Laura Price

Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review

IntroductionPulmonary vascular dysfunction, pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance (PVR). We therefore provide a detailed update on the management of PH and RV failure in adult critical care.MethodsA systematic review was performed, based on a search of the literature from 1980 to 2010, by using prespecified search terms. Relevant studies were subjected to analysis based on the GRADE method.ResultsClinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. The following GRADE recommendations (evidence level) are made in patients with pulmonary vascular dysfunction: 1) A weak recommendation (very-low-quality evidence) is made that close monitoring of the RV is advised as volume loading may worsen RV performance; 2) A weak recommendation (low-quality evidence) is made that low-dose norepinephrine is an effective pressor in these patients; and that 3) low-dose vasopressin may be useful to manage patients with resistant vasodilatory shock. 4) A weak recommendation (low-moderate quality evidence) is made that low-dose dobutamine improves RV function in pulmonary vascular dysfunction. 5) A strong recommendation (moderate-quality evidence) is made that phosphodiesterase type III inhibitors reduce PVR and improve RV function, although hypotension is frequent. 6) A weak recommendation (low-quality evidence) is made that levosimendan may be useful for short-term improvements in RV performance. 7) A strong recommendation (moderate-quality evidence) is made that pulmonary vasodilators reduce PVR and improve RV function, notably in pulmonary vascular dysfunction after cardiac surgery, and that the side-effect profile is reduced by using inhaled rather than systemic agents. 8) A weak recommendation (very-low-quality evidence) is made that mechanical therapies may be useful rescue therapies in some settings of pulmonary vascular dysfunction awaiting definitive therapy.ConclusionsThis systematic review highlights that although some recommendations can be made to guide the critical care management of pulmonary vascular and right ventricular dysfunction, within the limitations of this review and the GRADE methodology, the quality of the evidence base is generally low, and further high-quality research is needed.

Prognostic factors of acute heart failure in patients with pulmonary arterial hypertension

Acute right ventricular failure in the setting of pulmonary arterial hypertension (PAH) often requires hospitalisation in intensive care units (ICU) to manage the subsequent low cardiac output and its consequences. There are very few data on these acute events. We recorded demographic, clinical and biological data and therapy in consecutive patients suffering from acute right heart failure requiring catecholamine treatment in the ICU of the French referral centre for pulmonary hypertension. These variables were analysed according to the survival status in ICU. 46 patients were included, the mean age was 50.3 yrs. ICU mortality was 41%. We found no difference in terms of demographics, clinical data, last haemodynamic measurements at admission. Systemic arterial pressure was significantly lower in the subgroup of patients whose clinical course was fatal. Plasma brain natriuretic peptide (BNP), C-reactive protein (CRP), serum sodium and creatinine at admission correlated with survival. Demonstration of an infection during the ICU stay was associated with a worse prognosis. These preliminary results underline the importance of some simple clinical and biological parameters in the prognostic evaluation of acute heart failure in the setting of PAH. Whether these parameters can guide therapy needs to be further investigated.

C-kit-positive cells accumulate in remodeled vessels of idiopathic pulmonary arterial hypertension.

RATIONALE C-kit(+) cells, including bone marrow (BM)-derived progenitors and mast cells, may participate in vascular remodelling. Because recent studies suggest that c-kit may be a target for innovative therapies in experimental pulmonary hypertension, we investigated the contribution of c-kit(+) cells in human idiopathic pulmonary arterial hypertension (IPAH). OBJECTIVES To investigate the contribution of c-kit(+) cells in human IPAH. METHODS Single c-kit, CXCL12/SDF-1α, CXCR4, CD34, and multiple c-kit, α-smooth muscle actin (α-SMA) and tryptase immunostainings were performed in IPAH lungs. C-kit mRNA expression was quantified by real-time polymerase chain reaction in microdissected pulmonary arteries from patients with IPAH and control subjects. Phenotype and function of circulating progenitors were analyzed by flow cytometry. Plasma levels of soluble c-kit and CXCL12/SDF-1α were measured by ELISA. MEASUREMENTS AND MAIN RESULTS Infiltration of c-kit(+) cells in pulmonary arterial lesions was associated with an increase in c-kit mRNA expression (P < 0.01 compared with control subjects). Both c-kit(+)/tryptase(+) mast cells and c-kit(+)/tryptase(-) BM-derived cells were increased in pulmonary arteries of patients with IPAH compared with control subjects (106.6 ± 54.5 vs. 28 ± 16.8/mm(2) and 143.8 ± 101.1 vs. 23.3 ± 11.9/mm(2); all P<0.01). Plasma-soluble c-kit was increased in IPAH compared with control subjects (27.4 ± 12.4 vs. 19.5 ± 5.8 ng/ml; P<0.05). Two populations of circulating BM-derived cells (lin-CD34(high)CD133(high) [c-kit(high)CXCR4(low)] and lin-CD34(low)CD133(-) [c-kit(low)CXCR4(high)]) were increased in IPAH compared with control subjects (P=0.01). Pulmonary arterial lesions were associated with vasa vasorum expansion expressing CXL12/SDF-1α that may recruit c-kit(+) cells. CONCLUSIONS In IPAH, c-kit(+) cells infiltrate pulmonary arterial lesions and may participate to vascular remodeling. Therefore, c-kit may represent a potential target for innovative PAH therapy.

