TABLE.

Strategies for drug conservation and proposed therapeutic alternatives in anticipation of critical care drug shortages

ESSENTIAL DRUGS AT GREATEST RISK OF SHORTAGE
Sedatives: propofol, midazolam, dexmedetomidine, ketamine
Conservation strategies to consider first: • Consider an escalation strategy whereby intermittent enteral dosing is preferred followed by intermittent IV dosing followed by continuous infusions. • Analgesia-based sedation: mechanically ventilated patients who need only light sedation can receive infusions or intermittent doses of opioids alone (e.g., hydromorphone, fentanyl) that provide mild sedation. • Adjunctive use of intermittent sedatives (e.g., clonazepam, lorazepam, diazepam, clonidine, ketamine, atypical antipsychotics) with sedative infusions require lower doses of the IV infusion. • Nurse-managed sedation titration using a validated sedation scale (e.g., RASS15) and clearly defined sedation targets to ensure lowest effective dosing Other conservation strategies: • Daily sedative interruption or sedation vacations may reduce sedative requirements in select cases	Therapeutic alternatives to consider first: • Intermittent clonazepam, lorazepam, diazepam clonidine, or atypical antipsychotics instead of continuous infusions of sedatives in patients who only need light sedation • Analgesia-based sedation • Ketamine infusions may be considered as an alternative sedative strategy for short-term sedation (e.g., 24–48 hr) Other potential therapeutic alternatives: • Phenobarbital can be administered enterally or intravenously in conjunction with benzodiazepines and titrated to provide sedation • Inhaled anesthetics can also be considered in select patients and settings (consider the risk of aerosolization in COVID-19 patients)
Opioid analgesics: hydromorphone, fentanyl, morphine
Conservation strategies to consider first: • Nurse-managed analgesia titration using a validated pain assessment tool (e.g., NRS,22 CPOT23) with clearly defined pain targets to ensure lowest effective dosing • Consider an escalation strategy whereby intermittent enteral dosing is preferred followed by intermittent IV dosing followed by continuous infusions • Multimodal approach to pain using non-narcotic medications such as acetaminophen, pregabalin, NSAIDS, ketamine, methadone, lidocaine, and tapentadol can reduce the need for opioids Other conservation strategies: • Analgesia vacations/interruptions in selected patients receiving continuous infusions to ensure the lowest effective dose is being used	Therapeutic alternatives to consider first: • Intermittent enteral administration of hydromorphone, oxycodone, or morphine can be used in place of opioid infusions and titrated to the same pain score (e.g., CPOT23) • Fentanyl patches (although less easy to titrate) can be used in place of opioid infusions Other potential therapeutic alternatives: • Remifentanil or sufentanil may be considered as alternatives for continuous infusion • Lidocaine infusions can be used in combination with opioids for pain • Some long-acting preparations (e.g., Hydromorph Contin, M-Eslon) can be administered via large bore feeding tubes
Neuromuscular blocking agents (NMBAs): cisatracurium, rocuronium
Conservation strategies to consider first: • Use both train-of-four monitoring and observed respiratory effort when titrating NMBA infusions to ensure the lowest effective dose is being used • Intermittent NMBA dosing (as opposed to continuous infusion) guided by train-of-four monitoring and respiratory effort may reduce total daily dosing and durations Other conservation strategies: • Magnesium infusions can boost the effect of neuromuscular blockers	Therapeutic alternatives to consider first: • Limited options exist if these agents are no longer available. Succinylcholine could be used for intubation and procedural paralysis in select patients • Health Canada has permitted the importation of pancuronium and vecuronium
Vasopressors and inotropes: norepinephrine, epinephrine, vasopressin, dopamine, dobutamine, milrinone
Conservation strategies to consider first: • Stress-dosed corticosteroid therapy (e.g., hydrocortisone) has been shown to reduce vasopressor requirements • Targeting lowest effective sedation dose can reduce vasopressor requirements • Concurrent enteral midodrine can reduce IV vasopressor needs Other conservation strategies: • For vasopressor dependent patients consider targeting a lower mean arterial pressure	Therapeutic alternatives to consider first: • Phenylephrine can be administered as intermittent boluses or as a continuous infusion for patients in distributive shock • Intermittent dosing of oral midodrine can be used in patients in place of low dose vasopressors to improve vascular tone Other potential therapeutic alternatives: • Ephedrine can be used intravenously, enterally or intramuscularly
Drugs used in cardiac arrest and rapid sequence intubation (RSI): ACLS drugs, propofol, rocuronium, succinylcholine, ketamine, fentanyl, phenylephrine
Conservation strategies to consider first: • Code/crash carts and intubation kits should be designated as such; kept in COVID-19 areas so unused drugs can be reused in the same area • Drugs in crash carts and intubation kits could be place in sealed plastic bags to minimize exposure in contaminated rooms • Keeping code/crash carts outside of the room and having the drugs passed in as needed may reduce the risk of contamination	Therapeutic alternatives to consider first: • Etomidate could be used in place of propofol for RSI induction • Epinephrine, norepinephrine, or ephedrine can be administered as IV push in place of phenylephrine for RSI • Lidocaine IV can be used in place of fentanyl for RSI pre-treatment • Succinylcholine can be used in place of rocuronium for intubation paralysis in select patients
OTHER DRUGS POTENTIALLY AT RISK OF SHORTAGE
Metred-dose inhalers: salbutamol, ipratropium, and others
