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So far, we have refrained from discussing the COVID-19 pandemic, largely because all of you have been deluged by articles about it. But there have been a few good recommendations recently that pertain specifically to patient safety issues that we feel merit your attention. We probably should not call these “tidbits” because they actually represent extremely serious issues in patient (and staff) safety.
The first time we heard President Trump hyping chloroquine or hydroxychloroquine plus azithromycin for COVID-19, our patient safety antenna popped up. Those drugs are on our list of drugs that can prolong the QT interval and predispose to Torsade de Pointes (see our columns on Torsade listed below). We immediately sent a warning to residents of our local community, advising those who were considering use of these drugs to make sure their physician was aware of the danger and planned EKG monitoring if those drugs were to be used. We have no comment on the efficacy of these antimalarials in COVID-19 but they are being widely used. Hence, it is critical that the risk for Torsade be considered.
The Presidents of the American Heart Association, American College of Cardiology, and Heart Rhythm Society have issued recommendations on using hydroxychloroquine and azithromycin to treat COVID-19 in patients (Roden 2020). They recommend the following mechanisms to minimize arrhythmia:
Electrocardiographic/QT interval monitoring:
Correction of hypokalemia to levels of >4mEq/Land hypomagnesemia to levels of >2 mg/dL.
Avoid other QTc prolonging agents whenever feasible.
Mayo Clinic cardiologist Michael Ackerman was quite vocal in an interview with NBC News (Przybyla 2020) about laymen and physicians talking about use of these antimalarial drugs without discussing the potential serious cardiac rhythm implications. Ackerman and his Mayo Clinic colleagues have created a nice algorithm, published in Mayo Clinic Proceedings (Giudicessi 2020), to help physicians more safely prescribe hydroxychloroquine by identifying patients at greatest risk for drug-induced sudden cardiac death.
ISMP (Institute for Safe Medication Practices) also warned about the potential arrhythmogenic effects of these drugs (ISMP 2020a). They note that ventricular arrhythmias and torsade de pointes have been reported, and drug labeling warns against administering these drugs with other drugs that have the potential to prolong the QT interval. They note that azithromycin itself may prolong the QT interval, so taking the drug in combination with hydroxychloroquine or chloroquine may enhance the overall QTc-prolonging effect. Patients with additional risk factors for QTc prolongation may be at even higher risk. Thus, patients taking this combination should be monitored for QTc interval prolongation and ventricular arrhythmias.
Combinations of drugs that can prolong the QT interval might be expected to be particularly dangerous. Hence, the extreme concern about adding azithromycin to one of the antimalarial agents. Patients with COVID-19 and other multiple comorbidities are likely to be on other medications that may prolong the QT interval. Also, since COVID-19 may also present with gastrointestinal symptoms, some patients may have been taking the commonly used anti-diarrheal loperamide (Imodium and numerous OTC formulations) that the FDA warned about in 2016 (FDA 2016).
For a full list of drugs that commonly cause prolongation of the QT interval and may lead to Torsade de Pointes, go to the CredibleMeds® website. That extremely valuable site provides frequent updates when new information becomes available about drugs that may prolong the QT interval.
The only study we know of where the effects of this hydroxychloroquine/azithromycin combination on the QT interval has not been peer reviewed but showed the QTc was prolonged maximally from baseline between days 3 and 4 (Chorin 2020). In 30% of patients the QTc increased by greater than 40msec and in 11% of patients the QTc increased to >500 msec (considered the dangerous level in most).
Furthermore, the additive effect of drugs on the QT interval may not just apply when the drugs are given concomitantly. ISMP (ISMP 2020b) described a patient who suffered cardiac arrest while on hydroxychloroquine after azithromycin had been discontinued. The hydroxychloroquine was started one day after azithromycin had been discontinued. On day 5 the patient developed ventricular fibrillation and cardiac arrest and subsequent EKG showed a QTc of 605 msec (a QTc above 470 msec is considered abnormally long in women). The article goes on to describe the long half lives of each of these drugs (hydroxychloroquine 40 days, chloroquine 5 days, azithromycin 72 hours).
If use of any of these drugs is considered, the patient should have both a baseline EKG to measure the QTc interval and regular EKG’s to monitor for prolongation. For those patients who are hospitalized, many physiological monitoring systems have the capability of monitoring the QT interval and can provide alerts. In those patients not on continuous monitoring (or where the monitors cannot determine QT intervals) daily 12-lead EKG’s should be done.
Congenital and drug-induced QT prolongation are not the only factors putting these patients at risk for malignant arrhythmia. Hospitalized patients have a whole host of other factors that may prolong the QT interval and precipitate malignant arrhythmias in vulnerable patients. These include underlying heart disease, electrolyte abnormalities (eg. hypokalemia, hypomagnesemia, hypocalcemia), COPD, renal or hepatic impairment, and bradycardia) all of which may be precipitating factors. Many seriously ill patient hospitalized with COVID-19 may also share some of these conditions.