Targeted therapies in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of small pulmonary arteries that leads to elevated pulmonary arterial pressure and right heart failure. During the last decades, an improved understanding of the pathophysiology of the disease has resulted in the development of effective therapies targeting endothelial dysfunction (epoprostenol and derivatives, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors). These drugs allow clinical, functional and hemodynamic improvement. Even though, no cure exists for PAH and prognosis remains poor. Recently, several additional pathways have been suggested to be involved in the pathogenesis of PAH, and may represent innovative therapies. In this summary, we review conventional therapy, pharmacological agents currently available for the treatment of PAH and the benefit/risk ratio of potential future therapies.

Cautious epoprostenol therapy is a safe bridge to lung transplantation in pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease (PVOD) carries a poor prognosis and lung transplantation is the only curative treatment. In PVOD, epoprostenol therapy is controversial, as this condition may be refractory to specific therapy with an increased risk of pulmonary oedema. We retrospectively reviewed clinical, functional and haemodynamic data of 12 patients with PVOD (10 with histological confirmation) treated with continuous intravenous epoprostenol and priority listed for lung transplantation after January 1, 2003. All PVOD patients had severe clinical, functional and haemodynamic impairment at presentation. Epoprostenol was used at low dose ranges with slow dose increases and high dose diuretics. Only one patient developed mild reversible pulmonary oedema. After 3–4 months, improvements were seen in the New York Heart Association functional class (class IV to III in seven patients), cardiac index (1.99±0.68 to 2.94±0.89 L·min−1·m−2) and indexed pulmonary vascular resistance (28.4±8.4 to 17±5.2 Wood units·m−2; all p<0.01). A nonsignificant improvement in the 6-min walk distance was also observed (+41 m, p = 0.11). Two patients died, one patient was alive on the transplantation waiting list on December 1, 2008 and nine patients were transplanted. Cautious use of continuous intravenous epoprostenol improved clinical and haemodynamic parameters in PVOD patients at 3–4 months without commonly causing pulmonary oedema, and may be a useful bridge to urgent lung transplantation.

Phosphodiesterase Type 5 Inhibitors in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary arterial resistance, right heart failure, and death. The pathogenesis of PAH is multifactorial, with endothelial cell dysfunction playing an integral role. This endothelial dysfunction is characterized by an overproduction of vasoconstrictors and proliferative factors, such as endothelin-1, and a reduction of vasodilators and antiproliferative factors, such prostacyclin and nitric oxide. Phosphodiesterase type 5 (PDE-5) is implicated in this process by inactivating cyclic guanosine monophosphate, the nitric oxide pathway second messenger. PDE-5 is abundantly expressed in lung tissue, and appears to be upregulated in PAH. Three oral PDE-5 inhibitors are available (sildenafil, tadalafil, and vardenafil) and are the recommended first-line treatment for erectile dysfunction. Experimental studies have shown the beneficial effects of PDE-5 inhibitors on pulmonary vascular remodeling and vasodilatation, justifying their investigation in PAH. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil, which are therefore currently the approved PDE-5 inhibitors in PAH treatment. Sildenafil and tadalafil significantly improve clinical status, exercise capacity, and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in the management of PAH although further studies are needed in this area. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia. Mild and moderate renal or hepatic failure does not significantly affect the metabolism of PDE-5 inhibitors, whereas coadministration of bosentan decreases sildenafil and tadalafil plasma levels. Due to their clinical effectiveness, tolerance profile, and their oral administration, sildenafil and tadalafil are two of the recommended first-line therapies for PAH patients in World Health Organization functional classes II or III.

Dexamethasone reverses monocrotaline-induced pulmonary arterial hypertension in rats

