What you get is a quad-camera setup consisting of a 48MP wide, an 8MP ultrawide, a 2MP depth, and a 2MP macro. The only one that takes good images, though, is the primary one. The Poco X3 Pro isn’t just a sprinter—it can go the distance.

• The 8 MP wide-angle camera delivers good results on a sunny day.
• Coming to the display, the POCO X3 Pro has the same 6.67-inch IPS LCD panel as the regular X3.
• The first image shows the scaled photograph of the test device.
• For its part, the Poco X3 Pro has a larger IPS LCD screen that consists of a 6.67-inch diagonal and has a FullHD + resolution of 2,400 x 1,080 pixels.
• The high refresh rate is good, and HDR kicks in when playing videos on YouTube.

It’s always advisable that you backup your device Firmware after purchasing it. You are going to need your device stock Rom for the following reasons someday. According to the changelog, the update brought January 2023 security patch and increased system security. Here are the complete changelogs of the latest POCO X3 Pro update. Here you can Download and install Xiaomi Poco X3 Pro Android Phone device USB (Universal Serial Bus) drivers for free. This file can be used for fix hang on logo and bricked device. Poco X3 Pro Run on Android 11 & it is Powered by QCOM SD860 Processor.

• The POCO X3 Pro marks the debut of a rather special chipset from Qualcomm, the Snapdragon 860.
• To keep the price under control, Poco has opted for a dual-tone plastic back on Poco X3 Pro, where the glossy part in the middle easily picks up fingerprints.
• This means that when the games are launched the hardware of the smartphone will work as intended.
• Yes, you can easily get a decent AMOLED screen for under 20K, and that’s the trade-off you make for the excellent performance hardware.
• In the photographic section, there are several differences to take into account.

When it comes time to charge the phone, the X3 Pro falters a bit. 33W isn’t nearly best in class, and it takes almost an hour to fully charge the phone. As you’d expect for the price, there’s no wireless charging support. The display size we measured, is 6.67 inches IPS LCD Display that supports HDR10 alongside 450nits brightness. The POCO X3 pro has featured a 120Hz refresh rate on the screen along with a 240Hz touch sampling rate. Both phones support HDR10, which is a high dynamic range (HDR) format that offers better contrast and color accuracy than standard SDR displays. The Poco X3 Pro, by and large, has not received a large number of updates compared to the Poco X3 NFC safe for more productive hardware.

Now, stock firmware on the screens of each terminal, the one we find in the Poco M5 is a 6.58-inch IPS LCD technology. This has a FullHD + resolution of 2,408 x 1,080 pixels and boasts a refresh rate of 90 Hz, at the same time that it is protected by a Corning Gorilla Glass 3 glass. In the photographic section, there are several differences to take into account. The first thing that stands out when comparing these devices is how little they resemble each other. The Poco X3 GT has a slightly more pronounced chin on the front than the Poco X3 Pro. The Poco X3 Pro edges out the Poco F3 with a better battery setup as it comes with a 5160mAh battery compared to the 4520mAh battery on Poco F3. Both phones support 33W fast charging so that puts them on the same level in terms of charging speeds.

• It is very much possible to manually remove the issue, but it is way more time-consuming and you may cause even more problems if you are not sure what you’re doing.
• To fix the issue, refer to this post – 5 Ultimate Fixes to Windows 10 Stuck on Repairing Disk Errors.
• The steps involved in this method use bootable installation on Windows.
• If you have any questions, please let us know in the comments section below.
• Figure 11.The Non-System Disk or Disk Error Message Windows Shutting Down Message Will Not Disappear Sometimes Windows will freeze during the shutdown process.

I am trying to replace some more complex logic by copying the Name field into a hidden unique field. The copy is done as part of a Before Insert/Update trigger. The Salesforce system does a great job of validating the uniqueness both in manual entry and in large import lists. However, their default message does not always give the users enough info. For example, I have some objects with a multi-part unique key, not just one field. Preview the data, and once you’re done selecting the files, you’d like to get back, hit the “Recover” icon to start recovering the data. Navigate to the folder where you lost the necessary files.

My Badges – Dynamics 365 Community

Want to get issues with your Windows Photos app fixed quickly? Resetting it is something you should try if the method above doesn’t get the File system error fixed. That helps to refresh the app to the state it was when you first used it on your PC.

If taking this step still doesn’t fix the issue, there could be larger issues with your hardware. In rare cases, you may need to replace the graphics card altogether to solve the issue. However, in most cases, the issue is 0x80190194 win 10 software-related.

Fix 3. Run CHKDSK

If you decide to perform a clean install, you first want to confirm that the computer can start from USB. This means that you may need to change the boot order of the Unified Extensible Firmware Interface or Basic Input/Output System firmware to configure the correct boot order. If you continue with the same problem, you should consider using the Update Assistant utility to perform an in-place upgrade. Or, if the utility does not work, try using the Media Creation Tool to create an installation media to install the new version of Windows 10. When you reinstall Windows XP, make sure you delete all partitions and create the partitions you need to install XP.

The system may not even warn the user when a user error is made, which can be frustrating when things go wrong and the user has no idea why. In some communities, there is a certain degree of snobbery about user errors. Many people faced with this situation resort to reinstalling the operating system but this is often not necessary.

David Morelo is a professional content writer in the technology niche, covering everything from consumer products to emerging technologies and their cross-industry application. To fix System Restore that failed on Windows 11, you can run it again with your anti-malware software disabled. Microsoft explains how to turn off Windows Defender on its support website, and other anti-malware software vendors provide similar instructions.

• The Anniversary Update added Windows Subsystem for Linux , which allows the installation of a user space environment from a supported Linux distribution that runs libeay32.dll natively on Windows.
• If the Done.dll and Unarc.dll files get corrupted or missing, you may encounter the error.
• The update also enabled the first livestreaming functionality through Facebook Live.

Deleting the content of a DLL file may cause a root error with the program trying to reference the file. Generally DLL files can not be opened or edited easily. Binfer is a file transfer software for sending and receiving large files such as videos, pictures and documents without uploading them anywhere. Fast, easy to use, practical and time saving alternative to website uploads, email attachments. Our Forum is where you can get help from both qualified tech specialists and the community at large. Sign up, post your questions, and get updates straight to your inbox. I have seen some Java projects using taucs.dll, TAUCS—a C library of sparse linear solvers, through JNI in Windows.

Simple Dll Files Systems Simplified

Twas the last Spark before Christmas and all through the office, no tickets were popping, not even a toner change, cried for attention. The changes and moves had been handled with care, in the hopes that a day off, …

• As such, the authentication token transmitted to the server is harder to crack.
• 3 In Brink’s procedure for changing the Registry entries he/she/it/they suggest changing the ownership back to the system after the changes are made.
• NetBIOS was initially created to allow applications to communicate without understanding the details of the network, including error recovery….
• Adding a .reg file to your registry simplifies the process of performing registry hacks.

As Android and iOS rose in popularity, Facebook shifted its focus, creating dedicated apps for each platform. However, Facebook was still not entirely convinced, using a “hybrid” solution of native computing code as a sort of “picture frame” for its mobile website.

An Analysis Of Solutions In Missing Dll Files

In case of Outlook, you don’t have any option that lets Outlook connect on metered connection so you won’t be able to do anything as long as you are on a metered connection. If you are having problems with the metering, it is recommended that you check your active and passive usages of the internet connection. If nothing is found during this search it is recommended that you contact your internet service provider. It should open a window that looks something like below. Under “Status” section, you will see the current network connection status of your PC. You can see whether the PC is connected through Wi-Fi or Ethernet. Also you will see an indication, you can change the connection to metered if you have a limited internet plan.

• Hello, My old cellphone is going to die, so I am buying a new “LG K10” cellphone.
• Double click on Network adapters category to expand it.
• When updating drivers on Windows, you can find updates in “Update & Security”.
• Feedback is shared with the IHV and may result in further driver updates.

Also if you need i can zip the complete driver from cd, and upload it online and give you link here. Also consider using a virtual machine- e.g. free VirtualBox- install and run e.g. And if you can give me an example of how we can install

dual boot. Dummies has always stood for taking on complex concepts and making them easy to understand. Dummies helps everyone be more knowledgeable and confident in applying what they know. Go Back is a feature that returns your computer to the operating system that was installed before you installed Windows 10. Sign in to the Windows Store and update any Windows apps.

A Background In Real-World Device Manager Methods

Just like real nuts and bolts, the bits of software that make up drivers get rusty over time. The older your device is, the more likely you need to update graphics drivers and update audio drivers just to have decent picture and sound quality. No drives can be found because the Media Creation Tool does not provide the storage drivers. Follow these steps to create installation media, locate and install the missing storage drivers, and complete the Windows 11 or Windows 10 installation. System File Checker is a troubleshooting tool available in Windows 10 by default.

The application requires HID Crescendo 2300 smart cards or Crescendo Keys. The change is expected hit the stable Windows 10 version with the Windows 10 Sun Valley update, in the second half of the year. It is currently available in the preview builds of the operating system. Check the driver that you want to update and click on Download and install. Select the specific category of driver that you’d like to update. Software is designed to be run on particular hardware.

Thoughts On Vital Elements In Driver Updater

This is caused by Windows detecting errors in the filesystem of the drive, or the drive not being unmounted properly. To never get this prompt you can make sure to use the safely remove option built into Windows before pulling out your drive. Today, let’s have a close look at how to fix the stuck “scanning and repairing drive” in Windows 10. As long as your PC meets the minimum requirements and you have ample free space available, there shouldn’t be an issue. However, it’s important to note that Windows 11 is switching from Master Boot Records partitioning to GUID Partition Table partitioning, so older drives may need to be converted first. When you download and extract the files, select the right tool for your Windows version.

The problem with this is that as time passes, your Windows machine will be bogged down Hp Officejet 5255 drivers with lots of unnecessary and old drivers, which eventually may result in problems on your PC. After that, select Create installation media for another PC. I know it’s just a guess, but I would say about 200MB when the image is not captured.

Other apps have indicated that they might actually move closer to Facebook. For example, Bumble, founded by a former Tinder executive, said they had already reached out to Facebook regarding how to collaborate. And, “One thing everyone seems to agree on is that Facebook’s effectively endorsing online dating will be a huge legitimization event for the industry,” says Jefferies Internet analyst Brent Thill. According to Amanda Bradford, chief executive of The League, an elite dating app, “Facebook is validating that dating is a high-tech industry with really interesting and hard problems to solve. Still, Facebook could face some obstacles in building enough separation between the dating service and the legacy social network; some users might not like having both activities live on one app.

After giving him some time to cope with his cat passing away, he made plans to see her again and she was thrilled. He canceled the date last minute again because he said his grandma had died. Although this seemed too tragic to be true, she gave him the benefit of the doubt that he was telling the truth. Additionally, if someone is giving you a checklist right away of all of the things they want in a future partner, this may be a red flag for some controlling behaviors. It’s one thing if they express their non-negotiables but it’s another thing entirely if they are listing required traits. If you feel like someone is already trying to change things about you to suit their needs, that’s not okay. How someone initiates a conversation with you will say a lot about how they view you as a person and how they might treat you as a partner.

Online dating users are more likely to describe their overall experience with using dating sites or apps in positive, rather than negative, terms. Some 57% of Americans who have ever used a dating site or app say their own personal experiences with these platforms have been very or somewhat positive. Still, about four-in-ten online daters (42%) describe their personal experience with dating sites or apps as at least somewhat negative. Happily, there are some dating services that are looking to overcome the vanity. For example, Hinge matches people based on personality and preferences and lets you create a more interesting and rounded profile to draw people in. One of the few dating sites designed for affairs, Ashley Madison connects users for discreet encounters.

Basically all a guy like you has to do is instantly grab her attention in a memorable way with both your profile and your messages, then spend the least amount of time possible convincing her to meet you in person. For those who are hesitant to enter the online dating world for reasons related to safety or awkward conversation lulls, Double aims to take the pressure off with Double dates as opposed to one-on-one.

State things that are really important to you and be done with it. Connor turned an attempt at small talk into a rant about “gold-digging whores,” and the dating app was not having it. Matt- But what about when you said you would meet me in real life and we would lose our virginity together. One Love educates young people about healthy and unhealthy relationships, empowering them to identify and avoid abuse and learn how to love better. If you are going somewhere that serves alcoholic beverages, most bartenders are using secret codes to help customers signal, privately, when they need help if they’re getting harassed or feeling unsafe on a bad date.

With no financial requirement, free sites will naturally attract a greater proportion of people who are not really committed to finding a genuine relationship. Memberships you gain additional features such as being able to send more messages and receiving event discounts.

This topic will discuss the epidemiology, clinical features, and management of patients who become critically ill due to COVID-19. Other aspects of COVID-19, and other coronavirus-related diseases (severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]), are discussed separately.

(See “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention” and “Coronaviruses” and “Severe acute respiratory syndrome (SARS)” and “Middle East respiratory syndrome coronavirus: Virology, pathogenesis, and epidemiology”.)

GUIDELINES AND HOSPITAL POLICIES — The advice in this topic is based upon data derived from the management of patients with acute respiratory distress syndrome, emerging retrospective data in patients with COVID-19, expert opinion, and anecdotal observations of clinicians treating patients with COVID-19 in China, Italy, and Washington state (USA), where the large outbreaks have occurred. Guidelines have been issued by several societies and organizations including the Society of Critical Care Medicine, the Chinese Thoracic Society, the Australian and New Zealand Intensive Care Society (ANZICS), the World Health Organization and by the United States Centers for Disease Control and Prevention and National Institutes of Health [2-7]. (See “Society guideline links: Coronavirus disease 2019 (COVID-19) – International and government guidelines for general care”.)

Learning from regions that have dealt with the overwhelming burden of COVID-19 to date, it is essential that all hospitals and health systems develop task forces to manage patients admitted with this disorder. This involves, but is not limited to, designating COVID-19-specific intensive care units (ICUs) and ICU teams, creating back up and expanded staffing schedules, utilizing detailed protocols for infection prevention and medical management, accessing research trials for patients with COVID-19, ensuring adequate personal protection equipment (PPE) supplies and training, forecasting demand, and prioritizing diagnostic lab testing.

EPIDEMIOLOGY — Reports suggest that among those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), up to 20 percent develop severe disease requiring hospitalization [8-15]. Although rates vary, among those who are hospitalized, up to one-quarter need intensive care unit (ICU) admission, representing approximately 5 to 8 percent of the total infected population. Differences in the rates of ICU admission may relate to cultural differences in practice and admission criteria for ICU as well as differences in predisposing factors such as age and comorbidities and testing availability in the populations served.

• China – In the Chinese cohorts, rates of ICU admission or severe illness ranged from 7 to 26 percent [9,10,15,16]. 
• Italy – Consistent with the range reported in China, preliminary reports from Italy suggest that the proportion of ICU admissions were between 5 and 12 percent of the total positive SARS-CoV-2 cases, and 16 percent of all hospitalized patients [17,18]. 
• United States of America – In an early study of 21 critically ill patients in Washington State, USA, 81 percent of patients with COVID-19 pneumonia were admitted to the ICU and 71 percent were mechanically ventilated [19]. However, this high rate likely reflects the older age of the population which largely came from a nursing home in the region. A larger analysis of 2449 patients reported hospitalization rates of 20 to 31 percent and ICU admission rates of 4.9 to 11.5 percent [20].

While three-quarters of critically ill patients were male in the Chinese cohorts, data are mixed with some reports suggesting an equal proportion of men and women [18,19] and other suggesting a male predominance [21,22].

CLINICAL FEATURES IN CRITICALLY ILL PATIENTS

Clinical features, complications, and pathology — General clinical features of COVID-19 patients and risk factors for progression are discussed separately (see “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Clinical features’ and “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Risk factors for severe illness’). Discussion here is limited to clinical features in those who are critically ill.

