of TCR were obtained using the chemiluminescent microparticle in human whole blood immunoassay method (CMIA, Abbott Lab., Brazil) after the patients fasted for 3.5 hr. Of the patients evaluated, 64.3% were men, and 35.7% were women. In total, 28.6% of patients received living donor kidneys, and 71.4% of patients received deceased donor kidneys. The mean age of the patients was 43T13 years, and the average time since transplant was 41T32 months. The mean serum creatinine and urea levels were 1.6T0.5 mg/dL and 59T27 mg/dL, respectively, and the mean hemoglobin level was 13.7T1.9 g/dL. We found no significant difference in the mean serum TCR concentrations measured under the placebo or OMP regime (15.8T8.7 ng/mL vs. 15.7T6.8 ng/mL, respectively, P=0.92) (Fig. 1). Compared with the placebo period, there was an increase in the serum TCR concentration greater than 10% in 13 patients and greater than 20% in 10 patients, which corresponded, respectively, to 46.4% and 35.7% of the studied patients.
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These data suggest that OMP may increase the serum TCR concentration if ingested 2 hr before TCR ingestion, likely through alkalization of the intestinal contents. These prevalence rates should be used to calculate the sample sizes needed for future studies with larger numbers of patients. Leonardo Jose´ Peloso Priscila Neves Faria Maria Vito´ria Bossolani Heleno Batista de Oliveira Sebastia˜o Rodrigues Ferreira Filho Nephrology Division Internal Medicine Department Federal University of Uberlandia MG, Brazil The authors declare no funding or conflicts of interest. Address correspondence to: Sebastia˜o Rodrigues Ferreiras-Filho, M.D., Ph.D., Federal University of Uberlandia, MG, Brazil. E-mail: [email protected] Received 29 May 2014. Accepted 11 June 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9806-e63 DOI: 10.1097/TP.0000000000000351
Maguire M, Franz T, Hains DS. A clinically significant interaction between tacrolimus and multiple proton pump inhibitors in a kidney transplant recipient. Pediatr Transplant 2012; 16: E217. Tsuchiya N, Satoh S, Tada H, et al. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 2004; 78: 1182. Venkataramanan R, Swaminathan A, Prasad T, et al. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet 1995; 29: 404. Venkataramanan R, Jain A, Warty V, et al. Pharmacokinetics of FK 506 following oral administration: a comparison of FK 506 and cyclosporine. Transplant Proc 1991; 23: 931. Jones D, Howden C, Burget D, et al. Acid suppression in duodenal ulcer: a metaanalysis to define optimal dosing with antisecretory drugs. Gut 1987; 28: 1120. Marchetti S, Mazzanti R, Beijnen JH, et al. Concise review: clinical relevance of drugdrug and herb-drug interactions mediated by the ABC transporter ABCB1 (MDR1, P-glycoprotein). Oncologist 2007; 12: 927. Homma M, Itagaki F, Yuzawa K, et al. Effects of lansoprazole and rabeprazole on tacrolimus blood concentration: case of a renal transplant recipient with CYP2C19 gene mutation. Transplantation 2002; 73: 303.
