In December 2019, dozens of cases of atypical pneumonia of unknown origin were diagnosed, with a possible suspected zoonosis in Wuhan, China.1 The pathogen was subsequently identified as a new coronavirus (SARS-Cov-2) with low lethality (2–3%) and a high infection rate. The onset of signs and symptoms of this disease occurs 5–6 days after contracting the infection, and the incubation period ranges from 1 to 14 days.2

The entry of SARS-CoV-2 into the cell is mediated by the angiotensin-converting enzyme 2 receptor, which is highly abundant in the lungs and musculoskeletal tissue.3 However, the virus affects not just the lung parenchyma, given that the release of inflammatory mediators (interleukin-6),4 along with other not well-known mechanisms, triggers the involvement of skeletal muscles, producing myalgia, fatigue, weakness and atrophy (present in 25–50% of patients hospitalized with this infection).5

The diaphragm is characterized by resistance to fatigue, thanks to aerobic metabolism that uses type 1 or slow-twitch muscle fibers, which are highly prevalent in its structure.6 Hypoxia impedes the ability to obtain energy, initiating anaerobic metabolism, which in turn results in reduced contraction strength of the diaphragm and increases its fatigue.7 Diaphragmatic weakness, either by mechanical, inflammatory or infectious factors, causes dyspnea.8 The combination of these two factors (hypoxemia and dyspnea), along with muscle involvement, is present in most patients hospitalized with COVID-19 after a few days of contracting the disease.9 Patients with this infection undergo an inflammatory storm that significantly affects the skeletal muscles, including the diaphragm.10

Ultrasonography performed at the bedside (known as point-of-care ultrasound) has been shown to be a highly useful tool in monitoring patients with COVID-19 pneumonia.11,12 Diaphragm ultrasound (DUS) is a non-invasive technique by which the patient can be examined at the bedside with no risk. The usefulness of DUS has been demonstrated in intubated critical patients in predicting the success of withdrawing the invasive mechanical ventilation (IMV).13 DUS has also been employed for patients with chronic obstructive pulmonary disease (COPD) to predict the failure risk of noninvasive mechanical ventilation (NIMV) in exacerbations and to analyze the prognostic factors for the success of NIMV.14

Under the hypothesis that infection by COVID-19 produces a multisystem involvement that includes the diaphragm (Fig. 1), we proposed a study to determine the morphological and functional ultrasound condition of the diaphragm of patients admitted for COVID-19 pneumonia during their first 24h and its relationship with hospital morbidity and mortality.

Fig. 1.

Work hypothesis.

(0.15MB).

This prospective study demonstrated that the patients with COVID-19 pneumonia experienced more or less severe diaphragm function impairment and that the implementation of DUS at admission is able to predict short-term outcomes. The parameter that presented the best predictive power in our study was the diaphragmatic fractional shortening, with a cut-off of <20%. The study also provides more evidence for the hypothesis that this virus affects the diaphragm and that this involvement is maintained over time, causing diaphragmatic weakness that is maintained even months after the initial infection in those patients who continue with dyspnea, regardless of whether they required IMV or not.16,17

In our sample, the patients who subsequently presented poor outcomes, requiring RMU admission, had more cardiovascular comorbidities but not more respiratory diseases. However, the overall analysis of comorbidities using the Charlson index showed them to be greater in the patients who subsequently had poorer outcomes. Similarly, the group admitted to the RMU exhibited higher CK levels at the time of admission. These findings agree with other patient series reported in the literature.18,19

The respiratory function impairment of the hospitalized patients revealed the need for developing specialized units: intermediate respiratory care units (IRCUs) and RMUs for administering non-invasive respiratory therapies outside of the ICU.20,21 The patients who were admitted to the RMU experienced more severe pneumonia; therefore, their mortality rate was significantly higher than those who only went through conventional hospitalization. The creation of the RMU in our facility avoided ICU admission for 64.8% of the patients who were candidates for the ICU and for 44.2% of those who were not candidates for ICU.22 This type of unit has undergone a transformation to successfully respond to the COVID-19 pandemic. These units have incorporated new diagnostic techniques such as thoracic ultrasonography, which is present in 85% of these units.21,23

Thoracic ultrasonography for patients with COVID-19 has been shown to be a highly useful prognostic tool, given the complexity of managing these patients.24 The baseline values for diaphragmatic excursion in healthy individuals were already established by 2009.25 The right diaphragm mobility was greater in men than women, measuring 1.8±0.3cm versus 1.6±0.3cm for excursion at tidal volume and 7±1.1cm versus 5.7±1cm for excursion at maximum volume. The excursion at tidal volume in our study was above the normal limits. In contrast, the mobility at maximum volume was below normal limits, especially in the group who ultimately required RMU admission.

Diaphragmatic mobility has been employed to determine the outcome of patients hospitalized in an IRCU for undergoing NIMV due to hypercapnic respiratory failure.26 The study by Cammarota et al. observed that the mobility was significantly less in the patients for whom this therapy ultimately failed. Taking into account the 2 aforementioned studies,25,26 the diaphragmatic excursion in our sample's patients was significantly decreased, especially in the forced maneuvers, in those who presented more severe symptoms and required RMU admission.

