Research ArticleOriginal Research

Clinical Findings and Outcomes From Subjects With COVID-19 Pneumonia in an Intermediate Respiratory Care Unit

Daniel Laorden, Soraya Gholamian-Ovejero, José Rafael Terán-Tinedo, Miguel Lorente-González, Eduardo Cano-Sanz, María Ángeles Ortega-Fraile, Roberto-Martínez Alejos, Joaquín Hernández-Nuñez, Isabel De La Calle-Gil, Rosalía Navarro-Casado, Fernando Neria, Annette Zevallos-Villegas, Pablo Mariscal-Aguilar, Miguel Suarez-Ortiz, María Cristina Plaza-Moreno, Daniel Carballo-López, Berta Gallego-Rodríguez, Mariara Calderón-Alcala, Aylaf Latif-Essa, María Churruca-Arróspide, Manuel Valle-Falcones, Elena María Saiz-Lou, Carmen Rodríguez-Calle, Clotilde Funes-Moreno, Tomas Villén-Villegas and Pedro Landete on behalf of the UCRIZENDAL Study Group Investigators
Respiratory Care January 2023, 68 (1) 67-76; DOI: https://doi.org/10.4187/respcare.10193

Abstract

BACKGROUND: Many patients with COVID-19 require respiratory support and close monitoring. Intermediate respiratory care units (IRCU) may be valuable to optimally and adequately implement noninvasive respiratory support (NRS) to decrease clinical failure. We aimed at describing intubation and mortality in a novel facility entirely dedicated to COVID-19 and to establish their outcomes.

METHODS: This was a retrospective, observational study performed at one hospital in Spain. We included consecutive subjects age > 18 y, admitted to IRCU with COVID-19 pneumonia, and requiring NRS between December 2020–September 2021. Data collected included mode and usage of NRS, laboratory findings, endotracheal intubation, and mortality at day 30. A multivariable Cox model was used to assess risk factors associated with clinical failure and mortality.

RESULTS: A total of 1,306 subjects were included; 64.6% were male with mean age of 54.7 y. During the IRCU stay, 345 subjects clinically failed NRS (85.5% intubated; 14.5% died). Cox model showed a higher clinical failure in IRCU upon onset of symptoms and hospitalization was < 10 d (hazard ratio [HR] 1.59 [95% CI 1.24–2.03], P < .001) and PaO2/FIO2 < 100 mm Hg (HR 1.59 [95% CI 1.27–1.98], P < .001). These variables were not associated with increased 30-d mortality.

CONCLUSIONS: The IRCU was a valuable option to manage subjects with COVID-19 requiring NRS, thus reducing ICU overload. Male sex, gas exchange, and blood chemistry at admission were associated with worse prognosis, whereas older age, gas exchange, and blood chemistry were associated with 30-d mortality. These findings may provide a basis for better understanding outcomes and to improve management of noninvasively ventilated patients with COVID-19.

Introduction

COVID-19 was first reported in Wuhan, China, in early December 2019.1 Since then, it has spread rapidly worldwide and resulted in more than 446 million confirmed cases and more than 6 million deaths as of March 2022.

Large differences in outcomes and respiratory disease management have been reported for different countries as the pandemic evolved.2 Independently, worldwide health care systems and workers have faced surges of infected patients who need hospital care; consequently, this unexpected burden led to building new hospitals and acute care facilities to specifically admit patients with COVID-19. In Spain, the Isabel Zendal Emergency Hospital (Madrid) emerged in December 2020 as a new facility fully dedicated to managing patients with COVID-19 with 3 separate units: general hospitalization, intermediate respiratory care unit (IRCU), and ICU and with a maximum capacity of 1,000 beds, 96 of which were dedicated to the largest IRCU in Europe.

The IRCU is logistically a step-up or step-down unit between ICU and general hospitalization, additionally admitting patients transferred from the emergency department.3 This unit allows for an easy and dynamic patient management, rapidly developing treatment algorithms, and implementing new health care protocols.4 Furthermore, IRCU promotes an earlier discharge of some ICU patients; is an alternative to ICU for patients only requiring intensive monitoring, specific support, or procedures5,6; and significantly reduces ICU mortality.5

Some studies have recently reported mixed results on noninvasive respiratory support (NRS) in subjects with COVID-19 in the IRCU7-10; however, the sample sizes were modest and with important heterogenous care between centers.

