Neuroleptics used in critical COVID associated with moderate- severe dyspnea after hospital discharge

doi:10.21203/rs.3.rs-2838045/v1

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Neuroleptics used in critical COVID associated with moderate- severe dyspnea after hospital discharge

https://doi.org/10.21203/rs.3.rs-2838045/v1

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Background

Dyspnea is a central symptom in patients with long-term COVID, both because of frequency and clinical impact. The effect of the drugs most used in critically ill patients on long-term dyspnea is not known. The aim of this study was to assess the risk factors and impacts associated with moderate to severe dyspnea in COVID-19 survivors.

Methods

Patients admitted to a university hospital between April 2020 and April 2021 were evaluated. It was collected data associated with clinical preconditions, hospital and ICU stay, use of corticosteroids, neuroleptics, neuromuscular blockers, midazolam, fentanyl, and noradrenaline. After hospital discharge, patients were evaluated in 1 and 12 months. In the evaluations, dyspnea, frailty, quality of life, functional capacity, anxiety and depression were measured. Descriptive statistics in the form of frequencies and percentages and a logistic regression analysis were done to assess the factors associated with moderate to severe dyspnea after 1 and 12 months from hospital discharge and statistical significance was set at P < 0.05.

Results

100 patients were prospectively included, with 100 patients underwent the 1-month evaluation and 63 underwent the 12-month evaluation. Presented with limiting dyspnea (defined as mMRC score > 1) 56.6% of patients after 1 month and 33.9% after 12 months. Independent factors associated with limiting dyspnea 1 month after hospital discharge were the total dose of neuroleptics used during hospitalization and the presence of comorbidities prior to hospitalization. Use of corticosteroids, neuromuscular blockers, midazolam, fentanyl, and noradrenaline were not associated with limiting dyspnea. Dyspnea 1 month after hospital discharge was an independent risk factor for the occurrence of limiting dyspnea 12 months after discharge. Patients with limiting dyspnea 12 months after discharge showed more depression, anxiety and frailty, and had lower quality of life and functionality.

Conclusions

Patients with long-term severe COVID have a high frequency of limiting dyspnea. The total dose of neuroleptics used in hospital and the presence of comorbidities were independently related to the presence of limiting dyspnea after hospital discharge. After 12 months, patients who maintained limiting dyspnea presented in high frequency with other physical and mental dysfunction that should be evaluated and treated in the aim of reducing the burden of disabilities.

Health sciences/Health care

Health sciences/Medical research

Health sciences/Risk factors

ARDS

Neuroleptics

COVID-19

long covid

dyspnea.

First documented in China in late 2019 and declared a pandemic in March 2020, COVID-19 has led to millions of deaths in Brazil and worldwide and led to high rates of dysfunctions in patients still in recovery. The WHO recommends that patients with confirmed and suspected COVID-19 have access to follow-up care if they have persistent symptoms.(1)

Long-COVID, defined as symptoms that continue or develop after more than 4 weeks after getting COVID-19, has been associated with numerous dysfunctions (2). Described as one of the most prevalent symptoms in long-term, dyspnea is an important multifactorial symptom patient-centered that remains in high proportions since the first evaluations after hospital discharge and persistent in a group of patients even 2 years of follow-up.(3)

Among the responsible mechanisms for the COVID long-term complications, could be included direct viral tissue damage (4) and the intensity of the inflammatory response (5). In patients with ARDS, respiratory mechanics is related to respiratory dysfunction and mortality in the acute phase (6) and long-term (7). In COVID, respiratory mechanics is also associated with acute outcomes (8). During critical treatment of severe patients, drugs have been used in high doses and for a long time and the effects on long-term remain unknown.

There is a critical need to better understand risk factors and identify mechanisms of post-COVID breathlessness. Inconsistent results for multiple risk factors have been reported, however none focused on the use of medication during hospitalization.(9)

The aim of this study was to explore factors associated with limiting dyspnea after discharge from hospital, especially the use of medications in the context of severe COVID-19 and identify possible impacts of limiting dyspnea to the long-term.

We conducted a 1-year follow-up among patients who were admitted to referral hospitals for SARS-CoV-2 infection between April 2020 to April 2021.(10) After discharge from hospital, patients were evaluated at two points: 1 and 12 months after hospital discharge. The study was approved by the Ethics Committee for the Analysis of Research Projects of the HCFMUSP (approval number: 31942020.0.0000.0068). We confirm that all method was performed in accordance with relevant guidelines and regulations.

