The term “Primary Graft Dysfunction” (PGD) describes an entity that has received different names in the past (e.g. reperfusion injury, reperfusion edema, re-implantation response, re-implantation edema, primary graft failure, and early graft dysfunction) [30]. This complication occurs in up to 25 % of lung transplant recipients and represents the main cause of early mortality and morbidity [2]. In addition, this condition has other poor outcome consequences, including increased ICU and hospital length of stay, increased duration of mechanical ventilation and decreased exercise capacity [31]. PGD is a form of early ALI that leads to acute lung allograft failure. One of the leading mechanisms responsible for this form of ALI is the development of ischemia–reperfusion injury. The clinical syndrome consists of development of acute diffuse alveolar infiltrates consistent with pulmonary edema of noncardiogenic origin and secondary severe hypoxemia.

The ISHLT Working Group on PGD provided a standardized definition in their 2005 consensus statement. The definition includes the presence of “diffuse allograft alveolar infiltrates” by radiography within 72 h of reperfusion and hypoxemia based on partial pressure of oxygen (PaO₂) to FiO₂ ratio (PaO₂/FiO₂) (Table 10.1). The working group recommends inclusion of the timing of lung dysfunction (T ₀—within 6 h of lung perfusion, T ₂₄, T_48, and T₇₂—24, 48, 72 h after first blood gas) [30]. They also recommend mentioning certain subgroups in the description while defining PGD; pulmonary venous occlusion, left ventricular dysfunction, hyper-acute rejection, and infectious process. Importantly, patients who develop grade 3 PGD have increased long-term mortality, as well as increased incidence of chronic allograft rejection (or Bronchiolitis Obliterans syndrome) and decreased maximum allograft function [22, 32] The clinical risk factors identified for PGD are: transplantation of an organ with donor history of smoking, elevated FiO₂ during allograft reperfusion, preoperative sarcoidosis or pulmonary arterial hypertension, use of CPB, single lung transplant, large-volume blood product transfusion, elevated postoperative pulmonary arterial pressures, and overweight or obese recipient body habitus [22]. Other previously associated factors included prolonged ischemic time, donor lung contusion or aspiration, and the use of high-potassium preservation solutions [33, 34]. The mechanisms involved are multiple but they involve a common path to endothelial and epithelial lung damage, which includes release of cytokines, cell damage by neutrophils and lymphocytes activation, complement activation, upregulation of multiple inflammatory cascade mediators, oxidative stress and reduction in endogenous NO production. The final result is increased cell death and apoptosis [35–37].

The above mentioned observations have led to the development of several strategies in order to prevent or reduce the incidence and severity of PGD with particular emphasis in modifiable clinical risk factors observed in a large prospective study (e.g., FiO₂ on reperfusion, avoiding the use of CPB, and pretransplant recipient weight loss) [22]. Otherwise, suggested preventive interventions include standardizing enhanced procurement and preservation of donor lung techniques, controlled intraoperative reperfusion pressures, and leukocyte depletion of transfused blood products. Interestingly, there are reports about the use of NO added to the flush solution at time of harvest, as well as early use of iNO to attenuate the incidence and severity of PGD [38–40]. Inhaled NO is effective in reducing pulmonary arterial pressure, improving ventilation-perfusion matching and optimizing PaO₂/FiO₂ ratio, and has potential anti-inflammatory properties [9, 29, 40]. The use of this and other approaches deserve further investigation in order to address if they improve outcomes. However, neither iNO nor other pharmacologic interventions when formally studied have been shown to be clearly effective in preventing PGD following lung transplantation [41–43].

