Consensus for the management of analgesia, sedation and <i>delirium</i> in adults with COVID-19-associated acute respiratory distress syndrome

Donato, Manuel; Carini, Federico Carlos; Meschini, María Julia; Saubidet, Ignacio López; Goldberg, Adela; Sarubio, Marisol García; Olmos, Daniela; Reina, Rosa

doi:10.5935/0103-507X.20210005

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Revista Brasileira de Terapia Intensiva

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SPECIAL ARTICLE • Rev. bras. ter. intensiva 33 (1) • Jan-Mar 2021 • https://doi.org/10.5935/0103-507X.20210005 copy

Consensus for the management of analgesia, sedation and delirium in adults with COVID-19-associated acute respiratory distress syndrome

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Objective:

To propose agile strategies for a comprehensive approach to analgesia, sedation, delirium, early mobility and family engagement for patients with COVID-19-associated acute respiratory distress syndrome, considering the high risk of infection among health workers, the humanitarian treatment that we must provide to patients and the inclusion of patients’ families, in a context lacking specific therapeutic strategies against the virus globally available to date and a potential lack of health resources.

Methods:

A nonsystematic review of the scientific evidence in the main bibliographic databases was carried out, together with national and international clinical experience and judgment. Finally, a consensus of recommendations was made among the members of the Committee for Analgesia, Sedation and Delirium of the Sociedad Argentina de Terapia Intensiva.

Results:

Recommendations were agreed upon, and tools were developed to ensure a comprehensive approach to analgesia, sedation, delirium, early mobility and family engagement for adult patients with acute respiratory distress syndrome due to COVID-19.

Discussion:

Given the new order generated in intensive therapies due to the advancing COVID-19 pandemic, we propose to not leave aside the usual good practices but to adapt them to the particular context generated. Our consensus is supported by scientific evidence and national and international experience and will be an attractive consultation tool in intensive therapies.

Keywords:
COVID-19; SARS-CoV-2; Pain; Analgesia; Deep sedation: Delirium; Respiration, artificial

Drug	Dilutions Stable concentrations/compatible diluents	Initial dose and maintenance infusion	Dose adjustment	Precautions/interactions with COVID-19 management/serious adverse events
Fentanyl ampoule 250mcg/5mL	CS: in SS, maximum 20mcg/mL (in PVC or PP) In DX5%, 5mcg/mL (in PVC or PP) Pure (in PVC or PP containers) Example: 10 ampoules (2500mcg) + 100mL of SS (final volume 150mL)	Initial dose: 1mcg/kg Maintenance: CI 0.7 - 2.5mcg/kg/hour Not to exceed 10mcg/ kg/hour	Severe LF: use alternative or lower effective dose	Adverse events: hypotension - histamine release - respiratory distress Interactions: LPV/r: potential interaction, risk of accumulation. Use minimum effective dose
Remifentanil vial 5mg	Reconstitute the vial with 5mL of DW CS: in SS/DX5%, 5 - 20mcg/mL Maximum volume restriction: 400mcg/mL Caution! In RL, it is only stable for 4 hours Example: 2 vial + 100mL of SS (final volume 110mL)	Initial dose: not applicable Maintenance: CI 0.5 - 15mcg/kg/hour	RF or LF: no adjustments	Adverse events: hyperalgesia after discontinuing. Hypotension, respiratory distress Interactions: none
Morphine ampoule 10mg/1mL	CS: in SS, 0.14 - 1.5mg/mL Maximum 2.5mg/mL In DX5%, 0.1 - 1mg/mL Example: 10 ampoules (100mg) + 100mL of SS (final volume 110mL)	Initial dose: 0.05 - 0.1mg/kg Maintenance: CI 0.07 to 0.5mg/kg/hour	RF: accumulation risk Adjust: GF > 50mL/minute: 0.02 - 0.15mg/kg IV c/4 hours; GF 20 - 50mL/minute: 75% of the dose; GF: 10 - 20mL/minute: 50% of the dose LF: advised against, risk of hepatic encephalopathy	Adverse events: hypotension - histamine release Interactions: LPV/r: moderate interaction, morphine levels may decrease, implying a risk of withdrawal syndrome

