Perioperative Intensive Care Unit Management

On transfer to the intensive care unit (ICU), patients are often managed using a lung-protective strategy that limits tidal volumes to 3 mL/kg per allograft and plateau pressure to less than 32 cm H₂O. Five to 10 centimeters of positive end-expiratory pressure (PEEP) are applied to the allograft, and fractional inspired oxygen concentration (FIO₂) is set initially at 0.30 to 0.40 and titrated higher if arterial oxygen saturation (SaO₂) is less than 90%. If there is minimal evidence of postoperative allograft dysfunction, liberation from ventilation can proceed expeditiously once the patient has recovered from general anesthesia. Using 10 cm H₂O of pressure support in the continuous positive airway pressure (CPAP) mode of mechanical ventilation helps counteract the airway resistance of the endobronchial tube during weaning if an EBT is left in place at the end of the case. Expeditious pulmonary toileting maneuvers including incentive spirometry, chest physiotherapy, and therapeutic bronchoscopy must be pursued without concerns for anastomosis complications. Patients undergoing LDLLT are typically kept sedated on mechanical ventilatory support for at least 72 hours to optimize expansion of the lobes.

Hyperinflation

In SLT with emphysema, the transplanted lung can be relatively noncompliant. As a result, the native lung may be hyperinflated. This is one reason that chronic obstructive lung disease recipients are preferably offered bilateral lung transplantation.⁴ This problem becomes even more apparent when higher levels of PEEP are needed because of allograft dysfunction. Hyperinflation of the native, more compliant lung leads to mediastinal shift, deterioration in gas exchange, and hemodynamic instability. Although inserting an expiratory pause into the ventilator cycle can be used to assess the level of intrinsic PEEP (“autopeep”), excessive air trapping is easily diagnosed by disconnecting the patient’s ETT from the ventilator tubing for 5 to 10 seconds. In patients with significant air trapping and hyperinflation, “popping the patient off” leads to a significant improvement in blood pressure and oxygenation. Management strategies using only a single ventilator to provide ventilation include reducing PEEP, reducing tidal volume, and accepting a modest level of respiratory acidosis. Alternatively, conversion to independent lung ventilation may be appropriate, particularly in the setting of significant allograft dysfunction and high PEEP requirements. In order to switch to independent lung ventilation, an EBT is advanced into the left mainstem bronchus, and the bronchial balloon is inflated. Positioning can be verified by measuring tidal volumes delivered to and returned from each lumen of the EBT. Bronchoscopy with a small-caliber bronchoscope is appropriate to verify that (1) the left bronchial balloon is distal to the carina and (2) that the end of the left endobronchial tube does not protrude too far distally into the left lung, compromising flow to either the upper or lower division bronchi. Ventilator settings are adjusted for each machine individually. Initially, PEEP for the allograft is set at 10 cm H₂O, tidal volume is set at 3 mL/kg and rate is set at 20 to 25 breaths/min. Initial settings for the emphysematous native lung typically use a larger tidal volume and a slower rate with 0 to 2.5 cm PEEP. There is no need to synchronize the ventilators. Lung hyperinflation is associated with a longer ICU stay, longer duration of mechanical ventilation, and a trend toward worsened mortality.⁸

Early Postoperative Respiratory Complications

Airways are affected variably by the ischemic/implantation insult. Anastomotic dehiscences are rare, although a recent report suggests incidence of this complication is increased when sirolimus was used as an immunosuppressive agent.⁹ Anatomically, the transplanted bronchus derives its blood supply from the lung and pulmonary blood flow, since the bronchial arteries are not typically anastomosed. The longer left mainstem bronchus, particularly adjacent to the anastomosis, is at higher risk for ischemic injury compared with the right bronchus, which generally is anastomosed adjacent to the right upper lobe take-off. Early bronchoscopy often demonstrates relatively normal epithelium. However, more severe airway injury patterns can become apparent over the next several days. The earliest findings are patchy areas of subepithelial hemorrhage that can become confluent. In more severe cases, white plaques can form, and frank areas of desiccated sloughed epithelium become evident. In the most severe cases, eschar is evident, and bronchial cartilage may be exposed. Severe airway injury poses the risk of infection and bronchomalacia. The infections are typically due to Candida and Aspergillus species.¹⁰ In many centers, lung transplant recipients are treated prophylactically with antifungal agents such as inhaled amphotericin or an azole such as voriconazole. This strategy seems to reduce the rate of airway infection.¹⁰ If suspicious plaques are evident bronchoscopically, we perform bronchial biopsy to exclude invasive disease. Inhaled amphotericin B (50 mg twice daily) is generally administered to patients with severe airway injury and those with cultures demonstrating growth of fungus. Bronchomalacia is generally a long-term complication, although in some cases, this complication can become evident within the first 6 weeks after transplantation. Dynamic airway collapse or fixed stenoses are diagnosed by bronchoscopy. In addition to endobronchial infections, malacia, and stenosis, other airway complications include dehiscence, granulation tissue formation, and fistulas.¹¹ These are not necessarily early complications, but increased awareness of their potential occurrence is warranted.

