Abstract
In a resource-limited country like India, rationing of scarce critical care resources might be required to ensure appropriate delivery of care to the critically ill patients suffering from COVID-19 infection. The position paper—part II attempts to address basic issues regarding use of antibiotics, management of sepsis, acute respiratory distress syndrome (ARDS), and thromboprophylaxis.
Role of Prophylactic/Empiric Antibiotics
Secondary infections or coinfections are uncommon, especially in the early phase, in patients with COVID-19 infections. Hence, routine use of antibiotics is not indicated. However, use of antibiotics may be justified in specific subgroup of patients admitted in intensive care units (ICUs).
Recommendations
Start empiric antibiotics in patients who have hypoxemic respiratory failure needing mechanical ventilation in COVID-19 patients.
Do not start prophylactic antibiotics to prevent pneumonia in COVID-19 patients.
A recent meta-analysis of 3,834 patients showed that the rate of secondary bacterial infection was only 7% in hospitalized patients but increased to 14% among patients admitted in ICU. Empiric antibiotics should be considered in severe cases of suspected or confirmed COVID-19.
Which Antibiotic to Start and Duration of Therapy
Recommendations
• β-lactam antibiotics may be added as first line in patients with severe COVID-19 infection.
• Atypical coverage may be added where appropriate.
• Antibiotic treatment duration should not exceed 5 to 7 days in most cases.
Antibiotic prescription may follow the community acquired pneumonia (CAP) guidelines. β-lactam antibiotics maybe the first choice of antibiotic and macrolides may be added for atypical coverage. Antibiotic treatment duration should not exceed 5–7 days in most cases, as generally recommended for CAP. Appropriate preventive, diagnostic, and therapeutic measures need to be taken in such patients and local antibiogram should be followed for the choice of antibiotics.
Management of Sepsis
Patients with COVID-19 infection may present with signs and symptoms of sepsis/septic shock. Apart from this viral sepsis, these patients are also at risk of developing secondary bacterial and fungal infection which may further lead to secondary sepsis.
Fluid Resuscitation
Recommendations
• To assess fluid responsiveness, dynamic parameters like stroke volume variation (SVV), and stroke volume change with passive leg raising (PLR), should be preferred over static parameters.
• Conservative fluid management therapy should be preferred over liberal fluid resuscitation.
• For patients with shock, crystalloids should be preferred over colloids for acute resuscitation.
• Routine use of albumin should be avoided for initial acute resuscitation.
• Balanced solutions should be preferred over unbalanced crystalloids for acute resuscitation.
Despite several research, there is no direct evidence regarding fluid therapy in managing sepsis/septic shock secondary to COVID-19 infection. Dynamic variables like SVV, pulse pressure variation (PPV), and stroke volume change with PLR or fluid challenge have been found to be better in predicting fluid responsiveness as compared to static parameters like central venous pressure (CVP) and mean arterial pressure (MAP).
PLR has been shown to have better accuracy in predicting fluid responsiveness than PPV and SVV. Among the crystalloids, there is growing evidence in favor of balanced solutions, especially when a large volume is required for resuscitation.
Vasopressors
Recommendations
• In patients with shock, not responding to fluid therapy, noradrenaline should be used as the first-line agent.
• Adrenaline or vasopressin may be used in case of non-availability of noradrenaline.
• Vasopressin may be added as a second line agent, in patients with shock refractory to noradrenaline therapy.
• In patients with cardiac dysfunction, dobutamine may be added in shock refractory to fluid resuscitation and noradrenaline.
Noradrenaline is the most widely studied agent for the management of septic shock in general critical care. A large meta-analysis of 28 RCTs including 3,497 patients proved its role as the best first-line vasopressor.
Vasopressin or adrenaline may be used in case of non-availability of noradrenaline, on a case to case basis depending on the presence of contraindications or each agent.
Steroids
Recommendations
• In patients with septic shock refractory to vasopressor therapy, low-dose corticosteroid therapy may be used (GRADE IIIB).
The use of low-dose corticosteroids may lead to early resolution of shock, and reduce the length of stay in hospital and ICU, without having any effect on mortality and serious adverse events. The most commonly recommended regimen is of intravenous hydrocortisone 200 mg/day either as a continuous infusion or divided in 6 hourly doses.
