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Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Penn Presbyterian Medical Center, Philadelphia, PA, USAPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Interstitial lung disease represents a group of diffuse parenchymal lung diseases with overwhelming morbidity and mortality when complicated by acute respiratory failure. Recently, trials investigating outcomes and their determinants have provided insight into these high mortality rates. Pulmonary hypertension is a known complication of interstitial lung disease and there is high prevalence in idiopathic pulmonary fibrosis, connective tissue disease, and sarcoidosis subtypes. Interstitial lung disease associated pulmonary hypertension has further increased mortality with acute respiratory failure, and there is limited evidence to guide management. This review describes investigations and management of interstitial lung disease associated acute respiratory failure complicated by pulmonary hypertension. Despite the emerging attention on interstitial lung disease associated acute respiratory failure and the influence of pulmonary hypertension, critical care management remains a clinical and ethical challenge.
Interstitial lung disease (ILD) is defined by cellular proliferation, interstitial inflammation, and/or fibrosis within the alveolar wall, not caused by infection or malignancy [
]. ILD is characterized by its known cause or as idiopathic (Fig. 1). Acute respiratory failure (ARF) is an acute and rapid deterioration of respiratory function over a time period of a few days [
]. ARF due to ILD exacerbations are defined by the following criteria: subjective worsening of dyspnea within the month prior to presentation; new ground glass opacities or consolidation by chest imaging; hypoxemia with >10 mmHg decline in PaO2; and no evidence of lung infection, pulmonary embolism (PE), congestive heart failure (CHF), or pneumothorax [
]. The definition has been modified in acute exacerbation of idiopathic pulmonary fibrosis (IPF) to include pulmonary infection as an etiology, but this has not been applied in other ILD subtypes [
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
]. Group III PH is now defined as a right heart catheterization (RHC) confirmed mean pulmonary arterial pressure (mPAP) 21–24 mmHg at rest with a pulmonary vascular resistance (PVR) of ≥3 Wood Units, or ≥ 25 mmHg at rest (irrespective of PVR), in the setting of known pulmonary disease [
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
Treatment of ILD associated PH (ILD-PH) in the outpatient setting is primarily directed at optimizing the management of the underlying pulmonary disease, which may include immunosuppressive therapy, anti-inflammatory regimens, and/or anti-fibrotic agents. Supplemental oxygen is indicated for the prevention and therapy of PH due to hypoxia, but there is no evidence regarding its impact on long-term survival [
]. Diuretics are used to maintain euvolemia and reduce right ventricular congestion. In the acute setting, ILD-PH management is focused on treating potential triggers of ARF (Fig. 2), supportive care with respiratory adjuvant therapy, and obtaining/maintaining euvolemia.
Fig. 2Common Causes of Acute Respiratory Failure in ILD and Management.
Iatrogenic causes of ARF commonly fall within the Volume Overload/CHF, Arrythmia, and Anemia categorizations. This is commonly seen in aggressive volume resuscitation, with the use of inhaled respiratory medications, and over phlebotomizing or during bedside procedures, respectively.
ILD associated ARF (ILD-ARF) often requires aggressive respiratory support and high mortality rates have been reported. ILD-PH has even further increased mortality with ARF; this is clinically challenging and is an indication for lung transplant (LTx) evaluation [
]. Rapidly progressive ILD and new onset ARF in ILD-PH patients may be obscure at presentation, and both are indications for LTx referral. We reviewed the literature on ILD-ARF and the influence of co-existing PH to provide a systematic approach to management of ILD-ARF complicated by PH.
2. Epidemiology of pulmonary hypertension in ILD subtypes
Different ILD subtypes have different risk of PH development and its prevalence is described in 14–73.8% of ILD patients [
]. Knowing the risk of coexisting PH helps with the clinical suspicion and management of PH during ARF (Table 1). Different observational studies have used different definitions to define the presence of PH in ILD patients; such as various echocardiography parameters or RHC. Additionally, the studies in Table 2 are at various disease stages and are generally low powered. Thus, it is difficult to make accurate epidemiological assessments of PH presentation in ILD patients.
Table 1Prevalence of PH amongst various forms of ILD.
