J Artif Organs (2003) 6:282–285 DOI 10.1007/s10047-003-0233-9
© The Japanese Society for Artificial Organs 2003
CASE REPORT Cataldo Doria, MD · Lucio Mandalà, MD Victor L. Scott, MD · Ignazio R. Marino, MD Salvatore Gruttadauria, MD · Roberto Miraglia, MD Claudio H. Vitale, MS · Jan Smith, MD
Noncardiogenic pulmonary edema induced by a molecular adsorbent recirculating system: case report
Abstract Noncardiogenic pulmonary edema is a wellrecognized manifestation of acute lung injury which has been related, among others, to blood or blood-product transfusion, intravenous contrast injection, air embolism, and drug ingestion. We describe two cases of noncardiogenic pulmonary edema after use of a molecular adsorbent recirculating system, a cell-free dialysis technique. Patients in this series presented at our institution to be evaluated for liver transplantation. Subsequently, they developed an indication for the molecular adsorbent recirculating system. Two patients of 30 (6.6%) treated with the molecular adsorbent recirculating system for acute-on-chronic liver failure and intractable pruritus had normal chest X-rays before treatment and developed severe pulmonary edema, in the absence of cardiogenic causes, following use of the molecular adsorbent recirculating system. For each patient we reviewed the history of blood or blood-product transfusion, echocardiograms if available, daily chest X-rays, and when available pre- and postmolecular adsorbent recirculating systemic blood pressure, central venous pressure, pulmonary arterial pressures, cardiac output, cardiac index, systemic vascular resistance index, and arterial blood gas. Our
Received: April 14, 2003 / Accepted: July 28, 2003 C. Doria (*) · I.R. Marino Liver Transplantation and Liver Surgery, Transplantation Division, Department of Surgery, Thomas Jefferson University, 1025 Walnut Street, Suite 605 College Building, Philadelphia, PA 19107, USA Tel. ⫹1-215-955-8708; Fax ⫹1-215-923-1420 e-mail:
[email protected] L. Mandalà · S. Gruttadauria · R. Miraglia · C.H. Vitale Department of Surgery, Mediterranean Institute for Transplantation and Advanced Specialized Therapies IsMeTT – UPMC Italy, Palermo, Italy V.L. Scott Department of Anesthesiology, Allegheny General Hospital, Pittsburgh, USA J. Smith Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, USA
data suggest that the molecular adsorbent recirculating system may cause noncardiogenic pulmonary edema, possibly by an immune-mediated mechanism. Key words Albumin · Dialysis · Artificial liver · Cytokine · Lung edema · Hepatitis
Introduction The molecular adsorbent recirculating system (MARS) (Teraklin, Aktiengesellschaft, Rostok, Germany) is an artificial liver support system first introduced into clinical practice in 1993.1 MARS aims only at clearing the blood of metabolic waste products normally metabolized by the liver. It is, essentially, a modified dialysis system, employing an albumin-containing dialysate that is recirculated and perfused in-line through charcoal and anion exchanger columns. This effects the removal of albumin-bound toxins together with free solutes that are removed by standard dialysis.2 Noncardiogenic pulmonary edema is a well-known immunologically mediated complication of blood or blood-component transfusion.3,4 Noncardiogenic pulmonary edema has also been reported as a consequence of intravenous administration of contrast media, drug ingestion, recurrent venous air embolism, and postextubation.5–8 Many extracorporeal blood circulation devices have also been reported to be able to activate an immune-mediated reaction, secondary to the contact of the patient’s blood with filters, membranes, and/or charcoal, which can cause activation of the complement cascade with cytokine release, subsequent increase in the pulmonary capillary permeability, and development of pulmonary edema.9,10 Our protocol includes 7 MARS sessions, on consecutive days, for each treatment. A single MARS session is 6 h in duration. A second MARS treatment is started in cases of partial response to the first treatment. MARS treatment was performed through a hemodialysis double-lumen catheter. A flush of the extracorporeal circuit
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with 1 l of heparinized saline solution (1000 U heparin sulphate/l) was carried out before commencement of MARS treatment. Therefore, no systemic heparinization was obtained and heparin allergy could not be advocated as a reason for the development of pulmonary edema. The extracorporeal blood circuit was driven by a standard dialysis machine (D-85716, Baxter, Unterschleibheim, Germany) at a flow rate of 100 ml/min initially, increasing to 200 ml/min if the patient remained hemodynamically stable.
