High-Flow Nasal Cannula therapy: A Feasible Treatment in Vulnerable Older COVID-19 Patients on the Wards

Job van Steenkiste (  jobvansteenkiste@gmail.com ) Maasstad Ziekenhuis https://orcid.org/0000-0002-5062-5397 Michael C. van Herwerden Maasstad Ziekenhuis Dolf Weller Maasstad Ziekenhuis Christiaan J. van den Bout Maasstad Ziekenhuis Rikje Ruiter Maasstad Ziekenhuis Jan G. den Hollander Maasstad Ziekenhuis Rachida el Moussaoui Maasstad Ziekenhuis Gert T. Verhoeven Maasstad Ziekenhuis Charlotte van Noord Maasstad Ziekenhuis Marinus van den Dorpel Maasstad Ziekenhuis


Background
At the end of December 2019 the province Hubei in China experienced an outbreak of multiple cases with unexplained low respiratory tract infections. The etiology of this illness is now attributed to the new coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Evidence indicates that SARS-CoV-2 was transmitted from wildlife animals to humans at the Huanan Seafood Market in Wuhan [1]. By the 14th of January 2020 human-to-human transmission of the coronavirus was reported. Following this outbreak in China, rapid worldwide spread occurred and by March 11, 2020, The World Health Organization has proclaimed Coronavirus disease 2019 (COVID- 19), which is the infectious disease caused by the SARS-CoV-2 virus, to be a global pandemic [2]. By May 1th 2020, more than 4.893 proven COVID-19 patients in the Netherlands have died with total hospital admissions rising to 10.854 cases [3].
In approximately eighty percent of COVID-19 cases, respiratory symptoms occur [4]. Roughly twenty percent develop severe respiratory symptoms requiring hospital admission [5]. Of these, a quarter needs invasive respiratory support. Multiple case series and cohort studies have been published suggestion factors associated with poor clinical outcomes in COVID-19 disease including older age, hypertension and diabetes [4][5][6][7].
With the lack of high quality evidence for any speci c antiviral drug, symptomatic treatment with oxygen and, in severe cases, invasive mechanical ventilation remains the cornerstone of the current treatment for COVID- 19. As an intermediate step up between conventional oxygen therapy and invasive mechanical ventilation, High-ow Nasal Cannula (HFNC) is widely used to treat severe respiratory infections. It allows non-invasive ventilation in a relatively comfortable way using high ow with pre-heated, humidi ed air containing large oxygen concentrations. Rapidly after the outbreak of the virus, HFNC therapy was implemented on our hospital wards for patients who failed on conventional high dose oxygen administration and were considered not eligible for invasive mechanical ventilation in the Intensive Care Unit (ICU) due to frailty, functional status, comorbidity or following a speci c wish of the patient. HFNC was the last available strategy of oxygen administration on the wards. Nurses and staff were properly trained, and surveillance was done by continuous remote monitoring systems measuring heart frequency and respiratory rate. So far, only two studies [8,9] have described the clinical course of COVID-19 patients treated with HFNC. Large cohort studies assessing clinical outcomes are missing in this group.
Here, we describe the clinical course of a cohort of vulnerable elderly patients with respiratory failure despite conventional high dose oxygen administration, treated with HFNC for whom long standing invasive mechanical ventilation was not eligible due to functional status. The primary outcome was survival. Furthermore, we aimed to identify determinants associated with survival.

Study design and population
This was a retrospective, single center cohort study in the Maasstad Medical Centre, which is the largest (600-bed) non-academic teaching hospital in the Rotterdam area, the Netherlands. This study was approved by the Hospitals Medical Ethical Committee, application number W20.081.
We conducted a study amongst patients older than 18 years who were admitted with a COVID-19 infection between the 9th of March 2020 and 1th of May 2020 and were admitted to the hospital with severe respiratory insu ciency. Laboratory con rmation of SARS-CoV-2 was done using PCR techniques on a nasopharyngeal swab with a Roche analyzer on admission.
Mechanical ventilation in the Intensive Care Unit was declined in a portion of the admitted patients because of clinical frailty status, performance status or history of disease (e.g. severe cardiopulmonary conditions). These decisions were made in accordance with the patient and his or her relatives and were discussed on a daily basis in a multidisciplinary team together with Critical Care, Internal Medicine, Pulmonology and Palliative Care Specialists. During these meetings, performance scores, comorbidities, cognitive functioning and frailty were used to make a considered decision. When there was unanimous agreement that patients were too frail for mechanical ventilation, HFNC was the only alternative treatment. We started HFNC with a ow of 60 liter per minute with a temperature of 37C and titrated oxygen fraction based on oxygen saturation (spO2 >92%) and respiratory rate (<25 per min).
Data was collected using SQL Server Management Studio version 18.3 from our electronic patient record Chipsoft: Healthcare Information X-change. A rst check was performed by the hospital's data manager (GW) after automatic extraction. A nal check on the database was then performed by the two principal investigators (JvS and MvH).