The objective of this study was to examine an extensive and homogenous population of subjects with COVID-19 admitted to the IRCU to assess the prognosis depending on their physiological and biological characteristics, likewise the rate of intubation and mortality 30 d after.

QUICK LOOK

Current Knowledge

The literature highlights the importance of early treatment of hypoxic mechanisms in patients with COVID-19 to avoid intubation and decrease mortality. Conversely, it’s unclear which are the most common noninvasive respiratory strategies implemented in patients with COVID-19. We need a deeper insight to better understand prognosis depending on their physiological and biological characteristics, and likewise the clinical evolution.

What This Paper Contributes to Our Knowledge

In subjects with COVID-19, we found that male sex, rapid symptoms onset, lower PaO2/FIO2, ratio of oxygen saturation (ROX) index, and blood chemistry at admission were associated with increased risk of clinical failure. Older age, rapid symptoms onset, lower PaO2/FIO2, ROX index, and blood chemistry at admission outcomes were associated with increased risk of 30-d mortality. There was significantly higher clinical failure in subjects with < 10 d between symptoms onset and hospitalization and in those with a PaO2/FIO2 < 100 mm Hg but no implication regarding 30-d survival.

Methods

Study Design and Participants

This retrospective, observational, cross-sectional study was performed in the IRCU of the Isabel Zendal Emergency Hospital (Madrid, Spain) between December 2020–September 2021. The protocol was approved by the local regulatory ethics committee (ethics committee La Paz University Hospital, Madrid, Spain) and respected the ethical principles of the Declaration of Helsinki.

We enrolled all consecutive subjects admitted first in conventional hospitalization > 18 y, presenting firmly established pneumonia secondary to COVID-19 infection and causing hypoxemic acute respiratory failure requiring supplementary oxygen via a Venturi mask or reservoir oxygen mask (FIO2 ≥ 0.50) to maintain a peripheral SpO2 > 94% and a breathing frequency < 24 breaths/min. Patients were excluded from the study if they spent < 24 h in the IRCU, if they were readmitted after ICU admission, or if they were admitted to the IRCU with a condition unrelated to respiratory failure (eg, additional diagnostic tests, electrocardiographic surveillance).

After IRCU admission, we implemented a well-structured algorithm to standardize NRS in all admitted patients (Fig. 1). This algorithm was agreed upon, validated, and updated regarding current evidence by all medical specialties ensuring consistent care in the IRCU. Therefore, subjects systematically received high-flow nasal cannula (HFNC) and, if necessary, noninvasive ventilation (NIV) or CPAP. HFNC was applied through a nasal cannula with a V60 Plus (Philips Respironics, Murrysville, Pennsylvania) or Airvo 2 (Fisher and Paykel Healthcare, Auckland, New Zealand) ventilator. Following previous studies, initial settings were determined with maximum flows of 60 L/min and FIO2 1.0.11 One h after HFNC initiation, arterial blood gases were performed to calculate the PaO2/FIO2 to grade severity according to Berlin criteria12 with titration to achieve parameter targets for oxygenation and ventilation. NIV was set in case of hypoxemic respiratory failure13 as well as CPAP, initiated indistinctively at medical discretion. Both were applied through a V60 Plus or a Trilogy Evo device (Philips Respironics) connected to a single-limb circuit and a heat and moisture exchange filter. Initial settings were CPAP at 8–12 cm H2O or expiratory positive airway pressure at 8–12 cm H2O with pressure support set to achieve a tidal volume (VT) of 6–8 mL/kg14 and FIO2 adjusted to maintain SpO2 > 94%. Oronasal mask or total face mask selection depended on subject tolerance and comfort. NIV was performed twice per day, 2 h each session, and additionally for a minimum of 6 h during the night. The remaining time subjects were switched to HFNC, except subjects with an SpO2 < 90%, who were maintained continuously on NIV. Similarly, awake prone position sessions were performed for a minimum of 2 h, twice per day, and were considered starting at admission, as previously reported.15

Fig. 1.
Fig. 1.

