Sustained Low-Efficiency Daily Diafiltration with Hemoperfusion as a Therapy for Severe Star Fruit Intoxication: A Report of Two Cases

Abstract

Over the past decade, star fruit (Averrhoa carambola) intoxication decreased in the Taiwanese society due to improved public education on chronic kidney disease (CKD). Various complications including hiccups, altered levels of consciousness, coma, and seizures have been reported in individuals with renal failure who ingested fresh star fruit or star fruit juice. A high mortality rate (from 33 to 80%) was observed in patients with altered levels of consciousness, despite prompt dialysis and supportive care. According to previous case reports, the proposed treatment of choice for severe star fruit intoxication may be continuous renal replacement therapy with or without hemoperfusion. We report two cases of star fruit intoxication with stage V CKD (one case is predialysis) presenting with coma and generalized tonic-clonic seizures. The two patients were treated with sustained low-efficiency daily diafiltration (SLEDD-f) and charcoal hemoperfusion. Status epilepticus was controlled fairly quickly after treatment with SLEDD-f and hemoperfusion. However, the outcomes in this report are still poor (both remained comatose; one of two patients died). Currently, there are no data for the use of SLEDD-f with hemoperfusion for severe star fruit intoxication. SLEDD-f with charcoal hemoperfusion may play a role in managing refractory status epilepticus in patients with severe star fruit poisoning.

• star fruit intoxication
• chronic kidney disease
• status epilepticus
• sustained low-efficiency daily diafiltration
• hemoperfusion

INTRODUCTION

Averrhoa carambola (star fruit) intoxications have been reported in patients with advanced kidney dysfunction and patients receiving dialysis therapy.^1–3 Star fruit may induce a variety of neurological toxicity symptoms including hiccups, altered levels of consciousness, seizures, and coma.^1,2,4 Intoxication from star fruit can result in death despite prompt and aggressive management. The mortality was extremely high (75–80%) in patients with seizures compared with normal levels of consciousness.^2,5 Authors had suggested that in severe star fruit intoxication, continuous renal replacement therapy with hemoperfusion, in addition to early recognition, may provide improved outcomes.⁶ In many instances, sustained low-efficiency daily diafiltration (SLEDD-f) offers outcomes as effective as conventional hemodialysis or hemofiltration in the treatment of certain intoxications.^7–9 We report the use of SLEDD-f and hemoperfusion in two patients with severe star fruit intoxication who presented with intractable status epilepticus.

CASE REPORTS

Two cases are described below. The laboratory values for these patients are presented in Table 1.

Table 1. Clinical features of two patients with severe star fruit intoxication.

	Patient 1	Patient 2
Age (years)	63	75
Gender	Female	Male
CKD stage	5, ESRD	5, predialysis
Primary renal disease	Diabetic nephropathy	Hypertension
Ingested star fruit	2	1
Time between symptoms and intensive treatment (day)	4	1
Response to hemodialysis	No	Not performed
Initial manifestation
Central nervous system	Hiccups, dizziness, coma, status epilepticus	Hiccups, dizziness, agitation, confusion, coma, status epilepticus
Other organ system	Acute respiratory failure, vomiting	Acute respiratory failure, nausea, vomiting
Laboratory
White blood (cells/μL)	8500	8150
Hemoglobin (g/dL)	11.1	11.9
Platelets (10^3/μL)	220	189
Alanine aminotransferase (units/L)	16	31
Blood urea nitrogen (mg/dL)	54	64
Creatinine (mEq/L)	6.46	4.04
Sodium (mEq/L)	141	141
Potassium (mEq/L)	3.2	4.9
Calcium (mg/dL)	9.1	8.9
Phosphorus (mg/dL)	2.5	2.3
Glucose (mg/dL)	205	131
Albumin (g/dL)	3.7	3.7
Mechanical ventilation	Yes	Yes
Antiepileptic drugs^a	1, 2, 3, 5, 6	1, 2, 3, 4
Modality of intensive treatment (session)	SLEDD-f (7) + CHP (1)	SLEDD-f (3) + CHP (1)
Behavioral seizure after intensive treatment	No	No
EEG after intensive treatment	Periodic spike-wave	Alpha wave
Hospital stay (day)	73	48
Outcome	Died of VAP	Survived