• Rate of progression – Retrospective studies of critically ill patients have suggested that among patients who develop critical illness, including acute respiratory distress syndrome (ARDS), onset of dyspnea is relatively late (median 6.5 days after symptom onset), but progression to ARDS can be swift thereafter (median 2.5 days after onset of dyspnea) [9,10,19,23,24]. 
• Clinical features – Among those who are critically ill, profound acute hypoxemic respiratory failure from ARDS is the dominant finding [8-10,19,21,22,24-28]. Hypercapnia is rare. Fevers tend to wax and wane during ICU admission. The need for mechanical ventilation in those who are critically ill is high ranging from 30 to 100 percent [9,19,21,22,25,28]. 
• Length of stay – Early clinical reports suggest that length of intensive care unit (ICU) stay appears to be long with many patients remaining intubated for one to two weeks or longer [22]. Reports from experts in the field suggest that many patients fail early attempts at weaning (eg, within the first week), although this does not appear to predict their eventual ability to wean and extubate. Only a small proportion of patients require tracheostomy. (See ‘Extubation and weaning’ below and ‘Tracheostomy’ below.)
• Complications – Common complications of COVID-19-related ARDS include acute kidney injury (AKI), elevated liver enzymes, and cardiac injury including cardiomyopathy, pericarditis, pericardial effusion, arrhythmia, and sudden cardiac death. As an example, in a single-center retrospective cohort from China of 52 critically ill patients with COVID-19, complications included AKI (29 percent; half of whom needed renal replacement therapy), liver dysfunction (29 percent), and cardiac injury (23 percent) [9]. 
• Cardiac injury appears to be a late complication, developing after the respiratory illness improves. A high rate of cardiomyopathy was noted in a United States cohort (33 percent), and may relate to the older age in that population [19]. In another United States cohort in New York City, cardiac complications among mechanically ventilated patients included atrial arrhythmias (18 percent), myocardial infarction (8 percent), and heart failure (2 percent) [27]. One case series reported five patients who developed acute cor pulmonale, most of which occurred in association with hemodynamic instability or cardiac arrest [29]. All cases were thought to be most likely due to pulmonary embolism (PE), although a definitive diagnosis of PE was confirmed in only one case. Cardiac complications of COVID-19 are discussed in detail elsewhere. (See “Coronavirus disease 2019 (COVID-19): Myocardial injury” and “Coronavirus disease 2019 (COVID-19): Arrhythmias and conduction system disease” and “Coronavirus disease 2019 (COVID-19): Myocardial infarction and other coronary artery disease issues”.)
• Sepsis, shock, and multi-organ failure do occur but appear to be less common when compared with non-COVID-19-related ARDS. The need for vasoactive agents is variable, although a significant proportion need vasopressor support for hypotension (often due to sedation medications or cardiac dysfunction). In the cohort study from Wuhan, China, 35 percent of 52 patients received vasoactive agents [9]. In contrast, in the case series from New York City, 95 percent of the 130 patients who received mechanical ventilation required vasopressor support; the reasons for this were not specified [27]. 
• As above, acute kidney injury is common among critically ill patients with COVID-19, and many require renal replacement therapy. This is discussed in detail elsewhere. (See “Coronavirus disease 2019 (COVID-19): Issues related to kidney disease and hypertension”, section on ‘Acute kidney injury’.)
• Data on the risk of secondary bacterial pneumonia are limited, but it does not appear to be a major feature of COVID-19. In a cohort of intubated patients from China, hospital-acquired pneumonia, in many cases with resistant pathogens, was reported in 12 percent [9]. This finding may be related to the high use of glucocorticoids for ARDS management in China. Further data are needed to elucidate the rate of superinfection in other countries.  
• Lung compliance is high compared with other etiologies of ARDS and the rate of barotrauma appears to be low with only 2 percent developing pneumothorax, compared with 25 percent of those with severe acute respiratory syndrome coronavirus (SARS-CoV) [9,30]. There are limited data describing the lung pathology in patients with COVID-19. Case reports from post mortem cases and patients undergoing biopsy for another reason suggest a wide variation from mononuclear inflammation to diffuse alveolar damage, classic of ARDS [31,32]. (See “Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults”, section on ‘Pathologic stages’.)
• Neurologic complications in critically ill patients are common, especially delirium or encephalopathy which manifests with prominent agitation and confusion along with corticospinal tract signs (hyperreflexia). Consistent with this, intensivists have observed that sedation requirements are high in this population, particularly immediately after intubation. In one series of 58 patients with COVID-19-related ARDS, delirium/encephalopathy was present in approximately two-thirds of patients [33]. In addition, three of 13 patients who had brain MRI had an acute ischemic stroke; eight MRI studies demonstrated leptomeningeal enhancement. Cerebrospinal fluid (CSF) in seven patients was acellular and only one had elevated CSF protein; PCR assays of CSF were negative for the virus. It is unclear whether the neurologic complications noted in this and other reports are due to critical illness, medication effects, or represent more direct effects of cytokines or the SARS-CoV-2 virus [33-35]. Encephalitis, while reported, is rare [36]. Similarly, Guillain-Barré-barre syndrome following SARS-CoV-2 virus infection has also been described in a small case series [37]. 
• COVID-coagulopathy is common in this population with some patients developing abnormal coagulation profiles and other developing thrombosis. These features are discussed separately. (See “Coronavirus disease 2019 (COVID-19): Hypercoagulability”.)
• Laboratory – Laboratory findings in critically ill patients (eg leukopenia, lymphopenia, leukocytosis, elevated D-dimer, lactate dehydrogenase, and ferritin, normal or low procalcitonin) are initially modest and similar to those with milder illness, although the procalcitonin level may be more elevated and lymphopenia more profound in critically ill patients [8,10,26]. (See “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Laboratory findings’ and “Cytokine release syndrome (CRS)” and “Procalcitonin use in lower respiratory tract infections” and “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”, section on ‘IL-6 pathway inhibitors’.)

Some patients with severe COVID-19 have laboratory evidence of an exuberant inflammatory response, similar to cytokine release syndrome (CRS), with persistent fevers, elevated inflammatory markers (eg, D-dimer, ferritin, interleukin-6), and elevated proinflammatory cytokines; these laboratory abnormalities have been associated with poor prognosis [38]. Clinical trials of anti-IL-6 agents for the treatment of COVID-19 are in progress. Further details regarding CRS are provided separately. (See “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Laboratory findings’ and “Cytokine release syndrome (CRS)” and “Procalcitonin use in lower respiratory tract infections” and “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”, section on ‘IL-6 pathway inhibitors’.) 

The presence of antiphospholipid antibodies has also been described; however, they are mostly of the IgA subclass, and the clinical significance is unclear [39]. Abnormal coagulation parameters which are commonly seen in COVID-19 patients (eg, elevated D-dimer, prolonged prothrombin time) are also discussed separately. (See “Coronavirus disease 2019 (COVID-19): Hypercoagulability” and “Diagnosis of antiphospholipid syndrome”.)

• Imaging – Typical imaging findings do not appear to be different in mild or severe cases of COVID-19 (eg, ground-glass opacification with or without consolidative abnormalities, consistent with viral pneumonia, minimal or no pleural effusions) [9,40,41]. While imaging with chest computed tomography (CT) was commonly performed in Chinese cohorts, we prefer to avoid its use, unless necessary; if chest CT is used as a diagnostic tool, its use must be balanced with the risk to other patients and healthcare workers during the process of patient transport and time spent in the CT room. Characteristic findings on bedside lung ultrasound include thickening of the pleural line and B lines supporting alveolar consolidation. Pleural effusions are unusual [42]. (See “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Imaging findings’.) 
• Pathology – There are a paucity of data describing lung pathology of COVID-19 pneumonia in critically ill patients. Most autopsy reports describe hyaline membrane changes and microvessel thrombosis suggestive of early ARDS (ie, exudative and proliferative phases of diffuse alveolar damage [DAD]) [32,43-48]. Other findings include bacterial pneumonia (isolated or superimposed on DAD) and viral pneumonitis [44,48]. Less common findings include acute fibrinous organizing pneumonia (AFOP; in the late stages) [49], amyloid deposition (heart and lung), and rarely alveolar hemorrhage and vasculitis [48]. Evidence of pulmonary embolism is found in up to one-third of autopsy cases [44,48]. Distant organ involvement has also been seen with the demonstration of virus in organs other than the lung and, in some cases, acute tubular necrosis and a generalized thrombotic microangiopathy in the kidney [44,48]. (See “Interpretation of lung biopsy results in interstitial lung disease”, section on ‘Diffuse alveolar damage’.)

Risk factors for progression — Age appears to be the major risk factor that predicts progression to ARDS [12,19,20,25]. Comorbidities, high fever (≥39°C), history of smoking, and select laboratory features also predict progression and death from COVID-19. Importantly, adults of any age may develop severe disease and experience adverse outcomes, especially those with comorbidities. Further details regarding the risk of disease progression are provided separately. (See “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Risk factors for severe illness’.)

RESPIRATORY CARE OF THE NONINTUBATED PATIENT — Specific aspects of respiratory care relevant to deteriorating patients with COVID-19 before admission to the intensive care unit (ICU) are discussed here (table 1). These include oxygenation with low flow and high-flow systems, noninvasive ventilation and the administration of nebulized medications. For hospitalized patients who develop progressive symptoms, early admission to the ICU is prudent when feasible. 

Self-proning — Some experts are encouraging that the hospitalized patient spend as much time as is feasible and safe in the prone position while receiving oxygen; the rationale for this approach is based upon limited direct evidence [50,51] and anecdotal observations in the field as well as indirect evidence of its efficacy in ventilated patients. (See ‘Prone ventilation’ below.)

Oxygenation targets — The World Health Organization (WHO) suggests titrating oxygen to a target peripheral oxygen saturation (SpO2) of ≥90 percent. For most critically ill patients, we prefer the lowest possible fraction of inspired oxygen (FiO2) necessary to meet oxygenation goals, ideally targeting a SpO2 between 90 and 96 percent, if feasible. However, some patients may warrant a lower target (eg, patients with a concomitant acute hypercapnic respiratory failure from chronic obstructive pulmonary disease [COPD]) and others may warrant a higher target (eg, pregnancy). (See “Overview of initiating invasive mechanical ventilation in adults in the intensive care unit”, section on ‘Fraction of inspired oxygen’.) 

Low flow oxygen — For patients with COVID-19, supplemental oxygenation with a low flow system via nasal cannula is appropriate (ie, up to 6 L/min). Although the degree of micro-organism aerosolization at low flow rates is unknown, it is reasonable to surmise that it is minimal.

Higher flows of oxygen may be administered using a simple face mask, venturi face mask, or nonrebreather mask (eg, up to 10 to 20 L/minute), but as flow increases, the risk of dispersion also increases, augmenting the contamination of the surrounding environment and staff. 

Many experts have patients who wear nasal cannula also wear a droplet mask, especially during transport or when staff are in the room. Data to support this practice are largely non-peer-reviewed or derived from simulation experiments but make practical sense as a maneuver to reduce the infectious risk associated with potential aerosolization [52-54]. Additional information on the provision of low flow oxygen is provided separately. (See “Continuous oxygen delivery systems for the acute care of infants, children, and adults”.)

Patients with higher oxygen requirements — As patients progress, higher amounts of oxygen are needed. Options at this point in non-COVID-19 patients are high-flow oxygen via nasal cannulae (HFNC) or the initiation of noninvasive ventilation (NIV). However, in patients with COVID-19, this decision is controversial and subject to ongoing debate [55,56]. Despite this controversy, both modalities have been used variably. In retrospective cohorts, rates for HFNC use ranged from 14 to 63 percent while 11 to 56 percent were treated with NIV [9,22,25,28]. While, there are no prospective data describing whether these modalities were successful at avoiding intubation, one retrospective study described the highest level of respiratory support in hospitalized COVID-19 patients was noninvasive modalities (HFNC and NIV) in 5.4 percent of patients and invasive ventilation in 30 percent [28].   

Deciding on a modality (noninvasive or invasive ventilation) — We believe that the decision to initiate noninvasive modalities, HFNC or NIV, should be made by balancing the risks and benefits to the patient, the risk of exposure to healthcare workers, and best use of resources; this approach should be reassessed as new data become available. We encourage the development of hospital protocols and a multidisciplinary approach, which includes respiratory therapy staff, to facilitate this decision. In patients with COVID-19 who have acute hypoxemic respiratory failure and higher oxygen needs than low flow oxygen can provide, we suggest that noninvasive modalities, may be used selectively rather than proceeding directly to intubation (eg, a younger patient without comorbidities who can tolerate nasal cannulae). On the other hand, some patients may warrant avoidance of HFNC and may benefit from proceeding directly to early intubation (eg, elderly or confused patient with comorbidities and several risk factors for progression). 

Many experts advocate the avoidance of both modalities (ie, proceeding to early intubation if escalating beyond 6 L/min with continued hypoxemia or increased work of breathing). This is predicated on an increased risk of aerosolization and high likelihood that patients who need these modalities will ultimately, rapidly deteriorate and require mechanical ventilation (eg, within one to three days). This approach may be reasonable when resources are available. However, using this as an absolute rule may result in an excess of unnecessary intubations and place an undue load on ventilator demand as the disease surges. In addition, this is particularly problematic for patients under investigation (eg, COVID-19 testing pending), patients who have chronic nocturnal NIV requirements, patients with chronic respiratory failure who have high baseline oxygen requirements, and patients with do-not-intubate status but who might benefit otherwise from NIV or HFNC. Ultimately, these recommendations may change with time depending on the case load of COVID-19 patients in a given location.   

Oxygen via high flow nasal cannula versus noninvasive ventilation — Among the noninvasive modalities, we prefer HFNC. Our preference for HFNC is based upon limited and inconsistent data, which, on balance, favor HFNC compared with NIV in patients with non-COVID-19-related acute hypoxemic respiratory failure, the details of which are provided separately (see “Heated and humidified high-flow nasal oxygen in adults: Practical considerations and potential applications”, section on ‘Medical patients with severe hypoxemic respiratory failure’). In addition, limited data suggest a high failure rate of NIV in patients with Middle East Respiratory Syndrome (MERS) [57] and other causes of acute respiratory distress syndrome (ARDS) (see “Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications”, section on ‘Hypoxemic nonhypercapnic respiratory failure NOT due to ACPE’). However, NIV may be appropriate in patients with indications that have proven efficacy; these include patients with acute hypercapnic respiratory failure from an acute exacerbation of chronic obstructive pulmonary disease (AECOPD), patients with acute cardiogenic pulmonary edema, and patients with sleep disordered breathing (eg, obstructive sleep apnea or obesity hypoventilation). These data are provided separately. (See “Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications”, section on ‘Patients likely to benefit’.)  

Monitoring on noninvasive modalities — If HFNC or NIV is administered, vigilant monitoring of patients is warranted for progression with frequent clinical and arterial blood gas evaluation every one to two hours to ensure efficacy and safe ventilation (eg, frequent coughing may not be “safe”). We advocate a low threshold to intubate such patients, particularly if they show any signs of rapid progression. (See ‘Timing’ below.)

Although unproven, some experts, including us, provide HFNC (or NIV) while the patient is in the prone position. Limited evidence from case reports in non-COVID patients with acute respiratory distress syndrome and anecdotal evidence suggest feasibility and improvement in oxygenation in some patients [50,58,59].  

Technical details regarding application of HFNC and NIV are provided separately. (See “Heated and humidified high-flow nasal oxygen in adults: Practical considerations and potential applications” and “Noninvasive ventilation in adults with acute respiratory failure: Practical aspects of initiation” and “Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications”.)

Precautions for noninvasive modalities — HFNC and NIV are considered aerosol generating procedures. Thus, when HFNC or NIV is used, airborne in addition to standard precautions should be undertaken (ie, airborne infection isolation room [also known as a negative pressure room], full personal protective equipment). (See “Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings”, section on ‘Patients with suspected or confirmed COVID-19’.)

• HFNC – We advocate additionally placing a surgical or N95 mask on the patient during HFNC when healthcare workers are in the room, but the value of this practice is unknown [3]. Additional precautions for HFNC that have potential to reduce risk include starting at and using the lowest effective flow rate (eg, 20 L/minute and 0.4 FiO2). Inhaled medications or gases (eg, epoprostenol, nitric oxide bronchodilators) should be avoided during HFNC. 
• NIV – If NIV is initiated, a full-face mask rather than a nasal or oronasal mask is preferred to minimize particle dispersion. The mask should preferably have a good seal and not have an anti-asphyxiation valve or port. Use of a helmet has been proposed for delivering NIV to patients with COVID-19 [60]. However, experience is limited with this delivery method, especially in the United States. If NIV is used, dual limb circuitry with a filter on the expiratory limb on a critical care ventilator may decrease dispersion compared with single limb circuitry on portable devices, although data to support this are lacking. We also suggest starting with continuous positive airway pressure (CPAP) using the lowest effective pressures (eg, 5 to 10 cm H2O).

There are few data regarding aerosolization during HFNC and NIV. In a normal lung simulation study, dispersion of air during exhalation increased with increasing HFNC flow from 65 mm (at 10 L/minute) to 172 mm (at 60 L/minute) mostly along the sagittal plane (ie, above the nostrils) [61]. Similar distances were found when CPAP was delivered via nasal pillows (up to 332 mm with CPAP 20 cm H2O). However, there was no significant leakage noted when CPAP was administered via an oronasal mask with good seal (picture 1 and picture 2). Air leak increased when connections on any device were loose. Dispersion seemed to be reduced when the simulator simulated injured lung. 

