ness [103, 104]. The Fluid and Catheter Treatment Trial compared a liberal versus a conservative fuid management strategy in ARDS as well as methodology for monitoring fuid management, and the investigators found that a conservative strategy of fuid management improved lung function and shortened the duration of mechanical ventilation [105]. Additionally, investigation into the optimal management of analgesia and sedation, liberation strategies from mechanical ventilation, nutritional management, the prevention of hospital acquired conditions (catheter related blood stream infections, ventilator associated pneumonia, pressure ulcers, venous thromboembolic disease, etc.), and restrictive transfusion strategies have all contributed to the improvements seen in the management of the critically ill patient including those with ARDS. Hence, the 28-day mortality has declined from 35% to 40% to approximately 20–25% [99].

Miscellaneous Causes

Etiologies

Human Immunodefciency Virus (HIV)

Infection with HIV predisposes patients not only to its all too well-known infectious complications but also a broad array of non-infectious pulmonary complications such as Kaposi sarcoma, interstitial lung disease (non-speci c interstitial pneumonitis, lymphocytic interstitial pneumonitis, organizing pneumonia), pulmonary hypertension, and alveolar hemorrhage. Vincent and colleagues prospectively analyzed the BAL results of a cohort of HIV-infected patients undergoing bronchoscopy as part of their evaluation for new respiratory symptoms and/or fever and found that approximately one-­ third of patients had evidence of DAH [106]. Independent risk factors for DAH in this study were (1) pulmonary Kaposi sarcoma, (2) hydrostatic pulmonary edema, (3) cytomegalovirus pneumonia, and (4) thrombocytopenia (platelets <60,000 cell/μL). However, the absolute degree of hemorrhage was relatively mild and did not appear to affect survival. Treatment is largely supportive care combined with treating reversible, underlying pulmonary processes (i.e., pneumonia or Kaposi).

Pulmonary Capillary Hemangiomatosis

Pulmonary capillary hemangiomatosis is an exceedingly rare entity characterized by diffuse proliferation of the pulmonary capillary network. Patients present with signs and symptoms of both alveolar hemorrhage (secondary to capillary rupture into the airspaces) and pulmonary hypertension (secondary to obstruction to fow at the capillary/post-­ capillary level) [107]. Given its rarity, no effective therapies other than lung transplantation have been identi ed. There is one case report of clinical improvement following treatment with interferon alpha-2a [108].

Treatment

When approaching a patient with hemoptysis, bilateral in l- trates with hypoxemia, or known lower respiratory tract bleeding, the differential diagnosis remains quite broad, and yet, the bedside clinician must support the patient’s vital physiologic functions, and correctly diagnosis and reverse the disease process in an ef cient and timely fashion. Moreover, the degree and severity of dyspnea, hypoxia, and/or respiratory distress can vary dramatically between patients from the asymptomatic to profound hypoxemic respiratory failure. Nevertheless, the initial steps of management revolve around supportive care and distinguishing between a focal source of hemorrhage, a non-hemorrhagic diagnosis, and DAH.

From a supportive care standpoint, oxygen therapy titrated to a saturation of arterial hemoglobulin ≥90% is recommended for all patients. Similarly, reversing any contributing coagulopathy is recommended unless rm contraindications or mitigating circumstances exist (i.e., antiphospholipid antibody syndrome with active or life-threatening thromboembolic disease). In those patients who are unable to protect their airway or who require ventilatory support, endotracheal intubation and initiation of mechanical ventilation are recommended. Still, to date, no randomized trials have been performed to determine the most effective mode of mechanical ventilation in DAH. Extrapolating from the extensive data informing the ARDS literature, most experts would recommend a lung-protective, low tidal volume strategy (tidal volumes of 6 mL/kg ideal body weight), goal plateau pressures less than 30 cm H2O, and potentially, prone ventilation in patients with more severe disease. Given the clinical similarities between DAH complicated by respiratory failure and ARDS, it is reasonable to extrapolate this data to the care of the patient with DAH.

