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Rescue Sepsis Campaign: The first update of the ICU management guidelines for adults with critically ill COVID-19 patients.
The list produced by the Critical Traveler Translation Group can be remembered.
The coronavirus disease-2019 (COVID-19) pandemic continues to affect millions of people around the world.
In view of the rapid growth of the evidence base, we have developed a guideline that keeps pace with the times to provide guidance for the management of severe or critical COVID-19 patients admitted to the ICU.
Method: The members of the expert group on the Surviving Sepsis Campaign Coronavirus Disease 2019 (SSC COVID-19) guidelines for adult coronavirus disease-2019 have been expanded to include 43 experts from 14 countries; all members of the group Members have filled out an electronic version of the conflict of interest disclosure form.
In this update, the expert group elaborated on 9 issues related to the management of severe or critical COVID-19 patients in the ICU.
We used the World Health Organization (WHO) definition of severe or critical COVID-19.
The systematic review team searches the literature for relevant evidence to identify systematic reviews and clinical trials.
At the right time, we conducted a random effects meta-analysis to summarize the treatment effect.
We use Grading of Recommendations, Assessment, Development and Evaluation Approach to evaluate the quality of evidence, and then based on the benefits and harms, resource and cost impacts, fairness and feasibility The balance between using the evidence-decision framework to generate recommendations or recommendations.
Results: The SSC COVID-19 expert group issued a total of 9 recommendations (3 new and 6 updated) on the management of severe or critical COVID-19 patients in the ICU.
For severe or critical COVID-19, the expert panel strongly recommends the use of systemic corticosteroids and venous thrombosis prevention, but strongly does not recommend the use of hydroxychloroquine.
In addition, the expert group recommends the use of dexamethasone (compared to other corticosteroids) and recommends against the use of convalescent plasma and therapeutic anticoagulation outside of clinical trials.
The SSC COVID-19 expert group recommends that remdesivir should be used in severe COVID-19 patients who are not receiving mechanical ventilation, and it is recommended not to use remdesivir in critically ill patients outside of clinical trials.
Due to insufficient evidence, the expert group did not make recommendations on the use of the awake prone position.
Conclusion: The SSC COVID-19 expert group issued several recommendations or suggestions to guide ICU medical professionals in the treatment and care of adult patients with severe or critical COVID-19.
Based on a guideline model that keeps pace with the times, these recommendations or recommendations will be updated as new evidence emerges.
In the process of responding to the COVID-19 pandemic, the expert group of the Save Sepsis Campaign (SSC) has issued guidelines on the management of critically ill COVID-19 patients.
In view of the ever-changing evidence, the SSC COVID-19 expert group held a meeting and issued the latest guidelines and recommendations.
Method: We used WHO's definition of severe and critical COVID-19 (Table 1), and also used a method similar to the first edition of the SSC COVID-19 guidelines.
We formally used the Evidence for Decision (EtD) framework to generate recommendations .
For more detailed information about the method, see the appendix and Figure S1-S3 (http://links.
The detailed evidence summary and decision table evidence are shown in Tables S1-S23 (http://links.
We have listed the updated guidance statement and recommendations in Table 2, and the complete list of recommendations in Table 3.
Definitions of severe and critical COVID-19 Table 2.
Recommendations and statements Table 3.
SSC COVID-19 Recommendation Update List ARDS = Acute Respiratory Distress Syndrome; ECMO = Extracorporeal Membrane Oxygenation; HFNC = Nasal High Flow Oxygen therapy; MAP = mean arterial pressure; NIPPV = non-invasive positive pressure ventilation; NMBA = neuromuscular blockers; PEEP = positive end-expiratory pressure ventilation; PPE = personal protective equipment, SPO2 = blood oxygen saturation; VTE = venous thrombosis embolism.
Appendix: I Management of Respiratory Failure in Non-intubated Patients Wake Prone Position Statement: 1.
There is insufficient evidence to recommend the use of the awake prone position in unintubated adults with severe COVID-19.
Reason: The concept of the awake prone position comes from the literature of mechanically ventilated patients.
In these literatures, prone position ventilation improves the drainage of secretions in mechanically ventilated patients, increases the ventilation of the atelectasis, and reduces the weight of the heart on the left and right lungs.
