Unexplained and prolonged perioperative hypotension after orthotopic liver transplantation: Undiagnosed systemic mastocytosis

Abstract

Arterial vasodilation is common in end-stage liver disease, and systemic hypotension often may develop, despite an increase in cardiac output. During the preparation for and the performance of orthotopic liver transplantation, expected and transient hypotension may be caused by induction agents, anesthetic agents, liver mobilization, or venous clamping. A mild decrease of the already low systemic vascular resistance is often observed, and intermittent use of short-acting agents for vasopressor support is not uncommon. In this report, we describe a patient with unexpected and prolonged hypotension due to vasodilation during and after orthotopic liver transplantation. The preoperative end-stage liver disease evaluation, intraoperative events, and intensive care unit course were reviewed, and no cause for the vasodilation and prolonged hypotension was evident. The explant pathology report was later available and showed systemic mastocytosis. We hypothesize that the unexpected hypotension and vasodilation were caused by mast cell degranulation and its systemic effects on arterial tone. Liver Transpl 15:701–708, 2009. © 2009 AASLD.

A 74-year-old white man presented for evaluation and consideration for orthotopic liver transplantation after receiving the diagnosis of cryptogenic cirrhosis and a referral from another transplant institution. His medical history was remarkable for obesity (body mass index, 36 kg/m²), weight loss of approximately 100 pounds during the past 3 years (attributed to exercise, diet, malaise, fatigue, ascites burden, anorexia, and other reasons), intermittent diarrhea-constipation cycles, and a 14-year history of partial complex seizures that were controlled with medication. Thrombocytopenia was identified during routine laboratory evaluation of an exercise-related injury. Further evaluation included a liver biopsy, which showed fibrosis (stages 3 and 4) and chronic biliary injury. Gastric and colon polyp biopsies performed before liver transplantation did not show any mast cell infiltration. A transjugular intrahepatic portosystemic shunt was placed to manage refractory ascites.

Physical examination showed a tall, severely muscle-wasted man with moderate ascites and palpable splenomegaly. The patient was not febrile, flushed, or diaphoretic. Blood pressure variation was not extreme. He had no skin lesions, dermatographia, or lymphadenopathy. Results of preoperative laboratory tests at our institution are shown in Table 1. The patient had leukopenia, thrombocytopenia, and microcytic, normochromic anemia. A computed tomography scan of the abdomen showed splenomegaly, a large amount of ascites, gallbladder and bowel wall thickening, a liver with cirrhotic morphology, and 3 small cysts in the posterior right hepatic lobe. An ultrasonogram of the abdomen showed a patent transjugular intrahepatic portosystemic shunt and no intrahepatic biliary abnormalities. An echocardiogram had unremarkable findings, and a dobutamine stress test showed no inducible ischemia. He had a Model for End-Stage Liver Disease score of 17.

Table 1. Preoperative Laboratory Findings

Test	Value	Reference
Hemoglobin, g/dL	11.0	13.5–17.5
Hematocrit, %	32.8	38.8–50.0
White blood cell count, ×10^9/L	3.1	3.5–10.5
Platelet count, ×10^9/L	77	150–450
International normalized ratio	1.9	—
Total bilirubin, mg/dL	1.7	0.1–1.1
Direct bilirubin, mg/dL	0.4	0.0–0.3
Alkaline phosphatase, U/L	154	45–115
Alanine aminotransferase, U/L	23	7–55
Aspartate aminotransferase, U/L	19	8–48
Iron, μg/dL	85	50–150
Total iron binding capacity, μg/dL	213	250–400
Iron percent saturation, %	40	14–50
Ferritin, μg/L	181	24–336
Transferrin, mg/dL	172	170–340
Creatinine, mg/dL	1.1	0.8–1.3
Sodium, mEq/L	134	135–145
Vitamin B12, ng/L	932	200–650
Folate, μg/L	7.8	≥3.5
25-Hydroxyvitamin D, ng/mL	20	25–80
Total testosterone, ng/dL	105	240–950
Free testosterone, ng/dL	1.8	9–30
Immunoglobulin A, mg/dL	439	60–400
Immunoglobulin G, mg/dL	1860	600–1500
Immunoglobulin M, mg/dL	26	60–300
α1-Antitrypsin, mg/dL	268	100–190

