|
 
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| REVIEW ARTICLE |
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| Year : 2020 | Volume
: 4
| Issue : 2 | Page : 45-57 |
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COVID-19: What we all intensivists should know
Srikant Behera1, Simant Kumar Jha2, Nitesh Kumar Singh2, Gopi Chand Khilnani2, Anurag Mahajan2, Shiv Kumar2, Alok Kumar2, Sudhanshu Sant2
1 Department of Anesthesiology, Pain Medicine and Critical Care, All India Institute of Medical Sciences, New Delhi, India
2 Department of Critical Care Medicine, PSRI Hospital, New Delhi, India
| Date of Submission | 20-Apr-2020 |
| Date of Decision | 09-May-2020 |
| Date of Acceptance | 01-Jun-2020 |
| Date of Web Publication | 1-Jul-2020 |
Correspondence Address:
Simant Kumar Jha
Flat No. 503, T-11, Taksila Heights, Sector-37C, Gurgaon - 122 001, Haryana
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/sccj.sccj_16_20
Coronaviruses were identified as a viral family in the 1960s and are known to infect both humans and animals. Novel strain of coronavirus was identified when some cases of pneumonia began to arise in Wuhan province of China without any apparent cause. Later, this novel strain was called as coronavirus disease 2019 (COVID-19). Since 2002, coronavirus has been known to cause two widespread outbreaks in humans: severe acute respiratory syndrome coronavirus in 2003 and Middle East respiratory syndrome-CoV in 2012. The present crisis began to arise in late November of 2019 and then rapidly grew to become a pandemic. The present medical crisis resulted because high virulence of this virus simultaneously infected large number of patients. Although only a small proportion of COVID-19-infected patients require hospitalization, mortality is significantly higher in elderly and in patients with preexisting diseases. Patients with COVID-19 can present with an array of symptoms such as fever, dry cough, myalgia, vomiting, and loose motions. In later stages, it can progress to breathing difficulty. High virulence of COVID-19 puts the health-care workers (HCWs) at extreme risks of contacting this infection. COVID-19 is mainly diagnosed on the basis of clinical symptoms along with reverse-transcription polymerase chain reaction (RT-PCR). However, sensitivity of RT-PCR is 67% in the first 7 days and subsequently it falls to below 50% from the 2nd week onward. Total antibody has also been used to diagnose COVID-19. They have a lower sensitivity in initial days, but their sensitivity increases to 90% above from the 2nd week onward. Currently, management of COVID-19 is focused on supportive treatment as no drug till date has proven efficacy against novel coronavirus. Current trials have shown some promise with remdesivir. Although hydroxychloroquine rose to fame with earlier studies, its role in the management of COVID-19 was not established in further research. Current focus of the world to control this pandemic is on prevention through social distancing, use of face mask, regular hand washing, cough etiquette, and isolation of suspicious and confirmed cases. This article deals with nature, progression, and possible outcomes of this infection along with necessary steps that must be taken by a HCW to preventing himself from catching COVID-19.
Keywords: Coronavirus disease-2019, critical care unit, mechanical ventilation, novel coronavirus, severe acute respiratory syndrome coronavirus 2
How to cite this article:
Behera S, Jha SK, Singh NK, Khilnani GC, Mahajan A, Kumar S, Kumar A, Sant S. COVID-19: What we all intensivists should know. Saudi Crit Care J 2020;4:45-57 |
How to cite this URL:
Behera S, Jha SK, Singh NK, Khilnani GC, Mahajan A, Kumar S, Kumar A, Sant S. COVID-19: What we all intensivists should know. Saudi Crit Care J [serial online] 2020 [cited 2023 Mar 31];4:45-57. Available from: https://www.sccj-sa.org/text.asp?2020/4/2/45/288729 |
| Introduction | |  |
Coronavirus belongs to a family of RNA viruses that cause common cold, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome. At the end of 2019, a cluster of pneumonia cases were reported from Wuhan city in Hubei Province of China. The causative agent of this pneumonia case was identified to be a novel coronavirus. This is called as novel coronavirus as it is a new strain which was has not been identified in humans before. Over a short span of time, the disease spread rapidly, affecting a large number of countries throughout the world with tremendous increase in number of cases. In February 2020, the World Health Organization (WHO) designated the disease as coronavirus disease 2019 (COVID-19). The novel virus causing COVID-19 is designated as SARS coronavirus 2 (SARS-CoV-2; initially called as 2019-nCoV). As per initial reports from Wuhan, about 5% of COVID-19 patients develop severe disease requiring intensive care. Case-fatality from COVID-19 in Hubei Province (Wuhan) was 7-fold higher compared with those outside of the region (2.9% vs. 0.4%), emphasizing the importance of health system capacity in the care critically ill patients. The disease burden highlighted how quickly health systems can be challenged to provide adequate care.[1],[2],[3]
This article discusses details of COVID-19 disease and what we intensivists should know from epidemiology, pathophysiology, and evaluation to management and prevention of disease transmission, keeping in mind issues pertaining to critical care units. As the capacity for providing care for critically ill patients could be exceeded in many places, the utmost care should be taken to deliver the maximum level of care to the patients while ensuring the protection of health-care workers (HCWs).
| Epidemiology | | |
The COVID-19 is affecting almost all countries and territories except a few around the world with a tremendous increase in the number of cases as well as deaths. At the time of preparation of this article, the COVID-19 has affected 208 countries and territories around the world. The total number of cases is about 4.8 million with >3.2 lakhs deaths, and the numbers are increasing steadily.
