key: cord-0778999-3vr4st6r authors: Shirk, Spencer; Kerr, Danielle; Saraceni, Crystal; Hand, Garret; Terrenzi, Michael; McDermott, Andrew; Paz, David A title: The Challenging but Imperative Path to Monoclonal Antibody Use Against COVID-19 for a Small Overseas Military Hospital date: 2021-05-16 journal: Mil Med DOI: 10.1093/milmed/usab193 sha: 5beba47e6706d206596e13928c211fcc73cf5142 doc_id: 778999 cord_uid: 3vr4st6r Upon the U.S. FDA approval in early November for a monoclonal antibody proven to potentially mitigate adverse outcomes from coronavirus disease 2019 (COVID-19) infections, our small overseas community hospital U.S. Naval Hospital Rota, Spain (USNH Rota) requested and received a limited number of doses. Concurrently, our host nation, which previously had reported the highest number of daily deaths from COVID-19, was deep within a second wave of infections, increasing hospital admissions, near intensive care unit capacity, and deaths. As USNH Rota was not normally equipped for the complex infusion center required to effectively deliver the monoclonal antibody, we coordinated a multi-directorate and multidisciplinary effort in order to set up an infusion room that could be dedicated to help with our fight against COVID. Identifying a physician team lead, with subject matter experts from nursing, pharmacy, facilities, and enlisted corpsmen, our team carefully ensured that all requisite steps were set up in advance in order to be able to identify the appropriate patients proactively and treat them safely with the infusion that has been clinically proven to decrease hospital admissions and mortality. Additional benefits included the establishment of an additional negative pressure room near our emergency room for both COVID-19 patients and, when needed, the monoclonal antibody infusion. In mid-January, a COVID-19-positive patient meeting the clinical criteria for monoclonal antibody infusion was safely administered this potentially life-saving medication, a first for small overseas hospitals. Here, we describe the preparation, challenges, obstacles, lessons learned, and successful outcomes toward effectively using the monoclonal antibody overseas. On November 9, 2020, the U.S. FDA issued an Emergency Use Authorization (EUA) to permit the utilization of the monoclonal antibody bamlanivimab for the treatment of mildto-moderate coronavirus disease 2019 (COVID-19). The EUA was based upon positive outcomes found in clinical trials for adults and pediatric patients who are considered high risk for progressing-to-severe COVID-19 requiring hospitalization. 1 For a small, overseas military hospital, without an organic infusion center or an intensive care unit (ICU), the challenges of preparing to properly provide this potentially life-saving treatment were significant. Additionally, in a host nation whose normal ICU capacity had been surpassed with COVID-19 patients several times, 2 it was imperative that we overcome any obstacles in order to not just keep our patients from contributing to the host nation patient burden but also give our patient population the optimal medication to combat COVID-19 and mitigate severe disease. Applying the principles of high reliability, a stepwise multidisciplinary approach was deployed, leveraging subject matter experts from pharmacy, nursing, corpsmen, facilities, and medical staff members. This team developed a local standard operating procedure, established the requisite negative pressure infusion room in a location capable of responding to a severe adverse reaction and screened all COVID-19-positive patients to proactively identify those meeting the clinical criteria. Within 2 months of receipt, the first patient was successfully infused with bamlanivimab, with a marked clinical improvement in symptoms within 24 hours and proof of concept of an infusion team capable of quickly administering the medication to additional patients. In November, 2020, our host nation was entering a second wave of infections and hospitalizations during the COVID-19 pandemic. Our small, overseas military hospital without an organic ICU was closely tracking host nation's ICU capacity, which had been surpassed and survived via augmented ICU beds several times previously. With proactive COVID-19 transmission mitigation strategies in place since March 2020, we had zero evidence for intra-hospital COVID-19 transmission and demonstrated Force Health Protection success, successfully meeting DoD guidance. 3 With a patient population that included beneficiaries at higher risk to severe COVID-19, we were constantly preparing for any treatments to provide world-class health care during the pandemic. In October 2020, the DoD prepared for the acquisition of the investigational therapeutic to treat COVID-19-bamlanivimab. 4 On November 9, 2020, the FDA issued the EUA for bamlanivimab. 