Upon arrival in the operating room, intravenous access was established with an 8.5F antecubital catheter and a 9.0F internal jugular high-volume introducer (Advanced Vascular Access, Edwards Life Sciences, LLC, Irvine, CA), through which a flow-directed continuous cardiac output and venous saturation pulmonary artery catheter was placed. Arterial pressure was monitored by 2 arterial cannulae. Anesthesia was induced with a rapid-sequence technique with propofol, succinylcholine, and fentanyl. We used a balanced technique with isoflurane and fentanyl guided by the bispectral index.

The donor liver was a standard-criteria organ from a brain-dead donor with a cold ischemia time of 10 hours. Orthotopic liver transplantation was performed with a cava-sparing technique (piggyback), and all anastomoses were anatomic.

After induction of anesthesia, the hemodynamic profile indicated arterial vasodilation and elevated cardiac output (Fig. 1 and Table 2). Hypotension developed during the hepatectomy and persisted after the patient was anhepatic (stages 1 and 2). The intravascular volume was maintained by an infusion of colloids, crystalloids, and a transfusion of red blood cells and clotting factors, as guided by filling pressures, cardiac output, hematocrit values, and thromboelastograph data. Intermittent arterial vasodilation, which resulted in increasingly severe hypotension, was managed with boluses of phenylephrine to maintain adequate perfusion pressure. After reperfusion (stage 3), arterial vasodilation, shown by the low calculated systemic vascular resistance, was more profound and persistent. We maintained intravascular volume as noted previously and managed hypotension with continuous infusions of phenylephrine and vasopressin, which were supplemented with boluses of neosynephrine and epinephrine.

Figure 1. (A) Changes in MABP and SV over time. (B) Changes in CO and SVR over time. For both parts, x axes are not drawn to scale. Stage 1 is induction and recipient hepatectomy. Stage 2 is the anhepatic stage. Stage 3 is the neohepatic stage (after reperfusion of the grafted liver). Some measurements were obtained 5 minutes before stages 2 and 3 began. Abbreviations: CO, cardiac output; MABP, mean arterial blood pressure; SV, stroke volume; SVR, systemic vascular resistance.

Table 2. Hemodynamic Changes and Use of Pressors During Liver Transplantation

Variable	Stage 1*	Stage 2†		Stage 3‡
		−5 Minutes§	−5 Minutes§	+10 Minutes	+10 Minutes	+70 Minutes
* Stage 1: Induction and recipient hepatectomy (baseline values, obtained after induction and line placement, are shown). † Stage 2: Anhepatic stage. ‡ Stage 3: Neohepatic stage (after reperfusion of the grafted liver). § These measurements were obtained 5 minutes before the stage began. ∥ Estimated as mean pulmonary arterial pressure/cardiac output. ¶ The patient received dopamine (2 μg/kg/minute) throughout stages 2 and 3 of surgery.
Heart rate, beats/minute	82	105	108	114	110	110
Blood pressure, mm Hg	100/65	110/66	110/69	110/70	97/60	106/67
Mean arterial blood pressure, mm Hg	77	81	83	83	72	80
Pulmonary arterial pressure, mm Hg	39/23	34/23	38/23	46/26	57/35	54/30
Mean pulmonary arterial pressure, mm Hg	28.3	26.6	28	32.6	42.3	38
Pulmonary vascular resistance, dyn s cm^−5∥	165	146	170	170	195	171
Central venous pressure, mm Hg	16	12	13	16	23	18
Cardiac output, L/minute	13.7	14.6	13.2	14	17.4	17.8
Systemic vascular resistance, dyn s cm^−5	356	377	412	382	225	278
Stroke volume, mL/beat	167	139	122.2	122.8	158	161.8
Pressors¶	Phenylephrine bolus, 300 μg	Phenylephrine bolus, 500 μg		Epinephrine bolus, 100 μg (total dosage)	Epinephrine bolus, 30 μg (total dosage); phenylephrine bolus, 1200 μg (total dosage); vasopressin bolus, 2 U (3 times); vasopressin, 0.02 U/minute (infusion); norepinephrine, 17 μg/minute (infusion)	Epinephrine bolus, 60 μg (total dosage); phenylephrine bolus, 200 μg (total dosage); vasopressin, 0.04 U/minute (infusion); norepinephrine, 42.5 μg/minute (infusion)