The causative virus: Severe acute respiratory syndrome coronavirus 2
There are three important parameters to assess the risk posed by this dangerous novel coronavirus. These factors are transmission rate (Ro), case fatality rate (CFR), and asymptomatic transmission. Transmission rate (Ro):- The transmission rate of a virus is indicated by its reproductive number (Ro, pronounced R-naught or r-zero). Ro is defined as the average number of people to whom the virus is transmitted from a single infected person. An agent having a high Ro will propagate rapidly, whereas we need a Ro value less than one for disappearance of an outbreak. According to the estimation done by WHO (as on January 23rd 2020), Ro for SARS CoV 2 lies between 1.4 and 2.5. Preliminary studies had estimated Ro for this virus to be between 1.5 and 3.5. However, the recent studies have estimated a Ro for this virus ranges from 2.24 to 3.58 and from 3.6 to 4.0. Hence, if we compare the Ro value of SARS-CoV-2 with common flu (Ro = 1.3) and SARS (Ro = 2.0), this agent is having a considerably high Ro value. CFR of SARS-CoV-2:- CFR of a disease is defined as the percent of cases that result in death. The CFR of COVID-19 is estimated to be about 2%, as per the WHO press conference held on January 29, 2020, though a prior estimate had put that number at 3%. However, it is too early to pin point the CFR, without adequate knowledge about how many were infected. Hence, at present it difficult to put a percentage figure on the mortality rate of this pandemic. In addition, CFR may change at any time as the virus can mutate. If we compare with other coronavirus diseases, the CFR for SARS and MERS was 10% and 34%, respectively. Asymptomatic transmission of SARS-CoV-2: During the incubation period, the infected person does not display any symptom, but is able to transmit the infection/virus to other people. That means the infected person in spite of being asymptomatic remains contagious. This is called asymptomatic transmission.[4],[5],[6]
Route of transmission
Complete understanding regarding transmission of this novel coronavirus is still lacking. Understanding of the transmission risk is incomplete. The available literature suggests that, the outbreak was started by transmission of infection from animals to humans in the wet market of Wuhan, China. It appears that bats are the likely primary source; and the virus may be directly transmitted from bats or through an intermediate host. Also, there may be some other mechanisms for virus transmission, yet to be found out. However, as the outbreak progressed, person-to-person spread became the main mode of transmission. The transmission of virus is now believed to be via respiratory droplets and direct contact. Respiratory droplets are usually produced during coughing, sneezing, etc., Transmission via direct contact occurs when there is contact of mucus membranes such as mouth, eyes, and nose with virus-laden fomites. Furthermore, there is some possibility of aerosol/airborne transmission specifically during high-risk activities such as aerosol generating medical procedures. So, HCWs working in critical care units should take airborne precautions when handling COVID-19 patients. There is some evidence of excretion of virus particles in feces also, even after nasopharyngeal swab report being negative, but whether this leads to feco-oral transmission of the virus is yet to be worked out.[7],[8],[9]
World Health Organization risk assessment: Global emergency
The WHO declared the novel coronavirus outbreak a global public health emergency on January 30, 2020. This is based on the following data: (1) considering SARS, a disease caused by a coronavirus that originated from Beijing, China, spread to 29 countries, infecting 8096 people which lead to 774 deaths with a fatality rate of 9.6% (November 2002 to July 2003). The SARS ended up infecting 5237 people in mainland China. This novel coronavirus surpassed SARS when Chinese officials confirmed 5974 cases of the novel coronavirus (2019-nCoV) on January 29, 2020. Also, 1 day later, on January 30, 2020, number of cases due to this novel coronavirus surpassed the total number of SARS cases worldwide (8096) as per final count in 2003.[2] An estimated 290,000–650,000 people die from complications of seasonal influenza (flu) virus diseases in the world to every year. This corresponds to 795–1781 deaths per day due to the seasonal flu.[3] Similarly, MERS (in 2012) caused by another coronavirus, infected 2494 cases which lead to death of 858 people with A fatality rate of 34.4%.[10]
| Pathophysiology | | |
The SARS-CoV-2 is an enveloped, positive-stranded RNA virus. Pathophysiology and virulence mechanisms of SARS-CoV-2 are dependent on its nonstructural as well as structural proteins. It is found that nonstructural proteins block the host innate immune response and leads to disease. Similarly, structural proteins including the envelope also have a crucial role in disease pathogenesis as it promotes viral assembly and release. Spike structured transmembrane glycoprotein are expressed on the surface of coronaviruses which help in attachment of the virus to the target cells and subsequent entry of the virus to host cells. These viruses have high affinity for human angiotensin-converting enzyme 2 (ACE2) receptors. The virus is attached to target cells via binding to ACE2 receptors and uses this receptor as an entry pathway to invade human cells. ACE2 is expressed predominantly on type II pneumocytes but also on upper respiratory tract epithelial cells, small intestine enterocytes and vascular endothelium. Once the virus is inside the host cell, replication of viral RNA occurs by utilizing RNA-dependent RNA polymerase. Whatever data are available, it shows that the viral infection leads to excessive immune reaction in the host which is called as cytokine storm. This cytokine storm leads to an acute systemic inflammatory syndrome, which is characterized by fever, extensive tissue damage, and organ failure. Another possible mechanism of hypoxic respiratory failure is infection-induced endothelial dysfunction, increased thrombin formation, and decreased fibrinolysis, leading to hypercoagulable state and thrombosis. This results in occlusion of pulmonary vasculature and leads to hypoxic respiratory failure. However, exact pathophysiology is yet to be described.[11],[12],[13]
A three-stage classification of COVID-19 has been described by Siddiqu and Mehra with an increasing severity. Stage 1: This is the stage of early and mild infection. In this stage, virus multiplies in the host cells primarily involving the respiratory system. Here, there are often nonspecific symptoms. Stage 2: This is the stage of moderate disease with viral multiplication and inflammation localized to respiratory system. There are symptoms of pulmonary involvement with or without hypoxia. Here, markers of systemic inflammation are raised but not so high. Stage 3: This is the most severe disease stage with features of extrapulmonary systemic involvement features. There is a marked elevation in systemic inflammatory markers. In this stage, there are features of multiorgan failure.[14]
Incubation period
