P0.1 is associated with duration of ventilation and mortality in patients with COVID-19 ARDS

doi:10.21203/rs.3.rs-4919933/v1

Rationale In acute respiratory distress syndrome (ARDS), optimal timing of transition from controlled to assisted ventilation and the ventilatory parameters which define this are unknown. Premature transition may impair recovery of an injured lung through patient self-inflicted lung injury.

Objectives To investigate whether the airway occlusion pressure (P0.1) directly after transition to assisted ventilation is associated with the duration of ventilation and mortality.

Methods Invasively ventilated patients with COVID-19 ARDS were retrospectively identified. P0.1 was recorded for 24 hours after transition to assisted ventilation. The primary endpoint was the number of ventilator-free days while being alive in the 28 days following the first transition from controlled to assisted ventilation (VFDav-28). Secondary outcome was ICU mortality. Multivariable logistic regression was used to identify variables independently associated with outcome parameters. ROC curves were generated to assess predictive values.

Measurements and Main Results 78 patients with COVID-ARDS were included. Higher (more negative) P0.1 was associated with less VFDav-28 and higher ICU mortality. The predictive value of P0.1 for both VFDav-28 and mortality was good (AUC 0.75).

Conclusions This study shows that P0.1 directy after transition to assited ventilation is associated with prolonged duration of invasive ventilation and ICU mortality.

COVID-19

acute respiratory distress syndrome

pressure support ventilation

patient self-inflicted lung injury

airway occlusion pressure (P0.1)

Optimal strategies for assisted ventilation in Acute Respiratory Distress Syndrome (ARDS) remain unknown. Notably, the best timing of the transition to pressure support ventilation (PSV) has not been elucidated. Premature transition may inflict injury due to excessive stress and strain on an injured lung caused by excessive inspiratory effort and high respiratory drive. This could lead to patient self-inflicted lung injury (PSILI), which impairs patient outcome (1). One important determinant of the development of PSILI in animal models is respiratory effort (2). The airway occlusion pressure at 100ms from the initiation of inspiration (P0.1) is a readily available ventilatory parameter reflecting respiratory effort. In this study, we hypothesized that P0.1 directly after the transition to PSV is associated with clinical outcomes, such as mortality and duration of ventilation.

We performed a single-center retrospective study within the University Medical Center Groningen in The Netherlands. The institutional review board waived the requirement for written informed consent (METc2023/10410707).

Invasively ventilated adult patients admitted to our ICU with PCR-confirmed COVID-ARDS who experienced a transition from controlled to PSV between March 2020 and April 2022 were retrospectively identified. In our institution, the timing of transition from controlled to PSV is not protocolized and, therefore, depends on the attending clinician.

Patient characteristics and ventilation parameters were extracted from the patient record (EPIC, Epic Systems Corporation, Verona, WI, USA). Our ICU is equipped with a SERVO-U (Maquet) ventilator, which estimates the P0.1 and exports these values to the electronic patient record every minute. We calculated the mean P0.1 value over the first 24 hours after transition from controlled to PSV or until failure (whichever came first).

The primary outcome was ventilator-free days and alive in the 28 days following the first transition from controlled to PSV (VFDav-28). This modified endpoint is similar to VFD28 used in many ARDS studies (3, 4). VFDav-28 was dichotomized with a cut-off at 14 days, in line with outcomes in critically ill COVID-19 patients in previous studies (5, 6). The secondary outcome was ICU mortality.

Mann-Whitney U and Fisher’s Exact Test were used to test which variables were associated with VFDav-28 < 14 days and ICU mortality. Two multivariable logistic regression models for both outcomes seperately were created, including the covariates P0.1 and predefined potential confounders (age, sex, and ARDS severity using P/F ratio). ROC curves were generated to assess the predictive value of these models. All analyses were performed using IBM SPSS Statistics version 28.0.1.0 (IBM, New York, NY, USA).