Notes: Conversion factors for units: Hemoglobin and albumin in g/dL to g/L, ×10; white blood cells in ×10³/μL to ×10⁹/L, ×1; platelets in ×10³/μL to ×10⁹/L, ×1; blood urea nitrogen in mg/dL to mmol/L, ×0.357; creatinine in mg/dL to μmol/L, ×88.4; glucose in mg/dL to mmol/L, ×0.0555; sodium and potassium in mEq/L to mmol/L, ×1; calcium in mg/dL to mmol/L, ×0.25; phosphorous in mEq/L to mmol/L, ×0.323; alanine aminotransferase units/L to U/L, ×1. CHP, charcoal hemoperfusion; CKD, chronic kidney disease; EEG, electroencephalography; ESRD, end-stage renal disease; SLEDD-f, sustained low-efficiency daily diafiltration; VAP, ventilator-associated pneumonia.

^aAntiepileptic drugs: (1) propofol; (2) midazolam; (3) valproic acid; (4) diazepam; (5) lorazepam; (6) levetiracetam.

Case 1

A 63-year-old woman with hypertension and diabetic nephropathy with stage V chronic kidney disease (CKD) receiving maintenance hemodialysis was presented at our emergency department with seizures. The patient’s Glasgow Coma Scale was E1V1M1, temperature was 36.6°C, pulse was 86 beats/min, blood pressure was 168/86 mmHg, and respiratory rate was 24 breaths/min. The remainders of physical examination findings were unremarkable. Serum creatinine was 6.46 mg/dL (571 μmol/L) and ammonia was 55 μg/dL (32.3 μmol/L). Cerebrospinal fluid was normal. Electroencephalography showed spikes and theta waves. Brain computed tomography was normal. Brain magnetic resonance imaging (MRI) showed high-intensity signals over the right temporal lobe and thalamus in T2-weighted and diffusion-weighted imaging (Figure 1A and B). No concomitant medication contributed to the altered level of consciousness. Her family reported that she ate two star fruits 2 days before admission and hiccups were noticed that afternoon.

Figure 1. Brain magnetic resonance imaging (MRI) in patient 1 (A and B) and patient 2 (C). Axial view of FLAIR (A), and DWI (B) obtained during the first day of hospitalization. (A) T2-weighted images show multifocal high-intensity signals over right temporal lobe (short arrow), periventricle (arrowhead), and right thalamus (long arrow). (B) DWI shows high signals at right temporal lobe (arrowhead), right thalamus (short arrow), and right temporal horn (long arrow). (C) Axial view DWI obtained during the first day of hospitalization. DWI shows restrictive diffusion at the bilateral temporal lobes (arrows), and pulvinar regions of bilateral thalami (arrowheads). Note: FLAIR, fluid-attenuated inversion recovery; DWI, diffusion-weighted image.

Hemodialysis (240 min/session) was performed daily from the first day of hospitalization. The patient experienced persistent status epilepticus despite anti epileptic drugs (AEDs) including propofol, lorazepam, levetiracetam, and valproic acid (Table 1). Therefore, daily hemodialysis was changed to SLEDD-f with charcoal hemoperfusion from the third day of hospitalization. After SLEDD-f and hemoperfusion, the dosage of AEDs was decreased. Regular hemodialysis continued after seven sessions of SLEED-f. During the next 10 days after SLEDD-f with hemoperfusion, AEDs were administered orally. However, the patient remained unconscious despite controlled status epilepticus and died on the 73rd hospital day due to ventilator-associated pneumonia with septicemia.