Algorithm to guide noninvasive respiratory strategies implementation in intermediate respiratory care unit. IRCU = intermediate respiratory care unit; HFNC = high-flow nasal cannula; ROX = ratio of oxygen saturation; WOB = work of breathing; NIV = noninvasive ventilation.

All subjects were continuously monitored regardless of the support. Similarly, they received an intravenous bolus of 20 mg dexamethasone at admission and every morning for 5 consecutive d and 10 mg bolus for 5 more d.16 Daily subcutaneous infusion of enoxaparin—combined with compression stockings17—were administrated at prophylactic doses of 40 mg or adjusted to weight in subjects > 120 kg or with body mass index > 40 kg/m2.17 Subjects with C-reactive protein levels > 75 mg/L were evaluated to initiate treatment with tocilizumab (8 mg/kg, 1 bolus).18 In dyspneic subjects with an increased respiratory drive (frequency > 24 breaths/min or VT > 8 mL/kg), we initiated intravenous infusion of morphine19 to minimize the risk of subject self-inflicted lung injury.14,19 Subjects who tolerated NIV poorly and presented with anxiety or discomfort received an intravenous infusion of dexmedetomidine.20 Finally, co-adjuvant to medical therapeutics, subjects were evaluated for chest physiotherapy and passive and/or active mobilization once daily.21

In addition to standard therapeutics, subjects with an increased work of breathing, SpO2/FIO2 < 90–94,22 ratio SpO2/FIO2 to breathing frequency (ROX index) < 4.94 after 12 h,10 or no clinical improvement in the first 48 h were candidates for ICU admission to avoid the risk of delayed endotracheal intubation. Subjects who were not admitted to the ICU or made do-not-resuscitate/do-not-intubate were maintained on NRS with sedation and comfort care provided as required, depending on clinical progression.23

Weaning from HFNC was initiated with a progressive FIO2 reduction, followed by a decrease in flows. Once FIO2 was ≤ 0.4, subjects were switched to an air-entrainment mask or conventional nasal cannula (< 6 L/min). Once the flow was ≤ 4 L/min with an SpO2 > 94% for a minimum of 24 h, subjects were discharged from the IRCU to general care.

Demographics, clinical symptoms, blood chemistry findings, and treatments implemented were collected within 24 h of study admission, during hospitalization, and up to 30 d afterward from the electronic medical records. Likewise, we collected time to discharge, intubation, or death until 30 d after admission. Clinical failure was defined as a combination of subjects transferred to the ICU and intubated and/or subjects who died in IRCU.

Statistical Analysis

Descriptive data are presented as mean ± SD for continuous variables and as absolute (n) and relative frequencies (%) for discrete variables. Comparisons were performed using Student t test for continuous variables and chi-square or Fisher exact test for categorical variables, as appropriate. A multiple logistic regression model was adjusted for either 30-d mortality and clinical failure as dependent variables, including sociodemographic and analytical data as independent variables. Kaplan-Meier analysis and Cox proportional hazards model were also developed for both dependent variables to particularly understand the influence of time between symptom onset and IRCU admission or PaO2/FIO2. A statistical significance level of .05 (2-tailed) was set. All analyses were performed with R v4.1 statistical software (R Foundation for Statistical Computing, Vienna, Austria).

Results

Of 1,360 individuals screened for this study, 1,306 subjects were included; the main reason for exclusion was time spent in IRCU < 24 h (Fig. 2). Demographic and clinical characteristics are shown in Table 1. Eight-hundred forty-four subjects (64.6%) were male, whereas 462 (35.4%) were female; mean age was 54.7 ± 13.7 y, and mean time between symptom onset and IRCU admission was 9.7 ± 3.1 d.

Fig. 2.
Fig. 2.

Flow chart. IRCU = intermediate respiratory care unit.

View this table:
Table 1.