Nebulized medications (spontaneously breathing patients) — Nebulizers are associated with aerosolization and potentially increase the risk of SARS-CoV-2 transmission. In patients with suspected or documented COVID-19, nebulized bronchodilator therapy should be reserved for acute bronchospasm (eg, in the setting of asthma or chronic obstructive pulmonary disease [COPD] exacerbation). Otherwise, nebulized therapy should generally be avoided, in particular for indications without a clear evidence-base; however some uses (eg, hypertonic saline for cystic fibrosis) may need to be individualized. Metered dose inhalers (MDIs) with spacer devices should be used instead of nebulizers for management of chronic conditions (eg, asthma or COPD controller therapy). Patients can use their own MDIs if the hospital does not have them on formulary.

If nebulized therapy is used, patients should be in an airborne infection isolation room, and healthcare workers should use contact and airborne precautions with appropriate personal protection equipment (PPE); this includes a N95 mask with goggles and face shield or equivalent (eg, powered air-purifying respirator [PAPR] mask]) as well as gloves and gown. All non-essential personnel should leave the room during nebulization. Some experts also suggest not re-entering the room for two to three hours following nebulizer administration. (See “Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings”.)

Other — Potential for transmission of SARS-CoV-2 should inform the use of other interventions in patients with documented or suspected COVID-19: 

• It is prudent to minimize the following: 
• Positive airway devices for chronic nocturnal ventilation support
• Chest physical therapy or oscillatory devices
• Oral or airway suctioning
• Sputum induction should be avoided

●Bronchoscopy should be avoided in spontaneously breathing patients and limited to therapeutic indications (eg, life-threatening hemoptysis, central airway stenosis)

If any of these therapies are performed, similar PPE to that described for nebulizer therapy should be used. (See ‘Nebulized medications (spontaneously breathing patients)’ above and “Flexible bronchoscopy in adults: Overview”.)

THE DECISION TO INTUBATE

Timing — Timing of intubation in this population is challenging. Most patients with acute respiratory distress syndrome (ARDS) due to COVID-19 will warrant intubation and mechanical ventilation. Delaying intubation until the patient acutely decompensates is potentially harmful to the patient and healthcare workers and is not advised. For patients with escalating oxygen requirements, we monitor clinical and gas exchange parameters every one to two hours and have a low threshold to intubate patients with the following:

• Rapid progression over hours  
• Lack of improvement on >40 L/minute of high flow oxygen and a fraction of inspired oxygen (FiO2) >0.6
• Evolving hypercapnia, increasing work of breathing, increasing tidal volume, worsening mental status 
• Hemodynamic instability or multiorgan failure

Most experts with experience managing COVID-19 patients suggest “early” intubation. However, the definition of what constitutes “early” is unclear. Use of noninvasive means are traditionally used to avoid intubation. However, their use is subject to controversy in patients with COVID-19 (see ‘Patients with higher oxygen requirements’ above). Clinicians should communicate closely and regularly about the potential for intubation in patients that are being followed and treated noninvasively so that the transition for intubation can be smooth and rapid once it has been identified that the patient needs intubation.  

Precautions — Intubation is the highest risk procedure for droplet dispersion in patients with COVID-19 [55,62]. The following discussion is suitable for patients outside the operating room (eg, intensive care unit [ICU] and emergency department) (table 2).

• We are proponents of the development of intubation kits and intubation checklists for performing rapid sequence intubation (RSI) in this population (figure 1).
• Attention should be paid to donning full contact and airborne personal protective equipment (PPE) (figure 2 and figure 3) [55]. Appropriate PPE includes a fit-tested disposable N95 respirator mask (picture 3), with eye protection or a powered air-purifying respirator (PAPR), also known as an isolation suit (picture 4 and picture 5). Also included are gown, caps and beard covers, protective footwear, neck covering, and gloves (using the double glove technique). (See “Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings”.)

• Intubation should be performed in an airborne infection isolation room, if possible.
  

• Intubation should be performed by the most qualified individual (eg, anesthesiologist) since delayed intubation with multiple attempts may prolong dispersion and place the patient at risk of a respiratory arrest.  

• Anecdotally, most experts suggest optimizing preoxygenation with nonaerosol-generating means (eg, avoidance of high flow oxygen delivered via nasal cannula) and intubation using video laryngoscopy. In patients previously on high flow oxygen, some experts switch to 100 percent nonrebreather masks for preoxygenation. 
• When manual bag mask ventilation (BMV) is needed, switching the mask to a supraglottic device for manual bagging is appropriate. When feasible, BMV should be minimized before and after intubation, and a bacterial/viral high efficiency hydrophobic filter should be placed between the facemask and breathing circuit or resuscitation bag. Having a pre-prepared bag-mask with filter attached in every room with a COVID-19 patient is prudent. Using a two-person technique for an adequate face mask seal is also suggested.
• Clamping the endotracheal tube (ETT) for connections and disconnections is appropriate (eg, capnography testing following intubation), only if the patient is NOT spontaneously breathing. 
• The ventilator and ventilator circuitry should be ready in advance with preplanned settings already entered so that as soon as the ETT is placed and confirmed with capnography, it can be connected directly to the ETT without additional manual bagging. In addition, if feasible, in-line suction devices and in-line adapters for bronchoscopy should be prepared and attached to the ventilator tubing in advance in order to avoid unnecessary disconnection for their placement at a later point in time. The expiratory limb on the ventilator should have a HEPA filter to decrease contamination of the ventilator and environment and protect staff when changing limb circuitry. 
• To minimize exposure, bundling intubation with other procedures is appropriate as is bundling the chest radiograph for ETT and central venous catheter placement.
• Doffing should follow strict procedure and some experts also advocate for the use of viricidal wipes for areas of exposed skin during intubation (eg, neck) (figure 3).

New proposals are emerging for novel barrier protections for intubation. In one such pilot study, manually performing intubation inside a transparent box was described (“aerosol box”) [63]. The box was designed so that it could be placed over a patient’s head allowing intubation to be performed through two circular ports on the cephalad side of the box. In a simulation experiment, cough was approximated using a latex balloon and fluorescent dye. Use of the box was associated with significant reduction in aerosol deposition to the individual performing intubation, their PPE clothing, and the surrounding environment, when compared with the same simulation without the box. While proposed as an adjunct to protection, restriction of hand movements may be encountered during airway manipulation that would necessitate abandoning the procedure and the simulation may not accurately mimic the aerosolization behavior of virus particles. Such devices are not yet commercially available.  

Detailed guidance regarding intubation in the operating room, optimal personal protective equipment, and procedural details regarding intubation itself are discussed separately. (See “Coronavirus disease 2019 (COVID-19): Anesthetic concerns, including airway management and infection control” and “Safety in the operating room”, section on ‘COVID-19’ and “Direct laryngoscopy and endotracheal intubation in adults” and “Rapid sequence intubation for adults outside the operating room” and “The decision to intubate” and “Induction agents for rapid sequence intubation in adults outside the operating room” and “Neuromuscular blocking agents (NMBAs) for rapid sequence intubation in adults outside of the operating room”.)

VENTILATOR MANAGEMENT OF ACUTE RESPIRATORY DISTRESS SYNDROME — Most patients with COVID-19 who are mechanically ventilated appear to have acute respiratory distress syndrome (ARDS). Accurate data on duration of ventilation are limited but suggest prolonged mechanical ventilation for two weeks or more (table 1). All of the steps discussed below should proceed as resources allow. 

Whether different phases of COVID-19 pneumonitis require different ventilatory strategies is unclear. One school of thought is that in the early phase of COVID-19, severe hypoxemia is associated with high compliance and low alveolar recruitability (atypical ARDS), while in the later phase, severe hypoxemia is associated with low lung compliance and high recruitability (classic ARDS) [64,65]. However, this hypothesis, remains unproven and optimal ventilatory strategies based upon it are unclear. Until further data are available, we prefer a strategy that promotes lung protection as outlined in the sections below.

Low tidal volume ventilation (LTVV) — As for all patients with ARDS, patients with COVID-19 pneumonia who develop ARDS requiring mechanical ventilation should receive LTVV targeting ≤6 mL/kg predicted body weight (PBW; range 4 to 8 mL/kg PBW (table 3 and table 4)). We typically use a volume-limited assist control mode, beginning with a tidal volume of 6 mL/kg PBW, which targets a plateau pressure (Pplat) ≤30 cm H2O, and applies positive end-expiratory pressure (PEEP) according to the strategy outlined in the table (table 5). This approach is based upon several randomized trials and meta-analyses that have reported improved mortality from LTVV in patients with ARDS. The experience among Chinese, Italian, and United States cohorts is that this approach is also beneficial in this population. Modifications to or deviations from this mechanical ventilation strategy may be required in the setting of severe hypercapnia or ventilator dyssynchrony (figure 4). (See “Ventilator management strategies for adults with acute respiratory distress syndrome”, section on ‘Patients who are not improving or deteriorating’.)

Anecdotal reports suggest that the COVID-19 ARDS phenotype is one of severe hypoxemia that is responsive to high PEEP with relatively high lung compliance such that Pplat ≤30 cm H2O is not difficult to achieve. As a consequence, we and other clinicians have a low threshold to start with higher than usual levels of PEEP (eg, 10 to 15 cm H2O).

Expanded details on LTVV and other ventilator strategies in ARDS are provided separately. (See “Ventilator management strategies for adults with acute respiratory distress syndrome”.)   

We believe that oxygenation goals in critically ill patients with COVID-19 should be similar to those in nonventilated patients (ie, peripheral oxygen saturation between 90 and 96 percent (see ‘Oxygenation targets’ above)). However, in patents with COVID-19, some experts use a higher peripheral oxygen saturation (SpO2) goal [7]. The rationale for this approach is that it may reduce the frequency of ventilator adjustments that require staff entry into the room, thereby reducing the risk to healthcare staff, although data are lacking to support it.

Reflecting the practice of LTVV, one retrospective Italian cohort reported that the median level of PEEP was 14 cm H2O (interquartile range [IQR] 12 to 16 cm H2O) [22]. Ninety percent of patients required an FiO2 >0.5, and the median PaO2/FiO2 ratio was 160 (IQR, 114 to 220).

Failure of low tidal volume ventilation — For patients with COVID-19 that fail to achieve adequate oxygenation with LTVV, we agree with other experts in the field who have chosen prone ventilation as the preferred next step. For its application, we use similar criteria to those in non-COVD-19 patients (ie, partial arterial pressure of oxygen/fraction of inspired oxygen [PaO2:FiO2] ratio <150 mmHg, a FiO2 ≥0.6, and PEEP ≥5 cm H2O; excessively high airway pressures; or recalcitrant hypoxemia), although some experts use a higher PaO2:FiO2 ratio, given the good response seen in this population.

Prone ventilation — Our preference for using prone ventilation is based on its known efficacy in patients with ARDS as well as limited and anecdotal observations of intensivists in the field who have noted that unlike patients who had severe acute respiratory syndrome coronavirus (SARS-CoV), patients with COVID-19-related ARDS respond well to this maneuver [66]. Those who are experienced in ventilating patients with COVID-19-related ARDS also promote ventilating patients prone for as long as is feasible without prematurely returning the patient to the supine position (ie, 12 to 16 hours prone per day) and to perform the maneuver at change of shift when sufficient staff are available. The utmost care should be taken to avoid ventilator disconnections during proning and the number of personnel should be limited to that required for turning. This video which describes the prone procedure is freely available. Additional details regarding the efficacy, contraindications (table 6) and application (table 7) of prone ventilation are provided separately. (See “Prone ventilation for adult patients with acute respiratory distress syndrome” and “Ventilator management strategies for adults with acute respiratory distress syndrome”, section on ‘Ventilator strategies to maximize alveolar recruitment’.) 

The good response to prone positioning may be due to preserved lung compliance in this population compared with patients who develop ARDS from other etiologies. Lung compliance is the change in lung volume for a given pressure. It can be measured using the following equations: lung compliance (C) = change in lung volume (V) / change in transpulmonary pressure (alveolar pressure [Palv] – pleural pressure [Ppl]); static lung compliance = tidal volume / Pplat – PEEP. The normal lung compliance is approximately 200 mL/cm H2O and in general compliance >50 mL/cm H2O has been noted by clinicians who have experienced ventilating patients with COVID-19. 

Optimal timing and criteria for discontinuing prone ventilation is unclear and should be performed on an individualized basis. It is not unreasonable to use criteria similar to that in studies that have shown benefit in non-COVID-related ARDS (eg PaO2:FiO2 ≥150 mmHg, FiO2 ≤0.6, PEEP ≤10 cm H2O) maintained for at least four hours after the end of the last prone session) [67].

Additional options — Additional options for patients in whom prone ventilation fails include the following:

• Recruitment and high PEEP – Recruitment maneuvers and high PEEP strategies (table 8) may be performed to address severe hypoxemia; data supporting their use in non COVID-19-related ARDS is described separately. (See “Ventilator management strategies for adults with acute respiratory distress syndrome”, section on ‘Ventilator strategies to maximize alveolar recruitment’.)
• Pulmonary vasodilators – Pulmonary vasodilators may improve ventilation-perfusion mismatch in those with severe hypoxemia and may be particularly helpful in those with hypoxemia from an acute pulmonary arterial hypertension crisis. The two most commonly used agents are inhaled nitric oxide (NO) and inhaled prostacyclin, which are administered as a continuous inhalation. Inhaled vasodilators should only be administered through a closed system and require skilled personnel for their use. Potential risks and challenges with COVID-19 patients include aerosolization and clogging of bacterial/viral filters used in ventilator circuits when these medications are being administered. Inhaled NO may be preferred since it is associated with a lower need to change filters with resultant reduction in the risk to the respiratory healthcare provider. Further details regarding their use are described separately. (See “Acute respiratory distress syndrome: Supportive care and oxygenation in adults”, section on ‘Nitric oxide’ and “Acute respiratory distress syndrome: Supportive care and oxygenation in adults”, section on ‘Prostacyclin’ and “Inhaled nitric oxide in adults: Biology and indications for use”, section on ‘Acute hypoxemic respiratory failure’.) 
• Neuromuscular blocking agents (NMBAs) – NMBAs may be reserved for patients with refractory hypoxemia or ventilator dyssynchrony. We do not favor their routine use in any patient with ARDS since data on outcomes are conflicting. (See “Acute respiratory distress syndrome: Supportive care and oxygenation in adults”, section on ‘Paralysis (neuromuscular blockade)’ and “Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects”.) 

●Extracorporeal membrane oxygenation (ECMO) – While the World Health Organization suggests ECMO as a rescue strategy, we only use it in those who fail prone ventilation and the other evidence-based medical strategies listed above. In addition, ECMO is not universally available. As many hospitals choose to cohort patients in COVID-19-only intensive care units (ICUs), there may also be the challenge of delivering ECMO in ICUs that do not routinely care for ECMO patients; this would require the recruitment of additional specialized nursing and perfusionist staff. ECMO can also reduce the lymphocyte count and raise the interleukin-6 level, thereby interfering with the interpretation of these laboratory results [68]. (See “Extracorporeal membrane oxygenation (ECMO) in adults”.)

Use of rescue strategies has varied among centers. In a single-center retrospective cohort of 52 critically ill patients with COVID-19 in Wuhan, China, approximately 12 percent received prone ventilation and 12 percent received ECMO [9]. In contrast, in the original cohort of 138 hospitalized patients with COVID-19, of the 17 patients who required invasive mechanical ventilation, 24 percent were treated with ECMO. Similarly, in an Italian cohort, only 1 percent of critically ill patients received ECMO [22]. 

Additional ventilator precautions — We recommend tight seals for all ventilator circuitry and equipment. For patients who have a tracheostomy, similar recommendations apply. Although the efficacy is unproven, some experts suggest placing the ventilator and intravenous (IV) line monitors outside the room, when feasible (eg, through a wall port). This allows frequent ventilator adjustments while simultaneously decreasing the risk of exposure to staff; although the efficacy of such maneuvers is unproven. 

It is prudent to avoid unnecessary disconnection with the endotracheal tube (ETT) in ventilated patients with COVID-19 in order to avoid derecruitment and unnecessary exposure of virus to the environment. For example, in-line suction devices and in-line adapters for bronchoscopy are preferred, if resources allow. If disconnection is necessary (eg, during transfer when portable ventilators are used or manual bagging), the ETT should be temporarily clamped during disconnection and unclamped after reconnection. This is considered an aerosolizing procedure in which case an airborne infection isolation room is preferable but is not always feasible.

Other infection precautions include use of dual limb ventilator circuitry with filters placed at the exhalation outlets as well as heat moisture exchange (HME) systems rather than heated humification of single limb circuits. HME should be placed between the exhalation port and the ETT (figure 5 and figure 6). (See “The ventilator circuit”.)

It is particularly important to adhere to the standard practice of maintaining the ETT cuff pressure between 25 and 30 cm H2O so that a tight seal exists between the cuff and the tracheal wall. (See “Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients”, section on ‘Maintain optimal cuff pressure’.)

All ventilators should have appropriate filters in place and agreed upon filter change schedule (eg, every six hours). The ventilator should be wiped down after every filter change. 