Incubation period of COVID-19 ranges from as few as 2 days to 14 days with a median of 4–5 days that means it may take up to 14 days from infection to manifestation of symptoms. During this period, the infected person although contagious remains asymptomatic. In about three-fourth of patients, symptoms develop between 2 and 7 days after infection. But, there are few reports of even longer incubation period.[15]
Asymptomatic infections
The true incidence is not known; about 1% infections are thought to be asymptomatic. However, a modeling study estimated that about 18% of infections are asymptomatic cases. Although they are asymptomatic, still these patients may have laboratory and radiographic changes.[2]
| Clinical Features | | |
The common symptoms are fever, dry cough, breathlessness, anosmia, taste disturbances, and sputum production. Although fever is the most common presenting symptom, its incidence varies. It may not be a universal finding or may present as very low-grade fever (temperature <100.4°F/38°C). Breathlessness tends to occur around day 6 of illness and there may be severe hypoxemia without breathlessness(silent hypoxia). Olfactory and/or taste disturbance is present in approximately one-third of patients. Other less common symptoms are headache, sore throat, rhinorrhea, myalgia, fatigue, anorexia, gastrointestinal symptoms (e.g., nausea and diarrhea) and features of CNS involvement (e.g., meningitis). Although the spectrum of COVID-19 ranges from self-limiting respiratory illness to severe acute respiratory distress syndrome (ARDS) and multiorgan failure, most of the infections are not severe. Mild disease with (no or mild pneumonia) is the most common presentation in about 80% of cases. Similarly, severe disease with dyspnea, hypoxia, or >50% lung involvement on imaging within 24–48 h occurs in about 15% of cases. Critical disease with one or more organ failure occurs in about 5% cases. Majority of cases (80%) have mild diseases and usually recover in 7 days. About 20% cases require hospitalization, mostly due to respiratory distress. A small proportion of cases (5%) develop life-threatening disease and organ failures requiring intensive care unit (ICU) admission and organ supportive therapy including mechanical ventilation, vasopressor support, and renal replacement therapy. Due to the evidence of virus infection and respiratory dysfunction, many patients with severe COVID-19 meet the Third International Consensus Definitions for Sepsis (sepsis-3).[6],[16],[17],[18],[19],[20],[21]
Factors affecting diseases severity: Age, sex, and comorbid conditions
Age is an important risk factor for COVID-19. From available literature, it is evident that though people of all ages can be infected, elderly (age >60 years) patients develop more severe disease. Also, the rate of hospital admission of patients with COVID-19 increased with increasing age. Less number of children developed severe or critical disease. As far as gender is concerned, males are affected more than females. People with preexisting medical conditions such as cardiovascular diseases, diabetes hypertension, chronic respiratory disease, chronic kidney disease, chronic liver disease, malignancy, and immunocompromised status are at risk of developing severe disease.[2],[15],[22]
Complications
The common complications of COVID-19 are ARDS (33%), acute cardiac injury (13%), acute kidney injury (AKI) (8%), and shock (6%). The other complications are elevated liver enzymes, sepsis, arrhythmia, disseminated intravascular coagulation (DIC), cytokine storm, hemophagocytic lymphohistiocytosis, secondary bacterial infection or coinfection, rhabdomyolysis, and multiorgan failure. In patients admitted to ICU, the most common complication was acute hypoxemic respiratory failure with or without hypercapnia due to ARDS in the tune of 60%–70%. Similarly, other common complication in ICU patients are shock (30%), myocardial dysfunction (20%–30%), and AKI (10%–30%).[23],[24]
Acute respiratory distress syndrome
ARDS is the most common cause of ICU admission in COVID-19 patients. In patients admitted to ICU, about 60%–70% cases had ARDS. In COVID ARDS patients, lung compliance is high compared with other etiologies of ARDS and risk of barotrauma is less in comparison to other ARDS cases.[25] According to Gattinoni et al., COVID-19 patients have two phenotypes of pneumonia: L phenotype and H phenotype. In L-phenotype, there is early presentation with typical features of viral pneumonitis. It is associated with type 1 respiratory failure, low elastance/high compliance, low V/Q matching and poor response to recruitment. In H phenotype, there are features of classic ARDS with type 1 and/or 2 respiratory failure. This group of patients are characterized by high elastance/low compliance, high V/Q mismatching and good response to recruitment.[26]
Acute cardiac injury/cardiomyopathy
It occurs in about 33% of cases, but it is not known whether this is due to direct cardiac injury caused by SARS-CoV-2 infection or as a result of overwhelming critical illness.[27]
Acute kidney injury
AKI is one of the common complications of COVID-19 affecting about 0.5%–7% of all cases and about 2.9%–23% cases of ICU patients. Though the exact mechanism of AKI in COVID patients is not known, it is postulated that cytopathic effect of SARS-CoV-2 on podocytes and proximal tubular cells is responsible for it. Almost 50% cases of AKI require renal replacement therapy (RRT).[27],[28]
Coagulopathy in coronavirus disease 2019
COVID-19 patients may have various coagulation abnormalities, hypercoagulable state being more common. There is an increased risk of deep vein thrombosis, venous thromboembolism, as well as pulmonary embolism. DIC has been reported in some severe disease. There is also increased risk of clotting in the extracorporeal circuit (continuous renal RRT and extracorporeal membrane oxygenation circuit). These thrombotic complications are common in critically ill COVID-19 patients, even with the use of prophylactic/therapeutic anticoagulation. The exact pathogenesis of hypercoagulability in COVID-19 is not completely understood, but it may be due to combination of endothelial cells injury from SARS-CoV-2 virus or cytokines, venous stasis in immobilization from critical illness, and increased expression of prothrombotic factors (e.g., factor VIII and fibrinogen) in COVID-19. In some cases, COVID-19 has laboratory findings similar to DIC (e.g., marked increase in D-dimer and thrombocytopenia); however, there is typical hypercoagulable features including high fibrinogen and high factor VIII activity which are not suggestive of any consumption of coagulation factors as in DIC. The common predisposing factors for thromboembolic phenomenon are male gender, obesity, presence of comorbidities (e.g., cardiovascular disease, hypertension, and diabetes mellitus). Apart from venous thromboembolism, there are also some reports of arterial thrombosis leading to acute limb ischemia, acute ischemic stroke, acute myocardial infarction, etc., There is also evidence of micro vascular thrombosis in the lungs and kidney. Similarly, at the other end of coagulopathy, bleeding manifestations can happen in COVID-19, but are less common than thrombosis. Bleeding usually occurs in the setting of anticoagulation and may manifests as intracranial hemorrhage, hemorrhagic complications related to ECMO apart from other minor bleeds. Similarly, DIC is significantly higher in nonsurvivors of COVID-19 (around 70%). There is significant rise in D-dimer, fibrin degradation products, Prothrombin Time (PT) and activated partial thromboplastin time (APTT) in nonsurvivors as compared to survivors. Severe COVID-19 is commonly associated with coagulopathy and DIC and could be one of the major causes of deaths.[29],[30],[31],[32]
