Intensive support recommendations for critically-ill patients with suspected or confirmed COVID-19 infection

ABSTRACT In December 2019, a series of patients with severe pneumonia were identified in Wuhan, Hubei province, China, who progressed to severe acute respiratory syndrome and acute respiratory distress syndrome. Subsequently, COVID-19 was attributed to a new betacoronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Approximately 20% of patients diagnosed as COVID-19 develop severe forms of the disease, including acute hypoxemic respiratory failure, severe acute respiratory syndrome, acute respiratory distress syndrome and acute renal failure and require intensive care. There is no randomized controlled clinical trial addressing potential therapies for patients with confirmed COVID-19 infection at the time of publishing these treatment recommendations. Therefore, these recommendations are based predominantly on the opinion of experts (level C of recommendation).


❚ INTRODUCTION
In December 2019, in Wuhan, province of Hubei, China, many patients developed severe pneumonia and presented severe acute respiratory syndrome (SARS) and acute respiratory distress syndrome (ARDS). (1,2) Later, the disease disseminated to other regions of China and to many countries in different continents, characterizing a pandemic. (3) The disease was attributed to a new betacoronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). (4) The disease caused by this virus was recently named coronavirus disease 2019 (COVID-19). (5) Patients with COVID-19 present mostly with fever, cough, dyspnea, myalgia, and fatigue. (6) Although most have a favorable progression, (2) approximately 20% develop severe forms of the disease, including acute hypoxemic respiratory failure (AHRF), SARS, ARDS and acute kidney failure (AKF) requiring admission to the intensive care unit (ICU). (1,2,7) It has also been found that some groups, especially the elderly and those with other underlying diseases, have greater risk of developing multiple organ dysfunction (MODS) and, ultimately, dying. (2,8) As of the publication of these treatment recommendations, no randomized controlled clinical trial (RCT) had yet evaluated potential treatments for patients with confirmed COVID-19 infection. (5,9) A search on ClinicalTrials.gov (10) using the term "COVID -19" resulted in 179 RCTs in the recruitment phase. A detailed narrative review of the specific treatments used to treat COVID-19 has been published recently. (9) Therefore, the material provided in these recommendations is based mostly on experts' opinion. Consequently, they should be considered with caution by healthcare professionals, considering the recommendation level C (case report, including cohort studies or lower quality case-control studies). (11)

❚ CRITERIA FOR ADMISSION TO THE INTENSIVE CARE UNIT
At least one of the following criteria is necessary for admission to the ICU: • Patients who need supplemental oxygen (nasal cannula -NC O 2 >3.0L/minute) to maintain peripheral oxygen saturation (SpO 2 ) >94% or respiratory rate (RR) ≤24rpm. • Patients who require non-invasive ventilation (NIV) to maintain SpO 2 >94% or RR ≤24rpm. • Acute respiratory failure requiring invasive mechanical ventilation (MV).

❚ PROCEDURES FOR OROTRACHEAL INTUBATION
• Team apparel during the OTI procedure: waterproof apron, sterile gloves, N95 mask, hair cap, goggles and face shield. • Only professionals who will actively participate in the procedure remain in the room. We recommend a trained professional stays by the door of the room for possible support during the OTI. • Prepare all materials for OTI, including capnograph, drugs, fluids and vasopressors, before beginning the procedure and out of room. • Vasopressors (norepinephrine) and crystalloids must be prepared and kept ready for infusion before beginning the procedure, due to the potential risk of hypotension after OTI. • Use orotracheal cannula with subglottic suction and closed suction system in all patients undergoing OTI and MV. • All OTI procedures must be performed with direct videolaryngoscopy. • All patients must be intubated with rapid sequence intubation (RSI). • SpO 2 drop below 70% is a common event immediately after OTI. Therefore, pre-oxygenation (100% O 2 ) and the proper preparation of both patient and materials to be used for OTI are crucial. • Avoid ventilation with bag-valve-mask before OTI, due to the increased production of aerosol. • In patients not using NIV at the time of OTI: preoxygenate with reservoir mask at the lowest possible air flow, to maintain effective oxygenation. Avoid assisted ventilation with the bag-valve-mask or use of supraglottic devices, due to the potential aerosol production and team contamination. • In patients using NIV at the time of OTI: start RSI with the patient in NIV. Remove NIV only to intubate, i.e., do not remove the mask before the OTI. • Sequence of medications for SRI: -Fentanyl 50 to 100mcg, intravenous (IV).
-Neuromuscular blockade with succinylcholine 1.0mg/kg IV (or rocuronium 1.2mg/kg IV, if succinylcholine is contraindicated), to facilitate OTI and avoid cough during the procedure. • After checking the adequate position of the orotracheal tube with the capnograph and installing the heat and moisture exchanger (HME) filter between the tube and the capnograph, the patient may be connect to the ventilator, installing the high efficiency particulate arrestance (HEPA) filter at the expiratory outlet of the ventilator to the environment.

