Critical Care Medicine

Respiratory failure in organ (non-lung) transplant

Respiratory Failure after solid organ (non-lung) transplantation

Related Conditions

Immunosuppression, TRALI, ARDS, pulmonary edema, hospital-acquired pneumonia, nosocomial pneumonia, aspiration pneumonitis, viral pneumonia, CMV disease, pneumonitis associated with mTOR (mammalian target of rapamycin) inhibitors, cardiac rejection, renal failure

1. Description of the problem

What every clinician needs to know

Respiratory failure is an important cause of death and morbidity after solid organ transplantation. Differential diagnosis is quite broad and depends largely on type of organ transplanted, time after transplantation and the patient's type and overall state of immunosuppression. Both infectious and non-infectious causes of respiratory failure may be seen.

Infectious complications include health care-associated infections, ventilator-associated pneumonia, aspiration pneumonia, community- or donor-acquired respiratory viruses, reactivation of latent recipient respiratory infections, and opportunistic infections. Non-infectious causes of respiratory failure include volume overload, cardiogenic and non-cardiogenic pulmonary edema, adult respiratory distress syndrome (ARDS), transfusion-related acute lung injury (TRALI), diaphragmatic dysfunction/phrenic nerve injury, massive pleural effusions, atelectasis, splinting secondary to pain, pulmonary embolism, drug toxicity (e.g., sirolimus-associated pulmonary toxicity), and metastatic pulmonary calcification.

Clinical features

In addition to the type of organ transplanted, it is important to consider the time course of development of respiratory complications and the patient's overall level of immunosuppression. Although the critically ill transplant recipient is in many ways similar to other patients in the intensive care unit, this patient population is distinguished by the exogenous administration of immunosuppressive therapy to suppress the allo-immune response.

Thus, the critical care physician must also assess the risk that an opportunistic respiratory infection may be contributing to the patient's respiratory failure. This may be achieved by reviewing the patient's history of prior infectious complications, estimating the patient's overall state of immunosuppression by reviewing the list of immunosuppressive medications, determining the duration and intensity of immunosuppressive therapy, and inquiring about the patient's compliance with these medications. In addition, the patient's history of taking prophylactic antibiotics should be reviewed.

Initial Considerations:

1. Type of organ transplanted and status of graft function

2. Timing of respiratory failure: early peri-operative period vs. later time points

3. Immunosuppressive regimen and history

4. Prophylactic antibiotic regimen

5. History of prior infectious complications

6. Presence of other comorbidities (e.g., function of organs other than the transplanted organ)

Key management points

Identifying the cause of respiratory failure is essential to implementing the correct treatment approach. Often a directed history (depending on the type of organ transplanted) and physical examination as well the CXR can provide important clues to readily identifying the etiology.

History

1. Were there any significant pre-operative complications?

- Was the patient encephalopathic prior to transplantation or have a history of fulminant liver failure? This may increase the risk of aspiration pneumonia and pulmonary edema.

- Does the patient have any pre-existing pulmonary or systemic disorders (e.g., COPD, asthma, cystic fibrosis, hepatopulmonary syndrome, portal-pulmonary hypertension, history of venous thromboembolism, colonization of the respiratory tract or sinuses with resistant pathogens, ANCA + vasculitis) that could contribute to post-operative respiratory compromise?

2. Were there any important peri-operative complications?

- How much volume did the patient receive in the OR, including quantity and type of blood products? This may help in assessing volume status, risk of TRALI.

- Did the patient have a witnessed aspiration event?

- Did the patient receive anti-lympholytic drugs (e.g., anti-thymocyte globulin) for induction immunosuppression? An important side effect of this class is the development of acute lung injury.

3. Were there significant post-operative complications?

- Is the allograft functioning well? For example, poorly functioning hepatic allografts increase the risk of non-cardiogenic and cardiogenic pulmonary edema while impaired cardiac and renal allograft function increases the risk that the patient may be volume overloaded.

- Does the patient have a fever, cough, purulent sputum production or pleuritic chest pain, to suggest pneumonia, pneumothorax or pericarditis?

