Tracleer and PPH News The Critically Ill Patient With Pulmonary Hypertension CME/CE
Andrew F. Shorr, MD, MPH Uniformed Services Pulmonary hypertension (PH) is a common problem in the intensive care unit (ICU). PH can arise in critically ill patients as a consequence of acute respiratory distress syndrome, as a result of the mode of mechanical ventilation (MV) used, or as complication of the patient's underlying disease (eg, emphysema). Additionally, there is growing appreciation of the significance of primary pulmonary hypertension (PPH) in the ICU. With newer therapies, many individuals with PPH are surviving longer and are, in turn, potentially more frequently in need of ICU care. Although many ICU providers have cared for subjects with PPH during vasodilator challenges, which are conducted in the ICU because of the need for a pulmonary artery (PA) catheter, management of the critically ill PPH patient is complicated and nuanced. This session at the 2005 Society of Critical Care Medicine meeting focused on this topic. Pathobiology
The program began with Ron Perl, MD,[1] from Stanford University, Stanford, California, highlighting the many recent insights into PPH pathobiology and genetics arising from animal studies. He demonstrated that animal models have proven valuable in understanding not only disease mechanisms but also in separating and differentiating inciting events from compensatory responses. With respect to genetic issues in PH, he illustrated how transgenic mice have allowed investigators to study a number of important genes such as BMPR-2, which is a member of the transforming growth factor-beta super family.[2] Other animal research has dealt with regulation of vascular epithelial growth factor and angiopoietin.[3] For example, from animal models, investigators have shown that the gene for angiopoietin can produce PH through the abnormal activation and proliferation of smooth muscle but at the same time protect against PH by decreasing endothelial apoptosis.[3,4] Of note, in a number of animal models, despite being able to produce PH, one rarely notes plexiform lesions. RV Dysfunction
Paul Hassoun, MD,[5] from Johns Hopkins University, Baltimore, Maryland, discussed the significance of right ventricle (RV) dysfunction in PH. He began by rhetorically asking several questions: Is the RV an innocent bystander? How does RV dysfunction affect outcome? Does therapy for PH affect the RV? As a review, he illustrated that mortality in PH is directly related to RV function. Specifically, the rise in pulmonary vascular resistance (PVR) that accompanies PH leads to an increase in RV end diastolic volume and a decrease in the RV ejection fraction. The mass of the RV expands, which results in a decrease in the patient's functional status and mortality. In short, cardiac function is what determines survival and not the extent of elevation in the PA pressure. To illustrate this point, Dr. Hassoun reviewed data from studies of the 6-minute walk test (6 MWT) in PH.[6] The 6 MWT is a good predictor of outcome in PH, and there is little correlation between distance walked and mean PA pressure.[6] Rather, the 6 MWT relates strongly to peak exercise VO2 and cardiac index. Bolstering this point, he also showed data from a landmark trial of vasodilators in PPH.[7] In general, nonresponders and those with a worse prognosis had lower cardiac indices at baseline. Similarly, in a study of prostacyclin therapy for PPH, this agent substantially increased cardiac index despite not changing PA pressure.[8] Finally, results from BREATHE-1, the central trial for the endothelial receptor blocker bosentan, indicated that this agent significantly decreased RV area compared with placebo.[9] Tying things all together, Dr. Hassoun suggested that different phenotypic RV patient types in PH result from some form of genetic programming. Individuals whose RVs can become hypertrophic and compensate for the elevation in PA pressure survive while those whose RV dilates substantially instead eventually decompensate and die. As such, future trials need to be focused on the RV, and newer RV imaging modalities, such as cardiac MRI, need to become a part of PPH clinical studies. Care of the Critically Ill PPH Patient
