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SAUROPUS ANDROGYNUS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sauropus androgynus, a member of the family Euphorbiaceae, is a vegetable with popularity in Southeast Asia as a weight reducing agent. Toxicity is primarily related to its respiratory effects, causing obstructive pulmonary disease after chronic consumption.

Specific Substances

    1) Asin-asin
    2) Cekur manis
    3) Chekor manis
    4) Chekurmanis
    5) Katuk
    6) Liuh-Jiann
    7) Sauropus albicans
    8) Sauropus androgynus
    9) Shoou-Gong-Muh
    10) Sweet shoot

Available Forms Sources

    A) FORMS
    1) Sauropus androgynus is a leafy vegetable which grows on a tall stem. An analysis of the leaves, for nutritive value, revealed that 100 grams of fresh leaves contain: moisture 69.9 gm, protein 7.4%, fat 1.1 gm, fiber 1.8 gm, carotene 5600 mcg, thiamine 0.5 mg, riboflavin 0.21 mg, vitamin C 244 mg, calcium 771 mg, phosphorus 543 mg, and iron 8.8 mg (Padmavathi & Rao, 1990). Additionally, the leaves have been reported to contain 580 mg papaverine per 100 gm of fresh leaf, which may contribute to the plants toxicity (Bender & Ismail, 1975).
    B) USES
    1) The vegetable has become popular as a weight-reducing agent, particularly in females.
    2) Other less common uses for S. androgynus have included management of hypertension, hyperlipidemia, constipation, and weight control (Ger et al, 1997).
    3) Raw leaves of this plant may be served as salads. Reportedly, this plant grows in Florida.
    4) In Thai traditional medicine, the roots have been used as an antipyretic agent, an antidote for food poisoning, and an antiseptic agent (Kanchanapoom et al, 2003).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) BACKGROUND: Sauropus androgynus, a member of the family Euphorbiaceae, is a vegetable with popularity in Southeast Asia as a weight reducing agent. PLANT: Sauropus androgynus is a perennial shrub commonly seen in Southeast Asia. It prefers a hot, humid climate and is native to lowland rain forests. The leaves, stems flowers and small fruits are edible.
    B) USES: As a vegetable it is consumed as a raw juice, sauteed, mixed preparation, or boiled for various lengths of time.
    C) TOXICOKINETICS: The bioactive substance responsible for obstructive pulmonary disease may be heat stable (ie, similar frequency of obstructive respiratory effects in patients using various preparation methods). T-cell-mediated immunological reactions may have a significant role in the pathogenesis of lung disorders (pulmonary toxicity) following exposure. On immunohistochemical staining of lung tissue obtained by open lung biopsy, T-cells predominated in the peribronchiolar inflammatory infiltrate. A slightly higher than normal concentration of tumor necrosis factor alpha was also found. Altered cytokine expression and infiltration of eosinophils and neutrophils may be involved in the pathogenesis of obstructive pulmonary disease resulting from regular S. androgynus ingestions.
    D) EPIDEMIOLOGY: Exposure has occurred. Cases have been typically reported in Thailand, Taiwan and Japan.
    E) WITH THERAPEUTIC USE
    1) CHRONIC TOXICITY: Toxicity is primarily related to its respiratory effects, causing obstructive pulmonary disease after chronic consumption. The main symptoms are associated with progressive dyspnea and persistent cough, followed by progressively worsening obstructive pulmonary disease.
    a) EARLY PHASE: In the first few days of consumption, symptoms may include signs/symptoms of dyspnea (clinical hallmark of pulmonary disease and can occur progressively after 4 weeks or more of consumption), anorexia, excitation and insomnia, agitation which may subside spontaneously, even with continued consumption. Tremor, palpitations, skin rash and chest tightness can also occur in the early stage.
    b) PROGRESSION OF ILLNESS: Gastric irritation, including vomiting and diarrhea, may occur during phase 2 of toxicity. More than a month later, signs and symptoms of progressive dyspnea, fatigue, chest tightness, cough, palpitations, dizziness and numbness of extremities may occur.
    c) LATE PHASE: The final phase, usually occurs between the third and seventh month of consumption, consists of pulmonary disease, often irreversible, constrictive bronchiolitis obliterans, and cardiac dysrhythmias (torsades de pointes).
    2) RARE: Torsades de pointes and other tachydysrhythmias have been reported in several cases of chronic consumption of S. androgynus. Hypokalemia and seizure activity have been observed in a small number of cases.
    3) FATALITIES: Deaths related to S. androgynus have occurred infrequently and are usually related to pulmonary complications (ie, respiratory failure).