- Is the patient in severe pain and is this impairing his or her ability to take deep breaths?

Physical examination

1. Does the patient have normal diaphragmatic excursion? Paradoxical movement of the diaphragm may suggest diaphragmatic dysfunction or paralysis.

2. Are breath sounds symmetric bilaterally?

3. Does the patient have diminished BS, dullness to percussion or rales?

4. Is the JVP elevated? Are cardiac heart sounds diminished? Is there a pericardial rub?

5. Does the patient have lower extremity edema and is it symmetric bilaterally?

CXR

1. Is the lung parenchyma clear?

2. Is the cardiac silhouette normal?

3. Are there parenchymal infiltrates (focal or diffuse)?

4. Is a pneumothorax present?

5. Are pleural effusions present and are they large enough to cause atelectasis and respiratory compromise?

2. Emergency Management

Initial management should focus on establishing respiratory and hemodynamic stability - this may include initiation of non-invasive or standard mechanical ventilation. If ventilatory support is not immediately required, attention should focus on management of clinical factors that may be contributing to respiratory compromise and initiating empiric treatment for certain potentially life-threatening complications and obtaining diagnostic testing to help determine etiology.

1. Assess need for ventilatory (non-invasive or invasive) support.

2. Initiate evaluation and treat potentially rapidly reversible causes of respiratory distress:

- Increase analgesia if patient is alert and complains of significant pain that may be causing splinting and impaired respiratory mechanics. Its presence may impair cough and increase risk of pneumonia and atelectasis.

- Initiate aggressive pulmonary toilet maneuvers (e.g., chest PT, incentive spirometry) to promote clearance of respiratory secretions, especially if mucus plugging and atelectasis is thought to be contributing to respiratory distress.

- Treatment with nebulized beta-agonists may benefit patients who have pre-existing asthma or COPD, especially if wheezing is present or patient exhibits difficulty clearing respiratory secretions. Treatment with beta-agonists may also reduce extravascular lung water in patients with acute lung injury/ARDS.

- Administer diuretics if volume overload is suspected.

- Large pleural effusions should be drained if significant associated atelectasis is identified. If a hemothorax is identified, coagulopathy should be corrected and transplant surgery consulted.

- There should be a low threshold for initiating broad-spectrum antibiotics to cover hospital- and community-acquired pathogens, especially if history, clinical or radiographic findings suggest this diagnosis of pneumonia.

- Consider empiric antiviral therapy for cytomegalovirus (CMV) for patients who are at high risk for this infection (more than 1 month post-transplantation, off anti-CMV prophylaxis therapy and especially those patients who were CMV-IGG negative prior to transplantation but received an organ from a donor who was CMV-IgG positive).Systemic signs of infection (e.g., fevers, leukopenia, elevated liver function tests) may further support the clinical diagnosis of CMV pneumonitis. Typically treatment with IV ganciclovir 5 mg/kg IV every 12 hours should be administered. Dosing is adjusted for renal function. If diagnosis of CMV pneumonitis is confirmed, intravenous CMV-immune globulin may be added to the treatment regimen.

- If the patient is mechanically ventilated, bronchoscopy with BAL should be strongly considered to assess for lower respiratory tract infections. BAL fluid should be sent for cytology (assess for fungal elements or Pneumocystis jirovecii) and microbiology - bacterial, fungal and viral pathogens. Transbronchial biopsy is almost never necessary and is potentially risky, especially in an intubated, coagulopathic patient.

- Consider treatment with corticosteroids for acute lung injury thought to be secondary to drug toxicity in addition to stopping the suspected medication (e.g., thymoglobulin, amiodarone). Dosing regimens for corticosteroids have not been established; however, anywhere from 1 mg/kg of intravenous methylprednisolone or oral prednisone once daily up to 4X/day could be considered.

See Figure 1 (Respiratory distress in the perioperative period).

Figure 1.

Respiratory distress in the post-operative period

3. Diagnosis

The differential diagnosis of post-transplant respiratory failure is broad. Most of these conditions and specific treatment/management recommendations are discussed in detail in separate chapters.