Liver injury
Liver injury in COVID patients usually manifests as abnormal rise in alanine transaminase/aspartate transaminase (ALT/AST) levels with a mild rise in bilirubin. The albumin may be decreased, but only in severe cases. The proposed mechanism of liver injury is due to due to damage of the bile duct cells (bile ducts express ACE receptors) as well from the cytokine storm.[33]
Pulmonary embolism
Many case reports have shown presence of pulmonary embolism in patients admitted with COVID-19. Hence, it is of utmost importance to follow prophylactic measures for prevention of venous thromboembolism.[34],[35]
Neurological complications of coronavirus disease 2019
Neurological manifestations are common in COVID-19 occurring in about one third of patients, and these are more common in severe disease. The common neurological features are agitation, inattention, confusion, disorientation, delirium, altered mental status, encephalopathy, hyperreflexia, ankle clonus, bilateral extensor plantar reflexes, etc., In COVID-19 patients with ARDS, delirium/encephalopathy is very common. Other features of COVID-19 involving neurological system is acute ischemic stroke, encephalitis and Guillain-Barré–Barre Syndrome (GBS). The GBS could be an axonal variant or due to demyelination. The exact pathophysiology of neurological manifestation in COVID-19 patients is not clear, but may be directly related to SARS-CoV-2 virus infection or due to effects of cytokine storm, critical illness, and or medications effects. The radiological features of CNS involvement are acute/subacute infarction, bilateral frontotemporal hypoperfusion, leptomeningeal enhancement, etc., Cerebrospinal fluid (CSF) analysis in COVID-19 patients with neurological features shows cell count within normal limit with rise in protein level. Similarly, there is no evidence of presence of the virus in CSF by PCR assay.[36],[37],[38]
| Evaluation and Diagnosis | | |
The diagnosis of COVID-19 is confirmed by real-time RT-PCR; however epidemiological, demographic, clinical, and radiological features as well as laboratory data need to be well evaluated considering the pandemic situation. Though laboratory testing for SARS-CoV-2 must follow Centers for Disease Control and Prevention (CDC) recommendation, prioritization should be given to symptomatic individuals with higher probability of poor outcomes, e.g., age ≥60 years, chronic medical condition, immune compromising conditions, and those with high exposure risk, e.g., recent travel to specific locations, contact with patients with COVID-19, or being a HCW. WCWs working in critical care units are always at risk for high inoculums of exposure.[6]
Sample collection and laboratory testing
The CDC recommends collection of a nasopharyngeal swab specimen to test for SARS-CoV-2. Sputum should only be collected from patients with productive cough, but induction of sputum is not indicated. Lower respiratory tract samples (endotracheal aspirates in preference to bronchoalveolar lavage [BAL] or bronchial wash) should be taken for diagnostic testing in intubated patients with suspicion of COVID-19. During sample collection in critical care units, HCWs should take all standard aerosol precautions for both droplet as well as airborne spread of virus. SARS-CoV-2 RNA is detected by real time RT-PCR. A positive test for SARS-CoV-2 confirms the diagnosis of COVID-19. If an initial test turns to be negative with high index suspicion for COVID-19, re-sampling and testing from multiple respiratory tract sites is recommended. At present, there is limited literature on accuracy and predictive values of SARS-CoV-2 testing. In a study done by Wang et al. in COVID-19 pneumonia patients; it was found that highest positive rates for SARS-CoV-2 was from BAL fluid specimens (93%) followed by sputum (72%t), and nasal swabs (63%) whereas pharyngeal swabs and stool sample have low yield (32% and 29%, respectively). Similarly only 1% of blood sample was positive for SARS-CoV-2 and all urine samples were negative. Hence, it may be concluded that though SARS-CoV-2 may be detected in several specimens, BAL, nasal swab and sputum may be given priority for detection of virus RNA. All due precautions should be taken by HCWs while collecting sample from suspected COVID-19 patients as it may lead to aerosol generation. Viral culture is not recommended for patient with suspected or documented COVID-19 for safety reasons.[6],[39],[40]
Coronavirus disease point of care test
There are many evolving serological tests which detect IgM and IgG antibodies against SARS-CoV-2 in serum or blood. This point of care tests just give evidence of recent viral infection, but do not detect the virus per se. There is also possibility of cross reactivity with other viruses. Another drawback of these tests is that it takes around 10 days for development of antibody which results in missing early cases.[41]
Radiological evaluation
Chest radiology of COVID-19 patients is nonspecific and findings are similar to other viral pneumonia. Chest imaging in these patients most commonly shows bilateral pneumonia or unilateral pneumonic infiltrates. The common chest computed tomography (CT) abnormalities are extensive mottling and ground-glass opacities with or without consolidative abnormalities, reticular pattern, crazy paving pattern. These are more likely to be bilateral, with a peripheral distribution, and involve the lower lobes. Less common findings include pleural thickening, fibrosis, nodules, pleural effusion, and lymphadenopathy. The chest CT has a high sensitivity, taking the RT-PCR tests as a reference, but has a low specificity which may be due to other etiologies causing similar CT findings. An important point to note is that, in COVID-19 patients, chest CT abnormalities has been identified prior to the development of symptoms and even prior to the detection of viral RNA from upper respiratory specimens. So, in critical care units, due consideration should be given for CT chest of suspected COVID-19 patients.[6],[42],[43],[44]
Lung ultrasound
Role of ultrasound in evaluation of COVID-19 patients is still to be defined. Yet, the common findings are irregular pleural line with small sub-pleural consolidation, B-lines (either irregular or confluent) and pathological areas are separated by uninvolved areas bilaterally.[45]
Other laboratory investigations
There are many laboratory abnormalities described in COVID-19 patients.[6] These are:
- Full blood count: Lymphocytopenia is characteristic and some patients may also show thrombocytopenia
- Coagulation studies: Increased PT/APTT and features of DIC
- Raised blood glucose level
- Liver Function: Elevated ALT/AST/bilirubin level
- Raised lactate dehydrogenase (LDH)
- Elevated acute phase reactants: Erythrocycte sedimentation rate, C-reactive protein (CRP), ferritin, D-dimer, troponin, procalcitonin
- Decreased albumin level.