Primary graft dysfunction (PGD) is a severe form of ischemia-reperfusion injury (IRI) and is the leading cause of respiratory failure and morbidity early after transplantation.¹² A recent consensus statement by the International Society of Heart and Lung Transplantation (ISHLT) Working Group on PGD standardized the grading of PGD on the basis of gas exchange (PaO₂/FIO₂ ratio) and plain chest radiologic findings.¹³ With this grading system, a grade 3 PGD (PaO₂/FIO₂ < 200 plus the presence of diffuse radiographic infiltrates) resembles the definition of acute respiratory distress syndrome (ARDS), and with this in mind, it has already been validated by demonstrating a worsened mortality and prolonged hospital stay.¹⁴ The reported incidence of grade 3 PGD ranges from 10% to 25%, with 30-day mortality close to 50%.^15,16 Over 95% of patients have infiltrates in the allograft by chest roentgenogram during the first 72 hours.¹⁷ Although edema and atelectasis contribute to these early changes, worsening or persistent infiltrates most likely reflect diffuse alveolar damage (DAD) secondary to PGD. Although many cases of PGD are evident on chest films obtained on the first postoperative day, in some cases, it does not become apparent radiographically or physiologically for up to 72 hours post transplant. The timing of appearance of clinical and radiologic respiratory failure is extremely helpful, then, to elaborate a judicious differential diagnosis, understanding that while PGD occurs within hours and up to 3 days after transplantation, infection and rejection are more common past the first 24 to 36 hours. In some cases, patients will be successfully extubated only to deteriorate 24 hours later. When uncertain about the etiology, aggressive diagnostic efforts should be made, employing bronchoscopy, bronchoalveolar lavage (BAL), and biopsy to exclude superimposed infection or rejection. If pulmonary edema is unilateral, a diagnosis of pulmonary venous obstruction must be entertained. Although the incidence of this problem is extremely low, a transesophageal echocardiogram (TEE) should be performed to exclude unilateral venous obstruction.

The level of respiratory dysfunction secondary to IRI depends on the extent of the injury and the residual lung reserve. The latter factor is particularly important in SLT for emphysema, because the remaining native lung may have substantial residual function. The functional capacity of the native lung often allows the transplant recipient to tolerate a significant degree of allograft dysfunction.¹⁸ Such is typically not the case for IPF patients or recipients with significant pulmonary hypertension, since perfusion to the native lung is minimal once a donor lung with low pulmonary vascular resistance is implanted.

The management of PGD is largely supportive, including judicious diuresis and a protective ventilatory approach.¹⁹ Inhaled nitric oxide may be utilized to help address early postoperative hypoxemia.^20,21 Extracorporeal membrane oxygenation (ECMO) remains a salvage therapy for severe PGD.^22–24

Muscular weakness or mechanical issues can embarrass postoperative respiratory function. Patients requiring delayed closure of the clamshell incision, which is required in some patients with excessive bleeding, are at higher risk for respiratory dysfunction on this basis. Preoperative muscle wasting is a major contributing factor in most cases. Clinically significant phrenic nerve injury is rare. However, when dissection of the native lungs was difficult due to dense pleural adhesions, phrenic nerve injury can be present and significantly prolong the weaning process. Postoperative neuromuscular blockade is rarely used because of synergistic adverse effects on long-term neuromuscular function that have been associated with simultaneous administration of corticosteroids (a component of most immunosuppressive regimens) and neuromuscular blocking agents.²⁵ If the patient has difficulty clearing secretions, tracheostomy should be performed early.