Oppression of leaves.
In addition, it homogenizes transpulmonary pressure, reduces lung strain, and reduces ventilation-blood loss adjustment.
However, it is not clear whether there are similar effects in patients who are awake, unsedated, and not receiving mechanical ventilation, and whether these effects affect the patient's important prognosis.
Our latest search found a systematic review summarizing the evidence for the awake prone position.
This review included 35 observational studies in ICU and non-ICU settings (n = 414 patients, 12 prospective cohorts, 18 A retrospective cohort and 5 case reports), 29 of which included patients with COVID-19.
A set of protocols was formed for the prone position in 15 studies, and the duration of the prone position varies greatly from study to study.
All reports show improvement in oxygenation in the prone position, but the extent of improvement cannot be accurately assessed.
In addition, once the patient returns to the supine position, the improvement in oxygenation disappears.
In view of the lack of randomization and control groups, the short-term oxygenation improvement, and the uncertainty of the safety of this intervention and its impact on the patient's important prognosis (such as tracheal intubation and mortality), we cannot recommend the awake prone position.
There are some ongoing trials (ClinicalTrials.
gov identification numbers: NCT04350723, NCT04407468, NCT04477655, NCT04395144, NCT04347941, NCT04547283, NCT04344587), and their recommendations will be provided when they are completed.
We did notice that the benefit of prone treatment is that patients actively participate in self-treatment, which is an indicator that may not be observed in clinical trials, and these clinical trials focus on more common outcome indicators such as treatment time, oxygenation status, and Complications of hospitalization.
II Drug treatment of COVID-19 In this section, we discuss possible treatment options for severe or critical adult patients with COVID-19 in the ICU, including antiviral drugs, immunosuppressants, anticoagulants, and immunomodulators.
Recommendations for glucocorticoids: 2.
For severe or critical adult patients with COVID-19, we recommend short-term use of systemic glucocorticoids instead of not using them (strong recommendation, moderate-quality evidence).
For adults with severe or critical COVID-19 considering the use of systemic glucocorticoids, we recommend the use of dexamethasone over other corticosteroids (weak recommendation, very low-quality evidence).
Note: If dexamethasone is not available, clinicians can use other glucocorticoids at a dose equivalent to 6 mg dexamethasone per day for 10 days.
Reason: In the previous version of this guide, the expert group referred to the application of glucocorticoids in the treatment of ARDS caused by SARS-CoV-2, and based on indirect evidence, made similarly applicable weak recommendations for COVID-19.
Since then, a number of randomized controlled trials (RCTs) on the use of glucocorticoids in COVID-19 patients have been published, including recovery trials.
These RCTs were summarized in a systematic retrospective analysis and meta-analysis, including a total of 7 RCTs based on 1703 COVID-19 patients.
Among them, 3 trials used dexamethasone, 3 trials used hydrocortisone, and 1 trial used methylprednisolone.
Overall, the use of glucocorticoids reduced the 28-day risk of death compared with no glucocorticoids or placebo (OR value 0.
69, 95% confidence interval 0.
86, high quality).
When only mechanically ventilated patients were included, the results were similar (OR 0.
66, 95% confidence interval 0.
82, medium quality).
This means that for every 1,000 patients receiving glucocorticoid therapy, there are 96 fewer deaths (95% confidence interval 142-47) (Supplementary information, http://links.
In the subgroup of trials using dexamethasone for up to 10 days, the 28-day mortality effect was the largest (OR0.
64; 95% CI 0.
82; moderate quality), followed by hydrocortisone (374 cases, OR 0.
69; 95% CI 0.
12, low quality) and methylprednisolone (47 patients, OR 0.
97; 95% CI 0.
22, very low quality).
These differences in effect sizes may be related to differences in sample size and design between studies.
Therefore, the comparison of the efficacy of different glucocorticoids cannot draw a clear conclusion.
Although most studies focus on the early use of glucocorticoids, the effect of late use of glucocorticoids in mechanically ventilated patients with COVID-19 remains unclear.
In addition, the optimal dose and duration of glucocorticoid therapy are unclear.
Until more evidence is obtained, we are inclined to use the dosing regimen in the RECOVERY trial (ie, dexamethasone 6 mg/d for 10 consecutive days or the same dose).
