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This article presents a case study demonstrating various rescue therapies considered in the care of a patient with severe, refractory hypoxemia secondary to acute respiratory distress syndrome. In particular, inhaled epoprostenol (Flolan) is becoming an increasingly common alternative to nitric oxide in the treatment of severe, refractory hypoxemia. Research comparing the 2 inhaled vasodilators suggests that epoprostenol is equally efficacious, easier to administer, less costly, and has fewer adverse effects. This article, using a case study approach, discusses the practical implications of this emerging therapy.
A 42-year-old previously healthy, nonsmoking European-American man was transferred to a tertiary care center with severe, refractory hypoxemia and a diagnosis of acute respiratory distress syndrome (ARDS). The patient's illness began approximately 1 month earlier when he presented to his primary care physician with symptoms of an upper respiratory tract infection. He was treated with sulfamethoxazole/trimethoprim (Bactrim DS; AR Scientific, Philadelphia, Pennsylvania) for 7 days, and when his symptoms did not improve, he received 7 additional days of the same antibiotic. After 14 days of the oral antibiotic, he was admitted to a community hospital with diaphoresis, chills, and respiratory distress. Initial arterial blood gas results on room air were as follows: pH 7.45; PaCO2 38 mm Hg; and partial pressure of arterial oxygen (PaO2) 38 mm Hg. A computed tomography (CT) angiogram of his chest showed bilateral lower lobe infiltrates and was negative for pulmonary embolus.
The patient was transferred to a nearby larger hospital, where a trial of bilevel positive airway pressure ventilation to manage his hypoxemia failed. He was intubated and mechanically ventilated. Over the next 2 weeks, the patient remained severely hypoxemic despite the administration of broad-spectrum antibiotics, appropriate fluid resuscitation, and multiple adjustments to his mechanical ventilator settings while implementing lung protective strategies. Repeat CT angiograms of the chest performed during the third and fourth weeks of the patient's illness confirmed bilateral infiltrates and no evidence of pulmonary embolus. An echocardiogram was negative for shunting or vegetation, and left ventricular ejection fraction was 50%. Bronchoalveolar lavage was negative for bacterial isolates or other pathogens. The patient was transferred to a tertiary care center with severe, refractory hypoxemia approximately 2 weeks after his initial hospitalization and 4 weeks after initial symptoms.
In the cardiac surgery intensive care unit, he was placed on veno-venous extracorporeal membrane oxygenation (ECMO). Over the next week, he required sedation, paralysis, and vasopressors and remained mechanically ventilated with lung protective settings. The patient received ECMO for 9 days, and upon discontinuation of ECMO, inhaled nitric oxide (iNO) was initiated. The pulmonary critical care team was consulted and the patient was transferred to the respiratory intensive care unit. The patient was unable to tolerate discontinuation of iNO and was eventually switched from iNO to inhaled epoprostenol at 0.05 [mu]g/kg/min. The health care team determined that epoprostenol was equally effective as a pulmonary vasodilator, was easier to administer, possessed fewer adverse effects, and afforded significant cost savings. During the 16 hours after initiation of epoprostenol, the patient's fraction of inspired oxygen (FIO2) was weaned from 100% to 40%, as detailed in Table 1.
Over the next 13 days, the patient did not tolerate weaning from inhaled epoprostenol. Additional methods of rescue therapy were attempted, including alveolar recruitment maneuvers and prone positioning, with no improvement in oxygenation. Inhaled epoprostenol therapy was the only identifiable measure that successfully maintained adequate oxygenation during this time. A CT of the chest during the sixth week of his respiratory illness revealed bilateral, diffuse bronchiectasis with subpleural cystic changes (honeycombing) and a dilated main pulmonary artery. Findings were interpreted as pulmonary hypertension and fibrosis consistent with ARDS.
Inhaled epoprostenol therapy was eventually discontinued after 13 days and the patient was maintained on pressure control ventilation, with a positive end-expiratory pressure (PEEP) of 10 cm H2O and FIO2 of 40% to 60%. At this time, the primary goals of care shifted toward ventilator weaning and rehabilitation of the patient. After a total of 2 months of mechanical ventilation, the patient was successfully weaned from the ventilator. He was discharged to a rehabilitation facility 3 months after his initial presentation with respiratory symptoms. At the time of discharge, the patient was alert and oriented, transferring out of bed with assistance, maintaining adequate nutritional intake by mouth, and requiring 4 L of oxygen by nasal cannula.
