50-year-old male received a kidney transplant 3 months ago and is on immunosuppression with prednisone, tacrolimus, and mycophenolate. Antiviral prophylaxis includes valganciclovir. He recently attended a wedding in Mexico and was noncompliant with his medication regimen. He now presents with persistent diarrhea, nausea, and abdominal pain. He is admitted to ICU in view of need for ongoing fluid resuscitation. Nuclear acid testing is suggestive of cytomegalovirus (CMV) disease. Treatment of this condition MOST likely includes:
Correct Answer: C
CMV can lead to either active CMV infection or CMV disease in transplant patients. Active CMV infection is defined as detection of CMV replication in the blood regardless of whether signs or symptoms are present. Tissue-invasive CMV disease is defined as the demonstration of CMV in tissue biopsy specimens by histopathology in the presence of clinical symptoms and signs of end-organ disease (enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, and retinitis). CMV disease can lead to allograft loss and mortality. Kidney transplant patients commonly receive CMV prophylaxis with oral valganciclovir for 3 to 6 months after transplantation. Oral valganciclovir has great bioavailability unlike oral ganciclovir. Oral ganciclovir is not available in the United States.
Patients with life-threatening CMV disease, high viral loads, or moderate to severe gastrointestinal disease are preferably treated with intravenous ganciclovir. While reduction of immunosuppression is reasonable in patients with CMV disease, it does increase the risk of rejection. Commonly, the antimetabolite mycophenolate is stopped during treatment of CMV disease while tacrolimus is usually continued.
Patients with mild CMV disease are often treated with oral valganciclovir. Patients with ganciclovir-resistant CMV may require intravenous foscarnet or cidofovir. These drugs are intensely nephrotoxic and have a worse side-effect profile as compared to ganciclovir.
Life-threatening CMV disease with high viral loads or moderate to severe gastrointestinal disease should be treated with intravenous ganciclovir.
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After initiation of appropriate drug therapy, the patient in the above stem demonstrates clinical improvement but develops leukopenia. He will MOST likely benefit from:
Correct Answer: D
Ganciclovir and valganciclovir may lead to bone marrow suppression and leukopenia. Caution is advised if the absolute neutrophil count is under 500 cells/µL or when the platelet count is under 25,000/µL. CMV disease in itself can suppress bone marrow production, but antiviral therapy with ganciclovir typically results in improvement of hematologic parameters. Worsening or unchanged leukopenia during ongoing anti-CMV treatment with ganciclovir necessitates use of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) or filgrastim to stabilize neutrophil counts. Growth factors also reduce the risk of bacterial infections which may be secondary to improved neutrophil chemotaxis and phagocytosis. Hematopoietic growth factors such as G-CSF or granulocyte-macrophage colony-stimulating factor, GM-CSF, are widely used to counter the effects of myelosuppressive drugs.
40-year-old male arrives to ICU from the operating room after undergoing an orthotopic combined liver kidney transplant. Intraoperative course was complicated by severe vasoplegic shock necessitating initiation of high-dose norepinephrine infusion.
Which of the following is LEAST likely to increase mean arterial pressure (MAP) in this patient?
Correct Answer: A
Vasoplegic syndrome during liver transplantation is potentially lethal. It is characterized by hypotension, normal or elevated cardiac index, decreased systemic vascular resistance, and an attenuated response to vasoactive medications. The incidence of vasoplegic syndrome in end-stage liver disease is unknown, but its etiology is most likely multifactorial.
Vasodilation of the splanchnic circulation in liver failure reduces systemic vascular resistance and contributes to a hyperdynamic cardiovascular profile. Patients with liver failure also have a deficiency of endogenous vasopressin when compared to healthy subjects. Vasopressin is a potent vasoconstrictor that binds to receptors on vascular smooth muscle and can be added to increase MAP. Abnormal nitric oxide (NO) metabolism also has been shown to play a prominent role in vasoplegic syndrome. Methylene blue has gained widespread use for the treatment of vasoplegic syndrome in both cardiac surgery and liver transplant patients because of its actions as an NO synthase inhibitor and guanylate cyclase inhibitor. Hydroxocobalamin (Vitamin B12a ) is used for the treatment of acute cyanide toxicity and often leads to hypertension. The exact mechanism is not well defined, but it is believed it may act as a scavenger of NO. Utility of hydroxocobalamin for vasoplegia has been demonstrated in patients undergoing cardiac surgery and liver transplantation. Angiotensin I has minimal hemodynamic effects. Angiotensin-converting enzyme converts angiotensin I to angiotensin II. The latter is a potent vasoconstrictor. Hydroxocobalamin may be a suitable alternative treatment of vasoplegic syndrome when methylene blue is ineffective or contraindicated.