Demographics, Medical history and Drug use
Demographic data and medical history were extracted from the medical record. The following demographic data were extracted. Age, gender, date of admission, days of hospital stay, body mass index (BMI) and survival. Comorbidities that were scored, were hypertension (de ned as the use of antihypertensives), diabetes mellitus type 2 (de ned as fasting plasma glucose level ≥ 6.1 mmol/L), asthma (bronchodilator use and spirometry with reversibility), chronic obstructive pulmonary disease (COPD Gold classi cation), smoking (current or former), chronic kidney disease (eGFR <60ml/min/1,73 m2), malignancy (history of malignant neoplasm), occlusive peripheral arterial disease, ischemic heart disease (de ned as obstructive coronary artery disease), non-ischemic heart disease, liver disease (radiological or pathological steatosis or cirrhosis) and the total number of comorbidities. Furthermore, out of hospital drug use (immunosuppressive drugs, ACE inhibitors and non-steroidal drugs) and in hospital drugs were scored (cefuroxime and azithromycin).

Signs and clinical parameters
Clinical parameters were extracted from the medical record for every patient on admission, these include pulse rate, blood pressure, temperature, respiratory rate and oxygen saturation. Patients were asked if, and since when they had the following symptoms: cough, dyspnea, weight loss, diarrhea and nausea.

Frailty assessment
For clinical frailty assessment we used the Clinical Frailty Score [10] ranging from 1 (very t) to 9 (terminally ill). In addition WHO performance status score was extracted from the medical record ranging from 1 (fully active) to 4 (completely disabled) [11].

Laboratory values and Radiological ndings
For each patient blood examinations including hemoglobin, leukocyte count with differential count, platelet count, d-dimer, alanine transaminase (ALAT), aspartate transaminase (ASAT), creatine kinase (CK), lactate dehydrogenase (LDH), troponin T and ferritin levels were collected. We choose for these speci c laboratory measures as most of them have already proved to be discriminating between mild and severe clinical courses [5]. Chest X-ray was performed on admission in every patient. If there was a high clinical suspicion on pulmonary embolism with elevated d-dimer levels in absence of pulmonary in ltrates on chest x-ray, an additional computed tomography (CT) pulmonary angiogram was performed.

HFNC
We registered days since admission before the start of HFNC. Furthermore, ow (liters per minute), fraction of inspired oxygen (FiO2) and reasons for failure of HFNC therapy were extracted from the medical record. FiO2 increase of ten percent in the rst 24 hours were scored separately.

Outcome
The primary end-point of our study was survival on the hospital ward in patients who used HFNC.
Furthermore, we checked for determinants associated with mortality during HFNC use.

De nitions
Fever was considered as a tympanic temperature lower than 36 or greater than 38 degrees Celsius.
Patients were considered infected if they were proven positive for SARS-CoV-2 using a nasopharyngeal PCR test.
Respiratory failure was de ned as persisting hypoxemia despite maximum conventional oxygen administration e.g. saturation (SpO2) lower than 92% despite maximum oxygen administration with a non-rebreathing mask (15 liters per minute). To assess the severity of Acute Respiratory Distress Syndrome (ARDS) SpO2/FiO2 ratios were calculated, as it was impossible to collect PO2/FiO2 ratios for all patients and because SpO2/FiO2 can be considered equally sensitive and speci c as compared to PO2/FiO2 ratios [12].

Statistical analysis
Baseline data is presented as median (IQR) or n (%) were appropriate. In order to compare differences between survivors and non-survivors, we used Mann Whitney U test for continuous data and Fisher's exact test for categorical data. P-values <0.05 were considered to be statistically signi cant. All statistical analysis were performed using R Studio version 3.6.3. Variables with clinical relevance and in between group differences were used in a univariate logistic regression model to calculate odds ratios in order to assess factors associated with in hospital mortality. No multivariate analysis was performed because of the size of cohort leading to high risk of over tting the model.

Results
Demographics, Medical history and Drug use Between 9th of March 2020 and 1th of May 2020, 297 COVID-19 positive patients were admitted to our hospital with a median age of 62.5 years (52.5-78.0), men being predominant (58%). Thirty-four (11%) COVID-19 patients received HFNC treatment. After excluding two patients that were still hospitalized during the analysis, 32 patients were included in the nal cohort. There were no patients with missing baseline data. Baseline data is shown in table 1. In the total cohort the median age was 79.0 years (74.5-83.0) and more than half were male (69%). Median BMI was 27.1 (26.3-31.4) and a median of three comorbidities were reported (3-4). Hypertension was the most frequently reported comorbidity (75%) followed by diabetes mellitus type 2 (44%). Sixteen percent of patients were current smokers and 19% had a history of tobacco use. With regards to medication use outside of the hospital, median number of drugs used for chronic purposes was seven (5-10).

Frailty assessment
The overall Clinical Frailty score was 4 (categorized as vulnerable) out of 9 (3-6) compared to a WHO performance score of 2 out of 4 (2-4).