For those of you who are interested, there is a YouTube video about multiple other aspects of chloroquine and hydroxychloroquine from the University of Washington Medicine (Escobar 2020).
Some of our prior columns on QT interval prolongation and Torsade de Pointes:
June 29, 2010 “Torsade de Pointes: Are Your Patients At Risk?”
February 5, 2013 “Antidepressants and QT Interval Prolongation”
April 9, 2013 “Mayo Clinic System Alerts for QT Interval Prolongation”
April 2015 “Anesthesia and QTc Prolongation”
October 10, 2017 “More on Torsade de Pointes”
June 25, 2019 “Found Dead in a Bed – Part 2”
Fire risk in an oxygen-rich environment
The UK National Health Services issued an alert warning of the risk of fire in the COVID-19 hospital environment (NHS 2020). The density of ventilators on COVID-19 units may lead to an oxygen-rich environment that can predispose to fires. In such and oxygen-rich environment, any spark or heat source (for example, from a defibrillator) could trigger a fire. One might anticipate that splitting ventilators (i.e. using one ventilator for two patients) might make oxygen leaks easier and increase the oxygen in the air. Even in non-ICU settings, the increased use of oxygen could be problematic. The NHS alert stresses facilities need to ensure there is good natural and mechanical ventilation in all areas where oxygen is being used.
COVID-19 has increasingly been associated with thrombotic events (large vessel clots, DVT/PE, arterial events, small vessel disease, and microvascular thrombosis (Phend 2020). The International Society on Thrombosis and Haemostasis (ISTH) has published guidelines regarding anticoagulants in COVID-19 patients (Moll 2020). An article on coagulopathy in COVID-19 (Shaw 2020) discusses multiple opinions on the issues of prophylactic anticoagulants versus full anticoagulation.
A recent correspondence in the New England Journal of Medicine (Zhang 2020) described an older man in China with a history of hypertension, diabetes, and stroke who developed COVID-19 and required mechanical ventilation. He had evidence of ischemia in 3 limbs and CT scan of the brain showed bilateral cerebral infarcts in multiple vascular territories. Lab findings included leukocytosis, thrombocytopenia, an elevated prothrombin time and partial thromboplastin time, elevated levels of fibrinogen and d-dimer, and antiphospholipid antibodies. Two other patients in the ICU had similar findings. They note that the presence of these antibodies may rarely lead to thrombotic events that are difficult to differentiate from other causes of multifocal thrombosis in critically patients, such as disseminated intravascular coagulation, heparin-induced thrombocytopenia, and thrombotic microangiopathy.
A cohort study from Wuhan, China found that D-dimer levels over 1 mcg/L at admission predicted an 18-fold increase in the odds of death before discharge, though the exact mechanism for this is unclear (Zhou 2020).
Independent double checks
We’ve discussed the pros and cons of double checks in numerous columns, Truly independent double checks do have a role in certain scenarios. But requiring a double check may increase the exposure of a healthcare professional to COVID-19. ISMP (ISMP 2020c) recently addressed the need to balance the benefits of double checks versus the risks of exposure and the need to conserve personal protective equipment (PPE) when doing double checks in the COVID-19 environment. They found that most organizations are establishing ways to conduct critical parts of independent double checks without entering a patient’s room. For example, a hard stop in EHR’s requiring
dual documentation of verification before proceeding now reflects only those components of the check that can be accomplished outside the patient’s room.
They also describe how some hospitals became innovative. Where infusion pumps remain in the patient’s room, the nurse who enters the room takes a picture of the pump screen using a mobile phone device left in the room, and sends the picture to a nurse outside the room via a secure messaging system. This allows most components of the independent double check to occur. (We’ll have to add that to our list of pros and cons of smartphones in healthcare!).
Medication reconciliation and discharge communication
ISMP Canada (ISMP Canada 2020) received a report about a student health care provider who obtained a best possible medication history (BPMH) from a patient in a face-to-face interview. It was later discovered that the patient was under investigation for suspected COVID-19 virus. A review of the circumstances of this incident brought to light an opportunity for improvement. The facility consequently planned to implement a process to conduct medication history interviews by phone.
That means you need to evaluate (both on the hospital side and the patient side) the availability for telephone, video-calling, and email communication, including security and practicality of internet access, email accounts, in-room telephone, mobile phone, internet-based video-calling platform, intercom, or 2-way communicating baby monitors. Staff in your registration department will need to document the patient’s mobile phone number and email address to facilitate virtual conversations and reduce the need for in-room meetings.
They go on to describe the process of medication reconciliation, including not only digital identification of medications but also visual identification (via video or sending photographs of the pills or containers via email).
They go on to describe how the same systems can be used to educate patients at or just after hospital discharge (including ways to involve the patient’s PCP and community pharmacy).