The ARDS Definition Task Force describes ARDS as "a type of acute, diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, increased lung weight, and loss of aerated tissue."1 As a result of direct or indirect injury (with pneumonia and sepsis as leading causes), neutrophils migrate into the alveolar space, causing damage to the pulmonary vascular epithelium. Subsequent flooding of the alveoli with protein-rich fluid leads to intrapulmonary shunting, decreased lung compliance, and refractory hypoxemia.2 In addition, activation of the clotting cascade during ARDS leads to the development of fibrin-rich microthromboemboli, both in the lungs and systemically.2,3
As many as 92% of patients with ARDS develop some degree of pulmonary hypertension as a result of inflammation, mechanical obstruction from microthromboemboli, and hypoxic vasoconstriction.2,4,5 In the later phase of the disease, alveoli may undergo a fibroproliferative process in which the patient develops a pulmonary fibrosis-like picture.2
Traditionally, treatment of ARDS involves addressing the underlying cause, conservative fluid management, lung protective ventilation strategies, and supportive care of the patient.2 A subset of patients with ARDS develop severe, refractory hypoxemia. Rescue therapies used in this population include ECMO, high-frequency oscillatory ventilation, prone positioning, iNO, and inhaled prostacyclin therapy. Although rescue therapies have been shown to improve oxygenation, none have proven to improve mortality rates.2,5 In 2012, the ARDS Definition Task Force reported mortality rates ranging from 27% to 45%, with the varying mortality rates depending on the stage of the disease.1Table 2 describes the stages of ARDS. Most deaths in ARDS result from sepsis and multiorgan failure, with refractory hypoxemia accounting for less than 15%.3,6
The management of patients with refractory hypoxemia and ARDS is extremely challenging. The purpose of this article was to describe a strategy to improve oxygenation through pulmonary vasculature dilation. Two drugs, iNO and epoprostenol, are detailed as potential interventions.
In the past 2 decades, inhaled vasodilators have been considered as a potential rescue therapy for severe, refractory hypoxemia in ARDS. The therapy is thought to selectively recruit blood flow to the ventilated alveoli and spare nonventilated areas of lung parenchyma.5,7 Absorption of the aerosolized vasodilator directly by the alveolar epithelium has proven to improve ventilation/perfusion matching, increase arterial oxygenation, and decrease pulmonary artery pressure (PAP).5,8 In addition, as a result of a decrease in PAP, afterload in the right side of the heart is reduced, lessening the propensity for right ventricular failure.4,5 In particular, iNO and inhaled epoprostenol have been used as adjuncts to lung protective strategies in severe, refractory hypoxemia.8 Inhaled epoprostenol has been gaining favor more recently as an equally efficacious, easier to administer, and less costly option as compared with iNO.
Nitric oxide is a potent vasodilator that facilitates smooth muscle relaxation in the pulmonary vasculature through the production of cyclic guanosine monophosphate.7 Because of the short half-life (measured in seconds), there is lack of systemic vasodilation when administered via the inhalation route.7 However, the equipment used to administer iNO is technologically sophisticated and incurs substantial costs.8 The charge for nitric oxide therapy is approximately $115 per hour. The dose range for iNO is 2 to 80 parts per million (ppm). Substantial improvements in oxygenation have been confirmed at low doses of 20 ppm or less.5,7 At higher doses of greater than 40 ppm, concern for methemoglobinemia arises because of the interaction of nitric oxide and oxyhemoglobin. Doses higher than 40 ppm can also lead to a decline in oxygenation. This is thought to be caused by an overabundance of nitric oxide spilling into poorly ventilated lung tissue, causing recruitment of blood flow to these areas, resulting in increased pulmonary shunting.7 In addition, the proinflammatory effects of reactive nitrogen species (from the interaction of nitric oxide and high levels of oxygen) on pulmonary vasculature are concerning.5,7 Although iNO can improve oxygenation in refractory hypoxemia, no study has proven survival benefit.5