As with diaphragmatic excursion, diaphragm thickness presented significant differences depending on sex (greater in the men than in the women) but was not affected by BMI or age.27,28 The normal range for diaphragm thickness is very wide, ranging from 1.3 to 3mm for expiration in women and 1.1 to 2.7mm for men; forced inspiration ranges from 2.8 to 5.9mm in men and from 2.4 to 5.4mm in women.27 Our study's results are within the normal range according to these ranges. Nevertheless, the diaphragm thickness in forced inspiration was smaller in those who ended up in the RMU. If we compare them with the mean thickness observed in healthy individuals, it was also smaller when taking the baseline values both for men (4.3mm) and for women (3.9mm).

COVID-19 infection produces muscle damage defined by generalized arthromyalgia and increased creatine kinase (CK) levels above 200U/L, which occur in more severe conditions of the disease.29 In our sample, there was no relationship between CK levels and diaphragmatic measurements (Table S2). Patients with COVID-19 pneumonia who require IMV experience rapid muscle impairment, including a significant reduction in diaphragm thickness at the seventh day of ICU hospitalization.30 In the DUS of patients with severe symptoms of COVID-19 pneumonia who required IMV, there was a higher incidence of DD than in other convalescents with other non-COVID-19 conditions.31 An important confounding factor is whether the location of parenchymal involvement influences on DD. In our sample, no differences were observed in the location of parenchymal involvement and the presence of DD.

DUS at emergency department admission due to COVID-19 infection is an easy and reproducible technique, although its findings have not been related to the 30-day prognosis.32 Our study confirmed the usefulness of this technique and shows its usefulness in the prognosis of patients hospitalized for this disease. TfDi had the best power in predicting poor outcomes in our study, unlike other studies such as the one conducted by Adolf Helmy et al. in which the reduction in forced diaphragmatic excursion at ICU admission was a predictor of mortality and the requirement for IMV.33 This study did not analyze the diaphragm thickness or its associated measures. However, the DD measured by TfDi was shown to be a predictor of continuous positive airway pressure treatment failure in 27 patients hospitalized in the ICU for respiratory failure due to COVID-19 pneumonia.34

Diaphragm thickness at the end of expiration has also been analyzed in patients admitted to the IRCU, observing that the reduction in this measure was an independent predictor of mortality and the need for IMV. This same study set 2.2mm as the cut-off below which the probability of a poor outcome increases.35 In our sample, the diaphragm thickness at the end of expiration was above this value (2.4mm); however, the DUS in our case was performed at ward admission, and the DUS in the Corradi et al. group was performed at IRCU admission. This difference could be explained by the severity of the infection, given that in our case, we excluded patients who initially went to the RMU.

It is worth noting the study by Formenti et al. who employed ultrasound to determine the prognostic role of the respiratory (intercostal and diaphragm) and skeletal muscles (rectus femoris) in 32 patients admitted to the ICU.36 In this case, the authors analyzed not only the muscle thickness but also its echogenicity. This parameter is measured using a greyscale and indicates the muscle quality, which is directly proportional to the fatty infiltration and of connective tissue (poorer quality). In their study, the authors concluded that the echogenicity of all the muscle groups, including the diaphragm, was greater in those who died. In contrast, only the thickness of the rectus femoris was reduced in those who died. This finding does not agree with our study's observations, although the analyzed factors are not the same and shows a new method for analyzing respiratory muscle function.

Our study has significant limitations that need to be considered when interpreting its results. The DUS was performed by a single operator; therefore, the interobserver variability of the examinations was not considered due to the difficulty entailed in its implementation. The examinations were performed at the patients’ point-of-care, with the examiners dressed in their individual protection equipment. We also did not compare the DUS with the gold standard, the stimulation of the phrenic nerve to confirm the DD.37 Another limitation was the absence of a control group of patients with COVID-19 who did not require hospitalization, as well as healthy individuals. We encountered difficulties in performing the point-of-care ultrasound for patients with high BMIs, given that the ultrasound probe had insufficient penetration to obtain accurate results. In certain patients undergoing high-flow therapy, the measurement could not be performed given that their physical limitations impeded collaboration, both when adopting appropriate postures for the taking of certain measures and in the collaboration when following the instructions to obtain others. Due to the technical difficulty in performing an ultrasound examination of the left diaphragm, combined with the clinical and epidemiological situation at the time of the fieldwork, the decision was made to only conduct a study of the right diaphragm.

In conclusion, the performance of a diaphragmatic ultrasound to determine the mobility and rate of diaphragmatic shortening in the first 24h of hospitalization for COVID-19 pneumonia was useful for determining the short-term outcomes and the need for admission to a respiratory monitoring unit. The DUS is a highly useful and accessible tool, but its use and its baseline values need to be standardized with prospective studies that include patients of differing ages, sex and body mass index.

This project was granted funding by the Sociedad Aragonesa de Patología del Aparato Respiratorio (SADAR) in their 2020 call for proposals.

JLS, as the principal investigator, designed the study, conducted the ultrasounds, performed the statistical analysis, and drafted the final manuscript. MDA participated in performing the ultrasounds and in manuscript writing. PCM, MTR, MASL, LPG, TL, MZL, ABL, AH, and DN contributed to patient recruitment. MASL, SGS, and JAC reviewed and approved the manuscript once finalized.

None.