Baseline Characteristics

Sixty-six subjects (5.1%) were do-not-resuscitate/do-not-intubate and, therefore, not eligible for intubation. These subjects were older than those eligible for intubation (78.4 ± 6.0 y vs 53.5 ± 12.8 y, P < .001) and presented with higher Charlson comorbidity (5.7 ± 1.9 vs 1.6 ± 1.6, P < .001), Sequential Organ Failure Assessment (4.0 ± 1.0 vs 3.5 ± 0.8, P < .001), and Simplified Acute Physiology Score II (40.4 ± 5.9 vs 29.1 ± 7.2, P < .001) scores. However, their PaO2/FIO2 (106.2 ± 47.1 vs 120.3 ± 55.4, P = .033) was lower. Laboratory findings at admission showed higher creatinine (0.86 ± 0.30 mg/L vs 0.73 ± 0.24 mg/L, P = .002) and lower platelets (229.7 ± 83.7 units/mL vs 262.6 ± 94.8 units/mL, P = .003) in this subgroup. Finally, subjects not eligible for intubation showed a higher 30-d mortality than subjects eligible for intubation (36 [54.5%] vs 69 [5.5%], P < .001).

During IRCU admission, 345 subjects clinically failed NRS, of which 309 (85.5%) were intubated, and 36 (14.5%) died during their IRCU stay. Clinical failure was significantly higher in males compared to females (242 [70.1%] vs 103 [29.9%], P = .01) and occurred more often in individuals > 60 y old (184 of 506 [53.3%]) than in those younger (161 of 800 [46.7%], P < .001). At admission, clinical failure subjects showed a lower mean PaO2/FIO2 (103.6 ± 43.7 vs 126.0 ± 57.2, P < .001), and ROX index (4.6 ± 1.4 vs 5.3 ± 1.7, P < .001) than those who did not clinically fail NRS during their IRCU stay (Table 2). Regarding laboratory results, clinical failure was observed in those with higher levels of lactate dehydrogenase, procalcitonin, D-dimer, and lower levels of lymphocytes and platelets (P < .02 all) (Table 1) (supplementary content, see related supplementary materials at http://rcjournal.com).

View this table:
Table 2.

Clinical Failure During Intermediate Respiratory Care Unit Stay and 30-Day Mortality Descriptive Statistics

Thirty-day mortality was 8% (105 of 1,306 subjects). The main reasons were likely the same as those for IRCU failure, except for sex, which was no longer significant (71 male [67.6%] vs 34 female [32.4%], P = .51) (Table 2). Similarly, laboratory findings stayed significant as well, with the exception of D-dimer (1,625.5 ± 2,596.4 ug/mL vs 1,167.0 ± 2,822.1 ug/mL, P = .11) (Table 1) (supplementary content, see related supplementary materials at http://www.rcjournal.com).

After multivariable adjustment, male sex, less time from symptoms onset to admission, lower PaO2/FIO2, ROX index, and blood chemistry at admission were associated with increased risk of clinical failure (Table 3). Also, older subjects, rapid symptoms onset, lower PaO2/FIO2, ROX index, and blood chemistry at admission outcomes were associated with increased risk of 30-d mortality (Table 4).

View this table:
Table 3.

Full Multivariate Model Assessing Predictors of Clinical Failure in Intermediate Respiratory Care Unit at Admission

View this table:
Table 4.

Full Multivariate Model Assessing Predictors of 30-Day Mortality at Admission

Kaplan-Meier analysis is shown in Figure 3. We identified a significantly higher clinical failure in IRCU in subjects with time between symptoms onset and hospitalization < 10 d (hazard ratio [HR] 1.59 [95% CI 1.24–2.03], P < .001) and in subjects with a PaO2/FIO2 < 100 mm Hg (HR 1.59 [95% CI 1.27–1.98], P < .001). Conversely, these findings were not significant regarding 30-d survival (HR 1.54 [95% CI 0.98–2.44], P = .061; and HR 1.39 [95% CI 0.89–2.17], P = .15, respectively) (Fig. 4).

Fig. 3.
Fig. 3.

Cox proportional hazards method to assess risk factors associated with clinical failure and mortality. (A) Kaplan-Meier analysis of clinical failure probability in intermediate respiratory care unit (IRCU) depending on time of symptoms onset and IRCU admission; (B) Kaplan-Meier analysis of 30-d survival probability in IRCU depending on time upon symptoms onset and IRCU admission; (C) Kaplan-Meier analysis of clinical failure probability in IRCU depending on PaO2/FIO2 at admission; (D) Kaplan-Meier analysis of 30-d survival probability in IRCU depending on PaO2/FIO2 at admission.