| Management of Coronavirus Disease 2019 | | |
Initial management should consist of early recognition of suspected cases, immediate isolation, and institution of infection control measures followed by notification. When a patient presents with acute respiratory illness, mild or severe pneumonia, ARDS, sepsis, and or septic shock; COVID 19 should be considered as a possible aetiology keeping in mind the pandemic scenario. Management of patients with mild disease is focused on isolation at home, prevention of transmission to others, symptomatic treatment, self-monitoring of any clinical deterioration and hospitalization, if needed. Patients with moderate to severe disease (having any one of-respiratory rate [RR] >24/min, Spo2 <94% on room air, confusion/drowsiness/altered mental status, shock) should be hospitalized. The patients with severe disease (e.g., RR >30/min and Spo2 <90% on room air) or requiring mechanical ventilation and or other organ support are to be admitted to ICU. Evidences in hand shows that about 20% cases develop hypoxic respiratory failure, 14% requiring oxygen therapy, 3%–6% become critically ill, and about 5% COVID patients require mechanical ventilation. All patients admitted to ICU should receive comprehensive supportive ICU care (FAST HUG BIDS) as per existing guidelines.[6],[39],[46]
Infection control
Infection control is the key component in management of COVID-19 patients and should be given utmost importance while caring for these patients. HCWs involved in performing aerosol-generating procedures should use fitted respirator masks along with other personal protective equipment (PPE). Similarly, HCWs involved in the usual care of nonventilated patients and performing nonaerosol-generating procedures on mechanically ventilated patients can use standard surgical mask in addition to other PPE. Endotracheal intubation should be performed by the most experienced person in order to minimize the number of attempts as well as the risk of transmission. The use of video laryngoscope is preferred. Aerosol-generating procedures should be performed in a negative pressure room. If negative pressure chamber is not available, high-efficiency particulate air (HEPA) filters can be used to minimize SARS-CoV-2 infection risk to HCWs.[39]
Role of high-efficiency particulate air filters
The possibility of infection from SARS-CoV-2 increases for HCW from the air circulated in the patients' environment. COVID-19 patients should be managed in negative pressure room, to prevent spread of infection. In the absence of negative pressure chambers, if we can decrease the viral load in the environment by filtering the air around a patient, it will substantially decrease the virus spread. Hence, air purifiers (HEPA) can be used in the patient surroundings to reduce the virus load. This can reduce the risk of infection among HCW because of inadvertent breach in PPE. HEPA filters are capable of capturing particles of droplet size (nearly 5 μ), and are capable of decreasing contamination in patient care area by cycling air through a HEPA by trapping virus particles before they get attached to a surface. These filters can be used in patients rooms, at the site of any aerosol-generating procedure, hospital environments, etc.[47]
Use of intubation box to aid in infection control
Many HCWs are getting infected and even losing battle against COVID-19 in this pandemic. Being an aerosol generating procedure, the risk of exposure to HCWs fromSARS-CoV-2 during intubation of COVID-19 patients is significant. Hence, it is important to ensure safety of HCWs dealing with the COVID-19. To enhance the safety of HCWs, we can use protective novel barrier enclosures (intubation box) during endotracheal intubation along with use of PPE. The intubation box is made up of transparent plastic cube and having two circular ports on head end. It covers patient's head and the two circular ports allow the HCW to perform the airway procedure. Hence, the intubation box may play a major role in reducing droplet exposure to the HCW handling airway. However, as there is limited hand movement of the operator handling airway, it needs adequate training before using intubation box in patient care and may have to abandon use of the box in case of difficult airway. Furthermore, such novel devices are yet to be available in market.[48]
Role of viral filters
There are three types of filters usually used i.e., mechanical filters, electrostatic filters, and heat and moisture exchange filters (HMEFs). The mechanical filter is made from a sheet of thick hydrophobic filter material, have small channels and depth to traps particles, having viral filtration efficiency (VFE) >99.99%, and its VFE is not degraded by exposure to humidity. The electrostatic filter is composed of a thinner sheet of filter material which is loosely woven, having electrostatic charge to attract and trap particles and its VFE is nearly 99.99%, but efficacy declines when exposes to humidity. HMEF is a combination of a heat and humidity exchanger and a filter in the same unit. These filters when used decrease the risk of viral exposure to HCWs.[49],[50]
Respiratory failure and oxygenation/ventilatory strategy
Acute hypoxemic respiratory failure is the most common complication of COVID-19. Supplemental oxygen therapy is given to a target of SpO2 >94% but not higher than 96%. He/she must be monitored for severe hypoxemic respiratory failure. In case a patient does not respond to conventional oxygen therapy, high-flow nasal cannula (HFNC) is preferred over NIPPV. If HFNC is not available and there is no urgent indication for endotracheal intubation, a trial of NIPPV may be given with close monitoring, and early intubation is indicated if worsening occurs. But, the safety of HFNC or NIPPV is uncertain, and they should be considered aerosol-generating procedures that warrant specific isolation precautions. At present, there is no recommendation regarding the use of helmet NIPPV. Some patients who develop ARDS, warrant intubation with mechanical ventilation and should be managed with lung protective ventilation strategy (low tidal volume: 4–8 mL/kg of predicted body weight, plateau pressures: <30 cm H2O). In patients with moderate to severe ARDS, a higher positive end-expiratory pressure (PEEP) strategy should be preferred (i.e., PEEP >10 cm H2O) and patients should be monitored for barotraumas. Deep sedation and muscle relaxants may be used as appropriate in patients who are difficult to ventilate. Recruitment maneuvers including prone ventilation may be considered, but recommendation is against using staircase (incremental PEEP) recruitment maneuvers. In severe ARDS COVID-19 patients having hypoxemia in spite of optimal ventilation strategies and use of other rescue strategies, a trial of inhaled pulmonary vasodilator therapy may be tried (but the recommendation is against the routine use of inhaled nitric oxide) and if there is no rapid improvement in oxygenation, the treatment should be weaned off. V-V ECMO may be performed on a limited scale in some centers, but no data is currently available regarding clinical outcomes. A fluid-restrictive strategy is appropriate among patients who are not in shock; diuretic therapy may be considered to remove excessive fluid and aim for a negative balance. Whatever evidence available shows, majority of the patients (75%) require supplemental oxygen therapy, whereas few patients (4%) needed NIV and or invasive mechanical ventilation.[39]