For participation, the individual should be aged 18 years, agree to participate in this study, and sign the informed consent form. The patient must have been admitted to the hospital with a confirmed diagnosis of COVID-19.

Patients were evaluated initially with an interview to collect personal and sociodemographic data (name, age, date of birth, sex, race, marital status, education level, telephone, and address), prior history (Charlson Comorbidity Index, previous frailty and EQ-5D-3L questionnaire) and natural history of the disease (day of symptom onset, initial symptoms, history of hospitalization, need for respiratory support and oxygen).

Dispneia was evaluated using modified British Medical Research Council (mMRC) dyspnea scale.(11) The mMRC Dyspnea Scale is simple to administer as it allows the patients to indicate the extent to which their breathlessness affects their mobility. The 0–4 stage scale is used alongside the questionnaire to establish clinical grades of breathlessness. Those who graded themselves in mMRC grades 2, 3, or 4 were considered as presenting moderate to severely disabling post-COVID dyspnea.

Frailty was evaluated using the clinical frailty score, an instrument comprising nine clinical items, in which patients can be classified as frail, pre-frail, and non-frail, according to the observation of a healthcare professional and the verification of patient information.(12) Anxiety disorders and depressive symptoms were evaluated using Hospital Anxiety and Depression Scale (HADS). HADS-Anxiety consists of 7 items assessing anxiety symptoms whereas HADS-D consists of 7 items evaluating depressive symptoms. Each item is scored on a 4-point Likert scale (0–3) providing a maximum of 21 points for each subscale. We applied a cut-off score of ≥ 8 points for each scale since this value has shown good sensitivity and specificity to determine the presence of anxiety or depressive symptoms, respectively.(13)

Quality of life was evaluated using EQ-5D, a generic, standardized and simple health instrument. The EQ-5D-3L descriptive system of health states comprises 5 dimensions (‘5D’): mobility; self-care; usual activities; pain/discomfort and anxiety/depression. Those are rated by a verbal 3-point rating scale allowing for distinction of five levels (‘3L’) of severity: Level 1: no problems; Level 2: some problems; Level 3: extreme problems per dimension and providing a 1-digit number for each dimension.(14)

Medical Research Council (MRC)-sumscore evaluates global muscle strength. Manual strength of six muscle groups (shoulder abduction, elbow flexion, wrist extension, hip flexion, knee extension, and ankle dorsiflexion) is evaluated on both sides using MRC scale. Summation of scores gives an MRC-sum score, ranging from 0 to 60. Despite its ceiling effect, this score reliably identifies significant weakness (< 48) and even better in severe weakness (< 36).(15)

The 1-min sit-to-stand test was also carried out after recording the baseline heart rate, blood pressure, respiratory rate, and SpO2 with a chair of standard height placed next to a wall, as previously described.(16) The subject was seated on the chair, feet a hip-width apart on the floor, knees and hips at right angle and hands stationary on hips. The subjects were requested to repeatedly stand up and sit down at a pace they felt comfortable at, as many times as possible, for a duration of 1 min. They could rest if required, but not use their arms for support while standing up or sitting down. Saturation was monitored during and after exercise till it returned to the baseline. The nadir of the desaturation was noted, along with post-exercise heart rate and respiratory rate.

Were evaluated as possible risk factors for dyspnea after 1 month and 12 months from hospital discharge: sex, age, frailty pre-COVID, Charlson comorbidity index, length of stay in ICU and hospital, total hospital corticosteroids doses (doses of corticosteroids used were converted in dexamethasone doses and divided in quartiles)(17), total hospital neuroleptic doses (doses of neuroleptic used were converted in quetiapine doses and divided in quartiles)(18), time in days using midazolam, fentanyl, muscle relaxants, and norepinephrine. To evaluate risks for dyspnea after 12 months we additionally added frailty and dyspnea 1 month after hospital discharge.

Demographic characteristics and long-term consequences of COVID were presented as median (IQR) for continuous variables and expressed as absolute values along with percentages for categorical variables. For the comparison of frailty, HRQoL, clinical functionality, muscle weakness, and HADS score for anxiety and depression between patients with and without limitant dyspnea we used the Wilcoxon signed-rank test. To explore the association of moderate to severe dyspnea with risk factors pre-selected at 1 and 12 months from discharge to COVID, we used a multivariate adjusted logistic regression model.

