Pulmonary edema is a severe and life-threatening. Etiology of Acute Pulmonary Edema During Liver Transplantation*

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1 Etiology of Acute Pulmonary Edema During Liver Transplantation* A Series of Cases With Analysis of the Edema Fluid C. Spencer Yost, MD; Michael A. Matthay, MD, FCCP; and Michael A. Gropper, MD, PhD, FCCP Study objectives: To describe the clinical features of a group of patients who acutely developed pulmonary edema during orthotopic liver transplantation and to determine the nature (transudate vs exudate) of the edema. Design: Retrospective review of clinical records and radiographic studies. Setting: Operating room and ICU of a tertiary-care medical center hospital. Patients: End-stage liver disease patients undergoing orthotopic liver transplantation under general anesthesia. Interventions and measurements: Pulmonary edema fluid obtained from seven patients within 15 min of first appearance was analyzed for protein content and compared with the protein content of a simultaneously obtained plasma sample. Hemodynamic data, fluid administration totals, and length of postoperative intubation and ICU stay were also collected. Results: Eight patients were identified. Six of the seven patients whose edema fluid was analyzed had edema fluid/plasma protein ratios > 0.75, characteristic of increased permeability pulmonary edema (the one other patient had a ratio of 0.73). Hemodynamic monitoring at the time of onset of the edema effectively ruled out a cardiogenic etiology. One patient died intraoperatively; at autopsy, the cause of death was determined to be pulmonary fat embolization. In the other seven patients, production of edema fluid resolved within 6 h of admission to the ICU. The duration of ventilatory support ranged from 23 to 96 h, with a mean of 49 h. Conclusions: The most likely cause of the reaction is transfusion-related acute lung injury (TRALI). An incidence of TRALI that is higher than previously reported in this population indicates that other elements, such as of the newly implanted liver, may be contributing factors. (CHEST 2001; 119: ) Key words: ARDS; liver transplantation; lung injury; pulmonary edema; transfusion Abbreviation: TRALI transfusion-related acute lung injury Pulmonary edema is a severe and life-threatening condition that can complicate the clinical course of hospitalized patients. The development of pulmonary edema may result from an acute increase in lung microvascular pressure, as in heart failure or valvular dysfunction (cardiogenic pulmonary edema), or from an increase in lung vascular permeability as in acute lung injury from sepsis (noncardiogenic pulmonary edema). Analysis of the protein *From the Departments of Anesthesia and Perioperative Care (Drs. Gropper and Yost) and Medicine (Dr. Matthay), Herbert C. Moffitt Hospital, University of California, San Francisco, CA. Manuscript received January 8, 2000; revision accepted May 11, Correspondence to: C. Spencer Yost, MD, Department of Anesthesia and Perioperative Care, Room S-261, Box 0542, University of California, San Francisco, CA 94143; spyost@itsa.ucsf.edu concentration in pulmonary edema fluid produced can be used to determine the mechanism of the pulmonary edema. 1 Liver transplantation is a complex operation involving, at times, substantial blood loss, massive transfusion, and large fluid shifts. Pulmonary complications occur with high frequency, as high as 75% in some studies, 2 and may significantly contribute to perioperative morbidity and mortality. 3 In this observational study, we determined the etiology of acute pulmonary edema that complicated the perioperative course of eight patients undergoing liver transplantation. We measured the protein composition of an edema fluid sample and a simultaneously obtained plasma sample to determine the nature of the edema (cardiogenic vs noncardiogenic). Hemodynamic measurements were obtained at the time to corroborate the etiology of the pulmonary edema. CHEST / 119 / 1/ JANUARY,