Wow! They did this because of the COVID-19 pandemic, but think how this could be used at any time. Particularly now that CMS is relaxing its guidelines on telemedicine, what better way to conduct the annual “wellness visit” than by using telemedicine. The patient doesn’t have to bring in their “brown bag” of medications but can simply show everything in their medicine cabinet to you via these communication links. It saves all time and still allows for face-to-face interaction.
Prehabilitation for COVID-19
Last week’s Patient Safety Tip of the Week “From Preoperative Assessment to Preoperative Optimization” discussed how prehabilitation may help reduce complications prior to surgery. An opinion piece (Silver 2020) in the most recent issue of the British Medical Journal suggests we should use prehabilitation to prepare patients for COVID-19 infections. Julie Silver, Chair of Harvard’s Department of Physical Medicine, notes that strategies we’ve employed to slow the spread of COVID-19 (eg. social distancing, sheltering in place) could have the unintentional effect of decreasing physical activity and contributing to cardiopulmonary deconditioning. That would be particularly devastating in the elderly, who are already at risk of increased morbidity and mortality if they get COVID-19. She goes on to posit that there currently exists a window of opportunity whereby physicians can recommend a best practice approach and advise patients and the public about how to maintain and optimize their baseline fitness and nutritional health, using techniques used prior to surgery, such as a combination of exercise, nutrition, smoking cessation, and stress reduction. She emphasizes that small changes in cardiopulmonary fitness may have a large impact on patients who are frail, including elderly patients with multiple comorbidities. All these interventions can be delivered while patients are practicing social distancing or are sheltering in place and can be easily delivered via telemedicine. These are great recommendations. Don’t just think about managing patients once they contract or have been exposed to coronavirus. Identify your highest risk patients (the elderly, those with multiple comorbidities, and the frail) and interact with them via telemedicine to get them involved in prehabilitation to improve the chances of survival if and when they do develop COVID-19.
Roden DM, Harrington RA, Poppas A, Russo AM. Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 2019) Treatment. Circulation 2020; Published ahead of print April 8, 2020
Przybyla H. Mayo Clinic cardiologist: 'Inexcusable' to ignore hydroxychloroquine side effects. NBC News 2020; April 7, 2020
Giudicessi JR , Noseworthy PA, Friedman PA, Ackerman MJ. Urgent guidance for navigating and circumventing the QTc prolonging and torsadogenic potential of possible pharmacotherapies for COVID-19. Mayo Clin Proc 2020; 95(x): xx-x [published online ahead of print March 25, 2020]
ISMP (Institute for Safe Medication Practices). Limit use and protect supplies of unproven but widely prescribed COVID-19 treatment. ISMP Medication Safety Alert! Acute Care Edition 2020; Special Edition 25(6): 1, 3-5 March 26, 2020
FDA (US Food and Drug Administration). FDA Drug Safety Communication: FDA warns about serious heart problems with high doses of the antidiarrheal medicine loperamide (Imodium), including from abuse and misuse. FDA Safety Announcement June 7, 2016
Chorin E, Dai M, Shulman E, et al. The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin. medRxiv 2020; 2020.04.02.20047050; Preprinted without peer review April 3, 2020
ISMP (Institute for Safe Medication Practices). Patient taking hydroxychloroquine right after discontinuing azithromycin develops QTc prolongation and cardiac arrest. ISMP Medication Safety Alert! Acute Care Edition 2020; Special Edition 25(7): 1, 3-4 April 9, 2020
Escobar ZK. Chloroquine & Hydroxychloroquine. University of Washington Medicine. YouTube March 19, 2020
NHS (National Health Services UK). Novel coronavirus (COVID-19) standard operating procedure. Design note: COVID-19 ward for intubated patients. NHS 2020; March 22, 2020
Phend C. Anticoagulation Guidance Emerging for Severe COVID-19
— Pragmatic choices dominate as guidelines are shaping up. MedPage Today 2020; April 8, 2020
Moll S. COVID-19 and Coagulopathy – Two Management Guidance Documents For Health Care Professionals. Clot Connect 2020; Posted on March 26, 2020
Zhang Y, Xiao M, Zhang S, et al. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19. NEJM 2020; April 8, 2020
Shaw G. Abnormal Clotting and COVID-19. Infectious Disease Special Edition 2020; April 9, 2020
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet 2020; 395(10229): 1054-1062
ISMP (Institute for Safe Medication Practices). Suspending independent double checks. ISMP Medication Safety Alert! Acute Care Edition 2020; Special Edition 25(7): 1-2 April 9, 2020
ISMP Canada. Virtual Medication History Interviews and Discharge Education. ISMP Canada Safety Bulletin 2020; 20(2): April 7, 2020
Silver JK. Prehabilitation could save lives in a pandemic BMJ 2020; 369 :m1386
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