The burden of symptoms at the end of life of COVID-19 patients and helpful treatments
COVID-19 patients may show symptoms such as breathlessness or delirium at the end of life. The goal of palliative medicine is to relieve such symptoms with specific treatments. Treatments can be drugs, for example opioids, or non-drugs, such as breathing techniques or relaxation.
What was the aim of our review?
To explore how well different interventions (drugs and non-drugs) work for the treatment of palliative symptoms in COVID-19 patients at the end of life. We included patients of all ages and with all comorbidities (additional medical conditions).
What type of studies did we search for?
We searched selected medical databases and trial registries until 23 March 2021. We included studies looking at how well different palliative treatments work to relieve COVID-19-associated symptoms at the end of life. We wanted to compare studies investigating different medicines or therapies, but we only found studies without a comparison group. Only one study reported the specific drugs used for individual symptoms.
Key results
We found four studies that were published in five papers. Individual papers included between 61 and 2105 participants, and two papers partially reported on the same participants. All of the included studies investigated different drug treatments for palliative symptom management in people with COVID-19.
Drugs for symptom control at the end of life
All of the included studies reported on the effectiveness of palliative care for symptom relief. In all studies, clinicians or nursing staff rated symptom relief rather than the patients themselves. Since the quality of the evidence was very low, we do not know the true effect of drug treatments on symptom relief and have very low confidence in the results of the studies. We did not find any data on quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; or safety of the drug treatments.
Non-drug therapies for symptom control at the end of life
We did not find any data on the benefits and harms of non-drug therapies for symptom control of COVID-19 patients at the end of life.
Conclusions
Based on our findings, we could not draw any conclusions on palliative symptom control of people with COVID-19. Future studies need to be designed better so that we can determine which treatments work for symptom control in people with COVID-19.
We 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. More 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.
Individuals dying of coronavirus disease 2019 (COVID-19) may experience distressing symptoms such as breathlessness or 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 COVID-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 specific symptoms of COVID-19 patients is required.
To assess the efficacy and safety of pharmacological and non-pharmacological interventions for palliative symptom control in individuals with COVID-19.
We searched the Cochrane COVID-19 Study Register (including Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (PubMed), Embase, 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 to identify completed and ongoing studies without language restrictions until 23 March 2021.
We screened the reference lists of relevant review articles and current treatment guidelines for further literature.
We followed standard Cochrane methodology as outlined in the Cochrane Handbook for Systematic Reviews of Interventions.
We included studies evaluating 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, or ethnicity. Interventions comprised pharmacological as well as non-pharmacological treatment (e.g. acupressure, 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. If studies enrolled populations with or exposed to multiple diseases, we would only include these 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.
We used a modified version of the Newcastle Ottawa Scale for non‐randomized studies of interventions (NRSIs) to assess bias in the included studies. We included the following outcomes: symptom relief (primary outcome); quality of life; symptom burden; satisfaction of patients, caregivers, and relatives; serious adverse events; and grade 3 to 4 adverse events.
We rated the certainty of evidence using the GRADE approach.
As meta-analysis was not possible, we used tabulation to synthesize the studies and histograms to display the outcomes.
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. Two references used the same register to form their cohorts, and 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 participants. Participants received multimodal pharmacological interventions: opioids, neuroleptics, anticholinergics, and benzodiazepines for relieving dyspnea (breathlessness), delirium, anxiety, pain, audible upper airway secretions, respiratory secretions, nausea, cough, and unspecified symptoms.
Primary outcome: symptom relief
All identified 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, and benzodiazepines.
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; and 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.