Prevalence of moderate to severe PH in patients with SSc with and without ILD (Retrospective study)
Not specified
197
Moderate to severe PH was suspected in 36 patients (18.3%) and confirmed in 32 (16%) with RHC Prevalence of moderate to severe PH was similar in SSc patients with and those without ILD In patients with ILD, a lower PaO2 was the unique independent indicator associated with PH.
PH in IPF patients awaiting lung transplant (Retrospective study)
1995–2004
3457
46.1% of patients had PH based on RHC. ~10% had severe PH based on RHC Lower FEV1, increased PCWP, and need for supplemental O2 correlated with presence of PH
]. Patients with IPF can develop PH at any point of the disease course, however there is evidence that it correlates with disease severity. In the early stages of IPF, the prevalence of PH has been reported as low as 8% [
]. Caminati et al. (2013) argued that data regarding the epidemiology of PH in IPF are limited for a couple major reasons: (1) the diagnosis of PH is generally at advanced stages of IPF making the incidence difficult to study; and (2) most of the data comes from lung transplant candidates which is not reflective of the general IPF patient population [
PH has been reported in 47% of sarcoidosis patients with exertional dyspnea out of proportion to pulmonary function test (PFT) results, low PaO2, low carbon monoxide diffusion capacity (DLCO), and advanced radiographic changes [
]. Patients with SSc have another unique utility for predicting the presence of PH. The DETECT study showed utility in using a Forced Vital Capacity predicted (FVC%)/DLCO% predicted ratio, along with other noninvasive PH predictor variables, to increase the sensitivity of suspected patients with PH in need of RHC [
]. No study has used this ratio to determine epidemiological data at this time.
PH has a reported prevalence in systemic lupus erythematosus (SLE) of up to 17.5% by transthoracic echocardiography (TTE) and is associated with increased mortality when present with ILD [
]. There is limited data combining ILD and PH in relation to specific prevalence and mortality.
In patients with nonspecific interstitial pneumonia (NSIP), there is no data on PH prevalence. One study described an estimated incidence of PH in NSIP as 46%, but this was based on low sample sizes and the inclusion of the IPF subtype for comparison [
]. NSIP is commonly associated with CTD, HIV, or drugs/inhalational exposures. When no association is identified, it is labeled as idiopathic NSIP (iNSIP) and development of PH correlates with poor clinical outcomes [
]. Shared pathophysiological mechanisms of ILD and PH involve oxidant-antioxidant imbalance, decreased production of nitric oxide, increased production of endothelin-1, and profibrotic mediators [
PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation.
Am. J. Physiol. Lung Cell Mol. Physiol.2008; 294: L24-L33
Distinct differences in gene expression patterns in pulmonary arteries of patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis with pulmonary hypertension.
]. These increase resistance within the pulmonary vascular circuit contributing to PH and right ventricular failure (RVF). ILD-ARF has profound consequences in PH patients through hypoxia-induced stress on the right ventricle (RV), potentially spiraling into decompensated RVF and cardiogenic shock.
The RV is normally thin-walled and unable to compensate for acute changes in afterload [
]. Rising RV afterload results in increased RV wall stress, impaired myocardial contractility, and progressive tricuspid regurgitation with distention of the RV [
] as the RV becomes overloaded and bulges into the left ventricle (LV) due to restrictions imposed by the pericardium and reduces LV preload and output [
]. Uncoupling describes insufficient energy transfer from the ventricle to the arterial load, increasing the myocardial oxygen demand.
4. Clinical presentation
ILD and PH share characteristic symptoms (fatigue, dyspnea, and exercise intolerance), which is diagnostically challenging on patient history. These symptoms reflect impaired gas exchange as a result of pulmonary capillary inflammation and increased stress on the right ventricle. Fig. 4 depicts common signs and symptoms of ILD and PH/RVF. Respiratory distress (i.e tachypnea) is generally identifiable on clinical examination, however the etiology is not always apparent.
Fig. 4Clinical Signs and Symptoms of ILD and/or PH/RVF.