Epoprostenol (Flolan; GlaxoSmithKline, Research Triangle Park, North Carolina) is the synthetic form of prostacyclin, a prostaglandin derived from arachidonic acid in the vascular epithelium. Prostacyclin binds to prostanoid receptors, causing an increase in cyclic adenosine monophosphate, leading to vasodilation of smooth muscle.9,10 In addition to its vasodilatory effects, prostacyclin is also an inhibitor of platelet aggregation.11 This is a potential added benefit given the development of microthromboemboli associated with ARDS; however, consideration must also be given to the theoretical risk of bleeding.9,10 Epoprostenol is metabolized into a much weaker metabolite and has a half-life of 3 to 6 minutes.7,10 When given in the recommended dose range of 5 to 50 ng/kg/min (using ideal body weight) via the inhalation route, the effects of the drug are localized to the lung tissue with reduced risk for systemic hypotension.8,11,12 As with iNO, excessive dose of inhaled epoprostenol could theoretically cause systemic effects if nonventilated areas of lung vasculature are vasodilated.7 This is also a concern associated with administering epoprostenol via the intravenous route for the treatment of refractory hypoxemia in ARDS. Although intravenous administration has been approved by the Food and Drug Administration since the 1990s for the treatment of pulmonary arterial hypertension, its nonselective vasodilation would likely cause adverse effects such as hypotension, flushing, headache, nausea, dizziness, chest pain, and increased shunting, resulting in a worsening of oxygenation.9,11
A standardized method of administration for inhaled epoprostenol has yet to be developed. Institutions use various concentrations of the drug and different administration systems; however, the basic concept of delivery is universal.4 Epoprostenol is supplied as a powder that must be reconstituted with a manufacturer-provided glycine buffer and is delivered continuously through a nebulizer system attached to the inspiratory line of the ventilator.9,12 The equipment is far less space consuming than iNO and therapy is substantially cheaper. A 50-mL bag of epoprostenol (which lasts up to 8 hours) costs approximately $75. Although neither drug is currently approved by the Food and Drug Administration for use in adults, cost recovery is less of an issue with inhaled epoprostenol. Greater detail on the administration of epoprostenol will be discussed later in this article.
Inhaled epoprostenol given at low doses has been shown to improve pulmonary arterial blood flow and decrease PAP, thereby improving arterial oxygenation.8 Compared with iNO, its use with refractory hypoxemia in the ARDS population shows promise, especially upon consideration of seemingly fewer and less toxic adverse effects.7,8 However, as with iNO, although inhaled epoprostenol has been shown to improve oxygenation in ARDS, research has not yet proven survival benefit.4
The use of iNO as a rescue therapy for severe, refractory hypoxemia has been well studied in the past 2 decades. Inhaled epoprostenol has historically received less attention. In 1993, Walmrath and colleagues13 published data on the effects of aerosolized epoprostenol in the ARDS population. This initial, small study enrolled 3 patients with ARDS and a PaO2/FIO2 ratio lower than 150 mm Hg despite maximal ventilator settings. During treatment with inhaled epoprostenol at 17 to 50 ng/kg/min, mean PAP (mPAP) decreased from 40.3 to 32 mm Hg, pulmonary vascular resistance decreased by 30%, and PaO2/FIO2 increased from a mean of 119.5 to 173 mm Hg. Cardiac output and pulmonary capillary wedge pressure were essentially unchanged. After discontinuation of therapy, gas exchange parameters returned to pretreatment levels within 60 minutes. Walmrath and colleagues13 hypothesized that this route of administration targeted well-ventilated alveoli, improving ventilation/perfusion matching owing to the redistribution of blood.
