Inhaled Vasodilators as Salvage Therapy in ARDS Caused by H1N1 Infe...

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INHALED VASODILATORS AS SALVAGE THERAPY IN ARDS CAUSED BY H1N1 INFECTION

Critical Care
Clinical Education Clinical Cases Ethics Information for Patients Journal Club Links Podcasts Procedures Research Statements & Guidelines Get Involved Jason T. Poston, MD Katherine D. Mieure, PharmD, BCPS Ishaq Lat, PharmD Sherwin E. Morgan, RRT From the Section of Pulmonary and Critical Care Medicine and the Pharmacy and Respiratory Therapy Departments University of Chicago

Background
Patients suffering from acute respiratory distress syndrome (ARDS) commonly require support with mechanical ventilation, a high fraction of inspired oxygen (FiO2), and positive end-expiratory pressure (PEEP). Outcomes for these patients are optimized by utilizing a lung protective ventilation strategy (LPVS) characterized by low tidal volumes (4 to 6 mL/kg of ideal body weight), minimalization of FiO2, and adequate PEEP. Supportive therapy with LPVS typically allows the care team to ensure adequate delivery of oxygen, and only infrequently do these patients die due to refractory hypoxemia. Providers that care for a large number of patients with ARDS will invariably encounter the patient with hypoxemia refractory to standard LPVS, even when the FiO2 is 1.0 and the PEEP is increased until limited by circulatory compromise. Likewise, elevated pulmonary vascular pressures and right heart insufficiency may complicate ARDS. Several therapies, deemed salvage therapies when used as adjuncts to LPVS, have been used for patients with refractory hypoxemia or right heart insufficiency due to ARDS. While these therapies have not clearly demonstrated survival benefit in randomized trials, improvement in physiology (P/F ratio, mean pulmonary pressures) have been demonstrated, and these salvage therapies are considered reasonable for this select population of patients with exceedingly high mortality.

Rationale for Inhaled Vasodilators

While ARDS is characterized as a diffuse lung lesion, high resolution chest tomography and pathologic samples have made clear that the disease is actually quite heterogeneous across the lung parenchyma. Certain lung segments are more affected than others, and likely contribute more to the shunt physiology that manifests clinically. Said another way, while much of the lung is damaged and contributes to the shunt, there is functional lung that exchanges oxygen normally and delivers fully saturated blood into the pulmonary venous circuit. This presents a therapeutic opportunity: redistribute blood flow to normally functioning lung to decrease the overall shunt fraction. This feat may be accomplished by inhalation of a selective pulmonary vasodilator. The inhaled vasodilator, by virtue of its route of administration, reaches normal lung but not diseased lung. The vasodilatory effect, concentrated in normal lung segments, recruits blood flow to functional alveoli where it is oxygenated. This not only decreases shunt fraction, and thus hypoxemia, but also attenuates the regional hypoxic vasoconstriction that leads to pulmonary hypertension and right heart failure. Nitric oxide (iNO) and prostacyclin therapy (epoprostenol) are two inhaled agents which have been used and are described in more detail below.

Targeted Titration of Inhaled Vasodilator Therapy

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Inhaled vasodilator salvage therapy is utilized in ARDS to ameliorate refractory hypoxemia and right heart failure. For this reason, its use should be targeted and titrated to measures of blood oxygenation and hemodynamic performance. The following measures have been proposed: Oxygenation: PaO 2/FiO2 A-a O 2 gradient Central or mixed venous saturation (SvO 2) Mean pulmonary artery pressure (MPAP) Cardiac output or index (CO or CI) Central venous pressure (CVP)

Hemodynamics;

Both measures of oxygenation require knowledge of the FiO2 and arterial blood gas sampling. Choice of a hemodynamic endpoint is often determined by the information readily available. The SvO 2 or CVP are commonly used as they require only a central venous catheter. The MPAP, CO, and CI require a pulmonary artery catheter, and evidence is insufficient to justify insertion specifically for inhalational vasodilator titration in patients with ARDS. The continued use and titration of these agents should be guided by the changes in these parameters associated with a change in dose of the inhalational agent. Prior to initiating therapy, the clinician should determine what constitutes a clinically meaningful change that can be attributed to the agent rather than variability in assessment. A 15-20% change in one of these parameters is generally considered to be clinically significant.