The abrupt increase in pulmonary arterial pressures after reperfusion raised concern about reperfusion syndrome, but cardiac output and stroke volume were elevated. The more likely explanation was that increased pulmonary arterial and central venous pressures resulted from volume overload. Unfortunately, a measurement of the pulmonary arterial occlusion pressure was not obtained to confirm left atrial hypertension.

Euthermia was maintained throughout the procedure, and hypothermia (a precipitant for mast cell degranulation) did not develop during reperfusion. The total surgical time was 260 minutes. Blood loss was replaced with a total transfusion of 6 units of packed red blood cells. After surgery, the patient was transferred to the intensive care unit (ICU). Immediate postoperative liver function tests (Table 3) showed mild preservation injury. Blood count, electrolytes, and acid-base status confirmed the adequacy of intraoperative resuscitation.

Table 3. Immediate Postoperative Laboratory Findings

Test	Value	Reference
Hemoglobin, g/dL	10.4	13.5–17.5
Hematocrit, %	30.7	38.8–50.0
White blood cell count, ×10^9/L	18.8	3.5–10.5
Platelet count, ×10^9/L	153	150–450
International normalized ratio	1.8	—
Total bilirubin, mg/dL	2.5	0.1–1.1
Direct bilirubin, mg/dL	1.2	0.0–0.3
Alkaline phosphatase, U/L	175	45–115
Alanine aminotransferase, U/L	350	7–55
Aspartate aminotransferase, U/L	590	8–48
Creatinine, mg/dL	1.2	0.8–1.3
Sodium, mEq/L	134	135–145
pH	7.235	7.320–7.420
Anion gap, mmol/L	15	9–15

During his ICU stay, the patient had an episode of hemodynamically significant atrial fibrillation with rapid ventricular response. Chemical cardioversion treatments included β-blockade, calcium channel blockade, and amiodarone, but direct-current cardioversion was required to reestablish normal sinus rhythm. Hemodynamic changes and pressor requirements during his ICU stay are shown in Table 4. Vasopressor dosages were tapered by the 22nd postoperative hour. Donor cultures and perioperative cultures were negative. The patient was successfully extubated approximately 48 hours after arrival in the ICU and was transferred to the ward a day later.

Table 4. Hemodynamic Changes and Pressor Requirements During the Intensive Care Unit Stay

	0 Minutes*	15 Minutes	30 Minutes	45 Minutes†	1 Hour‡	2 Hours	11 hours	13 Hours	14 Hours	16 Hours	18 Hours	21 Hours
Abbreviations: Epi, epinephrine; NE, norepinephrine; VP, vasopressin. * Arrival at the intensive care unit. † Atrial fibrillation occurred. ‡ Direct-current cardioversion was performed.
Heart rate, beats/minute	110	120	140	167	120	118	92	87	100	92	91	85
Blood pressure, mm Hg	95/58	101/62	82/67	74/59	66/44	86/41	114/61	122/64	115/62	121/62	114/63	139/72
Mean arterial pressure, mm Hg	75	79	63	65	57	67	79	83	83	81	81	100
Central venous pressure, mm Hg	11	—	—	—	—	—	20	18	17	19	—	10
Pulmonary arterial pressure, mm Hg	41/21	44/29	50/30	39/24	38/21	39/22	44/28	41/25	38/24	39/25	38/24	37/16
Mean pulmonary arterial pressure, mm Hg	27.6	34	36.7	29	26.6	27.6	33.3	30.3	28.6	29.6	28.7	23
Cardiac output, L/minute	8.9	18.2	—	14.8	—	—	10.3	10.7	10.7	10.3	—	11.4
Systemic vascular resistance, dyn s cm−5	508	—	—	—	—	—	467	485	492	481	—	631
Pressor	NE, 4 μg/minute; VP, 0.04 U/minute	NE, 5 μg/minute; VP, 0.04 U/minute	NE, 5 μg/minute; VP, 0.04 U/minute	NE, 9 μg/minute; Epi bolus, 10 μg; VP, 0.04 U/minute	NE, 9 μg/minute; VP, 0.04 U/minute; esmolol, 40 mg (3 times); amiodarone, 150 mg (1 time); diltiazem, 5 mg/hour (infusion)	NE, 9 μg/minute; VP, 0.04 U/minute	NE, 15 μg/minute; VP, 0.04 U/minute	NE, 10 μg/minute; VP, 0.04 U/minute	NE, 5 μg/minute; VP, 0.04 U/minute	NE, 2.4 μg/minute; VP, 0.04 U/minute	VP, 0.04 U/minute	VP, 0.02 U/minute