The mainstay of critical care management and treatment of patients with PGD is a multisystem approach that minimizes further injury by using low pressure protective ventilatory strategies, and by controlling existing pulmonary edema and minimizing further pulmonary edema formation. The use of veno-venous ECMO in cases of severe PGD intends to avoid the use of injurious mechanical ventilator settings, therefore avoiding additional pulmonary insult [44]. Otherwise, treatment and prevention of pulmonary edema requires the use of intravenous diuretics and a fluid management strategy that avoid pulmonary vascular congestion. In a recent study, a central venous pressure (CVP) > 7mmHg was associated with prolonged mechanical ventilation and also with a tendency to increased ICU and in-hospital mortality [45]. Nonetheless, it is important to highlight that is necessary to assume an strategy with careful hemodynamic monitoring and management relying in the use of inotropes, pulmonary vasodilators, and vasopressors; while minimizing intravascular volume resuscitation and maintaining hemodynamic stability and adequate global perfusion and oxygen delivery. Typically a pulmonary artery catheter is required to provide pertinent hemodynamic measurements and help guide resuscitative efforts.

The occurrence of hyperacute/humorally-mediated rejection is uncommon in the literature, but is more likely in patients with high levels of preformed anti-Human Leukocytes Antibodies (HLA) (i.e. panel reactive antibody (PRA)) [9]. The clinical syndromes of acute rejection , infection, and PGD can be difficult to differentiate. Patients with acute rejection present with inflammatory response-like syndrome (including low-grade fever) and dyspnea, along with hypoxemia and perihilar infiltrates. In many cases, patients receive empiric therapy for rejection after infectious etiologies are ruled out. In this regard, acute rejection findings are nonspecific and the diagnosis is made retrospectively. The gold standard for diagnosis of acute rejection is the pathologic evaluation of serial transbronchial biopsies. However, the use of transbronchial biopsies can underestimate the incidence of acute rejection when compared with open surgical biopsy [46]. The risk of open surgical biopsy must be weighed against the diagnostic yield in selected cases. Acute rejection is a common complication presenting in the first year following lung transplantation, with about 40–60 % of recipients having at least one episode of acute rejection during the first year [2]. This complication is characterized by airway-centered inflammation in the pathologic form of lymphocytic bronchitis / bronchiolitis. There is a clear association between the frequency and severity of acute rejection episodes and later development of chronic allograft dysfunction characterized by bronchiolitis obliterans . The treatment of acute rejection aims to address the acute episode and to decrease the possibilities of further events. The main therapy is the use of methylprednisolone 10–15 mg/kg for 3–5 days, followed by an oral steroid taper for 2–3 weeks, depending on the maintenance steroid dose. There is some controversy as to the need to treat clinically undetectable grade 1 acute rejection episodes that may be diagnosed by surveillance bronchoscopy. Much emphasis in the prevention of acute rejection is made on the use of induction protocols based on interleukin-2 receptor blockers (e.g. basiliximab) or antibody depletion with antithymocyte globulin.

This complication occurs in patients who have received single lung transplantation for emphysematous diseases. In the postoperative period, there is preferential gas flow to the highly compliant, diseased, native lung with its progressive over distension and potential mediastinal shift with hemodynamic instability in severe cases. The pathophysiology of this entity is caused by the difference of compliance between the donor allograft and the remaining lung, which causes differential gas flow with positive pressure ventilation. That process is aggravated by the occurrence of PGD in the allograft. In such cases, the donor lung becomes less complaint, causing further native lung over distension. As a result, the PVR in the native lung increases and causes increased shunting of blood to the dysfunctional lung allograft with subsequent worsening of ventilation-perfusion mismatch. Management of this situation requires use of ventilator strategies that avoid air trapping, including decreasing tidal volume, lower respiratory rates, low PEEP, and long expiratory times; or converting the patient to a spontaneous ventilatory mode whenever possible. The patient should also receive aggressive bronchodilator therapy and lateral decubitus ventilation with the transplanted side up in order to maximize gas flow to the allograft. This approach can cause a mild degree of hypoxemia and hypercarbia with respiratory acidosis that are usually transient and well tolerated. In cases of hemodynamic instability or severe hypoxemia and hypercarbia, the patient can be managed with independent / differential mechanical ventilation, after other causes of instability and hyperinflation, such as tension pneumothorax and allograft mucous plugging are ruled out. This later approach requires placement of a double lumen endotracheal tube and use of separate mechanical ventilators with settings appropriate for each lung. Limitations for the use of this technique are the specialized management required for endotracheal tube placement, and the challenge that represents maintenance of proper position. Dynamic hyperinflation improves when the compliance of the transplanted lung increases, usually after 24–72 h. Although there is not enough evidence of improved outcomes to support the routine use of this technique, there are reports of successful management in several patients [47, 48].