Although an airborne isolation room is ideal, if not feasible, patients can be ventilated in a non-isolation room but need to be transported to an airborne isolation room when aerosol generating procedures take place (eg, extubation, bronchoscopy). Having a protocol in place for transport is prudent. 

INTERVENTIONS — Ventilated patients require frequent evaluation and develop complications that require intervention. Details relevant to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection are included in this section and mostly relate to infectious precautions. 

In a biodistribution study of 1070 specimens obtained from 205 patients with COVID-19 pneumonia, bronchoalveolar lavage fluid specimens showed the highest positive rates (93 percent), followed by sputum (72 percent), nasal swabs (63 percent), fibrobronchoscope brush biopsy (46 percent), pharyngeal swabs (32 percent), feces (29 percent), and blood (1 percent). No urine specimens tested positive [69]. These data demonstrate that SARS-CoV-2 may be detected in several specimens, although the reported rates in this study may have been determined by the severity of illness of the individual tested. 

In a systematic review of 10 retrospective cohort studies which evaluated transmission of severe acute respiratory syndrome coronavirus (SARS-CoV) to healthcare workers, endotracheal intubation had the highest risk (odds ratio [OR] 6.6, 95% CI 2.3-18.9), followed by noninvasive ventilation (OR 3.1, 95% CI 1.4-6.8), tracheostomy (OR 4.2, 95% CI 1.5-11.5), and bag-mask ventilation [70]. Other procedures were associated with a lower or insignificant risk of transmission but it is not known whether they can be applied to SARS-CoV-2. For example, duration of close contact during aerosolizing procedures and precautions used were not described. 

Collection of respiratory specimens in the intubated patient — Some intubated patients require upper or lower respiratory tract sampling for diagnostic purposes (eg, diagnosis of COVID-19 or ventilator-associated pneumonia [VAP]). Technically, nasopharyngeal and oropharyngeal swabs do not have to be taken under airborne precautions. However, we prefer to obtain naso-and oropharyngeal swabs and tracheal aspirates under airborne precautions in the intensive care unit (ICU). Nonbronchoscopic alveolar lavage (“mini-BAL”) may also be performed as an alternative to bronchoscopy, although experience in this procedure is not universal among ICUs. If mini-BAL is performed for the diagnosis of COVID-19, use of smaller aliquots of lavage fluid is prudent (eg, three 10 mL aliquots to obtain 2 to 3 mL of fluid). (See “Clinical presentation and diagnostic evaluation of ventilator-associated pneumonia”, section on ‘Invasive respiratory sampling’.)

Bronchoscopy — We agree with the American Association for Bronchology and Interventional Pulmonology (AABIP) that bronchoscopy should have a limited role for the diagnosis of COVID-19 and should only be performed for this indication when upper respiratory samples are negative (ie, nasopharyngeal and oropharyngeal swabs, tracheal aspirates, or non-bronchoscopic bronchoalveolar lavage) and the suspicion remains high. Bronchoscopy may also be performed when another diagnosis is being considered and a bronchoscopic sample would change management (eg, suspected Pneumocystis jirovecii in an immunosuppressed patient) or when therapeutic bronchoscopy is indicated (eg, life-threatening hemoptysis or airway stenosis).  

Bronchoscopy is an aerosol-generating procedure and should only be performed when necessary and likely to change management. Bronchoscopy through an established airway (eg, endotracheal tube [ETT]) likely carries less risk than bronchoscopy in a spontaneously breathing patient. In patients with COVID-19, bronchoscopy should be performed in an airborne infection isolation room. Airborne precautions and personal protective equipment (PPE) should be donned before entering the room. Using PPE similar to that described for intubation is appropriate. (See ‘The decision to intubate’ above and “Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings”.)

Using ETTs with inline adapters for bronchoscopy is ideal to prevent disconnection from the ventilator and aerosolization. If bronchoscopy is needed for the diagnosis of COVID-19 pneumonia, then we suggest small aliquots of 10 mL to obtain 2 to 3 mL of lavage fluid placed in a sterile leak-proof container. Clamping suction tubing or turning off suction after the sample has been obtained before disconnecting the sample from the device is also prudent. Specimens should be in a double zip-locked sealed plastic bag, handled with the usual precautions, and labelled clearly as “COVID-19.”

We prefer the use of disposable bronchoscopes, although these are not universally available. For nondisposable equipment, we recommend cleaning the suction channels with standard cleaning solutions typically used for highly infectious material. We also suggest covering or sealing any vessel containing the bronchoscope during transport after use and wiping down the transport cart and bronchoscope display tower before leaving the room. Wipe down solution should be hydrogen peroxide or equivalent and should be left wet on all surfaces for at least one minute. 

Extubation and weaning — Patients are often ready for extubation while they remain infectious, and because extubation is frequently associated with some coughing, it is considered an aerosol-generating procedure. Similar to intubation, we encourage the use of extubation protocols and check lists specific to each institution.

• Weaning – Readiness for extubation should follow standard practice of performing spontaneous breathing trials (SBT). However, COVID-specific approaches include the following:
• Equipment – We suggest using closed systems and not using a T-piece trial for SBTs.
• SBTs – To reduce the risk of reintubation following extubation, we prefer a higher degree of readiness in patients with COVID-19. This practice varies and may include higher criteria for passing an SBT. For example, some experts use lower pressure support ventilation [PSV] parameters (eg, 0 to 5 cm H2O) rather than the typical 7 cm H2O during the trial while others promote SBT for longer periods (eg, two to four hours rather than the typical two hours). The rationale for altered criteria is based upon the observation that patients with COVID-19 are intubated for longer periods than non-COVID-patients [22] and anecdotal evidence that suggests a high volume of secretions and airway edema; all of these factors place the patient at high risk of post extubation respiratory failure requiring reintubation. In addition, we prefer extubating patients directly to low-flow oxygen rather than high flow oxygen delivered via nasal cannulae (HFNC) or noninvasive ventilation (NIV), which may risk virus aerosolization. (See “Weaning from mechanical ventilation: Readiness testing” and “Methods of weaning from mechanical ventilation”, section on ‘Spontaneous breathing trial’ and “Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings”.)

Cuff leak test – Whether the cuff leak test (CLT) should be performed routinely prior to extubation is unclear. However, its performance may be guided by clinical suspicion for upper airway edema (eg, fluid overload) or the presence of risk factors for post extubation stridor (eg, prolonged intubation ≥6 days, age >80 years, large endotracheal tube, traumatic intubation). Performing the cuff leak test should be weighed against the potential risk of aerosolization, and similar to extubation, it should be preferentially done in an airborne isolation room. In our institution, we routinely administer glucocorticoids (eg, methylprednisolone 20 mg intravenously every four hours for a total of four doses) to most patients with COVID-19 before extubation and only extubate those in whom the CLT is positive after glucocorticoids. We base this practice upon the high rate of airway edema noted in our population but understand that practice may vary depending upon the population served. (See “Extubation management in the adult intensive care unit”, section on ‘Cuff leak’.)

• Extubation – We prefer to perform extubation in an airborne isolation room. Respiratory therapists and others in the room during extubation should adhere to airborne precautions including N95 masks with eye protection or equivalent. In general, only two people are needed and extra staff outside the room should be available to help with additional equipment. Some experts use medications to decrease coughing (eg, lidocaine via ETT, low-dose opioid bolus, dexmedetomidine, remifentanil if available), although data to support the routine use of anti-tussives are limited. In the ICU, close communication with a clinician experienced in intubation regarding the occurrence of extubation in a COVID-19 patient is prudent, in case rapid reintubation is needed, particularly for patients pre-designated as having a difficult airway.

Both low-flow and high-flow oxygen systems should be set up and readily available. We drape the patient’s chest and face with a plastic cover to provide barrier protection between the patient and the operator (eg, a plastic poncho). We typically put the ventilator in standby mode (or switch off) immediately prior to extubation. After balloon deflation, extra care should be taken during extubation to keep the inline suction catheter engaged during cuff deflation and to have another handheld suction catheter available for the removal of pharyngeal and oral sections. The endotracheal tube should be removed as smoothly as is feasible during inspiration, and disposed of into a biohazard plastic bag bundled together with the ventilator tubing, the plastic drape, and tape/ETT holders, and inline suction catheter. The bag is sealed and disposed of immediately. Further details regarding extubation are provided separately. (See “Extubation management in the adult intensive care unit”, section on ‘Extubation equipment and technique’.)

• Post-extubation care – The patient is monitored following the procedure. The threshold to reintubate patients with postextubation respiratory failure should be low. Postextubation care should support the application of supplemental oxygen at the lowest fraction of inspired oxygen (FiO2) possible, preferably via low flow nasal canula. Because patients are often extubated while they remain infectious, we would advise adhering to a similar approach to oxygen delivery as before intubation. (See “Extubation management in the adult intensive care unit”, section on ‘Postextubation management’ and ‘Oxygenation targets’ above.)

The procedure for palliative extubation should be similar except care following extubation also includes palliative medication and cessation of neuromuscular blockade. 

Precautions for extubation in the OR are provided separately. (See “Safety in the operating room”, section on ‘COVID-19’.)  

Tracheostomy — Reports from experts in the field suggest that many patients fail early attempts at weaning (eg, within the first week), although this does not appear to predict their eventual ability to wean and extubate. However, some patients require tracheostomy (in our experience <10 percent of ICU admissions). 

• Indications – Indications appear to be similar to non-COVID patients (eg, failed extubation, secretion management, airway edema, neurological impairment such as that which impairs airway protection).
• Timing – The optimal timing for tracheostomy is unknown in COVID-19 patients. In non-COVID patients, changes in practice have led to most intensivists performing tracheostomy around day 7 to 10 following initial intubation. Although most intensivists perform tracheostomy approximately 7 to 10 days following initial intubation in patients without COVID-19, it seems reasonable to defer tracheostomy in patients with COVID-19 beyond this time frame. COVID-19 patients appear to require mechanical ventilation longer than other patients (eg, two to three weeks), but can still be successfully extubated after this point.  
• Procedure – Tracheostomy is considered a high risk procedure for aerosolization. 
• Both open and percutaneous tracheostomy procedures are acceptable in COVID patients. 
• The exact procedure should be determined in advance and at the discretion of the operator with the minimum number of personnel. 
• To minimize cough, neuromuscular blockade is prudent. 
• It is preferable that the procedure be done at the bedside in an airborne isolation room. The operator should wear appropriate PPE similar to other aerosol generating procedures. The tracheostomy tube should have the syringe attached for immediate balloon inflation once inserted. In addition, adapters with inline suction catheters attached is also appropriate. (See ‘Precautions’ above and “Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings”.)
• Procedures such as open suctioning, dressing changes, inner cannula care, and tracheostomy changes are also considered as aerosol-generating. Thus, post tracheostomy care should also occur in an airborne isolation room, if feasible (if not, consider a portable HEPA-filtration unit). 

Novel barrier protections for performing tracheostomy have been proposed. In one report, tracheostomy was performed under an aerosol-reduction cover with a high-efficiency particulate air filtration unit placed close to the surgical field [71]. However, no description of aerosol deposition was provided. 

• Prolonged weaning – Tracheostomy collar trials can be safely done in an airborne isolation room with resumption of ventilation and a closed loop system following the trial. However, some institutions use a portable HEPA filter to generate negative pressure in a room or use closed systems and dual limb circuitry with a HEPA filter attached to the exhalation limb to minimize environmental contamination. A surgical mask over the tracheostomy itself may also theoretically limit droplet spread.  

Once a patient can breathe for 24 hours on a tracheostomy collar (or similar), they can undergo trials of a speaking valve and “capping” with the balloon deflated. Placing a speaking valve and capping would be considered aerosol generating so airborne precautions are warranted. However, once a speaking valve is in place or the tracheostomy is capped, aerosolization is less of a consideration and is the equivalent of a patient with a cough and on low flow oxygen and the patients may wear a mask over their nose and mouth. 

Decannulation is considered an aerosol-generating procedure, and provided the patient remains infectious, all the usual airborne precautions should be taken.  

• Repeat testing – Some institutions perform repeat SARS-CoV-2 testing to determine when to discontinue infection control precautions and inform resource allocation. Whether tracheal or nasopharyngeal swabs should be used for this purpose is uncertain. If patients are tested and have a positive test, we continue precautions until two tests collected 24 hours apart are negative; however, it remains uncertain whether viral RNA detection during recovery reflects transmissible infection. (See ‘Precautions’ above and “Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings” and “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Viral shedding and period of infectivity’.) . 

Further details regarding tracheostomy are provided separately. (See “Overview of tracheostomy”.)

Cardiopulmonary resuscitation — In the event of a cardiac arrest, cardiopulmonary resuscitation (CPR) should proceed with all members of the team wearing appropriate PPE. Practicing a test run of a COVID-19 patient cardiac arrest is prudent. Bag-mask ventilation should be avoided (if feasible); the ventilator can be used instead to deliver a respiratory rate of 10 breaths per minute (bpm). Guidance for advanced cardiac life support and CPR in patients who are prone and cannot be returned to the supine position is provided separately. (See “Advanced cardiac life support (ACLS) in adults” and “Coronavirus disease 2019 (COVID-19): Arrhythmias and conduction system disease” and “Coronavirus disease 2019 (COVID-19): Arrhythmias and conduction system disease”, section on ‘Patients requiring cardiopulmonary resuscitation (CPR)’ and “Basic life support (BLS) in adults”.)

Other interventions — Guidance is lacking regarding other procedures commonly performed in the ICU. Many intubated patients have routine indications for central venous and arterial access for monitoring and for vasoactive drug infusion. Grouping standard procedures such as central venous catheter and arterial lines immediately following intubation is appropriate to minimize the frequency of exposure. The transmission risk of blood is unknown but likely to be low [69]. 

Significant pleural effusions and barotrauma appear to be unusual as a manifestation of COVID-19. In general, emergently indicated procedures and interventions should be performed as indicated, with appropriate infectious precautions. (See ‘Clinical features in critically ill patients’ above and “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Clinical manifestations’ and “Safety in the operating room”, section on ‘COVID-19’.)  

Transfer of COVID-19 patients should be limited to necessary trips (eg, imaging for a diagnosis that would change management, travel to an airborne isolation room for high risk aerosol-generating procedures such as intubation and extubation). 

SUPPORTIVE CARE — General supportive care of the critically ill patient with COVID-19 pneumonia is similar to that in patients with acute respiratory distress syndrome (ARDS) due to other causes and is discussed in detail separately. Select issues pertinent to COVID-19 are discussed in the sections below. (See “Acute respiratory distress syndrome: Supportive care and oxygenation in adults”, section on ‘Supportive care’.) 

Routine measures — The supportive care of mechanically ventilated patients that also apply to patients with COVID-19 are provided in several linked topics. However, potential differences that may pertain to COVID-19 patients are discussed in this section:

Venous thromboembolism prevention — We agree with the American Society of Hematology and the Society of Critical Care Medicine that routine pharmacologic venous thromboembolism (VTE) prophylaxis is warranted, preferably with low molecular weight heparin (LMWH; eg, enoxaparin 40 mg SC once daily), unless there is a contraindication (eg, bleeding, severe thrombocytopenia). (See “Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults”.)

Because the risk of VTE appears to be higher than usual in this population, use of more aggressive VTE prophylaxis in the form of increased intensity of a pharmacologic agent (eg, enoxaparin 0.5 mg/kg every 12 hours, unfractionated heparin 7500 units every eight hours) and/or the addition of a mechanical device is prudent. Markedly elevated D-dimer levels, which correlate with a poor prognosis, are used by some experts to guide intensification of anticoagulation (eg, >6 times the upper limit of normal). For patients with a creatinine clearance <30 mL/minute, enoxaparin should be reduced to 30 mg daily or changed to unfractionated heparin depending on the severity of kidney impairment and patient weight. Fondaparinux is appropriate in those with heparin-induced thrombocytopenia. 

We believe that administering therapeutic anticoagulation (as a form of prophylaxis) may be assessed on an individual basis. However the indications for therapeutic anticoagulation, outside of documented VTE, are unclear but may include those with presumed VTE (eg, sudden unexplained deterioration in oxygenation or hemodynamic instability, acute cor pulmonale) and clotting of vascular devices (eg, venous, arterial devices, and hemodialysis devices). 

Detailed descriptions of the VTE risk and management of COVID-19 patients with hypercoagulability are provided separately. (See “Coronavirus disease 2019 (COVID-19): Hypercoagulability”.)