Inhaled Nitric Oxide

Inhaled nitric oxide (iNO) is a widely used selective pulmonary vasodilator in patients with ARDS. While iNO clearly improves physiologic parameters in ARDS, randomized trials have failed to show an effect on duration of mechanical ventilation or mortality. For this reason iNO is not recommended for all patients with ARDS, but there may be a role for it as salvage therapy for patients with intractable disease. Delivery iNO is delivered utilizing the INOtherapy system (Ikaria, Clinton, NJ), which includes nitric oxide gas (INOmax; Ikaria, Clinton, NJ) and delivery device (INOvent; Datex-Ohmeda, Madison, WI or INOmax DS; Ikaria, Clinton, NJ). The system delivers the desired concentration, in parts per million (ppm), into the humidifier in the inspiratory limb of the ventilator. Additionally, the system continuously monitors nitric oxide, nitric dioxide, and oxygen levels being delivered to the patient. The specialized equipment and training to safely and effectively use this system require advanced planning. Dosing and Titration When iNO is efficacious in improving physiologic parameters in an ARDS patient, the effect is seen rather quickly. This allows the clinician to determine the efficacy of the therapy and the utility of its continued use in a short time frame. Once titration endpoints have been chosen and assessed at baseline, iNO should be initiated at 5 ppm, and reassessment of the endpoint can be made within 30 minutes. If a clinically significant response is not seen, iNO dose should be doubled to 10ppm and the patient reassessed. This doubling of the dose should be repeated up to 40ppm to determine which dose, if any, provides the optimal benefit. The patient should be maintained on the lowest effective dose that demonstrates a positive clinical effect using the parameters defined above. In the circumstance of no positive clinical effect, iNO should be discontinued and other salvage therapies considered. Adverse Reactions and Considerations iNO can cause methemoglobinemia. Patients receiving iNO should be assessed daily for this toxicity. Additionally, administration of iNO is labor intensive and presently has a very high daily cost. Finally, abrupt withdrawal of iNO after prolonged use (days) can precipitate rebound hypoxemia and pulmonary hypertension. Extreme caution must be taken during routine bedside patient care and with transfer of patients between units to prevent unintended sudden discontinuation of iNO therapy. Weaning from iNO must be performed slowly and with close observation. Downward Titration Sudden discontinuation of iNO after prolonged use poses the risk for acute hypoxemia and sudden rise in pulmonary arterial pressures. For this reason, reducing the dose of iNO should be done in a stepwise fashion, approximately every 2 hours, with careful reassessment after each step. One successful strategy is to reduce the dose by 10ppm every 2 hours to a dose of 10ppm, and then reduce the dose by 2.5ppm in a stepwise fashion until full iNO discontinuation.

Inhaled prostacylcin (epoprostenol)

Inhaled epoprostenol has also been used in patient with ARDS, and seems to have similar physiologic effects as iNO. Like iNO, no study has demonstrated a clear survival benefit, and it is presently recommended only as salvage therapy for patients with severe, refractory disease. Epoprostenol is at present less expensive than iNO. Delivery Preparation of Epoprostenol for Inhaled Therapy Epoprostenol (Flolan, GlaxoSmithKline, Research Triangle Park, NC) is a salt that is reconstituted in a glycine buffer diluent (Sterile Diluent for Flolan, GlaxoSmithKline, Research Triangle Park, NC). Epoprostenol is available in 0.5 mg and 1.5 mg

