key: cord-0723248-x8upogco authors: Brown, Connor J.; Lai, Jason; Rubel, Nicolas; Ward, Christen; McLean, Justin; Wheelock, Martin; Steuerwald, Michael; Cathers, Andrew title: Initiation of Inhaled Nitric Oxide by Air Transport Team in Adult COVID-19 Respiratory Failure date: 2022-03-10 journal: Air Med J DOI: 10.1016/j.amj.2022.03.001 sha: 96a2436d361eee46d5ed3b0028e13589f0c3e231 doc_id: 723248 cord_uid: x8upogco The COVID-19 pandemic has caused a significant increase in the volume of critical care flight transports between outlying referral hospitals and tertiary care facilities. Due to the tropism of SARS-CoV-2, flight crews are often asked to transport mechanically ventilated patients in refractory hypoxemic respiratory failure. The authors present a case series of 5 patients with COVID-19 acute respiratory distress syndrome (ARDS) who were initiated on inhaled nitric oxide (iNO) by the transport team prior to rotor-wing transport and survived the journey in stable or improved condition upon arrival. Previously, no case reports have described adults with COVID-19 ARDS transported after iNO initiation by the transport team. This case series shows the feasibility of iNO initiation by trained air medical transport teams and suggests a short-term stabilizing effect of iNO in patients with ARDS from COVID-19. CoV-2, flight crews are often asked to transport mechanically ventilated patients in refractory hypoxemic respiratory failure. The authors present a case series of 5 patients with COVID-19 acute respiratory distress syndrome (ARDS) who were initiated on inhaled nitric oxide (iNO) by the transport team prior to rotor-wing transport and survived the journey in stable or improved condition upon arrival. Previously, no case reports have described adults with COVID-19 ARDS transported after iNO initiation by the transport team. This case series shows the feasibility of iNO initiation by trained air medical transport teams and suggests a short-term stabilizing effect of iNO in patients with ARDS from COVID-19. The COVID-19 pandemic has created a significant strain on the interfacility transport system due to the high volume of critically ill patients with respiratory failure. 1 Transport teams are being called upon to transport patients from hospitals due to lack of local advanced critical care capabilities or lack of beds at the referral center's intensive care unit. Many of these patients are hypoxemic even with aggressive ventilatory settings and pose a significant risk of decompensation during air medical transport. Nitric oxide is an endogenously produced compound that causes vascular smooth muscle cell relaxation and subsequent pulmonary vasodilation. 2 Clinically, the administration of exogenous gaseous nitric oxide has known therapeutic effects for select respiratory pathologies. However, because nitric oxide diffuses into the bloodstream, where it rapidly reacts and is rendered inactive, the half-life is seconds long and therefore iNO must be administered continuously to elicit a lasting response. 3 Because iNO exerts its effect locally, it primarily dilates the pulmonary vasculature and can relieve pathologic pulmonary hypertension. In patients with acute respiratory distress syndrome (ARDS), iNO preferentially vasodilates pulmonary arterioles, which feed pulmonary capillaries that participate in gas exchange. Via this mechanism, iNO reduces right-to-left intrapulmonary shunting with subsequent improvement in ventilation-perfusion matching. 4, 5 Although not routinely used in ARDS, iNO is currently considered a potential bridge therapy in mechanically ventilated ARDS patients with refractory hypoxemia. 6, 7, 8, 9 While heavily researched in the era prior to COVID-19, existing literature on the use of iNO in COVID-19 ARDS consists primarily of small studies and hypothesis-generating reviews. 10, 11 Severe COVID-19 infection frequently presents with acute hypoxemic respiratory failure, often with ARDS. Additionally, it has been shown that COVID-19 accelerates endothelial cell dysfunction, leading to endogenous nitric oxide deficiency. 