Early (first 30 days)

1. Volume overload

2. Acute lung injury/ARDS

3. TRALI

4. Pneumothorax/hemothorax

5. Cardiogenic pulmonary edema - consider myocardial infarction. After heart transplantation performance of endomyocardial biopsies with standard immunohistologic staining to assess for acute cellular rejection and immunofluorescence or immunoperoxidase staining for antibody-mediated rejection should be considered in patients with significant left ventricular dysfunction.

6. Community- or hospital-acquired/ventilator-associated pneumonia, aspiration pneumonia

7. Large pleural effusions with compressive atelectasis

8. Critical illness polyneuropathy/myopathy may be a neuromuscular cause of prolonged VDRF in patient unable to wean from mechanical ventilation despite resolution of the primary event.

9. Diaphragmatic dysfunction/paralysis - phrenic nerve injury - the most sensitive diagnostic test is transcutaneous electrophysiologic testing of the phrenic nerves. In non-intubated patients, fluoroscopic evaluation of diaphragmatic motion or diaphragmatic ultrasound may be a useful, less invasive test.

10. Drug toxicity - acute lung injury secondary to lympholytic agents (e.g., anti-thymocyte globulin, rituximab, alemtuzumab). Consider toxicity to drugs such as amiodarone that have also been associated with acute pulmonary toxicity.

11. Pulmonary embolism

Later causes of respiratory failure

1. CMV pneumonitis

2. Respiratory viral infection

3. Fungal infections

4. Pulmonary embolism

5. Drug toxicity - acute lung injury secondary to lympholytic agents (e.g., anti-thymocyte globulin, rituximab, alemtuzumab). The immunosuppressive class of drugs called mTOR inhibitors such as sirliomus (rapamycin) and everolimus have been rarely associated with pneumonitis. Consider toxicity to drugs such as amiodarone that have also been associated with pulmonary toxicity.

6. Other - rare causes of respiratory failure should also be considered in the appropriate clinical setting. For example, although metastatic pulmonary calcification is a rare and usually asymptomatic finding after renal and liver transplantation, it may progress over time to respiratory failure.

Although the differential diagnosis of respiratory failure is broad, most of the possibilities can be ruled in or out relatively quickly after review of history, performance of physical examination and performance of specific diagnostic testing such as bronchoscopy to assess for bacterial pathogens, pneumocystis infection, respiratory viruses or fungal, mycobacterial or other opportunistic (e.g., Nocardia) infections. PCR testing of serum may identify patients with active CMV infection.

Echocardiography is a useful tool for identifying patients with cardiac dysfunction or valvular abnormalities. Thoracentesis of large pleural effusions can result in symptomatic improvement, and analysis of the fluid is useful for identifying the etiology - assess for empyema, chylothorax, hemothorax, urinothorax.

Transplanted organ-specific causes of respiratory failure

Kidney Transplantation

Respiratory failure in the early post-operative period after kidney transplantation is uncommon. In a recent study of almost 7000 consecutive kidney transplant procedures at a single center, 3.1% of patients developed respiratory failure. with median time to development of respiratory failure of about 17 months. Respiratory failure in study was associated with high mortality and morbidity rates, with 22.5% mortality at 90 days and 25% of survivors losing their graft function and requiring dialysis.

Both non-infectious and infectious causes of respiratory failure should be considered. In the setting of impaired graft function, volume overload with pulmonary edema and bilateral pleural effusions may be present. Other causes of pulmonary edema include acute pericardial effusions, usually due to uremia or chronic constrictive pericarditis after prior episodes of acute pericarditis. Patients with longstanding end-stage renal disease also have significant risk factors for coronary artery disease and may develop myocardial infarction and congestive heart failure.

Unilateral pleural effusions may rarely be the result of urinothorax caused by obstruction of the transplanted ureter with subsequent extravasation of urine and migration to the pleural space through diaphragmatic passages. Treatment with the immunosuppressive drug sirolimus (also known as rapamycin) has been associated with pneumonitis, pulmonary hemorrhage and pleural effusions and should be considered in the differential diagnosis in the appropriate setting. Unlike induction immunosuppression or treatment of graft rejection with the monoclonal lymphocyte-depleting agents OKT3 or alemtuzumab, the polyclonal agents ATGAM and Thymoglobulin are only rarely associated with cytokine storm and acute lung injury.