The important clinical distinction that should be emphasized immediately is if the patient is hemodynamically unstable and if is there concern for co-existing decompensated right heart failure leading to cardiogenic shock. ILD-ARF in the presence of PH has increased susceptibility to cardiogenic shock secondary to RVF. Different phenotypes have been described in cardiogenic shock, such as the “cold and wet” or “wet and warm” presentations [
]. Cold refers to decreased vascular flow in the extremities and cool temperature when feeling the extremities. Warm refers in a vasodilatory state in which the extremities are warm to touch. Wet refers to findings on physical exam suggestive of volume overload that include; hearing rales in the lungs during auscultation from pulmonary edema, and pitting edema on palpation of the lower extremities or sacrum. Typically isolated RVF is without the “wet” lung phenotype, but ILD is associated with increased left heart disease and pulmonary edema is certainly possible [
]. Additionally, the presence of inspiratory crackles in ILD can confound clinical assessment.
5. Initial investigations
General work up for ARF in ILD-PH involves routine investigations that are discussed briefly below. When severe ARF in ILD-PH is suspected, referral to an ILD center with expertise in PH is recommended.
Complete blood counts and metabolic panels should be trended every 12–24 h as they provide valuable data regarding oxygenation, presence of infection, electrolyte status, and end-organ damage. Blood gas determinations and lactic acid and should be trended every 1–6 hours. In a patient with suspected underlying pulmonary hypertension, elevated troponin can be associated with either demand ischemia from an impaired right ventricle or acute coronary syndromes and should be correlated with electrocardiogram (EKG) and/or an echocardiogram. Natriuretic peptides (i.e NT-proBNP) elevation results from ventricular stretch and imply increasing right-sided pressures in patients with PH. Higher mortality is associated with elevated cardiac enzymes and lactic acidosis [
Electrocardiogram should be ordered on presentation. EKG findings are generally nonspecific but those that are suggestive of PH include: right axis deviation, p-pulmonale, right bundle branch block, tall R waves in V1, and right ventricular strain. Arrhythmias are common in PH and should be excluded as a cause of ARF.
Chest radiography is typically obtained and may suggest the etiology of respiratory failure (i.e pneumonia, CHF, or pneumothorax) and cardiovascular engorgement. Chest CT is invaluable to evaluate the degree of ILD burden or progression of disease if prior imaging is available. Zafrani et al. (2014) reported that traction bronchiectasis and/or honey combing on CT scan is associated with increased hospital and increased 1 year mortality rates [
]. They found that patients with fibrotic changes had ~15% survival at 1 year compared to ~60% survival at 1 year without fibrosis. Advanced progression of ILD on CT imaging also correlated with worse DLCO and reduced pulmonary compliance. CT scans also allow for the evaluation pulmonary artery enlargement, cardiac size, presence of pulmonary embolism, pneumonia, and many other contributing cardio-pulmonary disease processes. In patients with renal dysfunction, non-contrast CT imaging is still valuable for many cardiopulmonary disease processes that can contribute to ARF.
PH is commonly screened for using transthoracic echocardiography (TTE). Limitations of TTE include suboptimal tricuspid regurgitation measurement leading to inaccurate systolic pulmonary artery pressure (sPAP) estimate. sPAP cannot be estimated in absence of tricuspid regurgitation; while this is infrequent in severe PH, this represents a limitation to screening for mild to moderate PH [
]. In patients with advanced ILD, estimation of sPAP by TTE is often inaccurate with both over and under diagnosis of PH, necessitating the need for RHC confirmation [
]. Despite its limitations in the diagnostic workup of PH, TTE is invaluable in the acute assessment of ARF in ILD-PH patients. TTE allows for non-invasive assessment of acute changes in cardiac function that involve: volume status, regional wall motion abnormalities, pericardial effusion or tamponade, chamber sizes, and the contribution of left sided heart disease.
6. Stabilization and resuscitation strategy
Most treatment practices regarding PH are extrapolated from expert opinion in Group 1 PAH management and there is little data for guidance in ILD-PH. The general treatment strategy for ILD-ARF in PH patients is to address the underlying cause of ARF while providing necessary hemodynamic support.