Drug	Dilutions Stable concentrations/compatible diluents	Initial dose and maintenance infusion	Dose adjustment	Precautions/interactions with COVID-19 management/serious adverse events
Paracetamol vial 10mg/mL	Compatible with SS and DX5% CS: 1mg/mL (use immediately) Can be administered directly without prior dilution	Maintenance: 650mg every 4 hours - 1000mg every 6 hours Maximum dose ≤ 4000mg/day	LF: contraindicated in patients with severe LF RF: CrCl ≤ 30mL/minute Consider an increase in the interval between doses and a decrease in the dose	Adverse events: nausea, vomiting, headache, insomnia Interactions: none
Ketamine vial 500mg/10mL	CS: in SS, 1mg/mL (dilute 500mg in 500mL)	Initial dose: 0.1 - 0.5mg/kg Recommended: 0.15mg/kg Maintenance: CI 0.1 - 0.4mg/kg/hour Not to exceed 2mg/kg/hour	RF or LF: no adjustment required	Adverse events: psychiatric symptoms (hallucinations); respiratory distress; hypotension Interactions: LPV/r: potential interaction, risk of accumulation. Use minimum effective dose
Dexmedetomidine vial 200mcg/2mL	CS: in SS, 4mcg/mL Example: 2 vials in 100mL of SS (final volume 104mL)	Maintenance: CI 0.2 - 0.7mcg/kg/hour Recommended use for 24 hours	LF: use 0.2 - 0.7mcg/kg/hour	Adverse events: bradycardia and hypotension Moderate interaction with LPV/r (monitoring) and with HCQ Monitor the QT interval
Ketorolac ampoule 30mg/mL	CS: in SS, 0.3 - 0.6mg/mL (in PVC containers) In RL and DX5%, 0.6mg/mL (in PVC containers).	Initial dose: 30mg, then 15-30mg every 6 hours for 5 days Maximum dose: 120mg/day for 5 days Direct IV bolus, administered in no less than 15 seconds	RF: 15mg every 6 hours Maximum dose: 60mg/day	Adverse events: hypertension, edema, adverse skin reactions Interactions: None
Diclofenac ampoule 75mg/3mL	CI: mix 100mL - 500mL of SS or DX5% with an injectable solution of sodium bicarbonate (0.5mL of 8.4% solution or 1mL of 4.2% solution) Intermittent infusion: mix 1 ampoule with 50mL of SS	Maintenance: 75 mg every 12 hours Maximum recommended dose: 150mg/day	Severe LF and RF: its use is not recommended	Adverse events: renal failure, edema, cardiac arrest, skin reactions Interactions: unlikely with dexamethasone and hydrocortisone
Tramadol ampoule 50mg/mL	CS: in SS and DX5%, 0.4 - 0.5mg/mL (PVC) In RL, 0.4mg/mL (PVC)	Maintenance: 50 - 100mg every 6 hours	RF: CrCl < 30mL/minute; increase the dosing interval to every 12 hours Maximum dose: 200mg/day CrCl < 10mL/minute: 50mg every 12 hours Severe LF: 50mg every 12 hours	Adverse events: skin and gastrointestinal reactions Interactions: potential with LPV/r and with HCQ Monitor the QT interval
Carbamazepine tablet 200mg	CS: in SS and DX5%, 0.4 - 0.5mg/mL (PVC) In RL, 0.4mg/mL (PVC) NA	Initial dose: 50 - 100mg Maintenance: 100 - 200mg every 4 - 6 hours Maximum dose: 1200mg/day	Severe LF and RF: its use is not recommended	Adverse events: skin and gastrointestinal reactions, hypotension, atrioventricular block Interactions: do not administer with LPV/r and HCQ Probable interaction with dexamethasone and hydrocortisone, ivermectin and less likely with remdesivir
Gabapentin tablet 100, 300, 600mg	NA	Initial dose: 100 mg every 8 hours Maintenance: 900 - 3600mg 3 times per day	RF: CrCl 30 - 59mL/minute: 400 - 1400mg/day 2 times per day CrCl 15 - 29mL/minute 200 - 700mg/day once per day CrCl 15mL/minute: 100 - 300mg/day CrCl <15mL/minute adjust the dose in proportion to the dose for a CrCl of 15mL/minute	Adverse events: skin and gastrointestinal reactions, dizziness, drowsiness Interactions: none
Pregabalin tablet 25,50,75,150,300 mg	NA	Initial dose: 75 - 150mg Maintenance: 150 to 600mg/ day 2 times a day Usual dose: 300 - 600mg/day	RF: CrCl 30 - 60mL/minute: 75 to 300mg/day in 2 or 3 divided doses CrCl 15 - 30mL/minute 25 -150mg/day once or twice per day CrCl less than 15mL/minute 25 - 50mg once per day	Adverse events: can cause excessive sedation and hypotension. Interactions: None