Ventilatory strategy based on L versus H phenotype
As we have discussed above, the available evidence shows that, the pneumonia in COVID-19 patients may be classified into two phenotypes as per ventilatory strategy is concerned. This classification is preliminary, and hence management should be optimized for each individual patient in compliance with the established standard guidelines for the management of ARDS. L-PHENOTYPE: It is typical presentation of viral pneumonitis in early stage with features of type 1 respiratory failure and low elastance(i.e., high compliance), low V/Q matching (possibly due to abnormal hypoxic vasoconstriction), low recruitability (poor response to PEEP and PRONING). H-phenotype: It is typical presentation of later stage of viral pneumonia with features of classic ARDS (type 1 and/or 2 respiratory failure), and potentially having coexisting lung disease, complications such as ventilator-induced lung injury from noninvasive ventilation. In H-type, there is high elastance (i.e., low compliance), high V/Q matching and high chance of recruitability (i.e., response to PEEP and proning). So, the pathophysiology of two phenotypes of respiratory involvement in COVID-19 being different, the respiratory support provided to them must be different. In L-type patients, the first step in reversing hypoxemia is through increasing FiO2 if they are not dyspneic and to use noninvasive strategies for oxygenation such as HFNC, CPAP, or NIV when dyspneic. When intubated, L type patients require low PEEP (8–10 cmH2O), and if hypercapnic, can be ventilated with higher tidal volumes (up to 8–9 ml/kg), as there is less chance of VILI due to better compliance. Recruitment maneuvers including prone positioning are less effective in these patients. H type patients are having poor compliance, are to be treated like severe ARDS, with higher PEEP and recruitment maneuvers including prone positioning. Hence, we can say in L-phenotype, mechanical ventilation may be avoided with appropriate oxygen therapy, whereas in H-phenotype, it may be better to use protective lung ventilation strategy with open lung approach.[26]
Role of awake proning in oxygenation
According to some reports, prone position improves oxygenation in nonintubated patients receiving O2 supplementation for maintaining required oxygen saturation. This is based on proven efficacy of prone position in ventilating severe ARDS patients and some reports which showed improvement of oxygenation in COVID-19 patients without having severe ARDS. Proning helps in improvement of oxygenation by recruiting posterior portions of the lungs as well as by increasing perfusion to oxygenated lung segments. Better response to prone positioning in COVID-19 may also be due to preserved lung compliance in initial stage compared with ARDS from other causes. There are increasing recommendations from various experts regarding the benefits of proning in awake hypoxemic COVID-19 patients.[51],[52]
In intubated patients, all precautions (e.g., maintenance of appropriate ETT cuff pressure, tight circuit connections, and use of closed suction) to reduce risk of aerosol generation must be taken. As far as the weaning and extubation is concerned, there is no consensus regarding how to deal with these issues. Most intubated patients are ready for extubation while still being infective. As extubation is an aerosol generating procedure, due care must be taken while performing it. Also timing and criteria for tracheostomy in these patients has not been well defined.[6]
Septic shock
If there is presence of shock, it should be managed as per standard guidelines. Dynamic parameters should be used for assessment, a conservative fluid strategy is to be followed (in absence of tissue hypoperfusion), crystalloids should be preferred over colloids and buffered/balanced crystalloids over unbalanced crystalloids. A target MAP of 60–65 mmHg (rather than higher) and lactate <2 mmol/L should be maintained. Similarly, recommendation is against use of hydroxyethyl starches; gelatins, dextran should not be used and albumin should not be used for initial resuscitation. Norepinephrine (NE) is to be used as the first-line vasoactive agent and if target MAP cannot be achieved by NE alone, vasopressin may be added as a second-line agent. If NE is not available, then either vasopressin or epinephrine may be used as the first-line vasoactive agent. Recommendation is against the use of dopamine. Dobutamine can be added in case there is persistent hypoperfusion despite adequate fluid resuscitation and NE. In patients with refractory shock, low-dose corticosteroid therapy (200 mg/day) may be used (administered either as an infusion or intermittent doses) over no corticosteroid.[39]
Coagulopathy in coronavirus disease 2019 and controversy
Though hypercoagulability adversely affects the prognosis in COVID-19, its management is very challenging and at present we do not have robust evidence to support anticoagulation therapy beyond standard indications. There are also a few reports of bleeding complications in severe disease as well as from antithrombotic therapies. All COVID-19 patients requiring ICU admission should receive thromboprophylaxis as per standard guidelines unless otherwise contraindicated. However, as we have discussed above, some patients on prophylactic dose of anticoagulation still develop VTE and may need therapeutic dosing. Apart from standard indications of therapeutic anticoagulation as in Deep Vein Thrombosis (DVT)/Venous Thromboembolism (VTE), it may be indicated in conditions such as rapid deterioration in respiratory status not explained by ARDS, fluid overload or heart failure, especially when there is high fibrinogen and/or D-dimer value. Similarly, we can consider for therapeutic anticoagulation in sudden unexplained deterioration in hemodynamics (acute cor pulmonale) and clotting of vascular devices (e.g., venous catheters, arterial lines, and hemodialysis device). Though some centers advocate therapeutic anticoagulation, at present, we do not have adequate data to compare different levels of anticoagulation (e.g., prophylactic, therapeutic, or something intermediate) in COVID-19 patients, and so, level of anticoagulation should be advised on case to case basis.[53]