Several case reports of non-cardiogenic pulmonary edema have also been reported after use of the interleukin-2 receptor antagonist basiliximab for induction immunosuppression. Rarely metastatic pulmonary calcification has been reported to result in respiratory failure at both early and later time points after kidney transplantation. Finally, recurrence of a systemic condition post-transplantation may cause respiratory compromise after transplantation. For example, pulmonary hemorrhage has been reported to occur at various time points in renal recipients with ANCA (+) vasculitis.

Although renal recipients are generally thought to be at lowest risk for developing infectious pulmonary complications compared to other organ transplant populations, both community- and hospital-acquired bacterial pathogens may cause pneumonia. Opportunistic infections typically occur beyond the first post-transplant month and include pulmonary nocardiosis, mycobacterial infections with tuberculosis as well as other atypical mycobacterial species. Pneumocystis jirovecii pneumonia is notably rare but may be seen after prophylaxis has been stopped and during periods of increased immunosuppression. In the study discussed above, 18% of respiratory failure cases were caused by this infection. CMV pneumonitis occurs in less than 1% of patients and is most likely to occur in patients who are CMV seronegative and receive an organ from a donor who is CMV seropositive.

Liver transplantation

Respiratory complications may be seen in more than 50% of patients early after transplantation. The most common causes of significant respiratory distress or failure include large pleural effusions, atelectasis, transfusion-related acute lung injury (TRALI), pulmonary edema and ARDS. ARDS is the most dangerous complication and associated with a very high mortality rate after liver transplantation. Risk factors for ARDS include sepsis, massive transfusions, aspiration and induction therapy with the lympholytic agent OKT3.

Patients with longstanding cirrhosis may also develop a cardiomyopathy associated with both inotropic and chronotropic incompetence as well as impaired systolic and diastolic function. Although the cardiomyopathy typically improves after liver transplantation, this takes time and cardiac function may remain abnormal in the early post-operative period and even deteriorate in association with volume overload and tremendous fluid shifts. Other factors that may contribute to respiratory failure include mucus plugging and right-sided phrenic nerve injury (from placement of the suprahepatic vena caval clamp) with associated diaphragmatic paralysis. Infectious pulmonary complications are not uncommon.

In the early post-operative period, bacterial pathogens - hospital-acquired pathogens predominate while at later time points community-acquired pathogens emerge as the most common cause of bacterial pneumonia. Liver recipients with cystic fibrosis may have respiratory tract colonization with highly resistant pathogens and are at increased risk of developing severe pneumonia from these infections. For these patients, it is particularly important to review pre-transplant sputum culture history and consider empiric antibiotic therapy for highly resistant gram-negative infections (e.g., pseudomonas) and MRSA.

In general, opportunistic pathogens such as Nocardia and other mycobacterial infections typically occur beyond the first post-transplant month. Fungal infections, especially invasive aspergillosis, most commonly occur in the first 6 months after transplantation and may be seen in the early post-operative period. Recovery of the organism from sputum or bronchoscopic cultures has a high positive predictive value.

CMV pneumonitis is only rarely seen and similar to other solid organ transplant populations typically occurs beyond the first post-transplant month. The group at highest risk for developing CMV disease are patients who are CMV seronegative and receive an organ from a donor who is CMV seropositive and who are no longer on anti-viral CMV prophylactic therapy.

Heart transplantation

Respiratory failure after heart transplantation is less common. The differential diagnosis includes non-infectious conditions such as cardiac allograft dysfunction that results in cardiogenic pulmonary edema, drug-related parenchymal lung disease (e.g., the mTOR inhibitors sirolimus and everolius have been associated with the development of pneumonitis and use of OKT3 for induction immunosuppression or treatment of rejection has been associated with acute lung injury/noncardiogenic pulmonary edema).