Sedation and analgesia — Anecdotal evidence suggests that requirements for sedation and analgesia appear high in mechanically ventilated patients with COVID-19 and that heavy use of sedatives and analgesic medication is required for ventilator synchrony. In our practice, we target a Richmond Agitation-Sedation Scale (RASS (table 9)) of -1 to -2 (or similar on a different scoring system), and in patients with ventilator dyssynchrony, a RASS of -2 to -3. RASS of -4 to -5 are targeted in those with severe dyssynchrony and those requiring neuromuscular blockade. For those requiring intravenous (IV) infusions, propofol and fentanyl are generally the preferred agents. However, shortages of sedatives may influence the choice of agent. We also quickly transition to oral medications, provided that fluid resuscitation is adequate (eg, oxycodone, hydromorphone, lorazepam, diazepam). Further details regarding indications, daily awakening, protocols, and dosing are provided separately. (See “Sedative-analgesic medications in critically ill adults: Selection, initiation, maintenance, and withdrawal” and “Sedative-analgesic medications in critically ill adults: Properties, dosage regimens, and adverse effects” and “Pain control in the critically ill adult patient”.)

Others — Other supportive measures are included here.

• Nutritional support – The same principles of nutrition in non COVID-19 critically ill patients should be applied to critically-ill COVID-19 patients. We are not proponents of extra protein supplementation, vitamin C or D supplementation, or trace element supplementation over and above the usual recommended daily doses. (See “Nutrition support in critically ill patients: An overview” and “Nutrition support in critically ill patients: Enteral nutrition” and “Nutrition support in critically ill patients: Parenteral nutrition”.)
• Glucose control. (See “Glycemic control and intensive insulin therapy in critical illness”.)
• Stress ulcer prophylaxis. (See “Stress ulcers in the intensive care unit: Diagnosis, management, and prevention” and “Management of stress ulcers”.)
• Hemodynamic monitoring. (See “Pulmonary artery catheterization: Indications, contraindications, and complications in adults” and “Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults” and “Novel tools for hemodynamic monitoring in critically ill patients with shock”.)
• Fever management. (See “Fever in the intensive care unit”, section on ‘Outcomes’.)
• Early physical therapy. (See “Post-intensive care syndrome (PICS)”, section on ‘Prevention and treatment’.)
• Ventilator-associated pneumonia precautions. (See “Risk factors and prevention of hospital-acquired and ventilator-associated pneumonia in adults”.)

Monitoring for complications — Critically ill patients with COVID-19 should be followed routinely for the development of complications associated with critical illness from COVID-19 or extrapulmonary manifestations of SARS-CoV-2 infection. Only essential personnel should enter the rooms of infected patients when performing daily examinations, care, and procedures.

Common complications include acute kidney injury, mild transaminitis, cardiomyopathy, pericarditis, pericardial effusions, arrhythmias, sudden cardiac death, and superinfection (eg, ventilator-associated pneumonia [VAP]) (see ‘Clinical features, complications, and pathology’ above). We suggest that daily laboratory studies include complete blood count with differential, chemistries, liver function and coagulation studies, arterial blood gases, ferritin level, D-dimer level, and lactate dehydrogenase. Serial measurement of cardiac troponins and a low threshold transthoracic echocardiogram may be helpful to evaluate for suspected cardiac injury.

Daily chest radiographs are not recommended routinely for mechanically ventilated patients with or without COVID-19. In patients with COVID-19 who are mechanically ventilated, chest radiographs should only be performed when there is an indication (eg, catheter- or endotracheal tube [ETT]-placement or a relevant clinical change). Chest computed tomography and other imaging should be limited to those in whom testing would change management. This rationale is based upon the increased risk of viral shedding with procedures that require transfer out of the intensive care unit (ICU). (See “Complications of the endotracheal tube following initial placement: Prevention and management in adult intensive care unit patients”, section on ‘Reassessment of position’.) 

Fluid and electrolytes management — Unless patients have sepsis or volume depletion from high fever or gastrointestinal losses, we prefer conservative fluid management typical of that advised for patients with ARDS. (See “Acute respiratory distress syndrome: Supportive care and oxygenation in adults”, section on ‘Fluid management’ and “Evaluation and management of suspected sepsis and septic shock in adults”, section on ‘Intravenous fluids (first three hours)’ and “Treatment of severe hypovolemia or hypovolemic shock in adults”.)

The management of patients who present with septic shock due to COVID-19 is similar to that in patients with septic shock from other causes. (See “Evaluation and management of suspected sepsis and septic shock in adults”.)

Glucocorticoids — We agree with the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) that glucocorticoids should not be routinely administered to patients with COVID-19, unless there is a separate evidence-based indication (eg, asthma or chronic obstructive lung disease exacerbation, refractory septic shock, and adrenal insufficiency). However, their administration in critically ill patients with COVID-19-related ARDS is controversial. Based on data suggesting potential benefit of glucocorticoids in patients with all-cause ARDS, the Society of Critical Care Medicine (SCCM) provides a conditional, weak recommendation in favor of glucocorticoids in patients with COVID-19 who have severe ARDS (eg, patients with a partial arterial pressure of oxygen/fraction of inspired oxygen [PaO2:FiO2] <100 mmHg). Although we also weakly recommend glucocorticoids in moderate to severe “all cause” ARDS (ie, non COVID-19-related ARDS) who fail low tidal volume ventilation, we do not suggest administering them routinely in the setting of COVID-19 and ARDS (see “Acute respiratory distress syndrome: Supportive care and oxygenation in adults”, section on ‘Glucocorticoids’). The rationale for not administering glucocorticoids in this population is that the data supporting any benefit did not include a sufficient proportion of patients with viral pneumonia to inform safety (eg, patients with severe acute respiratory syndrome [SARS], Middle East Respiratory syndrome [MERS], or influenza); this is especially important since data in patients with ARDS due to viral pneumonia were conflicting and some suggested harm [72-75].

If clinicians choose to administer glucocorticoids, the SCCM suggests that they should begin within the first 14 days, doses should be low, and courses should be short (eg, intravenous dexamethasone 20 mg IV once daily for five days, then 10 mg once daily for five days). 

Data in COVID-19 patients are limited to a single retrospective Chinese cohort, where methylprednisolone administration reduced the risk of death in patients with COVID-19 compared with patients who did not receive methylprednisolone (hazard ratio [HR] 0.38; 95% CI 0.2-0.71) [25]. However, these data are fundamentally flawed and new data gathered prospectively should shed light on this controversial issue. (See “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”, section on ‘Limited role of glucocorticoids’.)

As noted above, management of patients who present with shock due to COVID-19 is similar to that in patients with septic shock from other causes (see ‘Fluid and electrolytes management’ above). Low dose glucocorticoids are not routinely advised for septic shock. In the setting of COVID-19 and shock, we reserve low dose glucocorticoids (eg, hydrocortisone 200 to 400 mg/day in divided doses) for selected patients with refractory shock, in accordance with guidelines [7]. Low dose glucocorticoids are not routinely advised for non-refractory septic shock. The use of glucocorticoids in septic shock is discussed separately. (See “Glucocorticoid therapy in septic shock in adults”, section on ‘Administration’.)

Nebulized medication — Nebulization is considered an aerosol-generating procedure. For patients with COVID-19 who are intubated and require bronchodilators for an evidence-based indication (eg, acute bronchospasm from asthma or chronic obstructive lung disease exacerbation), we prefer the use of in-line metered dose inhalers (MDIs; ie, pressurized inhalers) rather than administration via a standard jet or vibrating mesh nebulizer due to the lower risk of aerosolization associated with MDIs [76,77]. 

For medications that can only be administered via a nebulizer, consideration should be given to stopping the medication if it is not essential for acute care (eg, inhaled colistin for patients with bronchiectasis) or using an MDI alternative, if available on formulary (eg, tobramycin capsule inhaler). Consideration should be given to the patient using their own supply if MDIs are not on formulary. 

Placement of a filter at the expiratory port of the ventilation circuit during nebulization is prudent to minimize aerosolization into the room. Ideally, patients who require nebulizers, should be in an airborne infection isolation room. Only the healthcare staff necessary for nebulizer administration (eg, respiratory therapists or nurse) should be in the room for the initiation of the procedure and airborne precautions similar to those for intubation should be taken. (See ‘The decision to intubate’ above and “Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings”.)

Investigational COVID-19 agents — Several investigational agents have been proposed and individual institutions should work with their pharmacists and clinical researchers to enroll patients in clinical trials. We suggest the development of protocols by individual ICUs for the off-label use of investigational agents. This area is rapidly evolving and is discussed in detail separately. (See “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”, section on ‘COVID-19-specific therapy’.)

Management of co-infections and comorbidities — Critically ill patients with COVID-19 who are intubated are at risk for developing VAP and other infections typical of all critically ill and/or intubated patients (eg, central line or urinary tract infections). When treating co-infections, potential drug interactions with any investigational COVID-19 agent should be assessed. Infectious disease experts should be involved early in the management of COVID-19 patients who are critically ill. Further details regarding management of chronic medications including nonsteroidal anti-inflammatories and angiotensin receptor inhibitors are provided separately. (See “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”, section on ‘Uncertainty about NSAID use’ and “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”, section on ‘Managing chronic medications’.)

SPECIAL POPULATIONS — There are no specific recommendations for pregnant women who are critically-ill with COVID-19 pneumonia. Management should be similar to uninfected patients. Issues regarding transmission and risk of acquiring SARS-CoV-2 in pregnant women is described separately. (See “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Pregnant and breastfeeding women’ and “Critical illness during pregnancy and the peripartum period” and “Acute respiratory failure during pregnancy and the peripartum period” and “Coronavirus disease 2019 (COVID-19): Pregnancy issues”.) 

In patients with sickle cell disease who are critically-ill with COVID-19 in whom acute chest syndrome is contributing to their illness, consideration of early exchange transfusions and surveillance for the development of acute pulmonary hypertension is prudent [78]. (See “Acute chest syndrome in adults with sickle cell disease”, section on ‘COVID-19’.)

Issues that arise for other populations are provided in the following links:

• Renal issues (see “Coronavirus disease 2019 (COVID-19): Issues related to kidney disease and hypertension”)
• Cardiac issues (see “Coronavirus disease 2019 (COVID-19): Myocardial infarction and other coronary artery disease issues” and “Coronavirus disease 2019 (COVID-19): Arrhythmias and conduction system disease” and “Coronavirus disease 2019 (COVID-19): Myocardial injury”)
• Airway management and operating room issues (see “Coronavirus disease 2019 (COVID-19): Anesthetic concerns, including airway management and infection control”)
• Cancer care (see “Coronavirus disease 2019 (COVID-19): Cancer care during the pandemic”)

PROGNOSIS

Mortality — Early data are emerging describing outcomes from COVID-19 in critically ill patients who develop acute respiratory distress syndrome (ARDS) [2,8-10,21,22,24-26]. Mortality appears lower than that in patients with severe acute respiratory syndrome (SARS-CoV) or Middle East respiratory syndrome (MERS). The mortality from COVID-19 appears driven by the presence of severe ARDS, and is approximately 50 percent (range 16 to 78 percent).

• In a single-center retrospective cohort of 52 critically ill Chinese patients with COVID-19, 62 percent had died by 28 days with a median duration of only seven days from intensive care unit (ICU) admission to death [9]. Among the 20 patients who survived, three remained on mechanical ventilation, three were receiving noninvasive mechanical ventilation or high flow oxygen via nasal cannulae (HFNC), and six were receiving low flow oxygen. 
• In a retrospective cohort of 201 Chinese patients with COVID-19, the mortality was 52 percent among those who developed ARDS [25]. Among those who received mechanical ventilation, 66 percent died, 21 percent were discharged and 13 percent remained hospitalized. 
• In a preliminary study of 21 critically ill patients in the United States, by day 5, 67 percent of critically ill patients had died, 24 percent remained critically ill, and 9.5 percent were discharged from the ICU [19]. 
• In an Italian cohort of 1591 patients, the ICU morality was 26 percent, but a significant proportion remained in the ICU at the time of the publication, which may have underestimated the true mortality [22]. 

Higher mortality was initially reported in males compared with females but this may have been due to the predominance of males affected with COVID-19 in the Chinese cohorts [8-10,25,26]; a similar difference has been noted in the preliminary reports from Italy but not from Washington state, USA [18,19]. 

Risk factors for death — Across countries, the consistent major risk factor associated with death in critically ill patients with COVID-19 is older age [9,10,17,20,22,24,25,79,80]. In two Chinese retrospective cohorts, death from ARDS was more likely to occur in those of older age ≥64 years (hazard ratio [HR] 6.17; 95% 3.26-11.67) [9,25]. Preliminary reports from Italy and the United States are reporting similar outcomes [17,18,20]. Other risk factors associated with death among critically ill patients include the following [9,10,17,20,22,24,25,81]:

• The development of ARDS, particularly severe ARDS, and the need for mechanical ventilation
• Comorbidities (eg, chronic cardiac and pulmonary conditions, hypertension, diabetes, chronic kidney disease)
• Markers of inflammation or coagulation (eg, D-dimer level >1 microg/mL admission, elevated fibrin degradation products, prolonged activated partial thromboplastin and prothrombin times)
  
  
• Select laboratory studies (eg, worsening lymphopenia, neutrophilia)

The rapidity of symptom progression does not appear to predict a worse outcome [9]

While high fever was associated with a higher likelihood of developing ARDS (HR 1.77; 95% CI 1.11-2.84), it appears to be associated with a lower likelihood of death (HR 0.41; 95% CI 0.21-0.82) [9,25], a phenomenon that has been noted previously in some critically ill patients. (See “Fever in the intensive care unit”, section on ‘Outcomes’.) 

Further details on the risk factors associated with severe disease are provided separately. (See ‘Risk factors for progression’ above.)

Long term sequelae — The percentage of patients that require long term care is unreported. Similarly, the incidence of critical care neuromyopathy is not yet documented. In our experience the rate may be higher than usual due to the prolonged nature of intubation in COVID-19 patients and higher use of neuromuscular blockade and sedatives, with or without concurrent glucocorticoid administration. (See “Neuromuscular weakness related to critical illness”.)

The incidence of post-intensive care unit syndrome (PICS) is also unknown in COVID-19 patients. Nonetheless, patients should be followed and treated for PICS which involves nutritional, physical, psychological, and occupational therapy. (See “Post-intensive care syndrome (PICS)”.)

END OF LIFE ISSUES — In a public health emergency, values other than autonomy predominate. Like any critical illness, severe illness due to COVID-19 carries the potential of significant psychosocial distress to patients, families, and surrogates. In addition, unique aspects of COVID-19 and its management portend greater trauma including anxiety and stigma surrounding a novel pathogen and high-level isolation precautions including visitation limitation or prohibition including at the end of life. High levels of patient, family, and surrogate psychosocial distress should be anticipated and combatted with clear communication strategies and early palliative care involvement. Even if in-person visitation is not allowed due to public health care concerns, hospitals should promote internet based visual communication such as video communication between clinicians, families, and isolated patients.  

Discussing end-of-life wishes with patients and their family should occur early in the course of management, including potentially even before diagnosis, especially in light of the poor outcomes for elderly patients with comorbidities who develop acute respiratory distress syndrome (ARDS) and require mechanical ventilation. Consultation with the palliative care teams and ethic experts should also be done to assist families in decision-making and assist clinicians with contentious issues or disagreement that may arise. 

Due to the unique aspects to addressing needs of patient and families in this pandemic, several online resources are available for clinicians to use when having COVID-19 specific discussions with patients and families. They provide helpful language and strategies for conversations about a range of issues including, but not limited to, triaging, discussing goals of care, resource allocation, and grieving including:

• VIITALtalk
• Center to Advance Palliative Care
• National Coalition for Hospice an Palliative Care

Further principles regarding ethical issues in the intensive care unit (ICU) and advance care planning are discussed separately. (See “Ethics in the intensive care unit: Responding to requests for potentially inappropriate therapies in adults” and “Ethics in the intensive care unit: Informed consent” and “Withholding and withdrawing ventilatory support in adults in the intensive care unit” and “Communication in the ICU: Holding a family meeting” and “Palliative care: Issues in the intensive care unit in adults” and “Advance care planning and advance directives”, section on ‘COVID-19 resources’.)

DISCHARGE AND LONG TERM CARE — For patients who extubate successfully and can be safely discharged home, routine community precautions apply. For patients who require a tracheostomy or are deconditioned from critical illness, transfer to a long term acute care (LTAC) facility is typical. However, there is no guidance on whether or when patients should be re-tested. Many, but not all, LTACs require two negative SARS-CoV-2 RT-PCR tests performed 24 hours apart before accepting a patient with COVID-19. If positive testing delays transfer to an LTAC, continued infection control precautions are advised, and rehab and weaning should begin at the acute care facility. Discontinuation of infection control precautions is discussed elsewhere. (See “Coronavirus disease 2019 (COVID-19): Infection control in health care and home settings”, section on ‘Discontinuation of precautions’.) 

Outcomes in patients who require long term care are unknown. Treatment of patients who require admission to an LTAC should be similar to non-COVID patients. Particular attention

should be paid to continuing venous thromboembolism prophylaxis until the acute illness fully resolves or the patient become mobile, although the efficacy of this approach is unknown. Duration of therapeutic anticoagulation should be guided by the indication; for example, a minimum of three months for documented or presumed VTE is appropriate while shorter durations are reasonable for device thrombosis. (See “Coronavirus disease 2019 (COVID-19): Hypercoagulability”.)