5 Subsequently, on November 20, 2020, the Defense Health Agency (DHA)'s weekly global chief medical officer's telephone call discussed the apportionment of bamlanivimab, and we requested to receive five doses, citing concerns for limited community resources for COVID-19-infected patients concurrently at risk for poor outcomes. We had already initiated the investigational phase for possible receipt, including a concept of operations for an infusion center based upon the EUA. The DHA concurred with our leadership that this treatment could be a promising mitigation strategy for the host nation and all categories of eligible beneficiaries and initiated the steps for shipment to us. Following bamlanivimab EUA approval, we were initially selected by the Defense Logistics Agency's Customer Pharmacy Operations Center to receive a shipment from allotments designated by the U.S. Department of Health and Human Services. Once identified as a receiving site, as above, the physical distribution of the bamlanivimab was coordinated by the U.S. Army Medical Material Agency (USAMMA) in conjunction with the Pharmacy Department and Materials Management Department at our hospital. Shipment to our military treatment facility (MTF) was contingent on accountability and acceptance of receipt, storage, and preparation for use. The bamlanivimab shipment was marked for overnight shipping via FedEx on December 4, 2020; however, with our MTF's strategic overseas location and subsequent extended medication shipping timelines, the medication arrived at the facility on December 11, 2020. Ensuring proper cold chain management in the shipping process for bamlanivimab was essential. Temperaturemonitoring software and devices were located inside the shipping container to document the container's internal temperature during the entirety of the journey. Upon receipt of the medication, the temperature-monitoring software had alarmed, indicating that during shipment, the internal temperature of the container exceeded the acceptable range. Owing to the alarmed temperature software upon receipt, the bamlanivimab was immediately placed in the refrigerator between 2 • C and 8 • C, segregated from other pharmacy stock, and labeled "Suspended: DO NOT USE!". Pharmacy staff then reached out to USAMMA to perform an in-depth review of the temperature software logs, and USAMMA subsequently released the product for immediate use on December 15, 2020. Before the arrival of the medication, a thorough review of the manufacturer's recommended administration protocols revealed that a multifaceted process, including procedure development, equipment procurement, space refurbishment, and staffing allocation, would need to be instituted in order to safely and effectively execute the infusion. Clinical and engineering subject matter experts met to establish a rapid needs assessment for creating an infusion space specific to COVID-19-infected patients, a concept for our small hospital that did not previously exist. The specific but extensive needs identified included establishment of negative pressure by modifying existing fixed window, ventilation assessment, plastic tarps to maintain negative pressure yet allow visible access, infusion supplies, ensuring Code Blue alarm system was placed, and an infusion gurney. Our hospital normally has six emergency department (ED) beds with an average of eight patients daily through the ED. Additionally, we have six labor and delivery rooms, two behavioral health inpatient rooms, and six inpatient beds, for a total of 14 total inpatient beds with an average daily inpatient census of 2.7 patients. The team opted to repurpose a room in the vicinity of the ED to provide supportive care in the event the patient experienced an adverse reaction. Additionally, this room had a short and direct route from outside of our MTF, which provided minimal exposure to other patients and staff in our facility and was key in its selection. This space was cleared of unnecessary equipment and then converted into a negative pressure capable room, utilizing direct access to outdoor ventilation and plastic barriers to ensure visualization of the patient (see Figs. 1 and 2) . Concurrently, nursing experts were diligently working to review available supply and solidify the clinical protocol, 6 which once completed was expeditiously reviewed by relevant committees and communicated to the administrative staff for approval. Equipment review was conducted, and it was found that the MTF had all components as identified by the manufacturer. Identification of patients considered at risk for poor outcomes that could include ICU admission or death were adapted directly from manufacturer's recommendations, current CDC guidelines, evidence-based medicine, 7 and DHA instruction as outlined in Table I . The manufacturer's (EUA) guidelines were strictly followed during the preparation of bamlanivimab. An onsite "go by" was developed and all pharmacy staff received competency training on the process. To ensure no doses of the medication were wasted, the pharmacy team did not begin preparation until notified by the provider that the patient was onsite and cleared for infusion. Once notified to begin medication preparation, the pharmacy department utilized a pharmaceutical aseptic isolator to maintain sterility of the product and prepared bamlanivimab according to the directions outlined in the EUA. 8 Real-time closed-loop electronic and verbal communication between members of the infusion team ensured smooth preparation, administration, and observation of patients. Patient candidacy was a looming challenge, given the process for COVID-19 testing and tracking would have to adjust proactively to identify patients early. A dedicated wing of the hospital with its own entrance was designated for all COVID-19 testing, and COVID-19-positive patients were tracked by the preventive medicine department. The lead physician preemptively