Drug	Dilutions Stable concentrations/compatible diluents	Initial dose and maintenance infusion	Dose adjustment	Precautions/interactions with COVID-19 management/serious adverse events
Midazolam ampoule 5mg/mL	CS: 0.035 -1mg/mL in PCV containers and up to 2mg/mL in PP containers for SS and DX5% Not compatible with RL; can be administered pure Example: 8 ampoules (120mg) + 100 mL of SS (final volume 124mL)	Initial dose: 0.01 - 0.05mg/kg Maintenance: CI 0.02 - 0.1mg/kg/hour Not to exceed 0.2mg/kg/hour	RF: start with the lowest effective dose CrCl < 10mL/minute, reduce the dose by 50% LF: Child-pug B-C is not recommended for continuous infusion	Adverse events: respiratory distress-hypotension. Interactions: LPV/r: Potential interaction Close monitoring; use minimum effective dose
Lorazepam ampoule 4mg/mL	Stability of solution difficult Protect from light CS: in DX5%, 1 - 2mg/mL (in polyolefins or PVC) In SS, 1mg/mL in PP; 0.04mg/mL in PVC; 0.1 and 0.038mg/mL in PE In RL, 0.1mg/mL in PE Example: 10 ampoules (40mg) + 30mL DX5% (final volume 40mL)	Initial dose: 0.02 - 0.04mg/kg' (≤ 2mg) Maintenance: CI 0.01 - 0.1mg/kg/hour Infusion rate ≤ 10mg/hour	Severe RF or LF: use alternative Risk of accumulation of the excipient	Precautions: risk of accumulation of toxic excipient (propylene glycol) in renal failure, limit infusion Adverse events: respiratory distresshypotension Interactions: none
Diazepam ampoule 10mg/2mL	Stability of solution difficult Protect from light SS, 0.01mg/mL, 0.05mg/mL, 0.08mg/mL and 0.2mg/mL; DX5%, 0.04mg/mL and 0.2mg/mL Dilutions compatible in PE and glass containers Compatible with RL in glass containers CS 0.05mg/mL	Initial dose: 5 - 10mg Maintenance: 0.03 - 0.1mg/kg every 0.5 - 6 hours CI: 0.05 - 0.2mg/kg/hour	RF or LF: does not require a specific adjustment, strict monitoring due to the risk of accumulation of the excipient	Precautions: accumulation of the propylene glycol excipient can generate toxicity Strict monitoring, risk of oversedation. Adverse events: respiratory distress Interactions: Potential with LPV/r
Propofol ampoule 200mg/20mL (1%) Propofol vial 1000mg/50mL (2%)	Place the ampoules in an empty PP or PVC bag 6-hour stability Example: 4 ampoules (800mg) in empty container (final volume 80mL)	Initial dose: 5μg/kg/minute Only if hypotension is not likely Maintenance: CI 0.3 - 3mg/kg/hour Not to exceed 4.5mg/kg/hour	RF or LF: use lower doses 0.3 - 2.4mg/kg/hour	Precautions: risk of accumulation in prolonged infusions; use minimum effective dose. Adverse events: respiratory distress, hypotension, hypertriglyceridemia; risk of PRIS increases with doses greater than 3 mg/kg/h; close monitoring. Interactions: potential with LPV/r and with HCQ Monitor the QT interval
	Use directly from the vial without transferring/diluting. Once opened, 12-hour stability		RF or LF: use lower doses 0.3 - 2.4mg/kg/hour
Dexmedetomidine vial 200mcg/2 mL	CS: in SS, 4mcg/mL Example: 2 vials + 100mL of SS (final volume 104mL)	Initial dose: (not recommended) 0.5mcg/kg in 15 minutes - strict HR monitoring Maintenance: CI 0.2 -1.4mcg/kg/hour	LF: monitor, use lower doses 0.2 - 0.7mg/kg/hour	Adverse events: bradycardia and hypotension Interactions: potential with LPV/r and with HCQ monitor the QT interval
Clonidine ampoule 150mcg/mL	Protect from light CS: 9mcg/mL in SS Example: 6 ampoules + 100mL of SS (final volume 106mL)	Bolus: 0.5mcg/kg (only in hemodynamically stable patients) Maintenance: CI 0.5 -2mcg/kg/hour Up to 3mcg/kg/hour	RF or LF: no adjustment	Adverse events: hypotension, bradycardia, atrioventricular block Interactions: none