Discussion

This report describes the largest cohort of subjects to date admitted in an IRCU of a hospital fully dedicated to patients with COVID-19. First, it provides information on NRS using a specific algorithm dedicated to individually manage these subjects, which can be used to advance practice and understand patients at risk of therapeutic failure and death. Second, these results may encourage the wider implementation of IRCU in hospitals. The IRCU seems to play a major role in patients with COVID-19 management, decreasing the burden associated with ICU hospitalization and hospital mortality.5

In our study, 26.4% of subjects clinically failed NRS (composite of endotracheal intubation 22.6% and mortality 3.8%) after IRCU admission. These findings are consistent with those from a recent publication assessing clinical features and respiratory management in subjects with COVID-19.24 However, our study suggests that subjects managed with a specific algorithm required intubation less frequently; and mortality was lower than in previous series, even though our cohort had moderate to severe ARDS. A potential explanation is that we rapidly admitted subjects with acute respiratory failure to the IRCU (< 24 h) and implemented NRS early, minimizing the risk of subject self-inflicted lung injury secondary to hypoxia and increased respiratory drive, characteristic of COVID-19 ARDS–related pneumonia.14 Furthermore, the combination of HFNC with CPAP or NIV seems to decrease the risk of ventilatory failure as it improves adherence and comfort, optimizes respiratory mechanics, and decreases dyspnea.25 A recent study from Perkins et al26 assessing the effects of NRS in 1,273 subjects with COVID-19 with acute hypoxemic respiratory failure concluded that CPAP decreased intubation rates compared to conventional oxygen (absolute difference −8% [95% CI −15 to −1], P = .03), but these results were not found when comparing HFNC to oxygen therapy (absolute difference −1% [95% CI −8 to 6], P = .83). This study must be carefully interpreted as they did not achieve the planned sample size (n = 4,002), and consequently, the research may have been underpowered to detect treatment effects for comparing HFNC and conventional oxygen therapy.

The risk of clinical failure seems to be dependent on multiple factors. As previously reported by Chandel et al,10 a ROX index < 4.94 is independently associated with an increased risk of intubation. Our results seem to corroborate these findings, as subjects with a lower ROX index in the first 6 h after treatment (4.7 ± 2.5) had greater intubation rates than those with higher values (5.3 ± 1.7, P < .001). Regarding PaO2/FIO2, values < 100 mm Hg were associated with clinical failure in 44–80% of subjects admitted in IRCU.6,9 Conversely, our subjects presented a lower clinical failure rate (35%) and 30-d mortality (12.1%). This seems to confirm that early implementation of NRS in these higher-risk subjects leads to improved prognosis; however, we should not neglect a close follow-up during the first 24–48 h to avoid any possibility of delayed ICU transfer. Similarly, in our Cox model to assess risk factors associated with clinical failure, a shorter time between symptoms onset and hospitalization seems to be an indicator of faster and worse evolution; in consequence, subjects admitted within < 10 d of symptoms onset and IRCU admission should be closely followed and rapidly screened for ICU admission.

Previous studies have reported a intubation rates ranging from 26.69–39.7%,10 with a mean PaO2/FIO2 at admission of 133 mm Hg,7,27 whereas our subjects had a much lower intubation rate (22.6%) with a similarly lower mean PaO2/FIO2 of 120.0 ± 54.8 mm Hg. A potential explanation of the discordance between results is that our subjects were immediately treated with HFNC at admission and assessed for eligibility for other NRS such as CPAP or NIV. Chandel et al10 previously reported in a retrospective, multi-center, observational study assessing 272 subjects with COVID-19 with hypoxemic respiratory failure that subjects seem to be highly responsive to HFNC in the first 12 h after initiation. Our results seem to corroborate those results.