Patients are treated with broad-spectrum antibiotics perioperatively. In patients without suppurative lung disease, antibiotics are stopped within 72 hours if samples from the donor trachea and from the explanted lung are without pathogens. If cultures are positive for potential pulmonary pathogens, a directed course of antibiotics is continued for 7 to 10 days. In patients with septic lung disease, an antibiotic regimen based on preoperative cultures is continued for a minimum of 2 to 3 weeks. Patients also may be treated with prophylactic regimens to prevent CMV infection with valganciclovir if either the patient or the donor is CMV immunoglobulin G(IgG) positive before surgery (dose will vary with kidney function). Aggressive prophylaxis against deep vein thrombosis (DVT) is mandatory.²⁶ At our center, critically ill transplant patients are screened liberally for DVT with lower extremity Doppler ultrasound examinations, with a low threshold for placement of an inferior vena caval filter when DVT is diagnosed.

New Pulmonary Infiltrates

Development of new infiltrates on the chest film after lung transplantation mandates diagnostic evaluation using fiberoptic bronchoscopy with BAL and transbronchial biopsy. If bacterial pneumonia is strongly suspected, particularly if biopsy is thought to be excessively risky, bronchoscopy with BAL and empirical antibiotic therapy is an acceptable alternative. If the Gram stain is unremarkable, and distal airways lack evidence of bacterial or fungal infection, transbronchial biopsy is necessary to exclude acute rejection or CMV infection. If a transbronchial biopsy continues to be unobtainable owing to tenuous respiratory status, open lung biopsy should be considered. Pending the results of biopsy or in lieu of one, empirical antirejection treatment may occasionally be considered on an individual basis, recognizing the potential risks of doing so.

Conditions other than PGD can lead to diffuse alveolar damage (DAD) as determined by transbronchial biopsy. DAD can result from pneumonia, rejection, CMV infection, systemic sepsis, or even subsequent to a BAL. The management of DAD is supportive, consisting of lung-protective ventilation as for ARDS. Management in severe cases can include administration of corticosteroids (e.g., prednisone 2-3 mg/kg/d), though the risk of infection in transplant patients does not support this approach.

Because the transplanted lung is in close contact with the external environment, the risk for infection is higher than is the case for other forms of organ transplantation. Accordingly, aggressive diagnostic efforts are the key to management of graft dysfunction after lung transplantation. Bacterial infections with traditional nosocomial pathogens are most common in the first 30 days. Subsequently, bacterial pneumonia is still responsible for the bulk of new infiltrates, although other etiologies must be considered as well. CMV infection, causing pneumonia among other problems, occurs in a large fraction of cases. Prophylactic and surveillance strategies to deal with CMV vary from center to center. Some institutions carry out weekly assays, seeking to detect CMV antigen in the bloodstream, and only institute early preemptive therapy when the antigen is present. Other centers provide prophylaxis using ganciclovir or valganciclovir for 3 to 6 months. Dosing of these antiviral medications will vary with the kidney function. Our center monitors CMV status via frequent plasma PCR assays.²⁷ Other viruses such as adenovirus, parainfluenza virus, influenza virus, and respiratory syncytial virus are community-acquired pathogens that can cause significant morbidity and mortality.²⁸

Fungal pneumonia with Aspergillus spp. occurs but is rare. Far more common is the colonization of airways with Aspergillus. Distinguishing between infection and colonization requires computed tomography (CT) scanning and bronchoscopic evaluation with directed biopsy to areas suspicious for invasive fungal disease. Successful treatment requires appropriate antifungal therapy and reduction in immunosuppression to the lowest levels tolerable. Candida albicans in the airway almost always reflects colonization, because pneumonia as a result of this organism is exceedingly rare. Pneumocystis carinii pneumonia is exceedingly unusual, especially when patients are treated perioperatively with trimethoprim/sulfamethoxazole as prophylaxis. Infections with toxoplasmosis, Nocardia, Histoplasma, coccidiomycosis, Cryptococcus, and mycobacteria are quite rare but do occur.

