Management of pulmonary vasodilator therapy in patients with pulmonary arterial hypertension during critical illness

Muzevich et al. Critical Care 2014, 18:523 http://ccforum.com/content/18/1/523 REVIEW Management of pulmonary vasodilator therapy in patients with pulmonary arterial hypertension during critical illness Katie M Muzevich1, Hadi Chohan2 and Daniel C Grinnan2* See related commentary by Bauer and Tonelli, http://ccforum.com/content/18/5/524 Abstract Pulmonary arterial hypertension (PAH) is commonly treated with pulmonary arteriolar vasodilator therapy. When a patient on PAH medication is admitted to intensive care, determining how to manage their medication during the critical illness is often complicated. There may be considerations related to the inability to take medication by mouth, related to acute renal failure or acute liver injury, related to altered mental status or delirium, or related to hypotension and bacteremia. Decisions of how to manage these medications can have a major impact on the patient’s clinical course. Presently, provider experience is the major tool in navigating the decisions regarding these medications. In this review, we offer our recommendations of how to manage PAH patients with critical illness who are on PAH medications. These recommendations include how to deliver medications via feeding tubes, how to dose medications in the setting of acute renal failure or acute liver failure, and how to manage medications during hypotension or when a tunneled catheter needs to be removed. Introduction Pulmonary arterial hypertension (PAH) is a progressive disorder of the pulmonary circulation, which leads to right ventricular failure and death. In the past two decades, advances have led to US Food and Drug Administration approval of several PAH therapies for the treatment of PAH, and their use is now widespread. Common side effects and use of these medications in the outpatient setting have been extensively discussed. However, we are unaware of a review of PAH therapies focusing on management when patients are admitted to an ICU. Many patients with PAH die in an ICU setting [1,2], and the reported prevalence of PAH may have increased from the 1980s, when a National Institutes of Health registry enrolled less than 200 patients [3], to the present, with more than 3,500 patients enrolled in the US-based Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) [4]. A discussion of how to manage existing PAH therapies in patients admitted to the ICU is therefore overdue. This management includes the use of phosphodiesterase inhibitors, endothelin * Correspondence: 2 Virginia Commonwealth University Health System, 1200 East Broad Street, P.O. Box 980050, Richmond, VA 23298, USA Full list of author information is available at the end of the article receptor antagonists and prostacyclin analogs. Our discussion will not include fluid management of PAH patients admitted to the ICU, because this topic has previously been discussed in other publications [5,6]. At our institution, we routinely care for patients on treatment for PAH during inpatient admissions. Often this includes transfer from another hospital. Over the past decade, we average over 30 PAH patients per year admitted with varying conditions. We offer our single-center experience with PAH therapies in the ICU setting, as well as our recommended approach to their use during ICU admission. Medication administration during critical illness Administration of medications may be compromised when patients require mechanical ventilation and enteral nutrition, but it is possible via an enteral feeding tube if the drug formation is suitable for enteral administration. Generally, liquid formulations are preferred over tablet or capsule dosage forms [7]. In the absence of a liquid dosage form, many solid dosage forms (tablets or capsules) can be crushed or opened and mixed with water for enteral administration. Dosage forms that should not be altered for enteral administration include those of extended or delayed release, and drugs with chemotherapeutic, teratogenic or © 2014 Muzevich et al.; licensee BioMed Central Ltd. The licensee has exclusive rights to distribute this article, in any medium, for 12 months following its publication. After this time, the article is available under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0) applies to the data made available in this article, unless otherwise stated. Muzevich et al. Critical Care 2014, 18:523 http://ccforum.com/content/18/1/523 Page 2 of 10 carcinogenic properties. Phosphodiesterase type 5 inhibitors (sildenafil and tadalafil), endothelin receptor antagonists (bosentan, ambrisentan and macitentan) and the novel soluble guanylate cyclase stimulator (riociguat) are oral medications for the treatment of PAH. Table 1 presents recommendations for the administration of these oral medications via enteral feeding tube. Additionally, nursing staff should be given detailed instructions regarding proper enteral drug administration procedures [7]. Administration of inhaled outpatient therapy is problematic when patients require mechanical ventilation. Products such as iloprost (Ventavis®; Actelion Pharmaceuticals, San Francisco, CA, USA) and treprostinil (Tyvaso®; United Therapeutics, Research Triangle Park, NC, USA) require delivery with specialized delivery devices: iloprost, I-neb® Adaptive Aerosol Delivery® (Philips Healthcare, Andover, MA, USA) or Prodose® Adaptive Aerosol Delivery® (Philips Healthcare) [20]; and treprostinil, Tyvaso inhalation system® (United Therapeutics) [21]. Although reports exist of successful inhaled iloprost delivery to patients requiring mechanical ventilation or high-flow oxygen [22], this delivery method has not been extensively tested, nor is it approved by the US Food and Drug Administration. Furthermore, patients requiring mechanical ventilation may benefit from a titratable medication that is delivered continuously rather than intermittently. Hence continuous administration of pulmonary vasodilator therapy (nebulized epoprostenol or inhaled nitric oxide) may be advantageous because of the ability to titrate the dose and the likelihood that continuous drug delivery will be less likely to alter hemodynamics compared with intermittent drug delivery (see Altered mental status section for more on inhaled nitric oxide and nebulized epoprostenol). Bacteremia and sepsis The incidence of bacteremia in patients with PAH is elevated compared with that in the general public. This is secondary to the central venous catheters used to deliver intravenous prostanoid therapy [23]. The incidence of bacteremia has been estimated at 0.118 episodes per 1,000 treatment-days in patients receiving epoprostenol and as 0.938 episodes per 1,000 treatme (...truncated)