The serious adverse events reported in different trials vary.
It is generally believed that glucocorticoids have a series of side effects.
Several studies have shown that for patients with ICU viral pneumonia, the use of glucocorticoids can increase or prolong the shedding of coronavirus RNA, which indicates that the virus may be actively replicating.
However, the clinical consequences of increased viral shedding are uncertain, as there are no reports that have an impact on the duration of mechanical ventilation, hospitalization and ICU stay.
In addition, indirect evidence from non-COVID -19 ARDS populations (7 randomized controlled trials, n = 851) showed that glucocorticoids not only reduced mortality (RR 0.
75; 95% CI 0.
59 ~ 0.
95), but also shortened the duration of mechanical ventilation (MD-4.
93 days; 95% CI -7.
81 ~ -2.
Glucocorticoids are available everywhere, and dexamethasone is on the WHO list of essential medicines.
Although there is no formal cost-benefit study, the cost impact of short-term use of corticosteroids is small and may save costs.
In view of the above reasons, the expert panel strongly recommends: short-term (up to 10 days) glucocorticoid therapy for severe or critically ill adults with COIVID-19, and recommends the use of dexamethasone instead of other glucocorticoids.
Recommendations for antiviral treatment of hydroxychloroquine: 4.
For adult patients with severe or critical COVID-19, we recommend not to use hydroxychloroquine (strong recommendation, moderate quality evidence).
Reason: Due to lack of data, we were unable to make recommendations on whether to use hydroxychloroquine in the first SSC COVID-19 guideline.
Although in vitro studies have shown that chloroquine and hydroxychloroquine can inhibit the replication of SARS-CoV and SARS-CoV-2, clinical trials have failed to prove that COVID-19 hospitalized patients can get clinical benefits.
We searched the literature since the release of the first SSC COVID-19 guideline and found five new RCTs.
Overall, hydroxychloroquine did not reduce the 28-day mortality (RR 1.
07; 95%CI 0.
19; moderate quality) or invasive ventilation requirements (RR 1.
11; 95%CI 0.
36; moderate quality) of adults hospitalized with COVID-19 , But increased adverse events (RR 2.
63; 95% CI 1.
09; low quality) (Supplementary file, http://links.
Similarly, a systematic review showed that the use of hydroxychloroquine may be associated with an increased risk of death (OR 1.
11; 95% CI 1.
The systematic review included 26 RCTs with published and unpublished data and included 10012 patients.
According to the dose of hydroxychloroquine (high dose and low dose), a subgroup analysis was performed, and no subgroup effect was found.
Current evidence shows that hydroxychloroquine will not reduce the risk of death in hospitalized patients with COVID-19, and may actually cause harm.
In addition, the routine use of hydroxychloroquine during this pandemic will increase costs and may harm fairness (Supplementary document http://links.
In view of this, the team strongly recommends not to use hydroxychloroquine to treat severe or critically ill COVID-19 patients.
Recommendations for convalescent plasma: 5.
For adults with severe or critical COVID-19, we recommend not to use convalescent plasma except for clinical trials (weak recommendation, low-quality evidence).
Reason: The researchers hypothesized that due to the SARS-CoV-2 specific antibody infusion, convalescent plasma (obtained from patients recovering from COVID-19) may provide passive immunity.
Convalescent plasma has been used to treat several other viral infections, including infections caused by SARS coronavirus, influenza A (H5N1) virus, and influenza A (H1N1) pdm09 virus.
A Meta-analysis of an observational study on the etiology of SARS virus in passive immunotherapy showed that plasma treatment during the recovery period was associated with a reduction in mortality (OR 0.
25; 95% CI 0.
Although no RCT confirmed its benefit, a large number of COVID-19 patients received convalescent plasma during the pandemic.
Due to lack of data, we did not give recommendations in the previous version of the guide.
Since then, we searched and found four new RCTs using convalescent plasma in COVID-19.
The largest RCT, the PLACID trial, recruited 464 non-severe adult COVID-19 hospitalized patients in 39 centers in India.
Patients in the intervention group received two doses of 200 mL of recovery plasma with an interval of 24 hours, while the control group received conventional treatment.
The other interventions (that is, glucocorticoids, hydroxychloroquine, and anticoagulation) were similar in the two groups.