Biomarkers
Recommendations
• High white blood cell (WBC) counts may suggest secondary infection or a more severe disease.
• C-reactive protein (CRP) levels should be measured at the time of hospital admission for early risk assessment and prioritization of high-risk patients (GRADE IIB).
• Procalcitonin levels should be measured at the time of ICU admission for early risk assessment and prioritization of high-risk patients (GRADE IIB).
• Repeat procalcitonin levels may be helpful in detecting secondary infections and in monitoring progression of severity of bacterial infection (GRADE IIA).
A meta-analysis of 5,350 patients showed that high CRP levels were associated with poor outcomes in hospitalized patients with COVID-19 infection. Procalcitonin may prove to be another valuable tool in the management of critically ill COVID-19 patients and may aid in early identification of patients at low risk for bacterial coinfection and adverse outcome.
Management of ARDS
Severe ARDS and hypoxemic respiratory failure have been shown to be the major cause of mortality in COVID-19. Respiratory support in the form of noninvasive ventilation (NIV), and invasive mechanical ventilition (IMV) remains the mainstay of care in ICU.
Oxygen Therapy
Recommendations
• Supplemental oxygen should be initiated if peripheral oxygen saturation (SpO2) is <92% .
• Supplemental oxygen therapy should be immediately initiated in patients with severe acute respiratory illness (SARI) and respiratory distress, hypoxemia.
• In patients with acute hypoxemic respiratory failure (AHRF) on oxygen, we suggest that SpO2 be maintained no higher than 96%.
• Recognize severe hypoxemic respiratory failure when a patient with respiratory distress is failing torespond to standard oxygen therapy and prepare to provide advanced oxygen/ventilatory support.
Hypoxemia, in critically ill patients has been shown to be associated with worse clinical outcomes. On the contrary, a large meta-analysis of 25 RCTs with 16,037 patients reported that liberal oxygen therapy targeting SpO2 above 96% was associated with an increased risk of hospital mortality.
Non-invasive Ventilatory Techniques in COVID-19
Recommendations
• High-flow nasal cannula (HFNC) or NIV should be considered in patients with AHRF not responding to conventional oxygen therapy.
• High-flow nasal cannula may be preferred over NIV in view of patient comfort and healthcare worker protection.
• If HFNC is unavailable, a trial of NIV may be given with close monitoring for worsening of respiratory failure.
• All aerosol-generating procedures should be performed in a negative pressure room.
High-flow nasal cannula can deliver up to 100% FiO2 at flow rates of up to 60 L/minute. The heated and humidified oxygen may improve secretion clearance, decrease airway inflammation, and also decrease energy expenditure, particularly in the setting of AHRF.
Another advantage of HFNC is that it flushes nasopharynx and eliminates dead space providing a continuous flow of fresh gas at high-flow rates.
When to Intubate
Recommendations
• In adults with COVID-19 receiving NIV or HFNC, we recommend close monitoring for worsening of respiratory status, and early intubation in a controlled setting if worsening occurs.
• Endotracheal intubation should be performed by atrained and experienced provider using airborne precautions.
Endotracheal intubation is recommended for patients showing no improvement in respiratory distress, tachypneaand poor oxygenation after 2-hour HFNC or NIV. Such early intubation was recommended as there may be rapid deterioration of patients with COVID-19 with silent hypoxemia and it takes time for preparation and performance of intubation.
Strategies for IMV
Recommendations
• Use low-tidal-volume ventilation (4–8 mL/kg of predicted body weight).
• Target plateau pressure below 30 cm H2O.
• Higher PEEP strategy may not benefit all COVID-19 patients with ARDS, hence PEEP should be titrated as per patient’s characteristics and response to PEEP.
• Use prone ventilation for 12–16 hours vs no prone ventilation.
• Neuromuscular blocking (NMB) agents may be used for lung protective ventilation especially in first 24–48 hours after intubation. 10
• Veno-venous extracorporeal membrane oxygen- ation (ECMO) should be considered in patients on IMV who have refractory hypoxemia.