Laboratory Monitoring

    A) Monitor oxygen saturation via continuous pulse oximetry.
    B) Monitor pulmonary function in symptomatic patients.
    C) Monitor ECG and electrolytes, especially serum potassium concentration.
    D) Chest x-ray may be diagnostic, or may be normal despite severe disease. Chest CT is a more sensitive diagnostic modality.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Acute toxicity is not anticipated in patients that ingest S. androgynus infrequently or sporadically. Generally, chronic consumption of S. androgynus can result in progressive pulmonary complications in some patients. Obtain a detailed history, if chronic use of S. androgynus consumption is reported or suspected.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor vital signs. Following chronic consumption, pulmonary complications have developed over a period of months in some patients. Monitor respiratory function. ACUTE LUNG INJURY: Maintain ventilation and oxygenation and evaluate with frequent arterial blood gases and/or pulse oximetry monitoring. Early use of PEEP and mechanical ventilation may be needed. SEIZURES: Seizure activity has been reported infrequently with chronic consumption. Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia. Treat seizures initially with benzodiazepines. CARDIAC DYSRHYTHMIAS: Cardiac abnormalities including prolonged QT interval and torsades de pointes have occurred infrequently following chronic consumption. Initiate continuous cardiac monitoring and obtain a baseline ECG as indicated. For torsades de pointes, hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    C) DECONTAMINATION
    1) PREHOSPITAL: Most reported cases of toxicity have involved chronic consumption of Sauropus androgynus. Consider activated charcoal after a recent, large ingestion.
    2) HOSPITAL: Most reported cases of toxicity have involved chronic consumption of Sauropus androgynus. Consider activated charcoal after a recent, large ingestion.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following a mild or moderate acute exposure. Airway support may be indicated in patients that develop respiratory symptoms following chronic exposure. Monitor pulse oximetry and begin oxygen therapy as indicated. Obtain baseline ABGs.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Hemodialysis is NOT expected to be of benefit for removal of the papaverine content due to its significant protein binding.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A minor acute ingestion is unlikely to produce significant symptoms. If the patient is asymptomatic, the patient can be monitored at home.
    2) OBSERVATION CRITERIA: Patients that develop significant respiratory symptoms or more than minor symptoms (ie, gastrointestinal effects) should be sent to a healthcare facility.
    3) ADMISSION CRITERIA: Patients who develop significant evidence of pulmonary disease or cardiac tachydysrhythmias should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Consult a pulmonologist if the patient presents with evidence of pulmonary complications and diagnostic changes suggestive of chronic exposure.
    5) PATIENT-TRANSFER CRITERIA: Consumption of S. androgynus may result in moderate to severe obstructive pulmonary disease (generally dose-dependent) within months of chronic consumption. Pulmonary changes appear to be irreversible in many cases, with progressive deterioration of FEV1. Lung transplantation may be necessary in some cases. Patients may require transfer to a higher level of care.
    H) TOXICOKINETICS
    1) The bioactive substance responsible for obstructive pulmonary disease may be heat stable (ie, similar frequency of obstructive respiratory effects in patients using various preparation methods). T-cell-mediated immunological reactions may have a significant role in the pathogenesis of lung disorders (pulmonary toxicity) following exposure. On immunohistochemical staining of lung tissue obtained by open lung biopsy, T-cells predominated in the peribronchiolar inflammatory infiltrate. A slightly higher than normal concentration of tumor necrosis factor alpha was also found. Altered cytokine expression and infiltration of eosinophils and neutrophils may be involved in the pathogenesis of obstructive pulmonary disease resulting from regular S. androgynus ingestions.
    I) PITFALLS
    1) Failure to obtain an adequate history of exposure.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. Obstructive pulmonary disease has been reported in patients following the consumption of 150 g daily of S. androgynus for up to 7 months.
    B) AVERAGE CONSUMPTION: In several Malaysian villages (asymptomatic population), the average consumption of S. androgynus was 156 g eaten once a week.