All significance tests were two-sided, and a P value less than 0.05 was considered significant. The missing data were not imputed. All statistical analyses were performed using R, version 4.2.2.

Over the recruitment period (april 2020– july 2021), 108 patients were referred after discharge to the post COVID service. We evaluated 100 patients after 1 month from discharge and 63 patients 12 months after discharge. (Fig. 1) There was no difference in terms of sex, age, comorbidities, length of stay in intensive care unit (ICU) or hospital and use of mechanical ventilation measured between patients followed up at month-12 and patients that were lost.

Of the enrolled patients, 50 were male, the median age was 59 years-old. 89 patients stayed more than 24 hours in ICU and 67 patients were in mechanical ventilation for more than 24 hours. Only 3 patients reported previous pneumopathy: 2 reported asthma and 1 reported bronchiectasis.

In terms of corticosteroids, 46 patients used dexamethasone, 39 methylprednisolone and 48 prednisone. After conversion to dexamethasone dose, a median of 60 (0-130.8) mg of total hospital corticosteroids doses was used. In terms of neuroleptics, 60 patients used quetiapine, 9 used risperidone and 23 used haloperidol. After conversion to quetiapine dose, a median of 225 (0-1158) mg of total hospital neuroleptic doses was used. Midazolam was used for 4 (0–7) days, fentanyl was used for 5 (0–10) days, muscle relaxants was used for was used for 2 (0–5) days, and norepinephrine was used for was used for 3 (0-7.5) days.

We evaluated dyspnea in 83 patients after 1 month and in 56 patients after 12 months. The proportion of limiting dyspnea, defined by an mMRC score higher than 1 was 47 (56.6%) 1 month after discharge from hospital and 19 (33.9%) after 12 months.

The descriptive baseline and hospital data for all randomized patients and for patients who presented limiting dyspnea after 1 and 12 months from discharge are described in Table 1.

Table 1

Características of all patients (100 patients), patients with moderate-severe dyspnea after 1 month (47 patients) and after 12 months (19 patients) from hospital discharge.
Parameter	All patients	Patients with dyspnea after 1 month	Patients with dyspnea after 12 months
Female sex N (%)	50 (50)	24 (51)	13 (68.4)
Age	59.5 (49–67)	63 (53-71.5)	63 (50–73)
Chalson	4 (2–5)	4 (2-6.25)	4.5 (3-6.75)
Frailty pre-COVID	3 (2–3)	3 (2–3)	3 (2.25-4)
Time simptoms to hospital admission	9 (7–12)	9 (7–12)	9 (6.5–11.5)
Muscle blocker days	2 (0–5)	2 (0-5.5)	1 (0-3.5)
Fentanyl days	5 (0–10)	5 (0–12)	4 (0-8.5)
Midazolam days	4 (0–7)	4 (0-7.5)	3 (0-6.5)
Noradrenaline days	3 (0-7.5)	5 (0-7.5)	2 (0-4.5)
Cumulative corticoid dose (after conversion to dexamethasone - mg)	60 (0-130.8)	85 (50-186.5)	66 (26.5-143.5)
Cumulative neuroleptic dose (after conversion to quetiapine - mg)	225 (0-1158)	725 (175–1838)	475 (12.5-2648.5)
Time in mechanical ventilation	6 (0-12.25)	7 (0–14)	11 (2–19)
Length of stay in ICU	12 (6–21)	17 ( 7.5–24)	11 (2–19)
Length of stay in hospital	23 (15-34.25)	30 (20–41)	23 (14.5–36.5)
ICU: Intensive care unit

Risk factors for dyspnea 1 month after discharge from hospital in univariate analysis were Charlson index, ICU length of stay, hospital length of stay, cumulative dose of corticosteroids and cumulative dose of neuroleptics (Table 2). After multivariate analyses were identified as risk factors to dyspnea after 1 month Charlson index (OR 1.27, CI95% 1.02–1.63) and cumulative dose of neuroleptics (OR 1.82, CI95% 1.10 to 3.14). (Fig. 2)