There are scarce data regarding mortality in subjects with severe COVID-19, particularly in the IRCU. Regardless, we had much lower mortality in our cohort (8% 30 d after admission) compared to previous reports (22.5–32.5%).6,7,23,28 An initial observational study in Wuhan by Li et al28 found mortality was associated with male sex, older age, leukocytosis, high lactate dehydrogenase level, cardiac injury, hyperglycemia, and high-dose corticosteroid at admission. In our subjects, we found mortality risk was associated with older age, a shorter time from symptom onset to IRCU admission, lower PaO2/FIO2 and ROX index, and higher lactate dehydrogenase levels at IRCU admission. Furthermore, corticosteroids may play a major role in mortality and may explain our results. As shown in the RECOVERY trial,16 6 mg doses significantly reduced morality in subjects with COVID-19 with hypoxemic respiratory failure. Our subjects had moderate to severe ARDS and consequently benefited from corticosteroid treatment, but the absence of a control group limits our ability to fully elucidate the potentially protective effect of this therapy combined with early NRS. Further studies are necessary to determine the risk factors and threshold of clinical values associated with mortality at admission.

Our rate of subjects non-eligible for ICU admission (5.1%) was consistent with a similar Italian cohort (4.2%)9; however, we observed a mortality of 54.5%, much lower than the 71.4% described in the aforementioned study. The main difference was that our subjects did not present high creatinine and low platelets levels, but these results are not consistent with a previous report where sensitivity analysis did not find any correlation between risk factors and NRS in non-severe versus severe subjects.28 Furthermore, our facility design limited the access of dependent, frail patients with severe comorbidities (that is, neurodegenerative disorders).

The retrospective nature of this study is its major weakness and affected several aspects of the study. There are biases inherent to this study design, such as confounders, making it difficult to establish cause and effect. We observe important differences in the baseline characteristics between groups, plausibly explaining our results. Previously reports of subjects with COVID-19 admitted in an IRCU included a higher percentage of males ranging from 67.97–75.3%,23 whereas in our cohort they only represented 64.6% of subjects, with a mean age of 54.7 y, which is younger than patients typically admitted in IRCU.7,23 As we observed in our multivariate analysis, age and sex seem to be correlated with an increased risk of clinical failure and mortality, respectively. Conversely, coexisting disorders and symptoms did not differ substantially from a previous study assessing clinical outcomes of subjects with severe COVID-19 admitted similarly in an IRCU in Spain.7 Information regarding awake prone position was restricted to the number of subjects benefiting from this strategy. Thus, we cannot exclude the possibility that its use as adjunctive treatment to other NRS influenced outcomes. Similarly, some laboratory findings such as interleukine-6 levels could have helped to better understand our results.

Our encouraging results may be explained because this study was performed in a novel facility fully dedicated to patients with COVID-19 allowing easy implementation of a standardized protocol to manage NRS in the IRCU; however, more severe patients (eg, oncological patients under active radiotherapy/chemotherapy, renal replacement therapy) were not transferred, possibly biasing some outcomes. Another strength of the study is that it provides crucial information about the outcomes of subjects during an extensive time frame (10 months), and the study’s design assured the completeness of data collection. Paradoxically, this strength is also a limitation of the study as Isabel Zendal Emergency Hospital opened in December 2020, which imply that our data were collected while vaccination campaign began in Europe; consequently, we could not include the first cases of COVID-19 who were more severe and with a worse prognosis. Furthermore, we did not record vaccination status to assess its impact on outcomes.

Conclusions

The data presented may be the basis for a new hypotheses and sample size calculations for future studies of NRS in subjects with COVID-19. In addition, these data could guide the adjustment of practices and the interpretation of management of COVID-19, keeping a periodic update of the algorithm as new results elucidating some questions may appear.

Acknowledgments

We want to thank to all the nursing staff of Isabel Zendal Emergency Hospital, and specially to the IRCU team. Similarly, we want to thank the admission staff who particularly helped to collect some of these data.

Footnotes

  • Correspondence: José Rafael Terán-Tinedo MD, Intermediate Respiratory Care Unit, Gregorio Marañón University Hospital, Av Manuel Fraga Iribarne, 2, 28055 Madrid, Spain. E-mail: joser_terant{at}hotmail.com

  • Mr Martínez-Alejos is part-time employee at Philips France. The remaining authors have disclosed no conflicts of interests.

  • Supplementary material related to this paper is available at http://www.rcjournal.com.

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