Clinical Effects

Summary Of Exposure

    A) BACKGROUND: Sauropus androgynus, a member of the family Euphorbiaceae, is a vegetable with popularity in Southeast Asia as a weight reducing agent. PLANT: Sauropus androgynus is a perennial shrub commonly seen in Southeast Asia. It prefers a hot, humid climate and is native to lowland rain forests. The leaves, stems flowers and small fruits are edible.
    B) USES: As a vegetable it is consumed as a raw juice, sauteed, mixed preparation, or boiled for various lengths of time.
    C) TOXICOKINETICS: The bioactive substance responsible for obstructive pulmonary disease may be heat stable (ie, similar frequency of obstructive respiratory effects in patients using various preparation methods). T-cell-mediated immunological reactions may have a significant role in the pathogenesis of lung disorders (pulmonary toxicity) following exposure. On immunohistochemical staining of lung tissue obtained by open lung biopsy, T-cells predominated in the peribronchiolar inflammatory infiltrate. A slightly higher than normal concentration of tumor necrosis factor alpha was also found. Altered cytokine expression and infiltration of eosinophils and neutrophils may be involved in the pathogenesis of obstructive pulmonary disease resulting from regular S. androgynus ingestions.
    D) EPIDEMIOLOGY: Exposure has occurred. Cases have been typically reported in Thailand, Taiwan and Japan.
    E) WITH THERAPEUTIC USE
    1) CHRONIC TOXICITY: Toxicity is primarily related to its respiratory effects, causing obstructive pulmonary disease after chronic consumption. The main symptoms are associated with progressive dyspnea and persistent cough, followed by progressively worsening obstructive pulmonary disease.
    a) EARLY PHASE: In the first few days of consumption, symptoms may include signs/symptoms of dyspnea (clinical hallmark of pulmonary disease and can occur progressively after 4 weeks or more of consumption), anorexia, excitation and insomnia, agitation which may subside spontaneously, even with continued consumption. Tremor, palpitations, skin rash and chest tightness can also occur in the early stage.
    b) PROGRESSION OF ILLNESS: Gastric irritation, including vomiting and diarrhea, may occur during phase 2 of toxicity. More than a month later, signs and symptoms of progressive dyspnea, fatigue, chest tightness, cough, palpitations, dizziness and numbness of extremities may occur.
    c) LATE PHASE: The final phase, usually occurs between the third and seventh month of consumption, consists of pulmonary disease, often irreversible, constrictive bronchiolitis obliterans, and cardiac dysrhythmias (torsades de pointes).
    2) RARE: Torsades de pointes and other tachydysrhythmias have been reported in several cases of chronic consumption of S. androgynus. Hypokalemia and seizure activity have been observed in a small number of cases.
    3) FATALITIES: Deaths related to S. androgynus have occurred infrequently and are usually related to pulmonary complications (ie, respiratory failure).