ILD-ARF requires prompt stabilization of hypoxia and often of co-existing hypercapnia. Nebulized beta agonists and anticholinergics in combination with supplemental oxygen are initial steps in the management of hypoxia associated with ILD-ARF. Hypercapnia is generally improved with positive pressure ventilation (PPV) and diuresis, if CHF or PH is present. Management of these patients should take place initially in the critical care setting due to their risk of decompensation. In-hospital mortality for PH patients with acute RVF has been reported as 14% overall and 48% in those requiring management in the intensive care unit (ICU) [
]. Up to one third of hospitalized patients with all cause PH admitted to the ICU develop ARF and require invasive mechanical ventilation (IMV), which is associated with up to a tenfold increase in mortality [
]. The clinical pathophysiology of acute RVF regardless of PH subtype is similar, with more pharmacologic treatment options currently available for Group 1 PAH. Resuscitation strategies focus on correcting hemodynamic instability by timely addressing the precipitating etiology, correcting hypoxia and hypercapnia, optimizing RV preload and afterload, maintaining perfusions pressures, and increasing right ventricular contractility. After stabilization is achieved, urgent referral for lung transplant evaluation at a specialized center for both ILD and PH is recommended.
6.1 Oxygenation and ventilation
Oxygenation management is largely based on anecdotal experience and individual hospital preference. Supplemental oxygenation should target a peripheral oxygenation saturation >90% [
]. There is little evidence in ILD-ARF to guide which oxygenation strategy is superior when comparing noninvasive positive pressure ventilation (NIPPV) to high flow oxygenation (HFO) delivered by mask or nasal cannula. Expert opinion has suggested that IMV should be avoided in Group 1 PAH associated ARF, but less is known concerning ILD-PH. Table 2 summarizes recent retrospective studies on PPV outcomes in ILD-ARF.
6.2 HFO and NIPPV in ILD-PH patients
Noninvasive oxygenation and ventilation options for ILD-PH patients include HFO and NIPPV. No current trials on ILD-ARF complicated by PH have addressed the effects of HFO in comparison to other oxygenation strategies. Even without co-existing PH, limited data is available on the general efficacy of HFO in ILD-ARF. Generally, NIPPV (i.e bilevel positive airway pressure) should be considered to improve ventilation when hypercarbia accompanies hypoxic respiratory failure. Olsson et al. (2015) described reduced systolic blood pressure and cardiac output in stable PH patients [
]. This raises concern regarding the negative hemodynamic effects NIPPV can have on patients with decompensated PH. While patients with chronic lung diseases were excluded from this study, it is reasonable to extrapolate these findings to the ILD-PH cohort. Therefore, patients requiring NIPPV may require co-administration of vasoactive medications for hemodynamic support. Further studies should address the hemodynamic effects of NIPPV in ILD-PH patients with ARF.
A retrospective study of 84 ILD patients with a “Do Not Intubate” status has identified that HFO via nasal cannula versus NIPPV has no mortality benefit, but HFO was associated with fewer treatment interruptions [
Efficacy and tolerability of high-flow nasal cannula oxygen therapy for hypoxemic respiratory failure in patients with interstitial lung disease with do-not-intubate orders: a retrospective single-center study.
]. Patient comfort and tolerance likely influence treatment interruptions favoring HFO over NIPPV. In another retrospective study, HFO had not been demonstrated to reduce the rate of intubation [
]. However, HFO was associated with reduced ICU mortality and improved 90-day survival when compared to standard supplemental oxygen therapy and NIPPV. Patients with chronic lung disease were excluded from this study which limits this finding's utility in ILD patients. General opinion has suggested that in the absence of hypercapnia, HFO should be considered an alternative to NIPPV in ‘de novo’ ARF [
]. The exclusion of chronic lung disease is again an issue in ‘de novo’ ARF. The combination of HFO via nasal cannula and inhaled pulmonary vasodilators have been suggested in the management of patients with PH and hypoxemic respiratory failure [
]. This demonstrates how the severity of ILD-ARF impacts mortality. For comparison, the all-cause hospital mortality in a prospective cohort of 8151 ICU patients receiving IMV has been reported as 35% [
]. Mollica et al. (2010) stated that all patients with end stage IPF associated ARF (IPF-ARF) had evidence of right ventricular failure (RVF), but there was no significant mortality difference between IMV and NIPPV treatment [