Aspiration pneumonia related to severe gastroparesis is quite common after combined heart-lung transplantation, but unusual after isolated heart transplantation. Although pleural effusions are frequently seen in the post-operative period, only rarely are they large enough to cause respiratory compromise. Effusions are usually left-sided or bilateral. In the early post-operative period, both transudative and exudative may be seen.

Etiologies include cardiac dysfunction, post-pericardotomy syndrome, hemothorax, parapneumonic process or empyema. Disruption of the thoracic duct during surgery resulting in a chylothorax has also been reported. Later development of pleural effusions may be due to infectious etiologies, malignancy or a complication of medications. For example, the nTOR inhibitors sirolimus and everolimus have been associated with the development of both pericardial and pleural effusions.

Pneumonia is an important cause of respiratory failure after heart transplantation. The pattern of infectious respiratory complications is similar to what has been seen in other organ transplant procedures, with hospital-acquired pathogens occurring most commonly in the early post-operative period and opportunistic infections and community-acquired pathogens emerging beyond the first post-transplant month. Risk factors for CMV pneumonia are also similar to other organ transplant recipients and include patients who are CMV seronegative and receive an organ from a donor who is CMV seropositive and patients who are no longer on anti-viral CMV prophylactic therapy and receive augmentation of immunosuppression for treatment of graft rejection.

Other conditions that may contribute to respiratory failure include diaphragmatic dysfunction secondary to phrenic nerve injury. In one study up to 12% of patients developed diaphragmatic dysfunction after heart transplantation. This is associated with impaired cough and respiratory mechanics and may be associated with pneumonia and prolonged mechanical ventilation.

4. Specific Treatment

See the specific chapters: ARDS, TRALI, hospital-acquired pneumonia,

aspiration pneumonia, invasive aspergillosis, nocardiosis, viral respiratory infections, CMV infections, pleural effusions, cardiac rejection, kidney rejection, liver transplantation, diaphragmatic paralysis, pulmonary embolism, pulmonary renal syndromes (e.g., ANCA + vasculitis).

5. Disease monitoring, follow-up and disposition

In general, the prognosis depends on the etiology of respiratory failure, prompt diagnosis and implementation of appropriate therapy.

Epidemiology

Pulmonary complications are not uncommon after solid organ transplantation. ARDS is the most-feared early complication after solid organ transplantation and is most commonly seen after liver transplantation. Variable incidence has been reported in the medical literature (4-16%) and it is associated with a very high mortality rate (>80%). Volume overload, transfusion-related acute lung injury, aspiration, release of inflammatory mediators associated with reperfusion of the liver graft and use of lympholytic agents for induction immunosuppression have been associated with an increased risk of post-liver transplant ARDS.

Prognosis

Mortality rates for patients who develop respiratory failure after solid organ transplantation are high, with some studies reporting less than 20% survival rate. Prognosis depends on the etiology of respiratory failure, with patients who develop ARDS generally having the poorest prognosis. Other factors associated with poorer prognosis include the development of multi-organ system dysfunction, advanced age, and need for mechanical ventilation (as opposed to non-invasive ventilatory support).

What's the evidence?

General

Kotloff, RM, Ahya, VN, Barth, S. Clinics in Chest Medicine. vol. 26. W.B.Saunders. 2005.

Dupont, LI, Verleden, GM. "Noninfectious pulmonary complications after organ transplantation". European Society Monograph. vol. 35. 2006. pp. 202-219.

Fishman, JA. "Infection in sold-organ transplant recipients". N Engl J Med. vol. 357. Dec 20 2007. pp. 2601-2614.

Antonelli, M, Conti, G, Bufi, M. "Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation: a randomized trial". JAMA. vol. 283. Jan 12 2000. pp. 235-241.

Jain, P, Sandur, S, Meli, Y, Arroliga, AC, Stoller, JK, Mehta, AC. "Role of flexible bronchoscopy in immunocompromised patients with lung infiltrates". Chest. vol. 125. Feb 2004. pp. 712-722.

Kidney Transplantation

Canet, E, Osman, D, Lambert, J. "Acute respiratory failure in kidney transplant recipients: a multicenter study". Crit Care. vol. 15. Mar 8. pp. R91.