12 Due to this, there has been a resurgence of interest in the therapeutic use of iNO during the COVID-19 pandemic. Management of acute decompensation in-flight poses challenges due to the natural limitations of the air-medical environment. The use of iNO in COVID-19 patients with ARDS and refractory hypoxemia may allow for the safe transport of patients who would otherwise be too unstable to fly. There is scant literature describing the initiation or use of iNO in COVID-19 ARDS patients in this environment. Here, the authors describe 5 cases from UW Health Med Flight in which iNO was utilized as therapy for safe transport in COVID-19 patients with refractory hypoxemia. In each of these cases, iNO therapy was initiated by a UW Health Med Flight rotor wing aeromedical transport team, which consisted of a flight physician, flight nurse, and flight respiratory therapist. A 55-year-old female with a past medical history of obesity and metabolic syndrome was diagnosed with COVID-19 at a rural hospital approximately 150 miles from the accepting tertiary care hospital. Ten days prior to transport the patient required intubation for hypoxemic respiratory failure with ARDS. During this time the patient was treated with remdesivir, dexamethasone, and convalescent plasma. Her hospital course was complicated by pneumomediastinum 5 days prior to intubation. Upon arrival of the air transport team, she was being sedated with fentanyl, midazolam, and ketamine and was chemically paralyzed with cisatracurium. Ventilator mode was volume control (VC) with a tidal volume (Vt, mL) of 420, respiratory rate (RR) 20, positive end-expiratory pressure (PEEP, cm H2O) 12, and fraction of inspired oxygen (FiO2, %) 100. The patient's ideal body weight (IBW) was 57 kilograms (kg). Arterial blood gas (ABG) was pH 7.41, partial pressure of arterial carbon dioxide (PaCO2, mmHG) 59, partial pressure of arterial oxygen (PaO2, mmHG) 57 with the patient in the prone position. The P:F (partial pressure arterial oxygen/fraction inspired oxygen) ratio was 57. Once supine, vital signs were heart rate (HR) 81, blood pressure (BP) 164/76), RR 20 mechanical, and oxygen saturation (SpO2, %) of 91. On transfer to the air transport team ventilator, ventilator settings and medications were maintained. iNO was initiated at 20 parts per million (ppm). Within minutes, SpO2 improved to 93-99% which was maintained throughout transport. ABG on arrival at the tertiary care facility was pH 7.44, PaCO2 60 and PaO2 of 83. iNO was discontinued 6 days later when the patient was cannulated for venovenous extracorporeal membrane oxygenation (V-V ECMO). After 41 days she died after extubation due to inability to wean from ECMO. A 48-year-old previously healthy male presented to a rural hospital in respiratory distress and was admitted after being diagnosed with COVID-19. He was initially started on bilevel positive airway pressure (BiPAP), but subsequently required intubation due to hypoxemic respiratory failure. He then developed a right-sided pneumothorax requiring chest tube placement after a right internal jugular central venous catheter insertion attempt. He was put in the prone position the day before transport due to persistent hypoxemia. The air transport team was dispatched to retrieve the patient and transport him for ECMO evaluation at the accepting tertiary care hospital. Upon arrival of the air transport team, the patient was in the prone position being sedated with midazolam and propofol infusions and chemical paralyzed with cisatracurium. Referring facility ventilator settings were volume control with Vt 420 ml, RR 32, FiO2 100, PEEP 24 while in the prone position. Preflight ABG had a pH 7.22, PaO2 70, and PaCO2 65. After supination, vital signs were SpO2 of 91% on FiO2 of 100 and PEEP of 14, BP of 117/72 and HR of 120. IBW was 73 kg. The patient was changed over to the transport ventilator and iNO was initiated at 20 ppm in anticipation of a likely desaturation event upon supination. After approximately 10 minutes on iNO therapy the patient was supinated, with an immediate desaturation to 69% that steadily recovered to 80%. The iNO dose was increased to 30 ppm, PEEP was increased from 14 to 20 and then again to 24, with subsequent improvement of the patient's SpO2 to 90%. During flight, sedation with propofol and midazolam were continued and supplemented with intermittent fentanyl boluses, and neuromuscular blockade was maintained. Ventilator mode was VC, with Vt 420, RR 32, FiO2 100 and PEEP 24. During flight, his SpO2 decreased to 88%. The BP also decreased to a systolic of 90 mmHg, after which the propofol dose was decreased. On arrival at the