Case 1 A 49-year-old white male affected by HBV/HDV-related cirrhosis presented at The Mediterranean Institute for Transplantation and Advanced Specialized Therapies to be evaluated as a potential candidate for liver transplantation (LTx). After completing the pretransplant work-up the patient was excluded from the LTx waiting list because he was found to have portal vein thrombosis. His course was complicated by recurrent upper gastrointestinal bleeding secondary to rupture of esophageal varices resistant to numerous sessions of banding ligation. In the process, he required multiple hospital admissions during which 2–3 units of packed red blood cells were transfused every week. Following an episode of uncontrollable upper gastrointestinal bleeding, after obtaining informed consent, the patient underwent a successful mesocaval shunt. Three months following surgery he developed acute-on-chronic hepatic failure, presenting with rapid development of worsening encephalopathy, rising bilirubin, and worsening coagulopathy despite intensive medical management. After obtaining informed consent, the patient was treated with MARS. Throughout MARS treatment the patient had negative blood cultures with no sign of infection or sepsis (i.e., fever, hypothermia, increase white blood cell count, and positive culture); was hemodynamically stable (no vasopressor requirement, mean arterial pressure ⱖ60 mmHg); and a normal chest X-ray (Fig. 1a). A pre-MARS echocardiogram showed an ejection fraction of 55%. His Child and MELD scores were C11 and 13, respectively. Blood analysis results
a
were: total bilirubin 10.66 mg/dl, aspartate aminotransferase (AST) 86 IU/l, alanine aminotransferase (ALT) 33 IU/l, gamma-glutamyl transpeptidase (γGT) 13 IU/l, prothrombin time (PT) 21.5 s, ammonia 103 mg/dl, creatinine 0.7 mg/ dl, creatinine clearance 140.5 ml/min, urine output 1.5 ml/kg/ h, and central venous pressure (CVP) 14 mmHg. Because of a partial response following the first full MARS treatment, a second course was started. During the 4th session of the second treatment course, the patient developed pulmonary edema (Fig. 1b) requiring orotracheal intubation. An even fluid balance was maintained throughout the entire MARS treatment. No blood/blood products were transfused in the 48 h prior to the development of severe pulmonary edema, nor could we identify other known causes of noncardiogenic pulmonary edema.5–8 MARS treatment was stopped and aggressive medical management of the pulmonary edema was initiated. The pulmonary edema was believed to be of noncardiogenic origin. Table 1 shows stable hemodynamic and arterial blood gas values before and after the development of pulmonary edema. Following the discontinuation of MARS treatment and the appearance of pulmonary edema, Child and MELD scores were C11 and 18, respectively. Blood analysis results were: total bilirubin 15.48 mg/dl, AST 55 IU/l, ALT 34 IU/l, γGT 13 IU/l, PT 19 s, ammonia 61 mg/dl, creatinine 0.6 mg/ dl, creatinine clearance 176.75 ml/min, urine output 1.1 ml/ kg/h, and CVP 4 mmHg. Twenty-four hours after cessation of MARS treatment and the application of aggressive medical management, the pulmonary edema resolved. Subsequently the patient became hemodynamically unstable requiring increased dosages of vasopressors without sign of infection/sepsis. Nine days after the last MARS session, the patient died of terminal end-stage liver disease and multiple organ failure; autopsy was declined.
Case 2 A 70-year-old white male presented at the Institute to be evaluated as a potential candidate for LTx. During the pretransplant work-up, after obtaining informed consent,
b
Fig. 1a,b. Patient 1 chest X-rays. a Before treatment with the molecular adsorbent recirculating system (MARS), b post-MARS
284 Table 1. Hemodynamic and arterial blood gas analyses pre- and post-MARS Variables studied
SBP (mmHg) DBP (mmHg) MAP (mmHg) CVP (mmHg) SPAP (mmHg) DPAP (mmHg) MPAP (mmHg) PAW (mmHg) CO (l/min) CI (l/min/m2) SVRI (dynes s/cm5) SO2 (%) pH PCO2 (torr) PO2 (torr) BE (mol/l) HCO3 (mmol/l) FiO2 (%)
Patient 1
Patient 2
Pre-MARS
Post-MARS
Pre-MARS
Post-MARS
113 47 69 14 n/a n/a n/a n/a n/a n/a n/a 96 7.47 37 84 4.1 27.1 40
96 42 60 4 n/a n/a n/a n/a n/a n/a n/a 99 7.43 46.8 148 7.5 32 n/a
176 68 104 9 30 18 22 17 9.1 4.9 1557 100 7.45 24.7 91 ⫺4.7 17.5 21
145 78 99 4 43 22 30 9 11 4.9 1145 100 7.47 31.7 94.5 1.1 23.7 30
MARS, molecular adsorbent recirculating system; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; CVP, central venous pressure; SPAP, systolic pulmonary arterial pressure; DPAP, diastolic pulmonary arterial pressure; MPAP, mean pulmonary arterial pressure; PAW, pulmonary arterial wedge pressure; CO, cardiac output; CI, cardiac index; SVRI, systemic vascular resistance index; SO2, oxygen saturation; PCO2, carbon dioxide tension; PO2, oxygen tension; BE, base excess; HCO3, bicarbonate; FiO2, fraction of inspired oxygen; n/a, not available
a
b
Fig. 2a,b. Patient 2 chest X-rays. a Pre-MARS, b post-MARS