Similarly, volume resuscitation is recommended for patients with clinical evidence of hypovolemia or shock. Following de nitive reversal of the hypoperfused state, adopting a conservative fuid strategy, again based on data from the ARDS literature, would also be advisable. For those patients with clinically signi cant anemia, transfusion may be necessary, but there are no data to speci cally inform transfusion thresholds in DAH. Recent data in more general populations of critically ill patients have found that blood transfusions increase the risk of adverse outcomes, particularly in younger and less severely ill patients, and many critical care units will now uniformly deploy restrictive transfusion strategies that transfuse to a goal hemoglobin of no higher than 7.0–9.0 g/dL [109]. Mitigating against this would be the rate of active bleeding and whether or not the hemorrhage is controlled at the time of decision-making.

As outlined earlier, the diagnosis of DAH rests upon bronchoscopy and bronchoalveolar lavage demonstrating an absence of clearing, or paradoxical worsening of hemorrhage during serial lavage. Competing considerations that

may be identi ed on bronchoscopy include focal hemorrhage (malignancy, arterio-venous malformation, bronchiectasis, necrotizing pneumonia, pulmonary embolus, tuberculosis/Rasmussen aneurysms, etc.), aspirated blood (gastrointestinal or upper airway bleeding), or non-­ hemorrhagic disease (ARDS, pneumonia, pulmonary edema, etc.). Once a diagnosis of DAH has been established, further distinguishing between capillaritis and non-capillaritis lesions determines whether or not additional targeted therapies may provide bene t. Generally, the speci c underlying etiology is not known even when a diagnosis of DAH is established, but rapid intervention may be required depending upon disease severity. Given the signi cant mortality associated with immune-mediated DAH, the importance of the prompt initiation of disease-modifying therapy cannot be overemphasized. Picard et al. created a scoring system utilizing data present at admission that was highly predictive of pulmonary capillaritis, as opposed to bland hemorrhage or DAD. This scoring system was developed by doing a multivariate analysis of 76 consecutive, symptomatic DAH cases. Four variables were identi ed as predictive factors of immune-mediated DAH including (1) more than 11 days since respiratory symptom onset, (2) arthralgias, (3) fatigue and/or weight loss, and (4) proteinuria > 1 g/L (Table 9.4) [110]. Validation from an external cohort demonstrated that a score ≥4 yielded a sensitivity of 100%, speci city 88%, positive predictive value 75%, and a negative predictive value of 100% [111]. Although this scale may suggest pulmonary capillaritis, the authors recommend refraining from initiating cytotoxic agents (i.e., cyclophosphamide) or plasma exchange based off of this scale alone.

For patients with suspected pulmonary capillaritis, in whom a diagnosis of GPA, MPA, SLE, or ABMA disease is seriously entertained and who demonstrate respiratory distress, respiratory failure requiring mechanical ventilation and/or demonstrate a clinically signi cant pulmonary-renal syndrome of DAH and glomerulonephritis, initiating therapy with IV corticosteroids and a cytotoxic or biologic agent should be performed in a timely fashion. Given the known ef cacy of plasmapheresis in ABMA disease and potential bene t in SLE, plasmapheresis should be initiated until

Table 9.4  Predicting immune capillaritis in DAH

A score ≥4 had sensitivity of 100%, speci city 88%, and a positive predictive value of 75% for diagnosing immune mediated causes of DAH [110, 111]

a Includes fatigue that is incapacitating and weight loss of at least 5% for at least 1 month prior to admission