The management of patients who require long term mechanical ventilation is discussed separately. (See “Management and prognosis of patients requiring prolonged mechanical ventilation”.)

SURGE CAPACITY AND SCARCE RESOURCE ALLOCATION — COVID-19 is a global pandemic and has placed significant increases in demand for acute and critical care services on hospitals in many regions. This has necessitated operations maneuvers to increase capacity to be able to provide care for more patients, for more higher acuity patients requiring intensive care unit (ICU) admission and mechanical ventilation, and for patients with special isolation requirements. Surge capacity may be achieved by maximizing resources across three domains: 

• Care spaces (ie, beds)
• Staff
• Physical equipment

In the COVID-19 pandemic, this has included expanding ICU care into non-ICU spaces, utilizing non-critical care trained staff to participate in delivering critical care, and innovative approaches to obtain, conserve, and increase the efficiency of physical equipment including personal protective equipment (PPE; eg, repeat use of N95 masks) and mechanical ventilators (eg, double ventilation, repurposing operating room ventilators). As an example, some experts have published preliminary data to highlight the use of one ventilator for use in multiple patients [82]. However, this maneuver was designed for a disaster setting where one might reasonably expect that several patients might need life support at similar levels. Use of this measure as a life-saving measure in patients with COVID-19 could be complicated if patients are not matched well in terms of their ventilator settings. Potential use of anesthesia ventilators for longer-term mechanical ventilation is provided separately. (See “Coronavirus disease 2019 (COVID-19): Intensive care ventilation with anesthesia machines”.) 

In some instances, such as in Italy, despite mobilizing to surge capacity, demand for care has still outpaced supply such that overt rationing has occurred [83]. All hospitals facing the potential of an acute surge event due to COVID-19 or another insult should have a process to approach the allocation of scarce resources such as ICU beds and mechanical ventilators. Most individual states in the United States have guidance documents which can be adapted for local institutions [84]. General principles that guide and underpin scarce resource allocation policies include: 

• Maximization of lives saved and/or life-years saved
• Transparency 
• Stakeholder and public input
• Separation between the clinical team and the triage process (eg, ethics committees for difficult triage decisions)
• Robust palliative care and supportive measures for patients who are not provided with critical care resources

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See “Society guideline links: Coronavirus disease 2019 (COVID-19) – International and government guidelines for general care” and “Society guideline links: Coronavirus disease 2019 (COVID-19) – Guidelines for specialty care” and “Society guideline links: Coronavirus disease 2019 (COVID-19) – Resources for patients”.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

• Basics topics (see “Patient education: Coronavirus disease 2019 (COVID-19) overview (The Basics)”)

SUMMARY AND RECOMMENDATIONS

• Among patients hospitalized with coronavirus disease 2019 (COVID-19), up to one-quarter require intensive care unit (ICU) admission. (See ‘Introduction’ above and ‘Epidemiology’ above.)
• Profound hypoxemic respiratory failure from acute respiratory distress syndrome (ARDS) is the dominant finding in critically ill patients. Common complications include acute kidney injury (AKI), elevated liver enzymes, and the late development of cardiac injury, including sudden cardiac death. Sepsis, shock, and multi-organ failure are less common. (See ‘Clinical features in critically ill patients’ above.) 
• For most critically ill patients with COVID-19, we prefer the lowest possible fraction of inspired oxygen (FiO2) necessary to meet oxygenation goals, ideally targeting a peripheral oxygen saturation between 90 and 96 percent. (See ‘Respiratory care of the nonintubated patient’ above and ‘Oxygenation targets’ above and ‘Low flow oxygen’ above.)
• The use of high-flow oxygen via nasal cannulae (HFNC) and noninvasive ventilation (NIV) is controversial based on infection control concerns and the frequent need for mechanical ventilation despite these measures. The decision to initiate noninvasive modalities requires balancing the risks and benefits to the patient, the risk of exposure to healthcare workers, and best use of resources; this approach should be reassessed as new data becomes available. (See ‘Patients with higher oxygen requirements’ above.) 
• In patients with COVID-19 who have acute hypoxemic respiratory failure and higher oxygen needs than low flow oxygen can provide, we suggest selective use of noninvasive measures rather than routinely proceeding directly to intubation (Grade 2C). As an example we might trial HFNC in younger patients without comorbidities who can tolerate nasal cannulae. In contrast, we may proceed directly to early intubation in patients at higher risk (eg, elderly patients and patients with comorbidities or risk factors for progression). 

•Among the noninvasive modalities we suggest HFNC rather than NIV (Grade 2C). Our preference for HFNC is based upon limited and inconsistent data, which, on balance, favors HFNC compared with NIV in HFNC in patients with non-COVID-19-related acute hypoxemic respiratory failure. NIV via a full face mask (with a good seal) may be appropriate in patients with indications that have proven efficacy including acute hypercapnic respiratory failure from an acute exacerbation of chronic obstructive pulmonary disease, acute

cardiogenic pulmonary edema, and sleep disordered breathing. (See “Heated and humidified high-flow nasal oxygen in adults: Practical considerations and potential applications”, section on ‘Medical patients with severe hypoxemic respiratory failure’ and “Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications”, section on ‘Patients likely to benefit’.).

• For patients with COVID-19 who receive HFNC or NIV, vigilant monitoring is warranted for progression with frequent clinical and arterial blood gas evaluation every one to two hours to ensure efficacy and safe ventilation. The threshold to intubate such patients should be low. 
• For critically ill patients with COVID-19, intubation should not be delayed until the patient acutely decompensates since this is potentially harmful to both the patient and healthcare workers. We have a low threshold to intubate those who have (see ‘Timing’ above):
• Rapid progression over a few hours
• Failure to improve despite HFNC >40 L/min and FiO2 >0.6
• Development of hypercapnia
• Hemodynamic instability or multiorgan failure 
• Intubation is a high risk procedure for aerosol dispersion in patients with COVID-19 and attention should be paid to donning full personal protective equipment (PPE) with airborne precautions (figure 2 and figure 3) as well using equipment that minimizes dispersion (eg, video laryngoscopy) and the development of protocols for the procedure (eg, check lists) (table 2 and figure 1). (See ‘Precautions’ above and “Safety in the operating room”, section on ‘COVID-19’.)
• We use low tidal volume ventilation (LTVV) targeting ≤6 mL/kg predicted body weight (PBW) (range 4 to 8 mL/kg PBW (table 3 and table 4)) that targets a plateau pressure ≤30 cm H2O and applies positive end-expiratory pressure (PEEP) according to the strategy outlined in the table (table 5). For patients with COVID-19 who fail LTVV, prone ventilation is the preferred next step (table 7 and table 6). (See ‘Ventilator management of acute respiratory distress syndrome’ above and “Ventilator management strategies for adults with acute respiratory distress syndrome” and “Prone ventilation for adult patients with acute respiratory distress syndrome” and “Extracorporeal membrane oxygenation (ECMO) in adults”.) 
• Several procedures, including the collection of respiratory specimens, bronchoscopy, extubation, tracheostomy, and cardiopulmonary resuscitation are aerosol-generating and should be avoided or minimized, if possible. All procedures should be grouped when possible. (See ‘Interventions’ above.)

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58. Scaravilli V, Grasselli G, Castagna L, et al. Prone positioning improves oxygenation in spontaneously breathing nonintubated patients with hypoxemic acute respiratory failure: A retrospective study. J Crit Care 2015; 30:1390.
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GRAPHICS

Rapid overview of initial ICU management of patients with suspected COVID-19 infection

ICU: intensive care unit; BAL: bronchoalveolar lavage; CBC: complete blood count; LFTs: liver function tests; CRP: C-reactive protein; CPK: creatinine phosphokinase; LDH: lactate dehydrogenase; IL: interleukin; POC: point of care; CT: computed tomography; ECG: electrocardiogram; QTc: rate-corrected QT interval; ARDS: acute respiratory distress syndrome; ABGs: arterial blood gasses; IV: intravenous; MDIs: metered dose inhalers; COPD: chronic obstructive pulmonary disease; SpO2: pulse oxygen saturation; NC: nasal cannula; NRB: non rebreather; HFNC: high flow nasal cannula; NIV: noninvasive ventilation; ACHF: acute congestive heart failure; FiO2: fraction of inspired oxygen; AC: assist controlled; TV: tidal volume; PBW: ideal predicted body weight; RR: respiratory rate; PEEP: positive end-expiratory pressure; ETT: endotracheal tube; NO: nitric oxide; ECMO: extracorporeal membrane oxygenation; WBC: white blood count; CAP: community acquired pneumonia; MRSA: methicillin-resistant Staphylococcus aureus; ICS: inhaled corticosteroids; NSAIDs: nonsteroidal anti-inflammatory agents; ACEi: angiotensin converting enzyme inhibitors; ARBs: angiotensin receptor blockers; ESR: erythrocyte sedimentation rate.

* The Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) note that a medical/surgical mask is an alternative in the absence of aerosol generating procedures (AGP) if N95 mask is not available. 

Evidence suggests that a subgroup of patients with severe COVID-19 may be eligible for immune suppression with tocilizumab in the setting of a trial or compassionate use. The rationale is that COVID-19 may have cytokine release syndrome (CRS) or a CRS-like presentation as suggested by organ failure, increasing ferritin, CRP, LDH, erythrocyte sedimentation rate, thrombocytopenia, and lymphopenia. Administration of tocilizumab warrants discussion with a subspecialist and eligible patients may need an interleukin-6 level measured. Troponins may be measured daily or as indicated if cardiac dysfunction is suspected. Triglycerides should be measured when patients are on propofol for sedation. Marker of disseminated intravascular coagulopathy including activated partial thromboplastin, activated thrombin, D-dimer, and fibrinogen are also regularly monitored as are LFTs and a complete blood count and differential. 

Δ Refer to UpToDate text on ventilator management strategies for adults with acute respiratory distress syndrome for information about permissive hypercapnia during low tidal volume ventilation.

• FACTT Algorithm: Composite Protocol-Version 2. http://www.ardsnet.org/files/factt_algorithm_v2.pdf (Accessed April 1, 2020).

• Barrot L, Asfar P, Mauny F, et al. Liberal or Conservative Oxygen Therapy for Acute Respiratory Distress Syndrome. N Engl J Med 2020; 382:999.

• Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med 2013; 368:2159.

• Sickle Cell Disease and COVID-19: An Outline to Decrease Burden and Minimize Morbidity. https://www.sicklecelldisease.org/files/sites/181/2020/03/SCDAA-PROVIDER-ADVISORY4-3-25-20-v2.pdf (Accessed April 1, 2020).
• Pregnancy & Breastfeeding: Information about Coronavirus Disease 2019. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/pregnancy-breastfeeding.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fprepare%2Fpregnancy-breastfeeding.html (Accessed April 1, 2020).

Individuals with COVID-19 may have a number of coagulation abnormalities (in the direction of an underlying hypercoagulable state), raising questions about appropriate evaluations and interventions to prevent or treat thrombosis.

Interim guidance has been published by the International Society on Thrombosis and Haemostasis (ISTH), and frequently asked questions are posted on the websites of the American Society of Hematology (ASH) and the American College of Cardiology (ACC).

This topic reviews evaluation and management of coagulation abnormalities in individuals with COVID-19.

Separate topics discuss the following:

• General management : See “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”.
• Critical care : See “Coronavirus disease 2019 (COVID-19): Critical care and airway management issues”.
• Extracorporeal membrane oxygenation (ECMO) : See “Extracorporeal membrane oxygenation (ECMO) in adults”.
• Pregnancy : See “Coronavirus disease 2019 (COVID-19): Pregnancy issues”.
• Anesthesia : See “Coronavirus disease 2019 (COVID-19): Anesthetic concerns, including airway management and infection control”.

PATHOGENESIS — The pathogenesis of hypercoagulability in COVID-19 is incompletely understood.

Virchow’s triad — Hypercoagulability can be thought of in terms of Virchow’s triad (see “Overview of the causes of venous thrombosis”, section on ‘Virchow’s triad’). All three of the major contributions to clot formation apply to severe COVID-19 infection:

• Endothelial injury : There is evidence of direct invasion of endothelial cells by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, potentially leading to cell injury. Other sources of endothelial injury include intravascular catheters and mediators of the acute systemic inflammatory response such as cytokines (eg, interleukin [IL]-6) and other acute phase reactants [1]. The contribution of complement-mediated endothelial injury has been suggested [2]. (See “The endothelium: A primer” and “Complications of central venous catheters and their prevention” and “Acute phase reactants”.)
• Stasis : Immobilization can cause stasis of blood flow in all hospitalized and critically ill patients, regardless of whether they have COVID-19.
• Hypercoagulable state : A number of changes in circulating prothrombotic factors have been reported or proposed in patients with severe COVID-19
  • Elevated factor VIII
  • Elevated fibrinogen
  • Circulating prothrombotic microparticles
  • Neutrophil extracellular traps (NETs)

Very elevated levels of D-dimer have been observed that correlate with illness severity; D-dimer is a degradation product of cross-linked fibrin indicating augmented thrombin generation and fibrin dissolution by plasmin. However, high D-dimer levels are common in acutely ill individuals with a number of infectious and inflammatory diseases. Likewise, antiphospholipid antibodies, which can prolong the activated partial thromboplastin time (aPTT), are common in viral infections, but they are often transient and do not always imply an increased risk of thrombosis. (See ‘Coagulation abnormalities’ below and ‘Clinical features’ below.)

Coagulation abnormalities : The predominant coagulation abnormalities in patients with COVID-19 suggest a hypercoagulable state and are consistent with uncontrolled clinical observations of an increased risk of venous thromboembolism (see ‘VTE’ below). This state has been termed thromboinflammation or COVID-19-associated coagulopathy (CAC) by some experts [5,6]. It appears to be distinct from disseminated intravascular coagulation (DIC), though DIC has been reported in severely affected patients.

Laboratory findings were characterized in a series of 24 selected patients with severe COVID-19 pneumonia (intubated) who were evaluated along with standard coagulation testing and other assays including von Willebrand factor (VWF) and thromboelastography (TEG)

• Coagulation testing
  • Prothrombin time (PT) and aPTT normal or slightly prolonged
  • Platelet counts normal or increased (mean, 348,000/microL)
  • Fibrinogen increased (mean, 680 mg/dL; range 234 to 1344)
  • D-dimer increased (mean, 4877 ng/mL; range, 1197 to 16,954)
• Other assays
  • Factor VIII activity increased (mean, 297 units/dL)
  • VWF antigen greatly increased (mean, 529; range 210 to 863), consistent with endothelial injury or perturbation
  • Minor changes in natural anticoagulants
    – Small decreases in antithrombin and free protein S
    – Small increase in protein C
• TEG findings
  • Reaction time (R) shortened, consistent with increased early thrombin burst, in 50 percent of patients
  • Clot formation time (K) shortened, consistent with increased fibrin generation, in 83 percent
  • Maximum amplitude (MA) increased, consistent with greater clot strength, in 83 percent
  • Clot lysis at 30 minutes (LY30) reduced, consistent with reduced fibrinolysis, in 100 percent

Testing in this study was performed on arterial blood because the patients had arterial catheters in place, but venous blood can be used. Heparinase was included since most patients were receiving low molecular weight (LMW) heparin.

Other studies have reported similar findings consistent with a hypercoagulable state, including very high D-dimer, VWF antigen and activity, and factor VIII activity. One study suggested that patients with COVID-19 have higher platelet counts than patients with other coronavirus infections

Early case series, including a series of 183 consecutive patients from Wuhan, China, suggested that thrombocytopenia and prolongation of the PT and aPTT were more marked. It is not clear why these results differed somewhat from later findings of less severe PT and aPTT prolongation. One possible explanation is that these patients were sicker, perhaps because earlier in the pandemic the disease was not recognized as quickly, resulting in delays in patient presentation and/or treatment.

Another explanation for an isolated prolonged aPTT is the presence of a lupus anticoagulant (LA) (see “Clinical use of coagulation tests”, section on ‘Causes of prolonged aPTT’). Two studies have found a high rate of LA in patients with prolonged aPTT (50 of 57 tested individuals [88 percent] and 31 of 34 tested individuals [91 percent]) . The presence of an LA may lead to an artifactual prolongation of the aPTT but does not reflect an increased bleeding risk; patients with an LA should receive anticoagulation if indicated. (See ‘Management’ below.)

Some of the markers of deranged coagulation (eg, D-dimer) appear to correlate with illness severity. D-dimer is often increased, sometimes markedly, in individuals with overt DIC and those in the intensive care unit (ICU).

Principles of TEG and interpretation of TEG tracings are illustrated in the figure (figure 1) and discussed in more detail separately. (See “Platelet function testing”, section on ‘Thromboelastography (TEG) and ROTEM’ and “Acute coagulopathy associated with trauma”, section on ‘Thromboelastography’.)