Table 2

Univariate and multivariate analysis for risk factors to moderate-severe dyspnea after 1 month and 12 months (P value)
Parameters	1 month		12 months
	P	OR (CI95%)	P	OR (CI95%)
Female sex	0.39	1.47 (0.62–3.51)	0.16	2.40 (0.77–8.10)
Age	0.05	1.03 (1.00-1.08)	0.29	1.02 (0.97–1.08)
Charlson index	0.04	1.20 (1.01–1.47)	0.11	1.19 (0.96–1.49)
Frailty pre-COVID	0.52	1.13 (0.76–1.72)	0.14	1.48 (0.88–2.60)
Corticoids (quartiles)	< 0.01	1.80 (1.18–2.82)	0.47	1.18 (0.72–1.98)
Neuroleptics (quartiles)	< 0.01	1.94 (1.33–2.92)	0.48	1.20 (0.76–1.89)
Muscle blocker days	0.28	1.10 (0.96–1.28)	0.19	0.90 (0.73–1.07)
Fentanyl days	0.13	1.06 (0.99–1.15)	0.36	0.96 (0.86–1.05)
Midazolam days	0.36	1.04 (0.96–1.14)	0.46	0.96 (0.85–1.07)
Noradrenaline days	0.14	1.07 (1.00-1.17)	0.87	0.99 (0.88–1.10)
Time in mechanical ventilation	0.24	1.03 (0.99–1.08)	0.81	0.99 (0.93–1.05)
Length of stay in ICU	0.01	1.05 (1.01–1.10)	0.73	0.99 (0.94–1.03)
Length of stay in hospital	< 0.01	1.05 (1.02–1.09)	0.50	1.01 (0.97–1.04)
Dyspnea 1 month after discharge	Not applicable	Not applicable	< 0.01	4.19 (2.07–10.2)
Frailty 1 month after discharge	Not applicable	Not applicable	< 0.01	2.27 (1.29–4.42)
ICU: Intensive care unit; OR: odds ratio; CI95%: Confidence intervals 95%

Risk factors for dyspnea 12 months after discharge from hospital were frailty after 1 month from discharge (P < 0.01) and dyspnea after 1 month from discharge (P < 0.01) (Table 2). After multivariate analysis we identified dyspnea 1 month from discharge (OR 3.65, CI95% 1.63–9.68) as the only risk factor for dyspnea after 12 months from COVID. (Fig. 3)

Patients with dyspnea 12 months after COVID were more fragile, had the worst quality of life, showed more mobility dysfunction, more depression and anxiety. (Table 3 and Fig. 4)

Table 3

Dysfunctions associated with moderate-severe dyspnea after 12 months from discharge by COVID
Parameter	No to mild dyspnea	Moderate-severe dyspnea	P Value
Frailty (CFS score)	3.00 (3.0–3.0)	5.0 (4.0–5.0)	P < 0.01
Muscle Weakness (MRC score)	56 (55-58.75)	53 (46.5-56.25)	P = 0.01
EQ-5D (VAS)	80 (80–90)	70 (50-78.75)	P < 0.01
Depression (HADS score)	8 (8-10.2)	16 (14-18.35)	P < 0.01
Anxiety (HADS score)	9.5 (8–12)	14 (12–20)	P < 0.01
Repetitions during sit up 1 minute test	20 (18-22.5)	13.5 (12-17.5)	P < 0.01
CFS: Clinical frailty scale; MRC: Medical research council; VAS: Visual analogue scale; HADS: Hospital anxiety and depression scale.

When evaluating limiting breathlessness in patients who survived hospitalization due to COVID, we found for the first time that the total dose of neuroleptics used during hospitalization was independently associated with the occurrence of limiting dyspnea in post-COVID. The association between dyspnea and neuroleptics was independent of other risk factors typically associated with COVID severity, such as duration of mechanical ventilation, noradrenaline use and length of ICU or hospital stay.

Dyspnea is a multifactorial and subjective experience of breathing discomfort involving the interaction between various physiological, psychological and environmental factors (19, 20). We confirmed, in agreement with previous studies, a high occurrence of dyspnea after severe COVID (2, 3), that could be associated with an association of still uncertain multiple factors. When identifying the use of neuroleptics as a risk factor for limiting dyspnea after severe COVID, we introduce another piece to this puzzle.

Rates of delirium in mechanically ventilated COVID patients were elevated, but comparable to patients with similar severity without COVID (21). Admission in ICU, longer mechanical ventilation and higher sedation doses are associated with delirium as well as possible direct neuronal damage due virus (22). Our population was at high risk to present delirium since they were predominantly admitted in ICU (89%) and required frequent mechanical ventilation (67%).

In this context, neuroleptics were used frequently, sometimes in high doses, during predominantly ICU stay. Among the adverse effects associated with the use of anticholinergic medications in critically ill patients, short-term sedation, drug-drug interaction, respiratory depression, QTc interval prolongation, daytime sedation and respiratory distress are relevant (23, 24) and might be associated with the observed findings in our study.