Case 2

A 75-year-old man with hypertension and stage V CKD was transferred to our emergency department with generalized tonic-clonic seizures. On the previous day, the patient ingested one star fruit in the morning and had hiccups in the afternoon. He was admitted to a local hospital and agitation and confusion were noted there. Generalized tonic-clonic seizures were noted the next morning and the patient was transferred to our hospital. The patient’s Glasgow Coma Scale was E1V1M1, temperature was 36.5°C, pulse was 117 beats/min, blood pressure was 162/88 mmHg, and respiratory rate was 18 breaths/min. The remainders of physical examination findings were unremarkable. Serum creatinine was 4.04 mg/dL (357 μmol/L) and cerebrospinal fluid was normal. Electroencephalography showed slow delta waves and spikes. Brain computed tomography revealed senile changes. Brain MRI showed high T2-weighted signals over bilateral temporoparietal lobes and thalami. Corresponding lesions were bright on diffusion-weighted imaging (Figure 1C).

Due to refractory status epilepticus despite AEDs including propofol, diazepam, and valproic acid (Table 1), SLEDD-f with hemoperfusion was performed on the first day of hospitalization. After treatment, the dosage of AEDs was decreased. Calculated 24-h creatinine clearance was 4.63 mL/min (0.08 mL/s) and the patient received maintenance hemodialysis thereafter. AEDs were administered orally during the next 3 weeks. Status epilepticus subsided without further epileptic spikes. The patient became stabilized gradually (stable hemodynamics and mild nosocomial infection) but remained comatose. He was transferred to the chronic care unit of a local hospital on the 48th hospital day.

In both cases, dialyzers (FX 60; 1.4 m², Helixone®, Fresenius Medical Care, Bad Homburg, Germany), dialysate, replacement fluid, treatment time per day (480 min), dialysate flow (200 mL/min), and blood flow (150–200 mL/min) were identical in the SLEDD-f session. SLEDD-f treatments were performed using the Fresenius 5008 system (Fresenius Medical Care). Hemofiltration was 35 mL/min in pre-dilution mode and Kt/V per complete treatment was approximately 1.4. The hemoperfusion device was manufactured by Gambro (Minneapolis, MN, USA). The charcoal cartridge used for hemoperfusion was DHP-1 (Kuraray, Tokyo, Japan). Blood flow through the hemoperfusion column was 200–250 mL/min. With informed consent of the family, SLEDD-f and an 8 h session of charcoal hemoperfusion was performed in both cases (Table 1). The courses of SLEDD-f and hemoperfusion were without incident and no severe complications occurred. No thrombocytopenia or hypocalcemia occurred during or after the hemoperfusion treatment, and there was no need of phosphate treatment during SLEDD-f treatment.

DISCUSSION

Star fruit is a popular fruit in tropical and subtropical countries such as Taiwan, Brazil, Malaysia, and Southern China.⁵ Star fruit intoxication is well known in patients with advanced renal failure. Some authors proposed that star fruit may have neurotoxic and nephrotoxic effects.^10–12 In 2005, Carolino et al.¹³ identified a dialyzable neurotoxic fraction (AcTx) in star fruit with a molecular weight less than 500 Da. AcTx is believed to cross the blood–brain barrier and induce neurotoxicity by affecting the balance between glutamatergic and GABAergic systems.^13,14 AcTx differs from oxalic acid and could induce behavioral changes and tonic-clonic seizures in experimental animals. Besides, Garcia Cairasco and coworkers¹⁵ demonstrated that intrahippocampal microinjection of star fruit neurotoxin (caramboxin) induced status epilepticus and neurodegeneration in adult male Wistar rats. Accordingly, caramboxin may be the most important neurotoxic component and potent excitatory convulsant in star fruit, but the chemical structure of caramboxin remains unknown to date.¹⁵ Although the proposed neurotoxin is considered as dialyzable, some patients respond poorly to hemodialysis. Currently, the exact nature of star fruit intoxication remains to be elucidated.