Distinction from DIC – The hypercoagulable state associated with COVID-19 has been referred to by some as a disseminated intravascular coagulation (DIC)-like state, especially because many affected individuals are acutely ill and meet criteria for probable DIC in a scoring system published by the International Society on Thrombosis and Haemostasis (ISTH) in 2009

However, the major clinical finding in COVID-19 is thrombosis, whereas the major finding in acute decompensated DIC is bleeding.

Likewise, COVID-19 has some similar laboratory findings to DIC, including a marked increase in D-dimer and in some cases, mild thrombocytopenia. However, other coagulation parameters in COVID-19 are distinct from DIC. In COVID-19, the typical findings include high fibrinogen and high factor VIII activity, suggesting that major consumption of coagulation factors is not occurring. See ‘Coagulation abnormalities’ above.

In contrast, acute decompensated DIC is associated with low fibrinogen due to consumption of clotting factors. In one of the largest series that reported on thromboembolic events, none of the patients developed overt DIC

Typically, bleeding predominates in acute decompensated DIC and thrombosis predominates in chronic compensated DIC, although there is significant overlap. Thus, the hypercoagulable state in patients with COVID-19 is more similar to compensated DIC than to acute DIC. However, in COVID-19, the platelet count and aPTT are typically normal. (See “Disseminated intravascular coagulation (DIC) in adults: Evaluation and management”, section on ‘Pathogenesis’.)

This ISTH scoring system is based on laboratory findings and is only intended for use in patients with an underlying condition known to be associated with DIC. COVID-19 would qualify based on being a severe infection. Points are given for thrombocytopenia (1 point for platelet count 50,000 to 100,000/microL; 2 points for < 50,000/microL), prolonged PT (1 point for 3 to 6 seconds of prolongation; 2 points for more than 6 seconds), low fibrinogen (1 point for < 100 mg/dL), and increased D-dimer (2 points for moderate increase; 3 points for “strong” increase). A score of 5 or more points suggests DIC is probable. Despite this, the diagnosis of DIC is made clinically; there is no gold standard and no single test or combination of tests that is pathognomonic. Compared with expert opinion, the ISTH scoring system is reported to have a sensitivity of 91 percent and a specificity of 97 percent. (See ‘Coagulation abnormalities’ above.)

Regardless of whether the differences from DIC or the similarities are emphasized, many of the basic principles of DIC management apply, including the importance of treating the underlying condition, the importance of basing interventions on the clinical picture rather than on laboratory testing alone, and the need to provide anticoagulation for thrombosis and appropriate hemostatic therapies for bleeding. (See “Disseminated intravascular coagulation (DIC) in adults: Evaluation and management”, section on ‘Treatment’.)

CLINICAL FEATURES

VTE : Venous thromboembolism (VTE), including extensive deep vein thrombosis (DVT) and pulmonary embolism (PE), is very common in acutely ill patients with COVID-19, seen in up to one-third of patients in the intensive care unit (ICU), even when prophylactic anticoagulation is used.

Two autopsy studies emphasize the contributions of hypercoagulability and associated inflammation in patients who die from COVID-19 :

• Post-mortem examination of 21 individuals with COVID-19 found prominent PE in four, with microthrombi in alveolar capillaries in 5 of 11 (45 percent) who had available histology [17]. Three had evidence of thrombotic microangiopathy with fibrin thrombi in glomerular capillaries. The average age was 76 years, and most had a high body mass index (BMI; mean, 31 kg/m2; normal 18.5 to < 25). Information on use of anticoagulation prior to death was available for 11, and all 11 were receiving some form of anticoagulation. Underlying cardiovascular disease, hypertension, and diabetes mellitus were common.
• Post-mortem examination of 12 consecutive individuals with COVID-19 (8 male; 10 hospitalized) revealed DVT in 7 of 12 (58 percent) [18]. All cases of DVT had bilateral leg involvement, and none were suspected before death. Of the 12 for whom lung histology was available, 5 (42 percent) had evidence of thrombosis. PE was the cause of death in four. In those who had D-dimer testing, some had extremely high values (two >20,000 ng/mL and one >100,000 ng/mL; normal value < 500 ng/mL [< 500 mcg/L]). Use of anticoagulation prior to death was only reported in 4 of the 12. The mean BMI was 28.7 kg/m2; only three patients had a normal BMI, and they had cancer, ulcerative colitis, and/or chronic kidney disease.

Both of these studies noted the preponderance of males with a high prevalence of obesity and other chronic medical comorbidities, especially cardiovascular disease, hypertension, and diabetes mellitus.

ICU – Case series of intensive care unit (ICU) patients have reported high rates of VTE (range, 20 to 43 percent), mostly pulmonary embolism (PE), and often despite prophylactic-dose anticoagulation:

• A series of 184 sequential patients with severe COVID-19 in the ICU reported PE in 25 (14 percent), deep vein thrombosis (DVT) in 1, and catheter-associated thrombosis in 2. The cumulative incidence of VTE (based on different durations of follow-up) was calculated at 27 percent. All were receiving at least standard dose thromboprophylaxis. The group as a whole was very ill, with 13 percent requiring renal replacement therapy and 13 percent mortality. Three-fourths of the patients were male, and several had active cancer (independent VTE risk factors).
• A series of 150 ICU patients reported VTE in 64 (43 percent, mostly PE) and clotting of the extracorporeal circuit in 28 of 29 receiving continuous renal replacement therapy and 2 of 12 undergoing extracorporeal membrane oxygenation (ECMO) [7]. All patients were receiving thromboprophylaxis (mostly low molecular weight [LMW] heparin), 70 percent with prophylactic dose and 30 percent with therapeutic dose.This study also compared the subgroup of 77 patients with COVID-19-associated acute respiratory distress syndrome (ARDS) to a matched cohort of 145 patients with non-COVID-19-ARDS and found the rate of thrombotic complications (mostly PE) to be higher in the COVID-19 patients (12 versus 2 percent).
• A series of 107 ICU patients reported PE in 22 (21 percent; cumulative incidence at 15 days, 20 percent). Of the 22 patients with PE, 20 were receiving prophylactic anticoagulation and 2 were receiving therapeutic-dose anticoagulation (for prior VTE and atrial fibrillation). By comparison, the incidence of PE in two matched cohorts (one from the same time interval in the previous year and one from concurrent patients with influenza rather than COVID-19) were 6 and 8 percent, respectively.
• A series that included 74 ICU patients reported VTE in 29 (39 percent), with a cumulative incidence of 25 percent at 7 days and 48 percent at 14 days. All of these individuals were receiving anticoagulation, most at prophylactic levels. None of the patients receiving therapeutic level anticoagulation at admission developed VTE.
• An earlier series of 81 patients with severe COVID-19 pneumonia reported VTE in 20 (25 percent)
• A study that performed screening leg ultrasounds in 26 individuals with COVID-19 in the ICU who were all receiving either prophylactic-dose or therapeutic-dose anticoagulation found VTE in 18 (69 percent), including bilateral clots in 10 (38 percent). Some of these individuals had additional VTE risk factors including cancer, recent surgery, high BMI, or prior VTE; 7 (27 percent) were receiving anticoagulation prior to admission.

VTE risk is in the range where some experts would suggest more aggressive thromboprophylaxis dosing of anticoagulants or even empiric therapeutic-dose anticoagulation for VTE prevention. Some of these studies noted a higher than average body mass index in affected individuals, suggesting that obesity, along with other risk factors, may warrant consideration in decision-making regarding the intensity of anticoagulation. (See ‘Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients’ below.)

Inpatients (non-ICU) – Data are more limited regarding the rate of VTE in inpatients who are not in the intensive care unit (ICU).

The series with a 39 percent rate of VTE in ICU patients above also included 124 non-ICU patients, and of those, only 4 (3 percent) were diagnosed with VTE

A series from Ireland that included 50 patients on the regular medical ward reported similar findings to those in ICU patients, including high D-dimer and fibrinogen and normal platelet counts and clotting times.

Outpatients – We are aware that thrombotic events have been observed in COVID-19 patients who were not admitted to the hospital, but data on the incidence are not available.

Arterial events – There are also reports of arterial thrombosis, including in the central nervous system (CNS). As examples:

• CNS : A single health system identified five cases of acute ischemic stroke associated with COVID-19 over a two-week period, with symptoms suggesting large-vessel occlusion; all patients were under 50 years of age. In other time periods before the pandemic, there were approximately 0.7 large vessel strokes per two-week interval in individuals under age 50. In one of the series of ICU patients discussed above, ischemic stroke was observed in 3 of 184 (cumulative incidence, 3.7 percent). In another one of the series discussed above, cerebral ischemia was seen in 3 of 150
• Limbs : A report described 20 patients with COVID-19 who developed acute limb ischemia at a single institution over a three-month period. This represented a significant increase in limb ischemia over the previous year (16 percent, versus 2 percent in early 2019). Most were male (18 of 20), and the average age was 75 years. Surgical revascularization procedures were performed in 17, of which 12 (71 percent) were successful, a lower-than-expected success rate. Individuals who received postoperative heparin did not require reintervention, although the benefits of postoperative heparin did not reach statistical significance.

Another report described four patients with acute limb ischemia due to thrombosis, two of whom were young and did not have any comorbidities (a 53-year-old man who developed aorto-iliac thrombosis and a 37-year-old man who developed humeral artery thrombosis). Both were receiving prophylactic-dose LMW heparin at the time thrombosis developed and both had very high D-dimer (>9000 ng/mL).

Myocardial infarction has also been reported but not emphasized in available series.

Microvascular thrombosis – Autopsy studies in some individuals who have died from COVID-19 have demonstrated microvascular thrombosis in the lungs. The mechanism is unclear and may involve hypercoagulability, direct endothelial injury, complement activation, or other processes.

In the absence of more definitive data regarding mechanisms or therapy, we would not pursue specialized testing for thrombotic microangiopathies (eg, ADAMTS13 activity, complement studies) or specialized therapies (eg, plasma exchange, anti-complement therapy) outside of a research study.

Bleeding – Bleeding is less common than clotting in patients with COVID-19, but it may occur, especially in the setting of anticoagulation. As an example, in a subset of 25 ICU patients who were evaluated for abnormal neurologic findings, one had evidence of intracranial hemorrhage as well as ischemic lesions. Three other patients in this series also had hemorrhagic complications, including two intracerebral bleeds associated with head trauma and one with hemorrhagic complications of extracorporeal membrane oxygenation (ECMO). Three others in this series had evidence of intracerebral ischemia. (See ‘Arterial events’ above.)

EVALUATION – The evaluation of patients with COVID-19 and coagulation abnormalities (suspected or documented) can be challenging due to the limited data on which clinical parameters or coagulation abnormalities should be acted upon and the concerns related to performing diagnostic imaging procedures on acutely ill and potentially contagious patients. A general approach is as follows, although other decisions may be made by the treating clinicians based on their evaluation of the patient. This approach is consistent with guidance from the International Society on Thrombosis and Haemostasis (ISTH), the American Society of Hematology (ASH), and the American College of Cardiology (ACC)

Routine testing (all patients)

Inpatients – We assess the following in inpatients with COVID-19:

• Complete blood count (CBC) including platelet count
• Coagulation studies (prothrombin time [PT] and activated partial thromboplastin time [aPTT])
• Fibrinogen
• D-dimer

Repeat testing is reasonable on a daily basis or less frequently, depending on the acuity of the patient’s illness, the initial result, and the trend in values. Measurement of the D-dimer more than once per day is generally not indicated. As noted above, common laboratory findings include (see ‘Coagulation abnormalities’ above):

• High D-dimer
• High fibrinogen
• Normal or mildly prolonged PT and aPTT
• Mild thrombocytopenia or thrombocytosis, or normal platelet count

We do not intervene for these abnormal coagulation studies in the absence of clinical indications. However, these findings may have prognostic value and may impact decision-making about the level of care and/or investigational therapies directed at treating the infection. As an example, increasing D-dimer is associated with poor prognosis. (See ‘Investigational therapies’ below.)

Atypical findings such as a markedly prolonged aPTT (out of proportion to the PT), low fibrinogen, or severe thrombocytopenia suggest that another condition may be present and additional evaluation may be indicated. (See ‘Role of additional testing’ below.)

We do not routinely test for thrombotic thrombocytopenic purpura (TTP), other thrombotic microangiopathies, or antiphospholipid antibodies (aPL). There are no therapeutic implications of transiently positive aPL in the absence of clinical findings. Transient aPL positivity is often seen in acute infections. (See “Diagnosis of antiphospholipid syndrome”, section on ‘Other conditions associated with aPL’.)

We do not routinely perform imaging for screening purposes, as there is no evidence that indicates this practice improves outcomes, and it may unnecessarily expose health care workers to additional infectious risks. However, imaging is appropriate in individuals with symptoms, as discussed below. (See ‘Role of additional testing’ below.)

Outpatients – For outpatients, routine coagulation testing is not required. Evaluation of abnormal symptoms or findings on examination is similar to inpatients. (See ‘Role of additional testing’ below.)

Role of additional testing

Diagnosis of DVT or PE — Evaluation for deep vein thrombosis (DVT) or pulmonary embolism (PE) may be challenging because symptoms of PE overlap with COVID-19, and imaging studies may not be feasible in all cases. The threshold for evaluation or diagnosis of DVT or PE should be low given the high frequency of these events and the presence of additional venous thromboembolism (VTE) risk factors in many individuals. (See ‘VTE’ above.)

DVT – Individuals with suspected DVT should have compression ultrasonography when feasible according to standard indications. (See “Clinical presentation and diagnosis of the nonpregnant adult with suspected deep vein thrombosis of the lower extremity”.)

PE – e agree with guidance from the American Society of Hematology (ASH) regarding diagnosis of PE, which includes the following :

• A normal D-dimer is sufficient to exclude the diagnosis of PE. An increase in D-dimer is not specific for VTE and is not sufficient to make the diagnosis.
• In patients with suspected PE due to unexplained hypotension, tachycardia, worsening respiratory status, or other risk factors for thrombosis, computed tomography with pulmonary angiography (CTPA) is the preferred test to confirm or exclude the diagnosis. Ventilation/perfusion (V/Q) scan is an alternative if CTPA cannot be performed or is inconclusive, although V/Q scan may be unhelpful in individuals with significant pulmonary involvement from COVID-19. Consultation with the pulmonary embolism response team (PERT) in decision-making is advised if possible. (See “Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism”.) The role of full-dose anticoagulation if CTPA or V/Q scan is not feasible is discussed below. (See ‘Documented or presumed VTE’ below.)

Infection control procedures should be followed in patients undergoing imaging studies. (See “Coronavirus disease 2019 (COVID-19): Epidemiology, virology, clinical features, diagnosis, and prevention”, section on ‘Infection control in the health care setting’.)

Evaluation of atypical laboratory findings —As noted above, typical laboratory findings of COVID-19 are monitored for their prognostic value. (See ‘Routine testing (all patients)’ above.)

Laboratory findings that are atypical for COVID-19, such as severe thrombocytopenia (eg, platelet count < 50,000/microL), a prolonged aPTT out of proportion to the PT, or a markedly reduced fibrinogen, should be evaluated as done for individuals without COVID-19, as discussed in separate topic reviews:

• Thrombocytopenia : (See “Approach to the adult with unexplained thrombocytopenia”.)
• Abnormal coagulation tests : (See “Clinical use of coagulation tests”, section on ‘Evaluation of abnormal results”.)

Evaluation of bleeding — The evaluation is discussed separately. (See “Approach to the adult with a suspected bleeding disorder” and “Clinical use of coagulation tests”, section on ‘Patient on anticoagulant’.)

Management of bleeding depends on the underlying cause. (See ‘Treatment of bleeding’ below.)

MANAGEMENT

Overview of management considerations — Management can be challenging. Hypercoagulability appears to adversely impact prognosis, but there are no high-quality studies to support interventions that go beyond standard indications, and antithrombotic therapies carry risks of increased bleeding [30]. In the absence of high-quality data to guide management, institutions may vary in how aggressively they approach prevention and treatment of thromboembolic complications. Enrollment in clinical trials is encouraged to help determine the best approach

Regardless of clinical trial enrollment, adherence to institutional protocols and input from individuals with expertise in hemostasis and thrombosis is advised to balance the risks of thrombosis and bleeding and guide decisions about antithrombotic therapy; bleeding caused by administration of excessive antithrombotic therapy may require prothrombotic treatments that further increase thrombotic risk.

Acknowledging the lack of evidence, we agree with interim guidance from the International Society on Thrombosis and Haemostasis (ISTH). Our approach is summarized in the table (table 1) and discussed in the following sections.

Management of coagulation abnormalities in patients with COVID-19 receiving extracorporeal membrane oxygenation (ECMO) is discussed separately. (See “Coronavirus disease 2019 (COVID-19): Critical care and airway management issues”, section on ‘Additional options’ and “Extracorporeal membrane oxygenation (ECMO) in adults”.)