Vital Signs

    3.3.2) RESPIRATIONS
    A) Dyspnea is a hallmark sign of S. androgynus poisoning, and is present in phase 1 and becomes progressively worse through phase 2 and 3 (Lai et al, 1996; Lin et al, 1996; Wu et al, 1997).
    B) Tachypnea, decreased breath sounds with crackles and wheezing may be present on physical examination (Wu et al, 1997; Higenbottam, 1997; Lai et al, 1996) .
    3.3.3) TEMPERATURE
    A) Subjective reports of fever were reported as a symptom of S. androgynus ingestion during phase 2 of toxicity.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) CHRONIC USE: Several patients ingested S. androgynus for 1 to 3 months and presented with palpitations, syncope, perioral cyanosis and seizures. ECGs showed significant QT prolongation and runs of torsades de pointes. Two patients were hypokalemic. None of the patients had a family history of cardiac disorders. Treatments consisted of cardioversion, IV magnesium sulfate, lidocaine and isoproterenol infusions. All patients recovered (Chen et al, 1996; Lin et al, 1996; Wu et al, 1997).
    B) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) CHRONIC USE: Chest tightness, palpitations, dyspnea and cough developed in 26 patients after an average of 43 days of S. androgynus consumption, all part of phase 2 clinical presentation (Lin et al, 1996).
    C) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Palpitations and tachycardia are common toxic effects of papaverine, which is found in the leaves of S. androgynus. Poisonings may result in tachycardia and premature ventricular contractions (Wu et al, 1997).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) ONGOING USE: An early stage of S. androgynus poisoning (phase 1) is characterized by the hallmarks of dyspnea and persistent cough, which may start in the first few days following ingestion, and progresses after 4 weeks of continued exposure (Lin et al, 1996; Lai, 1996).
    b) Phase 2 of S. androgynus poisoning includes progressive dyspnea, cough, palpitations, chest pain and dizziness (Lin et al, 1996).
    B) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) ONGOING USE: A late stage of poisoning (phase 3) presents with obstructive pulmonary disease with impairment of pulmonary function tests including decreased FEV1 and FEV1/FVC and severe impairment of alveolar permeability. Response to steroids and bronchodilators is minimal to none (Oonakahara et al, 2005; Hsu et al, 1998; Hsiue et al, 1998; Lin et al, 1996; Wu et al, 1997; Ger et al, 1997) (Yang et al, 1997). Constrictive bronchiolitis obliterans has been a recognized histologic finding in lung biopsies (Luh et al, 1999; Chang et al, 1997; Roggli & Chiang, 1996; Lai, 1996). Microscopic examinations of lung biopsies have shown peri-bronchiolar infiltrates which are predominantly composed of T-lymphocytes (Luh et al, 1999; Hsu et al, 1998), but also contain macrophages, mast cells, eosinophils, and fibroblasts (Wang et al, 2000).
    b) Wu et al (1997) and Hsiue et al (1998) reported that the reduction of FEV1 and FEV1/FVC were significantly associated with cumulative dosage and duration of exposure in independent studies (Hsiue et al, 1998; Wu et al, 1997).
    1) ONSET OF ILLNESS: In a recent Sauropus androgynus outbreak in Japan, the mean period to develop bronchiolitis obliterans was 6 months (Oonakahara et al, 2005).
    c) CT FINDINGS: Yang et al (1997) reported that high-resolution CT findings of air trapping correlated better with FEV1, FVC, DLco and the severity of obstructive lung disease than did bronchiectasis. Pulmonary function test results and high-resolution CT manifestations were typical of bronchiolitis obliterans in chronically poisoned patients.
    1) Chen et al (1996) reported mosaic perfusion of bilateral upper lobes and air trapping in bilateral lobes via high-resolution pulmonary CT (Chen et al, 1996).
    2) High resolution pulmonary CT demonstrated bilateral diffuse bronchiectasis and patchy low attenuation changes in lung parenchyma of 23 women after consumption of S. androgynus for an average of 10 weeks. There was a lack of improvement after 2 months of prednisolone treatment. All patients had severe air flow obstruction without a significant response to bronchodilators (Lai et al, 1996).
    d) CASE SERIES: Hsiue et al (1998) reported 49 patients (out of a total of 178) with moderate to severe obstructive pulmonary disease, who had decreased FEV1 and lack of bronchodilatory response (Hsiue et al, 1998).
    e) Hung et al (2000) reported that Tc-99m DTPA radioaerosol inhalation lung scintigraphy may be more sensitive than high-resolution CT and pulmonary function testing in detecting S. androgynus-induced lung injury (Hung et al, 2000).
    f) LONG-TERM FINDINGS: Patients with endstage bronchiolitis obliterans syndrome reported a history of chronic consumption of the extract from raw leaves of S. androgynus. Luh et al (1999) reported 5 patients who underwent lung transplantation for treatment of this disorder. Two patients died, one from posttransplant lymphoproliferative disorder and the other from bronchial stenosis with infection. The remaining 3 patients had improved pulmonary function (FEV1 and RV) at 29 to 34 month follow-up (Luh et al, 1999). Hsu et al (1998) also recommended single-lung transplantation for patients with endstage bronchiolitis obliterans (Hsu et al, 1998).
    C) TOXIC BRONCHIOLITIS OBLITERANS
    1) WITH THERAPEUTIC USE
    a) BRONCHIOLITIS OBLITERANS ORGANIZING PNEUMONIA
    1) SUMMARY: There appears to be an association between S. androgynus ingestion with the development of bronchiolitis obliterans. It has been suggested that genetic predisposition may have a significant role in the development of bronchiolitis obliterans (Ger et al, 1997).