Multiorgan failure
Multiorgan failure has been frequently reported in patients with COVID-19 disease. ARDS, AKI and septic shock are the common complications. RRT may be needed for AKI. Myocarditis, hepatic involvement, and other organ dysfunction may be there. Supportive care should be provided to each and every failing organ and these patients must be monitored vigilantly for any signs of clinical deterioration. Additionally, the presence of comorbidities should be monitored. Most common causes of death are ARDS and multi-organ failure.[6],[39]
Cardiopulmonary resuscitation CPR in coronavirus disease 2019 patients (AHA guideline)
Cardiac arrest in COVID-19 patients may result from hypoxia, myocardial injury, ventricular arrhythmias, shock, etc., CPR is critical component of health care and is a serious concern in this COVID-19 pandemic scenario as it increases the risk of exposure for rescuers. So, utmost care should be taken while performing CPR in order to minimize exposure to rescuers. CPR is an aerosol generating procedure; all rescuers should be well equipped with PPE to protect from both airborne and droplet particles. COVID status of the patient should be clearly communicated to all HCW concerned. The salient points in CPR are: (1) number of rescuers should be limited as only required; (2) automatic CPR machines to be considered if available; (3) in nonintubated patients, consider passive oxygenation with nonrebreathing face mask covered by a surgical mask; supraglottic airway or bag-mask device with a HEPA filter and tight seal; (4) if possible, bag-mask ventilation should be avoided; (5) if intubation is required; it should be done with a cuffed tube, by the most experienced team member to increase the first-pass success rate and with use of video laryngoscope to reduce aerosol exposure; (6) in intubated patients, use HEPA filter in the path of exhaled gas; and (7) use close suction catheter. As CPR is a high-intensity team effort and outcome of cardiac arrest in COVID-19 is not yet known; it is important to consider various factors affecting mortality such as increasing age, comorbidities, and severity of illness to balance between the likelihood of success and risk to rescuers and in such cases CPR should be avoided. As of now, there is limited data to support extracorporeal cardiopulmonary resuscitation for COVID-19 patients.[54]
Miscellaneous
In mechanically ventilated COVID-19 patients with respiratory failure, empiric antimicrobials/antibacterial agents should be used as per standard guidelines. Blood cultures for bacteria that cause pneumonia and sepsis should be collected before antimicrobial therapy. However, it must be ensured that the microbial therapy should not be delayed for sample collection. Acetaminophen/paracetamol is used for temperature control in patients having fever.[39]
Reporting of the cases
It is mandatory that every case, whether it be a suspected or positive case should be reported to the department of public health. The details of the reporting process can be found here – https://www.docplexus.com/#/app/posts/addb61f0-916a-4df2-9ced-5ceab1999d36.
| Specific Therapy | | |
Intense research is being done to find out a specific treatment to deal with this deadly disease. But, till date, there is no robust evidence available to support use of any specific agent to treat COVID-19, though several agents are being investigated for their effectiveness against SARS-CoV-2. So the use of specific agents in COVID-19 is limited to clinical trials or off label use.
Antiviral therapy under investigation
Though several antiviral drugs are being tried as part of the treatment strategy in COVID-19, there is no robust data to support the use of specific antiviral therapy.
Remdesivir
A novel nucleotide analogue, found to be active against coronaviruses including SARS-CoV-2 and MERS-CoV in vitro. Several randomized controlled studies are currently in progress and its clinical efficacy yet to be found out.[55]
Lopinavir-ritonavir
This protease receptor inhibitor drug combination commonly used in retroviral infection has been demonstrated to have activity against SARS-CoV. In spite of several reports on use and effectiveness of this combination in COVID-19 patients, a recently published randomized controlled trial by Cao et al. concluded that there is no improvement in clinical outcomes or reduction in viral shedding.[56]
Chloroquine/hydroxychloroquine
Both chloroquine and hydroxychloroquine have antiviral activity against SARS-CoV-2, though hydroxychloroquine appears to be more effective. At present, there is no robust data to recommend routine use of these agents in COVID-19 patients. Still, clinicians in some part of the world are using hydroxychloroquine in hospitalized patients with severe disease. Although optimal dosing schedule is not known, the FDA suggests hydroxychloroquine in a dose of 800 mg on day 1 followed by 400 mg daily and chloroquine 1 g on day 1 then 500 mg daily to be administered; and the treatment duration is 4-7 days depending on the clinical response. While using these agents, it is important to keep in mind the possible side effects (e.g. QTc prolongation and toxic retinopathy) and drug interactions. At present, several clinical trials are in progress to find out their effect on clinical outcomes in COVID-19 disease.[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58] A randomized trial of mild COVID 19 patients with pneumonia, but without hypoxia showed that adding hydroxychloroquine as a standard care resulted in early clinical improvement and had less likelihood of disease progression.[59] As of now, use of chloroquine is included in treatment guidelines of China. Similarly, hydroxychloroquine use is suggested in the ICMR (Indian) guidelines for the treatment of severe COVID-19 patients requiring mechanical ventilation.