Darren Taichman, MD,[10] from the University of Pennsylvania, Philadelphia, gave the third presentation. He reviewed the care of the critically ill PPH patient. Put simply, he said, there are no prospective data to guide the management of these individuals when they need acute ICU care. Rather, he urged that an appreciation of the unique pathophysiology of the disease needs to guide treatment in the ICU. Reasons for admission to the ICU for PPH patients vary and include: late recognition of the disease (eg, such that the patient presents in shock), acute medical failure, dietary indiscretion, infection, and venous thromboembolism. Usually when the patient decompensates, a vicious cycle ensues, and he/she can die rapidly. For example, hypoxemia from any cause can lead to an increase in PVR. This leads to an increase in RV oxygen demand and can worsen RV failure. As the RV dilates in response, the systolic blood pressure can fall and compromise already limited coronary perfusion. PPH patients are very sensitive to RV ischemia because of their already limited physiologic reserve, and this decrement in RV coronary flow exacerbates RV failure. At the same time, systemic hypotension and end-organ hypoperfusion create an acidosis. This acidosis itself can yield an increase in PVR, which further perpetuates the cycle of RV failure, as does ongoing RV ischemia. Therefore, in order to break this vicious cycle, clinicians must focus on decreasing oxygen demand while improving oxygen delivery. In general, most clinicians will tolerate an O2 saturation of 90% in an MV patient. For PPH, this is inadequate; these patients require a higher O2 saturation since oxygen is a good pulmonary vasodilator. Early intubation and MV are also necessary in this population. Use of MV in PPH is nuanced since the PVR can change at various lung volumes because of the differential impact of positive pressure on alveolar and extra-alveolar pulmonary vessels. Physiology studies suggest that PVR is minimized at functional residual capacity (FRC) as opposed to either total lung capacity or residual volume. When using MV, one should hence strive to ventilate near FRC in order to avoid both alveolar derecruitment and hyperinflation. High levels of positive end expiratory pressure (PEEP) should be avoided as well. High PEEP can compress alveolar capillaries and elevate PVR. Permissive hypercapnia, another tool often employed by ICU providers, is not well tolerated in PH. The ensuing rise in CO2 can directly increase PVR; hence, these subjects do better with a mild respiratory alkalosis. In attempting to achieve such an alkalosis, one must be cautious not to hyperventilate and cause air trapping since this too can increase PVR. Fluid management is similarly complicated. Although those with PH have higher right atrial pressures and may require a higher than normal preload to ensure forward flow, most acutely ill PPH patients are already fluid overloaded at presentation because of their chronic RV dilation. Gentle fluid challenges and earlier use of vasopressors and inotropes are preferred over aggressive fluid resuscitation. Intravenous vasodilators can be a useful adjunct in these subjects. However, these agents (eg, nitroprusside, prostacyclin) can cause systemic hypotension and can worsen VQ mismatch. Inhaled medications such as nitric oxide and iloprost should be utilized in this setting since their effects are limited to the pulmonary vascular bed. There are few direct data comparing these 2 agents, but Dr. Taichman did review a recent study suggesting that iloprost lowered the PVR more substantially than did inhaled nitric oxide.[11] He ended his presentation by observing that the outcomes for the acutely ill PH patient are dismal if they arrest. The overall survival from CPR in PH is dismal at 6%, and this is despite the fact that in most cases CPR is initiated in the ICU in less than 1 minute. Pulmonary Embolism
Dr. Peter Fedullo,[12] from the University of California, San Diego, gave the final presentation. He reviewed approaches to the invasive management of pulmonary embolism (PE). There are a half million cases of PE in the United States annually, and 85% of those who die from this do so within 6 hours of the event.[13] Incomplete resolution of the clot is seen in approximately 5% of patients. Normal persons can tolerate 60% to 70% obstruction of the pulmonary vasculature without adverse consequences, while individuals with impaired cardiopulmonary reserve can decompensate with even a small PE. Dr. Fedullo suggested a risk stratification scheme for PE that was based on the mortality associated with each specific presentation type. For example, patients presenting with a normal BP and no RV dysfunction would be associated with mortality rates of 0% to 1%; patients with a normal BP and RV dysfunction would have 5% to 8% associated mortality rates; patients with hypotension without shock: 15%; patients with shock: 25% to 35%; and patients presenting as an arrest: 65%. For those