Acute cellular rejection (ACR) occurs in 36% of patients at some time in the first year after transplant.⁴ Patients typically present with allograft infiltrates, worsening hypoxemia and dyspnea. Fever and pleural effusion may occur, and pulmonary secretions are uncommon. Clinical findings have been shown to be inadequate for diagnosing ACR; establishing the diagnosis requires transbronchial biopsy.²⁹ Maintenance immunosuppression in most centers is based on a three-drug regimen including either cyclosporine or tacrolimus, prednisone, and either mycophenolate or azathioprine. Sirolimus is also often included in the maintenance regimen in selected instances (Table 195-1). Episodes of significant acute rejection are treated with methylprednisolone (10-15 mg/kg intravenously [IV] daily × 3 days). Response usually occurs within 24-72 hours. Failure to respond should prompt re-biopsy to exclude refractory rejection.

Chronic rejection presents more insidiously. Findings are increased dyspnea, worsening pulmonary function test results, and sometimes cough. Pathologically, patients with chronic rejection manifest findings of OB with a lymphocytic infiltrate in the submucosa and epithelium plus submucosal fibrosis. These findings, however, can be missed on transbronchial biopsy. OB also can develop in the wake of other insults such as acute rejection, airway ischemia, lymphocytic bronchiolitis, and certain infections such as CMV. Patients with OB, in addition to developing progressive deterioration of lung function, are also at high risk for bacterial pneumonia and acute-on-chronic bouts of respiratory failure.³⁰ Pneumonia is commonly caused by Pseudomonas aeruginosa followed by Staphylococcus and Acinetobacter baumannii.¹⁰

Nonpulmonary Organ Support and Complications

Hemodynamic management following lung transplantation is similar to that of other ICU patients, with the exception of volume administration. Given the lack of lymphatics in the allograft and potential ischemic injury of pulmonary endothelium and epithelium, pulmonary edema occurs at lower filling pressures. For that reason, lung transplant recipients with postoperative hypoxemia should be maintained “on the dry side” using vasopressors or inotropes as needed to support blood pressure and cardiac output. Patients have been screened preoperatively for coronary artery disease and ventricular dysfunction, and ischemia or congestive heart failure (CHF) should rarely be complicating factors in lung transplant recipients. Atrial arrhythmias are common and can effectively be managed with β-adrenergic blockade or sotalol in most cases. Amiodarone should be avoided because of its potential pulmonary toxicity.³¹ Diltiazem can unpredictably and markedly affect calcineurin inhibitor levels (tacrolimus and cyclosporine) and should be used cautiously.

Patients with preexisting pulmonary hypertension will enjoy a 30% to 40% reduction in pulmonary artery pressure after SLT and normalization of pressures with a BLT. Postoperative pulmonary hypertension in patients with preexisting pulmonary hypertension is generally well tolerated, since the right ventricle (RV) is conditioned, and transplantation reduces RV afterload. Only patients with pulmonary hypertension and evidence of low output and high central venous pressure (CVP) require specific therapy. Inotropic agents may be needed for support for a short time following cardiopulmonary bypass.

Renal dysfunction is common, and some patients require renal replacement therapy. In these patients, bicarbonate should be aggressively supplemented enterally to reduce the need for pulmonary compensation for metabolic acidosis. Because transplanted lungs are so sensitive to excessive intravascular volume, ultrafiltration may be required more frequently than is typical for general ICU patients. Calcineurin inhibitor (tacrolimus or cyclosporine) levels should be closely followed. Efforts for precise timing of their administration for more reliable trough levels should be stressed. Goal levels may have to be readjusted in the setting of renal dysfunction. This practice, although not encouraged, is more often considered if induction immunosuppression has been administered prior to the patient’s arrival to the ICU. Other nephrotoxins such as nonsteroidal antiinflammatory agents must be completely avoided, and CT scans should be performed without IV contrast unless absolutely necessary.