]. This implies that PH development is a common complication of severe IPF; but its contribution to mortality is unclear as patients without PH still have high mortality, due to burden of their diffuse parenchymal disease progression. Mallick (2008) reviewed nine studies totaling 135 IPF patients treated with IMV, and found an ICU mortality rate of 87% and 3 month mortality post hospital discharge of 94% [
]. Gaudry et al. (2014) reported a 30-day and 1year mortality of patients admitted to the ICU for IPF-ARF and requiring IMV as 78% and 96.3%, respectively, without lung transplantation [
]. On average, IMV use in IPF-ARF have been demonstrated to have four times the hospital costs and seven times the mortality rate in comparison to patients treated with noninvasive strategies [
]. NIPPV should be considered prior to IMV and implemented with the avoidance of opioids or sedatives during treatment. Initial trial of NIPPV has been suggested to identify responders, avoid intubation, and improve mortality [
There is agreement that IMV should be avoided, if possible, in patients with RVF. Risks associated with IMV in ILD-ARF include ventilator induced lung injury (VILI) and exacerbation of RVF and co-existing PH due to effects from intrathoracic pressure changes. During intubation, the effect of anesthesia induction agents on cardiac function and their intrinsic vasodilating properties can contribute to systemic hypotension. When IMV is unavoidable, vasopressors and inhaled pulmonary vasodilators are often utilized prior to or during intubation to prevent hypotension and reduction in RV contractility [
There is no evidence that provides a preferred IMV mode. Fernandez-Perez et al. (2008) found that ILD non-survivors had been ventilated with lower tidal volumes with higher peak and plateau pressures, lower PaO2/FiO2 ratio, and higher positive end-expiratory pressure (PEEP) [
]. Lower tidal volumes in non-survivors likely reflected the consequences of advanced fibrosis and worse compliance. They also demonstrated that PEEP settings <5, 5–10, and >10cmH2O correlated with a 50% mortality at 1 year, 32 days, and 5.8 days, respectively [
]. Higher plateau and peak airway pressures during PEEP titration have correlated with advanced fibrosis on CT and with ICU mortality in patients with ILD-ARF [
The IMV management of ILD-PH patients should avoid factors exacerbating pulmonary vasoconstriction: hypoxia, hypercapnia/acidosis, atelectasis, and excessive changes in lung volume which negatively affect intrathoracic pressure [
]. Protective ventilation strategies in decompensated ILD-PH should focus on maintaining plateau pressure <28 cmH2O, partial pressure of arterial carbon dioxide <60 mmHg (8 kPa), tidal volumes <6 ml/kg, and titrating PEEP to RV function (ideally <10 mmHg) [
Contemporary management of acute right ventricular failure: a statement from the heart failure association and the working group on pulmonary circulation and right ventricular function of the European society of cardiology: contemporary management of acute RV failure.
]. Despite poor outcomes, IMV should be considered in subgroups of patients with potentially reversible causes of ARF or those listed for lung transplant [
Pulmonary vasodilators, which target afterload reduction, are often trialed in decompensated PH but there is limited data supporting their use outside of specific PAH subtypes. The use of pulmonary vasodilators, has not been validated in Group III PH. Therefore, there is no approved pharmacological therapy to target afterload reduction. Systemic vasodilator therapy may precipitate worsening ventilation perfusion matching (and hypoxemia) in areas of interstitial inflammation and fibrosis and therefore must be used cautiously [
]. Currently, there is an ongoing clinical trial evaluating the safety and efficacy of inhaled Treprostinil in adult ILD-PH patients (ClinicalTrials.gov Identifier: NCT02630316).
An exception to the use of systemic pulmonary vasodilators in ILD-PH has previously been suggested when the severity of PH is ‘out of proportion’ to the severity of ILD [
]. Recent guidelines have refrained from using ‘out of proportion’ and have described when to suspect PAH physiology that may be responsive to pulmonary vasodilators, as in Group 1 PAH. Group 1 PAH should be suspected in ARF patients with ILD characterized by a forced vital capacity (FVC) > 70% predicted and minimal parenchymal CT changes [
]. Additionally, a low DLCO in relation to an ILD patient's restrictive changes favor Group 1 PAH. Pulmonary vasodilators may be trialed in ILD patients with severe PH, which is defined by a mPAP ≥35 mmHg, or mPAP ≥25 mmHg with a low cardiac index (<2.0L⋅min −1⋅m −2) [
]. Patients with these features should be challenged with Group 1 PAH medications at specialized centers, for both ILD and PH. They should be closely monitored for tolerance and therapeutic benefit. The current recommendations for Group 1 PAH management are beyond the scope of this review and found in detail elsewhere [
]. The use of steroids has not been demonstrated to have impact on mortality in the acute decompensated PH and ILD-ARF patients and its use should be limited to on an individual basis.