❚ INITIAL ADJUSTMENTS OF THE MECHANICAL VENTILATOR
The following initial MV parameters are recommended immediately after OTI: • Pressure-controlled volume (PCV).
❚ ANALGESIA AND SEDATION  -For additional pain control (analgesia) during MV, additional IV bolus of fentanyl should be given (50mcg IV) and association with regular analgesics (e.g. dipyrone or paracetamol) to spare using opioids.
• Regarding the use of neuromuscular blockers, (NMB), administering cisatracurium 0.15mg/kg IV bolus is recommended, followed by infusion of 1 to 4mcg/kg/minute in continuous infusion pump (CIP), when one of the following is observed: -Persistent severe asynchrony characterized by worsening of oxygenation and ventilation after adjusting MV and sedation, in patients with PaO 2 /FiO 2 between 150 and 200; -PaO 2 /FiO 2 <150 with PEEP >15cmH 2 O. • In patients on NMB, based on current guidelines, (16,17) we recommend: -Bi-spectral index (BIS) targeting 40 to 60, with burst suppression rate (SR) > zero.

❚ HEMODYNAMIC SUPPORT
The algorithm for hemodynamic support of patients with COVID-19 is depicted in figure 5.
• Invasive blood pressure (IBP) monitoring is suggested, as well as the insertion of a central venous catheter (CVC) in patients receiving norepinephrine at a dose >0.1mcg/kg/minute and increasing. • Avoid using a peripherally inserted central catheter (PICC) to administer norepinephrine or maintain venous access, due to the increased risk of thrombotic events. • If norepinephrine >0.5mcg/kg/minute, starting epinephrine 0.01mcg/kg/minute is suggested.
• The administration of hydrocortisone 200mg IV in CIP is recommended if norepinephrine >0.2mcg/kg/ minute after 6 hours of resuscitation.
* Invasive monitoring of blood pressure and the insertion of a central venous catheter are suggested in patients receiving norepinephrine at a dose >0.1mcg/kg/minute and increasing. If norepinephrine dose >0.5mcg/kg/minute, we suggest starting epinephrine 0.01mcg/kg/minute. Start 200mg hydrocortisone continuous infusion if norepinephrine >0.2mcg/ kg/minute after 6 hours of resuscitation; † monitor cardiac output if two or more perfusion parameters are abnormal; ‡ check fluid balance every 6 hours and adjust the diuretic dose according to the target (zero or negative fluid balance). Consider fluid balance as zero/positive in case of increase in vasopressor drugs, abnormal perfusion markers, laboratory signs of dehydration (hypernatremia or metabolic alkalosis), altered kidney function and non-measurable losses (fever and/or diarrhea). SBP: systolic blood pressure; MAP: mean arterial pressure; GapCO 2 : difference between the partial pressure of venous carbon dioxide and the partial pressure of arterial carbon dioxide; CFT: capillary filling time; CO: cardiac output; FB: fluid balance; VAD: vasoactive drugs.  cases, such as in patients with serum interleukin 6 (IL-6) level ten-fold above the upper normal limit or more, elevated D-dimer, thromboelastrometry suggestive of hypercoagulability state and sequential organ failure assessment (SOFA) score (18) ≥4, in addition to no presumed secondary bacterial infection, or liver dysfunction (international normalized ratio -INR >2.0 or total bilirubin -TB >2.0). Liver function should be monitored. The dose should be 4 to 8mg/kg (maximum unit dose: 800mg), with a maximum of three doses, every 12 hours. • The use of lopinavir + ritonavir, remdesivir, convalescent serum, nitazoxanide, ivermectin and arbidol is restricted to clinical research protocols.
❚ ADDITIONAL TESTS • The following laboratory tests should be sampled on daily basis during the ICU stay: complete blood count; kidney function (creatinine -Cr -and urea -Ur); electrolytes including sodium, potassium, magnesium, ionized calcium and phosphorus; arterial blood gases and lactate (if in hypoxemic MV and/or shock) and/or central venous blood gas (if with no IBP, or if weaning from MV, or not on MV and without hypoxemia and without shock) and C-reactive protein (CRP). • If secondary bacterial infection is suspected, collect cultures and serial measurements of CRP and procalcitonin (PCT). • Collect D-dimer every 48 hours (acts as a severity marker). • Chest X-ray in case of clinical deterioration and always after procedures (OTI, CVC introduction, etc.). • Consider daily ECG if the patient is using macrolides and hydroxychloroquine. • Upon admission to ICU, collecting the daily tests described above, as well as troponin, type B natriuretic peptide (BNP), liver function, lactic dehydrogenase (DHL), ferritin, D-dimer, prothrombin time (PT), INR, activated partial thromboplastin time (aPTT), fibrinogen, thromboelastography, PCT, cultures, ECG and chest X-ray is recommended. Transthoracic echocardiography should be carried out within the first 24 hours of ICU admission.

❚ CONCLUSION
The clinical management of patients diagnosed with COVID-19 who develop severe forms of the disease and require intensive care is complex. Due to the complexity of patients, the exponential growth of new cases, and the einstein (São Paulo). 2020;18:1-x high demand for supplies, human resources and trained professionals, critically-ill patients with COVID-19 are a major challenge for care teams and health systems. The evidence available in the literature for the treatment of patients with COVID-19 is scarce and limited to noncontrolled studies. The recommendations presented in this document were developed to guide healthcare professionals who are directly involved in the care of COVID-19 patients, although predominantly based on experts' opinions. Robust evidence from randomized controlled trials is required so that COVID-19 patients can be provided with more effective and safer treatments.