    2) CASE REPORTS: A severe late stage poisoning with S. androgynus resulted in bronchiolitis obliterans organizing pneumonia (BOOP), which was seen on open lung biopsies in several patients following chronic consumption. There was a presence of alveolitis, with constrictive bronchiolitis and progression to BOOP (Lin et al, 1996; Deng & Lu, 1996; Wu et al, 1997).
    a) RISK FACTORS: In a case-control study conducted in Taiwan during 1995, the total amount (ie, large amounts were positively associated) of S. androgynus consumed, consuming S. androgynus without cooking, and the ingestion of S. androgynus prepared by local vendors were all significantly associated with bronchiolitis obliterans syndrome (Ger et al, 1997)
    b) PATHOLOGY FINDINGS: Excised lungs from patients receiving single lung transplants revealed focal fibromuscular sclerosis and obliteration of bronchial arteries in the wall of large bronchi, with segmental necrosis of bronchi 2 to 4 mm in diameter. Pathologic changes were consistent with segmental ischemic necrosis of bronchi at the watershed zone of bronchial and pulmonary circulation (Chang et al, 1998).
    3) CASE REPORT: A 42-year-old woman, with progressive dyspnea over 4 months, was admitted to the hospital. She had ingested about 150 grams of S. androgynus intermittently for constipation and weight control. She had insomnia during the first week. After 3 months of chronic consumption, she reported difficulty breathing, cough, chest tightness, palpitations, and subjective feelings of fever. She stopped eating the vegetable, however her dyspnea progressively worsened. On physical exam, chest auscultation revealed bilateral basal rales and wheezing over the right lower lung field. ECG and 2-D echocardiogram tests were normal. Arterial blood gas results were: pH 7.42; PaO2 67.7 mmHg; PaCO2 37.8 mmHg; and HCO3 24.3 mmol/L. Pulmonary function test results were: FEV1 27%; FVC 48%; FEV1/FVC 57%; VC 48%; and D1co 45%. The perfusion and ventilation studies demonstrated chronic obstructive airway disease in both lower and left middle lung fields. Results of an open lung biopsy showed fibroblastic granulation tissue in bronchiolar walls; mild hyperplasia of type II pneumocytes with fibrotic thickening of alveolar wall; macrophages in alveolar spaces; and hyaline thickening of some small blood vessels. Pathological findings appeared to be consistent with bronchiolitis obliterans organizing pneumonia (BOOP) (Wu et al, 1997).
    D) RESPIRATORY FAILURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: In a survey of 44 S. androgynus poisonings reported to the National Poison Center of Taiwan, 4 fatalities were reported. Three patients died of respiratory failure with pulmonary infections or pneumothoraces, and one patient died during transport to the hospital (Lin et al, 1996).
    E) HYPOXEMIA
    1) WITH POISONING/EXPOSURE
    a) Hypoxemia is commonly demonstrated via arterial blood gas analysis in patients presenting with dyspnea, decreased breath sounds and tachypnea with wheezing (Hsu et al, 1998; Lai et al, 1996).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CHRONIC USE: Several patients ingested S. androgynus for 1 to 3 months and presented with palpitations, syncope, perioral cyanosis and seizures. ECGs showed significant QT prolongation and runs of torsades de pointes. Two patients were hypokalemic. None of the patients had a family history of cardiac disorders. Treatments consisted of cardioversion, IV magnesium sulfate, lidocaine and isoproterenol infusions. All patients recovered (Chen et al, 1996; Lin et al, 1996; Wu et al, 1997).
    B) CENTRAL STIMULANT ADVERSE REACTION
    1) WITH THERAPEUTIC USE
    a) Initial symptoms have included temporary insomnia, excitation, poor appetite and sometimes tremor in the first phase of S. androgynus toxicity, occurring at an average of 2.5 days following ingestion (Lin et al, 1996; Wu et al, 1997).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) CHRONIC USE: Dizziness, vertigo, fatigue, headache and palpitations can occur in phase 2 of toxicity, generally within 43 days of daily S. androgynus consumption. These effects may be partially attributed to papaverine content in the leaf (Lin et al, 1996; Wu et al, 1997).
    D) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) CHRONIC USE: Numbness of the extremities has been reported during phase 2 of S. androgynus toxicity (Lin et al, 1996).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Poor appetite was reported in 31 of 41 patients at an average of 2.5 days of S. androgynus consumption (phase 1) (Lin et al, 1996).
    B) NAUSEA, VOMITING AND DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) Nausea, vomiting and diarrhea can occur during phase 2 of S. androgynus toxicity in a small percent of patients (Lin et al, 1996).
    C) ULCERATIVE STOMATITIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORTS: Nine out of 23 women reported oral ulcers following approximately 10 weeks of S. androgynus consumption (Lai et al, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) CHRONIC USE: Minor skin rash was reported during phases 1 and 2 of toxicity (Lin et al, 1996).
    B) FLUSHING
    1) WITH THERAPEUTIC USE
    a) Facial flushing may occur following significant toxicity, presumably due to the papaverine content of the S. androgynus leaf (Wu et al, 1997).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) WITH THERAPEUTIC USE
    a) CHRONIC USE: T-cell mediated immunity has been suspected in the pathogenesis of bronchiolitis obliterans following chronic consumption of S. androgynus. Open lung biopsy in 4 patients revealed histopathologic findings of predominant T cells over B cells. Tumor necrosis factor alpha was reported at higher serum concentrations in these patients than in normal controls (Luh et al, 1999; Hsu et al, 1998; Lai et al, 1996). Microscopic examination also demonstrated macrophages, mast cells, eosinophils, and fibroblasts (Wang et al, 2000).