In 1996, another pioneer in the study of inhaled epoprostenol compared the efficacy of epoprostenol with that of iNO. Van Heerden and colleagues14 studied 5 patients with refractory hypoxemia secondary to ARDS. In a crossover design, the patients received 30 minutes of either iNO at 10 ppm or inhaled epoprostenol at 50 ng/kg/min followed by 60 minutes of rest to allow drug clearance. This was then followed by administration of the opposite drug for 30 minutes. Inhaled epoprostenol was proven to be equally effective as iNO in improving oxygenation. There was no associated change in heart rate, blood pressure, central venous pressure, cardiac output, or pulmonary capillary wedge pressure with either of the agents.14 A subsequent study by van Heerden and colleagues in 200015 examining dose response with inhaled epoprostenol demonstrated that the largest incremental change in PaO2/FIO2 was upon initiation of the drug (0-10 ng/kg/min). Further increasing the dose (in the 10-50 ng/kg/min range) resulted in smaller incremental changes.15
Although not specific to ARDS, a recent study by Tabrizi and colleagues8 studied the use of inhaled epoprostenol as a less costly alternative to iNO. The study included 36 surgical intensive care patients with severe hypoxemia (PaO2/FIO2 <100 mm Hg or SpO2 <90% on FIO2 of 80%-100% and PEEP of >=10 cm H2O). PaO2/FIO2 increased from a mean of 67 to 142 mm Hg after 12 hours of therapy and further increased to a mean of 202 mm Hg after 48 hours of therapy. Within 48 hours, at least 90% of the patients tolerated an FIO2 of 60% or lower. Patients started on inhaled epoprostenol therapy within 7 days of intubation had greater improvements in mean PaO2/FIO2 compared with those started more than 7 days after intubation. The authors suspect that patients have a more favorable response if treatment is started during the acute stages of inflammation, rather than during the chronic state.8
In 2012, Mullin and colleagues16 reported a study involving 25 patients with either refractory hypoxemia or severe pulmonary hypertension who received inhaled epoprostenol. Administration of the inhaled vasodilator therapy was found to be effective in 84% of the participants, as evidenced by improved PaO2. No adverse effects were reported. Comparison of the cost of epoprostenol to comparable use of iNO yielded an average savings of $10 318 per patient.16
Domenighetti and colleagues17 took a unique approach in attempting to predict which patients were likely to have a favorable response to inhaled epoprostenol. Fifteen adults with ARDS were subdivided into 2 groups based on etiology of the disease. The primary group developed ARDS as a result of direct injury to the lung, such as from pneumonia or aspiration. The secondary group developed ARDS after indirect insult to the lungs, such as from sepsis or trauma. Inhaled epoprostenol was initiated within 24 to 76 hours of intubation. All participants from the secondary group (indirect injury) except 1 responded positively with an increase in oxygenation. All participants from the primary group (direct injury) and 1 participant from the secondary group were deemed to be nonresponders (PaO2/FIO2 unchanged or decreased with inhaled epoprostenol at 40 ng/kg/min). Domenighetti and colleagues17 attributed poor response in the primary ARDS group to extensive pulmonary consolidation and possible increased shunt from epoprostenol reaching poorly ventilated areas. The secondary ARDS group was more likely to have gravity-dependent consolidation and more alveoli available for vasodilation.17 These results conflict with other studies that note significant improvements in oxygenation with ARDS from various etiologies, including direct insult to the lungs. Timing of initiation, such as administering therapy very early in the course of ARDS as opposed to a later phase, may be a variable leading to the conflicting results.
Inhaled epoprostenol shows promise as being an equally efficacious alternative to iNO for the severely hypoxemic ARDS patient. Studies demonstrate decreased mPAP and improvement in oxygenation, without systemic adverse effects or toxicity. Inhaled epoprostenol also proves to be easier to administer and less costly. Although mortality rates remain unchanged, the therapy may buy time for the patient to overcome the systemic effects of ARDS.7
A multidisciplinary approach in the development of policy for the use of inhaled epoprostenol is essential. Key players should include pharmacy, respiratory therapy, intensivists, and nursing. It is important that all health care providers involved in the care of the severely hypoxemic patient understand the policy surrounding the administration of inhaled epoprostenol. It would be advantageous for various institutions that have experience with inhaled epoprostenol to share data and develop a standardized method of administration.
