, hinder the prediction of the response to therapeutic interventions such as recruitment maneuvers or prone positioning.(²⁵)

CONCLUSION

A strategy aimed at liberal oxygenation targets significantly deteriorated gas exchange indices, except for functional shunt, compared with a conservative strategy in COVID-19 related acute respiratory distress syndrome during invasive mechanical ventilation. The respiratory system mechanics were not altered by the fraction of inspired oxygen strategy.

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Edited by

Responsible editor: Alexandre Biasi Cavalcanti

Publication Dates

• Publication in this collection
  24 Jan 2022
• Date of issue
  2021

History

• Received
  21 Dec 2020
• Accepted
  07 Aug 2021