Laboratory Monitoring

Radiographic Studies

    A) RADIOGRAPHIC-OTHER
    1) Wu (1996) reports Tc-99m DTPA inhalation scan to be more sensitive than pulmonary function tests for the detection of acute lung injury.
    2) Hung et al (2000) reported that Tc-99m DTPA radioaerosol inhalation lung scintigraphy may be more sensitive than high resolution CT and pulmonary function testing in detecting Sauropus androgynus-induced lung injury (Hung et al, 2000).

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor oxygen saturation via continuous pulse oximetry.
    B) Monitor pulmonary function in symptomatic patients.
    C) Monitor ECG and electrolytes, especially serum potassium concentration.
    D) Chest x-ray may be diagnostic, or may be normal despite severe disease. Chest CT is a more sensitive diagnostic modality.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Monitor venous or arterial blood gas in symptomatic patients.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor serum electrolytes, especially serum potassium concentration, in symptomatic patients.
    4.1.4) OTHER
    A) OTHER
    1) PULMONARY FUNCTION TESTS
    a) Monitor pulmonary function tests in symptomatic patients.
    b) Tc-99m DTPA radioaerosol inhalation scan may be more sensitive than pulmonary function tests for the detection of acute lung injury (Hung et al, 2000; Kao et al, 1999; Wu, 1996).
    2) ECG
    a) Monitor ECG and vital signs in all symptomatic patients.
    3) PULSE OXIMETRY
    a) Monitor oxygen saturation via pulse oximetry.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop significant pulmonary disease or cardiac tachydysrhythmias should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A minor acute ingestion is unlikely to produce significant symptoms. If the patient is asymptomatic, the patient can be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Consult a pulmonologist if the patient presents with evidence of pulmonary complications and diagnostic changes suggestive of chronic exposure.
    6.3.1.4) PATIENT TRANSFER/ORAL
    A) Consumption of S. androgynus may result in moderate to severe obstructive pulmonary disease (generally dose-dependent) within months of chronic consumption. Pulmonary changes appear to be irreversible in many cases, with progressive deterioration of FEV1. Lung transplantation may be necessary in some cases. Patients may require transfer to a higher level of care.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients that develop significant respiratory symptoms or more than minor symptoms (ie, gastrointestinal effects) should be sent to a healthcare facility.