destination facility, initial ABG demonstrated a pH of 7.16, PaCO2 81, and PaO2 40. Vital signs were BP 105/74, HR 116, RR 32 mechanical, SpO2 76% after initial transfer to the ICU ventilator (on PEEP of 20). The patient was rapidly evaluated and initiated on V-V ECMO. The patient developed severe lung injury and was not a candidate for lung transplant and eventually died after withdrawal of life support after over one month of critical care at the destination hospital. A 54-year-old male with a history of hypertension and epilepsy was admitted to a local community hospital with hypoxemia after contracting COVID-19. Due to progressive hypoxemia he eventually required intubation after failing non-invasive ventilation (NIV). He had been treated with remdesivir, dexamethasone, and convalescent plasma. The hospital course was complicated by superimposed bacterial pneumonia treated with ceftriaxone and azithromycin. The patient underwent proning cycles on a 16-hour prone to 8-hour supine schedule, and while in the prone position he tolerated an FiO2 of 60; however when supine he required an FiO2 of 100 and a PEEP of 12 to maintain an SpO2 of 92-93%. A request for transfer to a tertiary care hospital was made due to worsening oxygenation with the goal of consideration for initiation of ECMO. Upon the air transport team arrival, the patient was being sedated with dexmedetomidine, propofol, and fentanyl, was chemically paralyzed with atracurium, and was requiring norepinephrine with concerns for septic shock. Ventilator mode was VC, Vt 450, RR 28, FiO2 100, PEEP 12. IBW was 71 kg. The last ABG prior to transport, taken with the patient in the prone position, was pH 7.17, PaO2 in the 60's, no PaCO2 available, with a P:F ratio in the 60s. BP was 100/60 and SpO2 was 92% with frequent desaturations into the mid-80's with any change in position. Sedation, the neuromuscular blockade and hemodynamic support were continued with the exception of discontinuing the fentanyl infusion and substituting it with intermittent fentanyl boluses. Ventilator settings were continued. iNO was initiated at 40 ppm and SpO2 improved to 93-96%. He was transported supine and transferred to the destination hospital with no desaturation events. ABG on arrival showed a pH of 7.24, PaCO2 51, PaO2 56. Vital signs were BP 120s/50s-70s measured by an arterial line, HR 80's, SpO2 93-96%. He was admitted to the ICU and was evaluated for and placed on V-V ECMO. He was admitted for 27 days with his course complicated by septic shock from Staphylococcus aureus bacteremia and the need for significant hemodynamic support. Due to his poor prognosis, the patient's family withdrew life support and the patient subsequently died. A 42-year-old female with comorbid conditions of obesity, type 2 diabetes, rheumatoid arthritis and asthma was admitted to a rural emergency department after 6 days of symptoms typical of COVID-19 infection. She was intubated 3 days later due to acute hypoxemic respiratory failure. She had been treated with convalescent plasma, remdesivir, tocilizumab, and antibiotics for possible superimposed bacterial infection. The air transport team was dispatched 6 days later to transfer the patient for consideration for V-V ECMO due to ARDS with limited improvement on current therapy. On arrival the patient was being sedated with propofol and fentanyl. She had previously required neuromuscular blockade with cisatracurium and hemodynamic support with norepinephrine, however, both of these had been discontinued by the time the air transport team arrived. Ventilator mode was VC with Vt 400, RR 30, PEEP 13, and FiO2 80. IBW was 62 kg. The most recent ABG had a pH of 7.30, PaCO2 56, PaO2 70 while in the prone position with a FiO2 of 100. P:F ratio was 70. Upon transfer to the transport gurney, she was supinated and placed on iNO which was initiated at 20 ppm. Her sedation medications and ventilator settings were continued during flight, with adjustment to Vt 350 and RR 32 titrated to an end-tidal CO2 of 42. Initial ABG on arrival was pH 7.39, PaCO2 49, PaO2 83. Vital signs were BP 116/72, HR 70, RR 32, SpO2 95%. She was admitted to the ICU and cannulated for V-V ECMO. Three days later she was cannulated for a tracheostomy. ECMO was discontinued 3 days later, and she was eventually discharged to a local long term care facility neurocognitively intact with her