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vials, and the diluent is available in a 50 mL vial. Reconstituted epoprostenol is photosensitive and must be protected from light. It should not be used after 8 hours at room temperature. The epoprostenol solution may be used for up to 48 hours after reconstitution if refrigerated between 2 and 8 C (36 and 46 F). For inhalational therapy, the solution is nebulized and delivered through the ventilator circuit. One way of dosing nebulized epoprsotenol is a concentration based dosing scheme. The volume of nebulization is held constant for inhaled therapy (8 mL/hour), and thus changes in dosage are achieved by altering the concentration of reconstituted epoprostenol solution. Concentrations of 20,000 ng/mL, 10,000 ng/mL, 5,000 ng/mL, and 2,500 ng/mL are achieved as described below. The protocol described utilizes the 0.5 mg vials. 20,000 ng/mL epoprostenol (1 mg epoprostenol in 50 mL diluent) Materials 0.5 mg vial of epoprostenol 50 mL vial of sterile diluent Preparation Instructions Quantity 2 1 Resulting Solution (mL) 0.1 mg/mL (5 mL) Mix 5 mL diluent in 0.5 mg vial of epoprostenol 0.1 mg/mL (5 mL) Mix 5 mL diluent in 0.5 mg vial of epoprostenol 20,000 ng/mL (50 mL) Add the 10 mL of 0.1 mg/mL solution from steps 1 and 2 to 40 mL diluent

10,000 ng/mL epoprostenol (0.5 mg epoprostenol in 50 mL diluent) Materials 0.5 mg vial of epoprostenol 50 mL vial of sterile diluent Preparation Instructions Quantity 1 1 Resulting Solution (mL) 0.1 mg/mL (5 mL) Mix 5 mL diluent in 0.5 mg vial of epoprostenol 10,000 ng/mL (50 mL) Add the 5 mL of 0.1 mg/mL solution from step 1 to 45 mL diluent

5,000 ng/mL epoprostenol (0.25 mg epoprostenol in 50 mL diluent) Materials 0.5 mg vial of epoprostenol Quantity 1

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50 mL vial of sterile diluent Preparation Instructions

1 Resulting Solution (mL) 0.1 mg/mL (5 mL)

Mix 5 mL diluent in 0.5 mg vial of epoprostenol 5,000 ng/mL (50 mL) Add 2.5 mL of 0.1 mg/mL solution from step 1 to 47.5 mL diluent

2,500 ng/mL epoprostenol (0.125 mg epoprostenol in 50 mL diluent) Materials 0.5 mg vial of epoprostenol 50 mL vial of sterile diluent Preparation Instructions Quantity 1 1 Resulting Solution (mL) 0.1 mg/mL (5 mL) Mix 5 mL diluent in 0.5 mg vial of epoprostenol 2,500 ng/mL (50 mL) Add 1.3 mL of 0.1 mg/mL solution from step 1 to 48.7 mL diluent

NOTE: The preparation of the 5,000 ng/mL and 2,500 ng/mL concentrations require more than 50 mL of the sterile diluent. However, the overfill in the 50 mL vials of sterile diluent is typically sufficient to account for this amount, allowing preparation of these concentrations with a single vial of diluent. At the constant nebulization rate of 8 mL/hour, a 50 mL preparation of reconstituted epoprostenol solution will be required at least every 4 to 6 hours (depending on nebulizer system chosen), but may be more frequent if the dose (concentration) is changed. Delivery Nebulization of Epoprostenol Solution Several nebulization systems have been successfully utilized to deliver inhaled epoprostenol therapy. Two such systems are the Aeroneb Solo Nebulizer System (Aerogen, Galway, Ireland) and the MiniHeart Nebulizer (Westmed, Tucson, AZ), which are described below. Regardless of the nebulization system, it should be noted that epoprostenol is incompatible with other nebulized medications. The MiniHeart Nebulizer is a continuous flow nebulizer. Two disposable non-HME filters are placed in the expiratory limb of the ventilator proximal to the water trap. These filters should be changed frequently (every 2 hours), and a ventilator heating coil may be used. Approximately 15 mL of the epoprostenol solution are placed in the nebulizer chamber, which is placed in the inspiratory side of the ventilator circuit. The remainder is delivered to the chamber at 8 mL/hour using an infusion pump while providing nebulizing oxygen at a flow rate of 2 L/minute. The flow rate remains constant for all delivered doses. Recall that the concentration of the epoprostenol solution is changed to achieve a change in the delivered dose of medication. It should also be noted that addition of the nebulizing oxygen at 2L/minute will increase the delivered tidal volume, and that ventilator-set tidal volume may be need to be reduced accordingly. The Aeroneb Solo Nebulizer System is a high-efficiency nebulizer that can provide continuous nebulization when used with the Aeroneb Pro-X controller. Nebulization should be visible with regular intermittent pauses, but is delivered to the patient as a continuous nebulized solution. Again, two disposable non-HME filters are placed in the expiratory limb of the ventilator proximal to the water trap. The nebulizer is attached in the inspiratory side of the ventilator circuit proximal to the patient wye site. The reconstituted epoprostenol is administered via an infusion pump connected to the Aeroneb Solo Nebulizer. The medication administration tubing should be primed and then connected to the Aeroneb Solo Nebulizer using a leur adaptor. Deliver the epoprostenol solution at a rate of 8 mL/hour. Do not adjust the rate.