reviewed, on a daily basis, all COVID-19-positive patients in order to ensure early identification of patients meeting the clinical criteria to potentially benefit from the infusion of bamlanivimab. In this way, an aggressive approach could quickly go from a diagnosis to the potentially life-saving treatment. A 79-year-old male was evaluated in the ED, with a selfreported 7-day history of diarrhea, fatigue, dyspnea, and chest congestion with additional concern for recent exposure to a laboratory-confirmed COVID-19-infected close contact. He had been evaluated earlier in the day in the "influenza-like illness" outpatient clinic where concern was raised that, based on symptom severity at presentation and past medical history, he may require admission. Subsequently, his COVID-19 test returned as detected. His medical history was significant for coronary artery disease, status post-coronary artery bypass graft 2 years prior, hypertension controlled on four antihypertensive medications, as well as chronic kidney disease. In the ED, his symptomatology did not necessitate admission, but due to the potential for decompensation and past history, the patient was determined to be a candidate for bamlanivimab infusion. The previously identified infusion team was notified, and timeline for administration was established. Utilization of the treatment option was concurrently reviewed with the patient before discharge from the ED, with the patient consenting to receive the treatment. On the following day, the patient returned to the MTF prepared to receive the infusion. As per protocol (Table II) , he entered the facility donned with surgical mask and was escorted directly through the external ED entrance into the negative pressure infusion room where he was then formally consented for treatment and venous access was established. Nursing staff reviewed the procedure with the patient and established a baseline of vital signs and symptoms. These would be utilized upon reassessment to gauge any changes that required intervention. It was at this time, the pharmacy team began the medication preparation as per manufacturer's recommendations. Once preparation was complete, the medication was transported directly to the nursing staff for infusion. As per local protocol, the infusion was completed via pump over 1 hour. Vital signs were documented before administration and again after the first 15 minutes, with visual/verbal checks for status change every 15 minutes after that, until full infusion • Air circulator machine should be turned on at least 5 minutes before patient's arrival. 3. Obtain baseline vital signs (VS). This will consist of blood pressure, heart rate, respiratory rate, temperature, and SpO 2 and document into the electronic medical record. 4. Ensure appropriate intravenous (IV) access before contacting pharmacy for medication. 5. Verify that provider's orders and informed consent for infusion are present in the patient's chart. 6. Explain the infusion procedure to the patient. • Ask the patient about any current symptoms that might be later confused with transfusion reaction symptoms (dizziness, itching, and difficulty breathing). • NOTE: Pre-medicate the patient with tylenol and benadryl if ordered by provider and not contraindicated. 7. Inspect the IV bag before administration. • Medication should be prepared by pharmacy as per manufacturer's guidelines for immediate infusion. • Preparation must be free of particulate matter. If present, contact pharmacy and do not administer. 8. Verify patient identity and medication with another registered nurse or provider. 9. Prime the administration set with a 0.20/0.22-micron inline filter with 0.9% sodium chloride. 10. Gently invert the medication 10 times to suspend the components, being careful to not create foam. 11. Spike medication bag with secondary tubing, prime, and connect to primary tubing. 12. Regulate rate of flow as ordered by provider. Goal of infusion is over at least 60 minutes, maximum infusion rate of 270 mL/h. • Monitor for transfusion reactions including fever, chills, nausea, headache, bronchospasm, hypotension, angioedema, throat irritation, rash (including urticarial), pruritus, myalgia, and dizziness. If any are observed, STOP THE INFUSION IMMEDIATELY and notify the provider. 13. Repeat VS 15 minutes after the start of the infusion. • If stable, staff may leave the room but be in the line of sight to minimize exposure until infusion is done and ensure that call bell is available for the patient. If done, then verbally check on the patient every 15 minutes. e.g., "How do you feel now? Any changes since last time we spoke?". 14. After 200-mL infusion is completed, repeat VS. Use normal saline to flush line and ensure the entire dose of medication has been infused (at minimum 25 cc of 0.9% sodium chloride). 15. Post-infusion observation: VS every 30 minutes and verbally check on the patient every 15 minutes, at a minimum of 60 minutes. 16. Remove IV access, discharge patient, and provide discharge education. Ensure patient has copy of "Fact Sheet for Patients, Parents and Caregivers". 