the patient was treated with MARS for HCV-related cirrhosis complicated by intractable pruritus, encephalopathy, and worsening renal function. At the time MARS treatment commenced and throughout the treatment, the patient had negative blood cultures with no sign of infection or sepsis (i.e., fever, hypothermia, increased white blood cell count, positive culture); was hemodynamically stable (no vasopressor requirement, mean arterial pressure ⱖ60 mmHg), and had a normal chest X-ray (Fig. 2a). A pre-MARS echocardiogram showed an ejection fraction of 60%. Before MARS, the Child and MELD scores were C10 and 14, respectively. Blood analysis results were: total bilirubin 3.21 mg/dl, AST 79 IU/l, ALT 57 IU/l, γGT 81 IU/l, PT 18 s, ammonia 94 mg/dl, creatinine 2.4 mg/dl, creatinine clear-
ance 29.6 ml/min, urine output 0.5 ml/kg/h, CVP 9 mmHg, and pulmonary arterial wedge pressure (PAW) 17 mmHg. He underwent 7 MARS sessions before developing pulmonary edema (Fig. 2b). An even fluid balance was maintained throughout the entire MARS treatment. No blood or blood products were transfused within 48 h prior to the development of severe pulmonary edema, nor could we identify other known causes of noncardiogenic pulmonary edema.5–8 MARS treatment was stopped and aggressive medical management of the pulmonary edema was initiated. The pulmonary edema was considered to be of noncardiogenic origin. Table 1 shows stable hemodynamic and arterial blood gas values before and after the development of pulmonary edema. Following the discontinuation
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of MARS and the appearance of pulmonary edema, the Child and MELD scores were C10 and 32, respectively. Blood analysis results were: total bilirubin 3.43 mg/dl, AST 29 IU/l, ALT 16 IU/l, γGT 23 IU/l, PT 28.5 s, ammonia 146 mg/dl, creatinine 2.3 mg/dl, creatinine clearance 30.9 ml/ min, urine output 1.5 ml/kg/h, CVP 7 mmHg, and PAW 9 mmHg. Twenty-four hours after cessation of MARS and the initiation of aggressive medical management, the pulmonary edema resolved. After completing the pretransplant work-up the patient was excluded from the LTx waiting list because he had been treated for urinary bladder cancer 2 years previously. Six months after completion of MARS treatment for intractable pruritus, the patient developed renal insufficiency requiring hemodyalisis. During the third hemodyalisis treatment he died of cardiac arrest, 201 days after the last MARS session. MARS has shown specific efficacy in the treatment of acute-on-chronic hepatic failure, improving cerebral blood flow, hemodynamic status, liver and renal function, coagulation, and survival.2 Because none of the known causes of noncardiogenic pulmonary edema could be identified, we postulate that MARS could have been the cause of noncardiogenic pulmonary edema in our two patients. MARS may have activated an immune-mediated mechanism similar to that described with other blood circulation systems using dialysis membranes,11 filters, and charcoal, items that are reported to activate the complement system and promote cytokine release from peripheral blood mononuclear cells.9,10 These cytokines may be responsible for the increased permeability of the pulmonary vessels promoting pulmonary edema. This theory is supported by previous reports indicating that cytokines have been implicated in various type of lung injury leading to various degrees of pulmonary edema.12,13 Ideally, any liver-assist device should decrease the level of circulating cytokines,14 but these may, in fact, increase during MARS.9 As a result of the cytokine release like tumor necrosis factor-alpha and interleukin-6,9,10, 12,13 permeability of the pulmonary vessels may be increased, which, along with vasodilatation, may trigger the development of pulmonary edema. In our two patients, noncardiogenic pulmonary edema appeared toward the end of the planned treatment course, supporting the suggestion that multiple immunological triggers are needed to increase the level of circulating cytokines above the threshold for inducing pulmonary edema. This complication was successfully treated within a 24-h period with cessation of MARS treatment and the initiation of aggressive medical management; we postulate that a significant decrease in the level of circulating cytokines, along with medical treatment, were sufficient to resolve the pulmonary edema. The observed peritreatment death (case 1) is probably unrelated to the development of pulmonary edema. It is more likely a result of the development of irreversible endstage liver disease presenting with worsening total bilirubin
unresponsive to MARS treatment. The patient in case 2 presented with a normal chest X-ray (Fig. 2a) and hepatorenal syndrome before MARS commencement. His creatinine levels remained high after completion of treatment. No apparent relationship could thus be identified between the development of non-cardiogenic pulmonary edema and the increased creatinine level. Therefore, noncardiogenic pulmonary edema, a potential and reversible complication of MARS, should not contraindicate MARS when its usage is clinically indicated.
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