2 Materials and Methods Pulmonary Edema Fluid Collection and Measurement We collected edema fluid and plasma samples from eight patients who acutely developed pulmonary edema perioperatively. The samples were collected within 15 min of the first appearance of fluid in the endotracheal tube. The endotracheal tube was suctioned with a catheter, and the edema fluid collected in a standard specimen trap without dilution. A peripheral blood sample was drawn at the same time in order to measure the corresponding plasma total protein concentration. Measurement of the total protein concentrations of the pulmonary edema fluid and plasma samples was done by the biuret and bromcresol green dye-binding technique. 4,5 Measurement of total protein concentration in the edema fluid and plasma correctly characterizes the type of pulmonary edema that results from either hydrostatic or increased permeability. 6,7 Statistical Methods The data are shown as a ratio of pulmonary edema fluid to plasma total protein concentration. Mean value ( SD) are calculated for the ratio and for other clinical parameters. Results Over the past 10 years, 1,101 liver transplants have taken place at the University of California San Francisco. These operations are divided into the following three phases: (1) dissection, during which the native, diseased liver is fully mobilized and the major supplying and neighboring blood vessels isolated and clamped; (2) anhepatic, during which the donor liver vascular anastomoses are made; and (3), during which bleeding is controlled, the biliary system is anastomosed, and the patient s abdomen is closed. At University of California San Francisco, veno-veno bypass is not employed during the anhepatic phase, which typically lasts 35 to 50 min. Total surgical time ranges from 5 to 10 h. We identified eight patients who developed severe acute pulmonary edema either in the operating room or within 2 h of admission to the ICU. All patients were hemodynamically monitored by central venous and/or pulmonary artery pressure monitoring or by transesophageal echocardiography. In all these patients, a cardiogenic cause of the pulmonary edema was unlikely based on the following criteria: central venous pressure 20 mm Hg, pulmonary capillary wedge pressure or pulmonary artery diastolic pressure 18 mm Hg, no evidence of ischemia by ECG, and no segmental wall motion abnormalities. In addition, no patient had received murine monoclonal anti-c3 antibody or anti-lymphocyte globulin prior to the appearance of edema fluid. Figure 1 shows the chest radiograph from one patient (patient 7), demonstrating the characteristic findings of bilateral patchy infiltrates. A similar Figure 1. Chest radiograph from patient 7 obtained on admission to the ICU following liver transplantation. radiographic picture was present in all patients. To further determine the mechanism, pulmonary edema fluid and plasma was collected and analyzed for protein content in seven of these eight cases. In the eighth patient, the pulmonary edema fluid was accidentally discarded before protein analysis could be done. Table 1 summarizes clinical and laboratory data for the eight patients. Six of the seven patients whose edema fluid was analyzed had edema fluid/plasma protein ratios 0.75, which is characteristic of increased permeability pulmonary edema. One patient had a ratio slightly lower at All patients had received several units of blood products prior to the onset of edema, especially large volumes of fresh frozen plasma for correction of coagulopathy, and three patients had received several units of packed RBCs. Platelet transfusions had also been administered to seven of eight patients. One patient (patient 4) died intraoperatively; all others survived their liver transplantation. At autopsy, the cause of death for the one intraoperative death was determined to be fat embolization to the lung following of a graft with a high content of microscopic and macroscopic fat. In the other seven patients, production of edema fluid resolved within 6 h of admission to the ICU, and the duration of ventilatory support ranged from 23 to 96 h with a mean of 49 h. Most patients were discharged from the ICU between 2 to 5 days postoperatively, and one patient who was discharged at 22 days. In our institution, patients are typically extubated within 12 h of completion of their transplant and transferred from the ICU 1 to 3 days postoperatively. In long-term follow-up, three pa- 220 Clinical Investigations in Critical Care