tracheostomy taken down prior to discharge. A 52-year-old male with comorbidities of obesity, hypertension, and type 2 diabetes presented to a rural community hospital after 2 weeks of weakness, progressive dyspnea, and cough and was diagnosed with COVID-19. He was treated with convalescent plasma, remdesivir, and dexamethasone. He was also empirically treated for suspected superimposed bacterial pneumonia and was receiving meropenem and tigecycline on the day of transfer. Over the week prior to transport he had progressively increasing oxygen demands, failed NIV, and was intubated for hypoxemic respiratory failure. On the day of transfer he was requiring an FiO2 of 100 and did not tolerate proning due to hypoxemia. Upon arrival of the air transport team, the patient was being sedated with fentanyl and propofol and was chemically paralyzed with vecuronium. Ventilator mode was VC, Vt 420, RR 29, PEEP 10, FiO2 100. IBW was 78 kg. Vital signs prior to transport were BP 172/91, HR 91, RR 28, with an SpO2 of 88%. ABG at that time demonstrated pH 7.26, PaCO2 76, PaO2 73. The P:F ratio was 73. iNO was initiated at 20 ppm by the air transport team with subsequent improvement in SpO2 to the low 90s. Sedation and neuromuscular blocking medications as well as the ventilator settings were continued for the flight. iNO was continued for the duration of the flight, resulting in stable SpO2 readings with a peak of 94% during the 25-minute flight. ABG upon arrival at the destination hospital was pH 7.25, PaCO2 77, PaO2 87. Vital signs were BP 188/72, HR 82, RR 29 mechanical with an SpO2 of 94%. He was admitted to the ICU and evaluated for ECMO but ultimately did not require cannulation. He was extubated 10 days later and discharged home after 15 days. These five cases highlight the potential for oxygenation improvement with iNO administration for adult patients with refractory hypoxemia due to severe COVID-19 ARDS. They also support the utility of iNO as a rescue therapy for air medical transport to a tertiary care facility. iNO has been used successfully in air and ground medical transport of neonatal patients since the 1990s. This practice fills the crucial role of connecting community hospitals, many of which do not have iNO capabilities, and tertiary care centers. 13, 14, 15 Prior to this case series, at least 2 interfacility transports have taken place in which iNO was continued for adult patients with COVID-19, though the mode of transport is not clear. 16 Notably these transports occurred in the setting of a patient already on iNO therapy at the referring facility. In contrast, this case series describes initiation of iNO therapy in patients by the flight team. iNO use in ARDS patients has been shown to cause a short-term increase in oxygenation, though large studies have failed to demonstrate a mortality benefit in the ARDS patient population. 17, 18, 19 However, a large portion of the available data on mortality with iNO use in ARDS does not include studies in which a lung protective ventilation strategy was used. 20 Additionally, none of the studies focused on its use as a bridge in critically ill patients who may not otherwise survive transport to tertiary care facilities with advanced capabilities such as ECMO. In several of the cases included in this series, transport was initiated with the goal of evaluation for ECMO upon arrival. Theoretical physiologic limitations of the use of iNO in the transport setting stem from its possible side effects, which include renal impairment and dose-dependent methemoglobinemia. Renal impairment was described in trials in which iNO was used in-hospital and for longer durations than would occur in the air transport environment. 21, 22 Methemoglobinemia is secondary to the metabolic breakdown of iNO, however in our series iNO was initiated at 20 or 40 ppm and studies have shown that methemoglobinemia does not occur at these doses. 