Pathological evaluation of the explant tissue showed a diffuse infiltrate of mast cells in the liver and gallbladder, suggesting systemic mastocytosis (SM). In the liver, the infiltrate was associated with periportal and septal fibrosis (Fig. 2A,B). The diagnosis of mastocytosis was confirmed by positive staining for tryptase and CD25 (Fig. 2C,D). Periportal and pericholedochal lymph nodes and a postoperative bone marrow biopsy specimen also showed mast cell infiltrates consistent with SM (Fig. 3). The tryptase level from a preoperatively obtained serum sample was 394 ng/mL. The postoperative (day 6) value had decreased to 84.9 ng/mL but still was nearly 6 times the upper limit of normal (reference range, 0-15 ng/mL). A postoperative analysis of serum samples (collected on the day of transplantation) showed an electrophoretic pattern suggestive of monoclonal gammopathy of unknown significance. A postoperative (day 7) liver biopsy specimen showed diffuse mast cell infiltration.

Figure 2. (A) The liver explant shows septal fibrosis and mast cell infiltrates (hematoxylin and eosin; original magnification, ×100). (B) The portal tract area of the liver explant shows a dense infiltrate of mast cells admixed with eosinophils (hematoxylin and eosin; original magnification, ×400). (C) Tryptase immunostaining of the liver explant shows mast cells (original magnification, ×400). (D) CD25 immunostaining of the liver explant shows mast cells (original magnification, ×100).

Figure 3. (A) Resected lymph node showing diffuse infiltration by mast cells (hematoxylin and eosin; original magnification, ×40). (B) Mast cells in the lymph node (hematoxylin and eosin; original magnification, ×400).

The postoperative course included recurrent ascites, recurrent diarrhea, asthenia, corticosteroid-induced hyperglycemia, and deconditioning. The patient was dismissed from the hospital but required readmission for diarrhea, dehydration, renal insufficiency and failure, hyperkalemia, and recurrent large-volume paracenteses. Symptomatic treatment consisted of blockade of the type 1 and type 2 histamine receptors (fexofenadine and ranitidine). The patient was instructed to carry an epinephrine autoinjector for severe reactions. He subsequently was treated with imatinib mesylate but was intolerant. Eight months after the liver transplant, the patient required a transjugular intrahepatic portosystemic shunt for refractory ascites. The patient remained symptomatic, with chronic diarrhea and persistent ascites 29 months after surgery.

DISCUSSION

Mastocytosis is a rare hematopoietic neoplastic disorder that originates in the bone marrow and is characterized by abnormal growth or accumulation of mast cells in 1 or more organs.1 Eighty percent of patients with mastocytosis present with disease that is limited to the skin (cutaneous mastocytosis). Spontaneous regression has been reported in children. SM involves 1 extracutaneous organ, with or without cutaneous manifestations.1

Patients are typically older than 30 years. Women are affected 3 times more frequently than men. The organs usually involved are the spleen, lymph nodes, liver, and gastrointestinal tract. Physical examination may show splenomegaly, lymphadenopathy, and hepatomegaly. Infiltration of the liver with mast cells results in fibrosis for 20% of patients and causes portal hypertension, noncirrhotic liver disease, and refractory ascites.2–4 SM symptoms reflect mast cell degranulation and include fever, weight loss, fatigue, sweats, pruritus, urticaria, dermatographism, abdominal pain, flushing, headache, tachycardia, hypotension, hypertension, syncope, arthralgia, fractures, and other symptoms.5