30-year-old female is admitted to the ICU in view of progressive shortness of breath and increasing oxygen requirements. She had bilateral lung transplant secondary to cystic fibrosis 3 month ago. The LEAST likely cause for this presentation is:
The differential diagnosis of a decline in allograft function after initial recovery includes infection, humoral rejection, airway complications (including stenosis at the bronchial anastomosis, bronchomalacia, and granulation tissue), chronic rejection (bronchiolitis obliterans syndrome), thromboembolism, and recurrent primary disease.
Anastomotic pulmonary arterial stenosis (PAS) is a rare complication with a reported incidence of less than 2%. A mild degree of stenosis at the arterial anastomosis without hemodynamic significance is a normal finding after transplantation secondary to donor-receptor size discordance or secondary to the suture technique.
Pulmonary venous stenosis (PVS) is a rare complication that occurs usually in early postoperative period (first 48 hours) after lung transplantation. If left untreated PVS may lead to venous thrombosis and transplant failure. Thrombus formation at the pulmonary venous/left atrial anastomotic suture line carries the risk of systemic embolization and cerebrovascular accident. The incidence of venous thrombosis is about 15%. The inferior pulmonary veins and particularly the left lower pulmonary vein are most commonly involved secondary to their anatomical position and predisposition to suture stenosis.
Complications of pulmonary arterial and venous anastomoses are less frequently seen than airway anastomotic complications. Pulmonary venous vascular complications including stenosis and thrombosis typically occur in early postoperative period.
25-year-old male undergoes a combined pancreas kidney transplant. Maintenance immunosuppression includes tacrolimus, mycophenolate, and prednisone. Infection prophylaxis includes valganciclovir and trimethoprim-sulfamethoxazole. Two months later, he presents to the emergency department with seizures necessitating intubation for airway protection. Per his family, recent medication changes include the addition of pantoprazole and diltiazem; they are unaware if he has been compliant. He has also been drinking grapefruit juice for the last 1 week instead of orange juice. He is admitted to the ICU for further workup. Computed tomography reveals hypodensity in the posterior white matter. Elevations in plasma levels of which drug is MOST likely responsible for this condition?
The clinical syndrome of reversible posterior leukoencephalopathy syndrome (RPLS) is characterized by headaches, altered consciousness, visual disturbances, and seizures. Although the pathogenesis of RPLS has not been completely elucidated, acute hypertension is often the precipitating event. Acute hypertension leads to disordered cerebral autoregulation and endothelial dysfunction resulting in vasogenic edema. Drugs that have commonly been implicated include cyclosporine, tacrolimus, sirolimus, cisplatin, and bevacizumab.
Tacrolimus is a potent calcineurin inhibitor currently used for prophylaxis and treatment of allograft rejection. Tacrolimus metabolism occurs via the cytochrome P450-3A4 (CYP3A4) and coadministration of drugs that inhibit this enzyme lead to increased plasma levels of tacrolimus. Such drugs include protease inhibitors, diltiazem, and most proton pump inhibitors with the exception of pantoprazole. Transplant recipients are instructed to avoid grapefruit juice as it is a potent inhibitor of CYP3A4 enzyme. Tacrolimus often causes renal artery vasoconstriction leading to hypertension. Diltiazem is commonly employed to treat hypertension in this setting as it reverses the renal vasoconstriction and allows for a lower dose of tacrolimus for immunosuppression. Trimethoprim-sulfamethoxazole does not have significant interactions with tacrolimus, diltiazem, pantoprazole, and grapefruit juice.
Tacrolimus has multiple drug interactions. Increased plasma levels have been associated with RPLS.
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