Inhaled epoprostenol is available under the brand name Flolan. A 1.5-mg vial of powdered epoprostenol sodium is reconstituted with 50 mL of manufacturer-supplied sterile glycine buffer diluent, yielding a concentration of 30 [mu]g/mL. Earlier research studies describe mixing variable concentrations of the drug (depending on desired dose) to deliver a constant nebulized dose at a rate of 8 mL/h. Our institution uses a standard drug concentration administered by the BodyGuard 575 Ambulatory Infusion Pump (CME America, Golden, Colorado). The patient's ideal body weight and desired dose are entered into the pump and the appropriate infusion rate is administered into the nebulizer, eliminating the need to mix different concentrations of medication. The pump comes with an attached lock box for the medication and has the ability to be pole mounted.18 We are currently using the Aerogen Pro X Controller in conjunction with the Aerogen Aeroneb Solo Nebulizer (Aerogen, Galway, Ireland). This system was chosen because of the small mass median aerodynamic diameter of the nebulized medication, minimal residual in the nebulizer cup, and overall efficiency of delivering the medication. Tubing from the infusion pump attaches directly to the Aeroneb Solo Nebulizer, which delivers a low-velocity aerosol that does not add additional flow to the circuit. The nebulizer attaches to a T-piece in the inspiratory limb of the circuit and has the ability to deliver continuous therapy without the need to open the circuit to refill the nebulizer. It can be used continuously for up to 7 days.19
Our institution uses inhaled epoprostenol as a rescue therapy for refractory hypoxemia or severe pulmonary hypertension in patients with an ideal body weight greater than 45 kg. Ideal body weight is used because it is appropriate to base the dose on lung size and not body mass.4 Physicians at our institution initiate epoprostenol at 0.01 [mu]g/kg/min (or 10 ng/kg/min, as mentioned in the literature). At 15 minutes, if there is no adverse response, the rate is increased to 0.03 [mu]g/kg/min (30 ng/kg/min). Again, at 15 minutes, if there is no adverse response, the rate is increased to the maximum dose of 0.05 [mu]g/kg/min (50 ng/kg/min). Once the maximum dose is achieved, the patient is assessed at 15 and 30 minutes for a response. Refer to Table 3 for a description of adverse and positive responses of epoprostenol. For a positive response, the medication is continued at this rate. If there is no response, the physician may decide to continue at this rate, discontinue the medication, or trial iNO. For an adverse response, the physician is notified. If the adverse response is noted at 0.01 [mu]g/kg/min, the medication is discontinued. If an adverse response is noted at 0.03 [mu]g/kg/min, the medication is weaned to 0.01 [mu]g/kg/min with reassessment in 15 minutes. Likewise, if the adverse reaction is noted at 0.05 [mu]g/kg/min, the medication is weaned to 0.03 [mu]g/kg/min, with reassessment in 15 minutes. There is close, sometimes constant communication among health care team members-physicians, advanced practice nurses, bedside nurses, and respiratory therapists-in particular, during initiation and upward titration of the medication.
Readiness to wean epoprostenol is assessed 12 hours after the maximum tolerated dose is achieved and is routinely reassessed twice a day by the attending physician. Weaning is performed by decreasing the dose in 0.01 [mu]g/kg/min increments every 2 hours. Response to weaning should be assessed at 15 and 30 minutes after downward titration of the dose. A failure to wean is described as an increased mPAP by 20% or greater or a decreased PaO2 by 20% or greater. In this case, the previous dose is resumed. The drug may be discontinued if the patient tolerates a dose of 0.01 [mu]g/kg/min for at least 2 hours. The patient should be assessed for adverse response 30 minutes after the inhaled epoprostenol is discontinued. In addition to routine nursing and respiratory therapy charting, the respiratory therapist routinely documents in an epoprostenol charting template.
Clinicians at our institution consider several patient characteristics to be contraindications to therapy. Inhaled epoprostenol is contraindicated in patients with hypersensitivity to epoprostenol or similarly structured agents. Therapy should be avoided in patients with severe left ventricular systolic dysfunction and those dependent on a right-to-left cardiac shunt. Epoprostenol is contraindicated in patients with significant bleeding and caution should be used in the setting of thrombocytopenia with a platelet count lower than 50 000. Although not a contraindication, care should be taken when inhaled epoprostenol is administered to patients with reactive airway disease. Reconstituted epoprostenol is extremely alkaline with pH 10.2 to 10.8 and use as an inhalation therapy leads to concern for airway irritation.7,11
It is recommended that respiratory therapists involved in administering inhaled epoprostenol attend annual competency training. As the respiratory therapist is likely to be responsible for setting up the equipment, attaching the delivery device, and titrating the medication, it is essential to know the nuances of epoprostenol administration. It is also beneficial for nurses to receive ongoing education regarding the drug's mechanism of action, careful hemodynamic monitoring, and accurate communication among health care team members, including shared goals for therapy.