A recent meta-analysis of 9 RCTs with 2,129 non-COVID ARDS patients showed improved mortality when prone ventilation was used for >12 hours. Intermittent boluses of NMB agents should be preferred over continuous for lung protective ventilation. Intermittent boluses of NMB agents should be preferred over continuous for lung protective ventilation. For those patients on IMV who have refractory hypoxemia despite optimization of ventilation and who have undergone rescue therapies and proning, veno-venous ECMO should be considered.
Thromboprophylaxis in COVID-19
Recent data and clinical experience suggest an increased prevalence of thrombosis and venous throm- boembolic (VTE) events in COVID-19, especially in those with more severe disease.
Coagulation Parameters Testing
Recommendations
• We recommend testing coagulation parameters in all hospitalized COVID-19 patients at least onceduring admission (GRADE IA).
• We recommend testing platelet counts, prothrombin time (PT), activated partial thromboplastin time, fibrinogen, and D-dimer levels in patients admitted to the ICU (GRADE IIB).
• We recommend viscoelastic tests like thromboelastography (TEG) to decide on thromboprophylaxis in patients with increasing trends of D-dimers who have clinical risk of bleeding.
D-dimers are a non-specific acute phase reactant which may be elevated in acute inflammatory illnesses, pneumonias, and other causes of sepsis and in patients in ICUs. But is unclear whether elevated D-dimer levels reflect inflammation or thrombosis or thrombolysis. Fibrinogen levels are also significantly elevated in COVID-19.
Initiation and Titration of Anticoagulation
Recommendations
• We recommend initiating prophylactic dose low molecular weight heparin (LMWH) for all patients hospitalized with COVID-19, unless absolutely contraindicated (GRADE IA).
• We recommend initiation of intermediate dose LMWH for critically ill COVID-19 patients in ICU (GRADE IIB).
• We recommend therapeutic dose of LMWH (enoxaparin 60 mg SC BD or 1 mg/kg SC BD) in suspected or confirmed VTE or PE (GRADE IB).
• We recommend therapeutic dose of LMWH (enoxaparin 60 mg SC BD or 1 mg/kg SC BD) in COVID-19 patients who were already on therapeutic anticoagulation for other purposes (GRADE IB).
• We recommend equivalent unfractionated heparin instead of LMWH as a choice in patients with creatinine clearance <15 mL/minute or on renal replacement therapy (GRADE IA).
• We recommend escalating dose from prophylactic dose to intermediate or therapeutic dose of LMWH in COVID-19 patients depending on risk assessment.
Currently, there is no conclusive evidence that increasing the dose of LMWH thromboprophylaxis improves clinical outcomes. Experts recommend intermediate-dose thromboprophylaxis for critical care patients requiring high-flow oxygenation or mechanical ventilation. Some guidelines stratify the thrombosis risk using D-dimer thresholds of <1,000, 1,000 to 3,000, and >3,000 µg/L to identify patients who should receiv standard-dose, intermediate-dose, and treatment-dose anticoagulation.
Anticoagulation at Discharge
Recommendations
• Extended home anticoagulation may be warranted in “high risk” COVID-19 patients after discharge.
• We recommend discharging COVID-19 patients with suspected or confirmed VTE or PE with home anticoagulation on therapeutic dose direct acting oral anticoagulants (DOACs) or LMWH for a minimum of 3 months (GRADE IB).
Extended thromboprophylaxis on discharge can be considered if the patient is at high risk of VTE. The nature and duration of thromboprophylaxis in patients recovering from COVID-19 pneumonia is not clear but a standard prophylactic dose of LMWH or DOAC for at least 1 to 2 weeks may be a reasonable approach.
Conclusion
While each one of the discussed entities have well-established evidence-based management protocols, whether the same can be extrapolated to the setting of COVID-19 remains dubious. Until better evidence emerges from the enormous database, the onus remains with the bedside intensivist to deliver care based on best judgment combined with available evidence.
Source: Juneja D, Savio RD, Srinivasan S, Pandit RA, Ramasubban S, Reddy PK, et al. Basic Critical Care for Management of COVID-19 Patients: Position Paper of the Indian Society of Critical Care Medicine, Part II. Indian J Crit Care Med 2020;24(Suppl 5):S254–S262