Inhaled Nitric Oxide as a Potential Rescue Therapy for Persistent Hepatopulmonary Syndrome After Liver Transplantation thotopic liver transplant because of decompensated liver failure secondary to hepatitis C and hepatocellular carcinoma. Before transplantation, patient had known hepatopulmonary syndrome (HPS) with a right to left shunt fraction of 15%. He was able to maintain pulse oximetry (SpO2) of 94% on 5 L per min O2 and perform his usual activities of daily living. Once admitted for transplantation, patient underwent surgery within several hours of arrival; no saturation on air was documented preoperatively, and no blood gas was obtained. After an uncomplicated surgery, patient was extubated to high flow oxygen at 30 L per min with fraction of inspired oxygen (FiO2) of 100%; on that arterial oxygen tension (PaO2) was 51 mm Hg, arterial oxyhemoglobin saturation (SaO2) 88%, and SpO2 readings were in the low 90s throughout the day. By postoperative day 2, SpO2 range on same amount of FiO2 dropped to mid to low 80s. Therefore,
inhaled nitric oxide (iNO) at 20 parts per million (ppm) was added for hypoxemia, which allowed gradual weaning of FiO2 with discontinuation of iNO by postoperative week 1; by then, SpO2 values ranged from upper 80s to low 90s on 6 L per min flow. Arterial blood gas was not obtained when iNO was stopped. Subsequently, patient experienced progressively worsening hypoxemia. By the end of the second week, his O2 requirements increased to 15 L per min to maintain SpO2 greater than 88%. Surveillance liver biopsy at 2 weeks demonstrated moderate acute rejection. By the end of the third week, patient had to remain recumbent at all times because of refractory hypoxemia, even while in sitting position on high flow oxygen at 30 L per min. While supine, patient was barely able to maintain SpO2 in the high 80s. Arterial blood gas on a 100% FiO2 was notable for a PaO2 of 212 mm Hg and an increase in right to left shunt fraction to
23%. Repeat biopsy at week 3 demonstrated minimal portal and lobular hepatitis and trace steatosis and was negative for acute cellular rejection. Computed tomography angiography scan was negative for a pulmonary embolus but demonstrated significant chronic pulmonary vascular remodeling and dilation (Fig. 1). Contrast echocardiography showed delayed opacification of the left atrium consistent with a large intrapulmonary shunt unchanged from pretransplant. Inhaled epoprostenol was administered the day after an increase in flow to 30 L per min as SpO2 remained in the upper 80s; however, when blood gas was obtained, PaO2 was only 48 mm Hg on the same amount of FiO2. Because of significant respiratory distress and persistent refractory hypoxemia, iNO at 40 ppm was started with an increase in PaO2 to 83 mm Hg within an hour of therapy. The next day, patient had less orthodeoxia and was able to sit upright without
FIGURE 1. Computed tomography scan image with contrast including coronal and cross-sectional cuts demonstrating significant pulmonary vascular remodeling and dilatation.
desaturating. After 1 week of reinitiating iNO (week 4 after transplantation), the patient was able to maintain SpO2 of 94% to 96% in a semirecumbent position, tolerated longer periods of sitting upright, and was able to start exercising with physical therapy while in bed. The iNO was gradually weaned and discontinued by the end of the second week (week 5 after transplantation) with supplemental O2 at 15 L per min. By week 6, after transplantation, the patient could ambulate in his room and was discharged to rehabilitation on 12 L per min O2. There was no further allograft rejection. By month 5, he was able to perform all activities of daily living on 5 L per min O2. At 1 year follow-up, he was no longer wearing oxygen and was exercising routinely. His SpO2 was 94% to 96% resting and 88% walking on room air. Figure 2 depicts a comparison of maximumintensity projection images on the computed tomography scan of the chest the month of transplantation (A) and a year after transplantation (B). See Figure 3 for the temporal association of iNO administration with oxygen requirements.
vasodilators and vasoconstrictors leading to ventilation or perfusion mismatch by causing preferential flow to less ventilated areas and a significant shunting of unoxygenated blood through the dilated capillaries leading to hypoxemia and increased intrapulmonary shunt. Normal hypoxic vasoconstrictor response is attenuated (3). Unlike portopulmonary hypertension, which can be managed with prostacyclin analogs, liver transplantation is the only curative treatment for HPS. Worsening hypoxemia is an indication for transplantation in selected patients; high (84%) but slow rate of reversal of the hypoxemia is usually observed (1). Administration of iNO at 80 ppm intraoperatively has been shown to inhibit ischemia-reperfusion injury,
resulting in improved liver function and decreased hospital length of stay (4). The shunt may also significantly worsen in the immediate posttransplant period with resulting severe hypoxemia and high mortality (5). There may be an increased risk for this complication among patients with severe HPS (PaO2G50 mm Hg) and among patients with an elevated shunt fraction (920%) (5). Unfortunately, there is no proven therapy for posttransplant hypoxemia because of HPS. Although inhaled epoprostenol has been used with variable success (5, 6), it was not effective in our patient. There have been reports of successful treatment of HPS using iNO after liver transplantation in pediatric patients (7). The duration of iNO therapy ranged from 2 to 15 days with resolution of hypoxemia between 21 and 360 days. In two published case series of adult patients with persistent HPS after transplantation use of iNO is reported, but no details on the patient’s oxygen requirements or how soon deterioration occurred postoperatively are provided (8, 9). Nayyar et al. (5) reported a series of four patients who developed refractory hypoxemia immediately after transplantation; all were managed with iNO (5Y19 days duration) immediately after surgery or later in the hospital stay (started on postoperative day 67 in one); two patients died. No information is provided on the status of the transplanted liver to correlate with the oxygen requirements. It is possible that allograft rejection may have precipitated worsening of the HPS
DISCUSSION Hepatopulmonary syndrome is a triad of hepatic disease, arterial oxygen defect, and pulmonary vascular dilation (1, 2). Pulmonary vascular dilation with failure of O2 to diffuse into the center of dilated capillaries creates a shunt. Severity is classified according to the resting PaO2 on room air with PaO2 less than 50 mm Hg being most severe. Long-standing HPS results from imbalance of pulmonary
FIGURE 2. Computed tomography scan of the chest with maximum-intensity projection images performed during the first month following transplantation (A) and a year later (B).