Clear communication with pharmacy will assist the provider with timely delivery of the medication and ensure that backup medication is available at all times. Because of the short half-life of the medication, inadvertently running a bag dry could be devastating due to rebound pulmonary hypertension.7,11 A replacement bag of epoprostenol should be kept in the unit refrigerator at all times. Epoprostenol is stable at room temperature for only 8 hours, so it is essential to keep the solution refrigerated until the moment it is administered. The bag containing epoprostenol should be labeled with the time it was spiked and the time of expiration. Medication left in the bag after 8 hours needs to be discarded and a new bag from the refrigerator hung. Newly reconstituted medication is stable for 48 hours when refrigerated at a temperature of 36[degrees]F to 46[degrees]F.20 The average patient will typically require 3 to 4 bags of epoprostenol in a 24-hour period.
It is helpful to keep the administration pump on a dedicated pole and labeled "FOR INHALATION ONLY" so as not to confuse it with intravenous administration pumps. Epoprostenol is photosensitive and must be kept in a light shielding bag at all times.20 There is also a need to change the bacterial filter on the expiratory limb of the ventilator circuit at least every 4 hours. Because the glycine buffer diluent is somewhat "sticky," the filter becomes clogged easily. Changing the filter every 4 hours and as needed prevents unintended reduction of drug delivery from a clogged filter. In addition, increasing auto-PEEP and peak airway pressures are indications that the filter may need to be changed.20 Inhaled epoprostenol may also be delivered by facemask or high flow nasal cannula system, although administration through the ventilator is most common.16
When administering inhaled epoprostenol, it is important to keep the nebulizer cup in the upright position at all times. Especially with smaller individuals and at lower doses, it can be several minutes between drops entering the nebulizer cup. If not kept in the upright position, the droplet can adhere to the side of the cup rather than become nebulized. It is possible to administer other nebulized medications through the same circuit, but they must be delivered through a separate nebulizer cup.
In addition to the ARDS population, inhaled epoprostenol shows promise in several other clinical areas. Research has examined its use with different subsets of patients with pulmonary arterial hypertension such as pediatrics, pregnancy, and those undergoing cardiac surgery.21-24 The use of inhaled epoprostenol has also been studied in infants with respiratory syncytial virus, heart and lung transplant recipients, and adults with portopulmonary hypertension preparing for liver transplantation.9,25,26 This therapy also shows potential for air transport of patients with refractory hypoxemia who require transfer to a tertiary care center. Although modern aircraft allows for the use of iNO and ECMO while in flight, inhaled epoprostenol offers a simpler, cheaper, and less space-consuming alternative for the severely hypoxemic patient who requires transport to a higher level of care.27
As illustrated in the case study, ARDS can quickly strike otherwise healthy individuals and cause devastating lung injury and serious systemic sequelae. The inflammation, vasoconstriction, and microthromboemboli that result from ARDS lead to pulmonary shunting and hypoxemia. Several rescue therapies have been used in the treatment of severe, refractory hypoxemia associated with ARDS. In particular, inhaled vasodilators such as nitric oxide and epoprostenol are rescue therapies often trialed in the critical care setting.
Inhaled nitric oxide has been used and studied since the 1990s. Recent research and anecdotal evidence describe inhaled epoprostenol as a favorable alternative to iNO.6 Inhaled epoprostenol is equally efficacious among patients with refractory hypoxemia. In addition, epoprostenol is easier to administer, has fewer potential adverse effects, and affords significant cost savings when compared with iNO. The mortality rate for severe ARDS is as high as 45%, and presently, the use of neither iNO nor inhaled epoprostenol has been shown to increase survival.1,5,7 Additional research in determining which patients are most likely to respond to inhaled vasodilators and the optimal timing for initiation of therapy is needed. Currently, the hope is that by using inhaled vasodilators to improve oxygenation in the short term, we can support the patient with severe hypoxemia until recovery occurs.4,7
The author gratefully acknowledges Madhu Sasidhar, MD, Chris Winkelman, PhD, RN, Rory Mullin, BS, RRT, and Joseph Lavelle, RRT, for sharing their expertise and assisting with manuscript editing.
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