Gastrointestinal problems include gastritis/ulcers, ileus, Clostridium difficile colitis, and CMV enteritis. In some centers, patients receive an H₂ blocker during their initial hospitalization as well as enteral metronidazole (500 mg orally [PO] 3 times daily) as prophylaxis against C. difficile infection. CMV enteritis can be difficult to diagnose, since tests for circulating CMV antigen can be negative in patients with disease localized to the GI tract. Endoscopy with biopsy is appropriate, particularly if thickened bowel is identified radiographically. Patients with cystic fibrosis should be placed on a bowel regimen with lactulose (10 mg PO twice daily) or polyethylene glycol (17 g PO 4 times daily) to prevent mucous impaction. Gastroesophageal reflux disease is common after lung transplantation, and there is evidence that effective treatment, including surgical interventions,^32,33 can improve lung allograft function as well as reduce the incidence of chronic rejection.³⁴ Pancreatitis, bowel perforation, and cholecystitis are uncommon GI problems. These issues should be addressed in the standard manner.

Neurologic sequelae after lung transplant include tremors, seizures, encephalopathy, myopathy, and neuropathy. Drugs such as tacrolimus and cyclosporine, antibiotics, corticosteroids, and perioperative neuromuscular blocking agents can be contributing factors. Hyperammonemia after lung transplantation is a devastating complication presenting as lethargy and unexplained hyperammonemia. Its mechanism is poorly understood and carries a grave prognosis despite aggressive measures including gut decontamination, high levels of dialysis, and pharmacologic treatments targeted at urea-cycle enzyme deficiencies.^35,36

Hemodynamic Support

Following orthotopic heart transplantation, patients return intubated and mechanically ventilated to the ICU. Inotropic and chronotropic support perioperatively is standard and includes dobutamine, milrinone, isoproterenol, or epinephrine. In occasional patients with excessive systemic vasodilatation, norepinephrine or vasopressin (0.04 µg/kg/min) may be appropriate adjuncts perioperatively. Inotropic support is weaned over the first few days in most cases.

Patients with preexisting pulmonary hypertension require more prolonged inotropic support of the unconditioned donor RV, typically with a milrinone taper. Overt RV failure generally becomes apparent in the OR when the chest is still open, but in some cases, increasing CVP and decreasing stroke volume will necessitate evaluation by TEE. RV failure is confirmed by visualizing the absence of tamponade, a hypokinetic and distended RV, and underfilling of the LV. The addition of inhaled nitric oxide (20-40 ppm) or inhaled prostaglandin E₁ or I₂³⁸ may be appropriate adjuncts immediately postoperatively in this setting. Care must be taken to avoid overdistension of the RV chamber in the setting of postoperative RV dysfunction, since continued volume loading with CVPs above 20 cm H₂O are unlikely to significantly improve flow and may lead to an acute hepatic congestion picture. Diuretics and ultrafiltration are employed early postoperatively if hemodynamically tolerated to keep CVP below 20 cm H₂O. Mechanical support with an RVAD may be indicated and should be entertained before a picture of shock emerges. RV dysfunction in the setting of relatively normal pulmonary vascular resistance suggests that the primary problem is myocardial dysfunction rather than excessive afterload. Humoral (hyperacute) rejection should be ruled out in such cases, particularly if issues of preservation were not a concern.

Arrhythmias are common in the early postoperative period. Bradycardia is most common. Owing to denervation of the transplanted heart, sinus bradycardia and atrioventricular (A-V) nodal block are common problems in the early postoperative period. Atropine has no effect on the denervated heart. An adequate heart rate (80-100 beats/min) is generally maintained with catecholamine infusions, temporary epicardial pacing, and occasionally the use of oral agents such as theophylline (50 mg PO twice daily) or terbutaline (5 mg PO 3 times daily). Rarely, patients require placement of a permanent transvenous pacemaker, though experience suggests that in most cases, deferring that decision for a week or so allows for conduction system recovery in the transplanted heart. Atrial fibrillation (AF) is much more common than other forms of supraventricular tachycardia (SVT). AF is managed with amiodarone (150 mg bolus over 10 minutes followed by 1 mg/min × 6 hours and 0.5 mg/min × 18 hours). Because digoxin decreases A-V conduction primarily by increasing vagal tone, this drug has little use in the acute management of AF in heart transplant recipients. β-Adrenergic blockers are generally avoided in the early postoperative period. Diltiazem can be used for acute rate control, but its effects on cyclosporine and tacrolimus metabolism render this drug a second-line agent.