Tocilizumab
As IL-6 is involved in the intensive inflammatory response occurring in the lungs of critically ill patients with COVID-19 disease, tocilizumab, being an IL-6 inhibitor, may have a beneficial effect among COVID-19 patients. Its role is being currently evaluated in a clinical trial.[60]
Ivermectin
Ivermectin is an antiparasitic drug having broad spectrum antiviral activity with multiple mechanisms of action. It is likely that inhibitory activity of ivermectin on nuclear transport is responsible for its effectiveness against SARS-CoV-2. In a study done by Caly et al., it was found that a single treatment with ivermectin was able to drastically reduce the virus load (5000 fold) at 48 h in cell culture. Hence, further clinical evaluation is needed to establish its possible benefits in COVID-19 patients.[61]
Convalescent plasma
The convalescent plasma is the plasma collected from a patient after recovering from an infection. The antibody present in convalescent plasma may help in fighting against the infection. At present, the role of convalescent plasma in treating COVID-19 patients is not clear. Surviving sepsis campaign guidelines on management of critically ill adults with COVID-19 is silent about it and does not make any recommendation. In a recently published case series (n=5) by Shen et al. of critically ill COVID 19 patients with persistent high viral load in spite of receiving antiviral treatment, and having ARDS requiring mechanical ventilation with were treated with convalescent plasma containing neutralizing antibody. This study reported that there is decrease in nasopharyngeal viral load, decrease in disease severity score, improvement in oxygenation, and better outcome in terms of weaning from ventilator and hospital discharge. Though from the limited sample size of 5 patients, it not possible to comment on definite role of convalescent plasma in treating critically ill COVID-19 patients, but this observation may help us in further studies keeping in mind all these aspects. Also, another important issue is finding an appropriate donor and overcoming logistic barriers to test neutralizing activity of the plasma.[62]
Intravenous immunoglobulin
Human polyclonal immunoglobulin has been evaluated in preclinical and phase 1 clinical trial. It is found to be effective in virus clearance in preclinical trial and evaluated to be safe in phase 1 clinical trial.[63]
Corticosteroids
As per our previous experience in MERS and SARS, corticosteroid use was associated with higher mortality, delay in viral clearance, and increased harmful effects. It is likely that the impact of corticosteroids in COVID-19 disease may also be similar. Hence, systemic corticosteroids are not recommended in COVID-19 patients except in mechanically ventilated patients with respiratory failure and ARDS (weak recommendation).[39],[64]
Regarding the management of critically ill COVID 19 patients, society of critical care medicine guidelines recommends that intravenous immunoglobulin, convalescent plasma, Lopinavir Ritonavir not to be used (weak recommendation) for treatment of COVID-19. Similarly, there is insufficient evidence on the use of other antiviral agents in COVID-19. Similarly, no recommendation can be made for use of rIFs, chloroquine, hydroxychloroquine, and tocilizumab to treat these patients.[39]
| Factors Associated With Poor Outcome | | |
The most important factors associated with poor outcomes are increased age, presence of comorbid conditions and increased severity of illness. Evidence shows that elderly people develop more severe disease and are more likely to succumb to the disease. There is increased risk of mortality with increasing number of comorbidities. A study from Italy by Onder et al. showed that patients with no comorbidities had <1% mortality whereas patients with one or two comorbidities had about 25% mortality and patients with three or more comorbidities had mortality rate of nearly 50%. The patients with more severe disease and high disease severity score (e.g., high SOFA score) are at risk of increased death. Similarly, there are various laboratory markers associated with poor outcomes such as leukocytosis with lymphopenia, anemia, thrombocytopenia, raised liver enzymes, LDH, CRP, ferritin, IL-6, D-dimer, PT, troponin, CPK, and presence of organ failure requiring support.[2],[65],[66],[67]
| Prevention: Protection of Health-Care Workers | | |
This deadly disease does not have a specific treatment till date. Also, there is no vaccine available for prevention of this disease. Though efforts have started in developing a vaccine, it may take at least few months for the same. Hence, prevention of transmission as a whole and reducing transmission of infection from COVID patients to HCWs is most important step. Every possible measure should be taken for preventing transmission of the COVID-19 in hospitals. It should be both at individual as well as hospital level. At individual level, every care should be taken to prevent droplet/contact transmission of COVID-19 infection from patients to HCWs. Similarly, HCWs involved in aerosol generating procedures should take airborne precautions as well. Role of basic hand hygiene cannot be over emphasized. Use of equipment should be minimized (e.g., avoiding use of stethoscope). At the system level, all arrangements should be done for social distancing of staff, cleaning of environmental surfaces and equipment at regular intervals, cohorting of patients as per risk factors, and allocation of patient care areas as per need. Also, training of HCWs should be ensured in handling droplet infection prevention and control precautions, including the use of relevant PPE. Also, the HCWs involved in aerosol-generating procedures must be trained to deal with airborne precautions.[68]
| Conclusion | | |
COVID-19 is an emerging disease caused by a novel coronavirus with an incompletely understood pathophysiology and clinical course. But, being a pandemic, it is a threat to global health. Considering the tremendous increase number patients, a large number of patients will require critical care service. Appropriate location of care should be identified for better utilization of resources. Though negative pressure isolation rooms are preferred, if this is not feasible, single isolation rooms are the next best option. A team of staff members need to be identified and offered training in the management of COVID-19 patients. Initial supportive measures include oxygen therapy; if no improvement is observed or the patient deteriorates, early intubation must be considered. High-flow nasal oxygen and NIV must be used judiciously considering the increased risk of aerosol generation and possible disease transmission. It is mandatory to follow lung protective ventilation strategy with titrated PEEP in all mechanically ventilated COVID-19 patients. Recruitment strategy including prone ventilation may help improve oxygenation. VV ECMO may be considered in case to case basis. Extrapulmonary organ failure including shock, myocarditis, and AKI may occur and to be dealt with appropriate levels of support. At present, there is insufficient evidence to use corticosteroids or any virus-specific treatment modalities in the treatment of COVID-19 disease.
In this review, we have tried to summarize various aspects of COVID-19 disease, from epidemiology to diagnosis and management of COVID-19. Due importance has been given to evolving treatment options and recommendations available for the treatment of COVID-19 critically ill patients. At the same time, precautions to be taken by HCWs during caring for critically ill COVID-19 patient are also explained.
This is an apparently new disease being caused by a novel coronavirus. Though the disease has taken pandemic form, knowledge about it is limited especially while caring for the critically ill patients. Till date, available literatures and evidences are mostly from China. There is a scarcity in global data on treatment of this disease, including its epidemiology and pathophysiology. New evidences and research paper on management of this disease are coming out each day which may change the present recommendation and the way in which these patients are being managed today. But, till date, we have no robust evidence for management of COVID-19.
As of now, the management of COVID-19 remains supportive. As there is no definite treatment for this deadly disease, prevention of virus transmission and slowing down the rate of new infections to accommodate patients within limit of available health-care facilities is the primary goal in handling this pandemic. Also extreme importance is to be given to prevent transmission of virus from infected persons to others (including HCWs). The pandemic will vanish in due course of time. How many more may be affected cannot be predicted even by the best epidemiological models. Most importantly we need to pray and hope for the best!
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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