Inpatient VTE prophylaxis

Indications – Venous thromboembolism (VTE) prophylaxis is appropriate in all hospitalized medical, surgical, and obstetric patients with COVID-19 (algorithm 1), unless there is a contraindication to anticoagulation (eg, active bleeding or serious bleeding in the prior 24 to 48 hours) or to the use of heparin (eg, history of heparin-induced thrombocytopenia [HIT], in which case an alternative agent such as fondaparinux may be used).

• ICU : All patients with COVID-19 in the intensive care unit (ICU) require thromboprophylaxis. As discussed below, some would empirically use intermediate-dose or therapeutic-dose anticoagulation in severely ill individuals in the absence of documented VTE. (See ‘Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients’ below.)
• Medical (non-ICU) : All hospitalized medical patients should be treated with prophylactic-dose low molecular weight (LMW) heparin (or unfractionated heparin if LMW heparin is unavailable) for thromboprophylaxis.
• Surgical : Perioperative VTE prophylaxis is especially important for patients with COVID-19 who are hospitalized for a surgical procedure. Details of the timing and choice of agent are discussed separately. (See “Prevention of venous thromboembolism in adult orthopedic surgical patients” and “Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients”.)
• Obstetric : We would also use VTE prophylaxis in obstetric patients with COVID-19 who are in the hospital prior to or following delivery. LMW heparin is appropriate if delivery is not expected within 24 hours and after delivery; unfractionated heparin is used if faster discontinuation is needed (eg, if delivery, neuraxial anesthesia, or an invasive procedure is anticipated within approximately 12 to 24 hours or at 36 to 37 weeks of gestation). (See “Coronavirus disease 2019 (COVID-19): Pregnancy issues”, section on ‘Medical and obstetric care of hospitalized patients’ and “Use of anticoagulants during pregnancy and postpartum”.)

Dosing – Dosing (subcutaneous) is generally as follows; however, many experts are recommending higher doses for critically ill individuals, especially those in the ICU (see ‘Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients’ below):

• Enoxaparin – For patients with creatinine clearance (CrCl) >30 mL/min, 40 mg once daily; for CrCl 15 to 30 mL/min, 30 mg once daily.
• Dalteparin – 5000 units once daily.
• Nadroparin – For patients ≤70 kg, 3800 or 4000 anti-factor Xa units once daily; for patients >70 kg, 5700 units once daily. In some cases, doses up to 50 anti-factor Xa units/kg every 12 hours are used.
• Tinzaparin – 4500 anti-factor Xa units once daily.

For patients with CrCl < 15 mL/min or renal replacement therapy, we use unfractionated heparin, which is much less dependent on elimination by the kidney. The tables have more information about adjustments for kidney impairment (table 2), obesity (table 3), and pregnancy (table 4).

Supporting evidence –LMW heparin is known to reduce the risk of VTE and may have antiinflammatory properties. In a retrospective series of 2773 individuals hospitalized with COVID-19, in whom 786 (28 percent) received systemic anticoagulation, anticoagulation was associated with improved in-hospital survival in intubated patients (71 percent, versus 37 percent for those who were not anticoagulated) [33]. Intubated patients represented approximately 14 percent of the cohort; in the cohort as a whole, anticoagulation was not associated with better in-hospital survival (78 versus 77 percent). Bleeding events occurred in 3 percent of the anticoagulated patients and 2 percent of those who were not anticoagulated (not a statistically significant difference). In a retrospective study of 449 individuals with severe COVID-19, enoxaparin (40 to 60 mg once daily) appeared to be associated with improved survival when compared with no pharmacologic prophylaxis, especially in those with a high D-dimer

• The survival difference was only seen in a subset of individuals with a high sepsis-induced coagulopathy score (28-day mortality, 40 percent with heparin versus 64 percent without) or a high D-dimer, not in the cohort as a whole.
• The magnitude of benefit was greater in those with higher D-dimer values. The reduced mortality became statistically significant at six times the upper limit of normal (33 versus 52 percent).

One small series (16 patients) used higher prophylactic doses of nadroparin along with clopidogrel and did not report any VTE events; the small size of the study and lack of a control group limits interpretation

As discussed above, a high percentage (25 to 43 percent) of individuals with COVID-19 in the ICU had VTE despite prophylactic-dose anticoagulation, prompting many experts to suggest higher doses. (See ‘VTE’ above and ‘Indications for full-dose anticoagulation’ below.)

One study monitored antithrombin (AT) levels and provided AT concentrate for those with decreased levels [4]. However, we generally would not measure AT levels or consider AT concentrate unless an individual was known to have inherited AT deficiency or exhibited heparin resistance in association with a very low AT level. (See “Antithrombin deficiency”, section on ‘Heparin resistance’.)

Indications for full-dose anticoagulation — Therapeutic-dose (full-dose) anticoagulation (eg, enoxaparin 1 mg/kg every 12 hours) is appropriate in the following settings, unless there is a contraindication to anticoagulation (eg, active bleeding or serious bleeding in the prior 24 to 48 hours) or to the use of heparin (eg, history of heparin-induced thrombocytopenia [HIT], in which case an alternative agent such as fondaparinux may be used) (algorithm 1):

Documented or presumed VTE —Therapeutic-dose (full-dose) anticoagulation is appropriate for documented venous thromboembolism (VTE), similar to individuals without COVID-19. (See ‘Diagnosis of DVT or PE’ above.)

Full-dose anticoagulation is also reasonable in some cases of suspected VTE in which standard confirmatory testing is not available or feasible, including the following:

• In patients for whom computed tomography with pulmonary angiography (CTPA) or ventilation/perfusion (V/Q) scan is not feasible, the following may be sufficient to initiate treatment:
  • Confirmation of deep vein thrombosis (DVT) using bilateral compression ultrasonography of the legs.
  • Transthoracic echocardiography or point-of-care ultrasound that demonstrates clot in transit in the main pulmonary artery.
• In patients for whom no confirmatory testing is possible, it may be reasonable to treat empirically with full-dose anticoagulation based on one or more of the following:
  • Sudden deterioration in respiratory status in an intubated patient consistent with pulmonary embolism (PE), especially when chest radiography and/or inflammatory markers are stable or improving and the change cannot be attributed to a cardiac cause.
  • Otherwise unexplained respiratory failure (eg, not due to fluid overload or acute respiratory distress syndrome [ARDS]), especially if the fibrinogen and/or D-dimer is very high.
  • Physical findings consistent with thrombosis (superficial thrombophlebitis or retiform purpura not explained by other conditions).

For patients with acute VTE who are discharged from the hospital, extended thromboprophylaxis may be reasonable. (See ‘Patients discharged from the hospital’ below.)

Clotting of intravascular access devices —Full-dose anticoagulation is appropriate for individuals with recurrent clotting of intravascular access devices (arterial lines, central venous catheters) despite prophylactic-intensity anticoagulation.

Full-dose anticoagulation is also appropriate in those with clotting in extracorporeal circuits (continuous renal replacement therapy, extracorporeal membrane oxygenation [ECMO]). Details are discussed separately. (See “Extracorporeal membrane oxygenation (ECMO) in adults”.)

Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients —The question of treatment-dose anticoagulation for thromboprophylaxis has also been raised in critically ill individuals and those in the ICU who have not had confirmed or suspected acute VTE but are at high risk, as described above. (See ‘VTE’ above.)

Many centers are recommending intermediate-dose or even therapeutic-intensity anticoagulation in these individuals (see “Coronavirus disease 2019 (COVID-19): Critical care and airway management issues”, section on ‘Venous thromboembolism prevention’). There are no data comparing different levels of anticoagulation in these patients (prophylactic, intermediate, or therapeutic dosing), and clinical trials are in progress. Enrollment in such a trial is encouraged.

As stated by the American Society of Hematology (ASH), empiric full-dose anticoagulation for individuals who do not have VTE remains controversial, since data demonstrating improved outcomes are lacking, and some of the risk factors for VTE are also risk factors for increased risk of bleeding [29]. Thus, if VTE is suspected, confirmatory testing should be obtained or other indications for full-dose anticoagulation should be sought if possible, especially in individuals who are not in the ICU. This testing and other findings that support therapeutic-dose anticoagulation are discussed above. (See ‘Diagnosis of DVT or PE’ above.)

Indications for tPA — Tissue plasminogen activator (tPA) is appropriate for usual indications, unless there is a contraindication:

• Limb-threatening DVT – See “Catheter-directed thrombolytic therapy in deep venous thrombosis of the lower extremity: Patient selection and administration”.
• Massive PE – See “Approach to thrombolytic (fibrinolytic) therapy in acute pulmonary embolism: Patient selection and administration”.
• Acute stroke – See “Approach to reperfusion therapy for acute ischemic stroke”.
• Acute myocardial infarction – See “Acute ST-elevation myocardial infarction: The use of fibrinolytic therapy”.

Consultation with the pulmonary embolism response team (PERT) or stroke team in decision-making is advised if possible.

In contrast, we are not using tPA in individuals with nonspecific findings such as hypoxia or laboratory evidence of hypercoagulability.

A case series described administration of tPA to three individuals with ARDS associated with COVID-19 who did not have access to or were not eligible for other interventions such as ECMO [34]. One individual had transient improvement in laboratory parameters but ultimately died. The other two had improvement in laboratory parameters; clinical outcomes were not described

Outpatient thromboprophylaxis

Patients discharged from the hospital —Individuals with documented VTE require a minimum of three months of anticoagulation, as discussed separately. (See “Overview of the treatment of lower extremity deep vein thrombosis (DVT)”, section on ‘Duration of therapy’ and “Treatment, prognosis, and follow-up of acute pulmonary embolism in adults”.)

Some individuals who have not had a VTE may also warrant extended thromboprophylaxis following discharge from the hospital:

• We would be most likely to use post-discharge prophylactic anticoagulation in individuals with other risk factors for VTE such as immobilization, recent surgery, or trauma.
• We would use other criteria similar to those used in the APEX and MARINER trials, including immobility and older age. Most hospitalized patients with COVID-19 would meet these criteria.
• However, bleeding risk also needs to be incorporated into decision-making.
• Options for post-discharge prophylaxis include those used in clinical trials, such as rivaroxaban 10 mg daily for 31 to 39 days

This subject is discussed in more detail separately. (See “Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults”, section on ‘Duration of prophylaxis’.)

Patients not admitted to the hospital —Outpatient thromboprophylaxis may also be appropriate for selected individuals with COVID-19 who are not admitted to the hospital, especially those with other thrombotic risk factors such as prior VTE or recent surgery, trauma, or immobilization, noting that this practice is based on clinical judgment. There are no trials that address thromboprophylaxis in outpatients with COVID-19.

If thromboprophylaxis is used in an outpatient, we would use a regimen such as rivaroxaban 10 mg daily for 31 to 39 days

Treatment of bleeding —Bleeding does not appear to be a major manifestation of COVID-19. However, patients may have bleeding for other reasons, including trauma and/or treatment with anticoagulation. (See ‘Bleeding’ above.)

The approach to bleeding is similar to individuals without COVID-19 and may involve anticoagulant reversal and/or discontinuation, transfusions for thrombocytopenia or hypofibrinogenemia, or specific therapies such as factor replacement.

• Anticoagulant-associated bleeding – (See “Management of warfarin-associated bleeding or supratherapeutic INR” and “Management of bleeding in patients receiving direct oral anticoagulants” and “Reversal of anticoagulation in intracranial hemorrhage”.)
• Trauma coagulopathy – (See “Acute coagulopathy associated with trauma”.)
• An underlying bleeding disorder such as immune thrombocytopenia (ITP), hemophilia, or von Willebrand disease (VWD) – (See “Immune thrombocytopenia (ITP) in adults: Initial treatment and prognosis” and “Treatment of bleeding and perioperative management in hemophilia A and B” and “von Willebrand disease (VWD): Treatment of major bleeding and major surgery”.)

Antifibrinolytic agents (tranexamic acid, epsilon aminocaproic acid) are generally not used in patients with disseminated intravascular coagulation (DIC), due to the concern that they may tip the balance towards thrombosis. Thus, they should be avoided in patients in whom the COVID-19-associated hypercoagulable state is the predominant finding. (See ‘Distinction from DIC’ above and “Disseminated intravascular coagulation (DIC) in adults: Evaluation and management”, section on ‘Prevention/treatment of bleeding’.)

Fibrinogen is often increased in COVID-19, and supplementation with fibrinogen is not required unless there is bleeding that is attributable to hypofibrinogenemia or dysfibrinogenemia (fibrinogen activity level < 150 to 200 mg/dL). (See ‘Coagulation abnormalities’ above and “Disorders of fibrinogen”, section on ‘Treatment/prevention of bleeding’.)

Investigational therapies —A number of therapies for COVID-19 are under investigation, some of which may impact thrombotic risk. However, effects of these treatments on hemostasis in this patient population have not been well studied. (See “Coronavirus disease 2019 (COVID-19): Management in hospitalized adults”, section on ‘COVID-19-specific therapy’.)

Participation in clinical trials is encouraged in order to improve understanding of the most effective and safest means of preventing and treating thrombotic complications of COVID-19. Investigational therapies may be appropriate in life-threatening situations or as part of a clinical trial, and markedly increased D-dimer may be used as one criterion for identifying individuals with a worse prognosis.

Close monitoring for clinical signs of thrombosis or bleeding is advised in all individuals with COVID-19, with input from an individual with expertise in hemostasis and thrombosis in those with severe or unusual presentations.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See “Society guideline links: Coronavirus disease 2019 (COVID-19) – International and government guidelines for general care” and “Society guideline links: Coronavirus disease 2019 (COVID-19) – Guidelines for specialty care”.)

INFORMATION FOR PATIENTS —UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

• Basics topic (see “Patient education: Coronavirus disease 2019 (COVID-19) overview (The Basics)”)
• Society guidelines for patients (see “Society guideline links: Coronavirus disease 2019 (COVID-19) – Resources for patients”)

SUMMARY AND RECOMMENDATIONS

• Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state associated with acute inflammatory changes and laboratory findings that are distinct from acute disseminated intravascular coagulation (DIC), save for those with very severe disease. Fibrinogen and D-dimer are increased, with typically only modest prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT) and mild thrombocytosis or thrombocytopenia. The presence of a lupus anticoagulant (LA) is common in individuals with a prolonged aPTT. The pathogenesis of these abnormalities is incompletely understood, and there may be many contributing factors related to the acute inflammatory response to the disease. (See ‘Pathogenesis’ above.)
• The risk for venous thromboembolism (VTE) is markedly increased, especially in patients in the intensive care unit (ICU), with case series reporting prevalences of 25 to 43 percent in ICU patients, often despite prophylactic-dose anticoagulation. The risk for other thrombotic events (stroke, microvascular thrombosis) is less clear. (See ‘Clinical features’ above.)
• All patients admitted to the hospital for COVID-19 should have a baseline complete blood count (CBC) with platelet count, PT, aPTT, fibrinogen, and D-dimer. Repeat testing is done according to the patient’s clinical status. Outpatients do not require coagulation testing. The main purpose of this testing is to obtain prognostic information that may be used to inform level of care. (See ‘Routine testing (all patients)’ above.)
• Imaging studies are appropriate for suspected VTE if feasible. If standard diagnostic studies are not feasible, other options for determining the need for therapeutic-dose anticoagulation are available, as discussed above. Laboratory abnormalities that are not typical of COVID-19 should be further evaluated, as described above. (See ‘Role of additional testing’ above.)
• Management is challenging due to the acuity of the illness and a paucity of high-quality evidence regarding efficacy and safety of different approaches to prevent or treat thromboembolic complications of the disease. Our general approach, which is summarized in the table (table 1) and depicted in the algorithm (algorithm 1), includes:
  • All inpatients should receive thromboprophylaxis unless contraindicated. Low molecular weight (LMW) heparin is preferred, but unfractionated heparin can be used if LMW heparin is unavailable or if kidney function is severely impaired. Some institutional protocols include more aggressive anticoagulation with intermediate-dose or even therapeutic-dose anticoagulation for thromboprophylaxis. (See ‘Inpatient VTE prophylaxis’ above and ‘Possible/uncertain role of therapeutic-level anticoagulation for critically ill patients’ above.)
  • Bleeding is unusual but can occur. If it occurs, treatment is similar to non-COVID-19 patients and may include transfusions, anticoagulant reversal or discontinuation, or specific products for underlying bleeding disorders. (See ‘Treatment of bleeding’ above.)
  • Participation in clinical trials is encouraged in order to improve understanding of the most effective and safest means of preventing and treating thrombotic complications of COVID-19. Disease-specific therapies under investigation may impact thrombotic risk, but the effects of these treatments on hemostasis in this patient population have not been well documented. (See ‘Investigational therapies’ above.)

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Thromboelastography (TEG) tracing parameters