At 28 days, there was no difference between the two groups in terms of disease progression or mortality (RR 1.
04; 95% CI 0.
Another RCT randomly enrolled 103 patients with severe and critical COVID-19 (25.
8% received invasive ventilation), who were distributed to receive recovery plasma or conventional treatment.
At 28 days, there was no significant difference in the risk of death between the two groups (OR0.
65; 95%CI 0.
The results of the other two studies have also been shared as preprints.
To summarize the evidence, we conducted a Meta-analysis of 4 RCTs (732 patients) and found that the recovery period plasma did not reduce hospital mortality compared with conventional treatment (RR 0.
77; 95% CI 0.
24; low quality).
But after we summarized the evidence, we published another trial, which randomly divided 228 patients with severe COVID-19 into convalescent plasma or conventional treatment groups.
There was no difference between the two groups in terms of mortality risk and other important patient outcomes, which is consistent with previous RCT results.
Although no adverse events have been reported, the incidence of adverse events (such as transfusion reactions, volume overload, and acute lung injury) of plasma infusion during the recovery period is low, which is generally close to plasma infusion.
It is worth noting that the severity of the disease is related to a higher level of antibody response, thus questioning the efficacy of using convalescent plasma for severe COVID-19 patients who may have high antibody levels.
Convalescent plasma requires apheresis/plasma separation from the donor to collect samples, which is expensive and cannot be widely used.
In addition, the optimal neutralizing antibody titer for SARS-CoV-2 is unclear.
During a pandemic, routine use of convalescent plasma may require moderate to large amounts of resources (Supplementary information, http://links.
The large-scale trials currently underway will provide higher-quality evidence of the effectiveness and safety of plasma from COVID-19 patients during the recovery period.
Considering the lack of benefit of published randomized controlled trials so far, the low quality of evidence, the uncertainty of some results, related costs and feasibility issues, the expert group proposed that it is not recommended to treat severe COVID-19 or severe COVID-19 outside the context of clinical trials.
Weak recommendations for the use of convalescent plasma in critically ill patients.
Remdesivir Recommendations: 6.
For severe adult patients with COVID-19 who do not require mechanical ventilation, we recommend intravenous remdesivir instead of not using it (weak recommendation, moderate quality evidence).
Remarks: Ideally, remdesivir should be started within 72 hours after the SARS-CoV-2 polymerase chain reaction or antigen test is positive.
For those critically ill adult patients with COVID-19 who require mechanical ventilation, we recommend not to start intravenous remdesivir (weak recommendation, low-quality evidence).
Reason: Remdesivir is a prodrug of an adenosine analogue, which is incorporated into the newly synthesized RNA chain of the virus, thereby interrupting the transcription of the virus.
Remdesivir can inhibit the replication of coronavirus in vitro, and it can also inhibit the replication of coronavirus to a certain extent in the non-human primate SARS-CoV-2 model.
In the first SSC COVID-19 guideline, due to lack of data, we were unable to make recommendations on the use of remdesivir.
Since then, 4 randomized controlled trials have been published to test the effectiveness and safety of remdesivir in the treatment of COVID-19.
The ACTT-1 trial randomly divided 1062 COVID-19 adult hospitalized patients into two groups.
One group received intravenous remdesivir (200 mg on day 1, 100 mg per day for up to 9 days), and the other group received placebo , Up to 10 days.
Although the 28-day mortality rate in the Redecive group was relatively low, the relevant influence of the 95% confidence interval could not be ruled out (hazard ratio 0.
73; 95% confidence interval 0.
The main result of this study is the recovery time.
The use of Redcivir improved this result (rate ratio 1.
29; 95% confidence interval 1.
49), thereby shortening the length of hospital stay (mean weighted mean difference -5.
0 Days; 95% confidence interval -7.
3), reduce the use of invasive mechanical ventilation.
However, a subgroup analysis showed that Remdesivir reduced the risk of death in patients with oxygen inhalation, but did not reduce death in patients who received high-flow intranasal oxygen (HFNC), non-invasive positive pressure ventilation (NIPPV) or invasive mechanical ventilation.
In addition, remdesivir does not reduce the duration of NIPPV or invasive mechanical ventilation.
Recently, the SOLIDARITY test results were published in the form of preprints.