There are multiple possible airway complications after lung transplantation including, bronchial anastomotic dehiscence, bronchial stenosis, obstructive granulomas, bronchomalacia, and bronchial fistula formation [49]. The incidence of central airway complications after lung transplantation ranges from 9 to 33 % with an associated mortality of 2–4 %. Importantly, among all airway complications, 9–13 % will require intervention [50]. The recognized risk factors for airway complications in lung transplantation are: ischemia of donor bronchi, surgical technique used, length of donor bronchi, presence of donor or recipient colonization or infection, donor/recipient bronchial size discrepancy, postoperative infection, postoperative mechanical ventilation, and use of immunosuppression [51, 52]. The improvement in surgical techniques as well as in donor and recipient management has greatly reduced the incidence of these complications. The most common airway complication is bronchial stenosis. This complication most commonly occurs between 2 and 9 months after transplantation. Such stenosis occurs after significant necrosis, dehiscence, and infections, particularly with Aspergillus species [50, 53, 54]. Another important complication is bronchial anastomosis dehiscence, which usually occurs within the first 5 weeks after transplantation, as a result of mucosal necrosis. This complication, thought quite uncommon is associated with high mortality and morbidity [55]. Although most airway complications are not fatal, they impose a high rate of morbidity and can require complex and multidisciplinary management that include interventional bronchoscopic airway treatment and airway stent placements. Ultimately, bronchomalacia and bronchial strictures can be the long-term result of anastomotic dehiscence and infections [49].

Both HUS and TTP are uncommon but potentially fatal causes of acute renal failure that occur as complications after solid organ transplantation. These syndromes are characterized by thrombotic microangiopathy due to platelet activation and microthrombi formation with consequent thrombocytopenia, hemolysis, and renal failure. Their occurrence is associated with the use of calcineurin inhibitors by poorly understood mechanisms. These syndromes occur early after lung transplantation, most commonly within 3 months. The mainstay of treatment is plasma exchange therapy , which can be combined with antiplatelet agent and glucocorticoids [61].

Thrombocytopenia remains a very common finding following lung transplantation. It is routinely a self-limiting state that reverts over the first few days after surgery. However, it can occasionally require platelet transfusion and can be associated with bleeding complications. Mechanical circulatory support, such as ECMO for PGD, commonly causes thrombocytopenia. Likewise, antimicrobial medications such as gancyclovir and voriconazole often lead to platelet consumption. Heparin-Induced Thrombocytopenia (HIT) occurs in up to 10–15 % of lung transplant recipients [62], as noted by presence of PF-4 antibodies or positive serotonin release assay. This can occasionally lead to a thrombotic phenotype (HITT) causing ubiquitous complications including deep venous thrombosis, pulmonary emboli, strokes, and ischemia. Treatment of this serious condition requires anticoagulation with pharmacologic agents alternatives to heparin, such as bivalirudin or argatroban, in order to minimize diffuse thrombotic events.

VTE occurs in up to a third of lung transplant recipients and can lead to symptomatic limb swelling, central venous occlusion, and pulmonary embolism. In addition to the usual risk factors of major surgery and immobilization, the placement of indwelling central lines during surgery, as well as long-term IV access such as with peripherally inserted central catheters (PICC) , can lead to lower or upper extremity DVTs . Sequential compression devices are routinely used on the lower extremities with uncertain benefits. However, early extubation, adequate pain control, and rapid mobilization are likely the best defenses against venous thrombus formation. The role of routine DVT prophylaxis with subcutaneous unfractionated or low molecular weight heparin (LMWH) is not firmly established in these patients. The bilateral thoracotomy incisions and extensive dissection of the hilar structures provide ample soft tissue for postoperative hemorrhage to occur and posttransplant decreases in GFR due to AKI may decrease LMWH clearance and increase the risk of bleeding. Although additional research is needed in this area, implementing routine DVT prophylaxis in our patients did not alter the rate of perioperative VTE complications, but was associated with an increase in bleeding complications [63].