3 Table 1 Characteristics of Liver Transplant Patients Developing Acute Pulmonary Edema* Patient Age, yr Diagnosis Onset of Edema Hemodynamic Measurements, mm Hg EF/P Ratio Pao 2 / Fio 2 FFP/pRBC/ plts, U Postoperative ICU Course 1 23 Cryptogenic 135 min after CVP, 12; PA, 38/ /1/2 Extubated, 23 h; discharged; 3 d 2 60 PBC 2 h after ICU admit CVP, 13; PCWP/ /3/0 Extubated, 24 h; discharged, 2 d 3 50 ALD 10 min after CVP, 17; PA, 41/ /11/3 Extubated, 52 h; discharged, 4 d 4 56 HCV 60 min after CVP, 10; PA, /21/2 Intraoperative death 25/ ALD 50 min after CVP, 8; PA, 27/ /3/3 Extubated, 57 h; discharged, 5 d 6 45 HCV, ALD 50 min after CVP, /16/1 Extubated, 96 h; discharged, 22 d 7 21 FHF 60 min after incision CVP, 6; no RWMA /0.3/0 Extubated, 42 h; discharged, 4 d 8 53 HBV 65 min after CVP, 11; PCWP, /2/1 Extubated, 48 h; discharged, 3 d Average CVP /7 8/1.5 1 Extubated, h; discharged, 6 7d *PBC primary biliary cirrhosis; ALD alcoholic liver disease; HCV hepatitis C virus; FHF fulminant hepatic failure; HBV hepatitis B virus; CVP central venous pressure; PCWP pulmonary capillary wedge pressure; PA pulmonary artery pressure; RWMA regional wall motion abnormality; FFP fresh frozen plasma; prbc packed RBCs; plts platelet pheresis pack; Fio 2 fraction of inspired oxygen; EF/P edema fluid/plasma protein. tients died 1, 15, and 47 months postoperatively due to sepsis, graft rejection, and lymphoma, respectively. One patient was retransplanted 9 years after the first transplant for rejection. The remaining three patients are alive and doing well. Discussion Fluid balance in the lung, as in any tissue, is determined by the Starling equation, which identifies the forces acting to produce net flow of liquid across the capillary membrane. This flow is determined by the balance of hydrostatic and protein osmotic pressures as modified by membrane fluid conductance (permeability). The Starling equation is commonly written as follows: Qf K [(Pc Ppc) ( c pc)] where Qf represents the net flow of a liquid across the membrane in question, K is a hydraulic conductance term describing the permeability and surface area of the barrier, Pc is the capillary pressure, Ppc is the pericapillary or interstitial pressure, is the reflection coefficient describing the protein permeability of the barrier, and c and pc are the capillary and pericapillary protein osmotic pressure, respectively. varies in value from 0 to 1, depending on the restriction of plasma protein by the endothelium. Cardiogenic pulmonary edema arises when Pc increases secondary to left atrial hypertension, causing transudation of fluid across the interstitium into alveoli. Noncardiogenic edema most commonly arises when the reflection coefficient ( ) is decreased due to endothelial injury. This injury allows the passage of normally restricted plasma proteins from the vascular space into the interstitium and alveoli, creating an exudative edema. In this study, the etiology of the pulmonary edema was determined by hemodynamic data and by analysis of the edema fluid/plasma protein ratio. In addition to diagnostic value, the edema fluid/plasma value has been shown to have prognostic significance as well. 5 The most common precipitating factors for noncardiogenic pulmonary edema are sepsis, pneumonia, gastric aspiration, and multiple transfusions. 8 All patients were carefully screened prior to transplantation to rule out active infection. In addition, aspiration of gastric contents was not reported to have occurred in these patients during the induction of anesthesia. Therefore, transfusion-related acute lung injury (TRALI) is the most likely cause, since all had received blood products immediately prior to the development of the pulmonary edema (Table 1). However this diagnosis is still speculative, made on the basis of excluding the other likely causes and not confirmed by laboratory testing. CHEST / 119 / 1/ JANUARY,

4 TRALI has been reported after the administration of packed RBCs, 9,10 fresh frozen plasma, 11 and platelets. 12,13 TRALI is most frequently caused by antibodies present in the blood product that are directed against recipient white cell antigens. When specific testing for the presence of these antibodies is undertaken, they most commonly occur in multiparous donors who have been immunized by exposure to paternal foreign antigens during pregnancy. 