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Starting Dose Once titration endpoints have been chosen and assessed at baseline, inhaled epoprostenol can be initiated at the 20,000 ng/mL. Obvious clinical deterioration should prompt immediate discontinuation. Otherwise, reassessment of the endpoint(s) can be made within 30 minutes. If no clinically meaningful response is seen, the therapy should be discontinued and other salvage therapies considered. If inhaled epoprostenol leads to improvement, the patient should be maintained on 20,000 ng/mL and then frequently reassessed to determine whether the dose can be titrated downward (see below). Adverse Reactions and Considerations Epoprostenol delivered as a continuous intravenous infusion is a potent vasodilator of all vascular beds. It commonly causes hypotension, flushing, musculoskeletal pain (particularly of the feet and jaw), hypercalcemia, and gastrointestinal complaints. When the delivered route is inhalation, these effects are less frequent. Due to the short half-life of epoprostenol, caution should be taken to avoid abrupt epoprostenol withdrawal to prevent hypoxemia and rebound pulmonary hypertension. Upon nebulization the glycine buffer diluent has a sticky characteristic and has a tendency to accumulate on and impair ventilator valve function, hence the need for frequently changing expiratory filters. Practitioners should monitor for signs of increased peak airway or end-expiratory pressures that may indicate clogged filters. Downward Titration Patients that improve on inhaled epoprostenol who remain stable for 4 or more hours should be assessed for downward titration. Decrease the concentration by 50% (e.g. from 20,000 ng/mL to 10,000 ng/mL, etc.) and observe initially for obvious hemodynamic decline. If the patient seems stable, reassess the titration endpoint(s) approximately 30 minutes after the decrease in concentration. If the patient has declined, the higher dose should be resumed. If the patient is stable, the titration (50% concentration reduction) should be repeated starting from the new lower concentration in approximately 4 hours. Once a patient is stably maintained on 2,500 ng/mL for four hours, the medication may be discontinued with the same careful observation used for a decrease in dose.

References
1. The Acute Respiratory Distress Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. New England Journal of Medicine. 342(18):1301-8, 2000 May 4. 2. Rossaint R. Gerlach H. Schmidt-Ruhnke H. Pappert D. Lewandowski K. Steudel W. Falke K. Efficacy of inhaled nitric oxide in patients with severe ARDS. Chest. 107(4):1107-15, 1995 Apr. 3. Dellinger RP. Zimmerman JL. Taylor RW. Straube RC. Hauser DL. Criner GJ. Davis K Jr. Hyers TM. Papadakos P. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Critical Care Medicine. 26(1):15-23, 1998 Jan. 4. Taylor RW. Zimmerman JL. Dellinger RP. Straube RC. Criner GJ. Davis K Jr. Kelly KM. Smith TC. Small RJ. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA. 291(13):1603-9, 2004 Apr 7. 5. Walmrath D. Schneider T. Schermuly R. Olschewski H. Grimminger F. Seeger W. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. American Journal of Respiratory & Critical Care Medicine. 153(3):991-6, 1996 Mar. The ATS is providing this information about salvage therapies that are available as a resource for those interested in this information, but it is important to note that none of these therapies have been shown to improve survival for patients with ALI/ARDS and that the ATS is not recommending the use of these therapies.

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