We included 78 patients. Baseline patient characteristics and ventilatory parameters are depicted in Table 1. Univariate analyses showed that patients with less ventilator-free days (VFDav-28 < 14 days) had a higher P0.1 compared to patients with VFDav-28 > 14 days; P0.1 3.4 (IQR 2.1–4.5) vs 1.6 (IQR 1.2–2.5), p < 0.001. Counterintuitively, these patients with less VFDav-28 days and higher P0.1 values, had lower RASSscores on the day of transition (Table 1.). Age, gender, BMI, ARDS severity, or other ventilatory parameters on the day of transition were not associated with VFDav-28 < 14 days or ICU mortality.

Table 1. Baseline characteristics and ventilatory parameters for the total population and stratified for VFDav-28 <14 days versus ≥14 days.

	Total population (n = 78)	VFDav-28		p-value
	Total population (n = 78)	<14 days (n = 29)	≥14 days (n = 49)	p-value
Age at ICU admission (years)	58 ± 13	58 ± 13	58 ± 14	0.848
Sex (male)	53 (68%)	22 (76%)	31 (63%)	0.252
Body-mass index (kg/m²)	30.1 ± 6.2	29.1 ± 5.4	30.7 ± 6.6	0.258
Severity of ARDS at initiation of invasive mechanical ventilation (P/F ratio)	135 (105 – 173)	133 (97 – 163)	139 (111 – 180)	0.207
ICU mortality	16 (21%)	16 (55%)	0 (0%)	<0.001
ICU length of stay (days)	14 (9 – 27)	28 (18 – 43)	12 (8 – 15)	<0.001
Duration of invasive mechanical ventilation (days)	12 (7 – 22)	24 (17 – 39)	9 (6 – 12)	<0.001
VFDav-28 (days)	20 (1 – 25)	0 (0 – 5)	24 (21 – 26)	<0.001
Time from intubation to PSV (days)	5 (3 – 8)	6 (4 – 12)	4 (3 – 7)	0.043
Prone positioning on the first day of ICU admission	29 (37%)	16 (55%)	13 (27%)	0.016
Extracorporeal membrane oxygenation	6 (8%)	3 (10%)	3 (6%)	0.665
Ventilatory parameters at the time of transition to PSV P0.1 during the first 24h of PSV (cmH₂O) Driving pressure (cmH₂O) PEEP (cmH₂O) Respiratory rate (breaths per min) P/F ratio (PSV) Tidal volume (controlled, mL/kg body weight) Tidal volume (PSV, mL/kg body weight)	2.1 (1.3 – 3.5) 11.5 (10 – 12) 12 (10 – 14) 22 (20 – 24) 193 (161 – 222) 4.8 (4.0 – 5.8) 6.7 (5.1 – 7.8)	3.4 (2.1 – 4.5) 12 (10 – 14) 12 (10 – 14) 22 (20 – 24) 174 (155 – 215) 5.1 (4.4 – 5.9) 6.2 (4.9 – 7.4)	1.6 (1.2 – 2.5) 11 (10 – 12) 12 (10 – 14) 24 (20 – 25) 206 (166 – 231) 4.5 (3.8 – 5.6) 6.6 (5.2 – 8.1)	<0.001 0.386 0.944 0.284 0.100 0.091 0.235
RASS on the first day of PSV	-3 (-4 – -1)	-4 (-4 – -3)	-2 (-4 – -0.5)	<0.001
Failed PSV	36 (46%)	24 (83%)	12 (25%)	<0.001
Data are presented as number (%), mean ± standard deviation, or median (interquartile range). Differences between VFDav-28 <14 days and ≥14 days were tested by Mann-Whitney U Test for continuous/discrete explanatory variables or Fisher’s Exact Test for dichotomous explanatory variables. Significant values are depicted in bold. ICU = intensive care unit; ARDS = acute respiratory distress syndrome; P/F ratio = the ratio of arterial oxygen partial pressure (PaO₂ in mmHg) to fractional inspired oxygen (FiO₂ expressed as a fraction, not a percentage); VFDav-28 = ventilator-free days and alive 28 days after first attempt of transition to assisted ventilation; PEEP = positive end-expiratory pressure; PSV = pressure support ventilation; P0.1 = negative airway pressure generated during the first 100 msec of an inspiration; RASS = Richmond Agitation-Sedation Scale.