either the former two entities are ruled out or a con dent diagnosis of AAV is made. Although plasmapheresis demonstrated no bene t in AAV, PEXIVAS did not nd any statistically signi cant difference in adverse events with plasma exchange. The data informing these treatment recommendations are derived primarily from the AAV and ABMA disease literature and have been discussed earlier. The optimal timing of the introduction of the cyclophosphamide, rituximab, or other disease-modifying agent in the critical care setting, especially in patients with concomitant infection and/or requiring mechanical ventilation remains subject to debate. With the results of PEXIVS, a reduced steroid dosing strategy seems to be non-inferior in severe AAV and may help mitigate against infectious complications from aggressive immunosuppression. Whether this strategy of corticosteroid dosing is bene cial for other forms of pulmonary capillaritis is unclear at this time. For patients with lesser degrees of disease severity, not requiring mechanical ventilation and without end-organ impairment, clinicians may elect to treat with corticosteroids alone pending the results of the de nitive evaluation (which in turn may then drive additional treatment decisions such as the introduction of a cytotoxic or biologic agent). However, these cases can often evolve rapidly, and close, serial observation is required. If patients demonstrate clinical deterioration, then therapy may need to be escalated.

As was discussed earlier, two randomized control trials were performed in generalized, active and severe AAV comparing cyclophosphamide to rituximab for the induction of remission, and based upon the nding of non-inferiority, rituximab may now be considered an alternative rst-line agent for the management of AAV [30, 112]. Furthermore, speci cally with the RAVE study, rituximab was found to be as effective as cyclophosphamide in patients with alveolar hemorrhage and more ef cacious than cyclophosphamide-­ based regimens for inducing remission of relapsing disease and PR3 positive patients [30, 33]. Thus, one may consider substituting rituximab for cyclophosphamide in patients with AAV and alveolar hemorrhage. However, recognizing that rituximab is a monoclonal antibody, the timing of its administration relative to any use of plasmapheresis must be carefully considered, and in point of fact, most experts would recommend beginning administration after completion of any plasma exchange (or limiting its use to those patients who do not require plasma exchange).

Additional therapies that have been considered in these severe cases of DAH include activated human factor VII and extracorporeal membrane oxygenation (ECMO). Exogenous activated factor VII has been used on a compassionate use basis and reported at the case report level to aid in hemostasis of cases of refractory DAH. ECMO is an advanced form of ventilatory and circulatory support and is used as a salvage therapy for refractory hypoxemia or cardiac failure.

An ECMO circuit consists of a cannula withdrawing blood from a vein, a pump, a membrane oxygenator, and a catheter returning blood either to a central vein (venovenous ECMO) or a central artery (venoarterial ECMO) [113]. Venovenous ECMO (VV ECMO) has been used most frequently in the management of severe ARDS. However, recent trials have shown no mortality bene t with the use of VV ECMO [114]. ECMO requires systemic anti-coagulation to maintain circuit patency and prevent thrombosis. Improved biocompatible circuits have led to a reduction in complications from ECMO usage. In non-bleeding patients, Extracorporeal Life Support Organization (ELSO) guidelines recommend anti-coagulation with heparin titrated to an activated clotting time (ACT) of 180–220 s [115]. In bleeding patients, the ACT goal may be reduced to 180 s [116]. Previously, alveolar hemorrhage was perceived to be a strong relative contraindication to the use of ECMO for fear of exacerbating underlying hemorrhage.

Given the rarity of DAH, the evidence for the use of ECMO in this condition is limited to case series. A review of 21 cases found AAV to be the most common cause for ECMO use in DAH accounting for 48% of cases [113]. Anti-­ coagulation use was documented in 82% of patients who were on ECMO. Survival to discharge was documented at a surprising 90% [113]. The reported survival with ECMO as salvage therapy for DAH is likely to be related to publication bias as these cases represent the potential discovery of a novel intervention for a life-threatening disease. Prospective randomized control trials are needed to fully ascertain the bene t of the ECMO in refractory cases of DAH.

Conclusions

DAH is a complex and life-threatening clinical-pathologic syndrome associated with a broad differential diagnosis and a number of distinct histopathologic patterns. Accurate and timely diagnosis of DAH and its speci c underlying cause permit the bedside clinician to effectively treat the majority of patients such that a detailed knowledge of its diagnosis and management is critical for the Pulmonary/Critical Care physician.

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