Laboratory values and Radiological ndings
For an overview of laboratory values on admission and during hospital stay, see table 3. Most of the patients had radiological ndings on chest x-rays during admission. Out of these, bilateral pulmonary in ltrates were the most frequently found (72%). Only 12 (38%) patients underwent a CT-scan, pulmonary embolism was con rmed in 5 (45%).

Survival and between group differences
Overall survival rate in the HFNC cohort was 25%. We found no statistically signi cant differences between survivors and non-survivors for BMI, comorbidities (including smoking), frailty and performance scores, medication use, HFNC settings, most of the laboratory values and radiological ndings.

Discussion
To the best of our knowledge this is the rst observational cohort study which describes the clinical course of a cohort of older COVID-19 patients with multiple comorbidities and frailty scores indicating vulnerability, treated with HFNC on the hospital wards because of failure of conventional administration with high volumes of oxygen, resulting in a survival rate of 25%. This survival percentage is similar to patients with multiple comorbidities admitted to Dutch, European and Northern-American intensive care units in the same age group [13][14][15]. Thus, in our opinion this study describes an alternative respiratory treatment strategy on the wards for vulnerable elderly COVID-19 patients for whom long standing invasive mechanical ventilation is not eligible due to frailty.
We found an overall case rate survival much lower than most reported survival rates on the clinical wards [6,16,17].However, our cohort is a selection of frail patients with severe respiratory failure and high ARDS scores. Recently two other studies were published describing the successful use of HFNC in COVID-19 patients [8,9]. Contrary to these studies, we did not use HFNC therapy as an intermediate step-up between invasive mechanical ventilation and conventional oxygen therapy. Success rate of HFNC seems to be mostly dependent on the severity of pulmonary infection, with lower PaO2/FiO2 ratios resulting in a higher chances of therapy failure. Wang et al. [9] described failure of HFNC in 63% when PaO2/FiO2 was below 200 mmHg, comparable with our group. Previous studies have shown that vulnerability is associated with worse clinical outcomes including mortality and duration of hospitalization in non-COVID patients [18,19]. In line with our results, increasing age [6,16,20] and hypertension [5,6,20] are independent risk factors for mortality in COVID-19 positive patient. The latter nding is paradoxical since hypertension in frail older people without COVID-19 is not associated with higher mortality [21].
Regarding factors associated with poor outcome we only found procalcitonin and leukocyte count to be associated with higher mortality, we think this is due to our small sample size. Earlier risk factor de ning studies in COVID-19 patients found neutrophilia, raised lactate dehydrogenase, leukocyte counts and raised ASAT are all associated with higher disease burden [4].
The ease of application of HFNC in comparison with noninvasive ventilation (NIV) makes HFNC an excellent strategy of oxygen administration on the wards. In line with the small case series on HFNC in COVID-19 patients published by Geng et al. [8] we have experienced HFNC to work in both a patient and staff friendly way. Staff reported HFNC to be an easy to work with machine while patients reported relatively high comfort breathing humidi ed and preheated air. The bene t of patient tolerance and assuring more reliable delivery of FiO2 due to dead space ushing makes HFNC an excellent method of oxygen supply [22]. Furthermore, as described by Marini et al. early initiation of HFNC can reduce inspiratory effort resulting in lowering pulmonary trans-vascular pressures and can protect lungs from patient self-in icted lung injury [23].
On initiation of HFNC in our hospital, a comment was raised about potential safety issues with regards to aerosol and viral spread with non-invasive mechanical ventilation like HFNC. Available literature did not reveal any evidence of increased risk of contamination while working with HFNC [24,25]. Only one retrospective study is available describing the infection rates of SARS-CoV-1 in hospital workers operating HFNC machines. As compared to tracheal intubation (35%) and NIV (38%), HFNC seems to be the safest option with a lower risk of infection (8%) [26]. Although we did not speci cally investigate these potential safety hazards, we did not nd a higher infection rate of staff who worked on the wards with HFNC patients during the study period. All of our staff operating HFNC machines used Filtering Facepiece Particles-2 masks and eye protection.

Limitations
This study has several limitations. First, randomizing between HFNC and continuing standard oxygen supply, which is the only reasonable alternative active treatment on the wards, was considered to be ethically incorrect since there was failure on conventional oxygen supply. This means that no conclusions can be drawn with regards to survival and clinical performance between HFNC therapy and conventional oxygen administration in COVID-19 patients with similar characteristics. Secondary, no conclusion can be made about survival if our patients would be admitted to intensive care for invasive mechanical ventilation instead of receiving HFCN treatment on the ward. Due to our relatively small cohort, it was di cult to demonstrate differentiating factors between survivors and non-survivors in our population. Further studies are necessary to nd factors for success or failure of HFNC therapy on the ward.

Conclusions
Our retrospective cohort study shows that HFNC is a hopeful respiratory treatment strategy on the wards for vulnerable elderly COVID-19 patients for whom prolonged mechanical ventilation is beyond limits.   Data are presented as n (%) or median (IQR).