The multivariate models revealed that only P0.1 was associated with VFDav-28 < 14 days (OR; 1.43, 95%CI: 1.06–1.93) and ICU mortality (OR: 1.45; 95%CI: 1.08–1.95).

Additionally, ROC curves showed a good predictive value of P0.1 for VFDav-28 < 14 days (AUC 0.75) and for ICU mortality (AUC 0.75) (Fig. 1). Optimal cut-off values (based on the highest sum of sensitivity and specificity) of P0.1 for predicting VFDav-28 < 14 days and ICU mortality were 2.0 and 3.5, respectively. To evaluate the impact of the chosen cut-off for VFDav-28, we conducted sensitivity analyses using the median cut-off within our patient population (VFDav-28 < 20). These analyses showed similar predictive values for P0.1 (not shown).

This study showed that higher (more negative) P0.1 is associated with less VFDav-28 and a higher ICU mortality.

The potential of P0.1 in predicting respiratory deterioration has been shown in another small study in COVID-19 ARDS patients (7). In comparison to this study, exploration of prediction in our cohort revealed lower optimal cut-off values for P0.1. Both cut-off values of 2.0, associated with VFDav-28, and 3.5 for mortality, are within the postulated physiological range, although this range lacks an empirical base (8). Lower P0.1 cut-off values for VFDav-28 compared to mortality could reflect multiple pathophysiological pathways contributing to prolonged weaning comprising both excessively high and low respiratory drive.

We acknowledge several limitations. Our study is single-center and included only COVID-19 ARDS patients. We did not account for possible interventions based on high P0.1 values (e.g., adjustments in ventilation and sedation). However, no protocolized interventions in our institution mandate ventilation adjustments based on P0.1, which is in line with a recent study showing that even excessive P0.1 values rarely lead to ventilatory adjustments (8). P0.1 values were derived from the SERVO-U (Maquet) ventilator, which estimates the P0.1. These values are lower than measured P0.1 values, and might explain our lower thresholds for P0.1 and limits generalizability (9).

This study does not imply causality between P0.1 and clinical outcomes. A higher P0.1 could reflect a sicker patient. Nevertheless, these measurements and described endpoints should be explored in all-cause ARDS to determine thresholds associated with outcome, and causality. Only then can we study the potential to improve outcomes by modifying patient care based on P0.1 values.

In conclusion, this study shows that higher P0.1 values are associated with prolonged duration of invasive ventilation and ICU mortality in patients with COVID-19 ARDS.

Availability of data and materials

Data is available upon reasonable request from the corresponding author.

Competing interests

Not applicable

Ethics Declarations and consent to participate

The institutional review board of the University Medical Center Groningen approved the study and waived the requirement for written informed consent (METc2023/10410707).

Funding

Janesh Pillay is supported by a research grant from the Netherlands Organization for Health Research and Development, The Netherlands (ZonMw Clinical Fellowship grant 09032212110044) and has received funding from ‘a Partnership of Siemens and UMCG for building the future of Health’ (PUSH MO24.00027)

Author contributions

E.A.M.D.t.H.: Study design, data collection and analysis; M.H.R, S.J.R data collection, review and editing; J.P.: Study conceptualization and design; J.M.V: Data analysis; H.W.Z., P.D., W.v.d.B, J.M.D.; review and editing. All authors participated in scientific discussions and manuscript editing.

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No competing interests reported.

P0.1 is associated with duration of ventilation and mortality in patients with COVID-19 ARDS

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