When routine interventions do not correct acidosis during ARF in ILD-PH patients, sodium bicarbonate should be considered. Acidosis augments pulmonary vasoconstriction as a result from an alteration of extracellular H+ concentration [
]. This further augments RVF during ARF in PH patients. No study has demonstrated the use of sodium bicarbonate with mortality benefit in PH patients with refractory acidosis. However, one randomized control trial did suggest that there may be a mortality benefit with sodium bicarbonate in patients with severe metabolic acidosis and acute kidney injury [
Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial.
Optimization of volume status is critically important in patients with PH. Hypovolemia and hypervolemia can each have profound hemodynamic effects, impairing cardiac function and organ perfusion. Pre-renal acute kidney injury (AKI) is difficult to diagnose based on laboratory investigation alone because poor forward flow from hypervolemia and hypovolemia appear similarly on serum and urine electrolyte panels. The presence of AKI has been associated with increased in-hospital mortality [
]. In patients with high suspicion of intravascular hypovolemia (i.e septic shock), trials of small fluid boluses should be attempted. Bedside echocardiography may be helpful to assess and guide the management of volume optimization.
In the setting of hypervolemia, negative fluid balances reduce right ventricular preload, right-left ventricular interdependence, tricuspid regurgitation, and end organ congestion [
]. Intravenous loop diuretics are used first line and combination with thiazide-type diuretics or aldosterone antagonist may be considered to improve urinary output [
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
]. The use of ionotropic agents may also be necessary in cases where patients are not responding to intravenous diuretics. Patients refractory to these options may benefit from hemodialysis or continuous renal replacement therapy (CRRT). One study reported a 57% in-hospital survival in all cause PH patients requiring CRRT [
Vasopressors and inotropes are used to improve cardiac function and to achieve/maintain targeted perfusion pressures. Dobutamine, milrinone, and levisomendan are ionotropic agents, among other properties, which may be used for cardiac output optimization [
]. Dobutamine and milrinone use is commonly limited by systemic hypotension and they are often combined with vasopressors to counteract this undesirable effect. Levisomendan is suggested to have less hypotensive effect and no increased myocardial oxygen demand [
]. Norepinephrine and vasopressin are typically first line agents used for systemic vasopressor support. Phenylephrine should be avoided due to its effect on increasing pulmonary vascular resistance, which worsen coupling between RV function and afterload [
Atrial arrhythmia management is challenging in ILD-PH because they are common and there are limited treatment options. There are no randomized studies comparing rhythm versus rate control in PH patients with atrial arrhythmias. Typically PH has been excluded in clinical trials of atrial fibrillation [
]. Cannillo et al. (2015) found that in patients with PAH, including a small representation of Group 3 PH, the presence of a supraventricular (atrial) tachycardia was associated with increased hospitalization and mortality [
]. Generally, rate control agents have negative inotropic effects and are often poorly tolerated in decompensated PH and therefore atrial rhythm control is preferred. Digoxin is a possible exception and has been associated with improved RV function in PH patients with acute RVF [
]. The use of amiodarone is controversial in the acute setting of ILD-ARF. While amiodarone associated pulmonary toxicity is well described, there is no evidence of increased risk with short term amiodarone use in atrial arrhythmias during severe ARF in ILD or in decompensated ILD-PH. Organizing pneumonia and eosinophilic pneumonia has been described in one case with use of sotalol [
]. Due to its rate control effects, through beta blockade, it would be advisable to avoid sotalol in decompensated PH. Class 1C antiarrythmics (i.e propafenone and flecainide) are other potential options, but have not been studied in PH.
Non-pharmacologic interventions for atrial arrhythmias include electrical cardioversion and catheter ablation. Electrical cardioversion has only been studied in a limited number of Group 1 PAH patients, with a failure rate of approximately 77% [
]. Radiofrequency catheter ablation (RFCA) has been demonstrated to be a successful option for PH patients with supraventricular tachycardia, but this has not been described in decompensated states. RFCA would require mechanical ventilation and anesthesia, which would challenge its utility in decompensated PH.
7. Hemodynamic monitoring
All patients with hemodynamic instability requiring ICU level care should have central venous access and arterial line placement. Continuous pulse oximetry, telemetry, temperature recordings, and urinary output are standard critical care measurements.