& Volume 98, Number 6, September 27, 2014 All of the authors participated in the case and in writing of the article. Received 14 April 2014. Accepted 13 June 2014. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0041-1337/14/9806-e64 DOI: 10.1097/TP.0000000000000364
FIGURE 3. Temporal association of iNO administration with oxygen requirements. iNO, inhaled nitric oxide.
in our patient because his respiratory status deterioration coincided with rejection. Nonetheless, we are not aware of a well-defined mechanistic link between acute rejection and delayed resolution of HPS as seen in this patient. In theory, anything that impairs the normal function of the graft may potentially impair the mechanisms of HPS resolution; therefore, the relationship in our case may only be casual. Mechanisms of iNO effect may be in selective vasodilation of ventilated areas, allowing for some correction of the ventilation or perfusion mismatch without adversely affecting intrapulmonary shunt. Dilatation of ventilated pulmonary capillaries may also decrease perfusion velocity which may further reduce shunting by increasing the transit time of erythrocytes and enabling increased oxygen binding.
The current case demonstrates the potential utility of using iNO as a rescue therapy to bridge patients with refractory hypoxemia while awaiting vascular remodeling to occur after orthotopic liver transplant.
Lioudmila V. Karnatovskaia Jasdip Matharu2 Charles Burger1 Cesar A. Keller1 1
Departments of Pulmonary and Critical Care, Mayo Clinic, FL 2 Lourdes Pulmonary and Critical Care Our Lady of Lourdes, Pasco, WA
The authors declare no funding or conflicts of interest. Address correspondence to: Lioudmila V. Karnatovskaia, M.D., Department of Pulmonary and Critical Care Mayo Clinic Florida 4500 San Pablo Rd, Davis Building E-7A Jacksonville, FL 32224. E-mail: [email protected]
Krowka MJ, Cortese DA. Hepatopulmonary syndrome: current concepts in diagnostic and therapeutic considerations. Chest 1994; 105: 1528. Yen KT, Krowka MJ, Lee AS, et al. Liver and lung: hepatopulmonary syndrome: recognizing the clinical features and selecting the right studies. J Crit Illn 2002; 17: 309. Rodrı´guez-Roisin R, Krowka MJ. Hepatopulmonary syndromeVa liver-induced lung vascular disorder. N Engl J Med 2008; 358: 2378. Lang JD Jr1, Teng X, Chumley P, et al. Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J Clin Invest 2007; 117: 2583. Nayyar D, Man HS, Granton J, et al. Defining and characterizing severe hypoxemia after liver transplantation in hepatopulmonary syndrome. Liver Transpl 2014; 20: 182. Krug S, Seyfarth HJ, Hagendorff A, et al. Inhaled iloprost for hepatopulmonary syndrome: improvement of hypoxemia. Eur J Gastroenterol Hepatol 2007; 19: 1140. Durand P, Baujard C, Grosse AL, et al. Reversal of hypoxemia by inhaled nitric oxide in children with severe hepatopulmonary syndrome, type 1, during and after liver transplantation. Transplantation 1998; 65: 437. Gupta S, Castel H, Rao RV, et al. Improved survival after liver transplantation in patients with hepatopulmonary syndrome. Am J Transplant 2010; 10: 354. Taille´ C, Cadranel J, Bellocq A, et al. Liver transplantation for hepatopulmonary syndrome: a ten-year experience in Paris, France. Transplantation 2003; 75: 1482.
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