In this trial, the researchers randomly assigned 11266 COVID-19 adult hospitalized patients into several groups, of which 2750 patients received remdesivir (the same dose as the ACTT-1 trial) and 4088 patients had no intervention.
Remdesivir did not reduce the 28-day risk of death (relative risk 0.
95, 95% confidence interval 0.
The author did another meta-analysis, including 3 trials, with a total of 7,600 cases.
All in all, the use of Remdesivir did not reduce the 28-day mortality rate (relative risk 0.
91, 95% confidence interval 0.
However, a subgroup analysis of severe COVID-19 (mechanical ventilation group, non-mechanical ventilation group) showed that remdesivir may reduce receiving oxygen therapy (relative risk 0.
80, 95% confidence interval 0.
01) the mortality of hypoxemia patients, but it did not reduce the mortality of patients in the mechanically ventilated subgroup (relative risk 1.
16, 95% confidence interval 0.
Our meta-analysis included two placebo-controlled trials, showing that remdesivir can shorten the clinical improvement time of all COVID-19 hospitalized patients compared with conventional treatment (MD – 3.
8 days; 95% CI – 5.
7 to – 1.
9, moderate Quality) and reduce serious adverse events (Supplement, http://links.
Only one placebo-controlled trial (ACTT-1) reported clinical recovery results, in which Remdesivir shortened the clinical recovery time by 4 days (95% CI decreased from -7.
15 to -0.
85, low quality).
These findings indicate that critically ill patients with COVID-19 are unlikely to benefit from remdesivir, and its application should be in hospitalized patients with severe illness and patients who have not received mechanical ventilation.
In addition, the ACTT-1 trial randomized patients within 72 hours of testing positive for SARS-CoV-2; therefore, it seems reasonable to encourage severe COVID-19 patients in the ICU to start treatment as soon as possible (test positive for SARS-CoV-2 Within 72 hours).
Recently, the World Health Organization issued a weak recommendation against the use of remdesivir in hospitalized COVID-19 patients regardless of the severity of the disease.
The recommendation seems to prioritize resources and equity rather than the severity of the disease.
Remdesivir is used for treatment.
However, due to its relatively weak recommendation level, this means that some patients and clinicians may still prefer to use treatment methods including Redecivir.
Considering that there is no benefit in terms of mortality (medium quality evidence), the uncertainty of the impact on other important patient outcomes, the uncertainty of related costs and feasibility issues (not widely available, only intravenous drugs), the expert group does not Remdesivir (weak recommendation) is recommended for patients receiving mechanical ventilation for COVID-19 (Supplement, http://links.
However, due to the possible effect of Remdesivir in reducing the mortality and disease duration of COVID-19 patients, as well as fewer adverse events, the expert group issued a support for the use of Remdesivir in non-mechanically ventilated patients with severe COVID-19.
Wei's weak recommendation.
Anticoagulation recommendations: 8.
For adults with severe or severe COVID-19, we recommend the use of drug-induced venous thromboembolism (VTE) to prevent rather than not prevent (strong recommendation, moderate quality evidence).
For adults with severe or severe COVID-19 and no evidence of VTE, we recommend that the routine use of therapeutic anticoagulants outside of clinical trials is not recommended (weak recommendation, low quality of evidence).
Reason: Although lung histopathological findings in severe COVID-19 may be similar to viral ARDS, recent studies describe some unique findings.
Multiple case series showed evidence of severe endothelial damage and microvascular thrombosis (alveolar capillary microthrombosis).
Clinical studies have shown that the incidence of VTE is high among hospitalized adults with COVID-19.
A systematic review and meta-analysis of observational studies found that the prevalence of VTE in hospitalized COVID-19 patients was 26% (95% CI 0.
Although there are no randomized controlled trials evaluating the effectiveness of VTE drug prevention in the COVID-19 population, evidence from the critically ill patient population suggests that drug prevention may be applicable.
A systematic review and meta-analysis of four randomized controlled trials comparing drug prevention and non-prevention in critically ill patients found that drug prevention can reduce deep vein thrombosis compared with no prevention (RR 0.
51; 95% CI 0.
63; moderate quality ) And pulmonary embolism (RR 0.
52; 95% CI 0.