Central venous access allows for measurement of mixed venous oxygen saturation (SvO2). Ideally this may be taken from the distal port of a right heart balloon flotation catheter. SvO2 saturation is non-specific when low and may reflect cardiogenic shock, hypovolemia, or obstructive shock. High SvO2 is typically seen in a patient with septic shock who may benefit from fluid resuscitation to improve cardiac output [
]. ILD-PH with ARF secondary to septic shock may also have low SvO2 in the presence of decompensated PH, and cautious interpretation of SvO2 is required. Serial SvO2 measurement should help assess response to therapy. Measurement of SvO2 should be performed early after central access is achieved, then repeated every 4 h in the resuscitation course. Catheter related infections may subsequently present as an acute decompensation of respiratory status and should be treated empirically with catheter removal and antibiotics while culture data is pending. High CRP levels have been described as suggestive of catheter related infections while further work up is pending [
RHC is beneficial for accurate volume assessment but it not commonly used in this cohort of PH patients. RHC is not always feasible and clinical management is frequently based on less invasive interventions, such as laboratory studies and bedside echocardiography. Although RHC is not without risk, early RHC has demonstrated improved survival when findings have influenced management [
]. Additionally, a PVR of greater than ≥7 Wood Unit was found to have three times the risk of mortality in Group 3 PH patients, highlighting the prognostic value of RHC [
]. Despite common reservation, RHC should always be performed when an ILD patient is suspected to have PH and PH specific therapy is being considered.
8. Advanced considerations
Lung or heart-lung transplantation remain the only definitive treatment option for advanced ILD or ILD-PH in suitable candidates. When maximum medical therapy has failed to improve RV function, oxygenation, and/or ventilation, the next step may be to consider extracorporeal membrane oxygenation (ECMO) candidacy as a bridge transplant or in patients with a reversible cause of RVF [
]. Trudzinski et al. (2016) retrospectively studied ECMO outcomes of patients with ILD-ARF. They reported: (1) ECMO is a lifesaving option for patients with ILD-ARF provided they are candidates for lung transplantation; and (2) patients with ILD on ECMO that are not lung transplant candidates have a high mortality rate, comparable with the mortality rate of those mechanically ventilated [
]. ECMO is associated with bleeding and infection, and should be limited to ILD patients who are transplant candidates or those with reversible causes of ARF.
Hemodynamic instability holds a grave prognosis for those patients unsuitable for ECMO or transplant. Hoeper et al. (2002) found that in 132 PH patients treated at PH centers, cardiopulmonary resuscitation (CPR) was acutely successful in only 21% patients; 60% of this group died within 7 days. 6% of patients in this study were considered as long-term survivors, defined as alive after 90 days, without neurological deficit [
]. In situations where transplant and aggressive interventions are no longer options, palliative care services and prognostic counseling for patients are essential.
9. Conclusion
PH often complicates ILD-ARF and the evidence guiding management is limited. At the current time, many guidelines are based on expert opinion and often extrapolated from evidence obtained from Group 1 PAH. The focus of treatment should be promptly addressing reversible causes of ARF and providing hemodynamic support that limits the risk of lung injury and exacerbation of RVF. Timely referral to a specialist center in ILD and PH is advised to optimize supportive therapy and to allow rapid lung transplant candidacy evaluation when appropriate.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European society of cardiology (ESC) and the European respiratory society (ERS): endorsed by: association for European paediatric and congenital cardiology (AEPC), international society for heart and lung transplantation (ISHLT).
PDE5A inhibition attenuates bleomycin-induced pulmonary fibrosis and pulmonary hypertension through inhibition of ROS generation and RhoA/Rho kinase activation.
Am. J. Physiol. Lung Cell Mol. Physiol.2008; 294: L24-L33
Distinct differences in gene expression patterns in pulmonary arteries of patients with chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis with pulmonary hypertension.
Efficacy and tolerability of high-flow nasal cannula oxygen therapy for hypoxemic respiratory failure in patients with interstitial lung disease with do-not-intubate orders: a retrospective single-center study.
Contemporary management of acute right ventricular failure: a statement from the heart failure association and the working group on pulmonary circulation and right ventricular function of the European society of cardiology: contemporary management of acute RV failure.
Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial.
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