Monitoring

    A) Monitor oxygen saturation via continuous pulse oximetry.
    B) Monitor pulmonary function in symptomatic patients.
    C) Monitor ECG and electrolytes, especially serum potassium concentration.
    D) Chest x-ray may be diagnostic, or may be normal despite severe disease. Chest CT is a more sensitive diagnostic modality.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Most reported cases of toxicity have involved chronic consumption of Sauropus androgynus. Consider activated charcoal after a recent, large ingestion.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Most reported cases of toxicity have involved chronic consumption of Sauropus androgynus. Consider activated charcoal after a recent, large ingestion.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Most reported cases of toxicity have involved chronic consumption of Sauropus androgynus. Treatment is supportive and directed at signs and symptoms of obstructive pulmonary disease. Noninvasive pressure support ventilation (bilevel positive airway pressure) has been used to support ventilation in severe cases (Wu et al, 1997).
    2) Following chronic exposure institute continuous cardiac monitoring and obtain a baseline ECG as indicated. Ventricular dysrhythmias have developed infrequently in patients following chronic consumption.
    3) In severe cases of bronchiolitis obliterans organizing pneumonia (BOOP), lung transplantation should be considered.
    B) MONITORING OF PATIENT
    1) Monitor oxygen saturation via continuous pulse oximetry.
    2) Monitor pulmonary function in symptomatic patients.
    3) Monitor ECG and electrolytes, in particular, serum potassium concentration.
    C) TACHYARRHYTHMIA
    1) TACHYCARDIA SUMMARY
    a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
    b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    c) ESMOLOL/ADULT LOADING DOSE
    1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).
    d) ESMOLOL/ADULT MAINTENANCE DOSE
    1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
    2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
    3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    e) CAUTION
    1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).
    D) VENTRICULAR ARRHYTHMIA
    1) Cardiac dysrhythmias have occurred infrequently following chronic consumption of S. androgynus. Treatment of ventricular dysrhythmias may include lidocaine or overdrive transvenous pacing. Atropine may be used when severe bradycardia is present and PVCs are thought to represent an escape complex. Do not administer quinidine or procainamide, which may increase the risk of torsade de pointes. Because sauropus androgynus has caused QT prolongation and torsades de pointes in a number of cases, amiodarone should only be used with extreme caution.
    2) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    3) AMIODARONE/INDICATIONS
    a) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    4) AMIODARONE/ADULT DOSE
    a) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    5) AMIODARONE/PEDIATRIC DOSE
    a) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    6) ADVERSE EFFECTS
    a) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    E) TORSADES DE POINTES
    1) Cardiac dysrhythmias including prolonged QT interval and torsades de pointes have occurred infrequently following chronic consumption of S. androgynus. Initiate continuous cardiac monitoring and obtain a baseline ECG as indicated. For torsades de pointes, hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    F) SEIZURE
    1) SUMMARY: Seizure activity has been reported infrequently with chronic consumption. Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia. Treat seizures initially with benzodiazepines.
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    G) ACUTE LUNG INJURY
    1) Following chronic consumption, significant pulmonary complications have developed over a period of months in some patients. Monitor respiratory function.
    2) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    3) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    4) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    5) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    6) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    7) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    8) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    H) TRANSPLANT OF LUNG
    1) In cases of end-stage bronchiolitis obliterans syndrome, which are unresponsive to treatment with steroids, cytotoxic agents, and other immunosuppressive agents (e.g., cyclosporine or lympholytic agents), lung transplantation may be the only effective modality of treatment (Luh et al, 1999; Hsu et al, 1998).

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis is NOT expected to be of benefit for removal of the papaverine content due to its significant protein binding.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. Obstructive pulmonary disease has been reported in patients following the consumption of 150 g daily of S. androgynus for up to 7 months.
    B) AVERAGE CONSUMPTION: In several Malaysian villages (asymptomatic population), the average consumption of S. androgynus was 156 g eaten once a week.