14 In most cases of TRALI, the episode of pulmonary edema is short lived, lasting 2 to 6 h, and this was the pattern observed in these patients developing pulmonary edema during liver transplantation. The one patient in our series who died intraoperatively had the most fulminant presentation of pulmonary edema and, based on postmortem studies, pulmonary fat embolization was the cause. Treatment instituted in this series of patients was primarily supportive in nature. Oxygenation was maintained by suctioning as much edema fluid as possible, by increasing the fraction of inspired oxygen, by applying positive end-expiratory pressure, and in some cases by administering a diuretic to lower pulmonary capillary pressure as much as possible. In all cases but one the one where TRALI was most likely did not occur the edema resolved within a few hours. The transient lung injury resulted in prolonging to a small extent the duration of postoperative intubation and ICU stay. Because the incidence of acute pulmonary edema in these patients (0.73%) was higher than that reported for TRALI in other large series of blood transfusion (0.075 to 0.12%), 14 there may be other factors that contribute to the development of acute pulmonary edema during liver transplantation. A two-event model has been proposed for the development of TRALI: first, a priming event caused by an underlying clinical condition such as surgical stress or active infection that attracts neutrophils to the pulmonary circulation; second, neutrophil activation by transfusion of the specific blood component containing inciting antibodies or possibly by active lipid compounds in stored blood. 15 In all but one case reported here, the pulmonary edema occurred after of the newly grafted liver. Thus may represent a priming mechanism for this model. The syndrome is a poorly understood phenomenon that occurs immediately following the establishment of portal blood flow through the graft. It is characterized by hypotension, bradycardia, vasodilation, pulmonary hypertension, hyperkalemia, and cardiac arrest in some but not all patients, and is attributed to mediators from the gut or liver that reach the systemic circulation. 16 A generalized endothelial injury, with a high incidence of pulmonary edema, occurs frequently in patients with fulminant hepatic failure. 17 Other factors, including occult sepsis or gastric aspiration, may also be present. However, the time course of resolution of the pulmonary edema in this study is consistent with a transient injury as occurs most frequently with TRALI. In summary, we have described the occurrence of acute pulmonary edema in patients undergoing liver transplantation. This group of patients had noncardiogenic, increased permeability pulmonary edema, as determined by hemodynamic measurements and an elevated edema fluid/plasma protein concentration ratio. The most likely reason for the acute lung injury is transfusion-related. The prognosis for recovery from acute pulmonary edema in this setting is good. These cases illustrate the acute increase in pulmonary vascular permeability that occurs with TRALI. Efforts should be made to identify the factors that lead to a higher incidence of TRALI in patients undergoing orthotopic liver transplantation. References 1 Gropper MA, Wiener-Kronish JP, Hashimoto S. Acute cardiogenic pulmonary edema. Clin Chest Med 1994; 15: Jensen WA, Rose RM, Hammer SM, et al. Pulmonary complications of orthotopic liver transplantation. Transplantation 1986; 42: O Brien JD, Ettinger NA. Pulmonary complications of liver transplantation. Clin Chest Med 1996; 17: Matthay MA, Eschenbacher WL, Goetzl EJ. Elevated concentrations of leukotriene D4 in pulmonary edema fluid of patients with the adult respiratory distress syndrome. J Clin Immunol 1984; 4: Matthay MA, Wiener-Kronish JP. Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. 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Br Med J 1997; 314: Ramanathan RK, Triulzi DJ, Logan TF. Transfusion-related 222 Clinical Investigations in Critical Care

5 acute lung injury following random donor platelet transfusion: a report of two cases. Vox Sang 1997; 73: Kopko PM, Holland PV. Transfusion-related acute lung injury. Br J Hematol 1999; 105: Silliman CC, Voelkel NF, Allard JD, et al. Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model. J Clin Invest 1998; 101: Matuschak GM, Shaw BW, Jr. Adult respiratory distress syndrome associated with acute liver allograft rejection: resolution following hepatic retransplantation. Crit Care Med 1987; 15: Trewby PN, Warren R, Contini S, et al. Incidence and pathophysiology of pulmonary edema in fulminant hepatic failure. Gastroenterology 1978; 74: CHEST / 119 / 1/ JANUARY,