23 Starting in the fall of 2020, advances in technology as well as clinical and operational capabilities have allowed UW Health Med Flight to expand its specialty flight profiles to include iNO. Our neonatal specialty team has utilized iNO on isolette transports on ground and rotor-wing missions for approximately a decade. The recent transition to the Hamilton T-1 ventilator and a larger airframe (Airbus EC145) introduced the option to expand iNO to adult and pediatric patients. Due to the potential technical complexity of these transports as well as the anticipated pathophysiology of the patients, we elected to include a transport respiratory therapist along with our typical nurse-physician medical crew configuration. After obtaining approval from our aviation vendor, we performed multiple in-situ lowfidelity simulations to fine-tune the bedside, loading, unloading and in-flight processes. We then provided in-person as well as asynchronous education to all of our team members, as well as additional low-fidelity simulation and hands-on practice. Given the heterogeneity of the patient population, relative novelty of COVID-19 respiratory failure, and lack of evidence-based guidance, there was no specific institutional protocol to determine which patients received iNO therapy during transport and at what dose to initiate iNO. Individualized treatment decisions were made for each of the patients in this case series based on their overall clinical status. Decisions regarding initiation and dosing of iNO involved collaboration among the referring facility physician, accepting facility intensivist, flight physician, and flight respiratory therapist. Our critical care transport program uses the AeroNox Ⓡ (International Biomedical, Austin, Texas) system for delivering iNO. The full system consists of the AeroNox and 2 D size nitric oxide cylinders. 1 cylinder is the primary cylinder for the AeroNox and the other is back-up for emergency hand ventilation. The secondary cylinder always has a regulator and patient-appropriate bag-valve-mask connected during transport and can supply up to 20 ppm iNO. Our program has 2 nitric oxide systems mounted to isolettes for use for neonatal patients. A third system is kept at the ready and can be mounted into any of the programs' EC145 helicopters or ground ambulances to deliver iNO during adult or pediatric transports outside of isolettes. The system is mounted in the back of the helicopter and can be easily reached to make any adjustments needed throughout the transport (Figure 1 ). iNO is delivered from the AeroNox to the ventilator which is mounted towards the front of the patient care area via a delivery line that inserts into the ventilator circuit at the manifold on the inspiratory side of the circuit. The sample line is inserted downstream on the inspiratory side of the circuit and back to the AeroNox. The lines are secured to the patient cot with carabiners to prevent them from becoming tangled or disconnected. In this case series, the air medical transport team affiliated with the tertiary care center brought an advanced therapy to a referring facility, offering a bridge therapy unavailable locally and allowing for the safe transport of multiple critically ill COVID-19 patients in a generally unforgiving environment. Given the retrospective nature of this case series, a potential confounder regarding the potential benefit of iNO therapy is that in cases involving both ventilator setting adjustments and iNO initiation, it may be difficult to ascertain the relative contributions of each towards any improvement in the patient's oxygenation. Given the severity of the patients' illnesses, all possible avenues to improve their stability for transfer were pursued, including ventilator adjustments and adjustments to medication infusions (such as vasopressors, analgo-sedatives, and neuromuscular blocking agents). Nonetheless, each patient within this series might not have survived transport without iNO. With the proper expertise, skill set, and credentialing, iNO can be initiated by air transport teams for adult COVID-19 patients. This case series illustrates how iNO initiation by an air transport team for adult COVID-19 associated hypoxemic respiratory failure with ARDS is feasible with proper staffing, training, and expertise. Each case presents a patient with significant respiratory compromise due to COVID-19 who had failed all available local therapy at distant rural hospitals. In each case, iNO may have contributed to improved oxygenation during helicopter transport to a tertiary care facility and, in some cases, served as a bridge to more advanced interventions. Further study is needed to validate the efficacy and safety of iNO administration in COVID-19 ARDS in the air medical transport environment. 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