Certainly, additional studies should evaluate this association, but our findings reinforce the evidence that suggest favoring the use of other drugs than neuroleptics in ICU delirium, as it has limited clinical efficacy and a high risk of adverse events (25).

The use of corticosteroids during hospitalization was not associated with the occurrence of dyspnea, a result compatible with a previous study (26). No relationship was identified between dyspnea and duration of drugs used exclusively during critical illness, such as fentanyl, midazolam, noradrenaline and neuromuscular blockers, usually associated with COVID severity.

Patients with dyspnea 12 months after hospitalization due to COVID have associated physical and mental dysfunctions and it is possible that these comorbidities contribute to the sensation of dyspnea and increase limitation associated with dyspnea. This finding highlights the need to explore and identify other dysfunctions in patients with limiting post-COVID dyspnea, especially when amenable to treatment, looking for a patient-centered approach. It is possible that the treatment of other comorbidities such as anxiety, depression and muscle weakness can reduce dyspnea, but this was not the scope of this study.

The strengths of our study are the longitudinal design with a long follow-up, associated data from hospitalization and a high proportion of patients who had been admitted to an intensive care unit. Our study has several limitations. First, the moderate response rate after 12 months of follow-up could introduce selection bias. However, no difference was observed among several parameters evaluated in the group of patients who were lost to follow-up and in the group of patients evaluated after 1 year. Second, No measurement of delirium was performed on ICU, so it is possible that the effect attributed to the neuroleptic could be associated with the occurrence of delirium. However, the observed dose-response effect and the non-occurrence of an effect associated with the use of other pharmacological risk factors to delirium such as midazolam, suggest that the neuroleptics may be linked with the occurrence of limiting dyspnea in an independent way. Third, this is a single-center study and COVID-19 survivors came from the early stages of the global pandemic, so the findings might not directly extend to the long-term health outcomes of patients infected with later SARS-CoV-2 variants. However, our hospital is the largest university hospital in our country and assists patients from all districts of the metropolitan region of Sao Paulo city (approximately 21 million inhabitants).(8) Fourth, similar to most follow-up studies of COVID-19, information bias was possible in self-reported comorbidities during the acute phase and several self-reported health outcomes during convalescence. Finally, we did not exclude patients with previous pneumopathy. Nevertheless, the number of these patients was small (3%), not impacting data accuracy.

Patients with long-term covid have a high rate of limiting dyspnea that does not depend only on the severity of the acute illness. The total dose of neuroleptics used during hospitalization was independently related to the presence of dyspnea 1 month after hospital discharge due to COVID. After 12 months, patients who maintained dyspnea had several other physical and mental disorders that should be evaluated and treated in order to reduce the burden of symptoms associated with long-term COVID.

mMRC	modified British Medical Research Council
WHO	World Health Organization
ARDS	Acute respiratory distress syndrome
HCFMUSP	Hospital das clínicas da Faculdade de Medicina da Universidade de São Paulo
HADS	Hospital Anxiety and Depression Scale
SpO2	Peripheral oxygen saturation
IQR	Interquartile range
HRQoL	Health-related quality of life
ICU	Intensive care unit
OR	Odds ratio
CFS	Clinical frailty scale
VAS	Visual analogue scale

Ethics approval and consent to participate

The study was approved by the Ethics Committee for the Analysis of Research Projects of the HCFMUSP (approval number: 31942020.0.0000.0068).

All individuals consent to participate in this study and sign the informed consent form.

Consent for publication

Not applicable

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

Not Applicable.

Authors contributions

CTJ designed the work, acquired, analyzed, interpreted the data for the work and drafted the work. GC designed the work, acquired, interpreted the data for the work and critically revised the work. JEP designed the work, acquired, interpreted the data for the work and critically revised the work. CRFC designed the work, acquired, interpreted the data for the work and critically revised the work. CRRC designed the work, interpreted the data for the work and critically revised the work. All authors read and approved the final manuscript.

Acknowledgements

We are grateful for the assistance given by Luciana Cassimiro Nóbrega, Vinicius Iamonti, Vivian Vieira Tenorio Sales, Caroline Gil de Godoy, Erika Christina Gouveia e Silva, Danielle Brancolini de Oliveira in acquired the study data.

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No competing interests reported.

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Neuroleptics used in critical COVID associated with moderate- severe dyspnea after hospital discharge

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