Maximum Tolerated Exposure

    A) SUMMARY
    1) LACK OF EFFECT
    a) In several Malaysian villages (asymptomatic population), the average consumption of S. androgynus was 156 g eaten once a week (Wu et al, 1997).
    B) CHRONIC USE
    1) CASE REPORT
    a) CASE REPORTS: Chang et al (1997) reported an average consumption of 3012 g, with a mean duration of exposure of 36 days in 4 patients presenting to the hospital in phase 3 of toxicity (constrictive bronchiolitis obliterans). No improvement occurred following treatment with bronchodilators and steroids. All patients showed progressive respiratory symptoms (Chang et al, 1997).
    b) CASE REPORT: A 27-year-old woman reportedly ingested approximately 15 kg of S. androgynus within a 2 month period and developed irreversible obstructive pulmonary disease (Chen et al, 1996).
    c) CASE REPORTS: Several patients ingested S. androgynus for 1 to 3 months and presented with palpitations, syncope, perioral cyanosis and seizures. ECGs showed significant QT prolongation and runs of torsades de pointes. Two patients were hypokalemic. None of the patients had a family history of cardiac disorders. Treatments consisted of cardioversion, IV magnesium sulfate, lidocaine and isoproterenol infusions. All patients recovered (Chen et al, 1996; Lin et al, 1996; Wu et al, 1997).
    2) CASE SERIES
    a) In a review of 178 patients (91% women, 9% men) who consumed S. androgynus for up to 7 months, the average daily dose was 150 g/day. Total doses consumed ranged from 1200 to 4800 g in two-thirds of the patients. 27.5% of these patients had moderate to severe obstructive pulmonary disease confirmed via pulmonary function testings, generally unresponsive to bronchodilators. Restrictive pulmonary disease occurred in 1.7% of patients. Frequency of obstructive pulmonary disease appeared to be dose dependent (ie, patients with a history of higher ingested amounts of S. androgynus developed pulmonary disease) (Hsiue et al, 1998).
    b) In a case series, patients with obstructive pulmonary disease consumed an average of 150 g/day for 4 consecutive days per week (Wu et al, 1997).

Pharmacology Toxicology

Toxicologic Mechanism

    A) The leaves of Sauropus androgynus contain approximately 580 mg of papaverine per 100 gm fresh leaves; however, this is not suspected to cause the obstructive pulmonary disease seen after chronic consumption. Whichever bioactive substance is responsible for the respiratory failure must be heat stable, since some studies suggest a similar frequency of pulmonary injury in patients following different methods of preparation of the vegetable, including boiling (Hsiue et al, 1998).
    1) In a case control study, subjects who consumed the raw juice of S. androgynus were at an increased risk of developing bronchiolitis obliterans organizing pneumonia (Ger et al, 1997).
    B) Wu et al (1997), in a case series of 90 S. androgynus chronic consumption, found that 46 of these patients studied with radioaerosol inhalation lung scintigraphy had abnormally rapid clearance of Tc-99m DTPA. Their results suggested that the alveolar epithelium is most likely damaged by S. androgynus. The proximal airway, probably the major contributing factor to severe air flow limitations, is involved in patient cases with severe alveolar injury.(Wu et al, 1997).
    C) An immunological response is suggested as an explanation of the pulmonary toxicity of S. androgynus. On immunohistochemical staining of lung tissue obtained by open lung biopsy, T cells predominated in the peribronchiolar inflammatory infiltrate. A slightly higher than normal concentration of tumor necrosis factor alpha was also found. T-cell-mediated immunological reactions may have a significant role in the pathogenesis of lung disorders in this poisoning (Luh et al, 1999; Hsu et al, 1998; Lai et al, 1996; Chang et al, 1997). Wang et al (2000) demonstrated a predominance of T-lymphocytes, macrophages, mast cells, and eosinophils in the inflammatory areas of the bronchioles (Wang et al, 2000).
    D) Altered cytokine expression and infiltration of eosinophils and neutrophils may be involved in the pathogenesis of obstructive pulmonary disease resulting from regular S. androgynus ingestions (Chen et al, 1996).

References

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