Welcome to the SCCM microlearning on analgesic, sedative, and paralytic shortages during the COVID crisis. My name is Paul Zemed. I'm a clinical pharmacy practice manager at Boston, Massachusetts, and I have no disclosures. Unfortunately, drug shortages, particularly of analgesic, sedatives, and neuromuscular blockers, are fairly common, even without the COVID crisis. Why do they occur and how to monitor? I'm going to refer you to these two webpages, the FDA, as well as ACHP's drug shortages webpages. Unfortunately, these drug shortages tend to increase with increased demand, but there's also manufacturing issues, of course, quality issues, production issues, quota issues, and discontinuations. What can be done? I think it starts with a multidisciplinary team, monitoring both the incoming of supply as well as the outgoing of demand of the individual patients being used. Having mitigation strategies as far in advance as possible, so recognizing that a drug might go on shortage and identifying what the mitigation strategies will be before it comes to the crisis mode, and having effective communication across disciplines and having everyone on the same page. Important to note that there are many mitigation strategies for pain, agitation, and delirium in the critical care setting, which are non-drug specific, such as setting a goal, assessing to that goal, having non-pharmacological strategies such as ventilator adjustments, having the default be awake and alert so we're using less medications, symptom trigger boluses, sedation holiday, analogous sedation, patient-specific pharmacotherapy, and rotations of medications to avoid accumulation. Each one of these strategies is going to be important during the COVID-19 crisis because at some point, most of these strategies are going to be used on an individual patient. Just to highlight three key recommendations from the 2018 PADAS guidelines. One is to have an assessment-driven, protocol-based approach. Two, have suggesting light sedation. And three, the avoidance of benzodiazepines when possible. We know that we should be targeting our pain, sedation, delirium, and neuromuscular blockers to specific goals with the key of having patients on the sedatives and neuromuscular blockers for the shortest amount of time possible. There are several analyses that suggest that lighter sedation will have patients off the mechanical ventilator and out of the ICU earlier. There's also some suggesting that it's at least no difference in the post-traumatic stress syndrome. In fact, there may even be less post-traumatic stress syndrome when patients are awake and alert in the ICU setting. The relatively early COVID-19 ICU patients have taught us a lot, in particular that many of these patients, at least earlier on in their critical illness, may need deep sedation for respiratory compliance. I think it's important to note, though, that we are using these drugs more for their side effects than they are for their therapeutic effect of pain or sedation, where it's more of trying to suppress the respiratory drive and make a patient compliant with the PDF ratio. Therefore, the PDF ratio has to be one of those goals. And once that PDF ratio improves, then we start to think about coming back on the sedatives. So there are many potentially unwanted effects of opioids, but unfortunately it's one of these situations where oftentimes we're going to be using some of these side effects for their therapeutic properties, such as respiratory depression and sedation with the opioids. But some things that are going to happen are almost universally are going to be patients going to get constipated. We have the risk of withdrawal and delirium. And there's some specific side effects of specific agents, such as fentanyl and zoofentanyl have the context-specific half-life, which grows over the course of time. Although it might be a relatively fast-acting drug, over the course of time, it'll stay in the system longer. Remifentanil has taxiphylaxis, methadone has QT prolongation, for example. One of the medications that's been commonly on shortage in the COVID-19 crisis is IV fentanyl. There's at least two analyses that suggest the hydromorphone may be equally as effective, if not, maybe even potentially more effective than observational data. The first graph shows when a patient was originally on fentanyl and then transitioned to hydromorphone, there was a massive reduction in the amount of propofol the patient needed. And the second graph was patients who were on ECMO actually had an increased delirium-free, coma-free days in the first seven days, hydromorphone versus fentanyl. So there may be a signal that hydromorphone is at least as good as fentanyl in the ICU. Of course, there are many potentially unwanted effects associated with our sedatives. Similar to the opioids, we are in many cases using these drugs for the suppression of the respiratory drive in patients with ARDS, but we need to recognize that that's the side effect of the drug and that delirium, hypertriglyceridemia can happen. And we know that with the COVID-19 patients that that actually happens at a pretty high rate, suggesting that hypertriglyceridemia is a real problem in the COVID-19. Of course, we don't want to use benzodiazepines and many of them have the same side effects that we've been talking about, contact-specific half-life, which grows, delirium accumulation, also propylene glycol toxicity with arazepam. We know that texametatomib really can't get you down to that deep level of sedation or suppress the respiratory drive. Therefore, really using it in the early stages when patients are getting neuromuscular blocked, et cetera, is likely not the best time for it, but could be a fantastic drug for patients as they have an improving PDF ratio and are trying to get to light sedation. Ketamine certainly plays a role, in particular if a patient has pain, but also when the patient is in neuromuscular blockade, if ketamine is a drug that you have available, that this is a drug that you can give the doses to get down to the anesthetic doses. And of course, we have the antipsychotics as additive sedatives. The PAD-IS guideline broke down the risk factors for delirium into modifiable and non-modifiable. And I want to just point out that benzodiazepines are a modifiable risk factor for delirium, but many of the risk factors are non-modifiable. The PAD-IS guideline recommends that medications aren't routinely used to treat or prevent delirium. However, in practice, I think the reality is that in patients who are, specifically the patients who are agitated, we will use drugs such as dexamethamidine, antipsychotics, palpebric acid, methadone, phenobarbital, and clonidine. Particularly in patients who are going from a deep level sedation to a lighter level of sedation, they may experience agitated delirium. So we could start to use some of these medications as additive sedatives as we come off the high-dose propofol and opioids, for example. Recent analysis on neuromuscular blockers in ARDS suggests that there was no difference between the control group and the intervention group, and the intervention group was early neuromuscular blockers for 48 hours. And in fact, there was increased likelihood that patients in the control group actually had a lighter level of sedation. The 2016 guideline on neuromuscular blockers in ICU patients suggested that a P to F ratio less than 150 should be a weak recommendation for early initiation of continuous neuromuscular blockers. However, the COVID-19 neuromuscular blocker suggestions that it would be intermittent boluses tried first, and if a patient was persistent, then the patient could be tried on continuous neuromuscular blockers. And the NIH had very similar recommendations. So in summary, medication shortages are common, particularly with the current increase in demand, and the management of pain, agitation, delirium, and neuromuscular blocking agents in patients with ARDS, secondary to COVID ICU, should be goal-directed. Continuous assessment of the patient-specific goal in response to therapy is really imperative.

drug shortages

COVID-19 crisis

multidisciplinary team

pain management

alternative drugs