17. Document pertinent observations and patient response in nursing notes as well as VS into the patient's AHLTA encounter. was completed. Post-infusion monitoring continued with vital signs every 30 minutes for 1 hour with frequent checks of patient status through the barrier. Nursing staff provided care utilizing full CDC-approved COVID-19 personal protective equipment, which included gown, gloves, N95 respirator, and face shield. The patient was provided a surgical mask to wear for the duration of the time spent inside the facility. The nurse remained in the room with the patient for the initial monitoring period and remained at least in the line of sight throughout. As discussed previously, the negative pressure room was constructed with translucent plastic to allow for adequate remote observation of the patient. The design also permitted communication through the negative pressure barrier, which assisted with continuous patient assessment. Once the patient exited the facility, the infusion room was terminally cleaned according to CDC protocol. 9 The infusion concluded without complication and the patient tolerated well. After the necessary 1 hour of observation, he was discharged to his residence to continue the prescribed medical quarantine. The patient continued to receive daily health checks from the MTF preventive medicine team, who establish and maintain contact with all known positives and persons under investigation. Additionally, the bamlanivimab infusion team called 3 days post infusion and then weekly afterward. Two days following the infusion, the patient noted significant improvement of his symptoms and was back to using his home exercise bike. The patient was considered recovered 2 weeks from his positive test result with no complications from the illness. Novel treatment options, 10 especially during a pandemic, may be more challenging to dispense to smaller overseas military hospitals for several reasons, including logistics and legalities of shipping and receiving biologics or medications, overall reduced co-morbidities in the beneficiary population through thorough medical prescreening, and general perception of low volume or low likelihood of use. In the instance of bamlanivimab, this opportunity presented as a Force Health Protection option that could provide significant positive clinical outcomes in an overseas community that was becoming increasingly overwhelmed with local COVID-19 disease burden. Additionally, there was concern regarding the network's ability to absorb the overflow of any MTF beneficiaries. More specifically, our ability to safely identify patients at high risk for either ICU admission or death from COVID-19, based upon Table II criteria, and subsequent treatment with bamlanivimab was crucial to not just marked improvement in the patient's symptoms but also to reduce the likelihood that the patient would require ICU admission or result in death. 11 A rapid, multidisciplinary approach was required to garner authorization to obtain bamlanivimab and execute the process quickly and safely. This was achieved in the transition from a difficult second wave and a burgeoning third wave of COVID-19 infection in our host nation, which has carried one of the highest COVID-19 incidences per 100,000 inhabitants. 12 Utilizing the principles of high reliability and deferring to expertise, the team included nurses, pharmacists, enlisted corpsmen, facility engineers, infection preventionists, industrial hygienists, and physicians. We faced unique procurement challenges due to the extended shipping timeline of an overseas MTF and consequent concerns regarding proper cold chain management. Identifying a point of contact at USAMMA and maintaining close communication were essential in the successful shipping and receipt of the novel monoclonal antibody. Preparation utilized existing procedures for sterile parenteral medication compounding in the pharmacy department. Clear communication between the infusion and pharmacy team ensured safe and efficient medication preparation while minimizing patient infusion wait time and potential for wasted or damaged product. Our goal was to produce a standardized process that could be easily replicable and executed within 24 hours so as to capture patients in the approved treatment window (up to 10 days from onset of symptoms). Preliminary data have suggested that outcomes improve the earlier the infusion can be administered, which emphasized the importance of having a smooth deployment process for bamlanivimab. 13 Owing to current staffing limitations, we targeted the treatment window to within 24 hours of diagnosis and determination of candidacy. Future planning has been aimed at leveraging staffing and resource allocation in order to initiate the infusion at the time of diagnosis. This goal will be largely dependent on broadening staff training and their availability to break from clinical obligations, resource allocation and availability, and background variables such as patient volume in appropriate treatment spaces at the time of presentation and diagnosis. Our MTF was the first Naval MTF in our region to identify an appropriate patient and successfully execute the administration of bamlanivimab. We believe that the above process could assist the ability to replicate outcomes at both large and small commands. The successful use of bamlanivimab was shared with military regional health command as were lessons learned for wider dissemination. This treatment will likely remain a significant and potentially life-saving tool in our continued fight against the COVID-19 pandemic worldwide. None declared. 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