Conservation strategies to consider first: • Avoid routine salbutamol and ipratropium dosing in the absence of bronchospasm • Patients prescribed MDIs at home could be asked to bring them in to use as “patient’s own medication” • Salbutamol/ipratropium combination nebules could be used in place of individual nebules • Long-acting beta-agonists (e.g., salmeterol, formoterol) could be used to reduce the need for salbutamol rescue therapy • Long-acting anticholinergic agents (e.g., tiotropium) could be used in place of ipratropium in eligible patients Other conservation strategies: • Same MDIs theoretically could be used for multiple patients with a spacer device (e.g., aerochamber) that is changed for each patient. The mouthpiece would need to be sterilized between uses • Upon discharge, rather than sending partly used MDIs home with the patient, these MDIs (or canisters) could potentially be redeployed after sterilization	Therapeutic alternatives to consider first: • Salbutamol and ipratropium could be administered via nebulizer to COVID-19-negative patients while MDIs are reserved for patients with suspected or confirmed COVID-19 • Systemic corticosteroids could be used in bronchospastic or asthmatic patients • Budesonide is available as a solution for nebulization • Respimat® inhalers may be considered in lieu of nebulizers for concerns related to asymptomatic transmission of COVID-19 • Similarly, Turbuhalers®/Handihalers® may be used by non-ventilated patients with manual dexterity for self-administration Other potential therapeutic alternatives: • Salbutamol is available as oral tablets and could theoretically be used for maintenance dosing in bronchospastic COPD patients • Theophylline could be used in asthmatic patients to reduce the use of salbutamol
Proton pump inhibitors (PPI) and histamine-2 receptor antagonists (H2RA): pantoprazole, lansoprazole, ranitidine
Conservation strategies to consider first: • Twice daily PPI could be used instead of continuous infusions for the management of gastrointestinal bleeding • Early enteral feeding could shorten the duration of pharmacologic stress ulcer prophylaxis • Avoidance of pharmacologic stress ulcer prophylaxis in hemodynamically stable patients without coagulopathy and limited risk factors	Therapeutic alternatives to consider first: • Several PPIs (e.g., pantoprazole, lansoprazole, omeprazole, esomeprazole, dexlansoprazole) and H2RA (ranitidine, famotidine, cimetidine) are available in Canada • PPIs and H2RAs could be interchanged to manage stress ulcers, reflux, and gastrointestinal bleeding • Antacids could be used in place of PPIs and H2RAs for reflux symptom management Other potential therapeutic alternatives: • Sucralfate is an alternative for stress ulcer prophylaxis
Diuretics: furosemide
Conservation strategies to consider first: • Furosemide infusions can be a more efficient method of fluid removal while minimizing the total dose used • Administering furosemide with metolazone can augment diuresis with theoretically lower doses of furosemide	Therapeutic alternatives to consider first: • Using enteral furosemide can be as effective as IV dosing • Ethacrynic acid is another loop diuretic that could be used in place of furosemide • Thiazide diuretics could be used in the event that loop diuretics are no longer available Other potential therapeutic alternatives: • Low dose dopamine infusions theoretically could augment urine output • Dialysis would be the definitive way to remove fluid in diuretic-refractory fluid overload or in the absence of other pharmacologic options
Antimicrobials: antibiotics, antifungals
Conservation strategies to consider first: • Ensure duration of antimicrobial therapy adheres to best practice guidelines • Engage with antimicrobial stewardship program where available to assist with antimicrobial therapy • Step down from IV to oral antimicrobials as soon as appropriate	Therapeutic alternatives to consider first: • For most classes of antibiotics more than one agent is available in Canada (e.g., in the event of a ceftriaxone shortage cefotaxime or ceftazidime could provide similar coverage) • Even for antimicrobials like vancomycin alternatives for gram-positive coverage exist such as linezolid, daptomycin, and trimethoprim-sulfamethoxazole • Antifungals options exist within the same class and between classes (e.g., fluconazole, itraconazole, caspofungin, micafungin, amphotericin, etc.)
Antiarrhythmic drugs: amiodarone
Conservation strategies to consider first: • Patients with hemodynamically stable new onset atrial fibrillation can be managed with rate control alone (e.g., beta blockers or non-dihydropyridine calcium channel blockers such as diltiazem) • Potentially reversible risk factors for supraventricular tachyarrhythmias should be addressed before resorting to pharmacologic antiarrhythmic therapy (e.g., electrolyte replacement, discontinuing pro-arrhythmic drugs, diuresis for fluid overload)	Therapeutic alternatives to consider first: • Other agents besides amiodarone to consider for the management of atrial fibrillation (e.g., magnesium, procainamide, sotalol, propafenone) • Electrical cardioversion, when successful, can negate the need for antiarrhythmic drugs for hemodynamically unstable atrial fibrillation

COPD = chronic obstructive pulmonary disease; COVID-19 = coronavirus disease; CPOT = critical care pain observation tool; H2RA = histamine-2 receptor antagonist; IV = intravenous; MDI = metred dose inhaler; NRS = numerical rating scale; NMBA = neuromuscular blocking agent; PPI = proton pump inhibitor; RASS = Richmond Agitation and Sedation Scale; RSI = rapid sequence intubation.

Hydromorph Contin®, Purdue Pharma, Pickering, ON, Canada.

M-Eslon®, Ethypharm Inc., Montreal, QC, Canada.

Respimat® Boehringer Ingelheim Canada, Burlington ON, Canada.

Turbuhaler® AstraZeneca Canada, Mississauga, ON, Canada.

Handihaler® Boehringer Ingelheim Canada, Burlington ON, Canada.