Interventions for palliative symptom control in COVID-19 patients.

Abstract

BACKGROUND\nIndividuals dying of coronavirus disease 2019\xa0(COVID-19) may experience distressing symptoms such as breathlessness\xa0or delirium. Palliative symptom management can alleviate symptoms and improve the quality of life of patients. Various treatment options such as opioids or breathing techniques have been discussed for use in COVID-19 patients. However, guidance on symptom management of\xa0COVID-19 patients in palliative care has often been derived from clinical experiences and guidelines for the treatment of patients with other illnesses. An understanding of the effectiveness of pharmacological and non-pharmacological palliative interventions to manage\xa0specific symptoms of COVID-19 patients is required.\n\n\nOBJECTIVES\nTo assess the efficacy and safety of pharmacological and non-pharmacological interventions for palliative symptom control in individuals\xa0with COVID-19.\n\n\nSEARCH METHODS\nWe searched the Cochrane COVID-19 Study Register (including Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed),\xa0Embase, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), medRxiv); Web of Science Core Collection (Science Citation Index Expanded, Emerging Sources); CINAHL; WHO COVID-19 Global literature on coronavirus disease; and COAP Living Evidence on COVID-19\xa0to identify completed and ongoing studies without language restrictions until 23 March 2021. We screened the reference lists of relevant review articles\xa0and current treatment guidelines for further literature.\n\n\nSELECTION CRITERIA\nWe followed standard Cochrane methodology as outlined in the Cochrane Handbook for Systematic Reviews of Interventions. We included studies\xa0evaluating palliative symptom management for individuals with a confirmed diagnosis of COVID-19 receiving interventions for palliative symptom control, with no restrictions regarding comorbidities, age, gender,\xa0or ethnicity.\xa0Interventions comprised pharmacological\xa0as well as non-pharmacological treatment\xa0(e.g.\xa0acupressure, physical therapy, relaxation, or breathing techniques). We searched for the following types of studies: randomized controlled trials (RCT), quasi-RCTs, controlled clinical trials, controlled before-after studies, interrupted time series (with comparison group), prospective cohort studies, retrospective cohort studies, (nested) case-control studies, and cross-sectional studies. We searched for studies comparing pharmacological and non-pharmacological interventions for palliative symptom control with standard care. We excluded studies evaluating palliative interventions for symptoms caused by other terminal illnesses.\xa0If studies enrolled populations with or exposed to multiple diseases, we would only include\xa0these if the authors provided subgroup data for individuals with COVID-19. We excluded studies investigating interventions for symptom control in a curative setting, for example patients receiving life-prolonging therapies such as invasive ventilation.\xa0 DATA COLLECTION AND ANALYSIS: We used a modified version of the Newcastle Ottawa Scale for non-randomized studies of interventions (NRSIs) to assess bias in the included studies.\xa0We included the following outcomes: symptom relief (primary outcome); quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; serious adverse events;\xa0and grade 3 to 4 adverse events. We rated the certainty of evidence using the GRADE approach.\xa0 As meta-analysis was not possible, we used tabulation to synthesize the studies and histograms to display the outcomes.\xa0 MAIN RESULTS: Overall, we identified four uncontrolled retrospective cohort studies investigating pharmacological interventions for palliative symptom control in hospitalized patients and patients in nursing homes. None of the studies included a comparator. We rated the risk of bias high across all studies. We rated the certainty of the evidence as very low for the primary outcome symptom relief, downgrading mainly for high risk of bias due to confounding and unblinded outcome assessors. Pharmacological interventions for palliative symptom control We identified four uncontrolled retrospective cohort studies (five references) investigating pharmacological interventions for palliative symptom control.\xa0Two references used the same register to form their cohorts,\xa0and study investigators confirmed a partial overlap of participants. We therefore do not know the exact number of participants, but individual reports included 61 to 2105\xa0participants. Participants received multimodal pharmacological interventions: opioids, neuroleptics, anticholinergics,\xa0and benzodiazepines\xa0for relieving dyspnea (breathlessness), delirium, anxiety, pain, audible upper airway secretions, respiratory secretions, nausea, cough, and unspecified symptoms.\xa0 Primary outcome: symptom relief All\xa0identified studies reported this outcome. For all symptoms (dyspnea, delirium, anxiety, pain, audible upper airway secretions, respiratory secretions, nausea, cough, and unspecified symptoms), a majority of interventions were rated as completely or partially effective by outcome assessors (treating clinicians or nursing staff). Interventions used in the studies were opioids, neuroleptics, anticholinergics,\xa0and benzodiazepines.\xa0 We are very uncertain about the effect of pharmacological interventions on symptom relief (very low-certainty evidence). The initial rating of the certainty of evidence was low since we only identified uncontrolled NRSIs. Our main reason for downgrading the certainty of evidence was high risk of bias due to confounding and unblinded outcome assessors. We therefore did not find evidence to confidently support or refute whether pharmacological interventions may be effective for palliative symptom relief in COVID-19 patients. Secondary outcomes We planned to include the following outcomes: quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; serious adverse events;\xa0and grade 3 to 4 adverse events. We did not find any data for these outcomes, or any other information on the efficacy and safety of used interventions. Non-pharmacological interventions for palliative symptom control None of the identified studies used non-pharmacological interventions for palliative symptom control.\n\n\nAUTHORS CONCLUSIONS\nWe found very low certainty evidence for the efficacy of pharmacological interventions for palliative symptom relief in COVID-19 patients. We found no evidence on the safety of pharmacological interventions or efficacy and safety of non-pharmacological interventions for palliative symptom control in COVID-19 patients. The evidence presented here has no specific implications for palliative symptom control in COVID-19 patients because we cannot draw any conclusions about the effectiveness or safety based on the identified evidence.\xa0More evidence is needed to guide clinicians, nursing staff, and caregivers when treating symptoms of COVID-19 patients at the end of life. Specifically, future studies ought to investigate palliative symptom control in prospectively registered studies, using an active-controlled setting, assess patient-reported outcomes, and clearly define interventions. The publication of the results of ongoing studies will necessitate an update of this review. The conclusions of an updated review could differ from those of the present review and may allow for a better judgement regarding pharmacological and non-pharmacological interventions for palliative symptom control in COVID-19 patients.