Shorr, AF, Abbott, KC, Agadoa, LY. "Acute respiratory distress syndrome after kidney transplantation: epidemiology, risk factors, and outcomes". Crit Care Med. May. vol. 31. 2003. pp. 1325-1330.

Champion, L, Stern, M, Israel-Biet, D. "Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients". Ann Intern Med. vol. 144. Apr 4 2006. pp. 505-509.

De Castro, N, Xu, F, Porcher, R, Pavie, J, Molina, JM, Peraldi, MN. "Pneumocystis jirovecii pneumonia in renal transplant recipients occurring after prophylaxis discontinuation: a case control-study". Clin Microbil Infect. Dec 23 2009.

Thurley, PD, Duerden, R, Roe, S, Pointon, K. "Case report: rapidly progressive metastatic pulmonary calcification: evolution of changes on CT". Br J Radiol. vol. 82. Aug 2009. pp. e155-159.

Carcillo, J, Salcedo, JR. "Urinothorax as a manifestation of nondilated obstructive uropathy following renal transplantation". Am J Kidney Dis. vol. 5. Mar 1985. pp. 211-213.

Dhaun, N, Blakeney, J, Richards, A, Bellamy, CO, Kluth, DC. "Recurrent ANCA-associated vasculitis after renal transplantation". Transplantation. vol. 90. Dec 15. pp. 1239-1240.

Liver Transplantation

Singh, N, Gayowski, T, Wagener, MM, Marino, IR. "Pulmonary infiltrates in liver transplant recipients in the intensive care unit". Transplantation. vol. 67. Apr 27 1999. pp. 1138-1144.

O'Brien, JD, Ettinger, NA. "Pulmonary complications of liver transplantation". Clin Chest Med. Mar . vol. 17. 1996. pp. 99-114.

Li, GS, Ye, QF, Xia, SS. "Acute respiratory distress syndrome after liver transplantation: etiology, prevention and management". Hepatobiliary Pancreat Dis Int. vol. 1. Aug 2002. pp. 330-334.

Yost, CS, Matthay, MA, Gropper, MA. "Etiology of acute pulmonary edema during liver transplantation: a series of cases with analysis of the edema fluid". Chest. vol. 119. Jan 2001. pp. 219-233.

Hong, SK, Hwang, S, Lee, SG. "Pulmonary complications following adult liver transplantation". Transplant Proc. vol. 38. Nov 2006. pp. 2979-2981.

Lin, YH, Cal, ZS, Jiang, Y, Lu, LZ, Zhang, XJ, Cai, QC. "Perioperative risk factors for pulmonary complications after liver transplantation". J Int Med Res. vol. 38. Sep-Oct. pp. 1845-1855.

Leo, SO, Razonable, RR. "Current concents on cytomegalovirus infection after liver transplantation". World J Hepatol. vol. 2. Sep 27 2010. pp. 325-336.

McAlister, VC, Grant, DR, Roy, A. "Right phrenic nerve injury in orthotopic liver transplantation". Transplantation. Apr . vol. 55. 1993. pp. 826-830.

Roberts, RJ, Wells, AC, Unitt, E. "Sirolimus-induced pneumonitis following liver transplantation". Liver Transpl. vol. 13. June 2007. pp. 853-856.

Heart Transplantation

Savas Bozbas, S, Ulubay, G, Sarinc Ulasli, S, Bozbas, H, Sezgin, A. "Risk factgors for post operative pulmonary complications and mortality in cardiac transplantation patients". Ann Transplant. vol. 14. Oct-Dec 2009. pp. 33-39.

Misra, H, Dikensoy, O, Rodriguez, RM. "Prevalence of pleural effusions post orthotopic heart transplantation". Respirology. vol. 12. Nov 2007. pp. 887-890.

Lenner, R, Padilla, MI, Teirstein, AS, Gass, A, Schilero, GJ. "Pulmonary complications in cardiac transplant recipients". Chest. vol. 120. Aug 2001. pp. 508-513.

Atasever, A, Bacakoglu, F, Uysal, FE. "Pulmonary complications in heart transplant recipients". Transplant Proc. vol. 38. June 2006. pp. 1530-1534.

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