Respiratory complications are similar to those seen with other types of cardiac surgery. In cases in which bleeding is excessive because of redo sternotomy, multiple transfusions pose a risk of acute lung injury. Additionally, several reports suggest a higher incidence of postoperative lung injury in surgical patients on amiodarone, frequently a component of the recipient’s preoperative medical regimen. Renal complications are similar to those of lung transplant recipients, with ATN related to perioperative perfusion issues. Hyperbilirubinemia may be seen in patients with postoperative shock and hepatic congestion and in cases with high transfusion needs such as redo sternums, particularly if prior VAD support and anticoagulation were used.

Rejection

Cardiac allograft rejection can occur early post transplant. Three drug regimens similar to lung transplants are the mainstays of maintenance therapy. Induction therapy with antilymphocyte antibodies (either interleukin [IL]-2 receptor antibodies or polyclonal antilymphocyte globulin/antithymocyte globulin) is used in about half of patients to minimize renal toxicity caused by calcineurin inhibitors—more so in those with preexisting renal disease.³⁷ Acute cellular rejection may present with arrhythmias, CHF, fatigue, abdominal pain, low cardiac output, or hypotension. Surveillance endomyocardial biopsies and right heart catheterizations are performed weekly in the early postoperative period. Methylprednisolone (1000 mg IV daily for 3 days) is the standard treatment for acute cellular rejection. A particularly aggressive form of rejection is called hyperacute rejection, and is mediated primarily by humoral factors. Myocardial biopsy reveals vascular deposition of immunoglobulin and complement, with evidence of vascular injury in the absence of a mononuclear cell infiltrate. Treatment includes therapy with corticosteroids, urgent plasmapheresis, and immunoglobulin infusion. Patients undergoing re-transplantation, multiparous women, and patients having received multiple blood transfusions are at particular risk for hyperacute rejection. For potential recipients with screening studies suggesting undesirable preformed antibodies, a negative prospective crossmatch or an induction regimen including preoperative plasmapheresis is undertaken before proceeding with transplantation in most programs.

Infections

Infectious complications include routine nosocomial infections such as pneumonia, catheter-related sepsis, and mediastinitis. Patients having been bridged to transplant with a VAD complicated by infection of the VAD pocket or driveline are more prone to wound infections following removal of the device and transplantation. CMV occurs in 10% to 25% of transplants.³⁷ CMV-negative recipients who receive a CMV-positive organ are at the highest risk. Surveillance with serum CMV antigen assays is the mainstay of management. Some centers employ prophylactic regimens with ganciclovir (5 mg/kg IV twice daily or daily) or valganciclovir (900 mg PO daily) for 3 to 6 months. Toxoplasma and P. carinii prophylaxis are also standard with trimethoprim/sulfamethoxazole (160/800 PO, 3 times a week).

Long-Term Complications

The bulk of early mortality (within 1 month) is caused by graft failure (primary nonspecific) (41%), multiple organ dysfunction syndrome (MODS) (13%) and non-CMV infection (13%). Between 31 days and 1 year, non-CMV infections account for almost 30% of deaths, followed by graft failure (18%) and acute rejection (12%). After 5 years, coronary artery vasculopathy, malignancies, and non-CMV infections are the main causes of death.³⁷ Coronary vasculopathy is the “OB” of heart transplantation and leads to deterioration in cardiac allograft function following transplantation.³⁹ Endothelial cell injury can be triggered by graft ischemia, rejection, viral infections, and hyperlipidemia. Endothelial injury or activation leads to concentric, distal coronary intimal proliferation, ultimately occluding coronary flow.⁴⁰ The absence of cardiac re-innervation in most heart transplant recipients precludes warning symptoms of angina. New onset of CHF, myocardial infarction, angina, ECG changes, or syncope, particularly in patients several years post transplant, are indications for cardiac catheterization. Stents may be of value in selected cases. Retransplantation is an option, although re-transplantation as an indication for transplant carries with it a significantly inferior outcome.³⁷

Although coronary vasculopathy impairs long-term results, heart transplantation nevertheless provides a durable treatment for patients with end-stage heart disease. Patients enjoy 50% survival at 10 years.³⁷ Donor availability remains the major limitation to more widespread treatment and success.

Key Points