Altered levels of consciousness in patients with reduced renal function, especially in advanced renal failure or dialysis, should alert to star fruit intoxication as a differential diagnosis. In previous case reports, star fruit intoxication manifested as hiccups, vomiting, dizziness, psychomotor agitation, confusion, and convulsions.^4,16 In 2000, Chang et al.² reported on 20 patients with star fruit intoxication. Total mortality was 40%, but mortality of the patients with abnormal consciousness was 80%. Seizures and altered levels of consciousness were considered an indicator of poor prognosis.¹⁴ Neto and coworkers⁴ suggested continuous renal replacement therapy as first choice treatment for patients with severe star fruit intoxication presenting with seizures and hemodynamic instability. Other investigators (Chen et al.¹⁷ and Wu et al.¹⁴) have proposed that hemoperfusion may be more effective than hemodialysis according to the possible liposoluble nature of caramboxin.¹⁴ Moreover, some authors effectively treated severe star fruit intoxication (coma, status epilepticus) using continuous hemofiltration with or without concomitant hemoperfusion in 2009.^6,18,19

Both our patients presented with severe poisoning, but patient 1 ingested more star fruit and presented 3 days later for intensive treatment. MRI findings in our patients are consistent with previous reports.^5,20 Patient 1 had more obvious lesions on MRI. This may explain why patient 1 had a poor prognosis. After SLEDD-f and hemoperfusion, status epilepticus of both patients subsided and the dose of AEDs were tapered. No further epileptic spikes were observed in patient 2. Although the level of consciousness of the two patients did not improve, behavioral seizures of both patients improved rapidly during the use of intensive treatment and subsided entirely. Thus, SLEDD-f with hemoperfusion may have some benefits in the patients, especially for the control of refractory status epilepticus. The possible causes of persistent comatose status could be irreversible brain damage of star fruit intoxication²¹ or prolonged refractory status epilepticus.²² It is difficult to identify whether the beneficial effect is owing to clearance of proposed neurotoxin merely and/or other mechanisms.

Sustained low-efficiency daily dialysis (SLED) and SLEDD-f is an increasing treatment modality for patients with renal failure in the intensive care unit.²³ SLEDD-f is primarily used to improve clearance of substances of middle-molecular weight and provides good clinical outcomes for critically ill patients requiring renal replacement therapy.²³ Newer high-flux membranes and hemodialysis technologies have allowed hemodialysis to achieve similar clearance rates when compared to the classical hemoperfusion technique in removing drugs or toxins which had been considered as poorly eliminated by conventional hemodialysis previously.²⁴ Physicians used SLED or SLEDD-f to treat intoxications including salicylate, valproic acid, lithium, carbamazepine, and thallium.^{7–9,25–28} Rebound phenomenons of offending toxins could also be prevented by SLEDD-f.⁹

Advantages of SLEDD-f include efficient clearance of small solutes, favorable cardiovascular tolerability, low risk of microbiological contamination, flexible treatment schedules, and reduced costs.⁸ Berbece et al.²⁹ reported that the daily cost for SLED is $240 compared with $370 for continuous renal replacement therapy in Canada.

In conclusion, star fruit intoxication remains a mystery due to unconfirmed offending neurotoxins and a variety of clinical outcomes with different treatments. Epilepsies and coma are known to be associated with poor prognosis and higher mortality. Refractory seizure could induce permanent neurological sequelae or death. Severe star fruit intoxication may result in death despite prompt and aggressive management.^2,18 Patients with CKD are advised not to ingest star fruit. In cases of intoxication with abnormal levels of consciousness and seizures, early suspicion and recognition with supportive management and intensive continuous hemofiltration may improve outcomes.¹⁸ The evidence that hemoperfusion improves outcome is limited although few case reports demonstrate significant neurological improvement with hemoperfusion.^6,14 The outcome of severe star fruit intoxication improves modestly despite the progress of the dialysis modalities. Therefore, prevention of the star fruit ingestion in patients with advanced renal failure is undoubtedly the most important approach. Currently, there are no experiences of the use of SLEDD-f in severe star fruit intoxication. In this report, SLEDD-f with hemoperfusion seems to be safe and may facilitate the treatment of status epilepticus. SLEDD-f with hemoperfusion may be a novel therapeutic approach in severe star fruit poisoning or patients with hemodynamic instability. Further investigation is needed to establish whether it improves clinical outcomes in patients with severe star fruit intoxication.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.