at highest risk of death, potential interventions include anticoagulation, thrombolytics, placement of an inferior vena caval filter, suction embolectomy, and surgical embolectomy. Catheter embolectomy is directed at disrupting the clot and improving flow. However, one risks dislodging the clot and sending it distal or making a partial obstructive central thrombus worse by breaking it and having its fragments occlude multiple smaller vessels. Dr. Fedullo stressed that there are very few data for this approach in humans and it is not approved by the US Food and Drug Administration. For surgical embolectomy, patient selection is key. If performed prior to arrest, this alternative is associated with a 5% to 30% mortality compared with death rates of 60% to 90% if attempted after arrest. One limitation with the data surrounding acute surgical intervention is that the outcomes are likely best in the patients who probably did not require the intervention in the first place. In general, both catheter and surgical embolectomy necessitate expert technicians and should only be done if there are contraindications to thrombolytics. In contrast to acute massive PE, chronic thromboembolic pulmonary hypertension (CTEPH) results from incomplete thrombus resolution and can lead to chronic PH. Once the mean PA pressure reaches more than 30 mm Hg, median survival is less than 1.5 years.[14] Hence, early identification of these patients is crucial, and surgical endarterectomy offers improved outcomes. In the evaluation of these patients, Dr. Fedullo stressed that VQ scan remains an important imaging modality and that CT scans can underestimate the extent of the clot and can be negative even in severe CTEPH because the clot is endothelialized. Indications for surgery include a PVR of > 300, an increase in the Vd/Vt if the PVR is < 300, and the presence of surgically accessible clot. The PVR prior to surgery is the best predictor of outcome. If it is less than 1000, short-term mortality is 1.3% compared with 10.1% in persons with PVRs > 1000.[15] In summary, PH is a complex disease with a unique pathophysiology. The approach to PH in the ICU needs to better incorporate an understanding of the central role of the RV, an appreciation of the risks and benefits of various interventions, and acknowledgement that outcomes are dismal without early intervention. References
Pearl R. Pathogenesis and treatment of pulmonary hypertension: lessons from animal models. Program and abstracts of the Society of Critical Care Medicine 34th Critical Care Congress; January 15-19, 2005; Phoenix, Arizona.
West J, Fagan K, Steudel W, et al. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res. 2004;94:1109-1114. Abstract
Budhiraja R, Tuder RM, Hassoun PM. Endothelial dysfunction in pulmonary hypertension. Circulation. 2004;109:159-165. Abstract
Jeffery TK, Morrell NW. Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension. Prog Cardiovasc Dis. 2002;45:173-202. Abstract
Hassoun P. Complications in respiratory failure. Program and abstracts of the Society of Critical Care Medicine 34th Critical Care Congress; January 15-19, 2005; Phoenix, Arizona.
Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2000;161(2 Pt 1):487-492.
Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med. 1992;327:76-81. Abstract
Hinderliter AL, Willis PW 4th, Barst RJ, et al. Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group. Circulation. 1997;95:1479-1486. Abstract
Galie N, Hinderliter AL, Torbicki A, et al. Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and Doppler measures in patients with pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:1380-1386. Abstract
Taichman D. Decompensated pulmonary arterial hypertension in the ICU. Program and abstracts of the Society of Critical Care Medicine 34th Critical Care Congress; January 15-19, 2005; Phoenix, Arizona.
Olschewski H, Ghofrani HA, Walmrath D, et al. Inhaled prostacyclin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Am J Respir Crit Care Med. 1999;160:600-607. Abstract
Fedullo P. Invasive management of pulmonary embolization. Program and abstracts of the Society of Critical Care Medicine 34th Critical Care Congress; January 15-19, 2005; Phoenix, Arizona.
Auger WR, Kerr KM, Kim NH, Ben-Yehuda O, Knowlton KU, Fedullo PF. Chronic thromboembolic pulmonary hypertension. Cardiol Clin. 2004;22:453-466. Abstract
Fedullo PF, Auger WR, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2001;345:1465-1472. Abstract
Fedullo PF, Auger WR, Channick RN, Kerr KM, Rubin LJ. Chronic thromboembolic pulmonary hypertension. Clin Chest Med. 2001;22:561-581. Abstract
|