Drug	Dilutions Stable concentrations/compatible diluents	Initial dose and maintenance infusion	Dose adjustment	Precautions/interactions with COVID-19 management/serious adverse events
Atracurium ampoule 50mg/5mL	CS: in SS/DX5%. 0.2 - 1mg/mL Max 5mg/mL; incompatible with RL Example: 10 ampoules (500mg) + 100mL of SS (final volume 150mL)	Initial dose: 0.4 - 0.5mg/kg Maintenance: 5 - 20mcg/kg/minute	RF or LF: no adjustment required	Adverse events: risk of histamine release (minimum) Tachyphylaxis (if continuous infusion is prolonged over time) Interactions: none
Vecuronium vial 10mg	Reconstitute each vial with 10mL of distilled water Compatible with SS, DX5%, RL Example: 5 ampoules (50mg) + 100mL of SS (final volume 150mL)	Initial dose: 0.08 - 0.1mg/kg Maintenance: 0.8 - 1.7mcg/kg/minute	RF or acute emergency RF: use minimum effective dose due to accumulation risk	Adverse events: vagal blockage with high doses Interactions: none
Rocuronium ampoule 50mg/5mL	Compatible with SS, DX5% and RL CS: SS, RL and DX5%, 0.5 and 2mg/mL Example: 4 ampoules (200mg) + 100mL of SS (final volume 120mL)	Initial dose: 0.06 - 1mg/kg Maintenance: 8 - 12mcg/kg/minute	RF or LF: no adjustment required, assess dose-response	Adverse events: bradycardia, vagal blockage with high doses Interactions: potential with LPV/r or with HCQ, monitor the QT interval
Pancuronium ampoule 4mg/2mL	Compatible with SS, DX5%, RL Example: 10 ampoules (40mg) + 100mL of SS (final volume 120mL)	Initial dose: 0.04 - 0.1mg/kg Maintenance: 1 - 2mcg/kg/minute	RF: use minimum effective dose, due to risk of accumulation Avoid its use in patients with severe RF, CrCl <10mg/mL	Adverse events: respiratory distress, hypertension, vagal blockage with high doses Interactions: none

Drug	Dilutions Stable concentrations/ compatible diluents	Initial dose and maintenance infusion	Dose adjustment	Precautions/interactions with COVID-19 management/serious adverse events
Quetiapine tablets 25, 50, 100, 200mg	NA	Maintenance: 50mg every 12 hours (maximum dose of 200mg every 12 hours)	LF: start at 25mg/day	Adverse events: prolongation of the QT interval, hypertension, tachycardia Interactions: LPV/r: Potential interaction. Could increase the concentration of quetiapine
Olanzapine tablets 2.5, 5, 10mg	NA	Maintenance: 5mg/day	RF: no adjustment LF: no adjustment	Adverse events: orthostatic hypotension, peripheral edema, hypercholesterolemia Interactions: unlikely with LPV/r
Risperidone tablets 0.5, 1, 2, 3, 4mg	NA	Maintenance: 0.5mg every 12 hours (maximum dose 4mg/day)	Severe RF: use minimal doses Severe LF: use minimal doses	Adverse events: prolonged QT interval, blood dyscrasias Interactions: LPV/r: potential prolongation of the QT interval; HCQ: potential increase in risperidone concentration
Haloperidol ampoules 5mg/mL	CS: 0.1mg/mL DX5% in glass container Not tested in other dilutions or containers	Maintenance: 2.5mg every 8 hours (maximum dose 20mg/day)	In older adults, use minimal doses	Adverse events: prolongation of the QT interval, hypotension, Torsades de pointes Interactions: do not administer with LPV/r or HCQ
Haloperidol tablets 1, 5, and 10mg	NA	Maintenance: 2.5 to 5mg every 8 hours	In older adults, use minimal doses	Adverse events: prolongation of the QT interval, hypotension, Torsades de pointes Interactions: do not administer with LPV/r or HCQ

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[1] Corresponding author: Manuel Donato Hospital General de Agudos José María Penna Avenida Almafuerte, 406 Código Postal 1437 Buenos Aires, Argentina E-mail: farmdonatomanuel@gmail.com