Abnormal laboratory test results in mastocytosis are often nonspecific and include anemia, leukocytosis, leukopenia, thrombocytosis, and thrombocytopenia. Eosinophilia has been reported. However, the relationship between SM and hypereosinophilic syndrome is controversial.6–12 The diagnosis of SM is supported by a total tryptase level greater than 20 ng/mL (reference range, 0-15 ng/mL).5 World Health Organization criteria for the classification and diagnosis of mastocytosis have been described previously.1, 5, 13–15 SM is characterized by a somatic mutation of c-KIT, a proto-oncogene that encodes a transmembrane tyrosine kinase receptor.16 Mast cells can be identified with tryptase, Giemsa, or toluidine blue stains. Affected tissues have positive immunohistochemical staining for KIT (CD 117).17

SM is incurable. Treatment with histamine receptor (H1 and H2) blockade may provide symptomatic improvement. More aggressive and invasive disease has been treated with interferon α-2b,18 with or without corticosteroids,19 2-chlorodeoxyadenosine, imatinib mesylate,20 or midostaurin,1, 21 and response rates have varied.

This patient's intraoperative and postoperative hemodynamic values were consistent with systemic effects of mast cell degranulation. Mast cell degranulation may have been precipitated by the stress of surgery or by anesthetic induction medications such as succinylcholine.5 Organ manipulation also may have contributed to degranulation and histamine release. Other known causes of degranulation are shown in Table 5. The preoperative administration of high-dose corticosteroids may have delayed the systemic fracture of mast cells until stage 2 or 3 of transplant surgery.

Table 5. Possible Causes of Mast Cell Degranulation

NOTE: Adapted from Escribano et al.5 with permission.

Physical stimuli

Heat

Cold

Friction of skin lesions

Pressure

Excessive sunlight

Exercise

Emotional factors

Stress

Anxiety

Medications

Aspirin and other nonsteroidal anti-inflammatory drugs

Alcohol

Morphine and derivatives

Polymyxin B

Amphotericin B

Quinine

Anesthetics [inductors and muscle relaxants (eg, succinylcholine, d-tubocurarine, gallamine, and decamethonium)]

Radiographic dyes

Dextromethorphan

β-Blockers

α-Adrenergic and cholinergic receptor antagonists

Venoms

Snake

Insect

Polymers

Dextran

Gelatin

Biological response modifiers

—Interferon-α

SM is a malignancy that is an absolute contraindication for liver transplantation. Unfortunately, this diagnosis was not considered for our patient until after his hemodynamic instability during surgery was managed and histopathologic findings were available. Postoperative analysis of serum obtained immediately before surgery showed a monoclonal gammopathy of unknown significance. Further investigation might have included bone marrow biopsy, which would have established the diagnosis of SM. Indeed, our subsequent review of a preoperative liver biopsy specimen obtained at the referring facility showed mast cell infiltrates.

For patients with liver disease, arterial vasodilation and hypotension are commonly encountered before, during, and after liver transplantation. Vasodilation and hypotension typically are attributable to liver failure, inhaled anesthetic agents, allograft dysfunction, or infection. Undiagnosed SM may present with similar hemodynamic derangement. Patient management included diagnostic evaluation (to exclude more common causes of hypotension) and vasopressor support. Histamine receptor blockade was added to the treatment regimen after the diagnosis of SM was established. Perioperative management with both H1 and H2 antagonists, strict temperature control, and simultaneous hepatic artery and portal venous reperfusion may help reduce the chance of mast cell degranulation and histamine release.

CO, cardiac output; Epi, epinephrine; ICU, intensive care unit; MABP, mean arterial blood pressure; NE, norepinephrine; SM, systemic mastocytosis; SV, stroke volume; SVR, systemic vascular resistance; VP, vasopressin.