Pulmonary arterial hypertension (PAH) is associated with dysregulated bone morphogenetic protein receptor (BMPR)-II signaling and pulmonary vascular inflammation. We evaluated the effects of dexamethasone on monocrotaline (MCT)-induced PAH in rats for potential reversal of PAH at late time-points. Saline-treated control, MCT-exposed, MCT-exposed and dexamethasone-treated rats (5 mg·kg−1·day−1, 1.25 mg·kg−1 and 2.5 mg·kg−1·48 h−1) were evaluated at day 28 and day 35 following MCT for haemodynamic parameters, right ventricular hypertrophy, morphometry, immunohistochemistry, and IL6 and BMPR2 expression. Dexamethasone improved haemodynamics and pulmonary vascular remodelling, preventing PAH development at early (day 1–14 and 1–28) and reversing PAH at late (day 14–28 and 21–35) time-points following MCT, as well as improving survival in MCT-exposed rats compared with controls. Both MCT-induced pulmonary IL6 overexpression and interleukin (IL)-6-expressing adventitial inflammatory cell infiltration were reduced with dexamethasone. This was associated with pulmonary BMPR2 downregulation following MCT, which was increased with dexamethasone, in whole lung and control pulmonary artery smooth muscle cells. Dexamethasone also reduced proliferation of rat pulmonary artery smooth muscle cells in vitro. Experimental PAH can be prevented and reversed by dexamethasone, and survival is improved. In this model, mechanisms may involve reduction of IL-6-expressing inflammatory cells, restoration of pulmonary BMPR2 expression and reduced proliferation of vascular smooth muscle cells.

Noncardiothoracic nonobstetric surgery in mild-to-moderate pulmonary hypertension

The anaesthetic management and follow-up of well-characterised patients with pulmonary arterial hypertension presenting for noncardiothoracic nonobstetric surgery has rarely been described. The details of consecutive patients and perioperative complications during the period January 2000 to December 2007 were reviewed. Repeat procedures in duplicate patients were excluded. Longer term outcomes included New York Heart Association (NYHA) functional class, 6-min walking distance and invasive haemodynamics. A total of 28 patients were identified as having undergone major (57%) or minor surgery under general (50%) and regional anaesthesia. At the time of surgery, 75% of patients were in NYHA functional class I–II. Perioperative deaths occurred in 7%. Perioperative complications, all related to pulmonary hypertension, occurred in 29% of all patients and in 17% of those with no deaths during scheduled procedures. Most (n = 11, 92%) of the complications occurred in the first 48 h following surgery. In emergencies (n = 4), perioperative complication and death rates were higher (100 and 50%, respectively; p<0.005). Risk factors for complications were greater for emergency surgery (p<0.001), major surgery (p = 0.008) and a long operative time (193 versus 112 min; p = 0.003). No significant clinical or haemodynamic deterioration was seen in survivors at 3–6 or 12 months of post-operative follow-up. Despite optimal management in this mostly nonsevere pulmonary hypertension population, perioperative complications were common, although survivors remained stable. Emergency procedures, major surgery and long operations were associated with increased risk.

Pathophysiology of pulmonary hypertension in acute lung injury

Acute lung injury (ALI) and acute respiratory distress syndrome are characterized by protein rich alveolar edema, reduced lung compliance, and acute severe hypoxemia. A degree of pulmonary hypertension (PH) is also characteristic, higher levels of which are associated with increased morbidity and mortality. The increase in right ventricular (RV) afterload causes RV dysfunction and failure in some patients, with associated adverse effects on oxygen delivery. Although the introduction of lung protective ventilation strategies has probably reduced the severity of PH in ALI, a recent invasive hemodynamic analysis suggests that even in the modern era, its presence remains clinically important. We therefore sought to summarize current knowledge of the pathophysiology of PH in ALI.

T-Helper 17 Cell Polarization in Pulmonary Arterial Hypertension

BACKGROUND Inflammation may contribute to the pathobiology of pulmonary arterial hypertension (PAH). Deciphering the PAH fingerprint on the inflammation orchestrated by dendritic cells (DCs) and T cells, key driver and effector cells, respectively, of the immune system, may allow the identification of immunopathologic approaches to PAH management. METHODS Using flow cytometry, we performed immunophenotyping of monocyte-derived DCs (MoDCs) and circulating lymphocytes from patients with idiopathic PAH and control subjects. With the same technique, we performed cytokine profiling of both populations following stimulation, coculture, or both. We tested the immunomodulatory effects of a glucocorticoid (dexamethasone [Dex]) on this immunophenotype and cytokine profile. Using an epigenetic approach, we confirmed the immune polarization in blood DNA of patients with PAH. RESULTS The profile of membrane costimulatory molecules of PAH MoDCs was similar to that of control subjects. However, PAH MoDCs retained higher levels of the T-cell activating molecules CD86 and CD40 after Dex pretreatment than did control MoDCs. This was associated with an increased expression of IL-12p40 and a reduced migration toward chemokine (C-C motif) ligand 21. Moreover, both with and without Dex, PAH MoDCs induced a higher activation and proliferation of CD4+ T cells, associated with a reduced expression of IL-4 (T helper 2 response) and a higher expression of IL-17 (T helper 17 response). Purified PAH CD4+ T cells expressed a higher level of IL-17 after activation than did those of control subjects. Lastly, there was significant hypomethylation of the IL-17 promoter in the PAH blood DNA as compared with the control blood. CONCLUSIONS We have highlighted T helper 17 cell immune polarization in patients with PAH, as has been previously demonstrated in other chronic inflammatory and autoimmune conditions.