97, medium quality), without increasing the risk of major bleeding (RR 0.
82; 95% CI 0.
56 to 1.
21; medium quality).
Several international guidelines recommend the use of drug-based VTE prevention for critically ill patients.
The expert group believes that these evidences are applicable to COVID-19 patients.
This method is feasible and acceptable and may save medical costs (Supplement, http://links.
Therefore, we strongly recommend the use of drug VTE preventive measures.
Clinical trials have shown that for critically ill patients, low molecular weight heparin (LMWH) has greater benefits than unfractionated heparin (UFH) in preventing VTE.
A meta-analysis of three RCTs (n = 5188) found that LMWH may reduce VTE without increasing the risk of bleeding.
Another systematic review and meta-analysis of 8 RCTs (including RCTs in traumatized populations) found that compared with UFH, LMWH reduced the risk of VTE without increasing major bleeding.
Therefore, if available, LMWH is more suitable for the prevention of venous thromboembolism than UFH.
Some clinicians advocate the use of medium-dose low-molecular-weight heparin or enoxaparin for severe or critically ill adult patients with COVID-19.
However, there is no published randomized controlled trial comparing conventional and moderate dose prevention.
It is unclear whether COVID-19 patients without VTE should be given therapeutic anticoagulation.
Although microvascular and macrovascular thrombosis are common, for these people (COVID-19 patients without VTE), there are no rigorous RCT studies that have investigated the effectiveness and safety of therapeutic anticoagulation.
In some studies and local practices, the concentration of D-dimer has been proposed as a threshold to initiate therapeutic anticoagulation, but there are no reliable data to support this approach.
A pilot RCT study randomly selected 20 mechanically ventilated COVID-19 hospitalized patients with elevated D-dimer levels to receive sufficient enoxaparin for anticoagulation or preventive doses of unfractionated heparin or enoxaparin; however , The test’s ability to detect meaningful clinical differences is insufficient.
Although some observational studies have shown that anticoagulation therapy is beneficial, these studies have a high risk of bias and should only be considered as hypotheses.
In addition, it is currently unclear which variables may increase the likelihood of a diagnosis of venous thromboembolism during ICU hospitalization.
A cohort study from the United States included 3334 hospitalized COVID-19 patients, of which 829 were admitted to the ICU.
In this study, males and elevated D-dimer were the only variables that were significantly associated with venous thromboembolism.
In addition, higher D-dimer levels are more correlated with VTE.
For example, D-dimer levels greater than 10000ng/mL are closely related to VTE, and the hazard ratio (HR) is 32 (95%CI17.
Although D-dimer levels were elevated in patients with and without VTE, the median level in patients with pulmonary embolism was higher (1,748 ng/mL; interquartile range was 398-10000), while patients without VTE ( 414 ng/mL; the interquartile range is 268-768).
However, the detection methods for measuring D-dimer levels are different, and the diagnostic utility is also different.
Although it seems reasonable for clinicians to assess the VTE of patients with new crowns based on D-dimers that have increased or rapidly increased, before clinicians implement empirical anticoagulation, decisions based on D-dimer levels are still needed.
Consider carefully, because elevated D-dimer levels may also indicate bleeding, and clinical evaluation is essential before making decisions based on laboratory values.
Considering that there are uncertainties in the effectiveness and safety of anticoagulation therapy in the absence of venous thromboembolism, the expert group has given a weak recommendation for opposing the use of anticoagulation therapy outside of clinical trials.
Summary In the evidence-based update of the SSC COVID-19 guidelines, the expert group issued 9 statements related to severe or critically ill COVID-19 ICU patients.
For severe or critically ill patients with COVID-19, the expert group strongly recommends systemic glucocorticoids and the prevention of venous thrombosis, and strongly recommends not to use hydroxychloroquine.
In addition, the expert group recommends the use of dexamethasone (and other glucocorticoids) and recommends not to use convalescent plasma outside of clinical trials.
The SSC COVID-19 expert group recommends the use of remdesivir in severe COVID-19 patients who are not mechanically ventilated, and recommends that remdesivir should not be used in critically ill COVID-19 patients outside of clinical trials.
Due to insufficient evidence, the expert panel cannot recommend the use of the awake prone position or empirical treatment for anticoagulation.
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